UNITED STATES OF AMERICA

 

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FOOD AND DRUG ADMINISTRATION

 

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OFFICE OF THE COMMISSIONER

 

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SCIENCE BOARD

 

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MEETING

 

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FRIDAY,

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.

MEMBERS PRESENT:

      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

            Commissioner

      NORRIS E. ALDERSON, Ph.D., Associate

            Commissioner for Science

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

 

ALSO PRESENT:

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

            Director, Office of Medical Policy, CDER

      ROBERT BRACKETT, Ph.D., Director, CFSAN

      ROBERT BUCHANAN, Ph.D., CFSAN

      KATHRYN M. CARBONE, MD., Associate Director for

            Research, CBER

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

            CDER

      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

 

PUBLIC HEARING PARTICIPANTS:

      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

            Foundation

                  C O N T E N T S

 

                                                PAGE

 

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

 

Adjourn

               P-R-O-C-E-E-D-I-N-G-S

                                         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 go