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APRIL 15, 2005


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            The meeting was held at 8:30 a.m. in Room 1066 of the Food and Drug Administration, 5630 Fishers Lane, Rockville, Maryland, Dr. Kenneth I. Shine, Chair, presiding.


      KENNETH I. SHINE, M.D., Chair

      GAIL H. CASSELL, Ph.D., Member

      SUSAN KAY HARLANDER, Ph.D., Member

      CATO T. LAURENCIN, M.D., Ph.D., Member

      F. XAVIER PI‑SUNYER, M.D., M.P.H., Member

      JIM E. RIVIERE, D.V.M., Ph.D., Member

      ALLEN D. ROSES, M.D., Member

MEMBERS PRESENT (continued):

      KATHERINE M.J. SWANSON, Ph.D., Member

      JOHN A. THOMAS, Ph.D., Member

      LESTER M. CRAWFORD, D.V.M., Ph.D., Acting


      NORRIS E. ALDERSON, Ph.D., Associate

            Commissioner for Science

      JAN N. JOHANNESSEN, Ph.D., Executive Secretary



      RACHEL E. BEHRMAN, M.D., M.P.H., Deputy

            Director, Office of Medical Policy, CDER

      ROBERT BRACKETT, Ph.D., Director, CFSAN


      KATHRYN M. CARBONE, MD., Associate Director for

            Research, CBER

      STEVEN GALSON, M.D., M.P.H., Acting Director,


      JESSE L. GOODWIN, M.D., M.P.H., Director, CBER

      MARY MALARKEY, B.S., Director, Office of

            Compliance and Biologics Quality, CBER

      JOHN R. MARZILLI, Deputy Associate Commissioner

            for Regulatory Affairs



ALSO PRESENT (continued):

      THERESA M. MULLIN, Ph.D., Assistant Commissioner

            for Planning

      ARMANDO OLIVA, M.D., Associate Director for

            Policy, Office of New Drugs

      DANIEL SCHULTZ, M.D., Director, CDRH

      PAUL J. SELIGMAN, M.D., M.P.H., Director, Office

            of Drug Safety, CDER

      STEPHEN SUNDLOF, D.V.M., Ph.D., Director, CVM

      JANET WOODCOCK, M.D., Acting Deputy Commissioner

            for Operations



      SADHANA DHRUVAKUMAR, Senior Scientific Research

            Specialist, PETA

      PAUL DRZAIC, Ph.D., Vice President, Advanced

            Development, Alien Technology Corporation

      JANELL MAYO DUNCAN, Legislative and Regulatory

            Counsel, Consumers Union

      G. MICHAEL FITZPATRICK, Ph.D., Chief of Policy

            and Chief Operating Officer, America's

            Blood Centers

      SANGTAE KIM, Ph.D., Division Director, Shared

            CyberInfrastructure, National Science


                  C O N T E N T S




Call to Order, Chairman Kenneth Shine........... 5


Welcome and Opening Remarks

      Dr. Lester Crawford....................... 8

      Dr. Janet Woodcock....................... 16


Introduction to Drug Safety, Dr. Steven Galson. 32


Pre-Market Drug Safety, Dr. Armando Oliva...... 42


Improvements in Drug Safety Information

      Labeling and Electronic Initiatives,

      Dr. Rachel Behrman....................... 62

      Drug Safety Initiative, Dr. Steven Galson 82


Post-Market Drug Safety, Dr. Paul Seligman.... 103


Drug Safety Resources, Dr. Theresa Mullin..... 113


Applying New Science to Drug Safety,.......... 141

      Dr. Janet Woodcock


Committee Questions and Discussion............ 154


Open Public Hearing

      Ms. Sadhanna Dhruvakumar ............... 192

      People for the Ethical Treatment of Animals

      Ms. Janell Mayo Duncan ................. 201

      Consumers Union

      Dr. Paul Drzaic ........................ 215

      Alien Technology Foundation

      Dr. G. Michael Fitzpatrick ............. 212

      America's Blood Centers

      Dr. Sangtae Kim ........................ 220

      National Science Foundation


Safety Systems to Vaccines, Blood and Tissue,. 227

      Dr. Jesse Goodman


cGMPs for Vaccines, Ms. Mary Malarkey......... 270


Committee Questions and Discussion............ 293




                                         8:25 a.m.

            CHAIRMAN SHINE:  Good morning.  I'm Ken Shine, currently chair of the Science Board Advisory Committee.  And I want to welcome you to this meeting.

            We will be shortly joined by Dr. Cassell who had another commitment but will be with us shortly.  I'm also pleased that Professor Barbara McNeil at Harvard has agreed to join the committee.  She couldn't be to this particular meeting but she will be at our next meeting.

            Before we actually begin the program, it would be useful, I think, for us just to go around the room and identify ourselves and our institutions for benefits of the group.  And perhaps we could start over here with --

            MEMBER PI-SUNYER:  Yes, my name is Xavier Pi-Sunyer.  I'm Professor of Medicine at Columbia University and I'm Chief of the Division of Endocrinology and Nutrition at St. Luke's Roosevelt Hospital in New York.

            MEMBER ROSES:  I'm Allen Roses.  I'm the Senior Vice President for Genetics Research in GlaxoSmithKline.

            MEMBER HARLANDER:  My name is Susan Harlander and I have a consulting company called BIOrational Consultants.

            MEMBER SWANSON:  I'm Katie Swanson, Vice President of Food Safety with Ecolab.

            MEMBER THOMAS:  I'm John Thomas, Vice President and Professor Emeritus from the University of Texas Health Science Center at San Antonio but now at Indiana University School of Medicine.

            MEMBER LAURENCIN:  I'm Cato Laurencin.  I'm a university professor and Professor of Orthopedic Surgery and Chairman of the Department of Orthopedic Surgery at the University of Virginia.

            MEMBER RIVIERE:  I'm Jim Riviere.  I'm a distinguished Professor of Pharmacology at North Carolina State.

            DR. CRAWFORD:  Les Crawford, FDA.

            DR. JOHANNESSEN:  I'm Jan Johannessen.  I'm the Executive Secretary of the Science Board to the FDA.

            DR. WOODCOCK:  Janet Woodcock, Acting Deputy Commissioner for Operations, FDA.

            DR. ALDERSON:  Norris Alderson, Associate Commissioner for Science at FDA.

            DR. BRACKETT:  Bob Brackett, Director for the Center of Food Safety and Applied Nutrition, FDA.

            DR. SLIKKER:  Bill Slikker, Deputy Director for Research, National Center for Toxicological Research, FDA.

            DR. GALSON:  Steve Galson, Acting Director, Center for Drug Evaluation and Research, FDA.

            DR. CARBONE:  Kathryn Carbone, Associate Director for Research, Center for Biologics Evaluation and Research, FDA.

            DR. SUNDLOF:  Steve Sundlof, Director of the Center for Veterinary Medicine, FDA.

            MR. MARZILLI:  Hi, I'm John Marzilli.  I'm with the Office of Regulatory Affairs, FDA.

            DR. SCHULTZ:  Dan Schultz, Director CDRH, FDA.

            CHAIRMAN SHINE:  Good.  I'm Ken Shine.  I'm sorry.  Did I miss somebody?  Yes.

            Again, I'm Ken Shine.  I've Executive Vice Chancellor for Health Affairs at the University of Texas.  And I sit at the fulcrum between FDA and the committee.

            I want to thank the staff of the FDA with regard to the creation of the agenda for this meeting.  A number of the issues that we're going to deal with are important and challenging issues and issues that the board is extremely interested in.  And we look forward to a good overview of a number of these issues and some important discussions.

            But I think it is appropriate to move quickly to hear from the Acting Commissioner of the FDA, Lester Crawford, who, with Janet Woodcock, will be giving us some opening remarks.

            DR. CRAWFORD:  Thank you very much, Dr. Shine.  It's a pleasure for me to be here.  And welcome you all back again.  Thank you for the commitment you've all made to serving FDA in this way.

            And we're grateful for it and we're also grateful for the new organization, Dr. Shine, that you have put forward on this board.  And I think we're going to be able to do bigger and better things as the result.

            I'd like to take this opportunity to briefly highlight some of the accomplishments over the past year at FDA.  By creating innovative initiatives and improving existing processes, the FDA was able to accomplish many goals that enhanced the lives of Americans in 2004.

            We introduced new initiatives to combat critical health threats such as obesity, counterfeit drugs, and medical errors.

            FDA's Innovation Initiative has met some important milestones.  First, a root cause analysis of multiple cycle reviews, a pilot program to test the effectiveness of earlier communication with product manufacturers, a cementing of our partnership with the National Cancer Institute, and the establishment of an Oncology Office within FDA to foster innovation in the treatment of cancer.

            We also launched the Critical Path Initiative, which we have presented to the board on previous occasions.  And Dr. Woodcock is going to update you on that initiative a little later in the program.

            We approved a substantially greater number of products, including an unprecedented number of generic drugs.

            We strengthened the security of the nation's food supply against potential bioterrorism attacks through the development of four important new  regulations.  We strengthened the food safety through measure initiatives and actions and we streamlined paperwork processes to reduce areas, reform outdated practices, and enhance new product innovation.

            We're extremely pleased with these accomplishments and we will continue to advance these initiatives.  But as you know, our successes are continually challenged by emerging health threats, changes in technology, and various global market forces.

            FDA's responsibilities are growing in scope and complexity and we're responding by focusing on new and better ways to perform our core mission.

            We have the following strategic areas for 2005 that I would like to mention.  First, enabling technology development and innovation.  Obviously we will be continuing our efforts in the area of critical  path to pinpoint those areas of product development that could benefit most from innovative approaches in emerging technologies.

            Second, protecting the homeland, counter-terrorism.  The past year has witnessed some of the most significant enhancements to our Food Safety and Security Program in decades.  Going forward, we will finalize implementation of our new food security laboratories, intensified inspections, and closer interagency collaboration.

            Next I'd like to talk about improving manufacturing practices.  Good manufacturing practices are not only vital to business success, they're also essential to FDA and they're essential to the public health.

            The FDA's overhaul of the pharmaceutical cGMPs encourages manufacturers to modernize methods, equipment, and facilities that will help eliminate both production inefficiencies and undue risk for consumers.  Our initiative also implements tougher inspection rules to make them more targeted and effective.

            We're improving FDA's business practices also.  We're seeking to create a stronger and more unified agency.  The increasing complexity of our regulatory mission requires that we look for new ways to create efficiency, standardized processes, enhanced infrastructure, and improved planning.

            Some highlights of our plan include full implementation of shared services, including consolidation information technology infrastructure, development of a common business process model.

            And finally the thing that I'm most pleased with and I think most FDAs are, the continued development of the White Oak facility as we move forward with total complete occupation in the year 2010.  By that time, we will have 8,000 FDA staffers in the White Oak facility and we're very much looking forward to its completion.

            Under the area of patient and consumer protection, as you know the issue of drug safety has received a lot of high profile media and Congressional attention since we last met in November of 2004 which is why this session of the Science Advisory Board is scheduled at a very opportune time.

            There has been a lot of public scrutiny over this issue with the recent concerns associated with SSRIs last fall and the inclusion of a black box warning on the label of Cox-2 inhibitors and the Merck withdrawal of Vioxx, the Pfizer withdrawal of Bextra, the recent recommendations of our Drug Advisory Committee on warning labels for over-the-counter NSAIDs as well as the prescription NSAIDs.

            Silicon breast implants has just come up.  And we will be processing over the next 90 days the recommendations of that Advisory Panel under the leadership of Dr. Schultz.

            It is important that these concerns do not distort the fact that drugs are safer today than they have ever been before and that millions of Americans each day benefit from them.  But in order to improve on current process, FDA has taken some bold steps to enhance the internal deliberations and decisions regarding risk and benefit analyses.

            FDA also is developing new communication formats to better inform the public of the Agency's deliberation process.

            Next I will discuss final risk minimization guidance.  Just a few weeks ago, FDA issued three final guidances: pre-marketing risk assessment, development and use of risk minimization action plans, good pharmacovigilance practices, and pharmacoepidemiologic assessment.  These guidances are evidence of FDA's commitment to transparency and risk management decision making.

            We have announced. Secretary Leavitt and I along with Dr. Woodcock, the Drug Safety Oversight Board in February.  The newly created Drug Safety Oversight Board will oversee the management of important drug safety issues within our Center for Drug Evaluation and Research under the leadership of Dr. Galson.

            The board will comprise members of the FDA and medical experts from other HHS agencies and government departments as well as consultation with people from the outside world.

            We have commissioned an Institute of Medicine study.  In November of 2004, we asked the IOM to carry out a top to bottom study of drug safety.  We've already transmitted two-thirds of the needed funding for this study to the IOM and they're moving forward in initiating the study.

            IOM has assigned one of their most senior study directors to oversee the study and have staffed up.  The proposed committee membership will be posted on the National Academy's website shortly, perhaps as early as Monday, April 18th.  We look forward to their results and will act swiftly to improve standards for American consumers.

            The second pillar of the Drug Safety Program is the Drug Watch webpage.  FDA is proposing to set up a new Drug Watch webpage for emerging data and risk information.  This 21st century electronic evolution will bring the power of information directly to consumers and increase the transparency of the Agency's decision-making process.  This site will also enhance public knowledge and understanding of drug safety issues.

            Now I would also like to posit a brief overview of the day's agenda, Dr. Shine, if I can.

            Our agenda today is devoted to these issues of pre- and post-market drug safety, drug safety information for health professionals and consumers, and safety issues related to blood products, vaccines, and vaccine manufacturing.

            You will be hearing detailed presentations on each of these topics throughout the day.  We're seeking your advice on several issues today relative to our efforts to strengthen drug safety monitoring and communication.

            For example, the Agency would value your input on the kinds of information needed by healthcare providers and patients about the safety of a drug and how FDA can best convey this information.  More and more we believe patients and consumers and general citizens look to FDA for information, perhaps more than in the past.

            We also seek your input on how the reporting of adverse events could be improved.  Are there additional sources of useful data that might help with post-market surveillance?  If so, how can FDA partner with the appropriate organizations to gain access to such data?

            Perhaps most importantly given FDA's resource situation, we seek your input as to the appropriate areas of focus of these existing resources to most effectively assure drug safety.  We look forward to your suggestions for improvement on this critical aspect of FDA's public health mandate.

            I want to reaffirm that your independent views are important to FDA and to thank you for your commitment to the Agency by participating as a member of this board.  I hope that your presentations today will give you a good understanding of FDA's commitment to this important issue of drug and biologic safety.

            Now it is my pleasure as always to introduce my distinguished colleague Dr. Janet Woodcock.

            DR. WOODCOCK:  Good morning.

            In the past, FDA and I have brought a number of initiatives before the Science Board.  The first one that I was directly involved in was the GMP Initiative which has come to a satisfactory conclusion and is ongoing.

            Today I'd like to update you on another initiative that we had gotten the input of the Science Board on and that is our Critical Path Project.  We, about a year ago, published the white paper on the critical path.

            And in that white paper, we promised to publish a report on the various challenges and opportunities, a project list almost of what had been identified as a work that needed to be done under the critical path.  We are working diligently on that report and expect to publish it soon.

            At the same time, we're identifying projects that FDA within its current resources can either carry out or lead in association with partners.  And I would like to tell you that numerous partners have emerged and although I can't go into detail about all those offers that we've received and so forth, we're in the process of setting up how to sort through and determine the priorities and which projects we actually can work on with various partners.

            And so I'd like to just talk about some of the areas of great need that have been identified and some of the things that we have done in the brief time that we have this morning.

            As you know, we talked about one of the needs is to improve product characterization and manufacturing scale-up issues.  And that was particularly identified by Dr. Carbone in the area of biologic, cellular, gene therapy, and so forth.  We are continuing to explore ways in which to get some of that work done and are hopeful that we can move forward in some areas.

            In the area of animal testing, the identification of the need for development of new animal models.  Particularly the Device Center had some very innovative ideas about using in silico animal models and computer modeling to eliminate some testing and keep up with the rapid evolution of devices.  And we are seeking to find out how we can move forward with those sorts of projects.

            Other areas that we are still exploring but it looks like we will have partners willing to work with us include toxicogenomics and various data mining projects.

            In the area of other broad projects, biomarkers, of course, were identified as an area that really needs to be developed and there has been considerable discussion about this.  We've had numerous workshops and conferences run by the various centers or by outside organizations to talk about this.

            And what we have identified is that the general conceptual development of how you qualify a biomarker for regulatory use needs to be further evolved.  There is a considerable amount of concern, if you recall those of you who were here for Dr. Califf's presentation, based on the experience in cardiology and the Cass trial in particular, there is concern about the use of biomarkers as surrogate endpoints.

            And that has, in my mind, put a chill over the entire field of biomarker development because it raises almost an insuperable barrier for the use of those, those types of biomarkers in regulatory decision making.  However, we have been able to tease this out and I'm going to talk about that a little bit more.  In addition, specific biomarkers need to be qualified further.

            We have kicked off the discussion of the conceptual framework for biomarker development at an advisory committee that we held.  And there is a general agreement that we should call this something else other than validation.

            Perhaps we can call it qualifying biomarkers for various uses or evaluating biomarkers for various regulatory uses.  But the term validation as always raises in people's minds some distinct barriers to accomplishment.

            So we are putting together an initiative  in regulatory policy to try to figure out for the various regulatory uses how you would describe and work up biomarkers.  This is going to require public process and development of various documents and so forth.

            I think FDA may have to lead this because it involves regulatory decision-making.  But we hope to involve an academic partner or many partners.  And this may require discarding some of the current ideas or framework about how -- the nature and use of these types of markers in development.  And we hope it will encourage people to use them more freely.

            I will say that there is a tremendous amount of enthusiasm now in the various sectors as the ideas have permeated.  And there is a lot of interest in supporting these kinds of projects and moving them forward including, you know, financial support.  So we think we can get this type of work done one way or another.

            Now we also though need to do some worked examples.  We need to pick some biomarkers and move them forward for regulatory decision-making because those concrete examples, I think, will be more persuasive than just a conceptual framework.

            We're working on two efforts right now where we have identified good biomarkers that we think are very close to having substantial regulatory use.  And one is in the area of imaging and one is the area of in vitro diagnostics of various types.  And obviously the three medical product centers are going to have to work very closely together on this because these involve devices, drugs, and often biologicals together.

            We have identified partners to work with us on these and I can't go into any more detail right now but we think what we will do, this would actually involve, at the end of the day, doing clinical studies to generate more information on the use of these biomarkers.  And I can tell you there is a tremendous  amount of enthusiasm in the relevant communities for getting this work done.

            Now the general process we think we need to go through is we need to identify this type of opportunity for biomarker.  We need to analyze the current available data on the marker.  And usually what we will find is there are gaps in the data and how it correlates with clinical outcomes or how predictive it is that prevent it from being used in various regulatory ways.

            We're going to identify those gaps in the marker performance -- in the understanding of marker performance and then devise trials that would actually answer those questions.  And then have those trials conducted or add the biomarker on to existing trials so that additional information can be generated.

            On the flip side of this, in the safety side which is actually the, of course, topic of much of the meeting today, there are many specific opportunities.  And I love Dr. Roses' term.  There are many forensic opportunities to use biomarkers, especially genomic biomarkers.

            We are very interested in conducting research in clinical trials where the agent is known to be toxic to a specific organ.  This is an opportunity to use new technologies such as genomics and proteomics and so forth to see if we can either predict who is at risk for such toxicities or pick up the evolution of the toxicity early.

            We also would like to go back and we're very interested in partners to go back and identify and test people who have experienced severe adverse events and see if genomic or other patterns can be identified that would identify people at risk for these adverse events.  We think, obviously, this won't completely abrogate drug safety problems but this could provide a great improvement.

            Now in specific biomarkers, we are working, as I said, with partners.  We had a meeting on Monday and Tuesday on pharmacogenomics drug development and in vitro diagnostic pharmacogenomic test development.  We had more than 500 people there.  And I would like to thank the Science Board.

            We brought this project to the Science Board, I think, about 18 months ago and we've had over -- I think we've had 12 voluntary genomic data submissions where we have in, you know, regulatory context, had extensive discussion of the genomic tests and how they might theoretically be used in the development program.

            This has also spilled over into the review side where these tests are then being integrated into the actual drug development program and in review.  And I think particularly in the cancer field, we can see already this is an urgent need right now in the cancer field to be able to link the diagnostic tests along with a drug.  And the Device Center and the Drug Center are working very closely together on this.

            So we have many more partners who have biomarkers than we have resources that will be able to collaborate with them.  So this is kind of an embarrassment of riches.

            But in the safety area, we are going to focus, we're going to look at padatoxicity.  We have many partners working with that, including NCTR is working with us on that.  And we're also working on further evolution of the QTC prolongation issue with drugs.

            Now in the clinical trial area, we're doing some worked examples of quantitative disease modeling and simulation.  And this is a tremendous opportunity, which maybe we'll have an opportunity to share with the Science Board later about a way to quantitate what we know about a disease and what we know about how a disease responds to therapy in a way that then the effect of new interventions can be modeled.

            And this can be used in the analysis of how you would conduct an additional trial.  This applies across the board to vaccines, cell therapy, devices, and so on.  And the Device Center is particularly interested in this, as I said, because of the rapid evolution of devices.

            In early clinical trials, this week we have just published the exploratory IND draft guidance.  This draft guidance is out there for comment and it is a document that talks about getting into people, not in the ordinary way of rapid dose, you know, escalation trials and so forth, or IND safety trials, but earlier using imaging, using micro dose techniques to look at metabolism, look at proof of mechanism for targeted therapy and so forth.

            So we will be seeking from the drug development community and the academic community, in particular, and put on this guidance.

            We're also doing a pilot on early meetings with sponsors that will allow us to talk about some of the quantitative modeling and also early strategies in development.

            We had already talked, when we presented  to the Science Board last time about the projects that we wish to take on in later clinical trials dealing with many of the analytic issues such as Bayesian designs and so forth.  And we are working on those.  We're moving ahead and trying to set up those projects.

            In later clinical trials, there's also a regulatory modernization piece that we found has to fit with any given modernization of the science.  So we move the science along, we have to move our mode of regulation along with it.  And so we have started what we call an analysis into how we do bioresearch monitoring.  We're moving along on that.

            And we also recently had a Part 15 hearing, which is a way of perhaps initiating regulatory changes on adverse event reporting to IRBs.  This is something the IRB community has brought up to us repeatedly as a problem.  We had a very good meeting on that.  And all of these efforts are intended to go along with trying to streamline the process.

            In addition, and I'll hurry, we're working on -- we're continuing to work on the automation and standardization of clinical trials.  We have gone a long way with our partners CDISC and working with HL7 on electronic data standards to be used in clinical trials.

            We are starting to work more on the content now.  Most of those standards have been worked  on electronic interchange standards.  Now we're starting to work on content standards.  And this will be a Critical Path Initiative that we will work on.

            And we're also partnering with the National Cancer Institute on electronic reporting of -- a repository for CVs of investigators, something that kind of plagues everyone who is involved in the clinical trial business, getting all this information about all the investigators around to all the parties who need it.  And so the idea of an electronic repository is something everyone agrees with basically.

            The final point I want to make is that training and infrastructure for this new kind of science or this enhanced kind of science continues to be a problem.  We hear from the various industries that they cannot hire and find the multidisciplinary scientists that are needed for this kind of work.  And that's true for the FDA as well.  These folks are in very short supply.

            These issues overlap with things that were identified by the NIH in their Roadmap Initiative.  And so I think there are opportunities here to make sure that programs are set up and people get trained.

            We have raised these needs with the academic policy sector and hopefully, you know, there will be a recognition of the need for more training.  If we're actually going to move biomedical science ideas into the clinic and get them to be commercial products available to patients, we have to train people who are expert at that interface.

            And the final note I would like to add before I close is one of the things we've all realized and we've learned throughout this year is the importance of diagnostics to this whole enterprise.  We realize that better diagnosis is really the foundation of improved therapy.  And perhaps we were all mistaken if we thought we could just determine better therapeutics without further advancing the science of diagnostics.

            We're focusing on this issue with the Device Center and with our partners.  And we hope this is something that can really be moved along.

            Now the remaining barriers on this initiative, obviously we lack staffing at the FDA to staff many of these projects.  And so that really slows down the rate of progress that we would have on them.

            Various partners are still trying to work out how we could work together in public/private partnerships.  And what the true, you know, arrangements would be.  There are ways to do this but they take time to make consortia.

            And we still, we're doing some analysis but we really need better incentive for diagnostic development and we really aren't sure how that is going to get done.

            So the next steps are we are going to publish our critical path opportunities list, hopefully very soon.  Subsequently, we plan to publish a description of the projects that we're actually able to be engaged upon at the FDA in the various centers.

            We hope to further develop these consortia.  In fact we will further develop these consortia, various types of consortia to get this work done.  And the good news is there are people who are really willing to put resources into this to make this happen.  This general recognition, this type of thing needs to be done.  And we will try to gather some resources up internally to continue to support these efforts.

            So the critical path concept has had a very positive response.  We think publication of our list will galvanize people to realize that there are huge gaps that need to be addressed in their areas of interest.

            We've identified many projects.  And within our ability to do them have begun work on them.  And right now the rate limiting steps are organizing these collaborations and obtaining the resources to get them done.

            CHAIRMAN SHINE:  Thank you very much, Dr. Woodcock.  Excellent.  I call to the committee's attention the large volume of guidance materials that we were provided in preparation for this meeting.

            And one of them is the piece on pharmacogenetics, which this board discussed extensively in April of last year.  And, Dr. Woodcock, I was very pleased to see the guidance that arose in terms of that piece.  We'll be talking about other portions of that guidance as we go forward.

            Are there comments or questions for Dr. Woodcock at this time?

            (No response.)

            CHAIRMAN SHINE:  The Commissioner has a conference call and he will be back.  And we do have some questions for him but we'll give him a chance to get some of his other business done.

            Before we proceed with formal presentations, Dr. Johannessen has a statement to make.

            DR. JOHANNESSEN:  Good morning.  The following announcement addresses conflict of interest  issues associated with this meeting of the FDA Science Board on April 15th, 2005.

            The Food and Drug Administration has prepared general matters waivers for the following special government employees: Dr. Kenneth Shine, Dr. Gail Cassell, Dr. Susan Harlander, Dr. Cato Laurencin, Dr. Xavier Pi-Sunyer, Dr. Jim Riviere, Dr. Allen Roses, Dr. Katherine Swanson, and Dr. John Thomas who are attending today's meeting at the FDA Science Board for the discussion of drug safety, safety systems for vaccines, blood, and tissue, and cGMPs for vaccine being held by the Office of the Commissioner.

            A copy of the waiver statements may be obtained by submitting a written request to our Freedom of Information Office.  Unlike issues before a committee in which a particular product is discussed, issues of broader applicability such as the topic of today's meeting involve many industrial sponsors and academic institutions.

            The committee members have been screened for their financial interests as they may apply to the general topic at hand.  Because general topics impact so many institutions, it is not practical to recite all potential conflicts of interest as they apply to each member.

            The FDA acknowledges that there may be potential conflicts of interest but because of the general nature of the discussion before the committee, these potential conflicts are mitigated.

            And I would just remind everyone to please turn their cell phones on vibrate and for the Members at the table to push the button when you talk.  Thank you.

            CHAIRMAN SHINE:  Thank you very much, Dr. Johannessen.

            I think we will now move directly to the first presentation, which is an introduction to drug safety by Steve Galson, Acting Director of the Center for Drug Evaluation and Research.

            Dr. Galson?

            DR. GALSON:  Thank you.  Okay.  Let me see if I can make this thing work.  Good.

            I'm very happy to be here and to see all of you today.  And we have a number of very, very interesting presentations about drug safety.  I'm going to give a brief introduction just to set the stage.  Don't have a lot of time in just ten minutes for much detail.

            But I think you don't have to be working with the drug industry to be aware that the drug safety policy environment has become more contentious.  This has been all over the news, as you know.  Among other things, there's been a lot of fuss about the risks of the SSRI class of antidepressants, the withdrawals of the Cox-2 analgesics that Dr. Crawford already talked about a little bit.

            There have been a lot of allegations thrown around, among them that the FDA doesn't care about drug safety, something that hits all of us very hard.  There are numerous, in fact a record number of Congressional oversight investigations and hearings that we're trying to slog through.

            Most recently, last month, Drs. Woodcock and Kweder engaged in a real testimonial tour de force in front of the Senate talking about our drug safety efforts and the history there.

            And what's been going on in the press that all of you are aware of has been very, very interesting.  It started out with a lot of very accusatory, very sharp articles and it has evolved somewhat.  And those of you who are students of the press probably recognize this sort of pendulum effect.

            Just last week, there was this article that came out in the Congressional Quarterly, which is a kind of low circulation, high impact periodical circulated on Capitol Hill.  The thrust of this is that a lot of the effort that has gone on to nail down what the problem is that FDA ignores the fact the drugs benefit patients and, in fact, ignores the fact that Congress has been very involved in the last decade at trying to help FDA get more resources to speed up approval of new and innovative products.

            And that when this is all over and the dust settles, Congress is realizing that they really set the stage for how the FDA is working today.  And they're going to accept responsibility for that and probably not make that much change although, you know, I'm not making an editorial comment on that.  Just noting that it has been very interesting to see how the changes have occurred.

            And then just this week, perfect timing for you all, there was an editorial, an op ed in the Washington Post by Ann Applebaum, who has been closely following drug safety and who many of us have talked to to try to educate her about the realities at FDA.

            And the interesting thing about this is it really describes the pendulum effect, how back and forth throughout the history of the last few decades at FDA, drug safety has come up and the pendulum is swinging now towards more concern about drug safety and expressing the real concern which is out there.

            We know from patient groups and from the industry as well that if the FDA becomes more strict and more careful about safety, there's going to be a real impact for patients.  So this side of the story is coming out as well.

            I think all of you know, and this addresses one of the major misconceptions that's been out there in the press about drug safety that it is, in fact, a top priority across the regulatory programs at the FDA.  It's not just an issue that we look at in post-marketing surveillance.

            It crosses all of our work from our new drug program to the manufacturing, regulation of drug quality, to our generic drug program, to the regulation of clinical trials, promotional activities, and all the other things we do.  Many of the resource decisions, the time that people spend on these problems are because of concerns about drug safety in various different realms.

            So I wanted to very, very quickly talk about where this all comes from and it really is derived from the Food, Drug, and Cosmetic Act which very vaguely but at the same time very clearly says that we're allowed to require all tests reasonably applicable to safety.

            And the way that we implement that is through our regulations, as you all know and among the millions of pages of those regulations that we have to assure that the product is safe for recommended use.  And that's the way that we decide what data gets sent to us from companies.

            And then after the regulations, we've issued a series of FDA and then worked very closely with the international community, as you know, on international guidance documents that specifically lay out in many, many different realms the level of evidence needed for safety evaluation.

            But one of the issues that I think is very, very relevant for you all on the Science Board, we talk about it a lot, but is sometimes lost in the public or lost to the public is that even though we are scientists and we have hundreds of scientists in the FDA, many of the judgments having to do with risk benefit and regulation involve more than science.  They involve judgment and they involve policy.

            And so when people say, you know, the science is broken or we're not following science, what that really avoids is the fact that a lot of the decisions that FDA makes have to consider non-scientific societal factors.

      And those of you that have been involved in regulation or involved in risk-benefit decision-making, which I know is a lot of the people in the room, already know this.  That you can't just go back to your biochemistry book and figure out how to answer questions of risk-benefit.  There is invariably judgment, invariably policy in there.

            So, of course, this means there is a huge amount of room for disagreement.  The most basic level of disagreement is how safe is safe?  How safe does a product have to be demonstrated to be before we decide that it is safe enough to be approved?

            I don't have to tell this audience that safety doesn't mean no risk.  The risk-benefit for an individual drug or class has to be done separately because of different severity of clinical conditions, different situations, different availability of data for drugs as they go through the pipeline.

            And so there is no formula that can be plugged in to say bingo, green light, safe enough, effective enough.  There are always going to be individual decision-making and this is why there is always room for disagreement.

            And then the fundamental double-edged sword, which Dr. Woodcock focused on very, very well at her testimony from the Health Committee, which is that if we are going to require more information be submitted to the Agency on safety, if we want to be more sure about safety, there are inevitable consequences.

            It would drive up the cost of drug development.  Or drive up post-market costs for companies and for the healthcare community as a whole.  And this has -- can have adverse consequences for innovation and availability of new products.

            So this zero sum game, double-edged sword concept is very, very important for you all and everyone to understand as we move forward.  And it is very much behind the efforts that are underway in the Agency.

            A lot of the questions that have been raised have been about whether the User Fee Program has changed how we balance benefit and risk in making drug approval decisions.  And I don't have time to go into the detail of this but we have done a very careful examination of the rate of drug withdrawals and how frequently we use black boxes in warning about drugs.

            And there is really no evidence of actual change in our risk threshold over time because of the User Fee Program.  Of course, there are lots of people that claim this and they throw data around.  But at least the careful evaluations that we have done, we haven't really been able to demonstrate that.

            And this is just a list -- I hope you can -- yes, you can read it there -- of the drugs that have withdrawn -- withdrawing drugs from the market is something that has happened since the beginning of FDA's regulations.  And as I mentioned, we've looked at, in what we think is the fairest way possible, the proportion of drugs that have been withdrawn as opposed to marketed before and after the User Fee Program was instituted.  And there really isn't any difference in the proportion.  And you can see throughout time it's been happening since way before the Drug User Fee Program.

            But have our data requirements changed with science?  Yes, they have.  We are now able to avoid some well-known safety problems that plagued earlier drugs.  We're far from perfect.  We're going to talk about that a little bit later as is Dr. Woodcock again.

            We have more data submitted to support applications than ever before and we do feel that the drug supply, because of this, is safer than it ever has been.  But there will continue to be, as I've already pointed out, many issues.

            And I'll just point out a few of these before moving on.  The first is that the bulk of the studies that are conducted really have as their main focus efficacy.  Science has moved ahead more with how to determine efficacy than it has with safety analysis.  And many of you involved in drug development know very well that, for example, with toxicology, we're doing almost exactly the same toxicology tests we were doing probably when I was born for drugs.  They haven't changed very much.

            The size of the pre-market safety database is usually determined by the size for what's needed for the efficacy studies.  Rare or time-dependent effects are not known at approval.  They're just -- with the number of people participating in the studies for the period of time that we require the drugs to be studied, we are not going to be able to see those rare or time-dependent effects.

            And we can't require additional safety studies after approval according to our regs.  Our only tool, which is somewhat like hitting an ant with a mallet, is that we can take a drug off the market.  And we can use that authority to get companies to do things.  We do it.  But we do have limits on our regulations.

            As I mentioned already, major additions to preapproval safety database would have potentially adverse consequences.  And then in the post-market area we don't, even as much as some other countries in the developing world, have an organized national pharmacovigilance system that automatically gets us information about drugs that run into trouble.

            We have a system of looking at spontaneous adverse events reports but that's very, very different from an organized national sort of certainly required pharmacovigilance system.

            So what we're going to do this morning is take you through a quick run through of our program.  Of course not enough detail but you guys already know a lot about our programs.  And then give you some time to look at the questions that you've heard about.

            Very, very quickly, Dr. Oliva is going to go through Pre-Market Drug Safety.  Rachel Behrman is going to talk about some of our very, very exciting initiatives on labeling and communicating with the public about drug safety which we think is one of the key issues for us.

            I'm going to come back and talk a little bit more about the drug safety initiatives that you heard about from Dr. Crawford this morning.  Dr. Seligman is going to talk about what we do in the post-market arena.

            Theresa Mullin, Dr. Mullin, from our Planning Office is going to talk about some very careful work that she and her staff have done to really document the resources that we spend on drug safety.  And then Janet will be back again to talk about critical path applications and applications of new science to drug safety.

            So with that, I'll let Dr. Oliva kick it off.  Thanks very much.

            DR. OLIVA:  Well, it's both a pleasure and an honor to address the committee this morning on the issue of pre-marketing drug safety.  As a former clinical reviewer, it's no exaggeration for me to say that the FDA spends a tremendous amount of time and effort on the evaluation of pre-marketing drug safety.

            And what I would like to do this morning is inform you on the contents of a new guidance that came out just last month on the review of pre-marketing drug safety.

            This is a guidance that represents the good review practices for the clinical reviewer on evaluating drug safety.  And it really represents the collective knowledge through many years of doing this in the Center.  And it was a collaborative effort across many offices within CDER, including Office of New Drugs, Office of Drug Safety, and Office of Medical Policy.  And I'm sure there are others that didn't get on this slide.

            Now the guidance says very specific purposes and first of all, it's meant to assist reviewers in how to conduct the clinical safety review of an NDA or BLA.  It does document good review practices, as I mentioned.

            And we think it's important in order to provide standardization and consistency across all our review divisions on what constitute an adequate evaluation of drug safety as well as provides instruction on the format actual review -- of the written review of drug safety.  It ensures that critical analyses and presentations of the data are included in the review.

            This guidance also dovetails very nicely with the clinical review template that we issued last July.  The two are completely harmonized so that a reviewer, once they're ready to document their review, has all of the headings of the drug safety guidance are included.

            And the guidance, what it does is it expands the headings of the clinical review template so it serves as a very nice reference to reviewers on each heading, which I'll go into.

            One of the important points that the guidance stresses is the need for collaboration.  Although this is a document geared towards the clinical reviewer, we do recognize the need for additional skill sets such as analysis of event rates and so forth.  And, therefore, it stresses the need for collaboration with biostatistical colleagues and other experts when necessary to get a complete picture of safety.

            So what exactly is in the guidance?  Well, there's advice on how to conduct and organize the review, of course.  And there's also an annotated outline of what the safety review should look like.

            The guidance identifies four important tasks for the reviewer when they evaluate a drug's pre-marketing safety risks.  First and foremost is to identify serious adverse events that might do these three things: might prevent use altogether, in which case we would not approve the application, that could limit use, and that may require special risk-management efforts.

            Secondly, the safety reviewer will estimate the frequency of commonly occurring adverse events, which will need to be communicated to the public.

            Third, the reviewer evaluates the adequacy of the data in the application.  For example, was exposures adequate and did they occur at relevant doses?

            And finally, it's important that the reviewer identify any unresolved safety concerns that may need further attention either pre-marketing or post-marketing.

            These are additional tasks for the safety review.  We need to identify factors that predict the occurrence of AEs, both intrinsic and as extrinsic factors, ways to avoid adverse events through monitoring or other techniques, and ways to manage them when they occur.  And finally we need to provide a comprehensive evaluation of risk information in support of labeling.  And Dr. Behrman will get into that in more detail.

            The guidance outlines the key sources of safety information.  Now I'm not going to go through all this long list, but I put it up there to emphasize that there are a lot of areas that we ask reviewers to look at when looking at safety in an application.

            We talk about causality determination which is heavily dependent on a comparison of event rates between treatment groups.  And it's also heavily dependent on proper coding of the adverse events.  And we ask reviewers to look very carefully at how adverse events are coded because this is the only way that we can get accurate numerators for event rate comparisons.

            And there's also an emphasis on the individual case reviews of deaths, serious adverse events, and drop-outs due to adverse events or adverse drop-outs.

            As far as the organization of the safety review, it's basically broken down into four broad areas that I show here.  And I'll walk you through to each one.  But this is what constitutes the documentation of the pre-marketing safety review.

            The first one is the methods and findings.  This is where the reviewer assesses the safety of the drug, describes what were the findings.  And they describe the relevant data sources that went into this determination, what safety assessments were conducted along with the major safety findings.  And it emphasizes the use of a very systematic approach.

            This section of the safety review, 7.1, is quite detailed.  And again, I won't go through each one of these.  But I put it up again to emphasize the fact that reviewers systematically go through each of these domains with each application and documents the findings in these areas.

            Section 7.2 is where the reviewer will assess the adequacy of the safety database.  Was patient exposure adequate?  Were sufficient numbers of subjects exposed for long enough duration at the appropriate levels?  Were specific subgroups analyzed for safety?  And what were those findings?

            We look at the quality and completeness of the safety evaluation, including what animal testing of safety occurred, what in vitro tests showed, what long-term safety can provide, as well as any specific assessments that were performed.  And we ask ourselves are additional safety testing needed either pre- or post-approval.

            The third section of the safety review is the summary section where we provide a brief summary of the critical findings of the safety review.  And this section also contains the adverse events that the reviewer considers are important and drug related that may need to be communicated post-approval.  And here is where we document any important limitations of the safety database along with our conclusions.

            The final section of the safety review is a general methodology section.  It's sort of an appendix.  This is where we get to describe the analytical methods that the reviewer used in reviewing the data along with a general discussion of any other methodological issues that were not discussed elsewhere, discuss the general idea of pooling, why was it done, how was it done, as well as how we explored the data for predictive factors and how we assessed and determined causality.

            So in summary, I want to leave you with the notion that this final guidance is really a culmination of many, many years of collective effort throughout the Agency in how to conduct a pre-marketing safety review.  It promotes good review practices.  We believe it will lead to increased standardization and consistency of format and content of the pre-marketing safety review.

            And it ensures the critical presentations of the safety data and the analyses are not omitted.  And it's entirely harmonized with the Clinical Review Templates so that our reports that are posted on the web all have the same look and feel and are consistent and complete.

            So with that, I'll end my talk and turn it over to our next speaker, Dr. Behrman.

            CHAIRMAN SHINE:  Yes, before we go further, we have a couple of minutes.  And I would like an opportunity -- if any members, this is a very important document.  If any members of the committee want to ask specific questions --

            DR. OLIVA:  Sure --

            CHAIRMAN SHINE:  -- about the document.  One thing you might help me with is a number of these documents are headed, "Contains non-binding recommendations."  And I wonder if you would -- or Janet or whatever -- help me with that.  Given that this seems to me to be a rather important set of criteria by which our reviewers operate, why do we use this kind of language that kind of implies that they may or may not do this?

            DR. OLIVA:  Sure.  Since this is a guidance and we abide by the good guidance practices by regulation, this is standard language.  And that unless it is something that is mandated by a statue or regulation, then it's by definition non-binding.

            And Dr. Woodcock, you may be able to elaborate further.

            DR. WOODCOCK:  Yes, that's true.  That provides the flexibility, obviously.  But we have -- the purpose of the supervisors here in the supervisory chain, if a reviewer decides that a different type of analysis is better, that's fine.  And they should do that.

            But then their supervisor has the right to say well, that analysis really wasn't -- doesn't get to the question that you were supposed to get to.  So that is part of the purpose of having various experts look at these reviews and so forth.

            But yes, we don't require in this guidance or any guidance that people do things a certain way.  If there is a satisfactory scientific way or superior way to get to the same result of the analysis in this case, then it can be done that way.

            CHAIRMAN SHINE:  But doesn't that increase the ambiguity for people who are developing drugs and so forth to understand, in fact, how that particular product is going to be evaluated since there would be  apparently this --

            DR. OLIVA:  Well, one of the principals in good guidance practices is that if someone is going to deviate from a guidance, that it has to be well justified and it has to be justified in writing.

            So the assumption is that reviewers will do it this way unless there is a very good reason that has been fully vetted internally to do it a different way or a better way because we realize that guidances are living documents and that they -- and through knowledge and experience can change.  And this allows the opportunity to improve on it.

            CHAIRMAN SHINE:  At what point in the process will the folks who are involved with the new product be notified that you're going to use a different methodology?

            DR. GALSON:  As -- I would say as early as possible, right?

            DR. OLIVA:  Sure.

            DR. GALSON:  I mean what we're trying to encourage is more intense early interaction between our reviewers and people from the companies, very early in the development.  And as soon as we would detect that there was going to be something different that we were interested in seeing, we would say that.  You know it's not a perfect system.  But that's what we try to do.

            CHAIRMAN SHINE:  Dr. Pi-Sunyer?

            MEMBER PI-SUNYER:  Yes, I wanted to ask you a question with regard to time-dependent adverse events.  You made the point that you cannot require additional safety studies after the approval of a drug so you don't have a way to do that after you've approved it.

            But if it is possible that you're really getting safety data mostly two years, at the most, and say something in a drug makes you think that there might be a time-dependent adverse event, can you add some kind of qualifier that will allow you to continue to survey that drug?

            DR. OLIVA:  Well, let me elaborate a little bit because I, you know, somewhat used shorthand.  We don't have the statutory ability to require something after approval.  But we can ask and we do ask and we get things done that way all the time.

            When there is an important safety question that has to be answered, we try to get it answered either by asking the company to do a study or working with other groups.  And so I don't want to convey that we have no tools at our disposal.  But it's not a you will do this and if you don't, X will happen kind of authority.

            DR. WOODCOCK:  Can I add to that?

            DR. OLIVA:  Yes.

            DR. WOODCOCK:  Can I add to that?

            CHAIRMAN SHINE:  Yes, absolutely.

            DR. WOODCOCK:  Yes, in addition, at the time of approval, if -- you know one of the important parts of the safety review is to identify the unanswered questions.  Not just to review whatever has been sent in but to think about what don't we know about this drug?  That's as important as what we do know about a drug.

            And at the time of approval if there is a very burning question that hasn't been answered but might require much additional work and we feel the benefit-risk is satisfactory for the drug, we can ask that either registry or study be done as a post-marketing commitment.

            DR. OLIVA:  Another useful tool that we have to get that information post-marketing is the label itself.  For example, if we have insufficient information to assess the risk of the drug in a special population such as hepatic or renal impairment, prior to approval we may contraindicate the drug in labeling in that population until that data are collected and submitted and reviewed.

            CHAIRMAN SHINE:  A key element, just to follow up, is the question that the reviewer is asked, namely is additional safety testing needed either pre-approval or post-marketing.

            DR. OLIVA:  Yes.

            CHAIRMAN SHINE:  My question is from a procedural point of view, who looks at that recommendation?  What's the process by which we are sure that a recommendation of that kind gets evaluated at a fairly high level in terms of the follow up?

            DR. OLIVA:  Yes, once the safety review is written, then it is reviewed internally at several layers.  There's usually a secondary reviewer as well as the division director and for a new molecular entity, the office director will evaluate those recommendations and look at the reasons for those recommendations and then act upon them and make a decision whether the uncertainty is great enough, whether additional work pre-marketing is needed.

            DR. WOODCOCK:  And whatever that decision is, it will be documented in writing.

            CHAIRMAN SHINE:  Yes, I just -- my concern is that we are very sure that those kinds of recommendations are evaluated at a high enough level in the organization so that we're quite comfortable that other kinds of interactions are put in the proper perspective in terms of doing that.

            One of the interesting things, as I read the material, was you point out the problem with the definition of symptoms, complications, and so forth.  I think one of the examples you use are the SSRI business, emotional disturbances versus suicidal ideation.

            To what extent could you, in fact, have a glossary of terms explicit enough so that investigators would, in fact, have a minimum opportunity to categorize items in ways that don't truly display the nature of the problem?

            DR. OLIVA:  Well, this is an ongoing challenge.  I mean there are numerous dictionaries and thesauruses available that will allow the mapping of investigator terms to standardized terms.  And those are readily available to the reviewers and they're routinely used in the evaluation of the coding of the adverse events.

            And if we see a problem, if we see that certain terms are being mis-categorized, then that would be a cause to have them re-categorized, if necessary either by an independent panel or --

            CHAIRMAN SHINE:  But the key is that the investigators are in the same thesaurus as you are, right?  In other words -- yes?

            DR. WOODCOCK:  This gets to the issue of standardizing the case report form and the reporting of adverse events out of clinical trials.  And as you probably well know, that hasn't -- but as I said in my introductory remarks, we are starting down that path.

            The use, for example, of electronic case reporting forms with pick lists and so forth will help with this.  But I think what Armando is reflecting is often we get, you know, like a company gets a narrative and an investigator has sort of decided what terms they're going to use for that particular adverse event or whatever.

            And we need to -- you're right.  We need to work on further standardization.  But we're not quite --

            CHAIRMAN SHINE:  Yes.

            DR. WOODCOCK:  -- the field isn't there yet.  Is that fair?

            DR. OLIVA:  Yes, no, exactly.  I mean in an ideal world, the investigator when they were ready to enter the adverse event onto the case report form, they would have the pick list, the standardized terminology readily available to them so they could make that call.

            CHAIRMAN SHINE:  Exactly.  And I think that's important.

            Dr. Cassell?

            MEMBER CASSELL:  Yes, I think Ken, following up on what you said, to me in terms of pre-approval, the collection of adverse events and the investigators is one thing because you have selected investigators very knowledgeable, hopefully, in the area and so forth.  But post-marketing when you're collecting adverse events, who is responsible for training of individuals, in communicating to individuals on the appropriate methods, terminology, et cetera, for collecting adverse event data?

            And I guess, Janet, I was thinking back to your comment about the need for training and where in the medical school curriculum as tight as it has gotten today, we all know in terms of pharmacology period, it has shrunk considerably as pathology and molecular biology have expanded.

            What are we thinking looking towards the future now as far as collection of adverse event data and the practicing physician?  Who will be responsible for the education?

            And again, just to add one more piece to that that I worry a lot about with all the changes and the way companies now are able to interact with the practicing physicians in educating in terms of drug use, again it just poses more limitations, I think, on getting to those individuals that are going to be collecting the data.

            DR. OLIVA:  Well, this is my own personal opinion, but I think standardization is the key.  I think that we're now moving to the area where we have standard variables for different types of adverse events.  And now, as Dr. Woodcock pointed out, standard terms for the actual adverse events themselves.

            And the next step is encouraging collection of the adverse events in clinical trials using these terms.  The next logical step will be the use of the very same terms in clinical practices and use in the electronic health record so that it is just one continuum from the doctor's office to -- every step along the way.

            CHAIRMAN SHINE:  Amen.

            Quick comments from Dr. Thomas.

            MEMBER THOMAS:  I was just curious how and what process you used for pooling data.  Whether it's at the pre- or post-surveillance stage?

            DR. OLIVA:  Well, my comments about pooling data were strictly relating to the pooling of safety data across clinical trials in pre-marketing -- during the pre-marketing review.  That's the easiest place to do that type of work simply because there is a certain amount of consistency already built in in the way they are collected.  And so they lend themselves readily for pooling.

            In the post-marketing world, I'll have to let Dr. Seligman weigh in on that and others.  But it's obviously much more challenging.

            MEMBER THOMAS:  There's probably a great adherence at the safety level --

            DR. OLIVA:  Yes.

            MEMBER THOMAS:  -- from the standpoint of protocol.

            DR. OLIVA:  Exactly.

            MEMBER THOMAS:  Than later.

            DR. OLIVA:  Yes.

            CHAIRMAN SHINE:  Dr. Laurencin?

            MEMBER LAURENCIN:  The guidance document that you put together appears comprehensive.  But every page says non-binding recommendations.  And so the two questions are number one, how much will it be utilized by the reviewers?  And what are the plans to monitor to what the extent the reviewers actually utilize this?  Because it is important for industry and for others who are looking to bring products through.

            DR. OLIVA:  Sure.

            MEMBER LAURENCIN:  That's the first question.  What are your thoughts?

            DR. OLIVA:  Well, you know why it says that.  Because it is a guidance.  And we have to say that if it's a guidance.

            But the nice thing about it, because it is a guidance to reviewers and it is an internal guidance, that we have other policy tools internally to make sure that reviewers adhere to it.  You know, the supervisors and team leaders and division directors all can expect, and as part of internal policy, can say this is the way that it will be done.

            And part of the secondary and teriary reviews will include a check -- does include a check to make sure that the reviews adhere to this document.

            MEMBER LAURENCIN:  Just as a follow up, what is the mechanism by which the changes in the guidance document will be relayed to all?  Because so many times it is a draft guidance document.  The phrase living document comes up and everyone smiles.  But how will these changes be relayed to the greater community?

            DR. OLIVA:  Well, guidances are updated.  A guidance can be modified and then that goes through the -- again, posted for public comment before it gets rewritten.  So there is a mechanism in place to update guidance.  And this one would go through that.

            CHAIRMAN SHINE:  We're going to have to move on.  I think -- at least my sense is that the committee -- the board is quite impressed with the document.  It really does show a good comprehensive kind of guidance with regard to it.

            Our hope is that it will be applied fairly consistently.  Dr. Woodcock has indicated there may be rare examples where a different methodology is involved which would require explicit kind of language.

            But I think this is a good step forward.  And I congratulate you on the accomplishment.

            Why don't we move forward?

            DR. OLIVA:  Thank you.

            CHAIRMAN SHINE:  We're going to hear from Dr. Behrman.

            DR. BEHRMAN:  Good morning.  Let me just make sure -- okay, thanks.

            Good morning.  I have actually the distinct pleasure this morning, unlike some others who have to discuss things that are in their infancy, to describe for you two initiatives that are nearing the end of development and will be rolled out shortly.  And that's the Physician Labeling Rule and structured product labeling.

            And just since we've had a discussion of standards, I'd just like to point out that Dr. Oliva and I, as members of the SPL team, have sacrificed our personal preferences and we present from a standard format.  Not required but we do it.


            DR. BEHRMAN:  In terms of today's topic, which is primarily focused on safety, one needs to think about information.  And FDA -- one can think about this in this way, FDA regulates information in two primary ways.  We regulate the development of information through clinical trials and that is not the topic today.

            And then we also regulate, to a certain extent, the dissemination of information.  And over the years, we've probably focused on that -- or we have focused on that substantially less.  And gradually have come to realize that this is clearly part of our mission and responsibility.

            We have statutory authority to do this.  The Federal Food and Drug Cosmetic Act clearly states that we regulate, we have authority over the content of labeling the way we speak.

            So a drug or device shall be deemed to be misbranded if its labeling is false or misleading in any particular.  And the Secretary cannot approve an application, can refuse to approve an application if the labeling is not adequate.

            Similarly, we have implementing regulations, specific requirements on the content and format of labeling for human prescription drugs, 21 CFR 201.57.  Those regulations were promulgated -- draft in `75 and the final in `79.  Clinical trials, drug information looked very different in the mid-70s than it does now and clearly it's time for those regulations to be updated.

            So the first topic that I'd like to cover for you is the Physician Labeling Rule, which I said is nearing completion.

            Now anyone who has thumbed through a PDR recently may be surprised to learn that in fact there is a very specific order to the information.  That's not obvious because there is no same look and feel and there's no application of the basic principals of communication in terms of white space and bolding and other means of emphasis.  But there is a very specific order.

            Unfortunately, the order is not one we would today say makes tremendous sense.  Generally the principal is you put the most important things either first or last.  Well, first is the description.  That tends to be the chemical structure.  Last is references.  That, again, tends not to be the first thing one might turn to.

            The safety information, as you can see, is sandwiched in the middle as is dosage and administration, for example.  So the information that one wants most quickly is difficult to find.

            So going back a number of years, the intent was to develop a tool that is more informative, that's more accessible, that's a better risk communication management tool.

            And the development process was quite lengthy and quite comprehensive.  It included focus groups.  It included a national physician survey, physicians being the primary user of drug labels although the public meetings that followed included pharmacists, nurses, et cetera, and the public, others who use the drug label.

            And finally, initiated a formal notice and comment rulemaking process with the review of, I believe, 93 written comments.

            So what will -- in the proposed rule, what did we propose that the drug will look like -- and because the rule has not been finalized, I'm going to stumble a little bit and keep referring to the proposed rule.  But it does give you the flavor of what we're thinking and certainly what was reflected in the comments.

            Well, the first is to start with the most important information.  And what is the absolutely most important information?  A box warning if there is, what the drug is used for, and then the dosage and administration.

            You'll notice that the safety information in terms of contraindications, warnings, precautions, adverse reactions, is consolidated.  It's worth noting also that in the current label, there is a warning section and there is a precaution section.  The distinction is not really clear to anyone.

            And precautions, which sounds like it might be safety information, includes many other things including use in special populations such as patients with renal impairment, et cetera.  So it's a mish-mosh or a potpourri.  And that's been separated out with new sections having their own -- let's see -- for example, use in specific populations would be separate, clinical pharmacology has been pulled out, et cetera.

            And then at the end, again putting something important last, patient counseling information.  There's clear information that prescribers should be communicating to the user of the drug and we want that highlighted so it is easy to pull out, easy to access for both the prescriber and for the patient.

            But perhaps the most novel and -- from the focus groups and from our point of view important notion would be of highlights, that a very quick summary of the most critical drug information up front where it can be easily accessed.  And the limitation statement is -- we'll just be describing the fact that it is not the entire label.

            But notice what one could see very quickly.  That -- well, first of all, what product it is.  But obviously if there have been any major changes since the last label.  Or not since the last label but any major changes.  Indications, dosage, contraindications, everything very important right up front.  And I'll show you an example of that in a moment.

            In addition, we feel it is important to establish minimum font requirements.  The one -- my favorite comment to the proposed rule came from an eye care company that said that under the proposed eight point minimum font, they would no longer be able to publish their label in a 4.5 font.  This is an eye care company.


            DR. BEHRMAN:  So we believe that no one should be asked to read such a label.  And, in addition, that standardized bolding and white space, all of us -- I mean there are, I'm sure, many in the room who try to use labels to prescribe drugs, the information is there.  It's very hard to scan it and find it.  With standardized bolding and white space, that would be changed.

            And as I mentioned, frequently referenced sections would be moved forward.  And, in particular, safety information should be consolidated.

            We heard pretty clearly that highlights not only being critical had to be limited to about a half page.  And that we should bullet the information, again, making it easy to scan.

            Moreover, that we should create some form of index.  This will be particularly important in the electronic era so that you can hyperlink.  But even if not, to get a quick, easy view of, in fact, what is the label, although what was proposed in the rule and what was discussed in the comments, in fact, is not an index.  It's a content but that's another point.

            And that we provide greater clarity in our requirements.  Again, if you go back to `75 and `79 and read these proposed rules, they were appropriate to the state of information in the mid-70s but not in 2005.

            So this is, we think, a thing of beauty.  But this is an example of a highlight --


            DR. BEHRMAN:  No, quite seriously.


            DR. BEHRMAN:  I mean can you imagine, those of you that have been in emergency rooms in the middle of the night being able to just scan down a drug with which you are not familiar or for an indication that you don't know or a dose that you don't know or just to make sure that nothing has changed since you used the drug a year ago or what the most important warning is because you're using it in a population you've never used it before.

            We think that in terms of importance of clear communication, safe prescribing, reducing medical errors, et cetera, that this will make a major contribution.

            Similarly, the index I described to you -- and this would give you a feeling of, again, not only what the sections look like and how the more important information is reordered forward, but also give you a sense of electronically how you would link, how you would just jump to the section that you wanted if you were, in fact, not in paper, which you probably won't be pretty soon.

            We're going to roll out, when this does roll out, a number of things with it.  One thing is companion guidance.  I know we've just had a bit of discussion about what guidance means but this is going to be a very new label for us, a very new label for industry.  We're going to have to help people learn how to write them.  It's not easy.  Those of us that spent some time doing it, it takes some getting used to.

            More detail, more clarity on what should be in the adverse reaction section and how it should be organized.  Clinical studies, again, an important place for information about how to use the drug safely.  And then warnings and precautions, contraindications, and boxed warnings, a section which we have never provided guidance and for which there is a lot of confusion about what the contents should be.

            And then switching gears slightly, clearly to move forward into the 21st century, into the electronic era, the way I've been thinking about it lately is think about everyone who is walking around with an iPod and what they can tell you about their music but they can't tell you that about their drug information.

            We want to support and are supporting the health information technology initiatives because the Physician Labeling Rule will be concise.  It will be clear.  And it will be easy to hyperlink.

            So the other major initiative that I want to describe in that vein is Structured Product Labeling.  And what is Structured Product Labeling?  Probably most people don't know.  But this is something that is going to roll out this fall so it's here.

            It's the content of labeling in standardized electronic file format.  So the blocks of text are tagged.  There we go.  So in pdf, you just have a lump of text.  But in SPL, you have a tagged section.  And, therefore, that means you can link it, you can move it.  If you want to standardize it, you can do that.  It's manipulatable.

            This is crucial to support a very important and exciting initiative called DailyMed which will be an electronic repository of current labeling.  It will be managed by NLM but it will be populated by FDA.  So it will be the most current labeling, vetted, approved, the gold standard of drug information.

            And I just wanted to add also it's responsive to the Medicare Modernization Act, which requires uniform standards.

            So what else do we need to do in order to be able to spit this labeling out on a daily basis to NLM?  Well, we need something called ELIPS, Electronic Labeling Information Processing System.  And the primarily important thing to you is the last bullet which is that we will be transmitting SPL with one business day lag.

            So this is really in real time.  We're giving ourselves one business day so that we -- the oops phenomenon, the not sending something out to the public that we later regret, but we'll be able to receive SPL.  We'll be able to reject it if it is missing something.  We will be able to review it, manipulate it, and then we will be able to shoot it out.

            And this is just portrayed graphically there for those of you that like that.  So the applicant will send us their SPL.  They will be required to do this starting in the fall.  Right now they're just required to send us an electronic copy but it will have to be structured starting in the fall to our document room.

            We will do what we need to do in terms of review and manipulation.  When it is ready to go out, it will be released by a labeling authority.  There will be a single labeling authority for each product.  And then it will go to the NLM.  And it will be accessible to whomever needs current labeling.

            And anyone who has tried to look for current labeling on the weekends, for example, not at FDA, it's extremely difficult to find.

            This is the most exciting part of this slide.  We will meet our October `05 target date.  We had our first demonstration.  What's the right word?  We had the first -- saw the first prototype this week.  And we are on schedule.

            And we will roll it out -- it will take a year to populate.  Companies have a year to get their current labeling in to us.  So by October of `06 -- and we may cut off at the end of the year just for convenience, the population -- the SPL ELIPS will be populated with current labeling for every product.

            In one sense this is a pilot in that we're starting only with prescription drugs.  And it's a pilot-approved concept.  But in the other sense, it is, in fact, it is the beginning because we will have one -- at least one center up.  And then we will expand to the other medical products.

            Phase Two will include unapproved prescription and OTC drugs.  That will -- the target date is August `06.  It will require a number of other things to happen, ELIPS to be up and running, which will be on time, Substance Registration System, which will require that someone assign a unique code to each ingredient so that then they can be linked and tracked.  And then we will need the Drug Listing System in place in August of `06.

            So in sum, we are poised to provide and can provide up-to-date labeling information.  We have, over the years, recognized that to support many of the things we do, some of the initiatives in providing information to consumers and to practitioners that Dr. Galson will discuss, initiatives such as providing the information with advertisements.

            Right now, the "brief summary", which you often see, is just -- well, it's not readable and it's not intelligible.  A year and a half ago, we promulgated draft guidance suggesting the companies might want to think about even before the Physician Labeling Rule was finalized, mocking up brief summaries that looked like highlights because ultimately highlights will exist.  It will be vetted information.

            We will have already decided it's the most crucial information.  And why not make sure that's what consumers see with a drug ad as opposed to something that can't read?

            So we're increasingly trying to educate ourselves in how to communicate.  We sit on the gold standard of information.  And we need to get a little bit better about, in fact, sharing it.  So the Physician Labeling Rule will ensure that the actual label, be it printed or electronic, will be readable and will be accessible.

            And that electronically, this will be available to anyone through NLM from any computer.  And it will be accurate and up to date.  And that will support, obviously, electronic prescribing, electronic health record, and decision supportware, really bring FDA in concert with others, into the 21st century.

            CHAIRMAN SHINE:  Thank you very much.  We have time for a question or two.

            Dr. Pi-Sunyer?

            MEMBER PI-SUNYER:  Will this be accessible to Palm Pilots?  You know the average physician --

            DR. BEHRMAN:  Right.

            MEMBER PI-SUNYER:  -- now doesn't use a big computer.

            DR. BEHRMAN:  Exactly.

            MEMBER PI-SUNYER:  He uses a Palm Pilot.

            DR. BEHRMAN:  This will be -- we will take it -- we will send it to NLM.  It will be available and accessible to anyone.  So whomever makes either your Palm Pilot or your Palm Pilot software can access that.  And then develop decision supportware or whatever search engine, if you will, that is appropriate for you.

            For example, if you're an infectious disease practitioner, you may have very specific sets of queries that you want.  And if you're a clinical pharmacologist, it may be very different.

            CHAIRMAN SHINE:  Dr. Thomas?

            MEMBER THOMAS:  I was going to ask you if the SPL would in any way replicate what we now know as the package insert with respect to information.

            DR. BEHRMAN:  Well, let me -- in case I didn't make it clear, let me walk through that.  Package insert, that's the printed piece of paper that comes with your bottle.  It will ultimately, if you will, replace that perhaps likely.  The package insert is required -- every drug is required to have the package insert go with it.  That's very expensive and it is not very accessible.

            So we believe that once the information -- it's the exact same information just delivered in a different way -- is available either electronically or some other way, the package insert will no longer be that useful.  But it will be the same.  The content will not change.

            So if you read the package insert or you  read it off the computer, it will be the same information.  Just how you choose to access it or how you able to access it.

            MEMBER THOMAS:  A follow-up question with regard to safety information, I didn't see quite as much safety information on your SPL.  Is that going to be --

            DR. BEHRMAN:  Should be go back?

            MEMBER THOMAS:  -- accommodated by a hyperlink?

            DR. BEHRMAN:  Can we go back?

            MEMBER THOMAS:  No, maybe I just missed it.

            DR. BEHRMAN:  No, it's all there.

            MEMBER THOMAS:  It's all there?

            DR. BEHRMAN:  In fact, it's -- the really exciting part, I think, is that it is consolidated.  And I probably didn't --

            MEMBER THOMAS:  Maybe that's why I missed it.

            DR. BEHRMAN:  Yes.  Well, we heard that it should be together.  So thinking about -- looking down, your box warning will likely to be short.  Indications and usage, dosage administration.  Then you get into what we consider the core safety information.  Contraindications, warnings, precautions, adverse reactions, all together right up front.

            So -- and if you go to the -- now remember this is just the highlights.  So this is not going to be the whole thing.  But you'll get your box warning.  Any major changes which typically are safety related.  And then you have all the safety information together.  Contraindications, warnings, precautions, adverse reactions.

            CHAIRMAN SHINE:  Dr. Laurencin?

            MEMBER LAURENCIN:  Thank you.

            I still have some concerns about the information being provided.

            DR. BEHRMAN:  Yes?

            MEMBER LAURENCIN:  And just as a preface, we've expressed this to the FDA.  I'm Speaker of the House of the National Medical Association in one of my roles.  And the NMA has expressed this that this information provides no information in terms of effects of drugs in the minority communities, specifically African-Americans --

            DR. BEHRMAN:  Well --

            MEMBER LAURENCIN:  -- in terms of one, degree of testing in the African-American and other minority populations, number two, adverse effects of drugs in minority populations.  It doesn't present the information.  Even trends, et cetera.

            And the concern is with so many drugs that may be utilized by minority populations, to a great extent there is no information really describing, at least what I see here, describing possible effects in minority populations especially.

            DR. BEHRMAN:  Well, you are correct that this does not address clinical trials.  So this will only address how to present the information that is developed in the clinical trial.

            Although the guidance documents do talk about what the importance, in fact stress the importance of special specific populations, but in fact it is highlight.  It will be easier to find information about specific populations.

            MEMBER LAURENCIN:  I mean my feeling is that --

            DR. BEHRMAN:  Yes?

            MEMBER LAURENCIN:  -- use in minority populations is so important that if it is not there, it should be specified that it is not there, it's not present, or it has not been studied.

            DR. BEHRMAN:  Right.  So in other words, you would want to highlight the absence of information as well.  And I'm just going back to the guidance documents that we're developing to -- I'm not getting there very quickly --

            CHAIRMAN SHINE:  But it would be appropriate in that section a use in special populations for that description to take place.

            DR. BEHRMAN:  Well --

            MEMBER LAURENCIN:  Agreed.

            DR. BEHRMAN:  -- but I wonder if you're saying should -- it was definitely not proposed to require the absence of information.  It's to require a description -- and again, I'm talking about the proposal -- would require a description of the information and discussion of what is missing.

            But I think that when you -- you have to think about the final rule plus the companion guidance documents.  And as we have discussed publicly a number of times, there is much greater emphasis on describing different populations and how drugs behave and the safety profile.

            CHAIRMAN SHINE:  Well, this would seem to me to be an appropriate thing to follow up on in terms of Dr. Laurencin's concerns.

            DR. BEHRMAN:  Okay.

            CHAIRMAN SHINE:  Perhaps you can discuss that with him a little further.

            DR. BEHRMAN:  Sure.

            CHAIRMAN SHINE:  One final question I have is are you -- you've gotten lots of guidance and input into this.  Are you doing marketing studies with the final product?

            DR. BEHRMAN:  Once the rule finalizes?  Or for --

            CHAIRMAN SHINE:  I mean are you --

            DR. BEHRMAN:  -- for the labeling rule for SPL or for --

            CHAIRMAN SHINE:  For the labeling rule, have you got focus groups where other --

            DR. BEHRMAN:  There have been tremendous -- the research that supported this, which was --

            CHAIRMAN SHINE:  I'm not talking about the research.  I'm talking about the final document being exposed to a variety of audiences in terms of whether it meets their needs.

            DR. BEHRMAN:  Our hope -- there is no plan to test the final Physician Labeling Rule in focus groups.  Our hope is that as we develop different types of consumer information and practitioner information, that will clearly have to be tested, for example, the new kinds of information that we are putting up on our website because that is something that has not yet been subject to focus groups and other kinds of testing.

            CHAIRMAN SHINE:  Okay.  All I was saying is that you go through an iterative process.

            DR. BEHRMAN:  Right.

            CHAIRMAN SHINE:  The question is is the final product carefully tested by consumers with a variety of backgrounds, age levels, things of this sort --

            DR. BEHRMAN:  Right.

            CHAIRMAN SHINE:  -- so we know that it works.

            DR. WOODCOCK:  I would just like to say it would be very nice to do this but under -- the rulemaking process takes about five years, okay, and so we try to do a lot more of this in guidance, which is more amenable to such an iterative process.

            DR. BEHRMAN:  And I just did want to add that we made use, in addition to our focus group testing and other testing, the work that CFSAN had done.  They had done tremendous work.  And also that the OTC regulations.

            CHAIRMAN SHINE:  I agree, Janet.  There are lots of ways to do rulemaking.

            Thank you very much, Dr. Behrman.

            Dr. Galson is coming back and talking to us about this drug safety initiative.

            DR. GALSON:  Okay.  I'm happy to be back here again.  And what I wanted to do now is take you through some of the recent drug safety initiatives that have been announced.

            The first is Dr. Crawford's announcement back last year in November and then our Secretary's announcement in February and a little bit more detail on those.

            First of all, the announcement from November, and Dr. Crawford went through some of this quickly, is first the Institute of Medicine study, and I want to just emphasize that again because we think it is so very important.  There are a lot of groups out there making comments about our drug safety system and investigations, GAO, Congressional committees, et cetera.

            But there really is no peer to the Institute of Medicine, as you all know, in terms of getting neutral experts involved in a very deliberative fashion.  And although the studies do take some time and require some investment of funds, we think this is going to be very, very important in the long run for helping us design a permanent system to improve, if improvements are needed in how we evaluate safety and what FDA's place is in the drug safety system.

            The second component of this announcement was a program for adjudicating differences of professional opinion, very, very important within the Center for Drugs.  As you all know, there are differences of opinion.  We've talked about this before a little bit.

            And two people looking at the same information can come to different conclusions.  And historically, there have been flare ups every once in a while in the Center for Drugs when there are these differences and reviewers don't think that their opinion or their analyses are being adequately considered in a final regulatory decision.

            So what we've done with this new policy, which was very, very carefully vetted internally, is create an organized way for a reviewer who has a difference of opinion to get that opinion examined and reviewed and moved up the hierarchy all the way to the Center Director so that if they really have a professional disagreement, it can be considered by others who can peer review it and look at the opposing views and help make a decision.

            And it is very, very organized and lays out in a step-wise way what those reviewers can do.  And we think this will help the sense among some reviewers that they have trouble getting their voice heard.  And I'm looking forward to getting involved in the first one of those adjudications.

            The third point here was that we've had a vacancy in the leadership of our Office of Drug Safety for some time with Acting Directors in place.

            And we've sort of taken a huge step in involving the federal government's Office of Personnel Management in helping us design a really state-of-the-art search nationally, which involves getting a group of experts in to figure out what the ideal components would be for a director, attributes for a director.  And that's moving along.  And hopefully we'll be able to get somebody in place there within the next few months.

            The fourth component of this was the acknowledgment that we need to do more in terms of getting input from outside experts in specific drug safety and risk management decisions.  And so we'll be planning more outside meetings similar to advisory committees but there are other sort of fora that we can use such as Part 15 hearings that you've heard about.

            And then the last part of this, the risk management guidances that Dr. Crawford talked about.  We've already published so I won't spend any time on that.

            And then a couple months ago, Secretary Leavitt, along with others, announced our Drug Safety Plan, which is very comprehensive and has as its overall goal the promotion of more of a culture of openness and enhanced oversight for drug safety within the FDA.  And involves several different areas of change.

            The first is more outside expert consultations feeding on to what I already mentioned.

            The second is improving the management of drug safety within the Center for Drug Evaluation and Research.

            The third is to change how we communicate about emerging drug safety risks to improve transparency.  And this is very, very important for patients, for practitioners, for those in academia and other places.

            And the fourth is to continue our work to improve scientific methods of improving adverse events.

            So the initiative will give patients, healthcare professional, and other consumers better access to information about medicine.  And this is all tied in as well to what you heard about from Dr. Behrman.

            And second, to make FDA's drug review approval and monitoring programs as transparent as we can make them under our statutes.

            We've got some new information outlets that we're putting together.  And these are going to be implemented immediately as opposed to some of the rules that take a long time and the systems that Dr. Behrman was talking about which, although will be implemented fairly quickly, are not going to be implemented immediately.  So these are things that we can roll out quite quickly.

            The first is a proposed Drug Watch Program.  I'll get into that a little bit more.

            And the second are patient information and healthcare professional information sheets.  These sheets are already being produced by the Center.

            They're already on the internet for some high profile drugs that you've heard about in the news recently: Celebrex, other drugs that have been the subject of Congressional scrutiny in other areas.  You can go on our website and see these sheets.  And I have some examples to show you in a minute.

            And the second big part of this is the creation of the Drug Safety Oversight Board.  I'm going to give you more detail about that.  The Drug Safety Oversight Board is going to provide independent oversight and advice to the Center for Drug Evaluation and Research Director on management of drug safety issues and policies.  And dissemination of certain safety information through our website on an emerging basis.

            So the oversight board will help select which drugs and which drug safety issues are important enough to be conveyed to the public on an emerging basis.  They need to go up right away even before we can change the drug labels so that practitioners and patients are aware of this information.

            And the second is when there are policy issues such as what is the threshold for putting a black box warning on a drug or other sorts of drug safety policy issues, this board will be convened and will help give important advice to the Center on it.

            It will be chaired by the Deputy Center Director of the Drug Center.  I don't know if Doug -- Dr. Throckmorton is here.  He's the Acting Deputy Director and he'll be hopefully, without too much delay, chairing the first meeting of this board.

            The Executive Director is going to be Susan Cummins, who I know is here.  Susan, if you would stand up a minute so everybody can see you.  She's agreed to take on these very, very important responsibilities.  And we're excited to have her get in place starting next week.

            The membership is going to include representatives from a number of different CDER offices, not just the people who were involved in looking at the drug.  In fact the people who have made decisions about the drugs that are coming from the board won't be able to vote on decisions having to do with that particular drug.

            What's really new about this, in addition to getting other offices across CDER involved, is that we're bringing in representatives from outside of CDER, membership from CBER, from CDRH, and even more significantly from outside FDA, from NIH and VA in the board.  We'll also have consumer and patient representatives and we'll have consultants from our advisory board also helping the Drug Safety Oversight Board.

            We do have restrictions having to do with the Federal Advisory Committee Act, which you are all aware of.  We've received some criticism on this.  Why aren't we having really completely outside people involved.  And this would turn the board more into an advisory committee and really make it very difficult to do the work as facilely and quickly as we'd like the oversight board to be able to do.

            We're going to be making our operating procedures available hopefully very, very soon so that all the questions that many people have about how we're going to operate in detail will be available to all of you.

            A little bit more detail on our proposed Drug Watch web page, again, this would be a section of our web page designed somewhat differently than what we currently have up there about drugs that we think, again, that the information that is coming out, that's emerging, is important enough that we need to make the public, both patients and healthcare providers, aware of it immediately.

            And I've got some examples here.  Again, there are already examples up on our website but just to highlight some of the features, you can see it is designed to be very clear and crisp, to just have a very limited amount of information, specifically some alert language that really is the crux of what we want the public or healthcare practitioners to know about, whether there are any specific recommendations.

            There may or may not be recommendations based on some of our dry runs with drugs.  The details of data, particularly changes, and then links to more information if people want to get specific information on their links to our MedWatch and how to call in and get additional information.  Again, this is the patient version of it.

            Again, like the drug information initiatives that Dr. Behrman talked about, this is really an enormous step forward in making information about our products really available at people's fingertips so they can get them very, very quickly and find out key facts about emerging drug safety changes.

            And this is just a proposal.  This isn't what our website is definitely going to look like.  But this is a proposal about how we would highlight, we could highlight specific and new drug safety information on our website.

            So, again, you can go to our website now.  It won't look quite like that but you can find some of this information very quickly.  What we'd like to do is highlight it even more.

            So in summary, we feel that we're being very responsive to the concerns that we've heard from all over about drug safety, decision-making, and communication on drug safety within the Agency and within CDER.

            While comprehensive review is underway at IOM, we are going ahead and implementing what we see as very, very important changes to improve public knowledge, how we manage drug safety, and how we involve the outside world in our decision-making.

            As you already know, and those of you who work for drug companies who are in the audience or on the board know, these changes are not free of controversy.  They have, perhaps, unexpected adverse consequences that we may have to deal with -- we will have to deal with.

            They certainly raise important policy issues in drug regulation.  We're here to talk about them and we know that we will be having to deal with them over the next period of time.  And we look forward to it.

            So thanks a lot.  I don't know, Dr. Shine, if you want me to stay up here for questions.

            CHAIRMAN SHINE:  Yes, please.  Yes, we do have some questions.

            Dr. Cassell?

            MEMBER CASSELL:  What criteria will you use to establish something as an emerging issue before it is posted?  And then I guess along those same lines, how much will be done to try to validate the events that someone is reporting as adverse events?

            DR. GALSON:  Yes, both of those are very complex questions.

            I think first of all, the board hasn't met yet.  And when the board meets, that's going to be the first issue that it on its table is to really establish policies.  In the meantime, we have, within the management structure of the Center for Drugs and in consultation with the Commissioner's Office, we have been making case by case decisions.

            And just like our normal risk-benefit decisions about individual drugs, there isn't a formula.  But in general, what we've -- the criteria that we've been using is when there is something that is emerging -- first of all, we think it has a very high likelihood of being real, it's not a specious kind of finding or something we think has another explanation.

            So first if it is something real.  And then if we think that patients and practitioners are going to use this information to perhaps change their risk-benefit analysis in using a product, that's when we have decided that this information would be available.

            So that's -- it's not mathematical.  But it is -- if this information can be used to perhaps change a decision, we think it goes out.

            MEMBER CASSELL:  And will biologics and vaccines also be taken into account by this --

            DR. GALSON:  Right.

            MEMBER CASSELL:  -- oversight body?  And, I guess, thinking about that, if they were, one of the things that was striking about the membership of your committee was the absence of a representative from the Centers for Disease Control, particularly, obviously, with respect to vaccines.

            DR. GALSON:  Right.

            MEMBER CASSELL:  And I wondered if that might not be a valuable addition to the committee.

            DR. GALSON:  Right.  As you know and you're going to hear more from Dr. Goodman, I think is going to be here this afternoon, the whole vaccine safety system which I know you are very familiar with is really very different from the one that is set up for drugs.  So initially we have not sought to include vaccines in this board.

            I can't say what's going to happen down the road.  But we felt like we were biting off a huge chunk here and really representing a very, very significant change with drugs.  So we haven't included -- the biological products that are regulated by the Center for Drugs will be included but not the other products that are in CBER.

            CHAIRMAN SHINE:  Dr. Thomas?

            MEMBER THOMAS:  Yes, I think one of the operative words in your presentation was threshold.  And I'm referring to Drug Watch.  And that, in part, has been elaborated on by our colleague.  My question, however, is once a drug does get on the Drug Watch and suppose this is some idiosyncracy and can't be re-documented, how does one get their drug off this drug alert?

            DR. GALSON:  Sure.  There is no question that a drug can both go on and go off the watch.  As a communications tool, it's not going to be very useful if it just grows and grows and grows and grows.  It won't be really -- people won't be able to highlight and prioritize the information.

            So as -- the board will have to set criteria and policies for putting drugs on.  We'll have to also set policies for taking drugs off.

            DR. WOODCOCK:  Can I make a comment, too?

            CHAIRMAN SHINE:  Dr. Woodcock?

            DR. WOODCOCK:  Yes, there will be a public document published, okay, for public comment on both of these issues that have been raised, the threshold for posting as well as the procedures and so forth for moving off.

            DR. GALSON:  Yes.  And also public meetings, I'm sure, to accompany the comments.

            DR. WOODCOCK:  Right.  So there will be a sense of discussion of this point.

            CHAIRMAN SHINE:  Dr. Galson, two questions.

            One is one of the concerns has been the resources available to FDA --

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  -- for working on safety.

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  Will the IOM Committee be asked to look at the resource issue?

            DR. GALSON:  Yes.  That's part of their charge.

            CHAIRMAN SHINE:  Thank you.

            The second is you made reference to outside consultants from an advisory board --

            DR. GALSON:  Yes.

            CHAIRMAN SHINE:  -- with regard to this.

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  What's that mean?

            DR. GALSON:  As you know, the chairs and members of our advisory committees are special government employees.  And we can bring them on, as we do already in the Center for Drugs in some circumstances, to give us advice outside of their work with an advisory committee.

            So if there is a specific drug safety issue that's coming from the board, we could ask either a chair or a member of the committee to come in and write a position paper or look at some data, prepare some materials that would then be presented to the board.

            CHAIRMAN SHINE:  I understand.

            DR. GALSON:  Yes.

            CHAIRMAN SHINE:  I understand that the organization of this board is designed to be operational, to have players and people who know about it to make decisions in a timely way.  I applaud the  inclusion of some patient or consumer representatives.  But this is still very much an inside board.

            DR. GALSON:  Yes, right.

            CHAIRMAN SHINE:  And the question I would raise is whether in view of the importance of these issues, there ought to be some mechanism for some little more distance oversight of this process --

            DR. GALSON:  Yes.

            CHAIRMAN SHINE:  -- whether it is in the form of a separate advisory panel, whether it is in the form of a subcommittee of this board which interacts or oversees it, whether it's a liaison member from this board, or whatever.

            DR. GALSON:  Yes.

            CHAIRMAN SHINE:  What I'm concerned about is that we, as you use the word openness on many occasions, is that we have a process by which this board is scrutinized --

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  -- regularly from a bit of distance --

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  -- in terms of the issues.  And I would just encourage you and the Commission to look very carefully at how we can structure.  I don't consider the consultation from a chair of one -- that's a science --

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  -- input.

            DR. GALSON:  Yes, yes.

            CHAIRMAN SHINE:  What I'm thinking about is some mechanism whereby we can assure that there is a real kind of oversight that goes beyond -- and, in fact, is designed specifically so that it doesn't involve people who have ever had anything to do --

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  -- with approving of a drug --

            DR. GALSON:  Right, right.

            CHAIRMAN SHINE:  -- at any time.

            DR. GALSON:  Sure, sure.

            CHAIRMAN SHINE:  But who can represent --

            DR. GALSON:  Yes.

            CHAIRMAN SHINE:  -- the public interest.

            DR. GALSON:  Yes, I think that is a very, very important concept.  As you know, we're just in the very early part of birthing this board.  It hasn't met yet.  We haven't put the guidance document on the web yet.  We will hopefully shortly.

            And I think that's a very important issue that we're going to have to address.  And there are lots of different options.  And I look forward to discussing with you --

            CHAIRMAN SHINE:  I would --

            DR. GALSON:  Yes.

            CHAIRMAN SHINE:  -- suggest that that is something that you folks ought to look at --

            DR. GALSON:  Yes.

            CHAIRMAN SHINE:  -- in preparation of a board because I don't know what their interests are and our interests are in terms of the public --

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  -- oversight of this kind of activity.

            DR. WOODCOCK:  I will point out there is an existing advisory committee --

            DR. GALSON:  Right.

            DR. WOODCOCK:  -- on risk management and safety, drug safety.

            DR. GALSON:  Right.

            DR. WOODCOCK:  An established advisory committee or subcommittee, I'm not really sure.

            DR. GALSON:  Yes, no, it's a full advisory committee.

            DR. WOODCOCK:  Full advisory committee.

            DR. GALSON:  Yes.  And, in fact, people have sometimes used too much shorthand because I'm so used to these issues.  We've been asked multiple times by members of Congress and from the outside as well.  Nothing that we're doing here in setting up the board is meant to diminish the role of our advisory committees.

            In fact, I expect that we will have more advisory committee meetings on specific drug safety issues over the next few years as the board gets going.  It's not meant to supplant the activities of our expert advisors on the outside.

            CHAIRMAN SHINE:  Well, there's a nice balance here --

            DR. GALSON:  Yes.

            CHAIRMAN SHINE:  -- because on the one hand, you don't want to supplant those functions.  On the other hand, you want at least the oversight of this to be such that it does not include people who have had a vested interest in prior --

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  -- drug approvals --

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  -- which might in any way influence their decisions about what the policies are to be in terms of thresholds.

            DR. GALSON:  Yes.

            CHAIRMAN SHINE:  So I really would like to see a very close look at this even before the board organizes itself --

            DR. GALSON:  Yes.

            CHAIRMAN SHINE:  -- because you're going to see their philosophy reflected in whatever those recommendations are.

            DR. GALSON:  Right.

            CHAIRMAN SHINE:  Any other comments?  Gail?

            MEMBER CASSELL:  With respect to the board, what do you include of your definition of consumers?  In other words, what will that group be representing?  What types of --

            DR. GALSON:  Right.  We have an established a group of consumer representatives that are the same group that are members of our specific advisory committee.  I'm sure you've worked with them if you've been on advisory committees.

            And they represent all of the patient groups, the cancer groups, the arthritis groups.  And they've all been gone through the SGE process and are vetted.  So we'll choose from those -- that group.

            CHAIRMAN SHINE:  Any other questions?

            (No response.)

            DR. GALSON:  Thanks.

            CHAIRMAN SHINE:  Very important activity, Dr. Galson.  Thank you.

            Let's take a ten-minute break.  And we'll promptly reconvene in ten minutes.

                     (Whereupon, the foregoing matter went off the record at 10:23 a.m. and went back on the record at 10:38 a.m.)

            CHAIRMAN SHINE:  Thank you very much.  We are now going to go to post-market drug safety and Paul Seligman is going to take us through his presentation.  Paul, thank you.

            DR. SELIGMAN:  Yes, Dr. Shine, good morning members of the board.  I have a slight case of laryngitis this morning so I'm not going to be my usual mellifluous self.  Maybe I'll try to speak in a lower register.

            But my objectives this morning are twofold.  First of all to describe how we monitor drug safety -- how we monitor the safety of drugs marketed in the United States and second to talk about some of the challenges we face in implementing this Post-marketing Drug Safety Program as well as the challenges we face as a society in the ongoing assessment of the benefits and risks of drugs as information and science continuously evolves.

            There are basically three pillars to pour Post-marketing Risk Assessment Program.  The first is the analysis and interpretation of case reports of adverse drug events and medication errors generated by healthcare professionals or by consumers and submitted to the FDA either directly or via the drug manufacturer or drug sponsor.

            The second pillar is the monitoring of how drugs are used or utilized in the marketplace.  And third is a program to conduct population-based observational studies either in collaboration with outside researchers or directly by FDA staff.

            What I will not be focusing on this morning in this short time is the full breadth of safety activities undertaken by the staff in the Office of Drug Safety.

            These include participation in pre-marketing safety assessments of drugs, particularly for those products with notable safety concerns that may require additional efforts in the post-marketing arena, whether it comes to risk minimization or risk management or whether it requires additional post-marketing surveillance.

            I believe all of you in your packages for today's meeting received the three guidance documents that we recently published on pre-marketing risk assessment, risk management as well as post-marketing pharmacovigilance.  And though I won't be discussing these in my presentation, we're clearly here and happy to answer any questions about those documents.

            Finally, as noted on my slide here, the Office of Drug Safety is also home of the MedWatch Program, which receives direct adverse event reports from consumers, healthcare providers.

            But it's also responsible for the regular communication of safety information to over 45,000 members of our listserv as well as 130 partner organizations I think in a vital, important risk communication vehicle that we have within the Agency.

            And finally as also noted in this slide, we play a major role in the prevention of medication errors by reviewing all of the proposed trade names to screen for look-alike and sound-alike names and for confusing packaging, which are a major sources of medication errors in the marketplace.

            Our Adverse Event Reporting System, or our AERS System, is an Oracle database.  It's a repository, an electronic repository that now contains over three million adverse event reports.  As you'll see in the next slide, there's been a steady increase in the number of reports every year.  In calendar year `04, we have now over 400,000 reports submitted.

            This is a publicly-available database.  You can access actually the last quarter of 2004's data on our website now.  It was previously available, and is still actually available through the National Technical Information Service.  We now provide the AERS data, redacted, of course, of personal identifier information, now directly on our website.

            This slide just basically shows the trends in adverse event reporting over the last decade and a half.  There are three important points, I think, here to note.  First the line in the center of the graph shows the point where we moved from what we called the spontaneous reporting system to our AERS System when it became an electronic system.

            And as you can see, there has been steady increase in reports but -- and I apologize.  Although you can't read the little teeny box up there on the left, I think you might note at least by the colors that some of the colored bars are changing.

            And one of the most important changes in the colored bars is the increasing proportion of serious adverse event case reports that we are receiving consistent with our emphasis with industry as well as in the medical community with reporting those serious reports.

            In response to a question that was asked earlier by one of the panelists, all of the coding of adverse event reports is done via the MedDRA system, which is an internationally-agreed to coding language for all adverse event reports.

            All the drug sponsors who code these reports and submit them to us use the MEDDRA system.  We quality control them and assess this coding on a regular basis as well as those reports that are submitted to us.

            One last point is that we employ via contract a staff that basically codes and enters these data 24 hours a day, six days a week.  And then eight hours on Sunday.  It's a huge expense for the Agency.  And we are moving increasingly towards electronic reporting of these data.  In fact, this year now over 50 percent of the serious reports are now sent to us electronically rather than in paper form.

            The second pillar of our program is the tracking of how drugs are utilized in the market.  This slide just simply points out that we use a variety of data sources, both to assess inpatient as well as outpatient use, looking not only at dispensed prescriptions, the sales, but data over time.  And we use a variety of different kinds of databases that are either based on pharmacy benefit management systems or surveys in both the in and outpatient realm.

            We use these data -- these drug utilization data in a variety of ways.  First they permit us the opportunity to create a crude rate or a reporting rate, using the case reports that we receive in AERS as the numerator.

            Second, these data in and of themselves give us a view of prescribing patterns by doctor, by patient, by diagnosis, by concomitant use medicine that provide us very important insights on how drugs are used both on and off label in the United States.

            And finally for those drugs for which there are risk management plans that may call either for limited or restricted use of a product, these kinds of databases allow us to track the utilization of these products that can provide information on whether or not the prescribing practices that are recommended in the risk management guidances are being adhered to.

            Finally, in the area of ongoing population-based studies, it's important to note that many of these studies are done by drug sponsors either at the behest of the FDA, as part of a Phase 4 commitment, and I'm sure you are all well familiar with that terminology, or are conducted on their own initiative, even sometimes without even the knowledge of the FDA being aware that such studies are being done.

            We at the FDA have a modest research program, the Cooperative Agreement Program, that we're conducting with three groups.  We have recently obtained access to the British General Practice Research Database or the GPRD.

            And are working with the Center for Medicare and Medicaid Services, CMS, as they implement the Medicare drug prescription benefit to utilize their national database as it is developed and comes online for the implementation of that program.

            We've also, to the degree that we can, have been opportunistic as the need arises in working with other groups such as the Veterans Administration, Kaiser Permanente of California, to conduct studies to clarify the relationship between drugs and adverse outcomes.

            Now I just show this slide simply to point out that the size of the populations covered by these various databases, the Cooperative Agreement Program, covers the Harvard Pilgrim HMO Network in the Northeast.  We use the Tennessee Medicaid Database and the UnitedHealth Group in the Midwest.

            But also to emphasize that, you know, the way our healthcare system is currently configured in this country, we have to rely on a variety of different kinds of databases to answer questions and these are, depending on your point of view, have fairly limited populations and often make it, you know, on occasion, difficult to project the national populations.

            Despite the limitations of adverse or spontaneous reporting as noted here, voluntary case reporting of adverse events still provides the bulk of information that results in label changes, warnings, safety alerts, and, on occasion, the withdrawal of a product.

            Although it is difficult to rigorously test, we rely on the eyes and the intellect of physicians, pharmacists, nurses, dentists, other healthcare providers to make the connection between a drug adverse event -- or drug and an adverse event and to file a report.

            But as we move into an age of bigger databases, linked databases, tools that can rapidly sift through huge volumes of data and records that are increasingly maintained on electronic media, I think we're all looking for ways in which to tap into these trends to improve both the thoroughness, efficiency, and timeliness of our ability to identify safety problems.

            If you believe, and I certainly believe that the learned intermediary still needs to make the call, then we need to figure out ways to facilitate and make reporting either a more valued part of every healthcare practitioner's daily life and figure out ways that we can facilitate reporting such as, for example, using the electronic medical record and figuring out ways that one might be able to push a report button and populate certain fields of our MedWatch form and then submit it directly to the FDA.

            But we also, you know, are very interested in the notion of being able to extract critical information directly from the medical record, key diagnostic, laboratory, drug use information, that may define an adverse event and then build the kind of algorithms to electronically scan databases and search for suspected cases essentially bypassing the role of the healthcare practitioner.

            Clearly what we do is critically dependent on the type and the nature of the information that is available to us, both in our ability to conduct timely surveillance as well as in our ability to study the relationship between the drug and its toxicity.

            What for me in my tenure at the FDA has been the most challenging is how to appropriately weigh evidence from different sources each of which has its own strengths and limitations.

            There is certainly no easy formula for how to continuously weigh, assess, and reassess the benefits and risks of products as we try to translate data from randomized clinical trials, adverse event reports, case reports, observational studies into actionable information.  And to me that synthesis can be, and I think will always continue to be, the greatest challenge for all of us.

            Nevertheless, we do act.  We act with label changes.  We act with warnings.  We act with alerts, medication guides for patients.  And all of these with an eye towards limiting the risks of these products.

            And what we sorely lack is a consistently applied regular program to evaluate the public health impact of our actions.  There is some good data in studies that, you know, our organization has conducted looking at whether people read their healthcare provider letters or the impact of various alerts.

            Think we're at least comfortable with the notion that while these efforts have influence, we really haven't carefully assessed how these products are received and what impact they have.

            And finally, our assessment of safety in my mind will always be circumstantial.  Until the science of drug-induced injury has advanced sufficiently for us to understand the mechanisms of injury, to identify markers for these mechanisms, and to help us identify which populations and even which individuals within these populations are at risk for drug-induced injury.

            I suspect, Dr. Woodcock, you'll probably  have more to say about this later.

            And with that, I'm happy to answer any questions, Dr. Shine, from you and the members of the committee.

            CHAIRMAN SHINE:  Thank you very much, Dr. Seligman.  I have to say that since the issue of packaging and names and drugs and so forth was one of the featured recommendations of To Err is Human, I'm delighted to see you taking a very close look at that and following it carefully.  Is industry responsive to concerns about similarities in names and packaging?  And have you had a reasonable response in terms of making sure that one can tell one Cephalothin from another Cephalothin?

            DR. SELIGMAN:  Well, you know, industry invests huge resources in choosing names.  They know that we carefully scrutinize these.  In fact, at present, we reject about a third of the names that are proposed to us because of sound-alike or look-alike or potential confusion issues.

            We have held public workshops on these matters.  We have, at present, a draft guidance in the works on good naming practices.

            But there again, in many ways somewhat dependent on the size of the company -- or actually definitely depending on the size of the company, lots of resources being invested particularly in the larger manufacturers on carefully screening and doing the kinds of either analyses or focus groups that we -- the techniques that we employ to try to determine whether or not there might be a drug name that would cause that kind of confusion.

            CHAIRMAN SHINE:  Questions from the committee?  Dr. Laurencin?

            MEMBER LAURENCIN:  How many people are working in the Post-market Drug Safety Risk Assessment Program?

            DR. SELIGMAN:  In the Office of Drug Safety, we have about 100 employees.

            MEMBER LAURENCIN:  And in terms of the adverse --

            CHAIRMAN SHINE:  They work on issues across the board in Safety.  Not just in Post-marketing --

            DR. SELIGMAN:  Well, no, just pretty much focused on the post-marketing arena.

            CHAIRMAN SHINE:  Just post-marketing?

            DR. SELIGMAN:  You'll see in --

            CHAIRMAN SHINE:  Okay.

            DR. SELIGMAN:  -- Theresa Mullin's next presentation sort of the breadth of how, you know, safety work is done throughout the Center.  But the 100 people that I described basically work on the adverse event, drug utilization, medication errors, sort of the limited activities that I just described in my presentation.

            MEMBER LAURENCIN:  Just as a follow up to that, 400,000 adverse events, fiscal year `04, how many drug label changes took place from those 400,000 adverse events that were reported?

            DR. SELIGMAN:  Oh, I don't -- someone else have -- I don't -- I know that there are lots of them.  But I don't know the degree to which -- I don't have that information right at hand.  Does anybody?

            Theresa, does anybody have the information on how many label changes there were in this last year?

            DR. MULLIN:  I don't know how many label changes there were.

            DR. SELIGMAN:  All right.  So what Theresa says, we currently have a study going on which is looking at black box warnings, in particular, and how many of those were done.  But I don't know to my knowledge whether we have data on the total number of label changes that occurred --

            CHAIRMAN SHINE:  It would be interesting to know that.

            DR. SELIGMAN:  -- in answer to your question.

            CHAIRMAN SHINE:  Dr. Roses?

            DR. ROSES:  You mentioned the timeliness, efficiency, and thoroughness of those issues with the AERS database.  What and if ever has anybody done to look at the accuracy and validity of the self-placed complaints?

            DR. SELIGMAN:  We look, particularly when we're looking at a case report, we look, you know, we often ask for hospital records, sometimes pathologic specimens, other data to help, you know, validate a particular report.  I mean it's, although I don't have any specific data, I can tell you that there's lots of missing information in these reports.  And missing information makes it difficult to interpret lots of these cases.

            These are often cases which are complex, individuals with complex medical histories, on medical regimens with lots of different, you know, products that, you know, could be responsible for the adverse event observed.

            Is that kind of what you were getting at?

            DR. ROSES:  Well, what I'm getting at is you said you act and I was wondering what you act upon.  And whether or not we could design a much better database that would get prospective data in a standardized form from patients taking new drugs.

            DR. SELIGMAN:  Well, I think that's why I mentioned in my presentation, you know, the possibilities that, you know, electronic medical records or others might offer us or, you know, databases where we could actually query directly then get that kind of information which would fill in many of the gaps that we get currently -- many of the gaps that currently do exist in our voluntary reporting system.

            CHAIRMAN SHINE:  Dr. Pi-Sunyer?

            MEMBER PI-SUNYER:  Yes, I have two questions.  The first is are there other countries that are doing this better that you can get information from?  Or not?

            DR. SELIGMAN:  Better.  That's one of those words.

            CHAIRMAN SHINE:  Yes, let me -- I was going to ask you a very similar question.

            DR. SELIGMAN:  Yes.

            CHAIRMAN SHINE:  Reference was made that we do not have a national pharmacovigilance program.

            DR. SELIGMAN:  Yes.

            CHAIRMAN SHINE:  And the question is what would be the ingredients of such a program?  And does such a program exist somewhere else?

            DR. SELIGMAN:  Well, to my knowledge, practically all countries, at least in Western Europe, rely in voluntary reporting.  France, for example, has a series of pharmacovigilance centers that are responsible for, you know, regions throughout France that are more active and aggressive in getting physicians and other healthcare providers to report to their center.

            You know the British carry on a regular standard survey for new products that are introduced into the British market.

            But many of these systems -- many of the Western European countries, because they have nationalized healthcare systems, have access to, you know, a national database, if you will, that allows them to do the kinds of things that we can't do in this country because we lack such a national database.

            That's why that slide of, you know, a little bit here with Tennessee Medicare and a little bit with, you know, Kaiser Permanente, and the Veterans Administration and all of these various pieces to try to assemble sort of the picture of the elephant.

            But, you know, I think many of the initiatives that are occurring elsewhere within the Department of Health and Human Services within the nation to try to, you know, standardize healthcare fields, data, electronic reporting, all of which, I think, will ultimately filter down to our benefit an be able to kind of access in a standard way the kind of information that will allow us to pick up on early signals.

            Absent that, we have to do sort of purposeful kinds of things in a variety of different environments to get that kind of information.

            CHAIRMAN SHINE:  And you had a second question?

            MEMBER LAURENCIN:  My second question is -- it's a follow up to Dr. Roses.  As you're trying to get information on reports, are you finding that HIPAA is a problem?

            DR. SELIGMAN:  No.  I mean well I shouldn't say that.  HIPAA -- there is, you know, an exemption or exception within HIPAA for, you know, public health activities and public health surveillance.  And we can assure the providers who give us information about our ability to protect the confidentiality of that information within the current privacy statutes.

            Nonetheless, you know, HIPAA has, you know, created a whole new level of, you know, concern and caution that we have to overcome on occasion.  But I'm not aware that it has, in any meaningful way, impacted our ability to gather and gain information.

            CHAIRMAN SHINE:  Thank you very much.  And your mellifluous tones --

            DR. SELIGMAN:  Okay.

            CHAIRMAN SHINE:  -- were well heard.

            DR. SELIGMAN:  Okay.  Thank you.

            CHAIRMAN SHINE:  All right.  Let's move on to Dr. Mullin.

            DR. MULLIN:  Good morning.

            CHAIRMAN SHINE:  Good morning.

            DR. MULLIN:  Let me know if you can't hear me using this.  I'm going to present today the results of an internal study that we did last winter to try to provide an estimate of the total resources devoted to drug safety within the Center for Drugs.

            We felt there was the need to do a study like this, because of the ongoing public discussion, and policy options being considered for dealing with and improving the drug safety approach within the agency.  But the information that was publicly available was incomplete and providing an incomplete picture, and the perception of an imbalance ‑‑ a pretty severe imbalance ‑‑ in the resources currently being devoted to drug safety.

            Well, what was available to inform those discussions?  The most readily available resource numbers that we could provide in response to questions from the press, for example, were budget figures for, say, components within the FDA Center for Drug budget.  Prescription Drug User Fee Program ‑‑ we have to report those numbers, so there were PDUFP numbers that could be provided.

            We've had special additional needs requests we've had over the years for the Office of Drug Safety, so we could provide a number for that office.  But these often were not tracking safety activities. 

            They were components within the organization, and, as a result, it would lead to statements sort of like this one I have here as an example.  This year, the Safety Office received less than $24 million of CDER's budget of almost $500 million.

            In addition, the reports in the media suggested that there was a limited understanding of the rather complex process of assuring drug safety within CDER, including the process of pre-market review.  And here are some quotes that illustrate, we think, that limited understanding that was being conveyed.

            FDA and industry have gotten very successful at getting drugs to market based on their efficacy.  Safety has become a stepchild to the ‑‑ of the agency in the process.

            Currently, drug review divisions generally oversee labeling and other decisions, even after medicines go on the market, with the Drug Safety Office in an advisory role.  And these statements on the face are true, but you're missing all of the other background and effort around that, and so it ‑‑ we are ‑‑ it tends to convey a partial picture.

            And so we wanted to do a study to try to provide a more complete account of the safety work and the resources devoted to that safety work throughout FDA, and answer questions like these.  What activities are considered part of the drug safety effort?  What level of effort does FDA devote to drug safety?  And how much drug safety effort is spent on pre-market versus post-market?

            Again, there was this notion being conveyed that safety was sort of a post-market concern for FDA, and mainly a post-market concern as opposed to pre-market and post-market.  So we wanted to understand better how that worked out across the different components within the Center for Drugs.

            The challenges that we faced in doing this included that the analysis of doing safety ‑‑ safety is integral to many of the functions within the Center for Drugs.  There is no easy pullout of that information.

            We had time reporting data that we wanted to use, but that was organized by stages in the life cycle of the drug, if you will, from pre-IND all the way through to special activities that we'd use to report. 

            And safety, again, is an integral part across those, and so we had to do something to get into ‑‑ dig deeper into that set of activities to pull out what was explicitly safety versus something else like assessment of efficacy and other issues.  We wanted to really drill down to the safety questions.

            So our overall approach included selecting a sample of experts.  We wanted to take expert judgments from within those offices within the Center for Drugs, technical expert judgments, and combine that with the time report data that we had to try to make an estimate of this.

            So we elicited those expert judgments on the percentage of the time they spent doing safety-related activities.  And we used the time reporting data to extrapolate from those individual assessments where ‑‑ I'll tell you in a minute how we used the sampling of experts that we involved.  And we used the time report data to weight the averages of that time across activities within each office and build up an estimate from that.

            I'd like to add at this point that we ‑‑ this was a two-month effort.  We wanted to get it done because of the urgency of the discussion.  We wanted to try to come up with an estimate that would account for the bigger picture of safety work, and we couldn't have done that without the help of the Office of Management in the Center for Drugs. 

            They were able to provide us the time report data, break it down into the levels at the office level that we needed it, and by job series, and so forth, and the work of the Office of Policy and Planning.

            And, in particular, in the CDER I'd like to mention that Richard Allen, Dong Kim, and Bob Linkous were pretty critical to our effort.  And in the Office of Policy and Planning, Kara Morgan and Corrina Sorensen worked a lot on developing the methodology and the protocol, and Malcolm Bertoni was leading the effort on developing the methodology and the modeling, which was utterly essential to producing the numbers I'm going to share with you today.

            Okay.  Here you see the offices that we involved in this study.  We had to look at the office level, because the percentage of time spent on safety work and what these offices did varied substantially.  The scientific expertise, you see over in the right-hand column, populated many of the offices, but what they were involved in was very different. 

            And so here we've got offices ‑‑ new drugs, pharmaceutical science, the pharmacoepidemiology and statistical science, clinical pharmacology and biopharmaceutics, the Office of Compliance Medical Policy, the Office of Counterterrorism and Pediatric Drug Development, and executive programs ‑‑ have somewhat specialized functions within the Center for Drugs.

            We took advantage of that, if you will, because there's a fair amount of homogeneity within those offices.  So you can go to a medical officer doing drug reviews and, by and large, the way ‑‑ the way they're spending their time in one division was rather similar to the kinds of questions and the way they'd spend their time in another division. 

            So we were able to use the sort of homogeneity within offices to extrapolate from experienced reviewers and scientists within those offices.  And that's really the approach we took on this.

            So we developed a multi-attribute model using the time report data.  Now, the time report data in the Center for Drugs has 400 categories ‑‑ pre-market and post-market distinctions.  To do specialized studies, we often want to go down to that level.  We didn't want to do that in this case, thought that would not be helpful.

            But we used the most recent four-week time reporting data, which was from mid-October to mid-November of 2004.  So that was ‑‑ people had just finished doing that time report cycle, and the technical staff do 100 percent reporting.  So basically we had a very good snapshot of where people were spending their time.

            We then, in order not to use the 400 categories, we had some of the experts in the Center for Drugs who are used to using that time reporting system, and performing the work within those offices, help us aggregate up to a smaller set that was still meaningful, and that the people using it could still connect what they're doing to those smaller number of bins, and we could still maintain that pre- versus post-market distinction which we wanted to keep as we got the estimates.

            We also wanted to pull out overhead activity, and so we didn't include that in the estimate because we're trying to drill down to safety work.  We conducted formal interviews.  We developed an elicitation protocol using the principles of the Stanford/SRI approach, which is a motivation of ‑‑ to try to be sure that people are willing to participate in the effort and understand and not going to produce a biased estimate. 

            And that they ‑‑ in fact, we would ask a particular person that we interviewed, "Do you feel you are able to speak and represent the typical work of somebody performing this function in your office?"  If they didn't think so, then they wouldn't be a good person to involve in this. 

            So we needed people who had some experience and who were very familiar with that function within their office, and we used that within our motivation phase.

            Structuring ‑‑ we used the time report categories to help structure their thinking about activities that involved safety, so we would take a particular activity ‑‑ and I'll show you in a minute the list of activities that we used, and it's in your presentation, if you have the handout. 

            Within that category, what kinds of activities do you engage in?  What would be ‑‑ if anything, would be explicitly safety?  Not efficacy, not something else.  This is directly related to product safety.  We'd have them define that, identify what those items were.

            Now, when you're reporting time to that category, on average, what percentage of it would be devoted to the things you just mentioned, you just described to me?  And we did that systematically in each of these categories.

            We conducted 51 of these interviews spread across those offices and those job functions that I showed you a minute ago.  We used the 2004 time reporting data and budget actual data, which is the number of FTEs spread across the organization to apply our time reporting ‑‑ to apply those percentages that we got from the interviews.

            And just quickly, although it's so small in your handout ‑‑ you may be not that quick to see this ‑‑ on the left you see the super categories that were used.  And this is what we have given to people, and it's a brief description of the activities that that included, which again track to things that they had been reporting in a more detailed time reporting format. 

            So this is ‑‑ these are familiar terms to the people who we're working with.  And it's important, of course, to have something that they can relate to and is familiar to them, in order to get a reliable estimate. 

            So we have a pre-IND category.  You can see the meetings, of course, that may occur and the things before an IND is submitted.  Here is the kind of activities you'd expect to see under the IND review, you know. 

            First, the review of it in the first 30 calendar days, and then beyond that, meetings on that application, and so forth, around the IND submission, and actually interactions that there might be that are of a more informal type throughout the development process would fall into that category.

            The pre-IND category focuses more on the formal meetings prior to the NDA.  So this would include the end of Phase II meetings and pre-NDA meetings ‑‑ time spent doing that, how much of that, what kind of safety questions come up, typically what part of that discussion and that interaction is explicitly on safety.  That's the kind of question we ask people.

            The NDA primary review ‑‑ and those activities, which are familiar to you all, the generics review process ‑‑ we included generics, of course, because generic drug review and generic drugs are just as important in this whole safety discussion.

            Continuing, here are the other categories.  We call out activities related to antimicrobial resistance, so that's in there as well.  NDA supplement reviews, of course, pharmacovigilance and epidemiology work, and then general post-marketing activities. 

            And this would include a variety of things, as you can see ‑‑ Phase IV activities, promotional material review, compliance activities; the Office of Compliance, including inspections, to make sure the product is safe; as it's being manufactured, the ingredients are safe; and then pediatric studies, which include, you know, the written requests, and so forth, you know, the range of things there.

            The result of this analysis, as we took the estimates ‑‑ and let me explain for a minute ‑‑ we talked to people in different disciplines and functions, and I'd like everybody ‑‑ now, there's a typo in the handout.  So if you can take your pen right now and correct your handout, because the numbers got flipped.  I don't know how, but it should be 32 percent in the pre-market and 18 percent post-market, adding up to 50 percent.

            Well, what we did with these 50 interviews spread through those functions and those offices is take those estimates and apply them to the hours and other people who are ‑‑ who reported their time across those time report categories and the percentage of safety that, say, you know, a pharmacologist will spend within that category to the pharmacologists in that office, and build up those hours office by office, because the percentages differed and the hours differed by the office that they were in. 

            So each office built up and we aggregated up through the organization.  You can imagine an org chart where we're aggregating up through the org chart to get the total effort for the whole Center for Drugs.  And that total came to 50 percent.

            And here's the ‑‑ a breakout for you to show you how that looked across the different offices.  And what you can see is that the percentages varied, but, of course, the size of these offices varies, so the number of FTEs as a result reflects that.  So in the Office of New Drugs, aggregating up 51 percent of the effort that they engage in over the course of their activities they considered to be explicitly safety.

            And that translates into 352 full-time equivalent staff.  That's what those hours translate into.

            Office of Pharmaceutical Science ‑‑ 51 percent is what the workup, the buildup number, was for them for their safety-related work, and that translates into 252 FTEs.  The Office of Pharmaceutical and Statistical Science as a whole, across all of the offices within that ‑‑ within that super office, 60 percent of the overall effort and 126 ‑‑ Office of Drug Safety, 100 percent of their time.  So you get 96, as Paul said, about ‑‑ about 100 people there.

            And you can just see the rest of the breakout there of how the percentage of time spent and what that translated into in terms of numbers of people, or FTEs is really a more accurate way to describe the level of effort.

            How does that fit in the context of the whole agency staffing?  This just shows you a summary of that, so the drugs ‑‑ you see it's about half of their folks, and here we have the FTEs on board for 2004 for the other components or the other centers within the agency.  And so it's about ‑‑ it's 50 percent of drugs, it's about 10 percent of our overall FDA effort, our overall FDA resources.

            So, in quick conclusion, ensuring safety involves the work of a lot of different offices and different disciplines, and they're doing different things, although it all is critical to safety. 

            So it begins at the earliest stages of drug development before early tests in humans, and it continues through the oversight of clinical trials and the marketing of applications, marketing application reviews, continuing through to post-market surveillance, risk management, epidemiological research, and it also involves oversight of commercial manufacturing to be sure that the product itself physically is safe, and proper labeling and monitoring of product promotion that assure that it's safely used, and overall about 50 percent of estimated staff effort.

            CHAIRMAN SHINE:  Thank you very much, Dr. Mullin.

            Dr. Cassell?

            DR. CASSELL:  Thank you.  Very interesting and very good to know, comforting.  I have two questions, and one of them is related to the antimicrobial resistance.  First of all, could you say a little bit more about the rationale for collecting that data?  In this particular survey ‑‑ and then, I'd be real interested to know what the actual percentage was.

            DR. MULLIN:  We could probably ‑‑ I could ‑‑ the second question I'm probably better able to answer.  The first one, we felt that any category where people have been reporting their time we wanted to explore. 

            And since there was enough time being reported there, we didn't assume that it was efficacy, just safety, either/or, it was just another way to frame our discussion systematically with the people that we were talking to throughout the organization. And it would be, we thought, an omission to not have it in there, and so we probably can pull that out.

            DR. GALSON:  You may be wondering, why do we even collect this?  Is that part of what ‑‑

            DR. CASSELL:  Well, kind of.  I mean, I'm really pleased to see it.  I've not ever seen that data, but I ‑‑ it would be enlightening I think to know ‑‑

            DR. GALSON:  Yes.

            DR. CASSELL:  ‑‑ in terms of what we know is going on on the outside ‑‑

            DR. GALSON:  Right.

            DR. CASSELL:  ‑‑ how much time you're actually spending on the issues internally.

            DR. GALSON:  Right.  The reason is very pragmatic.  When Congress gives us specialized funds for a certain topic, we need to track and make sure that we can justify that we're spending that money.  We have had targeted funds for antimicrobial resistance, not right now, but a few years in the past.

            DR. CASSELL:  But the percent you don't remember right off hand?

            DR. MULLIN:  I don't have it off the top of my head, but we have such vast and detailed spreadsheets that I suspect we could pull it out for you.

            DR. CASSELL:  The other question was with respect to the generics and the ‑‑ I guess the frequency with which you might have adverse events associated with the generic product versus the product still under patent life.  And in the event that you do have problems, in terms of safety issues with generics, do you go back to those companies, then, also, and ask for additional studies to be done?

            And excuse my ignorance, I should probably know this, but ‑‑

            DR. MULLIN:  No, no, no.  Well, I'm going to have to say excuse my ignorance, because I'm the economist and I work with the data.  I pull everything about the substance from those people over there, so I'm going to ask Dr. Woodcock ‑‑

            DR. WOODCOCK:  Yes.  There is a therapeutic inequivalence process.  The adverse events would be put through the same process that other adverse events and part of an analysis might be if, in fact, we found out whether it was a generic or not that was prescribed ‑‑ I mean, if we get the generic name, we may not know. 

            But we get reports of therapeutic inequivalence where people raise the issue, they believe a generic is not performing in the same fashion, and we have a whole process to deal with that.

            CHAIRMAN SHINE:  This appears to be a very careful, well-done study.  It roughly shows that about two-thirds of the effort is in pre-market safety activities and one-third in post-market safety.

            As an economist, what kind of methodology would be worth developing to decide whether that ratio is the right ratio?

            DR. MULLIN:  I think you can look at how many different ‑‑ the relative contribution to safety or preventing problems of different activities, and I think you wouldn't want to remove anything that's going on now. 

            I think there are areas which we have sort of chronically underresourced and maybe need to do a better job to catch up with the fact that ‑‑ well, we still ‑‑ we need better tools, I think, and this is what I hear from the scientists at FDA, to be able to predict safety in the pre-market period, and that's something that's I think in the works and of interest.

            But the new systems that we need to keep up with the utilization in the marketplace and the multiple prescriptions people use at the same time are creating a more complex environment, so I think maybe that's the area we need more ‑‑

            CHAIRMAN SHINE:  Yes.  It would be interesting to try to not necessarily ‑‑ it may not be about shifting resources.  It may be about the necessity for additional resources; it may not be.  But it might be interesting to develop some models which look at the overall rate of adverse events or new adverse problems that are identified in the post-market period, in comparison to what happens in the pre-market period.

            There are a variety of ways that ‑‑ none of them perfect, but it would be worthwhile, it seems to me, to try to ‑‑ to get a better handle on what would be an optimum distribution of resources over time. 

            Do you have some ideas about that, Dr. Woodcock?

            DR. WOODCOCK:  Definitely.  I will point out that some of the safety activities that are done in the pre-market period are overseeing the human experimentation, and that is a big effort.  And a lot of safety problems are caught during clinical trials, and it's in the best interest of everyone to make sure that enterprise remains safe and trusted by the public.

            So that's a chunk of resources.  It is also well known that one of the main causes of late failures of products to be marketed is safety issues that arise late, or maybe the FDA turns a product down because the benefit-risk analysis is not viewed to be adequately toward benefit.

            So I kind of agree with Theresa.  I'm not sure that ‑‑ I think there are analyses that could be done that would be very interesting.  It might relate to a question that was raised by the Board earlier about, actually, the rate of ‑‑ and magnitude of label change is very high in the post-market period. 

            There are large numbers of labeling changes that occur, and that accounts for a lot of the activity that goes on in the post-market period from those 400,000 reports that we get each year.

            CHAIRMAN SHINE:  When the fundamental rubric is balancing efficacy against safety, safety has to be, obviously, a major feature of everything that goes on pre-market.  I would be interested in seeing if we can't use some rubric, which over a period of time could help us with the idea of what would be the incremental resources that would be required to do the post-market surveillance if we did it, as well as the pre-market surveillance.

            DR. WOODCOCK:  We agree.

            DR. MULLIN:  Absolutely right.  And with better data we might even be able to have some marginal - you know, the marginal contribution estimate, and we can certainly be looking at cost effectiveness of interventions and new things that we try.  And we are looking at an evaluation component on the new initiatives that we're talking about, to see that we do get the most for the money that we spend on this.

            CHAIRMAN SHINE:  Thank you, Dr. Mullin.

            Oh, Dr. Roses I think has ‑‑ go ahead.

            DR. ROSES:  I was just going to comment on what you said.  One of the characteristics of the pre-market component is that people are being studied by protocols, and they're being looked at regularly.  The post-market component is a different system.  It's haphazard.  Medical care is haphazard.  And it's not being studied by the same protocols in the reports, and that was by my question about accuracy.  It can be very variable.

            CHAIRMAN SHINE:  Sure.  But that doesn't mean we shouldn't be looking closely at whether, in fact, we're adequately resourced to, for example, determine the accuracy of those reports.

            Let's move on.  I think Dr. Woodcock has a presentation before the discussion period.

            DR. WOODCOCK:  All right.  I'm going to talk about ‑‑ sort of pull all of this together and talk about sort of some of the ways we need to move forward I think. 

            What we've heard about the current drug safety system today is there is an extensive pre-market testing that is done of products and on protocol, and so forth, with frequent observations.  And then, there's a rigorous FDA review, which includes an evaluation of what are the remaining uncertainties after that clinical evaluation and testing has been done.

            Then, we have proposed implementing user-friendly communication with the drug label, a modified drug label.  It will be compatible with e-prescribing and the electronic decision support that we all hope will come very soon.

            We have implemented over the past five years a proactive risk management system whereby the risks that are identified ‑‑ and you heard this from Armando ‑‑ they have to be called out by the reviewers and then in the risk management plans around approval overt strategies for managing those risks need to be put into place.

            And then, we have post-market, we have what Paul described a voluntary adverse event reporting system, and with the FDA having limited capacity to do additional population-based studies to gain additional information.

            Now, the capacity of this system is it will generate a profile pre-market of common adverse events in the tested populations during the drug development process.  We also nowadays ‑‑ and this is new over the past decade ‑‑ understand drug metabolism and the common metabolism-based drug interactions, many of which caused severe harm in the past.

            We are able to develop plans for managing and evaluating these anticipated risks after marketing, and we can identify in the system the rare serious adverse events after marketing.  And despite all the flaws of the voluntary reporting system, it's actually quite efficient in identifying many of these rare adverse events.  The problem is determining whether or not they were linked to the drug.

            Now, what the current system does not elucidate, as we've heard over the past several months with regard to the NSAIDs and the COX-2s, it increases infrequency of events that occur commonly to uncommonly in the population that is not taking the drug.  In other words, if there is a background in the population that is not necessarily rare but not real common, it may not pick up that increase in frequency.

            Time-dependent events, as we've talked about earlier, it may take a much longer time to evolve and occur.  Events occurring more frequently in populations that are not tested in the trials, particularly the people who are very sick who weren't entered into trials, people who are in polypharmacy, for example, people with multiple medical problems, these we may not be able to extrapolate fully from the pre-market experience.

            And events ‑‑ and this is very common ‑‑ that occur much more frequently with off-label uses, and we ‑‑ although we have an extensive program, we don't always pick up products that are implicated in medical errors post-market.  We also don't always pick up products that people may abuse post-market, and this ‑‑ that's hard to predict in humans.  So the current system does have safety limitations.

            And as we've heard, we can utilize the emerging electronic medical records system better for surveillance, and that poses a great opportunity for finding things.  Also, doing randomized trials or registry ‑‑ registries in practice settings after marketing.  And, again, that also will be facilitated once we have a more coherent health care system in place.

            We also need ‑‑ and I think Paul Seligman's people are putting in place or making plans for doing more surveillance in specialized settings, such as from the ER.  The ER is a place you would expect to pick up a lot of adverse events, because that's where you go when you have one.  Or in nursing homes, where a tremendous amount of adverse drug problems occur.  So that's a very positive outcome.

            And all of these approaches should be implemented, and probably whatever the Institute of Medicine comes up will be a very comprehensive list of opportunities.  But the traditional focus here, I would like to remind you, is on detection, and then it's on communicating these problems through warnings, precautions, or whatever, and trying to manage the ‑‑ knowing the prediction, okay, knowing that these could occur with the drug.

            But we need to add, where possible, really being able to predict who is going to get these adverse events.  We need to move to a different level of management of adverse events.  We need to try and prevent them rather than simply describe their occurrence in the label.  We also need better measures ‑‑ and Paul mentioned this ‑‑ to monitor their emergence before they have fully occurred, and to mitigate them.

            The goal of the new science, I think, would be to avoid treatment of individuals at high risk for an event, because serious side effects, even in drugs that are withdrawn from the market, are usually only occurring in an extremely small number of patients. 

            And when these withdrawn drugs occur, we hear from many people who have benefitted from those drugs who are very bitter that it has been removed from the market.  And we need, as I said, to develop new ways of monitoring for emerging toxicity before it becomes severe.

            Now, I'd like to go over very briefly ‑‑ I won't take much time on this ‑‑ why we do have to make these changes as a society.  Right now, as Steven alluded to, drug development, including animal and human testing, is largely empirical in nature.  And this tradition focuses on the outcomes and population means, and then the observation of outliers.

            And if you look at the guidance that Armando presented, that's basically what it's going to talk about to a great extent.

            This empirical approach directly translates into the trial and error approach used in clinical medicine, which I think Dr. Roses just said was haphazard.  Something like that.  And that's because clinicians don't have, really, any better information right now.  And the way this is done creates, I think, a major loss of information that can be gained in the clinical development program and translated into clinical practice.

            But ‑‑ and this has led to many calls, as you all know, for many more clinical trials and significant more work pre-market, larger clinical trials, trials in many more populations, and so forth, specific trials.  But we all have to recognize there are significant limitations and a number of questions that can be answered via empirical testing. 

            There just aren't enough people in the world or money in the world to answer all of the kinds of questions you might want to answer about any given drug, much less the whole panoply of drugs.  And these limitations are imposed by the availability of people, by the practices evolving, even when you're trying to do these trials, by cost, and so forth.

            And the clear fact is despite the fact that any drug development program will cost hundreds of millions of dollars, we often lack information and approval of that drug that is important for prescribing.  We do know that the drug is effective in a defined population, and we can describe its common side effects in that population that was tested in the trials.

            But we know that many of the people who are subsequently exposed to the drug will not benefit from the treatment, and we know for any drug we approve that some people who are exposed to the drug will be harmed by the drug.

            Now, let's switch to another imperative.  Right now, the current data says that for drugs that enter into Phase I trials, they have already gone through perhaps five or more years of development work preclinically, and a huge investment of time and effort, their success rate of actually becoming marketed products is lower than 15 percent.

            And there's no other real part of our technological infrastructure, say building bridges or designing airplanes, or whatever, that operates at nearly this level of risk.  This is just an astounding level of risk ‑‑ of failure.

            The same evaluative tools that will ‑‑ I would like to explain ‑‑ or tell you or argue that the same evaluative tools that will improve predictability will also support markedly improved decisionmaking in clinical medicine, and, therefore, will impact significantly on the drug safety problems that we are currently experiencing, and much of this information can be developed.

            Now, I'm going to give you some examples to make this real.  Drug metabolism is a good example.  For example, there is a hepatic enzyme, which I have listed there ‑‑ and don't pay attention to all of the words and numbers and everything ‑‑ but this is an enzyme that is responsible for ‑‑ in many drugs for metabolizing it within the body, using it up.

            And this is ‑‑ there's a typo in here.  Drugs that are substrates of this enzyme may have up to 10-fold higher blood levels if you're a poor metabolizer.  So there are probably a person or people in this room who is a poor metabolizer of these drugs.

            It's a very bad choice of words.  The clinical pharmacologists made up the poor metabolizer.  But what it means is your enzyme uses a drug ‑‑ uses a drug up very slowly.  And if you took the normal dose of the drug ‑‑ and we don't know who in this room is this person, that's the problem ‑‑ if you took the drug, you would have 10 times the blood level of most of the other people in this room from that drug.

            And the distribution of alleles ‑‑ in other words, the distribution of really fast metabolizers, very slow metabolizers ‑‑ varies with ethnicity.  And this gets to some of the points that were raised earlier about the different profiles in different ethnic groups.

            The drugs that are substrate of this enzyme are frequently implicated and unavoidable ‑‑ they are called unavoidable right now ‑‑ side effects.  And we think that the exposure ‑‑ in other words, the fact that these perhaps 1 in 300 people walking around are getting extremely high exposure to this drug ‑‑ is probably a very large contributor to this ‑‑ to the problem of these drugs causing adverse events.

            Now, the Center for Devices recently approved a commercial test to determine ‑‑ you can determine your status, your enzyme status, and determine what kind of metabolizer you are.  All right?  But, of course, it's not being widely used clinically yet.

            Now, drug development, though, recognized this some time ago.  It used to be that these drugs were put on the market, drugs that were the substrate, and they got into a lot of trouble post-marketing.  What happened was FDA worked with industry to develop tools that could use human cells and other models, but mainly human cells, to predict the human metabolism of candidate drugs before they got into people and before they began to be developed.

            This caused the manufacturer to start eliminating candidates that were substrates of this enzyme system and not putting them into clinical development.  Okay?  Fifteen years ago, problems with metabolism was the number one ‑‑ and availability, and so forth, was the number one cause of late failures of drugs, if you can believe that. 

            In other words, drugs late in clinical development, they had already gone through many of the clinical trials and they had to be pulled from development, it was because of drug metabolism problems.  Since this screening has started, that has dropped down to an extremely minor cause of late failures in development, because those drugs are eliminated early from the pipeline.

            Now, this just shows the power of an evaluative, predictive tool that can be used early to remove this ‑‑ these problematic drugs from the pipeline and, thus, markedly improve the safety of marketed drugs. 

            Now, I'll tell you the critical path initiative is a great example.  It's focused on development of additional tools that would actually do this.  Unfortunately, the clinical test, a test just approved recently by the device center, for this metabolism has come much later. 

            All of the drugs that are on the market that are a substrate of this enzyme, the clinicians are not used to using this test and adjusting the dose of these products.  So safety problems continue to arise related ‑‑ because of variable metabolism.  One of the things we'd like to do is do some studies looking at can ‑‑ can metabolic testing like this decrease the frequency of adverse events of these marketed drugs.

            But, in general, these new technologies, including genomics, proteomics, metabolomics, and so forth, can really help us predict both in drug development and in clinical medicine, and that's really my point.  The drug safety problem is, to a great extent, related to the fact that so much of therapy is still empiric.

            We could go and do these tests in patients who have had serious side effects and study them versus patients who haven't.  And I would defer to Dr. Roses who has done a lot of this work.  We can study this both in prospective trials and in patients who have had serious events that are reported under MedWatch.

            We need to develop the ability to predict and avoid treatment of high-risk patients or monitor people for development of side effects before overt toxicity occurs.  And while we need to do all of this other safety surveillance, because we'll never be able to predict all adverse drug event problems prospectively, this is where we need to move ‑‑ toward prevention, targeting individualization of therapy overtly, to really deal with the safety issues.

            In addition, as we develop targeted therapeutics ‑‑ and this is beginning to happen in oncology ‑‑ we can identify subgroups of patients who have high response rates.  This means we avoid treatment of people who have very low probability of benefitting.  This is equally important.

            Right now, we just don't know for many therapies, because they're empiric, who is going to benefit.  This can help drug development, because it will remarkably decrease the needed power, how many patients you need to test, okay, before you find a positive result. 

            But on the other hand, out in the marketplace, it can significantly improve the benefit-risk of a therapy, because at least the people who are getting the toxicity had some chance of benefitting from the drug.

            So for the future of drug safety, we really do need to continue to improve the current system, and we look forward to the committee discussion, but we also have to start really focusing on delivering the right dose to the right patient, and to monitor those people for emergence of side effects, and to really focus on preventing serious side effects by predictive measures.  And that's one, as you know, of the very big focuses of the critical path initiative.

            The issues for this ‑‑ how would we get this applied science done?  Well, if you've heard some of this message before, it's because we're telling people this again and again to make sure that people really understand this is really part of drug safety.  Unfortunately, there has been no entity really charged with this task.  It has not really been seen as a job of the FDA, or any group really.

            Public-private partnerships, as I alluded to earlier, may be an ideal way to get some of this work done.  We need some venues to pull and itemize data from various trials, and so forth, and we need the ability to conduct studies or add-on modules to existing trials to develop some of these safety biomarkers.  But we are very optimistic that we can get this work going and remarkably improve drug safety, as I hope the drug metabolism example has ‑‑ has shown.

            Thank you.

            CHAIRMAN SHINE:  Thank you very much, Dr. Woodcock.

            Why don't we begin the discussion period, with specific questions for Dr. Woodcock you might start with, but I would raise any questions that you would like to.

            Dr. Riviere?

            DR. RIVIERE:  Yes.  I've had one general comment and one general question, and your last slide pretty much nailed the comment.  I think a lot of what has happened is that we have not got the resources and the base knowledge as to how to predict these side effects coming out that pick up in post-surveillance studies.

            It needs to be really underlined somewhere in here, either as a charge to the IOM Committee looking at this, that ‑‑ how do we actually direct research to start determining what are the signals that we're looking for?

            DR. WOODCOCK:  Right.

            DR. RIVIERE:  Your very clear example on the drug metabolism ‑‑ and this has happened with other areas ‑‑ when we actually had mechanistic information, we find it.

            DR. WOODCOCK:  Right.

            DR. RIVIERE:  The other ‑‑ the other question is is that we develop these preclinical toxicology databases.  I was a little bit disturbed in Dr. Galson's statement saying that the science of efficacy has advanced, but the science of toxicology has like sort of just been stuck and did not advance.


            That's really not true.  What I'm not sure of is how much of some of these areas ‑‑ and I know why it's not applied to preclinical studies.  Because it might generate false positive signals, nothing ever goes forward ‑‑

            DR. WOODCOCK:  Right.

            DR. RIVIERE:  ‑‑ and, you know, in that constant pendulum battle.

            Has anyone looked at these post-marketing adverse drug reaction databases, and then done studies to go back to the full preclinical data, not necessarily the univariate detection of a signal that we know cause and effect, but basically could we have come up with something to detect this earlier?  And I think that's an area that the data is there. 

            We have a lot of information on both approved drugs and non-approved drugs.

            DR. WOODCOCK:  Right.

            DR. RIVIERE:  You could pick it up right now.  If you knew this was a metabolizer of this specific enzyme, you'd know there was a problem.  But is there ‑‑ any attention been focused to basically let's go ad hoc ‑‑ post hoc go back now and look and see if we could have done better.

            DR. WOODCOCK:  These are the data mining efforts I alluded to earlier, and we do have some folks who have come forward and are interested in partnering with us to conduct these studies, or retrospective data mining efforts.

            Part of the problem is a lot of the data are not electronic, and so there's this huge data entry problem that occurs every time we have to go back and data mine the prior results.  But you're right, FDA is sitting on this huge repository of animal and human studies, and then have ultimate human outcome data to follow that.

            CHAIRMAN SHINE:  Dr. Roses?

            DR. ROSES:  I can add something to that.  I took the Lotronex database, the entire database, hired an outside firm, for privacy reasons, to track down every patient in that database to find out as much as we could about the adverse events that were happening.  I'll just make three quick remarks.

            The patients either came through self-referral, they came through physician referral, or they came through lawyer referral.  In no case of a lawyer referral were we ever able to gain the identity or a DNA sample anonymously from any patient.

            About half the patients were lost to followup in the physician referral.  In the self-referral database, out of 186 ‑‑ I think the number was ‑‑ 168, one of those two ‑‑ we got about 30 patients that we actually got to.  And of those 30 patients, three had never gotten a prescription for Lotronex, nor ever taken Lotronex.

            That's why I'm concerned about the quality of the data that we get.  And you can't go back.  It's not just the information to do this genetically, to do it ‑‑ just even a SIP-2D, you have to have a sample, even if it's an anonymous sample.

            DR. WOODCOCK:  Well, one of the thoughts we have, if I may partly respond to that, is it's possible that if FDA asked for some of these and conducted ‑‑ partnered and conducted some studies like this, we may get more willingness by patients to give us the samples.

            CHAIRMAN SHINE:  Other questions for Dr. Woodcock?  Oh, Jesse.  Dr. Goodman?

            DR. GOODMAN:  I was just going to amplify a little on the comments several people and Janet made.  And I'm not sure I completely got your original question, but I think part of the intent in some of FDA's pharmacogenomics initiatives, and the voluntary submissions, is to increase our power to do these kinds of things.

            And even in some of our products like the vaccines, etcetera, or gene therapies, you know, we're encouraging archiving during ‑‑ during studies of ‑‑ of information.  And, after all, DNA and genomics and results of microrays are just another form of information.  But it's one that already is pretty automated and accessible.

            A lot of the kind of concerns that somebody mentioned that you get all of these ‑‑ you get ‑‑ 2,000 genes go up, and some of them have ominous names.  What does that mean?  But the ability to then go back to them retrospectively, if a problem is discovered in a much larger population base and identified predictive tools, I think that's the kind of thing that can really move our ability to prevent some of these adverse events forward, much the same way it was done with metabolism.

            DR. RIVIERE:  And that's what I was really aiming at is ‑‑ is that it's not the real noise in the 80-odd databases.  It's these really serious ones that we now know as this class effects, and maybe subclass effects, to go back to that original data ‑‑ I mean, which there probably were samples even collected some of these analyses ‑‑ this is the animal database and the preclinical database ‑‑ to see if we could have looked at that differently to actually pick that up.

            CHAIRMAN SHINE:  Allen, go ahead.  Do you want to ‑‑

            DR. ROSES:  Yes.  In predictive tox experiments that have been done, and they're in the process of being reported, written ‑‑ they have been reported, the experiment ‑‑ it's done in a number of companies.  The experiment that we did was to ask the question:  if we have chemicals that pass four-day animal tox, then fail at 28 days, can we predict which ones they were?

            And some are using genetic-genomic kinds of techniques.  The answer is we found 10 markers that would predict, with 98 percent accuracy, that a drug that passed four-day tox, looked pretty good, would fail.  It's another way of asking the question:  can we make predictions?  The answer is, yes, we can, but now we have to get the database.

            DR. WOODCOCK:  Right.  But that's a tremendous opportunity.  Even there, it shows that you detected emerging toxicity before it became overt, and that's really one of the goals that we want to do in patients as well.

            Sorry to interject.

            CHAIRMAN SHINE:  Absolutely.

            Dr. Laurencin?

            DR. LAURENCIN:  I'm going to reflect back on some ‑‑ on the old science again.  I mean, to what extent does FDA, in examining the clinical trials, examine the study population and the population to which the drug is going to be administered to?  Because clearly, obviously, if the populations are different, then one would expect to have different adverse events.  And that may be what we're seeing.

            DR. WOODCOCK:  The indication that is given to the drug relates to what was tested ‑‑ what population was tested in the clinical trials.  So, yes, we look at that very closely.  We do a lot of subgroup analysis and cut the data many ways for the pre-market database.

            So whatever the company is granted reflects the patients who were studied.  However, the clinical usage of the drug will always or inevitably be much broader than whatever narrow indications are put on the label.  That's just how the practice is.

            CHAIRMAN SHINE:  Which leads to lots of questions about what, in fact, should have to happen in the post-approval state.

            Dr. Thomas?

            DR. THOMAS:  I was going to ask about your remarks with regard to polypharmacy in this geriatric generation that we now have and multiple drug use.  Do you have any way to specifically identify, say, drug-drug interactions or drug-nutrient interactions?  Or is this mostly in the post-surveillance phase?

            DR. WOODCOCK:  No.  First of all, we identify the drug metabolism prior to approval.  So those interactions that can be predicted based on metabolic knowledge and what we know about all the drugs on the market, that is already identified.

            In addition, companies are often asked to do specific drug-drug interaction studies with drugs that would commonly be used in that condition.  Okay?  But if you did a factorial design of all the drugs that are out there, and then added a new drug on, we cannot do ‑‑ or no one could do an empirical test of the interactions of all those drugs together and the pre-market period would never get done.  So that is not done, and that has to be picked up, and often is, in post-marketing.

            CHAIRMAN SHINE:  Cato, did you have another comment?

            DR. LAURENCIN:  A followup question.  NIH requires an assessment of numbers of ‑‑ contributions of women and minorities to clinical studies.  And, in fact, when we study a section, we actually grade the ‑‑ grade it unacceptable ‑‑ either give it a U or an A, unacceptable or acceptable.

            And it could actually mean that the clinical trial won't even be funded if it's got unacceptable numbers of women and minorities in the study.  Does FDA do that?  If FDA doesn't, why not?  And what's the plan?

            DR. WOODCOCK:  Well, there is reporting of enrollment, and so forth, and that was done in regulations and guidance sometime ago.  But since we do not fund clinical trials, we don't have the authority to tell people they can't do clinical trials, at the time of filing, then those subgroups are reported as part ‑‑ overtly as part of the NDA database, the representation of each subgroup.

            DR. LAURENCIN:  But you don't fund it if you ‑‑ if these ‑‑ if a guidance document states that these numbers are going to be important, and that they're going to be looked at, and that they will ‑‑ they will reflect whether a drug may be approved, then I think that ‑‑ that there may be a response corporately.

            DR. WOODCOCK:  Yes.  We've done everything we can to encourage enrollment.  As you know, we've worked with the National Medical Association, for example, in training investigators, and so forth, to try and increase enrollment of certain groups.

            CHAIRMAN SHINE:  Dr. Roses?

            DR. ROSES:  Yes.  I think this is being addressed also in a different way.  So if you take the SIP-2D case, just as itself, there's a very simple genetic trait that if you have one form you ‑‑ and you can measure the allele frequency of that trait in any population that you have 3,000 people.  So you can get that kind of information of who is at risk. 

            You turn that around, and there have now been adverse events that have been found ‑‑ for instance, in the caucasian population ‑‑ with a very, very high degree of sensitivity and specificity that have not been found in other populations, and, in particular, black populations where the recombination rate is much higher than in later populations, so that the differences between Japanese, Chinese, and African-American, or different African populations are quite different.

            But, fundamentally, when you're talking about adverse events, you're talking about the person who gets it.  The N is 1, and that's what we're aiming at.

            CHAIRMAN SHINE:  Dr. Woodcock, there are kind of two kinds of problems with the post-marketing issue.  One is the impact of time, and the other is the impact of ‑‑ of both the numbers and the nature of the population.  To what extent, on the time issue, is there any systematic attempt to follow at least some portion of a population involved in a short-term clinical trial for longer periods of time in order to begin to get more insight into the time dimension?

            And to what extent, given that, as you pointed out, invariably the population exposed is substantially larger and often quite different than the population ‑‑ or sometimes quite different than the population that is tested ‑‑ to, in fact, seriously require post-marketing clinical trials in a real population?

            DR. WOODCOCK:  Well, the first question was, is there a secular trend on hazard rates, or the hazard rate for some adverse event might increase the longer a patient is exposed to the drug. 

            And unfortunately ‑‑ I think Bob O'Neill was here before ‑‑ I think, you know, the problem is that usually requires randomized trial data very frequently to determine that.  You know, it's not the kind of thing that you would pick up in a ‑‑ you know, just post-marketing surveillance.

            So that would require ‑‑ I think this is something that obviously has come more to the forefront, say, with the COX-2 inhibitors, and so forth, that require longer randomized observation.

            For many populations that we have, it's ‑‑ people with symptomatic disease or serious disease, we can't keep them on placebo.  So then you have to do an active controlled trial, and then you have to know what the background rate is in that other group to calculate how you would set up the trial.  We often don't know that.  We are inheriting the uncertainties of the past, which create a great amount of problem in setting up trials of the future.

            The second is:  to what extent do diversity in the population ‑‑ how can you extrapolate from the clinical trials to this very diverse use of ‑‑ types of uses that are going to occur in the clinical situations? 

            Yes, sometimes we can require clinical trials ‑‑ as a post-marketing commitment that a company do post-marketing trials.  As Armando said, sometimes they would be done in people with liver failure, renal failure, some predicable group.

            But, Steven or Armando, do you have other comments on that?

            DR. GALSON:  We can require more studies; there's no question about it.  But, again, it's a balancing act.

            DR. WOODCOCK:  And it's hard for us to predict always how the clinical community is going to use that drug.  That's part of the issue ‑‑ that drug is introduced.  Sometimes it has to do with the way it's promoted.  Sometimes it simply has to do with somebody publishes and an article, and they say it's great for this, or in this group of patients, and then the use really takes off.  And we wouldn't have predicted that necessarily.

            CHAIRMAN SHINE:  Yes.  Dr. Thomas?

            DR. THOMAS:  Yes.  That strikes at the heart of off-labeled use, and probably you get more abuse of that in children and perhaps in the field of oncology.  What sort of proportion or percentages do you see with respect to off-label use of a drug and the incidence of AEs?

            DR. WOODCOCK:  You know, I think one of the things that ‑‑ based on many of the questions the committee has asked us this morning, one of the things it would be nice to have is for Theresa to have some staff to do studies of all these ‑‑


            ‑‑ all these things, because we don't really know ‑‑ we don't perform as much, you know, step back and look at the big picture analysis we should of all these things.  We know that in the pediatric world that the percentage of off-label use is extremely ‑‑ you know, is the majority of uses, basically, leaving aside antibiotics.

            And I don't know to what extent ‑‑ that we know to what extent that impacts adverse events.  But in the pediatric trials that have been done to date, we have had some very startling information on the need for dose adjustment, up or down, things that we would not have predicted a priori.

            CHAIRMAN SHINE:  The committee has been asked about a number of questions, and let me remind you of some of those.

            Thanks, Janet.

            And let me ask you to think about and make some comments about them.  The first is:  what kind of information do health care providers and patients need about a drug's safety?  And how can FDA best get that information across?  You've heard about some labeling proposals.  You've heard about the role of electronic communications in the National Library of Medicine.

            Other thoughts with regard to that issue, with regard to information?

            Dr. Harlander?

            DR. HARLANDER:  I'd like personally to see more information available electronically.  But I also assist with health care with some elderly former in-laws that don't have access to any of that ‑‑ that information.  And what I found in working with them, that it ‑‑ that their primary source of information is through their pharmacist.  And I know that's kind of lumped into the health care professional category probably, but I am wondering if there isn't a way to leverage that as a communication tool.  We all have to see a pharmacist when we pick up these prescriptions.

            The other issue that I've run into in dealing with these elderly relatives is the drug-drug interaction, and, you know, they will give me a list of the 11 drugs that they're taking, some of them picked up at different pharmacies and from different doctors.

            And, you know, I know there's no way to force people to go to the same pharmacist, but I think there is an educational avenue there that ‑‑ that could really be exploited very much more, even in taking out that ‑‑ that drug insert and helping people walk through it, even the first time, would give you, you know ‑‑ especially if the format is going to become more consistent, which I think would be excellent, to help consumers take more responsibility to look at ‑‑ at those kinds of drug inserts.

            And if there's any way to make ‑‑ because I took those lists of 11 drugs, and I tried to do some drug-drug interaction investigation myself, and it's like hopeless.  I mean, I can't find it.  If it was on FDA's website, I'm not even sure I could get to it.  You know, and I ‑‑ and I know a little bit about it and have gone to the website a lot. 

            So ‑‑ so I guess using ‑‑ the message would be using the pharmacists more, if we can, or find avenues directly to consumers and to provide more of that drug-drug interaction kind of information in a user-friendly way would ‑‑ I would encourage.

            CHAIRMAN SHINE:  Is there a website in which you could, in fact, put in the names of 11 drugs and have the computer tell you what interactions might take place?

            DR. GALSON:  Yes.  The PDR has a website that ‑‑ and a software that does that, and there are some software tools.  They're not from FDA, and I can't, you know ‑‑ I don't think ‑‑

            CHAIRMAN SHINE:  I just wonder how user-friendly those are.

            MR. GALSON:  They're pretty user-friendly.  I don't think they're ‑‑ you have to know a lot to use them effectively.  You can't count on them.  But there are some tools.

            DR. WOODCOCK:  Yes, the problem is ‑‑ and we would ‑‑ we would like to, if you don't mind ‑‑ I'm sorry ‑‑

            CHAIRMAN SHINE:  No.  Go ahead.

            DR. WOODCOCK:  ‑‑ we'd like to step into this realm ‑‑ this is another realm.  There are many interactions of drugs.  If you're taking more than five drugs, you're having interactions.

            The question is:  which ones are clinically significant?  And, unfortunately, the practice that FDA has had even is just to list all of the interactions, figure out ‑‑ let the professional figure out ‑‑ I can tell probably even a pharmacist could not figure out, without going to the literature, whether those 11 drugs were going to result in clinically significant ‑‑ I don't even know whether a pharmacologist could figure that out.

            It's very, very difficult, and we need to do a better job, and we know, of pulling out the really big ticket items and really highlighting those, so those people know, okay, well, you might ‑‑ every time you take more than five drugs, you're going to have some shifts.  But these you really have to be careful about.  That's the kind of message we need to get out.

            CHAIRMAN SHINE:  And are you working on that in terms of the actual project?

            DR. WOODCOCK:  Yes.  We have been discussing it, but we aren't very far along.  It's difficult for scientists to do.  They don't like ‑‑

            CHAIRMAN SHINE:  They don't like to ‑‑

            DR. WOODCOCK:  ‑‑ making ‑‑

            CHAIRMAN SHINE:  ‑‑ discuss the big ones.

            DR. WOODCOCK:  No.

            CHAIRMAN SHINE:  Right.  Dr. Thomas?

            DR. THOMAS:  Having written several articles over the years on drug interactions or drug-nutrient interactions, you always come to the situation where you've got a case study that's reported, one patient.  And now, what do you do with that?

            It gets in the literature and it gets carried along for the next 20 years as a drug interaction, and it probably ‑‑ it may or may not have any clinical significance.  And that's the sort of dilemma that you're dealing with when you get into that arena of drug-drug or drug-nutrient interactions.

            CHAIRMAN SHINE:  Yes.  The question is whether you're going to ‑‑ whether ‑‑ the perfect test to paralyze you in terms of being able to give people some reasonable guidance.  I think we've got to think that out in terms of ‑‑

            DR. THOMAS:  Well, if you listen to the evening news, and all of the side effects with respect to drugs, you get the feeling that that's one way that the public is being convinced of how dangerous drugs are, because they're all citing the worst AEs that you can possibly imagine, including death.

            CHAIRMAN SHINE:  Any other comments on this issue of getting information out?  Dr. Cassell?

            DR. CASSELL:  I don't know that it really has to do with getting information out, but in some respects it does.  And I may be off limits to Janet to ask this question, but would certainly value your thoughts on the role you think that clinical trial registries might play in overall drug development, but particularly as it might have bearings on the safety issue.  And what kinds of information do you think are absolutely crucial at the inception and completion of studies in such registries to really be impactful as far as public health is concerned?

            DR. WOODCOCK:  Well, I know registries have been advocated as perhaps dealing with a lot of these issues.  But registries, in my experience, are most helpful when you know the question you are asking as you go into the registry.  So you have a specific question or hypothesis you're trying to deal with, and you're able to design the registry very parsimoniously, you know, with very few data element collection to answer that specific question.

            But, in those circumstances, for certain especially safety questions, it may be extremely useful, because it can deliver to Dr. Seligman and his colleagues the denominator, a numerator and denominator, something we are very sorely lacking in many drug safety occurrences often.

            CHAIRMAN SHINE:  Any other comments?  One of the things I've wondered about, Dr. Woodcock, is whether some kind of ‑‑ you have the black warning with regard to the drug and its medical uses. 

            But in terms of drug-drug interactions, whether you could resolve some of the problems that Dr. Thomas is talking about by indicating there's a category of, if you will, red interactions, yellow interactions, whatever, which ‑‑

            DR. GALSON:  Like Homeland Security?


            CHAIRMAN SHINE:  ‑‑ purple interactions, magenta.  But, in other words, something that, in fact, gives the consumer an idea that this is a big one but doesn't necessarily mean you drop everything off.  But, clearly, there would be a hierarchy of things to worry about.

            DR. GALSON:  I think that's a good idea.  There is no question we're way in the last century somewhere in our communications tools.  And we're ‑‑ you know, we're playing catch up.  But there's ‑‑ I think there are some real hopes there.

            CHAIRMAN SHINE:  How can the reporting of adverse events be improved?  Question ‑‑ the cooperative agreements you have with Kaiser and VA, and so forth, what's the nature of that system?  What's happening in those cooperative agreements?

            DR. WOODCOCK:  Well, the cooperative agreements we have are ‑‑ you know, we provide money, and then they agree to do certain studies based on questions that arise.

            CHAIRMAN SHINE:  But these are research studies as opposed to ‑‑ I mean, VA has a very good electronic medical record.

            DR. WOODCOCK:  Right.

            CHAIRMAN SHINE:  Does this involve linking with their medical record?

            DR. GALSON:  They're not all ‑‑

            DR. SELIGMAN:  As Janet described, they are ‑‑ where we currently use them is actually to ask specific questions.  On occasion, we have used them to amplify certain signals that we've gotten from adverse event reportings.  We haven't used them in the way I think you're suggesting, which is to sort of systematically use their data in ways to ‑‑ you know, as an alternative to sort of voluntary or spontaneous reporting.

            CHAIRMAN SHINE:  Yes.  I was thinking in terms of a number of these representing opportunities to develop model reporting systems.

            DR. CASSELL:  Or couldn't you look at them as a ‑‑ somewhere like single sites as you would if you were doing infectious disease surveillance.

            DR. GALSON:  Yes.  We've certainly heard that suggestion, and we've done some explorations of that.  It would require substantially more resources than we have available.  But this ‑‑ it certainly is an option to do that as ‑‑ particularly as the health information infrastructure becomes more sophisticated, we'll be more able to do that specifically with certain kinds of adverse events.

            DR. SELIGMAN:  Right.  Just one quick comment.  This past week we announced in the Federal Register a request for information on pilot initiatives for active surveillance.  We're asking groups to sort of come to us with, you know, ideas and thoughts on how we might indeed, you know, work with existing databases or health care systems to do just that kind of work.

            CHAIRMAN SHINE:  Yes.  One of the thoughts that occurred to me is that, as Gail and others know, an awful lot of money is being spent on syndromic surveillance for infectious disease, including, for example, the network that ‑‑ in Pennsylvania on emergency room reporting. 

            And it would seem to me that trying to develop collaborations with those networks, so that you can do syndromic surveillance on drug interactions from those same sites with the same terminals, I don't know how much incremental cost it would add to it, but there you've got it.  And there are a number of those now around the country in terms of syndromic surveillance.

            It does emphasize again what we talked about before, and that's the need for standardization, so that you know that you're talking about the same things.


            DR. RIVIERE:  Shouldn't the pharmacy professionals be involved in this, too?  I know U.S. Pharmacopeia used to really be up on keeping track of adverse drug reactions, because of the same thing.  The person may call the pharmacist with an interaction.

            DR. GALSON:  And Gail asked about the pharmacist before, too, or you asked.  The pharmacy community is very, very interested in this.  The major problem, which no one has really come up with a workable solution, is that there is no funding model for pharmacists to get involved in this.

            And you all know what pharmacists are ‑‑ pharmacies are like.  There's a long line of people.  There really isn't much privacy.  They don't have extra time.  And if they are going to have extra time, there has to be some model that compensates them for that.  And we'd love to see them involved.  They are very highly trained, as you know, to detect, to counsel, and it needs some good brains working on that one.

            CHAIRMAN SHINE:  Dr. Thomas?

            DR. THOMAS:  I was just going to add with a somewhat cynical note one way to identify side effects is to threaten a class action, and all of a sudden you find out where all the side effects are across the United States.

            DR. GALSON:  As you've heard from Dr. Roses, you may hear about them, but that doesn't mean that they're actually legitimate.

            CHAIRMAN SHINE:  Thank you, Dr. Thomas.

            Dr. Cassell?

            DR. CASSELL:  So, Ken, it seems to me that it boils down to two things ‑‑ one, our resources, both the human capital, but the financial capital to do this and do it right, and the other thing is the implementation of the electronic medical records, or you can't really do it and do it efficiently.  So regardless of adding additional resources, it won't be as good as it could be. 

            So, in your opinion, what can this Board do to try to emphasize this, bring it to the attention of those that can do something about that.

            CHAIRMAN SHINE:  About which part of it, the resource issue and ‑‑

            DR. CASSELL:  The resource issue, both from the human capital standpoint as far as training is concerned, the funding issue as it relates to the pharmacy model, and then also just the resources here within FDA to actually get it done, or to bring the groups together like we were talking last night, so you can be sure that we can synergize and capitalize on the investment being made in IT resources and other federal agencies, including the CDC, including DHS, and why not also including NSF and FDA?  Like I hope we might hear about in the public comment period this afternoon.

            CHAIRMAN SHINE:  Yes.  Just a couple of thoughts.  I mean, obviously, this is a very difficult area.  A) I think clearly on the electronic health records side we're beginning to actually make some progress.  And a recent survey showed that some 24 percent of academic health centers in the country now have a working electronic medical record, and almost every other one is actively pursuing it.

            Working with NIH, in terms of both language and connectivity ‑‑ I'm sorry, HHS, and with Baylor and his office with regard to language, and the concept that the health information super highway should provide this kind of information, would be I think a very cost-effective and synergistic way to do it.  And I suspect some of those conversations are going on.

            As you know, the Congress did not provide the $50 million for that office that was requested, but I believe that money is going to get restored by another mechanism.  So I think that's going to happen.

            Secondly, you are seeing the proliferation of ‑‑ in using electronic medical records, of error reporting in institutions, where the institutions themselves are looking for ways that they can identify errors.  The question is:  can you link that?  Can you integrate that with the drug problem, whether it's an interaction, formally an error or not?

            And I think there are some very interesting opportunities, both in academic health centers and with a couple ‑‑ you know, this is a conversation that would be very worthwhile having with Reed Tuckson at United Healthcare, given the power of that electronic system.

            DR. CASSELL:  Well, could I suggest that maybe an interesting followup to our Board meeting today, which is all focused on safety, that there could be a followup meeting with an emphasis on the IT issue, the critical nature and urgency of that, and the resource issue, and to try to help identify opportunities for synergism amongst the agencies and other groups as you have just mentioned. 

            Should we consider that and maybe think about the fact that it might take more than just a day or part of day to really do it justice?

            CHAIRMAN SHINE:  Yes.  Well, I think your point is well taken.  I would also argue that this is clearly a public health problem, and so identifying it with some CDC's efforts, with regard to what they're doing in terms of monitoring, is another way to do that.  And I think there is some activity there.

            I mentioned syndromic surveillance, and DHS has some very interesting programs trying to move that agenda.  So I think the most likely way to get substantial additional resources is to show that by bringing a number of resources to the table that they could be leveraged ultimately into a national pharmacovigilance program.  I mean, that's really what you want, and you want to have it in a ‑‑ it seems to me, in a ‑‑ in a serious that would protect privacy.

            Incidentally, I strongly recommend to you Bernie Love's article in JAMA this last week on all of the misconceptions about HIPAA, and the notion that HIPAA prevents us from doing a lot.  It doesn't.  I mean, a lot of what we're talking about, HIPAA would be quite consistent with.

            But my thought, Gail, is that creating ‑‑ you know, clearly, the FDA needs more resources in this area, and that's one of the reasons I'm probing for a rationale in terms of the way in which you can articulate the need in some kind of formal way.

            But at the same time, I think to the extent that you can mobilize multiple agencies with a program, which shows that you're building on things that are of interest to a number of constituencies, we've got a better chance of making a significant investment.

            Other thoughts?  Dr. Goodman?

            DR. GOODMAN:  I'd just like to ‑‑ I concur with all of that.  I'd like to add a dimension which you probably have in mind, but it isn't always made explicit, which is we're in this situation of not having access to health care information, and there not being a health care information system.  So, rightfully, we say you really need that, and that's the most efficient system for looking at medical products and their adverse events.  That's all correct.

            But I think you also have to envision what will happen when that information becomes available.  And I think the issue ‑‑ one of the first issues there is going to be how to analyze it and interpret it.  And I would suggest that as we're seeking the information ‑‑ and maybe this is where also FDA can contribute ‑‑ we also examine, you know, what are going to be the tools ‑‑ the analytic tools and approaches to that information, not just getting the information.

            You and I know from rounds and things like that that even when we're seeing that very patient, and have been seeing them for two weeks, interpreting events in a medical chart, or some day an electronic medical record, when you have absolutely every bit of data, plus first-hand observation, is very difficult.

            And to do that with quantum increases in the amount of data, and number of data points, and patients, I think is something we need to look at.  And syndromic surveillance in a way is the analogy of why that ‑‑ that illustrates some of the problems.  There is something very simple.  You're just looking for infectious diseases, not even what they are.

            And we have a lot of ‑‑ I think those who are trying to do that are seeing a lot of challenges with the data that gets generated.

            CHAIRMAN SHINE:  I agree with you entirely, Jesse, but that's one of the reasons why I asked about doing the collaborations, whether it's with the VA or with some other organization that has a functioning EHR, so that you can begin to develop the methodologies as you generalize that.  And so I ‑‑ I'm pleased to hear about the inquiry that has gone out.

            But I would also think that there are some other places where there are ‑‑ this kind of information is available and we need to develop the methodologies that you're talking about.  Absolutely.

            DR. GOODMAN:  Yes.

            CHAIRMAN SHINE:  Other comments about reporting issues?  I think, Allen, your concern about the validity and the value of the data is extremely relevant.  Do you have any additional suggestions as to how in the world, given the current system, we can help with regard to the accuracy of the data?

            DR. ROSES:  Here I'm going to put my individual hat on, or my hat from 27 years at Duke, rather than eight years in industry.  Where I've been impressed ‑‑ and I didn't know about when I went into industry ‑‑ was some of these risk management programs that currently exist. 

            And I think we would be remiss if we didn't say that there are risk management programs in place that have provided valuable medicines for sometimes very severe illnesses that have side effects, and that there are ways that went ahead to keep the drug out there for the people who needed it, and to mitigate side effects.  That exists.

            If it exists in a risk management program, why can't it exist for the general population?  And one of the things that we ‑‑ that I've proposed within my company, and which I think is going to happen, is that we're going to take one of the drugs that we put out that has to be in a risk management program anyway, and we're going to get DNA and clinical followup on the first X-100,000 people who would take that particular medication.

            And what we would hope to be able to do would be to identify time-related or rare or even common side effects that may occur in one population and not occur in another population, and be able to have, in an anonymous way, so that the ‑‑ it's banked anonymously, but the bank gets contacted and we get the DNA anonymously, and by the time the FDA could call an Advisory Committee together to look at it, we would have the answer as to what it is that is a predictive classifier that says these people, no matter what ethnic group they come from, if they have these characteristics genetically, they shouldn't take the drug.

            Now, if we can do it on a drug-by-drug basis, one of the things that might actually happen in the future is that we could do this for everybody.  And the technology isn't quite there yet.  We can do it; but it's expensive. 

            But at some time in the very near future ‑‑ we all know what happened with the ‑‑ with sequencing the genome.  Costs came down when demand went up.  That the measurement ‑‑ standardized measurement of 500,000 variants across the genome could allow us to start to get at these answers.

            That's not in the context of public health, and it's not in the context of what we should be doing.  We should put in place, for planning a system, not to deal with the problems that we have today, but to deal with the opportunities that we have in the next 5 to 10 years.

            CHAIRMAN SHINE:  Well, we will follow with great interest, because that's exactly the kind of approach that I think Janet and others are ‑‑ have been promoting.  And the question is:  can you eventually do it, as you say, at a cost that makes it something that can be generalized?  So we will be very interested in the followup of that.

            We're going to break for lunch in three minutes.  One other element of all of this, as it relates to information, still is the fundamental problem we have in the United States with communicating risk ‑‑ what it is, what it means, what it means to individuals, what it means to populations.

            We still, as a society, believe that there should be zero risk associated with essentially every aspect of our lives.  And I was struck by the fact that after 9/11 people wouldn't fly planes but did drive very extensively, where the risk, and, in fact, the reality of death was substantially greater than if they had been flying.

            The thing that's remarkable in terms of the development of agents in the 20th and 21st century is that, in fact, they work.  They are potent.  And it's their very potency which in many ways confers a certain kind of risk on them, to which is added all of the other issues of accessibility and the fact that more people in the population have access to them, and, therefore, more likelihood that there's going to be problems, both with people in general and with special populations.

            So somehow communicating the notion of the benefit of these agents, the constant balancing act that's made between efficacy and "safety," it seems to me has to be one of our major challenges as we try to provide this information. 

            And we need, I think to find some rubrics, if you will, to do that.  You know, one of my favorite metrics is an LBU.  An LBU is a lightning bolt unit.


            I don't know, what is the probability in the United States of being killed by lightning?  Anybody want to tell me what that ratio is off the top of their head?  Hmm?  One in 750,000.  And yet people don't ‑‑ you know, they know to get off the golf course during a lightning storm, but they don't realize that something that was ‑‑ that is one in a million is actually less likely than being struck by lightning.

            So I ‑‑ I just emphasize, I think what we're doing ‑‑ what you're doing in terms of providing easier access, easily readable information, whether it's the internet, whether it's the pharmacist, and so forth, extremely important. 

            But the background to all of this is somehow those of us in health have to be able to help people understand that, if it works, it's likely to have some risk.  And the question is:  what's an acceptable risk?  And that's not just a hypothetical question.  I believe the Drug Safety Board is going to have to address that when it makes decisions as to what it says in terms of how do you decide what is an acceptable risk when you put something out.

            We're going to take a break for lunch.  We will convene precisely at 1:30, because we have five public presentations, and we're going to need to have them occur in a timely way.

            Thank you very much.

            (Whereupon, at 12:26 p.m., the proceedings in the foregoing matter went off the record for a lunch break.)

            CHAIRMAN SHINE:  Ladies and gentlemen, if we could reconvene.  We're now about to have an open public hearing.  Both the Food and Drug Administration, the FDA, and the public believe in a transparent process for information gathering and decision making.  To ensure such transparency at the open public hearing session of the advisory committee meeting, FDA believes that it is important to understand the context of an individual's presentation.  For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting.

            For example, the financial information may include a company's or a group's payment of your travel lodging, or other expenses in connection with your attendance at the meeting.  Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any such financial relationships.  If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

            We have five presenters in the course of a one-hour open public hearing.  Each has been asked to limit their comments to ten minutes, and we will have to be quite strict in terms of limiting to ten minutes.  At nine minutes for the speakers, I will try to give you a little signal that you're one minute from the end.  And then at the end of ten minutes, you'll have to conclude your remarks.  I apologize for having to abbreviate it in such ways, but we think this is important so that we can fairly hear from all of the speakers, and still maintain our schedule.

            The first speaker is Sadhana Dhruvakumar, who is from the People for the Ethical Treatment of Animals, and we'd ask Sadhana to come forward to make the presentation.

            MS. DHRUVAKUMAR:  I want to say that I appreciate this opportunity to address the science board, and also that I don't have any financial relationships of the type that you were mentioning.

            I just wanted to start by briefly telling you a little bit about PETA.  PETA is celebrating its 25th anniversary this year, and we're a non-profit.  We've been growing very quickly to 800,000 members now globally, and so far our work in animals used in experimentation has been with the EPA in terms of government work, but we have been developing a relationship with the FDA over the last few months.  So when it comes to animal experimentation, I'm going to be talking with a little bit of a focus on drug safety, since that's the topic.

            The scientific issues that we see with it, is that most of the animal tests that we're using for drug safety are decades old tests that may not be able to be validated today.  As Dr. Galson was saying, many of them are from before when he was born, and many of those are animal tests.  They're not reliably predictive of human responses, not that they can ever be predictive, but when you do an animal test, you don't know until you do the human test which species and what is actually going to be predictive.

            Extrapolating from different species results is always guesswork.  When you get disease models, the animal disease is an animal disease, and may not have the same ideology as the human disease that you're looking to study.  Of course, you have animals that are held in labs, in cages in labs.  They're fed lab chow of your choosing.  They have stress from being handled, and that type of thing really affects their physiology and the results that you're going to get.  And, of course, in terms of repeatability and reproducibility because of some of those factors, there's some problems.

            They also take a lot of resources, and basically I'm trying to convey that the whole paradigm that we have been having of using animals as surrogates - we work out something entirely in animals, and then we try to translate that to humans was something that we did in the past, because when there weren't as many tools as we have today for studying humans directly, and there really needs to be a transition from that paradigm to a more human-based paradigm.

            So what would that involve when it comes to medical products?  So in terms of target discovery, we've had pharmaceutical companies tell us that some of them have switched almost entirely to using human tissues, disease versus normal, early versus late-staged disease tissues, and doing genomics and proteomics profiles, and that kind of thing in order to map out human-specific disease pathways.

            We also, in terms of safety and efficacy testing, there's in vitro technologies, such as tissue cultures especially that based on humans, different physicochemical technologies.  When it comes to studying humans directly in terms of experimental medicine trials, microdosing, that's all being enabled, as Dr. Woodcock was speaking about in her speech, by some of these genomics, proteomics, different imaging technologies looking at biomarkers.  We can now go much more quickly and directly into humans without compromising their safety.  And a lot of pharmaceutical companies are doing that, just because they don't want to fail in clinical trials.  They want an earlier indication of human relevance.

And then, of course, bioinformatics, predictive toxicology in silicone modeling, which was also mentioned earlier.  So these are some of the alternatives, the way that things could go in the future. 

            The advantages of these in vitro technologies are numerous.  Basically, they should be very attractive to pharmaceutical and vaccine, and all kinds of medical products companies, or any kind of company because they're usually cheaper, quicker, and more consistent than the corresponding animal test.  Making a transition is hard, but in theory they're more attractive.

            The main problem with these in vitro technologies that people always raise is that they're not a whole animal test.  That's the main disadvantage that they have, but when you look at a whole animal, that isn't a human, you're not really sure of what you're getting anyway, so the value of this whole animal test is suspect.  It's more of an empirical test.  It's a little bit more of a black box, and you don't see what happens, but the way to get away from this is to move from the empirical to the mechanistic understanding that we're striving for.  And once we have that, we will be able to design in vitro technologies that test specifically for what we're looking for, and we won't necessarily need to do something in a whole animal, except for the human-based experimental medicine-type things, which we still will be able to do.

            So when you look at the price that we've paid by doing this animal research, of course animal research, if it predicts wrongly; one way it might predict wrongly is that it might say that a drug that would have been great for humans, might be bad in an animal, and we might never use it.  For example, penicillin is toxic to guinea pigs, has no effect whatsoever on rabbits because it's excreted too quickly, and is one of the biggest booms to human medicine.

            You might also miss problems when the animal tests do not -- when the drug doesn't have a deleterious effect on animals, but does have it on humans.  For example, with the COX-2 inhibitors that have obviously been so much in the news, and the animal studies actually found that COX-2 inhibitors had a protective effect on cardiovascular health.  So that's a missed opportunity to spot something in the preclinical stage and stop it right then, or at least understand that type of problem before you go forward to the clinical stage, where it would be a lot more expensive.  And also, Dr. Woodcock mentioned the whole example of the P450 enzymes, and the fact that so many more drugs used to fail because of metabolism issues.  I thought that was actually a perfect example, as well, because people are probably aware that animals have very different P450 enzymes.  That's some of the greatest areas of species divergence, and so for liver metabolism toxicity, animal models are not very good.  It was switching to human enzymes and human-based human cell tests that enabled that progress to be made which stopped so many of those studies that would have failed in late stage.

            The last quote I just always like, "We have cured mice of cancer for decades, and it simply didn't work in humans."  That's Dr. Rick Klausner of the NCI just pointing out the fact that if we devote our resources to studying animals, it may not pan out for humans, and that's where we spend a lot of resources.  So quickly, this is the type of data that someone might look at when they're trying to interpret what animal results mean for humans.  And as you can see, for any given chemical there's no consistency; even between mouse and rat, you don't even get a lot of concordance. 

            And so I think all of these issues have caused a lot of debate to be going on in the recent years scientifically.  People are trying to validate the previous animal tests; for example, human skin patch testing for irritation was found to be only -- the rabbit test was only 45 percent predictive, which isn't very good.  People are trying to look at and validate these animal tests, and they're finding that they're lacking.  And there was a paper in BMJ last year that I hope you'll look up because it was a really good paper, and it concluded that clinicians and the public often consider it axiomatic that animal research has contributed to the treatment of human disease; yet, little evidence is available to support this view.  They did some systematic reviews, so we really need to look at yes, we conduct these animal tests, but do they really make a difference to the end result, are they really utilized in that way?

            I wanted to quickly touch on animals in the critical path.  I was just speaking with Dr. Woodcock earlier about how this really fits with the concept of the critical path, which is about modernizing old technologies, and transitioning to the newer technologies, most of which are human-based or in vitro.  And if you look at the Critical Path Report,  there's actually statements in there about animal toxicology being laborious, time-consuming, and not predicting safety problems, and problems with currently available disease animal models, and things like that. 

            CHAIRMAN SHINE:  One minute, Sadhana.

            MS. DHRUVAKUMAR:  Okay.  I'm trying to rush.  I know I had a lot on these pages.  That's why I'm not touching on all of it, but I'm trying to kind of cover all of it. 

            I just wanted to raise the issue of international harmonization, obviously very important  in medical products, and the fact that our groups have been trying to work on that level, as well.  And the fact that there's an upcoming issue based on the fact that the EU does not accept animal tests when a validated alternative exists.  If that's every industry, so that when these alternatives exist in EU, if the FDA and other regions don't keep up, there's going to be harmonization issues with companies.

            And lastly, what can the FDA do next?  Basically, the regulations need to change.  The regulations have not been keeping up with the regulations, the guidances, and kind of a review processes with these validated non-animal technologies, things that have been validated by other countries and things like that. 

            We need to put a little more effort into getting some of these new technologies developed here.  I think a workshop would be great, because the European government has held many workshops.  The USDA has held workshops at the Center for Veterinarian Biologics specifically on alternatives, and the FDA could definitely get that dialogue going. 

            And lastly, just the fact that the animal protection community is getting involved.  And I think that what we can bring is the experience from working with these other groups, highlighting some of the tests that are valuable, that are validated, and kind of helping this transition where transition is really hard. 

            And the last few pages I'm not going to go over, but there are ways to move from the generalized idea of validated alternatives to specific examples that we can bring forward and highlight, different campaigns that we have, and information that we can bring forward to help guide that process.  Thank you very much.

            CHAIRMAN SHINE:  Thank you very much.  Fortunately, we have copies of your Powerpoint so the Committee can look in more detail at a number of those slides.  We appreciate your presentation.  Thank you.

            MS. DHRUVAKUMAR:  Thank you.

            CHAIRMAN SHINE:  Our next presenter will be Janell Mayo Duncan, the Consumers Union.  Janell.

            MS. DUNCAN:  Well, no slides, but I wanted to thank you for the opportunity to come and speak to you all today.  I'm Janell Mayo Duncan. I'm the Legislative and Regulatory Counsel at Consumers Union.  We publish Consumer Reports magazine, and we offer the following comments on pre and post marketing safety programs with a focus on broader safety issues.  And I ask that you take a look at our longer statement for a better look into our views.

            The recent controversies related to NSAIDs and anti-depressants have generated a lot of public concern.  And rather than outliers in an otherwise sound regulatory system, we're concerned that the recent drug safety failures might indicate serious structural and regulatory shortcomings here at FDA.  And we think that any attempt to improve the system must ensure that the agency is equipped to strike an appropriate balance between a drug's risks and benefits at the time of approval, conduct proactive post-market safety surveillance, and take timely action to mitigate unreasonable risks when they arise.

            And while FDA might make changes that could mitigate some of these problems, we very, very strongly urge the agency to work with Congress to develop fundamental reforms and ensure that it has the authority to address the problems, the tools, and the resources necessary to do its job, a lot of which resources is money.  And our recommendations are as follows.

            Relating to pre-approval safety improvements, first, we recommend that FDA routinely require post-market clinical trial commitments.  And we are concerned at the limited availability of pre-market clinical trials to identify safety issues because of their limited duration, small size, and enrollment by often healthier and younger subjects in patients likely to take the drug are of a concern.  And these shortcomings strongly argue for more post-marketing safety and study commitments as a condition of approval for new drugs, or at the very least, for drugs likely to have widespread public use, be prescribed off-label, or where pre-market trials raise unresolved safety concerns.

            We suggest that comparative trials be required, because comparison to more existing treatments would better allow the FDA to make comparative risk-benefit determinations at the time of approval, not years later after patients may have been put at risk.

            We recommend improved risk management at the time of approval.  We recommend that FDA manage risk more carefully at the time of approval, particularly for new drugs for which safety concerns are still unanswered.  With more active risk management at the time of approval, FDA would be in a better position to  lift risk management restrictions when safety concerns have been addressed, rather than imposing them after the patient population has already been at risk.

            To address post-market safety concerns, we recommend that FDA create a more - as I've heard a lot about today - a more active adverse event reporting system.  The weaknesses of a largely passive post-market safety surveillance system have been widely noted, and are of great concern.

            Among other shortcomings, adverse event reporting, though better equipped to identify rare side effects, is far less able to detect common adverse events, such as cardiovascular events.  And we are recommending an increase in resources and authority for the Office of Drug Safety.  With a staff of what we understand to be just over 100, the Office  of Drug Safety was responsible for this huge job of safety surveillance.  And the lack of personnel and funding, which we had understood to be $30 million annually, limit its ability to identify the safety risks that adverse event reports may not detect.  And with greater resources, independence, and authority we think that ODS could play a more effective and active role in ensuring the safety of prescription drugs.

            And we recommend the elimination of internal conflicts of interest.  Last year's reports of ODS drug reviewers, pressured to down-play safety recommendations, raised troubling questions about the power imbalance between ODS and the Office of New Drugs.  We recommend that these conflicts of interest be addressed and eliminated.

            And we think that FDA should seek the authority to mandate Phase 4 studies once a drug is approved, and to ensure compliance with all the post-marketing study commitments made at the time of approval, to impose civil monetary penalties for non-compliance, and the ability to mandate label changes, boxed warnings, medication guides, and other risk mitigation measures.  And finally, we believe that there should be an independent Office of Drug Safety, with sufficient authority and autonomy to ensure post-market safety. 

            In conclusion, thank you for the opportunity to share our views.

            CHAIRMAN SHINE:  Thank you very much, Ms.  Duncan.  Our next presenter will Dr. Paul Drzaic of the Alien Technology Corporation.  I probably should comment that because of the time constraints, we're not going to be able to discuss each of these at the time of the presentation, but I do hope that we're going to get back to a number of these issues in the course of our discussion at the end of the day, so please don't think that we're not listening carefully to your comments.  Dr. Drzaic.

            DR. DRZAIC:  Great.  Thank you, Dr. Shine.  My name is Paul Drzaic.  I'm Vice-President with Alien Technology Corporation in Morgan Hill, California.  I have no financial conflicts as outlined in the introductory talk.

            I am here not to discuss use of RFID within pharma.  I think the FDA has examined this on numerous occasions, and is taking very sensible steps to help protect the nation's drug supply.  And certainly, in nine more minutes I won't have time to review that.

            Reading through the FDA report, though, it appears that there could be a very rapid move towards adoption of RFID, and I have not seen, however, what I believe is an adequate description of the various technology platforms for RFID that you may move to implement.  So basically, why I'm here is to provide an update on the RFID industry, just some general trends that are happening in other areas outside of pharmaceuticals, and urge for some additional study before adoption is mandated.  So I have the summary up front.

            So RFID should provide tremendous benefits to the U.S. pharma supply.  There was a report that the FDA did last year, and again it outlined this in great, and I think good detail, providing electronic pedigree, enable improved track-and-trace for recalls or freshness, and efficiencies in the supply chain, which would make the pharmaceutical companies happy.

            Beyond that, though, there are a couple of different platforms that you might consider to adopt.  One is called HF or High-Frequency RFID.  This is a mature technology that's available today, if any of you have card access badges that has HF RFID inside of it.  However, there is tremendous investment occurring in what I'll call EPC UHF RFID, UHF for short, promising lower cost with equivalent or even better performance compared to HF RFID. 

            Additionally, I believe there are layers of protection that the FDA perhaps has not considered, that just due to the ubiquitous nature of the UHF RFID that's going to be appearing in consumer goods in the U.S. could provide some additional layers of protections to consumers.  So again, the bottom line is additional study is warranted before one type of RFID is selected for widespread adoption within pharma.

            Okay.  Just very briefly to remind you how RFID works.  It's a passive device in that there is a reader that sounds out an electromagnetic signal, a radio wave, that wakes the chip up.  There's no battery on the chip or on the tag.  And then by modulating that radio wave, it communicates a signal back to the reader.  And then that information then gets sent up to the network.

            So the two different types of RFID tags, the  High-Frequency tends to have a metallic coil antenna.  Also, and because of the coil, if you think about the geometry, you have to have a crossover so that the metals don't touch as you make the connection.  And while that's sort of an obscure point, it's an important one, because in terms of fabrication, it adds a tremendous amount of cost, or extra cost in terms of fabricating the devices. 

            In comparison, the UHF RFID, they can be about the same size, but they can be a very simple construction called a dipole construction, where you basically have two planes of metal.  So I have some examples I'm happy to leave behind for you to play with, if you'd like.  But you can also do some innovative things with the UHF RFID, so this is something we just pulled out of the lab very quickly before I left.  By cutting a slot in the blister pack here, and connecting the chip across it, we turned this blister pack into an RFID tag.  And in terms of thinking about low cost deployment on lots and lots of items, there are tricks like this that you can play with the UHF RFID that you can't necessarily do with the High-Frequency version.

            Okay.  There is a strong market pull for the UHF RFID led by Wal-Mart, the U.S. Department of Defense.  Again, I have this here basically for reference, but there's a very large infrastructure being built up to support the UHF RFID, primarily in consumer packaged goods right now, but other industries are looking at that, as well as pharmaceuticals, transportation.

            One outcome of this is that readers are likely to become ubiquitous, and perhaps even available to consumers, because these tags are going to be everywhere.  You can readily build the reader into a cell phone, and it's possible that you could actually push the reading of these RFID tags for safety purposes onto both retailers and also consumers, as well, which is something worth considering.

            Global availability - again, this is primarily for reference.  The UHF is going to be available worldwide, so there's no problems with shipment of drugs across borders.  I have, again, primarily for reference purposes, this table.  I think one of the issues that I want to point out is that the UHF tags typically start off with five or six times the range of the HF tags.  And while they are both degraded by metal, being close to metal if you don't deal with it properly, and the UHF tags are sensitive to water, the start-off with so much better performance and range that typically even a degraded performance of the UHF tag can out-perform the High-Frequency tag.

            The other thing I'll point is the HF tags are pretty mature.  Four hundred million tags have been shipped in the last ten years.  The UHF tags are still relatively new, but 50 million have been shipped in the last two years.  And Alien is constructing a plant in North Dakota right now which will be able to crank out 20 billion tags per year.  So again, there's the expectation that these tags are going to be everywhere.  Other details regarding the size, and regrade and the like that I don't have time to go into.

            I did pull this quote out of the FDA report from last September, that pointed out that "Regulatory or policy determinations should be made after experience in the marketplace".  And my point is that the HF technology, since it's been around for a while, does have pharmaceutical-specific products in the market.  So if you wanted to go out and buy an HF tag for pharma, you can probably find one or more products to do so.  For the UHF, because it's still relatively new, you can buy functional tags and readers, but not necessarily those aimed at pharma.  So again, I think that there is a strong interest.  I know within Alien, for example, there's a strong interest in the pharmaceutical marketplace, so again, these products will be coming.  And again, I'm here simply to caution against perhaps a rush to judgment on what's available today for your particular needs.

            Okay.  So the UHF RFID is going to become established.  Again, it's the choice of Wal-mart and the U.S. Department of Defense, among others.  These organizations, by the way, did examine the High-Frequency technology because it has been available for a number of years, and rejected it in favor of the developing UHF technology.  The UHF RFID is mature, but again it's going to be difficult to innovate further because they're pretty much done everything they're going to do with it.  And there's going to be a massive infrastructure deployed to read the UHF RFID tags. 

            Again, this infrastructure can be used to improve the visibility of pharmaceutical, the electronic pedigree for pharma and perhaps far more places outside simply the factories of the manufacturers and distributors of the manufacturers.

            So my recommendation, while the HF RFID technology is mature, we believe that the UHF RFID promises at least equivalent performance at lower tag cost.  Now I realize I zipped passed that part in the table.  Today, UHF tags cost about 30 cents in high volume.  We are selling UHF tags at 20 cents, and the expectation is that they'll be driven down to about a nickel.  And if you could do things like integrate them into the blister pack, they can come down to pennies.  So again, if you think about making these technologies affordable for widespread deployment, the UHF has a much better trajectory than the HF does.

            The reader infrastructure, again, is going to allow more visibility for UHF tags than you can with High-Frequency tags.  And simply, the relative benefits and difficulties of the High-Frequency versus the UHF RFID have not been established.  So I would urge you to give this some study before mandating any particular adoption mechanisms, so that we can have the best effect and usage of RFID in protecting the nation's pharmaceutical supply.  And then I have a little blurb about Alien. 

            CHAIRMAN SHINE:  Thank you very much.  Our next presenter will be G. Michael Fitzpatrick, who is ABC Chief Policy and Chief Operating Officer for America's Blood Centers.  Dr. Fitzpatrick.

            DR. FITZPATRICK:  Thank you.  I've got a copy of our written statement for the committee.  There are also extra copies outside.  There were some rapid changes this afternoon from the President of our association, so that will be a brief departure from the written statement, but we'll have that for the reporter, too.

            America's Blood Centers is an association of 76 U.S.-based not-for-profit community blood centers that collect nearly half the U.S. blood supply from volunteer donors, and we have two Canadian members responsible for all blood collection in Canada.  And I thank you for the opportunity to be here to address the Board.

            In anticipation of Dr. Goodman's talk, we want to emphasize that the critical need for scientific research to support the development of new knowledge and technologies that results in increased blood availability and improves transfusion safety is extremely important, but what is urgently needed are major changes in FDA's processes and infrastructure, and a focus on the path ahead.

            We believe that CBER, the center that regulates blood and blood products, needs to enhance substantially the infrastructure for basic research and evaluation of currently licensed blood components.  We believe as a regulator and a compliance agency, they need to be able to evaluate these products.

            We have confronted in recent years a number of incidents that raise serious questions and safety concerns about the availability of blood and blood components to patients in need.  Recent examples are the discovery of white particulate matter in red cells, and the appearance of hemolysis in a large number of red cell products subjected to leukofiltration using filters from one particular manufacturer. 

            What became evident during those investigations was that CBER lacks the infrastructure for basic research and evaluation of those blood components and those devices.  They had to rely on the industry and on the device manufacturers to generate the data required for science-based decision-making.

            Similar deficiencies in laboratory support can be seen in other regulated areas, such as the quality of life live plasma products, and products such as anticoagulants and collection bags or devices.  FDA does not have the ability to characterize these products as far as their basic chemical and molecular content.  Lot-to-lot variability has contributed to both the white particulate matter, and the hemolysis incident with the filters.  Yet, the very agency charged with the release of these lots lacks the capability to detect significant changes in the product itself.

            Quality of donor screening tests, particularly when new concerns are raised, as in the case of specificity for Hepatitis-B Surface Antigen, and new variants of HIV, HTLV, or the need for individual donor testing for West Nile virus have all been accentuated by this lack of infrastructure. 

            The closure of most research departments by the American Red Cross at the Holland Laboratories, reduced capabilities of the Army Blood Research Laboratory, and the closure of an independent laboratory run at the University of Boston by Dr. Bob Valeri under the auspices of the Naval Blood Research Laboratory, and the aging of primary investigators in our field should be sending signals to the FDA in this country that future regulatory decisions, and the available data about collection devices, blood components and modifications to current components will rely solely on data from manufacturers and institutions supported by the manufacturers. 

            To prevent this, either the government-based or independent laboratories must be supported, and be available for rapid analysis of devices and transfusable components, and be unimpaired by contractual obligations from revealing that analysis, and free from apparent conflicts of interest.

            We recommend that FDA adequately fund its own laboratories based on priorities and recommendations from an advisory panel.  FDA should have its own extramural granting mechanism, or NHLBI be directed to support research required to evaluate and characterize blood products and the devices and soft goods used in the collection, manufacture, and storage of blood products for regulatory compliance and safety.  If these were multi-year funds, a grant cycle could be developed that would guarantee funds are not wasted, and would always be available. 

            The most difficult aspect of administering a compliance and regulatory program for a research program that is focused on blood products is recruiting, supporting, and retaining accomplished scientists that are capable of merging their scientific investigative capability with the evaluation of the clinical impact of a slight lot-to-lot deviation or change in a manufacturer's specification or raw material.

            We would all like to believe that the collection of the right data in an appropriate scientific model based on a valid hypothesis will provide the information to tell us whether or not a product is safe for clinical use.  Unfortunately, the biological information organisms that receive the product are more diverse than any of us like to admit.  And the range of reactions induced in a patient is sometimes just as diverse as the patient population itself.

            The ability to interpret data from a small subset of patients and apply it to the entire patient population is a unique blend of scientific and clinical skills.  It is essential that the FDA and CBER be able to attract individuals with those skills, and have fellowship programs designed to mentor and train the next generation of regulators, will be facing far more complex sets of data and specialty products.  We believe that a well-funded, focused research program is the best way to attract, train, and retain such individuals.

            We're aware that CBER needs funding and resources to accomplish this.  However, the issues are bigger than just money.  FDA needs improved and more frequent dialogue with industry on guidances, regulations, and memoranda.  We are aware that a number of rules restrict FDA's ability to engage with industry after the internal decision is made to develop a guidance document, but we need a mechanism that allows open dialogue.

            We suggest that CBER hold an annual meeting or workshop to discuss guidance regulations that it intends to publish during the upcoming year.  This might eventually evolve into a review of priorities and an open discussion with stakeholders about what is needed to meet patient needs first, industry needs second, and regulatory and compliance needs, as required. 

            We also recommend that the Blood Product Advisory Committee have at least one meeting per year devoted to strategic planning and advising FDA on the needs of both patients and the regulated industry. 

            Ultimately, we are looking for far greater communication, and the use of a scientific approach to investigate threats to the blood supply.  FDA and CBER need to have the ability to rapidly investigate threats to the blood supply, such as white particulate matter, emerging diseases and incidents of hemolysis.  ABC believes that CBER does not have the necessary resources to perform its core functions. 

            Of course, industry needs to be inspected and be responsible with the compliance arm for meeting regulation.  AT the same time, the agency must respond rapidly to changes and advances in technology without tying the hands of industry.  FDA must have the qualified personnel in laboratories to make science-based decisions, and the scientists must understand blood and blood components in depth.

            We need to redefine the relationship and provide a framework that enhances patient care, product advancement, availability, and patient safety.  We could legitimately claim that the U.S. patients are at risk because clear safety enhancements that have been put in place outside of the United States; that is, the use of a product called PRISM, to test and evaluate blood products for infectious diseases, pre-pooled platelets which are used to provide a product that can be bacterially tested, and even frozen platelets that are available in some countries where inventories are not as short as they are here, are unavailable here because of what manufacturers see as an insurmountable roadblock at FDA. 

            Innovation in the United States is being stifled.  We need to work together to find a way to meet our patients' needs, improve the blood products we use to treat those patients. 

            I want to thank you for the opportunity to make these comments to you.

            CHAIRMAN SHINE:  Thank you very much, Dr. Fitzpatrick.  Our last presenter is Sangtae Kim of the National Science Foundation.  Dr. Kim.

            DR. KIM:  I'm here representing the National Science Foundation.  I am currently at NSF on loan from Perdue University, and I do not have any conflicts of interest as indicated at the beginning.

            In the brief time that I have here today, and especially since I'm just across the river, I'm sure if some of the officials at the FDA are interested in the linkages between the cyber infrastructure and IT granting activities of the National Science Foundation, and some of the critical IT issues in FDA's critical path, I'm certainly available for a subsequent meeting.  So in the brief time I have today, I'd like to convey to the Science Advisory Board the linkages between NSF activities and IT issues in the Critical Path Initiative, give a brief overview of the most salient points to set the stage for potential inter-agency collaborations, additional background materials for the record, including current activities of two large centers that are supported by the National Science Foundation.  And in terms of the highlights, I'd like to briefly describe the National Science Foundation's track record in setting the information technology infrastructure that we have today.  It's so ubiquitous that we almost take it for granted.  And also, highlight some of the emerging trends of potential interest to the FDA. 

            I just FDA RFID mandate as an example of a driver for some of the significant investments that we're currently making at the National Science Foundation in supporting research and development in middleware technologies.  Another example that I'll highlight is digital archiving.  With digital age less than three or four decades old, we face a new challenge of data permanence. 

            Many records from civilizations that last millennia, we take for granted that artifacts will be there for centuries and millennia to come.  No one has really thought hard about how do we take the most important artifacts that are produced in the digital age and guarantee that there are business processes and technologies to guarantee that digital records will be available not only for years and decades, but centuries and millennia.  So these are some of the fundamental issues that we are exploring at the National Science Foundation. 

            The track of NSF activities and cyber infrastructure, this chart shows just the past 20 years.  The National Science Foundation actually has made significant investments going back to the 1960s that largely fostered the creation of computer science departments in the universities today, including much of the campus computing infrastructure prior to 1985.

            In the mid-1980s, the National Science Foundation created both the networking, as well as the  Supercomputer Centers, and to just illustrate some of the impact of that, if you look at the past, just give you two examples of things that are important in modern society.  The NSF networking, otherwise known as NSFnet, in partnership with the ARPAnet, became the internet that we have today.  In fact, the original name of the internet was actually Inter-Net, indicating there was a linkage between NSFnet and ARPAnet. 

            Just another example of impact of the National Science Foundation Supercomputer Centers, the NCSA Mosaic project created the worldwide web browser, which then went on to become Netscape.  And even to this day, if you click on the Internet Explorer help button, it will acknowledge the NCSA Mosaic Project as the source of the web browser.  And some of the more technical details of the web services and the worldwide web today, everything that is so-called web-enabled, the actual technology on the server sites, the so-called Apache web server, which to this day is the dominant architecture, was also created by the Supercomputer Centers.

            If you look at the trends of the future, worldwide adoption of NSF Grind Engines - you may have heard the term "utility computing" or "grid computing".  What is not widely appreciated is that almost all scientific grid computing that is done worldwide today is done on computational grid middleware that has been developed and supported by the National Science Foundation. 

            And as I mentioned earlier, things like the RFID mandate of the FDA - the RFID tag itself is a relatively simple piece of hardware, as the previous speaker pointed out, that they're going now to literally just a few pennies in the future.  Now one of the reasons why they cost so little is they're a relatively simple device.  All the intelligence is on the software site, and one of the things to highlight is that the middleware to actually enable these technologies, much of that has yet to be done in terms of creating the right capabilities, and to fully utilize the potential of all these exciting possibilities.  So with regard to things like the FDA mandate, it's extremely important that we continue to make progress in research and development, and deployment of middleware software.

            And one of the things I did after coming to the National Science Foundation is double the annual budget of the NSF Middleware Initiative from approximately $10 million a year, to about $20 million.  Another example that I'll highlight, again in the interest of time I'll just touch upon it, is the San Diego Supercomputer Center is working with NSF, the National Archives, the Library of Congress, and I believe there's also some FDA involvement, as well, to create these new technologies for data permanence of digital archiving, looking at processes that can preserve data not just for years and decades, but into processes that will scale into centuries.

            The other thing to point out about the National Science Foundation is that the NSF doesn't do the work directly itself.  It is a funding or foundation agency.  In the area of IT and cyber infrastructure, the annual NSF grants budget is about $500 million a year, and it covers a very broad landscape of enabling cyber infrastructure over the entire science and engineering landscape.

            One of the things to think about in terms of the cyber infrastructure is we take the internet for granted, but right in front of our eyes, the internet is actually undergoing an information flow reversal.  The historical internet, until very recently, is a radio or broadcast model; that is, there are central stores of information - for example, at eBay, Amazon.com, university centers and so forth, that have information that everyone wants to access.  And then that information is broadcast to the peripheries. 

            RFID is just one example of the paradigm shift.  There are other technologies, like sensor nets, environmental monitoring and so on, and there's an information flow reversal where in the next wave the data at the peripheries, the massive generation of data at the peripheries, so the peripheries are no longer passive absorbers of information, but actually generators of information.  And so the information architecture of the internet has to be redone to recognize the fact that information is now going to be flowing mostly in the opposite direction, and RFID is just one example of that.  And so in my division at the National Science Foundation, an important strategic element of our funding strategy is to get the societal transformation and enabling role of cyber infrastructure to get ready for this information flow reversal.

            So the big picture at the National Science Foundation today is we understand and appreciate that in addition to the actual science and engineering research, that there's an enabling role of cyber infrastructure, not just for science and engineering research, but it has a parallel paradigm for a transformative power in the next wave of the "e" revolution, and there's immediate economic and societal impact.  So we feel very good about the fact that an otherwise very difficult federal budgetary climate, that we are prepared to spend a half a billion dollars a year.

            The drivers are massive data generation at the periphery, as I said; high-end computers at the core, and a new architecture, including middleware, to link the core to the periphery.  And just an example of what this looks like, as we transition to the next generation of cyber infrastructure, for example in like RFID technologies, that we continue the tradition of U.S. leadership in deployed cyber infrastructure, that there is a fundamental strategic advantage of the cyber infrastructure that's used worldwide to come from U.S. architecture and designs.  In the same way that the nation has an advantage in that the dollar is a worldwide currency, we believe that to the extent that the worldwide deployed cyber infrastructure comes out of our creations and efforts in this country, it actually creates a fundamental competitive advantage for the nation.

            So thank you very much for your time, and I'll leave the rest of the reading materials.

            CHAIRMAN SHINE:  Thank you very much.  I want to thank all of our presenters for being extraordinarily efficient in their presentation.  Is there anyone else who wishes to make any kind of public statement in the course of our public hearing?  Is there any question that any member of the board wants to direct?  We will be coming back to a couple of the issues that were raised, but any specific question you have of any of the presenters before we go back to our agenda?

            If not, thank you very much for your presentations, and we'll move on to our agenda with the next presentation by Jesse Goodman on safety systems for vaccines, blood, and tissue. 

            DR. GOODMAN:  Okay.  Well, good afternoon, and I do appreciate the chance to be here with the Science Board, and to get both their input and public input on this important issue of safety.  I'm going to give an overview of what I was asked to do about some of the patient safety and safety-related activities we do to assure that a really unique group of products, blood, vaccines, and tissues are, indeed, as safe as we can make them, and that we continue moving things in that direction.

            I'm going to discuss some of the unique issues about these products, and how we, as a center regulating them, deal with this organizationally, and from a systems point of view.  And then provide at least a couple of examples of how this plays out in practice.

            Now I think you'll see some of the differences in our products which I'll highlight, but I think you'll also see some of this will resonate with some of the common challenges in getting the right information in a timely manner, et cetera.  So with that note, I'll get started.

            Okay.  Actually, the history of biologic safety precedes in many ways the history of drug safety.  I'm not saying in absolute history, but certainly the regulatory mandate and the steps that led the American people to say we want an agency which protects the safety of our products.  And it all started with a horse named Jim, thirteen children in St. Louis, who during an age where serum therapies were regarded as miraculous, they were saving children with fatal diseases, but it was an unregulated industry with dozens, I think, of local manufacturers producing things pretty much in their - well, could be in their garage or whatever on their farms - and thirteen children in St. Louis died from tetanus after receiving diphtheria antitoxin from a horse that had tetanus.  And Margaret Pittman stated, "This tragedy convinced Congress and the public that producing antitoxin or vaccine was not a simple matter like weighing out a dose of a drug."

            Now we all see from this morning that weighing out a dose of a drug is not a simple matter.  This led to the Biologics Control Act of 1902, and just a couple of years ago, the Center for Biologics celebrated what is a centennial of a long organizational history in various forms.  And it said, "Although the preventive and curative powers of viruses, serums, toxins, et cetera, has long-since been established, certain unfortunate incidents have tended to discredit their use."  And I think that "discredit their use", talking about that even then is a very interesting comment.  History is always there in terms of confidence in products.  And, "The extreme value of the preparations in preventing and curing disease renders it of prime importance, therefore, that action be taken to preserve the confidence of the medical profession and the community generally in them."  So I think very telling words for them, and certainly for posterity, probably, because we're always going to face these challenges.

            Now particularly in biologics, we have this parallel, but you see it in drugs, too, between miraculous therapies, tragic events, regulation, and all of this informing product development.  These are just an example, but going back to Jenner, prevented Smallpox, but spread Syphilis with Smallpox vaccines.  The famous Cutter incident where inactivated polio vaccine was not properly inactivated, and a number of children died, and the product developer actually then committed suicide in this case, because he was so unhappy with what had happened.  Transmission of tetanus and other infectious diseases through serum, like I mentioned.  A more modern one, particularly HIV transmission through blood; a more recent one leading to an enhanced FDA role in tissue safety - some tissue contamination episodes; and then much more out there in new technology, successful gene therapy, and adverse events related to that.  So we live in a world of this kind of risk.  There are many things flying at us.  The actual predictive abilities are what we struggle with.

            Some of the big themes and cultural issues particularly for our products, but many of them apply in various degrees to other products, complex products and production, inherent risks, and I'll get to those a little more; but an example is the source material.  And some of these risks are predictable, but some of them are unpredictable.  All that is predictable is that there is risk, but what that risk will be, Mad Cow Disease, for an example, would have been unpredictable before that pathogen was discovered.

            These products, particularly vaccines, but also blood and tissues often given to healthy individuals in large numbers, and their safety is taken for granted.  On the other hand, there is a conflicting need for access and supply.  The markets here are particularly fragile, so they are sensitive to development cost.  But I'd like to point out, they're also sensitive to problems, so that if confidence or risk of products is perceived as a business liability, people will be less likely to make products.  On the other hand, if the cost of developing them is so much, due to over-regulation or undue demands, that may also affect supply.

            The confidence in the public health system is almost always at stake in our daily work in these products, and so there is a need to build safety into the products and production for many of these characteristics.  And there's a need to be a bit ahead of the curve here, and that's part of the culture; identify emerging safety issues, and respond before or as they evolve.

            And these are just an example of why we have very little business as usual in our center, vaccine safety concerns one minute, availability concerns the next, serious on both ends - blood safety and availability, same thing.  Emerging infectious diseases affect many of these products, and may not be predictable.  Increasing use of exciting new technologies ranging from tissues, to cells, to gene therapy, and then the external need for products to deal with counter-terrorism, many of which are developed in abbreviated, urgent manners, and sometimes which cannot be evaluated adequately in clinical trials before a possibility of use occurs.

            So all of these present both long-term and day-to-day safety and risk assessment issues.  So what's been our overall approach?  I think I would say prevention first, and that includes guidance and extensive pre-marketing interactions with sponsors around their products; labor-intensive, resource-intensive, a wise investment.

            Manufacturing process controls and oversight - Mary Malarkey will talk about this a little with vaccines, but we need to not do this in an uniformed way.  We want to do this in a continually updated manner, and that's part of what the agency's initiatives are about.

            We do have to find post-marketing safety responsibility in CBER in the Office of Prior Statistics and Epidemiology which does report to me, and it is responsible for the routine adverse event surveillance analysis and related research.  But they don't work in isolation, and we take a systems approach to this.  There is routine evaluation of serious adverse events for important wide-use products, such as blood, vaccines, and tissues.  And we are doing a periodic assessment and update of our current SOPs and approaches, so that's why again I look forward to being informed by what we're learning here by the IOM, et cetera, even if it's about a different class of products.  AS I said, there are some common challenges.

            Collaboration and communication is very important in how we do this.  These are complex products where our product experts, let's say, in vaccines and blood, have one whole universe of knowledge.  They must consider the epidemiological statistical aspects of the pre and post marketing information, so they need that communication.  And it's bidirectional - our expert epidemiologists, most of whom are physicians, may not be expert in specific vaccine, preventable disease, or a specific product, so they need that bidirectional collaborative approach.  So the data is generally shared and evaluated collaboratively, ultimately; even though post marketing data comes in for adverse event reporting, has a primary responsibility within this office.

            There is also collaborative work planning in safety studies, and this we're trying more and more to direct along the lines that Mike, I think, mentioned.  Our limited resources in terms of understanding or investigating new problems, whether they're laboratory science-based, or population-based in an agenda-driven manner.

            One of the important things we do is we do rely on our advisory committees a tremendous amount, and most significant adverse event issues or let's say safety threats, such as emerging threats to the blood supply, or safety allegations, are brought to our advisory committees.  And we do a lot of public discussion of these things.  And in addition, we have inter-agency partners who have important roles here, as well as resources, and ways they can contribute, and their own advisory committees which we also bring this information to.  And that includes CDC, NIH, and the Office of the Secretary, which for example, our of the Secretary's office, we have very public and open broad constituency advisory committees in the vaccine and blood area. 

            We get a lot of advice, whether we want it or not.  We get a lot of advice, so I think incorporation  - and actually that advice, and the diversity of it, is very, very important.  And also, it encourages on the part of the federal agencies, transparency and information sharing.

            The other thing we've done particularly in the last couple of years is recognize that a lot of what we do falls into the risk management, risk assessment paradigm.  And again, this is reflected to some degree at the agency, as well with the promulgation of guidances for new products, risk management programs, in effect. 

            We've also tried to incorporate a basal level of risk science training and modeling, training into our center so that modeling, regulatory mitigation and public health actions are seen in an analytic framework, and I'll say a little more about that.  And that let's us more objectively balance risks and benefits in the context of things like the intended use of the product, the alternatives to the product, et cetera.

            And I think a very important feature of how we as FDA, and especially on some of these products respond, is that we do need to continue to seek to recognize deficiencies of our information and data, and to keep an open mind.  Seek new data, pay attention to it, and reassess what we do as things go along, because I think in public policies, the biggest mistakes were made when somebody picks a course.  They've usually made the best decision they can, but then when they construct a construct where changing course and getting new information is difficult, and we try very hard not to do that, and I'll give some examples.

            So what are some unique attributes here?  Biological sources - you can get human and animal diseases; the mechanisms of action are very often quite complex; the predictors of toxicity are even more poorly established than for small molecules where there are still challenges.  The manufacturing processes for many biological -- well, some are becoming better characterized, still for others they're still poorly characterized.  And then there are some uncertainties in terms of emerging infectious disease threats, cutting edge technology.  And one important point is how people react to these things, that these are all products, particularly in cutting  edge technologies, but blood and vaccine have their own emotional dimensions, so there are emotional dimensions to how people view products.  And I don't, at all, discount those. I think how people feel about things is something very important, and you have to evaluate it in that framework; but it's often based on knowledge that maybe is harder to scientifically quantify, but often turns out to have value, but we need to consider it, at least.

            Other things is we have products that are often needed for public health and individual health, so if you are preventing spread of measles in a community, or polio by vaccine, obviously not having that vaccine impacts not just a patient, but a community.  And this gets to this issue of distributive risk and benefit.  And, for example, parents who may never have seen many of these vaccine preventable diseases and what they do to people, may see absolutely no reason to vaccinate their child, particularly if they've heard about a concern about the product.  And we have to deal with that, and recognize that.  And that requires multiple partners, medical care community and the public health community, industry, and our partners in government.

            There's often no substitute product.  And again in drugs, there are situations where this is true.  And you heard even with the COX inhibitors, that there are certain people for whom certain drugs  were viewed by them as lifesaving, or whatever; but we often have that very globally.  You saw what happened with the flu vaccine this last year.  We often have products where there's one or two manufacturers.  There's not a substitute for blood, if there's a blood shortage in the United States at this time.

            Everything seems to have a worse case scenario in these products, and it does keep me up at night.  It's not just that other people worry about it, we worry about it too.  There's a lot of interest.  And then often, as there is in these very charged situations, there's a perceived need or a real need for immediate action at a time when you may not have the data.  So how do we get it, do the best job we can under those circumstances, and what things could we use to improve it?

            One thing I mentioned, we put in a program of risk training.  We have a small risk assessment unit with an expert scientist, Steve Anderson leading it, and have worked collaboratively with a university to put together risk training.  This mentions courses we put on in management, risk assessment, risk communication and message techniques using biologic case studies.  And the idea here is to create a common understanding, and begin to create a common use of these tools across our organization.  We also want people to recognize the limitations of these tools.  It's something that I always give people a hard time about; the uncertainty around our estimates, and how to communicate those honestly. 

            Okay.  Now I'll just, since I was asked to go into some of the activities in each of the product areas. Blood safety, we traditionally say there are five layers of blood safety.  There's really a lot more, but we determine is the donor eligible by taking a history, and by doing then testing if they're still eligible.  If they're not, they wind up on a list which is really a registry that says you can't donate blood.  As I said, they're tested for communicable diseases.  Blood that is found to be from a unsuitable donor is quarantined and taken out of the system, and may be recalled if it's been issued. 

            There is a system, and this fits most with the paradigm of some of the questions that are coming up about drug safety, of investigation of problems and adverse events, and I'll get into that.  And all of these are also connected with anticipating and tracking emerging infectious disease problems.  And people don't realize the complexity, for example, of blood.  Mike mentioned it involves bags, involves filters, a whole host of things that we evaluate in the context of blood safety, as well.

            So what are we doing to try to find improvements in these areas?  In donor eligibility, the questions you ask are a safety issue, so we're working with the blood community to try to improve how we do that, developing a uniform donor history that's used across the industry to improve science-based results, and to improve the sensitivity and efficiency of that.  These things have been successful, so we should celebrate and appreciate our successes.  And I feel this is true in other product areas, too.  There are challenges, but there are also successes.

            Look at this dramatic reduction in the risk of viral disease transmission from blood in the last 20 years, to the point where those numbers are now more like one in two million for Hepatitis-C and HIV, the two most serious blood borne transmissible diseases.  So new technology, regulation, cooperation between the regulated industries, cooperation with FDA and the product developers have led to this.

            I could get my Powerpoint to do it, but I wanted to draw West Nile virus on here also to give an idea, but essentially West Nile virus in 2003 was kind of up in here, and that became the most common viral, and now it is down in here thanks to what has been accomplished, and I'll give those examples.

            Another thing, we cannot do all of this ourselves.  I realize the expectations are high.  This is not an industry which has tons of money and resources.  They would like us to do more.  We try to do what we can, but a lot of what we do is also in partnership.  And this is not exactly a classic safety thing, but as I said, blood isn't a classic drug substance. 

            Here we have worked with the American Association of Blood Banks, which basically represents the United States blood banks and supplies, and put together a task force on domestic disasters and terrorism.  And essentially, this integrates the public and private sectors, the Secretary's office, to be prepared and respond to emergencies, and not just things like what happened at the World Trade Center where we found ourselves all scrambling, but managed to coordinate.  But also, things like Mike mentioned, the white particle problem, so when we see a problem, we bring this right away to the blood community, and they help us collect information, and we work together to identify how to answer the scientific questions.  And try to respond in a calm and rational manner.

            A couple of examples.  A big concern is Mad Cow disease or Variant CJD, and the potential risk to the blood supply.  And this gives an example of how risk assessment and management can change over time, and how no matter what we do, we can always learn from it.

            So in 1999, we initiated donor deferral policies for people who have spent a certain amount of time in the United Kingdom.  And we got push-back on this.  There had been no transmission of classical CJD or Jakob-Creutzfeldt disease through the blood supply, but we got push-back on this.  And it was going to affect some of the supply, but there were scientific concerns.  As opposed to classical CJD, the prions or the presumed infectious particle, and perhaps their symptoms are seen in lymphoid tissue, the scope of the epidemic at the time was unclear.  It appeared to be increasing, and this was a precautionary measure, and it was taken to a level where modeling versus effects on supplies indicated that this could be done in a way to substantially reduce potential risk, while not creating new risk from supply disruption.  Not that this was easy for anyone, including the blood community, because blood is always in short supply.

            At the same time, we said the science does support that this isn't spread by classical CJD, so we removed for that previous agent of concern recall requirements, et cetera.  And we said again, this point of continuing assessment, we will re-evaluate this twice yearly, new scientific data; and the thought was the data would show we didn't have anything to worry about, probably, and you might scale these back. 

            However, in 2001-2 the scope of the epidemic was increasing, and animal studies showed that blood could, in an animal at least, animal model, transmit the disease.  So we actually found ourselves in the position of extending these deferrals to reduce risk further, and to include other geographic areas where the epidemic had spread.  And then in the last year or so, there have been two human transfusion-related cases occurring in the U.K.  And again, we're re-assessing risk for a variety of products, and trying to say what can we do from a more upstream version to reduce use of animal proteins, for example, in recombinant products, et cetera.

            Okay.  And then we're doing a bunch of other things.  As I said, we're going to periodically continue to re-review risk.  We are doing risk assessments for other products we're concerned about, including plasma derivatives.  But what could we do to really prevent this problem, rather than just pull donors out?  And this gets to areas, again, where there are technologies where judicious investments could have significant public health payoffs.  There are filters that may be able to remove prions from blood products, but we need to know how to evaluate them.  And there's going to need to be an honest evaluation of those products, and it's not cheap.  There's like two labs in the world that can handle these agents, two or three labs, and there's very limited capacity. 

            Same for putting together reference panels.  There's possible blood screening tests out there.  It would be wonderful to be able to screen the blood, very important especially for plasma recipients who get frequent transfusions.  And then there are manufacturing issues.  We know that certain manufacturing processes, for example, plasma derivatives, may remove prions and may do so effectively.  And we're working with the industry to identify what those are, and share that information.

            Here's another one I think that's been a success story, and most of you know about, the West Nile in summer of 2002, CDS and us identified that the epidemic was evolving, that there was asymptomatic viremia in patients, and issued an alert to the transfusion centers, and within weeks, the first cases were detected.

            Then we worked with our partners and challenged ourselves in industry to develop and implement screening.  We had a workshop to define pathways.  We tried to provide standards and shared samples, and guidances for donor deferral.  And this was a very successful approach.  Two very capable companies jumped in, used their platform technologies already being used for nucleic acid screening for HIV, et cetera, and filed INDs, and now recently have filed license applications.  But the result is, from 2003 on we were ready the next summer, and over a thousand infected units of blood have been removed since then and not transfused.  And I think this has been a model of both inter-agency and public/private cooperation in getting out ahead of the curve.

            Now I will say again, when we first started getting excited about this, people said why are you so excited about this?  Well, I was excited about it because I knew if it went the way it was going, the next year we were going -- if the epidemic continued, we'd have a major problem.  And that if we didn't get excited, we weren't going to get this accomplished by then.  This typically is a process that takes years.

            Now because of these successes, the risks from transfusion are changing.  So another thing in addition to always revisiting our risk mitigation or our regulatory decisions is revisiting our scientific agenda.  And again, this pertains to a couple of comments Mike Fitzpatrick made.  But you could see here that the risk from things like HIV all the way on the left are in the one in a million now, and now these more mundane, less seemingly dread, but just as bad risks are more common.  It's a rare problem, but mis-transfusion, getting the wrong unit, classic medical error or sometimes lung injury, cardiac injury, et cetera, bacterial contamination is a big one, and these are things that we have to work on.

            And just as an example to face these changing risks - and again, I would say industry was ahead of us on this one - was developing methods to try to detect and work on bacterial contamination. I won't say ahead of us, but they took the ball and moved it, and we had to scramble to find some regulatory ways of doing this.  But this is an example of a win-win regulatory approach, where people were developing rapid methods to detect bacterial contamination of blood.  This occurs mostly because when you take blood from a person and the skin isn't sterile, although some patients are just infected.  And we combined that with the need to have platelets that last longer, something you heard alluded to.  So in 1984, platelets had been allowed to be used seven days after they were collected but there were a lot of disease transmissions occurring and bacterial contamination.  So the ability to have more rapid testing for bacterial contamination, along with validated blood bags that have been shown to store platelets and keep their functionality for a longer time period allowed us to, in a sense, do what's almost a linked approval for use that will allow the duration of blood storage to be increased of platelet storage, but maintain product safety. 

            Okay.  Now more to the analogies, more to the drug situation or post-marketing surveillance.  It's not necessarily the same, but what happens to these products when they're transfused?  One thing we do look at is the performance of the devices used in testing the blood.  Are they performing the way the blood banks expect them to?  That is also a public health issue.  But for blood plasma and the rest of transfusion, we have two major areas, biological product deviation reporting, or BPDRs and required fatalacy and serious event reporting, and I'll tell you a little bit about that.

            Biological product deviation reports are almost analogous to reports of manufacturing problems.  They are required, if it's a deviation or event that could affect the safety, purity, or potency of the product, they have to be reported within 45-days of the discovery.  And there are similar provisions in our new framework for human cells and tissues that I'll get to. 

            Why do we do this?  Well, this kind of can serve as an early warning system for manufacturing problems.  This could be as simple as they did bad typing and released a unit that wasn't properly typed, to other things; such as, we notice clumps of platelets in product.  There wasn't the amount of red cells that there's supposed to be.  These things could indicate problems in a blood bank or in the manufacturing.  And they could lead to serious investigations, and even recalls.

            Surveillances can be trended.  If we normally see that well, 3 percent of stuff has this problem, the hematocrit is below whatever, and then we suddenly start seeing a change, it may tell us that some component in the system is broken.  For example, in 2004, there were about 38,000 such reports; and again, like you heard for the AERS, the medical AERS system, we've been able to make these electronically reportable, which helps everyone, I think.  And we post these.  So this helps direct training, outreach, and guidance, so we can look at what are the problems people are having, are they real problems, how can we prevent them?

            Fatality reports, this is inherently obvious.  If people die after a transfusion and it might be related, we really need to know about it.  And we do preliminary and seven-day follow-up information on all blood-related fatalities, whether it's believe caused or not.  We may send investigators to the site in many of these cases to be sure we're hearing the events properly, particularly if there were any issues raised by the reports.  And again, this is data very important to look at for trends and priorities.  And I've just given you an example of what are the related fatalities we see.

            Non-fatal adverse, serious adverse events are handled a little differently.  They're reviewed during establishment inspections at least every two years, but we have proposed a rule where they would be required to be reported in real time to provide us more information.  So that's an example of one of the enhancements we're talking about.  But as I said, we don't want to make it too burdensome either.

            Current priorities then are based on what I showed you, the changing epidemiology, which only our surveillance can tell us; so donor mismatch, bacterial contamination, TRALI which is a lung injury associated with transfusion, the emerging infectious disease issues, and I think some very good kind of critical path issues, areas where there's tremendous benefits that could occur, where our scientific infrastructure or others are collaboration supported, inactivation technologies, and particularly candidate tests and evaluation for TSEs.

            Now I'll have to pick up the pace.  Now on vaccines, this is done as a safety group collaboration between the Office of Vaccines, that's OVRR reviewers that exists already at the time of licensing with the post-marketing surveillance group.  What are the studies that are needed, what should be the pharmico vigilance plans? 

            The adverse events come in through a system like AERS, called VAERS, Vaccine Adverse Event Reporting Systems.  It's co-managed by FDA and CDC, so again we have a big partner here.  It adds some resources, it adds some complexity, but we work very well together with them on vaccine issues.  Cases are reviewed, case series can be constructed.  This is electronic reporting. 

            More modern systems are being increasingly used.  That is a passive reporting system, but there's a lot of reports.  Vaccine to safety data link is sort of like Paul and Steve were describing with some of the healthcare database systems.  We can ask specific questions in large managed care plans to look at hypotheses.  None of these are yet at the point of providing real time active surveillance data, but they're examples where people said although a vaccine causes arthritis, measles causes autoimmune disease, vaccines cause diabetes, and where controlled studies using these databases were able to examine those issues and were negative.  And there's an ongoing study about thimerosal in neurodevelopment. 

            CDC has the lead with the vaccine safety database but we worked closely with them there.  And CDC has clinical immunization assessment centers, and we also have pilots with CMS and with other healthcare databases on a variety of issues; for example, influenza vaccine and Guillain-Barre syndrome.

            We review these reports.  All licensed vaccines are assigned to a specific reviewer in the Division of Epidemiology Vaccine Safety Branch.  Fifteen-day and direct reports are forwarded by a contractor within a business day.  They are reviewed daily for unexpected events.  They're followed up, if needed, with the reporters, and there's a weekly meeting of this team to discuss the events, and periodic summaries of safety information are constructed.

            Qualitatively, this is to look for, detect signals and unexpected adverse events.  Of course, signals detected through this kind of passive reporting almost always require confirmation through a controlled study.

            More quantitative methods are applied to these databases, reporting rates versus background rates.  Data mining is now being routinely applied to our VAERS system to identify events that appear to be reported more commonly for one product than another, for example.  And there have been some things retrospectively, we could detect rotavirus into susception in this manner, and prospectively, we've detected allergic reactions with the typhoid vaccine.

Of course, these don't account for a variety of things, and medical judgment and follow-up is needed.  And based on time, I'll leave the obvious alone there.

            There are some challenges here.  Very low incidence of most serious vaccine adverse events and very few unvaccinated children to serve as controls.  Poor understanding - again, this is a recurrent theme from drugs, with the normal population incidences of diseases - did something cause, is two cases of lupus in a million vaccinated people out of line?  Reliance on passive surveillance.  And we do need resources and tools for more advanced approaches.  And then in this area particularly, political, cultural and communication issues.

            Our strengths are strong physician epidemiology staff.  These inter-relations, the collaborations, and that we can still use this passive surveillance to identify problems through careful review.  We can do safety reviews of new vaccines, and these are communicated to physicians in peer review journals, and we can do focus reviews of special issues.

            Here's a famous example, rotavirus, nearly a million deaths in developing countries, far fewer in the U.S.  Pre-licensure clinical trials show the vaccine was very effective.  Ten thousand vaccinees, two out of eight thousand receiving the vaccine, and one out of four thousand receiving placebo got this effect.  It is not obviously statistically significant; however, there was some concern about this.  And when the vaccine was licensed, we decided to include this in the label and require this to be evaluated in the post-marketing period.  There were studies required for a variety of reasons, but then we also coded into the VAERS system, intussusception as a specific term, so that if something happened, we would be liable to detect it quickly.  And bingo, that's what happened in May, very soon afterwards, a VAERS signal was detected.  Six cases, went up to nine, by July fifteen cases, eleven in the first week after vaccination.

            Now interestingly, if you looked at expected ratios based on known population incidence, and here we had some reasonable estimates - this wasn't higher.  In fact, it was lower.  But we don't expect 100 percent reporting, and so this raised a lot of concerns.  And to make a long story short, studies were set into motion, verified that this was a probably a true signal, and within a very few months the vaccine was first temporarily suspended as used, and then withdrawn.

            Another example of more pre-emptive action that I think is more related is related to a safety concern, but also related to public confidence in vaccines, thimerosal and mercurial preservative in multi-dose vials of vaccines.  A review was undertaken because of growing concerns about mercury as a neurotoxin, and this showed that some infants could exceed some recommended exposure when there's no direct evidence of harm, but a desire to reduce total mercury exposure. I mentioned the importance of confidence in vaccines, but on the other hand, if we had suddenly said we could not transition to a thimerosal-free vaccine supply overnight without causing disruption of vaccine availability, and probably epidemics of transmissible disease.  So what was done is the PHS got together, FDA contacted manufacturers stating that we had a goal to work with them to reduce thimerosal in vaccines as a precautionary measure.  We had a public workshop.  We expedited approval of new formulations without thimerosal, Institute of Medicine looked at this and concurred.  And the accomplishment is now that all current routinely recommended childhood vaccines are available in thimerosal-free or reduced formulation.  The science has still largely continued to be negative about this, but epidemiologic studies are ongoing.

            Okay.  Now to try to finish off with tissues, and then some conclusions.  IN fairness, to give me a little time, and I was asked to cover three areas in one talk, but the tissue safety - there's an increasing number and diversity of procedures.  People are shocked, I was shocked when I came to CBER and figured this out, but there are now over a million tissue transplants a year in the United States.  These are not the sexy liver transplants, these are tendons, muscle, skin for burns.  Some of these are elective processes, like plastic surgery, et cetera, et cetera.  But there were some cases of serious infection transmission in the last few years.  This led to a lot of attention, and a lot of people in our center working with a lot of other people put together a new risk-based tissue safety framework.  This requires establishments making these tissues to register and list with FDA.  It requires comprehensive donor eligibility screening and testing.  These are usually cadaveric donors similar in quality to what's done in the blood system.  It was much more limited before.  And a set of core good manufacturing practices, called Good Tissue Practices, to try to assure that measures to reduce contamination are in place in processing facilities.  And gets us adverse event reports which you can analyze, active surveillance is an alternate goal, and there's a lot of training, et cetera, done with this.

            Now one of the things we had an opportunity to do here is to do business a little differently and to say starting from the front of a safety system, how do you visualize this?  Now I have to say that is also under some real resource constraints.  But we formed a team, saying we're not going to silo this into different parts of the organization, compliance over here, communication over here, the product experts over here, the epidemiologists over here.  So we put them all together, this Alphabet Soup, and formed a safety team, and they've developed operating procedures to be sure we properly receive evaluated adverse reports, go out to the facilities if we need to, have databases which everyone has access to and can contribute to, and then liaison with our appropriate organizations; for example, CDS is involved in laboratory testing and field investigation, and helps us interact with the states, and there's many other components here.

            Here's an example we recently had a possible transmission of streptococcus through tissue alografts. Sounded good, a lot of concerns; three recipients with knee infections following transplants, all of the same bacteria, all from the same tissue bank, got CDC involved, got the State Department of Health out there to investigate, got our staff physician epidemiologist to make calls, get more historical information, conducted a directed facility inspection, Department of Health aided us on the epidemiologic investigation, CDC performed the cultures of retained tissues from these donors from the original samples, all of which were negative.  And the epidemiologic investigation showed other hypotheses for what could have happened.  And this was all done very quickly within days, and in this case was a negative study.

            I think based on time I'll try to just zip through this.  There are strengths of this which are obvious in what I just said, but there are also challenges.  There's a lot of education and outreach to do.  There's a lot of issues about workload.  There's hundreds of new establishments coming under at a time when our inspection resources are challenged.  We'd like for drugs and other products to have more active surveillance.  There is no reason that if we build an active surveillance system for medical products, that something like tissues would not be captured well under that.

            This is also an area which has been a little bit of an area not paid attention to by medicine or medical science.  And we need to look at what's happening out there now that we're going to get all this experience, and learn from it, and say are we doing this right?  What are the scientific needs? Can we sterilize tissues?  All kinds of nice things we could do here.

            We're doing a pilot with CDRH.  Again, this issue of when we have not enough resource - CDRH has an interesting active surveillance system, very labor-intensive called MedSUN, where they have people running around the hospital saying have you seen an adverse event from this or that?  And so they've agreed to work with us and do one at several of their programs, I think actually at all of them, to include tissue adverse events.  And this will help us a snapshot of what's going on with tissue transplantation, and identify causes of problems.

            Okay.  So to conclude, assuring the safety of vaccines, blood, and tissues, and I didn't get into our cell and gene therapy area, provides for pretty unique scientific and public health challenges, but there's also many common underlying principles and needs with the other medical products.  There's some differences and some commonalities.

            Stressing some of the commonalities, we need automated methods to screen databases for potential concerns.  And as I said, we're now doing that routinely with our passive vaccine adverse event reporting system.  We're doing the data mining, but there's a lot more that could be done, and it could be done better.  Increased availability and use of computerized healthcare databases - this is the holy grail.  It's really the healthcare system where much of that challenge lies, and the tremendous amount of resources that it takes to do that, and do it right, and my point before about infrastructure not only to get the data, but to interpret it, we all discussed.  It's a lot easier said than done, and I don't know why -- IT, why does it cost -- you can buy a Dell computer for $400, but if you want anything done in IT, how many more zeros do you have to put on that?  I wonder about it.  I often say I should get the kid who's calling me on the phone to just write the programs, and we'll be done with it - pay him twenty bucks an hour and he'll be very happy.

            We have new programs in science-based risk assessment, management, and communication, as I said, to help inform policy and the public.  We're implementing those, but again, that's resource-intensive to train your people, and to keep training them is something we need to keep doing to get the right outside connections. 

            We need a better science base.  That was emphasized in one of the comments for product safety and quality, including all the sciences, population, laboratory, manufacturing.  And again, I look on this as not deficiency, necessarily, but opportunity. 

            Our current systems and organizational interactions I think have generally functioned well in these areas, especially considering the terrible challenges we face, but I'm not sanguine about that.  They could be better, and they are at or beyond capacity.  Our people are working hard and burning the candles.  And we are also largely operating on 20th century technologies.  Now it's not because we're stupid, it's because those technologies work.  They work, they do what they can, and there have been a lot of successes.  But we need to be both doing what we do now, and looking forward, and building the future. 

            Meanwhile, the responsibilities and expectations are increasing; some very clear reasons - new industries, novel products, high information and safety expectations.  It's no longer enough to put information on the shelf and not share it, or not pay attention to it.  Demand for rapid access to promising technologies - everybody wants those technologies.

            One of the comments from America's Blood Centers was about, for example, a particular product.  Well, so there's a demand for access to new technologies.  On the other hand, we're here today because there's also a demand that FDA make sure these things be safe and work, and we cannot forget that. I still do view us as the gold standard globally for regulatory agencies, and we want to keep it that way.  So new approaches are needed, and while such innovation is underway, they require serious planning and long-term collaborative investments in multiple areas, the science, the methods, the training, and the implementation. 

            So I think FDA could play a constructive role.  It cannot do all of this, or even most of it in patient protection and innovation.  We need to have vigorous, yet thoughtful and collaborative approaches.  They can help innovative products with the appropriate risk benefit ratios come to market, and keep our public health measures particularly safe and available. 

            I think, as I've said, for products such as blood, vaccines, tissues, and cell and gene therapies, expectations are high, but innovation is very sensitive to both the risks and the costs, as I pointed out before.  IT and modern biological and physical sciences should be used to try to move this forward, and can be more efficient if we make the right kind of investments.  They can also be hopelessly inefficient if we make the wrong kinds of investments.

            And we need to develop best practices and tools, and share them across both the FDA and with industry, and the public.  And throughout all this, I still think whenever I see a problem, FDA has very complex product development, but I would say 90 percent of problems are communication issues, and that occurs whether it's within our agency or outside our agency.  And that's a very important part of the culture we need to keep building, so we'll try to keep Humpty-Dumpty together.  Thanks.

            CHAIRMAN SHINE:  Thank you, Dr. Goodman.  Questions from the committee?  Dr. Thomas.

            DR. THOMAS:  I've got a question.  How much -- with the reemergence of zoonotic diseases, how much research is being placed on them, whether it's at NIH or elsewhere?  You've had some interagency cooperation, but I don't see new technologies such as tissue culture, for example, in vaccine production.  We're still using the chicken egg.

            DR. GOODMAN:  So are we.  Yes, it's a very good question and a number of -- I serve on a similar committee that you're on with the CDC, their Board of Scientific Counselors of the National Center of Infectious Disease.

            And we have had sessions and we've also had sessions at the IOM in our forum on emerging infections highlighting the link between human and animal health and emerging infectious diseases.  So I think there's a lot more recognition than there was five years ago, but I don't think there's the kind of integration that I would like to see or the kind of support I would like to see. 

            I'm a tremendous believer in the value of veterinary medicine.  Steve's not there.  He would be nodding -- in informing medicine, in general, but I also think to monitor -- the pandemic flu threat is there's no more perfect example of that.  And I will say, NIH, for example, is putting a lot of funding into surveillance of avian influenza in Southeast Asia.  So the short answer is progress is being made, but this is way under-supported because again, there aren't economic drivers in terms of the products.

            CHAIRMAN SHINE:  DHS has established a center of excellence in zoonotic diseases that involves --

            DR. GOODMAN:  Excellent. 

            CHAIRMAN SHINE:  Have you been involved in that activity at all?  Do you have interactions with DHS on such activities?

            DR. GOODMAN:  I personally have not.  I would hope that at least they made the connect with CDC and USDA.  FDA should probably be involved.  Something that people often don't realize is actually the veterinary drugs are handled through Steve Sundlof's center, the Center for Veterinary Medicine at FDA.

            Veterinary vaccines are regulated at USDA which is an interesting situation.  But we -- so I don't -- I had not heard of that committee.  It's a good thing if they have it, but I'll try to find out about FDA participation.

            CHAIRMAN SHINE:  Other questions?  We heard from Dr. Fitzpatrick two major concerns.  One was whether CBER has the basic science expertise that it needs in order to do the investigations that are required.  And the second was that some of the safety enhancements which he mentioned, PRISM, are unavailable because of quote in his letter "insurmountable roadblocks at FDA."

            Do you have any comments about either of these in terms of your view of the resources that you have and the necessity to deal with these issues?

            DR. GOODMAN:  I think that supporting a strong science infrastructure at FDA under our current resource situation is extremely challenging.  And we are all doing what we can.

            So I would say I would love to be able to do a whole lot more.  We do have to view that number one of our responsibilities is the review and regulatory process and so we have to keep that perspective.  But myself as somebody who was in a sense a clinician/scientist in academic medicine, I very much believe in the model of having scientists and scientific expertise at FDA and with involvement and interaction with the review process and I think the critical path is an effort to help support that, but there are definitely resource challenges.

            Now taking that at the same, I don't think FDA is the NIH or that we can have expertise in-house in every conceivable subject and area.  So to some extent, it is not negative to collaborate, bring in and consult outside people, but there are certain areas where our expertise or where no one else is going to drive it, or our impartiality are essential and I think those are where the real opportunities are.

            CHAIRMAN SHINE:  So do you believe that there are limitations on your basic science infrastructure that inhibits your capacity to perform your function ensuring safety?

            DR. GOODMAN:  I think that there are -- I want to rephrase that a little bit, that there is a lot more things that one could do to support our scientists and support the breadth of expertise, if we were able.

            On the other hand, I feel that when we are confronted with issues where we do not have -- there's two important components.  One, you don't have -- we're talking about very specific things here like something about platelet function or something like that.  And I'm saying in those instances, what's really important is to know what expertise you need and be sure you avail yourself of it.

            And frankly, even if we had the scientific expert or somebody who was viewed as an expert in one particular area, I think even then we want to take their knowledge and expertise and not say that's it, guys, that's all we're going to hear.  But again, we're going to reach out and if it's an important decision and get other input.  But that's a long answer, but yes, I do think our resources in science are very strained.  Our ability to support that is strained.  But frankly, at the FDA now everybody is working very hard.  That's true of our full-time reviewers as well.  And I think we're doing a good job at a very, very challenging set of issues that we will never get perfect because one, it's impossible; and two, because one person or another will not like the answer or decision that we make.

            And I want to back to the issue about the technology you asked about --

            CHAIRMAN SHINE:  We're going to have to move on.

            DR. GOODMAN:  Okay, but you did ask the question about products.

            CHAIRMAN SHINE:  Yes.

            DR. GOODMAN:  And being held up and what I would like to say is again, that was my earlier statement that our job is to make sure before a product is licensed in this country that it is safe and effective and can be manufactured and that's what's expected of us and we are the only people doing that job.

            And I do want to say we meet with the blood industry extremely extensively.  We have regular meetings with American Association of Blood Banks.  And in the last two years, we've really increased those outreach measures tremendously.  We also are having our Blood Products Advisory Committee review the priorities of -- in that area, both scientifically and regulatorily, so we do seek the kind of input that I know people want to give us.

            CHAIRMAN SHINE:  I would emphasize a point that you made and that is that much of the surveillance activity which is likely to go on in drugs is applicable to biologics and devices and a variety of other things and I hope that you continue to work closely together as in FDA as you move forward with those experiments on reporting on the electronic health record, whatever, to make sure that we maximize those signatures.

            DR. GOODMAN:  No, absolutely, and we're doing that with CDC in both the blood and vaccine areas too.

            CHAIRMAN SHINE:  I think we better move on.  Let's hear finally from Dr. Mary Malarkey who is Director of the Office of Compliance and Biologics Quality.

            DR. MALARKEY:  Good afternoon.  I appreciate this opportunity to kind of deviate from the subject matter somewhat this afternoon and concentrate really on current good manufacturing practice, specifically for our vaccine products.  And I say deviate slightly because certainly the safety of vaccines is affected by or the continued safety of vaccines is affected by manufacturers' adherence to what we call good manufacturing practice.  And I'm just doing vaccines, by the way.

            So in summary, I'd like to touch a little bit on what the rules are, that is, what statutes and I say there are more than one here, and regulations that govern the manufacture and review of manufacture of our vaccine products.  And the unique challenges that we face with vaccines.  Blood and tissues do pose challenges, but vaccines have challenges of their own.

            I'd also like to talk a little bit about the problems that we've observed in the industry and I think you'll see that they're not unique to the vaccine industry which is why the pharmaceutical GMPs for the 21st Century initiative that we just completed the two-year assessment phase, I would say, is very applicable to the vaccine industry and there are things that we had in place at CBER that came out of the initiative for other pharmaceutical and animal drugs, but then there were other things that came out that we think will help the vaccine industry and we're interested in working with them going forward to see if there's more guidance that we can provide.

            There's also no question that we've had some recent lessons.  I think Dr. Galson mentioned this morning about the pendulum swinging and the press and how things can change with public perception.  In the compliance and enforcement area, sometimes I think that pendulum is more like a metronome.  On any given day, we can be told that we're too hard on the industry, that we need to make products more available, that we're inhibiting availability, but then on the very next day, we're told that we're not being hard enough.  so it is a challenge and a delicate balance.  So we'll talk a little bit about these recent lessons and other initiatives.

            Now first of all, vaccines, of course, are biological products and they were the first biological products that were recognized.  They are defined in the Public Health Service Act under Section 351(i).  However, vaccines are also drug products and they are defined as drugs under the Federal Food, Drug, and Cosmetic Act.  So there are the two statutes that govern -- well, actually the review of licensure manufacturer vaccines.  And vaccines, like other biologics, are licensed products and they're licensed after submission, review and that includes an inspection and approval of a biologics license application and you've heard BLA mentioned this morning and that's where that comes from.  It's actually a Public Health Service Act application as opposed to a Federal Food, Drug and Cosmetic Act application. 

            So technically speaking, vaccines are licensed biological drugs.  And like other pharmaceutical drugs, they are investigated with the same, under the same IND provisions, that is, parts 312 and 50 and preparation of vaccine products, like human and animal drugs are regulated under the GMP regulations that we're all familiar with under 21 CFR Parts 210 and 211.  And of course, these are the drug GMPs and these are the ones that were subject to our two-year initiative.

            Now we also have additional standards for vaccines.  These are, of course, the licensing standards and other testing and biological standards that are contained in Parts 600 to 680.

            Okay, that's enough of the regulations themselves, but I think it is important to note what vaccines are and again, they are drug products, but they are unique in that they're licensed and they are held to other standards.  They're also unique challenges, I think for both FDA and the industry, with respect to vaccines.  I won't get into the economic challenges and they are there.

            There is certainly the supply and demand and supply is a function of demand and it's often a problem.  But getting to the unique challenges that we face in our regulation of vaccines, unlike a substantial number of injectable pharmaceuticals, vaccines are administered to a large population of patients that are most often young and healthy.  In fact, they're mostly babies.  Most vaccines are, of course, childhood vaccines.  An exception, of course, is flu vaccine, which of course, the elderly would be considered the high risk population, although younger people are as well.  However, by and large, these are given to young and healthy people.

            The starting materials themselves may have inherent problems, such as inherent bioburden, that is, certain number of microorganisms that would be expected to come in with the starting material.  These egg-based vaccines which were mentioned quite recently are one of those types of vaccines that would be subject to problems with bioburden.

            Some vaccines are infectious until they're inactivated, so their manufacture can be a tricky operation.  And examples of these are many of our bacterial vaccines.

            This is, I think, a very important point.  From beginning to end, the manufacturing process, that is, to get one lot of vaccine product, can take several months, up to a year, so if something goes wrong along the way, you can well imagine what the impact would be.  We're talking here about delays or potential shortages and for those reasons I'll get to later, it is very, very important for adherence to certain standards and controls.  And of course, in some cases, given that these are very old products, many were licensed before we had modern thinking, modern standard, even our GMP regulations.  So that's a challenge.

            As with other biological products that we regulate, these products must be processed from beginning to end and again, we're talking about up to a year process now, under very defined conditions and controls.  Now this is an absolute must consistently produce a safe, pure and potent product and again to preclude the introduction of environmental contamination because these products are protein-based.  They are a nice growth media for a number of adventitious agents.

            And also because of that fact, they cannot withstand heat sterilization without affecting product quality.  This means we can't cook them at the end.  We can't sterilize them at the end in such a way to really ensure their sterility.  This is why these controls along the way are so very, very important.  They must be aseptically processed and I'll get back to that in a second for those of you who weren't familiar with that, but it is a different thing than terminal sterilization and it does provide a level of assurance of sterility, but certainly not the level that one could attain by terminal sterilization.

            Now some of the controls that we're talking about here and this is just an example of the types of things that we are looking for and that we are looking for more and more over let's say the last five or 10 years.  Bioburden testing, that is testing of the product at various points throughout the manufacturing process to show what the levels are.  There are certain steps in a process that should make the levels go down, for example, and there are other steps that you might see a concentration effect, but that should be consistent and at the end, you should be able to get rid of obviously the bioburden.

            Segregation of pre- and post-inactivation steps, this is to ensure that once activated, you're not going to have live infectious material within the product. 

            Cleaning of facilities and equipment using procedures shown to be effective for both removal of product residue as well as again that microbiological or what we call bioburden.

            And finally, monitoring the manufacturing environment itself to continuously assess conditions.  So all these things are GMP controls that are put into place during the manufacture of the vaccine and all these things should be in place in order to help ensure safety.

            Getting back to aseptic processing, what it basically is that product is filter sterilized at some point during the manufacturing process.  And basically, after that point that is the point of sterilization.  So everything that goes after that must be very, very carefully controlled and for vaccines, this may be very early in the manufacturing process.

            Once conjugated to an adjuvant, which is often an aluminum compound, sterile filtration is no longer possible because it would actually remove the product, so again, you have often this filter sterilization step early on and from that point, subsequent steps must be carefully controlled to ensure the safety of the product or to preclude the introduction of contaminants.  And this is a tricky matter and there are a lot of drug products that are produced in this fashion as well, but again, this makes it much more important for us to be concerned about controls.

            Certainly, all materials that contact the product after the step must be sterile and there's careful adherence to aseptic technique and practice by personnel and believe me, people are unpredictable and I think it's very true what they say that they can be one of the main causes of contamination of products in some cases.

            Now what problems have we seen in the industry?  Well, I think they very much mirror what I just went over which are the things that are important to have in place.  Often we haven't seen defined conditions or controls and this is often for the older products.  Now if you only test a product to point A and then again at point Z, and you fail at point Z, and you have no data points to look at between A and Z, you're in trouble.  You don't know what happened and if that happens a year into your process, then you're in really big trouble.  So it is important again to have these procedures in place and to be able to investigate if there is a problem.

            We have seen issues with segregation of pre- and post-inactivation steps.  That could be a serious safety concern.  And we have actually seen cross contamination, either contamination from the facility or from the equipment as a result of poor cleaning practices.  So that is a real concern.  It's not just something that we're saying is a good idea.

            We've seen environmental monitoring data collected vigorously, but not really looked at, that is, it's not evaluated and we particularly have seen where the actual organisms is in the product as well, and yet there's no connection made.

            And finally, inadequacies in the aseptic processing that I spoke about, the validation of such processes must simulate all the steps that are involved and basically what happens is media of bacterial growth media is substituted for the product, it's taken through all the steps and incubated and if it froze, that's a bad sign.  But obviously, that's got to mimic the manufacturing process.  And then again, poor aseptic technique by operators are often observed during operations. 

            Now many of these observed problems, the bottom line here is we're talking about what we call quality systems.  And these, as I said, are not atypical.  These are the same problems that we see in the pharmaceutical industry as a whole.  And we talked a lot about these problems during the two-year GMP Initiative.  As part of the steering committee, I can assure you that was a very, very big point that was made.

            And the key points to a quality system and this is just two key points, but I think very, very important ones and ones that we see over and over again in our consent decrees, for example, are management involvement.  Management is not involved at all levels and is not responsible and what happens is when problems occur, no one hears about them and they just continue to occur.

            Often we don't see adequate systems for identifying problems and correcting them to prevent their recurrence and it's very much like a snowball effect.  If you don't find out why a problem occurred and correct it, then it's going to come back and it's going to come back bigger and that has been seen time and time again.

            Also, one of the key points of a quality system is to have a system proactively identifying trends to prevent problems from occurring in the first place and these things, again, this is not just related to vaccines, but across the industry we've seen this as an issue. 

            And again, we talked about this for two years and I think we're going to be talking about it for a while longer in terms of implementation.  I did want to point out that CBER was a member.  I believe that the Board here has heard before of the Pharmaceutical GMP Initiative for the 21st Century, a risk-based approach.  We were involved in that initiative.  I want to point out that it wasn't just a risk-based, but a science-based initiative and for those of you who may be scholars or become scholars of the GMPs, if you read them carefully, you'll see that they really are science-based.  But they need to be updated like everything else.

            Now we had many working groups that came out of the GMP initiative and I have to be honest that for some of our procedures already in place at CBER, we had these things and we were happy to inform the other centers and ORA of our procedures and we'll continue to do so and we will continue to be a member of the Council on Pharmaceutical Quality which is now the body charged with going forward with implementation of what came out of the two-year initiative.

            What was already in place at CBER?  Well, we've had an integrated review and inspection process for some time.  What this means is our Biological License Application Review Committee consists of members, in this case, from our Office of Vaccines, but also from our Division of Manufacturing and Product Quality and my Office of Compliance, members from the Office of Biostatistics and Epidemiology and other CBER components as needed.  And we've also had consult reviews, of course, from our other centers, depending on the product type.

            Now these same components participate in all the meetings that are held with the regulated industry from the pre-IND stage to after the BLA is approved.  And we provide advice and guidance on all aspects, CMC facility, GMP compliance, in addition to the clinical aspects of an IND.

            We perform what we call pre-license inspections as opposed to pre-approval inspections, because under the Public Health Service Act, when a product is approved, a license is issued.  And again, we perform these inspections with a CBER lead.  That is, we have again, the DMPQ lead inspector.  We have a product reviewer or scientist that accompanies us on the inspection and actually looks at the manufacturing process and the data that come from the process and we invite always the Office of Regulatory Affairs to participate and welcome their participation when they can.

            We also resolve issues prior to the approval of the application and that's a somewhat different paradigm than is seen elsewhere and I have to say that we have a very small inventory of products compared to our sister centers, so we are able to, I think, do this, but again, some of these principles have been adopted under the Pharmaceutical GMP Initiative.  One is the pharmaceutical inspectorate and the other is having the product specialists participate during the pre-approval inspections.

            We have the same paradigm here for our pre-approval inspections for supplements, so for example, new facilities or renovated facilities.  And I think most people have heard of the Team Biologics Program which was established in 1997 and again the pharmaceutical inspectorate in many ways will be similar to this team.

            They began our vaccine post-approval inspections in 1999.  They are a highly specialized team of ORA investigators and we find that particularly in the area of vaccine production which is so complex, having the product specialists and scientists available during these inspections is absolutely essential.  The knowledge base is there and it's just really been helpful in conducting these inspections.

            Now as with any other program we recognize improvements must be made.  We've done an evaluation and we're putting many such improvements in place.  We are implementing a quality system internally which is always a good thing.  We expect that of industry.  We should have one ourselves.  And this will ensure continuous feedback to the investigations and compliance officers.

            And then we've established regular communications between investigators and the product specialists outside of inspections, that is, we have a monthly call and we have other training programs so that there's a continuous training process in place.

            It's also important to note that all Team Biologics findings are reviewed back at CBER.  We don't do an exhaustive review of each and every one, but we do look at the findings and the reports.  If there is an action that is recommended, on the other hand, we do a complete evidentiary as well as a scientific review and of course, if we agree, we send it to our Office of General Counsel as with all of our warning letters and actions today for their review.  So any action that is taken against the industry, whether it's vaccines, blood, tissue and otherwise, has levels of review before such action is taken.  So everything is weighed.

            Now again, getting back to the quality systems, we recognize this as a big issue in the GMP Steering Committee and we had several work products that came out.  Again, I wont mention one which are more the internal quality systems, but an extremely important one.  And I guess one could say it would impact on the vaccine and all of our industries for us to have a quality system in place, but I won't go there.

            Specific to impacting on the industry themselves were two particular documents that are in your briefing packet that you may be familiar with at least one of them and one is the final Guidance Document on Sterile Drug Products Produced by Aseptic Processing.  And again, given that vaccines are all aseptically processed and often aseptically processed from early in the manufacturing process, this document actually has recommendations for manufacturers, even those that start this early on.

            And then the Draft Guidance for Industry on Quality Systems Approaches to Pharmaceutical GMP provides the Agency's current thinking on these quality system principles that I mentioned, and right now, the working group is still working and reviewing comments to the docket.  And we intend to issue a final guidance and actually use the comments that we get from the industry to inform us on other parts of the initiative.

            And one of those that's near and dear to my heart is we actually -- this was the GMP Harmonization Analysis Working Group.  I have been honored being co-chair and we were charged with actually formally analyzing Parts 210 and 211 against a variety of other regulations including the EU GMPs, the pharmaceutical inspector cooperation scheme GMPs and other GMP regulations across the Agency.  The intent here, of course, was to highlight the differences of the various regulations and report back possible recommendations to the steering committee for modifications to our GMPs which I will add, have been in place since 1978.  So it's certainly high time to take a look and see what we can do.

            Now we had involvement across the board here and my co-chair was actually Kim Trautman from the Center for Devices.  So all the centers were involved and our Office of Combination Products and Office of Regulatory Affairs were as well.  And this project took about a year.  It was really a very large project where we can compare the drug GMPs to the food GMPs, what is called HACCP, which is Hazard Analysis Critical Control Points.  The device GMPs were the quality system regulations and Type A medicated articles, as well as, of course the EU GMPs.

            Now after this analysis, what did we conclude?  Well, the good news is there really are more similarities than differences between the various regulations.  Differences were often commodity-related.  It's not a surprise, certainly, for example, sanitation and personnel practices in the food area would be an expectation.  We presented our final results to the steering committee in June 2004 and some next steps were decided on by the steering committee.  And basically, we agree that modifications to the drug GMPs and Parts 210 and 211 will be undertaken using an incremental approach.  And we'll continue pursuit of international harmonization through the ICH and PIC/S processes.

            What are our goals?  We need to know why we want to do these modifications because they will take some time, I have to be honest.  I think that point was made earlier by Dr. Woodcock, maybe five years.  To encourage timely detection and response to emerging defects or indications that product quality has been compromised.  It's important to note that there are many of these principles in our GMPs today, but there does need to be, I would say, a beefing up or a modernization of those concepts.  And we also need to provide further clarity in addition to this modernization.

            We also, of course, would like to harmonize various aspects of the drug GMPs, both internationally and with other agency regulations as much as possible. 

            And on the note of harmonization, in September, we also announced that we will apply to this pharmaceutical inspection cooperation scheme and for those of you who aren't familiar with this, it is an interesting organization and that its membership consists of inspectors and investigators from around the world, unlike ICH which is an industry and regulator-based organization.  This is only regulators and specifically investigators.  So it's a very good opportunity for us to discuss approaches, to obtain information, exchange information and to harmonize where possible.

            And we've been active in this organization for a number of years in the blood area, so we would love to see this expand to vaccines, because we think this would be important and perhaps even to tissues down the road.

            Getting to those painful recently lessons, frankly, it has been a difficult year in the vaccine area and particularly in the flu vaccine area.  Now typically, we're able to have inspections of our biological drug manufacturers performed every two years and this is in keeping with our statutory requirement and again, we are fortunate here, but we have a very small inventory that allows this to be accomplished.

            However, given the importance of these products and the complexity, starting this year for influenza vaccine manufacturers, we began annual inspections.  Now keep in mind that the influenza vaccine really is a new product every year.  There's always some change in strain in the three strains that go into the vaccine.  So it's a particular challenge and there can be great variation in growth characteristics and potency, so it's always a surprise every year and there are often issues.

            We are also actively analyzing other manufacturers to consider increased coverage, particularly of medically-necessary products and products that may be produced offshore.

            Another lesson that we learned is the importance of partnering with foreign regulators, our foreign regulatory counterparts and sharing of information.  Certainly, the Chiron experience drove that home.

            After that, we were able to establish an agreement with Chiron and with the British Medicines and Healthcare Products Regulatory Agency, MHRA, that allowed sharing specifically in the Chiron case, so we were allowed for exchange of information.  Well, that was very good, but what's much better is that in February we signed, we and MHRA, signed a general formal confidentiality agreement that will allow sharing in all cases going forward.  So this is a very important milestone.

            We also have agreements in place with other regulatory counterparts in countries where vaccines are or may be manufactured for U.S. use in the future.  An example of this would be Health Canada or the EMEA.  And we are actively pursuing other agreements to facilitate sharing of information, specifically on vaccines now, but I'm sure that will branch out to other product areas as well.

            And finally, outreach to the vaccine industry.  And this is something that we have been doing, but obviously, we feel we need to do more, both pre- and post-approval.  We have been in discussion with the industry with some representatives of a possible workshop or a roundtable approach, maybe  more regular scheduled meetings that we would have with the industry.  We're very interested to know what they think of the guidance documents that have come out under the initiative and whether they feel that the Agency can provide additional guidance in this area.

            We have planned some sessions specifically on vaccines at several conferences that are going to be coming up this year and in the next fiscal year.  Some examples of that are the annual GMP by the Sea which is in August of 2005 and then we have a European conference planned on vaccines in the next fiscal year which October technically is.

            Also meeting with the individual manufacturers, again, we've been doing this, but this become even more and more important.  We want to discuss new technologies and other changes, increasing capacity is always an issue here, particularly with thoughts of a pandemic, for example.  And manufacturing control could always be increased through these new technologies as well.

            We also are happy to provide advice on potential pathways to approval and to facilitate approval of new vaccines whenever possible.  Again, we don't have a lot of suppliers here so this is something that we're very interested in. 

            So in conclusion, just like other drug products, manufacturers of vaccines are required to follow what we would all call the drug GMP regulations.  However, we feel that vaccines pose a unique challenge both to the FDA and the industry.  I think we've issued some useful guidance that will help the vaccine industry, but certainly we're interested in doing more, if we can.

            After the lessons of the last year our approach to regulation has been reviewed carefully and modified somewhat based on these lessons, for example, the increased inspections.  And partnering with our foreign regulatory counterparts I think is key, not only really in this industry, but we have such a global industry today with so many of our products that this becomes increasingly important and increased outreach is always important to the vaccine industry.  We want to increase communication and we want to facilitate improvements and approvals of new products.

            So I thank you very much and I'd be happy to answer any questions in this particular area.

            CHAIRMAN SHINE:  Thank you, Ms. Malarkey.  Questions from members of the Committee?

            Yes, Dr. Harlander?

            DR. HARLANDER:  Will the IOM study be focused on vaccines as well as on drugs, in general?

            DR. MALARKEY:  My understanding of the current study is no, it will not be focused on vaccines, but I think anything that we can learn from the study, as Dr. Goodman indicated, we would certainly be interested in pursuing avenues.

            CHAIRMAN SHINE:  Yes, Dr. Swanson?

            DR. SWANSON:  With regard to quality systems, you mentioned that management commitment and identification of corrective action are critical parts of that.  I wholeheartedly agree, having worked in HACCP systems for many years.

            But I found that emphasis of internal, on-going verification is also essential to make sure that the critical elements are done on an on-going basis.  Is that included as well?

            DR. MALARKEY:  That is included.  That is included, absolutely.  I agree.  It's the same thing with having the best procedures in place, but if people don't follow them and you don't verify, yes, that is certainly a cornerstone of a quality system.

            CHAIRMAN SHINE:  Help me to understand one conceptual issue.  My understanding is that in the area of pharmaceuticals, the FDA undertook a rather extensive iterative activity in collaboration with industry to agree on good manufacturing process or procedures.  And in fact, I think a year or so ago we had a report on that activity about which both industry and the FDA seem to be optimistic.

            I may be missing it, but I don't see the same kind of iterative interactive approach to manufacturing processes in vaccines that occurred in the same way that they occurred with pharmaceuticals.  A, am I wrong and if not, why not?

            DR. MALARKEY:  Well, I won't say you're wrong.  I think it's a confusion which is one of the reasons I brought up the initiative that you're speaking of which was the two-year pharmaceutical GMP initiative.  Vaccines, in fact, were part of that initiative and the vaccine manufacturers did participate in terms of the iterative process, certainly one of the public meetings that we had downtown, there were vaccine manufacturers that were represented.  And as I said, since CBER was involved, we reached out to our manufacturers in regard to this.

            We certainly received comments to the docket from a variety of the industry, but the GMPs are the same, so vaccines were actually part of this.

            CHAIRMAN SHINE:  And the industry, if you will, concurred with, agreed with the practices that emanated from that study, from that activity, so it did have, in fact, a parallel with the drug manufacturers?

            DR. MALARKEY:  That is correct.  And we have had very positive feedback from industry as a whole.  I think everyone has the concept of quality systems and believes in the concept of quality systems.  The implementation is really the hard part.  I think in many of the pharmaceutical industries, including vaccines, there has been a siloing effect through the years.  You've had departments that -- I'm talking about within a manufacturing facility, you have departments that aren't speaking to one another or you don't have management communicating down and the operators communicating up.  And that is really a big issue that needs to be dealt with with the industry as a whole.  Once that's in place, we think quality systems will move fairly smoothly.

            CHAIRMAN SHINE:  One of the big -- there was a lot of criticism, the Team Biologics approach, because of a concern that industry had not, in fact, either had enough advance understanding of where you were going or concurred in the directions.  Do you feel that since the GMP process that you've recently undertaken has developed, that there's a pretty good understanding as to what the expectations are and what they can look forward to in terms of inspections?

            DR. MALARKEY:  Yes.  I think again the Team Biologics began the vaccine inspections in 1999, so now there are six years of experience and we recognized several years into the program that we needed to really look at it critically and we did.  This is two separate things.  We have the GMP initiative and then we have the Team Biologics program which is already in place.

            CHAIRMAN SHINE:  Yes.

            DR. MALARKEY:  So we did a very extensive evaluation and we recognized that improvements were needed and I believe we've done quite a bit of outreach to the industry.  We've had public meetings on Team Biologics with the industry and specifically the biologics industry, of course, so I think people are understanding and I think the inclusion of the product specialists are really making sure that they participate, whether it's on site or being available by phone has helped as well as the continuous training and the communication between the investigators and the product specialists.

            But we always are improving the program.  It's not something that we stop doing.  We always are looking to improve.

            CHAIRMAN SHINE:  This may not be the perfect question for you, personally, but I'd be interested in anyone commenting.

            This country lacks a national vaccine policy.  We have serious difficulties in this country with how and in what we we're going to ensure the delivery of all the vaccines we need including ones which you're not going to make a profit on, it's very large and as you know from your own experience, we are dependent on single manufacturers for a number of vaccines.  If those production facilities go down, we don't have those vaccines and so forth.

            What role, if any, do you see the FDA playing in terms of its experience being reflected in the necessity to effect, move towards some kind of national vaccine policy?

            DR. MALARKEY:  Jesse?

            DR. GOODMAN:  Well, I mean I feel very passionately about vaccines and the need to strengthen and diversity this very fragile infrastructure in our country and I view events in recent years including the flu this year as what I describe as teachable moments and so I think one of the things FDA can do is working with our partners and HHS and the Congress, etcetera, is essentially try to facilitate strengthening our ability in this country to produce needed public health products.

            I do agree that a high level strategy is needed.  Now it's important to realize that and I said this in Congress, that the main drivers are the market forces and the demand for the vaccine.  And there are some positive things there.  Actually, Chiron, one of the issues for them was having an old manufacturing facility and they had actually made a choice that they were planning to build a new manufacturing facility.  So they have decided to invest in influenza manufacturing and we had already been in discussions with other manufacturers, some foreign manufacturers, also interested in entering the U.S. market, so I think in recent years, in part, because of increasing recognition of the public health benefits, the flu vaccine and increasing demand and use of the vaccine, we're starting to see something positive.

            The other positive thing that's happened is the incredible potential of vaccines for these next generation of diseases.  While people, as I said, may not pay attention to measles any more and view that as a commodity, the potential with at least two different major companies developing vaccines likely to be affected in preventing cervical cancer.

            The childhood pneumococcal vaccine which is the first billion dollar vaccine product, it's still minuscule compared to the drug market and the investment is minuscule compared to the public health benefit and importance, but I'm in the position of trying to really push to support this infrastructure while at the same time not being

-- you know, being somewhat a little more positive and again, I think you've seen publicly in the post-flu vaccine thing, you know that we have had at least two companies, one American, one Canadian state that they intend to enter the U.S. flu -- from the FDA point of view, what I view our job is is to help inform the policy makers in these areas and then be a facilitator, you know, and we've done that by coming up with a pathway using accelerated approval for flu vaccines and we do this by very intense interactions with the manufacturer.

            Now we still have to do our job.  We sometimes have to tell people things they may not like, but what I've told people is feel free to disagree and discuss them with us and I think we've had very constructive forward-looking relationships, but that's the FDA piece, but I completely agree with you and I'd also like to say that it's not limited to vaccines.  Look at drug products whether or not big market forces.  We have had shortages of penicillin, streptomycin.  We don't have a lot of investment in new antibiotics.

            Again, I'm seeing some positive trends, but as a society, the society benefits from these products that prevent and treat infectious diseases and yet our societal investment and the market investment is not commensurate with that benefit.  There's a disconnect between the benefit and the market.

            CHAIRMAN SHINE:  Thanks, Dr. Goodman.  My question is not totally idle.  I'm thinking very seriously that the Science Board ought to draw on FDA's experience in these issues, some of the insights that can be gained from these issues in terms of, in fact, communications through the Commission with regard to some of the issues that have to be resolved to deal with problems of vaccines.  And I think FDA, because of its experience and I think Ms. Malarkey made it very clear, the manufacturer of vaccines is a different kettle of fish than making pills and that that means there have to be some serious considerations to the way in which we create the incentives of people to want to do that.

            So this is something I hope we're going to come back to as a Science Board, because I think that it's a national problem for which FDA just has an enormous amount of insight and not necessarily that they're going to solve the problem.

            Yes, Alan?

            DR. ROSES:  I think if we're going to go off into that direction, I think we should.  And at the time that's brought before the Science Board, we also ought to have industry representatives --

            CHAIRMAN SHINE:  Absolutely --

            DR. ROSES:  Talk about the issues for that.

            CHAIRMAN SHINE:  Absolutely.

            DR. ROSES:  I just have one question that's been bothering me months ago, but it came up while you were talking.  So Chiron went down.  We did a quick count and found out that we had about four or five million extra doses available and I -- what was the barrier between taking a vaccine that was available on 61 other markets in the world which was the GSK form of flu vaccine and just bringing it in in a time of emergency?

            DR. GOODMAN:  Well, you know, we can have a very long conversation about that and some of that would involve perhaps your own commercial confidential information.

            What I would say is that, in fact, we were already working with GSK to do that and to help achieve U.S. licensure and as you know, GSK has said that they think they can provide the data to do that this year.  So that's pretty fast.  And we did recognize that one of the first things we did and I have to give Secretary Thompson and others credit, is we said let's do anything we can to get additional vaccine in case there is a major flu epidemic and we need it and GSK and other companies were extremely cooperative in identifying vaccine that had been evaluated by other regulatory authorities that might be available in the market and in fact, we conducted this very rapid evaluation of the manufacturing facilities, data master files.  We had people working day and night and weekends and the firms also were extremely cooperative and traveling all around the world.

            And within a couple of weeks performed an assessment on that and basically decided that -- and gave input to the Secretary's Office, we decided to go ahead and create contingency plans to bring that vaccine here, albeit under IND.

            But again, our regulations require a certain standard of demonstration of safety effectiveness and manufacturing quality which some vaccines licensed in other countries can meet, some may not and part of the purpose of the kind of efforts that Mary describe to harmonize also the inspection on regulatory processes would put us in a much better position to do that and in fact, I was contributing to a WHO meeting where we talked about trying to produce more global harmonization in regulation of flu vaccines for pandemic purposes.  It's a perfectly good question and I think we've accomplished a lot in that area.

            CHAIRMAN SHINE:  Thank you very much.  Thank you, Ms. Malarkey.

            For the remaining members of the panel, we do have a couple of other questions we've been asked for advice about and I would like to get any comments that you have before we sort of wrap up. 

            We were asked about additional sources of useful data that might help with post-marketing surveillance.  We've touched a little bit on that in our earlier discussion.  But we were also asked, given that FDA has limited resources, in what areas should the Agency focus those resources to most effectively assure drug safety?

            I wondered whether the panel has any advice with regard to either of those questions.

            John, any thoughts?

            DR. THOMAS:  Certainly incorporating new technologies into the various centers and we've heard some of that yesterday seems to be what I will call a generic enough issue that should get concern and support by most of the centers, I would think because there's some, what I'll call woefully inadequate technologies that are used in certain centers and I think generally if some R & D monies were put into method and analytic developments it would certainly be -- it would seem to me almost across the board type of benefit and it relates to R & D.

            But then you get into the argument should FDA be doing R & D or should NIH be doing some of these things or should it be done by industry.  The answer is probably all of them, but if no one has the incentive to take the lead, why oftentimes it gets overlooked.

            CHAIRMAN SHINE:  Thank you.  Dr. Swanson, thoughts?

            DR. SWANSON:  I think that some of the presentations that we heard today related to the guidance, the attempt to further standardize what you're doing, improve communications electronically will reap all kinds of benefits in efficiencies of work force that might help to find internal resources that are already there.  Systematic approaches sometimes can be viewed as bureaucratic and they can, if you let the system run the people, but if the people are looking at the systems that are developed, tweak them to make sure you maximize the efficiencies, I think that some of the steps they're taking are very worthwhile and can help in providing the resources to look at drug safety.

            CHAIRMAN SHINE:  Dr. Harlander?

            DR. HARLANDER:  I heard a little today and I think there can be some exciting opportunities in public/private partnerships.  I know that you mentioned that a lot of folks have come forward.  I think to accelerate those and to tap into any kind of private industry academic involvement with the Agency, to be able to tap into data, to do data mining.  I mean it looks like you're sitting on tons of wonderful information that engaging some academic institutions or even if there's some anonymous ways that industry can do data mining because they're pretty good at that too and I know there's lots of challenges around that, but I think there's huge opportunity there to leverage the limited resources you have within FDA, with private companies that I think you know, my experience was highly ethical and want to do the right things in this area.

            CHAIRMAN SHINE:  Thank you.  Dr. Roses, thoughts?

            DR. ROSES:  Yes.  When there's big problems I think the best way to try to approach them is at the pilot stage.  Trying to start off with an IT system, rather than a bioinformatic systems, top down system that already can do everything doesn't exist.  And so -- I had this conversation with Dr. Lightfoot yesterday or the day before yesterday about training of people and how to get them trained.  But I think the best way to do an industrial academic regulatory collaboration is actually to have the people doing the work together in the labs together.  Some of the things that require big laboratories of new technology are just not going to be available here, but they are available elsewhere and people learn how to use those.  I think, in particular projects. 

            And I've suggested a couple at the other end of the -- Larry Lesko, et al., but it would be very useful and wonderful if, in fact, in going ahead with some of the risk-management plans that we can go ahead with on our own, but it would be very, very useful and helpful if we had the positive collaboration in the planning and how we are going to look at some of those data.

            One part of industry that I know of is amenable to it.

            CHAIRMAN SHINE:  We heard in the public sessions the argument that there should be routine -- that FDA should routine require post-market surveillance of approved drugs including the special emphasis on those that are likely to be widely used and/or likely to have large off-label uses and we specifically heard a suggestion that FDA should seek authority, so called Phase 4 studies, I'm curious as to the Committee's reaction to those recommendations in terms of your view of those?

            Dr. Roses?

            DR. ROSES:  Well, I have actually published a view of this.  It's a personal view, but I did publish it.  I really think that all drugs should have post-marketing surveillance, but I think there has to be an inefficient surveillance system that allows for the accurate collection of data with some defined inputs by the people in the health care sector that use these drugs. 

            A lot of the managed care companies in large payer kind of group medicine have placed some of these systems into the way they practice medicine. I think if we're going to be in the position to develop predictors, that we ought to at least have the track record of what we collect to be accurate information and the first thing that I hope the Institute of Medicine really pays attention to is what goes in, what data comes in and how we can get it in real time.

            CHAIRMAN SHINE:  thank you.  Other comments?

            Well, let me just make some comments and then you can shoot them down.

            First of all, in the overall area of safety we have had a good report of the Agency's response with their five-part plan in terms of the IOM study, the Safety Board, getting ahead of the Safety Unit, improving the method for adjudicating internal disagreements with regard to the science and the importance of outreach of information regarding safety.

            I think the committee, from our discussions last time and this time, concur with the notion that these were very useful and important steps.

            I would suggest, however, that the IOM Committee be asked to look at vaccine and nonpharmaceutical safety.  It seems to me that if they're going to look at how and in what way we want a safe system, while I recognize the precipitating factor was drugs, to not take a holistic view of this, in my opinion, is not taking advantage of an opportunity and if it was possible, I would like to see that as a broader study.

            Secondly, I already made reference to the fact that I believe the concept of the Safety Board within the Agency is a wise and judicious one.  I would emphasize that no matter how efficiently and effectively it works, it is, in my view and in the Agency's best interest to have some mechanism by which some oversight, not of the operations, but of the overall policies and activities are carried out by either committee or an independent committee or a subcommittee, this committee, or some other mechanism such that individuals who are in no way connected with the drug approval process, but who can, in fact, understand the issues associated with safety and their impact, can on some kind of regular basis, report not to the Director of CBER, but to the Commissioner in a public statement that they are comfortable that the process is moving forward in a manner that is consistent with the public interest and I know all the arguments about you've got to have experts do all this stuff and so forth. 

            People who know all the ins and outs of the FDA, our regulation and so forth, I believe that some highly responsible individuals with proper perspectives and backgrounds would give enormous credibility to the process if they're included.

            John, are you going to --

            DR. THOMAS:  Yes.  I was just going to say the Consumer Product Protection Agency letter was very thoughtful and one of the issues was looking towards an independent Safety Review Board, probably legally speaking and I'm not a lawyer, that's not possible, but on the other hand, there's got to be a perception on the part of the public that there's sufficient independence of the Safety Drug Review Board to the extent that while these will be difficult decisions in many cases, it should have highly represented unbiased individuals.

            Having said that, there still needs to be the input from all of the stakeholders as well.

            CHAIRMAN SHINE:  I agree.  I personally believe that some of the suggestions about taking this process out of the Agency are not wise.  On the other hand, as I look at the proposed make up of that Committee, its chair, the other participants, it's a government organization with a couple of patient and consumer participants.  I would like to see some mechanism that's added to that that gives it --

            DR. THOMAS:  Perception is going to be extremely important.

            CHAIRMAN SHINE:  But I think this is what a lot of this is about.


            DR. ROSES:  I agree with most of what you said.  I just -- the word independent is what's throwing me off.  I think the Safety Board, first of all, it's a risk-safety analysis and a free-standing safety board is independent of the FDA, makes to me no sense at all.

            CHAIRMAN SHINE:  Absolutely, I agree.

            DR. ROSES:  But, in fact, it would be very, very useful if it did contain people experienced and had the proper backgrounds to actually be perceived and in real life being separate, not independent, but a separate review body.  So I agree.

            CHAIRMAN SHINE:  What I'm arguing is that the body as proposed is perfectly reasonable to do the business of identifying the risk in doing its work.  I'm not arguing with that.

            I think that's a sensible group.  I'm simply saying I'd like to have, in addition to that, some oversight that has some increase in -- some more distance from it so it can periodically review its activities and say yeah, it's functioning in the way the public would like to have it function.

            This is just my own personal view on that, asking for the Committee to endorse anything specifically.

            Let me make a few other observations.  I think we all agree that there are some really important opportunities for information gathering that should take advantage of other sources of information and I pick up again on Alan's use of the word pilot.  Some of the things we were talking about in terms of teaming up with existing electronic health records, new developing records so that we can do some of the things, solve some of the problems that Dr. Goodman has identified, namely, you've got to know what to do with the data, how to analyze it and what the infrastructure is, that those kind of pilots would be very important.

            On a number of occasions we emphasize standardization, standardization of terminology, standardization of approaches and analysis.  I think, although we need to think more about this, I think the sense of the Committee is that we must find a way to do more effective post-marketing surveillance and I would suggest to the Commissioner that the Agency do a briefing for us on what they would believe to be an optimum national pharmacovigilant system.

            In other words, I think it's worthwhile to do the exercise and without, at this point, limitations of cost and whatever and say what would you do if you were, in fact, going to invent a system that met the various needs and let's debate it.  Let's argue about it.  Let's see if it makes sense.  If it does, then the issue of resources obviously becomes important, but the Board can decide whether such an approach is likely to produce what we want.  We've talked about bits and pieces of how something might work, but I think it would be very useful if we took the time to actually say how would we invent such a system.

            Now the IOM may, in fact, make some recommendations of that kind but I don't believe that that should preclude us from thinking about a pharmacovigilant system as opposed to what they think about which may run the gamut in terms of how and what way they think business ought to be done.

            I think that -- yes ma'am.

            DR. HARLANDER:  When will be have the IOM study done?  Do we have an estimate of that?

            DR. WOODCOCK:  It's expected to last about 18 months from its inception.  It hasn't really started yet, but Steven said the membership will be posted soon.

            DR. HARLANDER:  Two years.

            DR. WOODCOCK:  Yes, something like that.

            CHAIRMAN SHINE:  And I don't think we should wait two years to try to think out what such a system might look like.  And in fact, if the Agency does have some suggestions that we can interact with, you can give the ideas to the IOM that they're not necessarily the font of all knowledge, even though certain times in my career, I believe that.

            But in any case, but I would like to challenge the Agency to help us in this regard and put some of the thoughts together that we've talked about.

            I think Cato was very concerned that the public information and the labeling material be more

-- have some more explicit information about special populations and I would argue, Dr. Woodcock, that it might say special populations, none identified or no data available or if there is data available, whether the special population is kids or women or the elderly or African Americans or Asians or whatever, that there be something in that block.

            I think that's the intent, but I think Dr. Laurencin wanted to see that that was very explicitly stated.

            I would love to -- yes, please.

            DR. THOMAS:  Let me throw out a thought while you're on the issue of pharmacovigilance.  Of course, we don't have socialized medicine and we don't capture all these things like some of the Scandinavian and European countries do, but do you suppose if you could marry pharmacovigilance with pharmacoeconomics, and then perhaps find a role for the Center for Medicare and Medicaid to monitor these things since you're going to single out a population of generics, perhaps, or geriatrics, excuse me.  But this might be a distance from the Agency itself and if you could incorporate the pharmacoeconomics that would have the interest for the Center for Medicare and Medicaid.

            CHAIRMAN SHINE:  Well, you could very easily -- I could conceive of a pharmacovigilance program which included a database which is a very rich system for identifying diagnoses, drugs, and could, in fact, try to college that information, particularly now.  If it's going to have a drug benefit, albeit with a hole in the donut, but still a drug benefit.

            I think there was some reference to that.  You may have already been thinking about something like that.  Someone said something about CMS.

            DR. WOODCOCK:  Yes, we're talking to CMS about -- Paul Seligman pointed out that as they assemble their drug benefit, a lot of this has to do with how you structure the data that you collect and make sure you can actually analyze it and so we are talking to them about that, but they don't currently have that kind of capability.

            CHAIRMAN SHINE:  I think there were a number of other specific ideas that deserve some additional thought.  One was -- and we understand the limitations -- was the role of pharmacists and pharmacy in this whole effort and obviously, there are resource issues there.  But we may be -- this may be an area that we ought to explore.

            The pharmacists certainly have been very interested in the medical areas, medication area business and the question is can we come up with some creative partnership to help with regard to adverse drug events.  The possibility of developing a website which would be easily accessible and which would allow people to look at the range of drug interactions perhaps with identifying the really important ones and the ones that are not so important.

            And I think repeatedly we've heard reference to the notion that we've got to find better ways to educate policy makers and the public about risk and risk benefit and the role of the FDA in balancing efficacy against risk and maybe the Board can think about some creative ways that we might accomplish that over time.

            Clearly, this is a work in progress and should fit into the continuous quality rubric that FDA and the Board has talked about so frequently in terms of trying to make sure that whatever we learn about adverse events is translated into appropriate kinds of programs.

            My own sense about where to put the resources is it's the data.  I mean I really think that at this stage trying to get rational ways that we can collect meaningful data, that we can mine the data within the institutions, that we can figure out ways to validate data.  Once you've got that, then you have an opportunity to see trends, to determine where your problems are and then to devote resources in each of those.  So I would concur, I think it was Dr. Swanson who emphasized the importance of that part of the equation.

            I was pressing Dr. Goodman about the science issue because I am worried about the overall commitment to science.  I know you're stressed.  I'd like the Board, as we think forward over the next year or two to think about whether we ought to do some kind of assessment with or without others, science based within the FDA, whether in fact, it's adequate, whether it needs strengthening.  If so, where and what kind of resources will be required to do it?  It seems to me that as Dr. Goodman articulated, it's tremendously stressed. 

            We've already heard one person in the public presentation argue for stronger science base.  Perhaps we ought to look at that very carefully.  Whether we do that in the course of our review of different components, whether we look at it across FDA, I would throw open both to the committee and to the Commissioner and ask his advice with regard to how we'd like to do it. 

            But I think for us, as a science board, to remain silent while the basic science capacity of the Agency is not getting what some of us think is the support that it should have, is not responsible.  And so we need to take a look at it.  Granted, there are all kinds of resource needs that the Agency has to deal with, but I think we have a responsibility as the Science Board to take a close look at that.

            I want to thank our colleagues.  I thought the morning presentations were terrific in giving us an overview of the safety and they were all on time.  The afternoon presentations were very comprehensive and they weren't on time.  But that's all right.  We learned a lot from them and the -- are there any other comments that any Members of the Board want to make?

            Dr. Woodcock, any final observations you'd like to make?

            DR. WOODCOCK:  No.  If the decision is to pursue more briefings on pharmacovigilance, we did publish a report, I believe in 2001 called "Managing the Risks of Medical Products From the FDA."  It was a comprehensive report at the time.  Obviously, our thinking has advanced, but you would probably want to get that well in advance of any briefing if, in fact, you decided to go down that path.

            CHAIRMAN SHINE:  We're going to do a little bit more thinking, Dr. Woodcock, about some of the priorities here and talk with you and the Commissioner about them, but my thought is that pulling that together with some focus so that we can, in fact, say well, what would the vision for that be, what can we get now, where could we go long term, what kind of resources would be required?  It could be something where we could be helpful to you over the long haul and I'd like to do that.

            I want to congratulate all of you on these -- if we can always get over this business that contains nonbinding recommendations --

            DR. WOODCOCK:  Talk to your lawyers.

            CHAIRMAN SHINE:  The quality of the material, I think, is outstanding.  I think the committee believes that and we congratulate you.  With that, we are adjourned.

            (Whereupon, at 4:22 p.m., the meeting was concluded.)