Prescription Drug User Fee Act Public Workshop Natcher Conference Center National Institutes of Health Building 45 Center Drive Bethesda, Maryland Monday, November 14, 2005 8:00 a.m. [PDF Version] P A R T I C I P A N T S Ernest R. Berndt, Ph.D. Bruce Burlington, M.D. Judith A. Cahill Perry Cohen, Ph.D. Diane Edquist Dorman Carole Redding Flamm, M.D., M.P.H. RADM Steven Galson, M.D. Jesse J. Goodman, M.D., M.P.H. Scott Gottlieb, M.D. Mary Gustafson, M.P.H. Deborah Henderson, R.N., M.S.N. Jeanne Ireland Kenneth I. Kaitin, Ph.D. Alison Lawton Arthur A. Levin, M.P.H. Alison Rein, M.S. Ellen V. Sigal, Ph.D. Hugh H. Tilson, M.D., Dr.P.H. Allen J. Vaida, Pharm.D. Bill Vaughan Andrew C. von Eschenbach, M.D. Susan C. Winckler, R.Ph., Esq. Janet Woodcock, M.D. Raymond L. Woosley, M.D., Ph.D. William A. Zellmer, M.P.H. Diana Zuckerman, Ph.D. CONTENTS Welcome Deborah Henderson, Moderator Opening Remarks Andrew von Eschenbach, M.D. Panel I - Presentations by FDA Scott Gottlieb, M.D. Janet Woodcock, M.D. Steven Galson, M.D., M.P.H. Jesse Goodman, M.D. Panel II - Presentations by Academic Research Groups Kenneth Kaitin, Ph.D. Raymond L. Woosley, M.D., Ph.D. Ernst R. Berndt, Ph.D. Hugh Tilson, M.D. Panel III - Presentations by Patient Advocacy Groups Ellen V. Sigal, Ph.D. Perry Cohen, Ph.D. Diane Dorman Jeanne Ireland Panel IV - Presentations by Consumer Groups William Vaughan Alison Rein, M.S. Arthur Levin, M.P.H. Diana Zuckerman, Ph.D. Panel V - Presentations by Industry Groups Alison Lawton Bruce Burlington, M.D. Mary Gustafson, M.P.H. Panel VI - Presentations by Health Professional Groups Carole Redding Flamm, M.D., M.P.H. Judith A. Cahill Susan Winckler, RPh., Esq. Allen Vaida, Pharm.D. William A. Zellmer, M.P.H. Open Public Comment Period P R O C E E D I N G S Welcome MS. HENDERSON: Good morning. If you will take your seats we'll get started. My name is Debbie Henderson. I'm the Director of the Office of Executive Programs at the Center for Drugs. And I'm very pleased to be your moderator for today. I have been told that my primary job is to keep us running on time. And so far, I'm failing miserably. I want to welcome you to this meeting of FDA and stakeholders public meeting to discuss the Prescription Drug User Fee program, which is now, as all of you, I'm sure, know, heading for its fourth iteration. In this meeting the Agency is seeking public comment on the current user fee program, including views on what features should be retained, and what we might do to further strengthen and improve the program. And your comments are, of course, very important to us. I am going to try from here on out to keep things orderly and on time. I expect we'll have a lot of people wandering in as it was quite difficult to get on campus. The way our program will go today is we will have opening remarks from Dr. von Eschenbach, and there are a total of six panels for the day; three of them which will occur before lunch. We will still try to get you out to lunch at around 11:50, and I will try to keep everyone's remarks short. I'm speaking particularly to the FDA panel over here. After lunch, we'll have three additional panels, and then public comment is scheduled to begin at 3:50. And we are scheduled to adjourn at 5:00. And so, without further ado, I am please to introduce to you our current acting Commissioner of the FDA. As most of you know, Dr. von Eschenbach is also the 12th director of the National Cancer Institute. A nationally recognized urologic surgeon, Dr. von Eschenbach's distinguished career as a key leader in the fight against cancer spans nearly three decades. Prior to accepting the appointment to lead the NCI in January of 2002, Dr. von Eschenbach served as executive vice president and chief academic officer of the University of Texas, M.D. Anderson Cancer Center in Houston, leading a faculty of nearly 1,000 cancer researchers and clinicians. At M.D. Anderson, he also served as vice president for academic affairs, and held the distinguished Roy M. and Phyllis Gough Huffington Clinical Research Distinguished Chair in Urologic Oncology. Dr. von Eschenbach joined M.D. Anderson as a urologic fellow in 1976, and was invited to join the faculty a year later. Just six years later, in 1983, he was named chairman of the department of urology. Himself a cancer survivor, Dr. von Eschenbach has had an impact on the fight against cancer that extends far beyond the clinical and academic communities. He is a founding member of C-Change, and was president-elect of the American Cancer Society at the time that he was appointed to the NCI. A native of Philadelphia, Dr. von Eschenbach earned a B.S. from St. Joseph's University in Philadelphia in 1963, and his medical degree from Georgetown University School of Medicine in 1967. Dr. von Eschenbach completed residencies in general surgery and urology at Pennsylvania Hospital in Philadelphia, and then was an instructor in urology at the University of Pennsylvania School of Medicine. He also served as a Lieutenant Commander in the U.S. Navy Medical Corps. And the FDA feels very honored now to have him now as our Acting Commissioner. Opening Remarks COMMISSIONER VON ESCHENBACH: Good morning, and thank you Debbie. I want to begin by thanking you, and also Theresa Mullen for the tremendous effort and hard work in putting this very, very important meeting together. And I also really appreciate and thank all of you. I want to thank you on behalf of not just the FDA, but the entire community for your interest and your effort and your commitment in coming here. I recognize how difficult it can be to get on the NIH campus. I just came from another meeting, and not only could they not get on the campus but, in their meeting room, they didn't even have any lights. So you're actually a little further ahead than some of the other groups meeting here this morning at NIH. But it is not just your effort in coming here, it's the effort that you put in throughout the entire year to work collaboratively and collectively together to help us as a community enhance the health and welfare of the American people. All of you here today play a very crucial role in helping the FDA fulfill our responsibility and part of that very important public health mission. Clinical drug review is one of the backbones of FDA. And it's thanks to people who have supported our drug review programs that we are continuing to bring safe, effective and affordable products to American consumers; and that we continue in that mission to product and advance the health and welfare of Americans and, in fact, people around the entire world. So it's a privilege to be with you and to join you for this important discussion about how we can better promote scientific innovation, and maximize the efficiency of the medical development process, especially through the reauthorization of the Prescription Drug User Fee Act. This has never been a more critical goal than it is today. We are in the midst of a virtual revolution in biomedical research. But despite the tremendous progress of recent decades that's led us to this very exciting time, most medical experts still believe that the most exciting and most important innovations are still ahead of us. And so today we are spending more on biomedical research and development than ever before. We are discovering and learning and understanding about diseases at their very fundamental genetic, molecular and cellular level. And not only are we understanding the disease processes, but we're understand the person affected by those disease processes. I have seen this research first-hand here at the NIH. And I, too, join all of the others who are extraordinarily optimistic about the future; so much so that four years ago, at NCI, when I became the director, we set a goal for the cancer program that we would capitalize upon this tremendous progress in biomedical research, and work to eliminate the suffering and death due to cancer, and bring that about by 2015. But now, having had the privilege to serve as the FDA's Acting Commissioner, I can see that this research being translated into safe and effective new medicines is a critically important step if we're going to have that impact on the patient and the public we are dedicated to serve. We are seeing opportunities emerge at the FDA as we are overseeing more and more investigational new drugs, and more innovative and targeted therapies than have ever before been possible or imagined. PDUFA has, in fact, enabled a lot of this progress to be made available in a timely way to be able to use these opportunities created into interventions that could be delivered to patients in the form of safe and effective medicines; medicines that are approved by the FDA through a process that is more rigorous and more transparent, and more efficient than it has ever been before; and, in large part due to what the opportunities have been provided for by PDUFA. PDUFA has enabled FDA to obtain the needed resources and adopt modern tools to review human drugs and to make much needed process improvements, such as management reforms and, most importantly, our opportunities in integrating modern information technologies. But even with all these promising new treatments that patients have available as a result of improvements that PDUFA has enabled, it is still more important to do more. It is still obvious how much more work yet needs to get done. And so at the same time that more innovative treatments are reaching patients there are, in fact, fewer new product applications reaching us than at any time in more than a decade. There is now appearing a fundamental disconnect between the tremendous potential that's been for 21st century biomedical technology, and the actual products that are reaching our patients in the future. There is a disconnect between good ideas in the lab, and even proof-of-concepts, versus the safe and effective treatments that are actually being provided reliably to patients. And so as we face a real challenge today to bring the promise of the 21st century medical breakthroughs to patients, our challenge for all of us is to find ways to make drugs and other new innovations both safe and affordable, and to continue to promote high levels of medical innovation that are then delivered to patients. Our challenge is to continue to adapt our regulatory approaches to accommodate and accelerate the pace of biomedical innovation and the introduction of safe and effective medicines. I believe that the reauthorization of PDUFA IV is critical and essential to enable a lot of these opportunities to be made possible. The discussion today marks the beginning of a public process to see how we can use new PDUFA legislation to continue to advance biomedical progress. To meet this challenge effectively we need to do much more than ever before. We need to improve the process for developing safe and effective new medical products by making it as clear, as fast and as cost efficient as possible. And once new treatments have been developed, we need to continue to reduce the cost and improve the quality and reliability of making them--like we have done in other high tech industries--opportunities that are impacting patients' lives. We also need to develop means of providing better and timelier information on the risks and benefits of medical treatments after they've been approved, so people can make fully informed treatment decisions. We need to empower doctors and patients to get the most value out of the medical products that are on the market. All of this is the critical path; the critical path for therapeutic development that we have been talking about at FDA; the path for moving from scientific breakthroughs, backed by NIH and the many research foundations that are creating this opportunity and discovery, to then to actual development of treatments that make the most difference in patients' lives. This encompasses not just the science of developing drugs and devices, but also the know-how for turning an experimental pharmaceutical or biological molecule revealed in a test tube into an effective medical product that can be safely delivered to a patient. This include all the many steps that need to occur after a new compound has been removed from the laboratory and is placed into and through clinical trials to become a finally finished drug. One of the major objectives at FDA is to clarify this critical path; simplify it; and help promising medical products navigate through it. To do so, we need to think about all 100 percent of the process, from the pre-clinical phase through the clinical trial period, through the eventual commercialization of the treatment. How do we do this? We need superior development science to translate basic discoveries into new and better medical treatments. We need to take the effort required to develop some better tools for developing medical technologies. And we need a knowledge base, built not just on ideas from biomedical research, but on reliable insights into the performance of drugs after they are approved. So we can continue to learn about risks and benefits in the post-market phase. Enabling these safe and effective new medical technologies is a fundamental part of FDA's principal mission to protect and advance the public's health. And it is a fundamental part of the goals of PDUFA. At FDA, we are already developing needed information systems and working on collaborations with the National Science Foundation and the NIH, and other research groups, to help provide guidance and support for applied research studies that have the goal of providing the knowledge needed to make the development pathway more clear and more efficient. And we continue to improve our own processes for evaluating new drugs and to advance our commitment for enabling their development through meetings and feedback that we give to scientists every day. I mentioned the word "collaboration." I mention it because it is a simple fact that we cannot do this alone. Even with all that we are doing, good medical ideas will not necessarily get translated into public health solutions without the collaborative, cooperative integration of all of our efforts; collaborations with our partners from drug-development companies and health care organizations, to academic institutions and, in fact, other government agencies, along with patient advocacy groups and consumers. All of these are key to making medical innovation a reality. And collaboration is going to be a key in enabling us to gain the feedback that we need to make sure that PDUFA IV is as forward-looking and as smart as it needs to be in order to advance the development of biomedicine and drug development. I'm confident that we'll bridge the gabs in medical innovation and succeed in providing both safe and affordable products to Americans nationwide. The opportunities that PDUFA enables are a big part--in fact, perhaps a crucial part--of achieving this promise. And so today we begin a discussions; a discussion of how we can use this important legislation to move forward; to move forward to seize these opportunities on behalf of Americans. In doing so, we will realize the full public health benefits of the incredible innovations that are being made in biomedical research. And I trust we will not only fulfill but exceed the wonderful promise that many envisioned when they labeled this "the biomedical century." I'm convinced that because of the work of FDA, and the work of this community, in helping to move opportunities like PDUFA forward to enhance and enable strategies like critical path, that you will make possible the fulfillment of a commitment and a goal just like the one we made at NCI to eliminate suffering and death due to cancer. Our opportunities go far beyond just being able to eliminate the suffering and death due to cancer, as incredible as that one initiative may be. What is occurring at FDA, what PDUFA will make possible, and what the critical path will lead us to is not just a transformation of one disease, but a transformation of all diseases; an opportunity to improve the welfare and health of all people and all diseases. And your work and your participation and your cooperation and your contributions today are a critically important step. And I wish you well in the intensive work of today, and thank the panel and participants for your commitment and contributions. Thank you. [Applause.] MS. HENDERSON: Thank you, Dr. von Eschenbach. Our first panel will include presentations from the FDA. And these individuals will also serve as our listening panel for today. And I'd like to briefly introduce them. I will introduce them all before they speak. Our first speaker, and second to my left, is Dr. Scott Gottlieb. Scott is the Deputy Commissioner for Medical and Scientific Affairs at the FDA. Immediately to my left is Dr. Janet Woodcock. Janet is the Deputy Commissioner for Operations, and the Chief Operating Officer at FDA. To the left of Scott is Dr. Steven Galson, who is the Director of the Center for Drug Evaluation and Research. And to his left is Dr. Jesse Goodman, who is Director for our Center for Biologics Evaluation and Research. We'll start with Dr. Gottlieb. Panel I - Presentations by FDA DR. GOTTLIEB: Thank you very much. I just wanted to start with a brief overview of the legislative history of PDUFA. And then Dr. Woodcock was going to discuss the impact that PDUFA has had on the drug review program at FDA. [Slide.] Modern drug regulation, as you all know, started in 1962 with the passage of amendments to the Food, Drug and Cosmetic Act that, really for the first time, put in place a requirement that drugs had to prove that they were effective pre-market. Before that, requirements were just focused on safety. But for the first time, manufacturers and product developers needed to conduct clinical studies to prove the effectiveness of drugs. [Slide.] Heading into the 1970s, there began to be some discontent that there was what was being termed a "drug lag" in the United States. Probably the landmark evaluation of this was done by a University of Chicago economist by the name of Sam Peltzman, who did an economic study showing that drugs were being approved first in Europe and that, in his estimation, his analysis, the delay in the market to new drugs was the deleterious effect of the delay on the public health was outweighing any benefits that were being accrued through that delay. This kind of analysis continued to build in the '70s, and really reached a peak in the '80s, with renewed emphasis on patient access issues, of getting drugs to patients more quickly, that heightened with the AIDS epidemic in the United States. And all of this discontent and this focus on review times culminated with the passage of the first Prescription Drug User Fee Act in 1992 which, for the first time, gave FDA new resources, based on user fees, for the review process. [Slide.] The primary focus of PDUFA I was on decreased review time, so the resources went to things like medical and scientific reviewers, and it was focused mostly on the pre-market review process, and getting resources for support personnel and field investigators to try to accelerate the pre-market review. The reauthorization in 1998, in PDUFA II, for the first time focused not just on review times, but development times. And so there was an emphasis on cycle times, and trying to build in resources for things that would enable shorter development time; so things like resources for more collaboration between industry and scientists and the FDA that could help improve the quality of applications that the received. So you saw things like that built into the second reauthorization, which I'll elaborate on in a moment. [Slide.] And then PDUFA III continued to build on that; put the Agency on a sound financial footing, and also continued to build on pilot programs and other mechanisms aimed at decreasing development times, and addressing issues of multiple-cycle reviews; issues where applications go through two or three cycles before the Agency is able to reach a final decision on their status, whether to approve them or not. [Slide.] One important point I just wanted to back up and make today is that user fees are not unique to the United States, although the United States, I think pioneered their use as a modern approach to funding a regulatory agency, they're now a mainstay in Europe, where the EMEA is funded in large measure by user fees paid by product developers. And the UK's drug authority is funded entirely through user fees. [Slide.] I said I'd get back to some of the goals that were built into the PDUFA legislation. Here you see a chart, a breakdown, of the growth in the goals that were incorporated into the PDUFA legislation through a goals letter that was signed with the Secretary of Health and Human Services. So the legislation itself didn't include these performance goals, but they were negotiated in a side agreement, in a goals letter. And you can see the growth in the number of commitments aimed at trying to foster increased scientific collaboration between the reviewers and FDA and product developers, all aimed at trying to bring more clarity to the development process and improve the quality of the applications themselves. [Slide.] I included this picture--it's a picture, I think, of Steven Galson fixing FDA's mainframe computer. [Laughter.] Steven doesn't fix it anymore. This must be when Janet was in charge of the drug center, because Doug Throckmorton's in charge of fixing it now. But I included this because one of the thing that came with PDUFA III--it actually was incorporated into PDUFA II, as well, but more so in PDUFA III--was a focus on IT as a big part of trying to enable a more streamlined, more clarity to the development process that FDA. And so for the first time, in PDUFA III you saw commitments built into the goals letter that were specifically aimed at trying to increase the IT infrastructure at FDA< and also increase the use of information technology to try to accelerate the development process, bring more transparency and clarity to it. [Slide.] So this is a list of the various goals aimed at electronic applications, specifically, that were incorporated into PDUFA III. And so explicitly in PDUFA III, there was a commitment for a five-year plan to be developed, an IT plan, with specific milestones; and also commitments made to foster the development of electronic applications and electronic submissions to FDA< which has progressed very well under the FDA leadership. [Slide.] PDUFA III, more than anything else, put the agency on a sound financial footing, with revenue targets that increased for inflation from 2003, and also adjusters built in to take account of increasing burdens put on the FDA through the submission of additional applications. And Dr. Woodcock and others are going to talk more about these adjusters that were built into the PDUFA III legislation, how well they've correlated or not correlated with the increasing workload that the Agency's been confronted with, particularly with respect to all that increased collaboration that was built into the successive PDUFA agreements, PDUFA II and PDUFA III, and the increased amount of meetings and other things that the FDA does to help bring clarify to product developers. [Slide.] Just to close: why does PDUFA continue to be important? Well, there's no question that the user fees add additional resources to the Agency, and help the Agency deal with the backlog of applications that existed at the time of the original legislation. But even more so than the resources that the PDUFA legislation enabled for the review process itself, PDUFA has enabled a fundamental management transformation inside the agency that I think sometimes isn't as widely recognized as the resources that it enabled for the review process itself. And, as Andy discussed, this kind of modernization to the process internally inside FDA is going to be critical, because the evaluation of the new technology that Andy discussed--Dr. Eschenbach discussed--may well be more resource intensive if we're going to make sure that these kinds of new products get to patients efficiently. Thank you. MS. HENDERSON: Thank you, Scott. Dr. Woodcock? DR. WOODCOCK: Thank you and good morning. Scott's told you about the background of the program and some of the different legislative phases it's gone through. I'm going to talk about the operation of the Prescription Drug User Fee program, what it really means inside the agency. And then Dr. Galson and Dr. Goodman are going to fill in the details for their specific programs. [Slide.] Now, one of the things I think that is of great confusion to the public is: what do these user fees pay for? I'm not going to go through the fee structure, but as many of you may know, it's divided up. Only a third of the fees come from applications; the rest of them come from levies on the manufacturing plants that are in production, and the products that are out there. And this was simply to spread the load around, and not burden any particular innovator when an application was submitted. [Slide.] The Agency doesn't give these fees directly to any entities within the Agency, they're administered in a central way and simply used to supplement the overall budget. And FDA must keep track, however, of how these fees are contributing to the overall process. In the statute they define something called the "process of review of new human drugs." And that "human drugs" covers drugs and biologics, and that process definition describes what, in fact, can be paid for by user fees; in other words, activities eligible for support from the fee program. So the Agency collects a centralized amount of money and then that is allocated to support these various activities. It isn't in any manner a fee gets paid in, and then the reviewers know about that. It's simply a support to the activities that go on at the FDA. And I'm going to explain this a little bit more. Now, what activities are covered? What exactly is paid for or supported by these fees? [Slide.] Well, during the investigational phase of product development, in the process of review of new human drugs, the following activities are covered. And isn't a totally exhaustive list, but it's most of the important activities. First of all, the FDA has to decided, when a compound is ready to go into people, whether or not the safety data that has been generated about the new compound, whether it's a gene therapy or a new molecular entity or a vaccine, or whatever it is, and whether the safeguards that have been put in place are adequate to put that compound into the first person, and to initiate human testing. So this is obviously an extremely important function, and this is supported by user fees. Secondly, as the investigational progresses, and more and more people are exposed at higher doses or whatever, the FDA sets standards for the safety evaluation at each stage of this development. So the FDA reviewers must specify what safety tests are going to be done on the patients--all the patients; how long they'll be followed, and so forth. And in many areas, as probably Jesse will tell you, this is extremely tricky; for example, in some of the newer areas such as gene therapy, how long should the people be followed, how should they be monitored? But in any new intervention, a lot of attention has to be paid to this. [Slide.] Thirdly, the FDA has to set the requirements for how the dose is arrived at. This is a very important aspect of development. It's important for safety and also for utility or usefulness of a drug or biological. And, finally, the FDA has to set standards for how the trials are conducted; what the design of the trial is. What are the endpoints for any given indication? In other words, what defines success? How long do people have to be exposed? What do you measure about the people? And all these activities, my point is, are covered by the user fee program. And you can see they're very essential to making sure that products are properly evaluated, and subjects are kept safe. This isn't all. [Slide.] As Scott alluded to, during the investigational phase, the FDA scientists must interact and advise developers on their trials; for their specific trial; not the standards, but that specific set of trials they're doing; what kind of safety monitoring they're going to do in that specific time. Trial endpoints should be agreed to with the FDA. In the past, during the drug lag times, one of the problems was that many volunteer subjects, patients and others, were exposed to trials that ultimately turned out not to be useful. Either the FDA would not accept them; they were poorly designed; or they had the wrong endpoints. This is basically not ethical. And therefore it is very important there be interaction between developers and the regulatory agencies to make sure the correct trials are done; trials that will yield the information that is desired, and that won't unnecessarily expose human subjects. [Slide.] Another important function that's covered by user fees is the need for the FDA to continually monitor the development of adverse event; side effects or other adverse events that occur in the clinical trials. And the FDA will place clinical holds on trials if some risk signal occurs in the trials, or require modification; for example, ask a firm not to study higher doses, continue accruing more patients at lower doses and so forth, to ensure maximal safety of the subjects. This is quite different than the role of the IRB--just for your information. The FDA has the scientific expertise in development of those specific products, and therefore has a lot of wide-spanning knowledge about the development programs; what can happen, and what to do. This is really synergistic with the IRB function. People in the IRB are looking for the ethical protection of the subjects: make sure that informed consent is accurate and that people are safe. But these are complementary functions. [Slide.] In addition, the FDA oversees clinical research through its bioresearch monitoring program. The FDA inspects IRBs that oversee trials of regulated products, and we also set standards and policy for these IRBs in this realm. We also inspect the conduct of the trials of regulated products, and we set standards for how those trials be conducted. And that's called the "good clinical practice standards." Those are internationally harmonized standards for trial conduct, record keeping and so on. This also is covered by user fees. This obviously is a very important activity. [Slide.] Now when an application--a marketing application--is submitted to the FDA, there's a whole other set of activities that are covered by user fees. The FDA must review how the product is manufactured, and what controls are put on the manufacturing, and what testing is done on the product to make sure that it can be manufactured reliably at high quality. The FDA also sends people out to inspect the manufacturing facility. And the FDA also looks at the packaging, or how the product is going to be shipped, and make sure it's stable and all sorts of things there. The reviewers must look at animal toxicology that probably will elucidate things that you won't have found in the clinical trials; for example reproductive toxicity. We don't really study pregnant women usually in trials, and therefore we're extrapolating our findings about reproductive toxicity from animal studies. Same with carcinogenicity: those are long-term studies that are done in animals to make sure that products are not going to be causing cancer; something you wouldn't find in the clinical trial program usually. [Slide.] What gets most attention during this phase is the FDA reviewers have to review the clinical data, both all the safety data. In addition, the FDA has to review the product for mix-ups; to look at the name of the product and other aspects of the product that could lead to confusion and medical errors, and potential deaths when the product was out in the market. And the efficacy data. And, finally, the FDA reviewers look at and negotiate with the company on what is said in the drug label, which is the standard for what is truthful about the drug. [Slide.] In addition, around an approval a number of other activities happen. These are also covered by use fees: holding public advisory committee meetings; evaluating risk-management plans. If there's an identified risk of a product, then it's very desirable to, instead of just waiting for something bad to happen, to have a plan in place to try and manage that risk. Agreement on Phase IV commitments, and then we have to review those Phase IV studies and the results. These are all covered by user fees. [Slide.] Now, that's the scope of the activities that are covered. And there are probably others that I haven't mentioned. There's certain product testing that goes on. There's other things that happen. Now, we've heard from our stakeholders over the years many, many times: there is wide support for FDA carrying out each of these activities. That is not to say there are always some people who think FDA shouldn't do these things. But the vast number of people believe FDA should carry out each one of these activities and, in fact, most of our stakeholders call for us to do more in each one of these areas, depending on what they're concerned about and what they're interested in. They want us to do more drug safety. They want to improve the development process for unmet medical needs--as you heard from Dr. von Eschenbach. They want more oversight of clinical trials of medical products and so forth. But each of these activities require adequate scientific staff, with appropriate IT and support staff. [Slide.] Now, what the user fee program did, by supporting these activities, is enable the FDA to increase the staffing and the bioinformatics, the information technology systems, for these processes. The blue bars here, starting in 1992 on your left, and going through 2004, the blue bars show the total number of people against these activities that I just talked to you about. And you can see there's been an increase from about maybe 1,300 in 1992, to a little over 2,500 now. So, there has been significant increase in the number of scientific staff that FDA has been able to put against these activities. And there has been a concomitant increase in many of these activities, as you'll see later. The pale yellow bars are the appropriated FTEs; in other words, the full-time-equivalents, or the number of people FDA has available fromappropriate dollars, to oversee these activities, conduct these activities. And you can see that that number has gone down from 1992 to 2004. So today, FDA has somewhat fewer people to perform these activities that are funded by appropriated dollars than we did in '92. The maroon bars show the growth in people that was provided by user fees starting in 1993. And you can see in 2004, the Agency had more staff provided by user fees against these activities than we had staff provided by appropriations. By putting these two bars together, though, and getting the blue bar, we do have staff that cover each one of the activities I went over. However I know the programs by no means feel they have excess capacity. [Slide.] Now, what happened with this increase is fairly well known. With more staff and also better managed process, FDA was able to reduce the review times. And overall, priority in the yellow bars here, that's really against unmet medical needs, basically. And then the standard applications are in the gray bars, where there are alternatives out there already. You can see that the time for review of each of those came down during the course of the program. And so there is a significant increase in access to new drugs and biologics. And you're going to hear more about that, I think, from the folks here, the other folks. But more staff and a better managed process have also resulted in better scrutiny by the agency of the applications, and better articulation of the standards. And this is very important. Just for example, CDER issued a reviewer guidance on how to do a safety review about a year ago; how to go through the safety review, and how to prepare a report on the safety review. This is an 85-page document. The current modern safety review is an extremely complex activity. And this is not only for the reviewers, but also explains in a way to the companies all the bases that need to be covered. The reviewers are not only asked to say what's in the application about safety, but what is missing; what hasn't been studied. Review templates by various centers have been developed. A huge number of guidances have been issued by FDA that explain the standards for many important topis. And the review function has been progressively organized and reorganized to really hone it, to make it efficient. [Slide.] PDUFA has also provided value for industry. Because of the decrease in review time, there are big savings for the companies because of the shortened time to get on the market. And the meetings that are held during the user fee program to provide consultation from the FDA are highly valued by companies, as a recent MIT study showed. [Slide.] What are the current challenges for this program, however? Number one is workload. As you'll hear probably from Dr. Galson and Dr. Goodman, one of the issues is the way the fee adjusters are structured really had to do with the number of applications coming in. But once the meetings program was established as part of the user fee program, the desire for meetings with the FDA in consultation has risen sharply. And this is not accounted for; this workload is not accounted for in the fee adjusters. There are additional challenges for the FDA which we could get into in the discussion, if we wish. One, the IT infrastructure and bioinformatics support is still very challenging. Many people have raised issues about direct consumer advertising regulation; the oversight of clinical trials. Again, that is one of the activities covered under the PDUFA program. Again, as a clinical trial conduct changes, it's becoming very challenging. And then preparing for the impact of the new science, as new science starts to really come into the Agency as very innovative products are developed, these tend to be more labor intensive and also raise challenges. So that's an overview, I think, of the program as it stands. And I thank you very much. Oh, one more. [Slide.] The fees--now the total fee, similar to the user fee FTEs, currently user fees in 2004 began outpacing the appropriated dollars for the program. So it is not a majority user fee funded program. Thanks. MS. HENDERSON: Thank you, Dr. Woodcock. And now, from the perspective of the Center for Drugs, Dr. Steven Galson. DR. GALSON: Thank you very much, Debbie. And I'm happy to be here to talk to all of you. I'll try to make up for a little bit of our being behind schedule, and zip through these. I'm going to talk about five issues. [Slide.] The first is a little bit more detail about the submission trends, and the data for the work coming in; the impact of that and PDUFA on the number of meetings that we have with sponsor companies; the result of all this being approval of more new lifesaving drugs; what we've been able to do in terms of increasing the expertise of our staff; and then a little bit on the very, very contentious issue of the connection of PDUFA with the safety of drugs on the market that I know you've all heard a lot about. There are a lot of different ways to measure how much work is coming into the Agency and into the Drug Center. And these are three graphs that cover NDAs, efficacy supplements and manufacturing supplements. And you can see, in general--you're not meant to look at the fine points here--but over the entire period of PDUFA, there's been a gradual increase in the submission of these documents for review by our staff, with ups and downs. It's leveled off pretty much in PDUFA III, but you can see the large trend. But that doesn't really tell the full story, particularly bout what's happened in PDUFA III. Dr. Woodcock touched on this already: and that is the fact that we've gotten a huge increase in the request for meetings, particularly under PDUFA III. You can see we're up almost to--we actually are up to 2,000 meetings a year in FY2005. That's a lot of meetings. And, of course, that doesn't tell the full story either, because with each meeting that we hold with a sponsor company, our staff has to have at least one, or probably two, preparatory meetings to figure out what the approach is going to be. And then after the meeting takes place, there have to be a series of meetings among the staff to figure out the actions that are going to be taken as a result of the meeting. So this is really a huge uncompensated area of growth in work under PDUFA; being very positive for public health and for review and access to new products, but putting huge pressure on our staff and managers. [Slide.] Another way to look at this is the special protocol assessments that we do associated with the early phase of drug development; again, very positive for getting new products on the market, but creating a huge workload for our staff. We provide an assessment in writing within 45 days of getting these special protocol assessments into the Agency. And you can see the large growth in those, again putting pressure on the staff to do more. And these cover clinical pharm tox and all sorts of other areas, as well: stability. [Slide.] The result of all this, again on the positive side, is that the cycle time, the number of times applications go back and forth between the agencies and the companies, has gradually reduced throughout the duration of PDUFA. And this was, of course, one of the goals. We're down to, you can see, in FY'04 really close to one to a cycle to NDA approval. And this is, of course, a huge improvement over two. And the result of all this is that lots of new products have come to market; very, very important for patients. [Slide.] There were 226 priority drugs that represent significant therapeutic advancements, including--and this is not a comprehensive list at all--59 cancer -related products, 144 products to treat infections of all kinds, 63 specifically for HIV and hepatitis viruses, and 73 cardiovascular drugs. So these really cover the gamut of the real pressing public health needs of American patients. [Slide.] And, again, just by way of example, not a comprehensive list at all--and I don't mean to insult any area that's being left out of this--touching on a few key cancer-related approvals, one from a few years ago: Gleevec, and then more recently for leukemia and lymphoma Arranon; drugs to respond to the counterterrorism threat, to treat people who have been exposed to radiation; Alzheimer's disease, a very, very difficult therapeutic area; again focusing on HIV in children; and a very, very important advance, Reyataz IV, enabling patients to take one-daily HIV treatment, instead of this huge cocktail of pills that have to be taken across the day in multiple different combinations; drugs to treat chronic problems like alcoholism; and, again, fairly recently, Bidil was approved to treat a specific sub-population in Black Americans who are particularly at risk for certain kinds of heart failure. So many of these represent important incremental advances in therapies, very important to patients and physicians who spend their lives trying to improve outcomes. [Slide.] The result of the program has as well been to allow us to dramatically increase our scientific expertise. And this again doesn't cover all of the areas of our scientific expertise, but just a few. And I'll point to some of these numbers. We've increased physicians by 40 percent; pharmacists by 47; general health sciences by 56 percent; toxicologists by 50 percent. And the pie chart covers some of the top five medical specialties. You can see: internal medicine, pediatrics, neurology have all grown substantially. And that's very, very important. That gives these applications the opportunity to be seen by more people, more people with a broad expertise across the board in medicine; very, very important to us doing a better job. [Slide.] There has been a lot of attention to safety investments, and safety improvements, and concern about the safety of our products. Some of this attention has caused us to go back and look very carefully at how much of our resources are spent on safety. And we've had to repeat this message over and over again: that safety is an important achievement and an important area of attention across the board in the Center for Drug Evaluation and Research and, I know, CBER as well. It's not just focused in one or even a couple offices. Across the board in CDER, we spend 50 percent of all of our resources on drug safety. And this touches every single one of our offices. There's a lot of additional work, attention, investment, and research, and procedure that has to happen in the drug safety area. But we have managed to make improvements and increases in investment in drug safety under the PDUFA program. Particularly with the last round of PDUFA, we're able to spend some of the user fee funds on post-marketing surveillance. We hope to see that continue and maybe be expanded. [Slide.] We've been working on reorganizations of the Center for Drug Evaluation and Research to focus more attention and staff on drug safety areas, both process of reviewing the drugs and developing policies, with appropriated funding earmarks, and increased focus on PDUFA IV as I've talked about. And we've got $10 million new dollars in the FY'06 budget that we hope will actually result in an increase as the budget process rolls up to a finish, which is going to be very, very important. So these changes have resulted in continued improvements in both pre- and post-market safety in products. [Slide.] But to really make important strides in drug safety--and we have to focus on this over and over again--we have to continue to keep our eyes on scientific investments; investments in ways of reviewing drugs, in ways of looking at data, and creating data that allows us to better predict the safety of products, and better identify safety problems that drugs run into after approval. Without that scientific improvement, it's going to be tough to really make important large-scale increases in the safety of products. There has been some attention among academic and outside researchers on the effect of PDUFA on drug safety. You're going to hear about those in more detail today from some of the authors. Researchers both at Tufts and MIT have shown that there hasn't been any difference in drug withdrawals across the PDUFA program as compared to the pre-PDUFA area. [Slide.] So, in summary, we feel that the program has dramatically contributed to public health and improved drug review; the expertise of CDER staff; the processes in CDER have dramatically improved over the course of the program. We've made some advances in safety, but we need a lot more. And I think we can all agree with that. And, lastly, again, we haven't seen any evidence of a relationship between these advances in speed and adverse impact on safety of the products that are approved. Thanks. MS. HENDERSON: Thank you, Steven. And last, but certainly not least, from the Center for Biologics, Dr. Jesse Goodman. DR. GOODMAN: Good morning. You're going to hear some recurrent Themes, and I'll try to zip through this quickly. [Slide.] But let me just say, as it says at the bottom here, when you look at the vision of our center, which is to improve public and individual health, including, where possible, globally; and truly not just assure products are safe and effective, but facilitate their development and access to them; and then strengthen us in terms of our expertise and abilities, PDUFA has provided essential support in those areas. And I think Janet's breakdown of the support that PDUFA has provided FDA is very illustrative. I should mention that this is a process that has global impact, not just U.S. impact. It's increasingly an international industry and, for example, I just came back from a WHO meeting where, if you look at some of the promise of some of the products developed here, vaccines for Rhoda virus, vaccines for haemophilus, which have pretty much eliminated that form of meningitis in this country, the potential benefits of those all over the world is just incredible. [Slide.] This is just a little bit about our performance under PDUFA. And as Steve and Janet have said, it's not just the funds--and Scott also mentioned--it's also how we look at and manage the process, and putting energy into the effectiveness and efficiency of what we do. And I think this shows you, going from '93 there on the left, to '97 here, the timeliness of meeting first actions within goal on PDUFA I, then PDUFA II, and most recently with PDUFA III. And you can see we've moved from an organization where there were these delays and lags, to one that is highly efficient in meeting what, for us, were very large and complex applications, I think is an efficient review process. [Slide.] Steven mentioned the meetings. These are extremely labor intensive. We find them very valuable, not just for companies, but also for our people to have an interactive, science-based process which leans much more to what I talk about as problem solving rather than just problem finding, which is what happens when a process is completely iterative. [Slide.] And here again you can see the improvements over time, PDUFA II, and the very high level of performance in meeting various meeting actions in PDUFA III. [Slide.] As you saw with the Center for Drugs, this has translated, I think, into a very development process. It doesn't mean there aren't challenges for development that remain for both the developers and the FDA, but I think you can see here the number of cycles has dramatically gone down for both standard and priority BLAs. And I think that's a very important accomplishment that indicates that a lot of this communication is working. And I have to say that I find usually when problems occur they're about communication. So I think communication is a very good investment. [Slide.] You heard a bit about the number of meetings, and we see similar things. In addition to these PDUFA meetings and formal meetings, we also have a tremendous number of informal meetings, phone calls, that both result from those meetings, or take the place of them. And, again, I think that this is a form of communication that, as Steve said, it's not just these formal PDUFA meetings that we track that have grown, but all the communication and planning that occur around them. And I think everybody agrees this is valuable, but labor intensive. [Slide.] What are some of the results on this health level? This is just an example again, as Steve provided, of some of the recent important approvals. The first accelerated approval based on probably surrogate markers of a vaccine this year, bringing another influenza virus vaccine manufacturer into the United States; a new technology of conjugate meningococcal vaccine; new combination products for boosters in immunization in the country; a number of new immunoglobulin, so important in treating immunodeficient patients, whether congenital or acquired; products for Rhesus immunization; products for preparing us for bioterrorism, such as vaccinia immune globulin, very high profile products. In addition, for many of our products, their use is broad, and they're assessed in different settings, and there are some important efficacy supplements for hepatitis A vaccines and coagulation factors. [Slide.] So, again, to summarize, PDUFA has been an important factor in supporting an expert and also efficiently managed review process at FDA, including CBER. I think an extremely important feature is the intensive interactions with sponsors during product development. And I would also say the impact of this goes beyond the meetings. There's a cultural impact, I think, for both manufacturers, investigators and academia and the FDA. I'd also like to say that for some the new technologies, as Janet mentioned and Dr. von Eschenbach mentioned, these interactions are particularly important. They enable us to share information with industry that can help them in the development process, and they also enable industry to keep us up to date. They also point out areas where there are needs for guidance, which again can be very important when you're dealing with things like cell and gene therapy, where you're sort of blazing new pathways, but can also be quite important for existing products as they evolve. And we think the result, in part, is earlier access to safe, effective and innovative products. And these are products, such as vaccines, and blood products, in our center, that are essential to both medical care and our public health system, and to our country's preparedness. So, that's our summary of performance, and the role of PDUFA in our center. So we'll look very much forward to your input today and in the coming months. Thank you. MS. HENDERSON: Thank you, Jesse. And thanks to our first panel. I'm going to ask our second panel to come forward an join me at the table to my right. That would be the panel of academic research groups, which includes Doctors Kaitin, Woosley, Berndt and Tilson. And while they're coming forward, I will introduce the first of the speakers on that panel, who is Dr. Ken Kaitin. Dr. Kaitin is the Director of the Tufts Center for the Study of Drug Development, an academic drug policy research group providing strategic information to help drug developers, regulators and policy makers improve the quality and efficiency of the drug-development process. Dr. Kaitin is also associate professor of medicine at Tufts University School of Medicine. And so, without further ado, will let Dr. Kaitin get started. Panel II - Presentation by Academic Research Group DR. KAITIN: Good morning. Welcome. It's a pleasure to be here, and I appreciate the opportunity to participate in this hearing. As you just heard, I am director of the Tufts Center for the Study of Drug Development. And for 30 years we have collected and analyzed drug development data to report on the time, cost and risk to bring new products to market. What I will talk about here is a series of analyses that we began in 1985 to look at new drug approvals by the FDA, and trends in times and marketing of those products. I believe that these three-year trends give us a good example, or good illustration, of changes that have occurred in the United States as a result of the Prescription Drug User Fee Act. My talk is going to be divided up into four themes. [Slide.] The first theme is something that we've already heard about to some degree, and certainly many people are aware of. There are conferences and other workshops that are devoted to the issue of productivity in the industry. Over the years we have looked at the numbers of products that have been approved. Again, these are in three-year intervals. [Slide.] If we look at the number of products approved, there was a big jump in 1996 to '98, as the FDA was clearing out the backlog as a result of the mandate of the Prescription Drug User Fee Act. And then that number declined. Now, what we had looked at and seen over the course of leading up to this last three-year interval, is that although there was--I don't know if you can see this--there was a drop in standard drug approvals, the number of priority approvals remained remarkably consistent over the past decade or so. However, in the most recent time period that we've looked at, we've seen a drop-off also in priority drug approvals, and that drop-off represents a drop of 34 percent. So the decline in productivity affects not just standard approved products but also priority approved products. Now, why is there this drop-off in productivity? [Slide.] One of the main reasons is the increasing time cost and, of course, the riskiness of new drug development times and approval times over two decades, again starting in this first time period, '84 to '86, and looking at the most recent time period, we've seen the well-described reduction in FDA approval times--these are not review times, but approval times--there was a slight increase, but that's an insignificant increase, in the 2002 to '04 period. However if we look at clinical development times over that same time period--and this refers to the time from IND filing to NDA submission--we see, after an initial drop-off after the '93 to '99 period, down to 6.4 and then 5.8 years, we've now seen a continuation of the trend that we were seeing prior to PDUFA of seven years to get these products through the clinical testing phase. That's an increase of 21 percent; certainly supporting the notion that it's getting more difficult, and consequently more expensive and difficult to get products through the clinicaldevelopment process. Very significantly, this affects not just standard drugs but also priority drug approvals. Again, prior to PDUFA we saw this steady increase in the amount of time that priority drugs took to get through the clinical development process. We did see a drop-off post-PDUFA, but now we're almost up to the level of the pre-PDUFA period in the amount of time it takes to get priority drug approvals, the most important drug approvals, through the clinical development process. This increase from 5.6 to 8.1 years represents a 45 percent increase in clinical development time. And, of course, if you add the increase in overall priority approval times of 33 percent, you end up with a considerably long period of time to get these products through the development process than we've seen in past years. And this is, of course, a cause of concern. [Slide.] And it's not just the priority versus standard. If we look across different therapeutic categories, we can see that, in fact, the trend is fairly consistent across those categories. Just to work you quickly through this slide, this is seven therapeutic categories, across the bottom: anesthetic/analgesic, endocrine, anti-infective, neuropharmacologic, cardiovascular, respiratory, and anti-neoplastic. And this is the clinical development time for the '96 to '98 time period. And then we can put the '99 to 2001. But if now we look at the most recent time period, in five of the seven therapeutic categories there, we see the longest clinical development time in the nine-year period for those categories; most significantly, 11.1 years in the neuropharmacologic area. Coincidentally, it was just about a month ago or three weeks ago that the FDA said that they were going to look into longer clinical development times to get more efficacy and safety data on neuropharmacologic compounds. In fact, the advisory committee that reviewed this voted unanimously not to extend the length of the clinical development times, or clinical trial size, for neuropharmacologics. And I would say this is an example of the process working the way it should. [Slide.] Drug Safety. Dr. Galson just discussed that. We are one of the groups that have been looking at this since we first looked at the drug-lag issue in the 1970s. At that time, the issue was: are we slower but safer? Now the question is: are we faster but less safe? [Slide.] And confirming some of the data that the FDA itself has put out, if we look at the total number of approvals going back from 1980 through 2004, these are the total number of approvals over those years. If we look at the withdrawals of products for safety reasons based on the year that the product was approved, we see no consistent trend, despite the increase of six numbers of products that were withdrawn from the 1997 time period. The fact is, there were very few before that, very few in the later years, despite the fact that some of these products may still come off the market, the fact of the matter is: there is no consistent trend in the products that have been taken off the market for safety reasons. [Slide.] And, in fact, if we look at the pre-PDUFA period of 1981 to 1992, and then the post-PDUFA period of 1993 to 2004, we see the total safety withdrawals of eight and 11, which is 2.8 percent for the first period, pre-PDUFA, and 3.1 percent--a slight increase; these are exactly the same numbers that the FDA put out in their safety report recently--this is an insignificant trend, again reflecting the fact that the overall percentage of products taken off the market for safety has not gone up post-PDUFA. Significantly, much of the debate is focused on whether there is a relationship between speed and likelihood of a product being withdrawn for safety reasons. Dr. Galson talked about this. [Slide.] If we look across therapeutic categories, we look at all approvals and then those that have been taken off the market, we see in some therapeutic areas--respiratory, cardiovascular--the time to approve the compounds that were withdrawn was faster than those that were not; but in other therapeutic categories, it's the same or even longer to review the compounds that were eventually taken off the market for safety reasons. The bottom line is that there is no relationships--no relationship whatsoever--in the time to approval and the likelihood of a product being withdrawn for safety reasons. [Slide.] The final theme I wanted to discuss is the attractiveness of the U.S. market. I think starting in the early 1990s with the Prescription Drug User Fee Act, as well as many other issues and features of the United States market, the United States market is a very attractive market for manufacturers to bring their products to market first in this country. [Slide.] In fact, in the most recent analysis, 55 percent of the new drug approvals in the United States were first marketed in the United States. And you can see the numbers for the prior marketing of those compounds. [Slide.] To get a better sense of how this has changed as a result of the Prescription Drug User Fee Act, in the top line here--the blue line--this is more than one year of foreign marketing. That was already declining somewhat, but I believe that PDUFA hastened that decline rapidly. And although there's been a slight increases, that's a very small increase. The fact of the matter is: the U.S. as a first market for new products has gone up consistently for this time period, despite the small change there, and now is at 55 percent of new product approvals marketed first in the United States. So, in conclusion: there is a decline in NME output, and that has declined over the PDUFA era, and that includes not just standard but also priority compounds. There is an increase in clinical times, and that has become somewhat of concern because it's offsetting some of the benefits that we have seen in terms of the reduction in approval time to get these products through the FDA. Despite this slight rise in percentage of products withdrawn for safety, there is no clear evidence that there is a correlation between speed of approval and the likelihood of a safety withdrawal. So the U.S. remains an attractive market for first launch of prescription drugs. So moving forward, I echo what was stated by Dr. von Eschenbach and others from the FDA: the FDA needs to continue working through the critical path to identify better mechanisms for assessing safety and efficacy, moving through the clinical development process; and also the FDA should be looking to identify and address regulation-related causes of lengthening clinical development times. And, in terms of drug safety--again echoing something stated by Dr. Galson--the FDA should be looking for better systems of identifying safety problems early on, before products move through the clinical development process, but also better systems for identifying and taking action on products that have significant adverse events, once those products are on the market. Thank you. MS. HENDERSON: Thank you, Dr. Kaitin, very much. Our next speaker, well known to this audience, is Dr. Ray Woosley. Dr. Woosley is currently the president and CEO of the Critical Path Institute, also known as C-Path, which is a nonprofit corporation formed by the FDA, SRI International, and the University of Arizona to accelerate the development of safe and innovative medicines. Since 1999 he has also directed one of seven federally-funded centers of education and research on therapeutics, also known as the CERTs. Dr. Woosley? DR. WOOSLEY: Thank you. Thank you for the invitation to say a few words about PDUFA and how important it is. As you can tell, I'm a devotee, a convert, to the critical path. I've been drinking from that lemonade that Janet's been serving, and have a great deal of concern about the drug development process. In the next few minutes, I'm going to quickly go through some slides, many of which you've already seen, to talk about the impact of PDUFA; talk about how it relates to the Critical Path Initiative; the purpose of the Critical Path Institute that we've created, but only as a model, not as a solution to the problem. I don't think we can take that on--but as a model for new relationships; and then a proposal for a PDUFA initiative. As you see, the review times have come down. [Slide.] I'm going to quickly go through this slides. You might say it was already heading down, but it clearly has had an impact, and there's no doubt about that. [Slide.] There has been a product approval increase transiently, as you've seen. And Ken has more recent data to reinforce that point. Also, the submissions increased transiently, but they've gone down again. [Slide.] At a time when we as a nation--and I think everybody here knows this diagram from the Critical Path Initiative showing the investment in U.S. pharmaceutical R&D increasing 250 percent, and the NIH budget doubling in recent years, so we've made a tremendous increased investment in science, but the number of new products, new drug applications during that time as decreased. New biological applications have decreased. So PDUFA has done some very good things. It's given the Agency the resources it needed to get rid of the backlog. But I think it's also unmasked another problem that exists in pharmaceutical or medical problem development. [Slide.] Part of that is in the success rate. It still remains a very high risk business, with these data in '04 showing 11 percent. That may be a decline from 19 percent success rates 10 years before that. So we still have either a declining, or at best, a very low success rate in a very high-risk business. And the question is: what is happening to the incentives? What's happening to the return on investment of the over $60 billion we spend on pharmaceutical R&D each year? [Slide.] Again, the Critical Path Initiative called this problem to my attention, and I think all of our attention, in the fact that pre-clinical development and clinical development these delays are the biggest part of the problem. And I think Ken's numbers that he showed today reinforce the increasing development time as the major disincentive to investment in new medical product development. [Slide.] The response to the Critical Path Initiative has, I think, been overwhelmingly positive. There have been very few negative responses. I think everybody wants new medicines. They want them quickly. They want them to be safe. In the pharmaceutical industry, several companies have created their own Critical Path Initiative task forces to work and develop their own internal processes for improving the processes. [Slide.] The NIH collaborations have grown. The FDA has collaborations with NCI, and Human Genome Research Institute, to address the Critical Path Initiative. And academic, as you've heard--well, I also mentioned the Critical Path Institute--we're really not part of academia. We're a nonprofit outside of the University, but partnering with several universities, including our founding partner, the University of Arizona. But within academia, without even funding available, units have been created at UCSF, the Center for Drug Development Science, that Carl Pack leave, and JETS, have begun to work on the Critical Path Initiative at MIT, I think you'll hear later, the Center for Biomedical Innovation was created; at Indian, ISIS; the ECG Warehouse, at Duke. And now we've just heard last week about 11 universities that are coming together to address the manufacturing challenges that are identified in the Critical Path Initiative. So I hope I can say with confidence that everybody believes that this is something who's time has come. [Slide.] We certainly looked at that and created a nonprofit, publicly funded. We have $10 million from the State of Arizona, and the community, to create neutral ground where scientists from the FDA, academia and pharmaceutical industry can work together to accelerate the development of safe medical products. Well, you may say: well, that's happening already. I think that's good. And we've heard about the collaborations. We believe that this "neutral ground" concept is important for some of the things, and some of the discussions that have to take place. C-Path won't develop drugs or medical products. We will work on the process. As happened with the Food Center--the National Center for Food Safety and Technology--we believe is a proven concept. It was established over 15 years ago as neutral ground. And in their website, the Moffett Center is described as "neutral ground where industry, academia and FDA scientists work together to address food safety. And that was the model that we were aware of and used as we created the Critical Path Institute, or C-Path. It's neutral territory, publicly funded. Industry consortia can fund projects if it's done with the industry and FDA come together and agree, as they do in the Food Center, that there's important work that needs to be done. And that would be done with transparency and oversight; project-specific funding; oversight board with the FDA, industry and consumer and patient representatives should be present. [Slide.] We believe that PDUFA, as I said, has uncovered this other problem. And the FDA has issued its White Paper, and it's willingness to work and partner on this. But there are some missing ingredients. A very big one is the lack of funding for the FDA to participate. How can they have the staff to work on these projects and attend these meetings? They need the internal funding. And then there needs to be a funding for the method development and validation that's part of the call in the Critical Path Initiative. Most industries invest 5, to 10, up to 15 percent of their annual budgets into changing the process that they use to make their process. So we believe that that kind of funding into developing the process--it's not, as I've said in other audiences--it's not sexy. You won't get an NIH grant for this. You won't get tenure, or you won't get publications for this kind of work. But it is essential in the development of new medical products. There's also a lack of a process to prioritize and coordinate the Critical Path Initiative activities. That's something that needs to be funded. There's also at this time a lack of an understanding of a laboratory for testing new methods and biomarkers. Many companies don't want people experimenting with their products as they develop new methods. So we've got to find a way where we can test those new methods in an acceptable environment. So the proposal that we have--on the next four slides-- [Slide.] --if Critical Path Initiative funding should be made available to the FDA, perhaps a small percent increase in the PDUFA fees, to fund the work at the FDA, with a match from Congressional appropriations, so that the Agency would have the funds to hire the staff to do the work on the process that needs to be changed. [Slide.] The funding for the methods development and validation also needs to be obtained. And, there again, industry consortia, operating with FDA advisors on, we think, neutral ground is important for that. We think that there needs to be a tie-breaker when the industry and the FDA may disagree about how to go forward with the process. Outside scientists can help generate the consensus for which methods need to be tested, and how. [Slide.] PDUFA grants and contracts for work mutually agreed upon by a CPI--Critical Path Initiative--steering committee would be one way to do that work. [Slide.] And how do you develop that process? We suggest using the Moffett Center model, where there's an oversight board, with FDA representatives, industry representatives, consumer/patient reps, and independent scientists and experts who work outside of the environment of the regulators and the regulated. [Slide.] And the testing environment is perhaps the most difficult area, but I would like to suggest that in life-threatening illnesses, many of the technologies could and should be applied to accelerate the development of safe drugs; orphan drug development. This is an area where Congress mandates the FDA to assist in the development of orphan drugs. Why not have that applied more broadly to all drugs, especially those with life-threatening illness, and for personalized medicine. I would suggest, and perhaps, others be considered as the laboratory for where the process of drug development, or medical product development can be applied. [Slide.] In summary, the regulators and the regulated, I believe, need neutral ground where they can work together to improve the process of drug development. I think PDUFA could be the catalyst for this change, and a shared investment by government and industry would be the way to do that. Thank you. MS. HENDERSON: Thank you, Dr. Woosley. Our next speaker is Dr. Ernst R. Berndt. He is the Louis B. Seley Professor of Applied Economics at the MIT Sloan School of Management, and co-director of the Biomedical Enterprise Program at the Harvard-MIT Division of Sciences and Technology. He's also the director of the National Bureau of Economic Research Program on Technological Progress and Productivity Measurement, and co-director of the Center for Biomedical Innovation at MIT. Of particular note, much of Professor Berndt's recent research has focused on price, output and outcomes measurement in the health care industries, and on regulatory policies at the U.S. FDA. Dr. Berndt? DR. BERNDT: Thank you. I have more slide material than I have time to discuss, so I'm going to skip through a number of the slides. You should have in your packets, however, a complete set of the slides. Today I'm going to talk about, briefly summarize, results from two recent research projects. [Slide.] The first was published this summer in a peer reviewed journal, Nature Reviews: Drug Discovery, and the second is soon to be published, but is publicly available, and if you want a copy, please let me know. [Slide.] Why PDUFA? Other speakers have discussed this briefly already. FDA, as you know, has two missions: one is to assure safety and efficacy of therapeutics; and the second is to help speed access, or marketplace access, to innovative therapies. And it was this second mission which seemed to be less completely fulfilled. You can see here that if you, depending on what particular two years you choose, you can see quite an increase here in terms of review time, from 22 months in 1970, to over 32 by 1990. In response to that, Congress addressed the issue by passing a serious of Prescription Drug User Fee Acts, in 1992, 1997 and 2002. [Slide.] And at least if you look at these rather quickly--this is a study that was published by a Tufts research--there appears to be a decline in the approval time at the FDA. [Slide.] Now, I should mention that under the PDUFA legislation, all that was mandated is that the FDA review and act on applications. This did not necessarily translate itself into more rapid approvals; simply "act and review on." And so the issue is: how are these linked? I might add that, as several of the speakers have mentioned, and as a White Paper that was released a few days ago emphasizes, to date the user fee program has been very important for funding at the FDA; roughly about 50 percent of money spent in review of human drug applications--I think it's up to 52 percent this last year--emanate from PDUFA. And, as Dr. Gottlieb mentioned, user fee programs have long been elsewhere. We've had it in the U.S. patent system for centuries, and we have it elsewhere in the world. The EMEA that about 75 percent of its funding come from industry fees. The U.K. is funded entirely through user fees. Japan has no user fee program. [Slide.] All right. So, for the first set of issues we wanted to ask is: to what extent have PDUFA I and II been associated with incremental reductions in NDA/BLA review time, controlling for other things that were happening, like patient advocacy groups, change in the composition of therapeutic class applications, and so forth. Secondly: what is the effect of PDUFA on safety withdrawal rates? And thirdly: what would the time trend of NME approvals have looked like in a world without PDUFA? Would the R&D slowdown have improved, or would it have been exacerbated? [Slide.] The research methods we employed in this first study were using the universe actually of 662 NMEs that were approved by the FDA between 1979 and 2004. And we used what's called multivariate regression analysis. And I won't go through the details of that here. [Slide.] These are just some of the explanatory variables that were employed. You certainly don't want to spend too much time on this, but if you look at the upper right-hand corner, the basic result is that while approval times at the FDA had been declining a bit pre-PDUFA, about 2 percent a year, during PDUFA I this accelerated to about 10 percent decline per year. Then, during PDUFA II, they continued to decline, but at a lower rate of around 5 percent a year; so, clearly, suggest that PDUFA is associated with shorter review times. [Slide.] You can simulate them using the estimated model: what would the world have looked like without PDUFA? As you see here, if you look at, for example, when PDUFA came in, that was about 24 months review on average. Had PDUFA not been implemented, that probably would have declined, at least the model predicts, to about 20 months. In fact, however, it declined to less than 15 months. [Slide.] I think is probably one of the most interesting slides of this presentation. What we did is we said: let's assume that the dates on which applications were filed at the FDA was unaffected by PDUFA, but that the previous sort of track record would have continued on. What would have happened instead? This is the number of new drug, or NME approvals, that actually occurred, in blue, versus what would have happened had PDUFA not been implemented, in orange. And what you see basically is that whole curve is shifted to the left. By 1997, for example, in the bottom of this figure, we say what's the cumulative number of NMEs that were approved, by 1997, at the end of PDUFA I, had PDUFA not been implemented, the model predicts that only 187 drugs would have been approved, whereas, in actuality, 220 were. So that's a 15 percent acceleration. By 2002, 389 drugs were actually approved. What would have happened in the absence of PDUFA is about 376, about 3 or 4 percent less. So you see this backlog that was basically filled out and much more rapidly acted upon in response to PDUFA. And the bottom line, then, is that effectively what PDUFA did is it meant that many patients now had more rapid access to innovative medical treatments. Now, what about safety? [Slide.] We can compute safety withdrawal rates, and there are only three problems that I can think of with safety withdrawal-rate calculations. One is the numerator; two is the denominator; and three is the time span. Other than that, they're just straightforward. So--numerator. What constitutes a safety withdrawn, when a drug is withdrawn and then reintroduced later on under more strict conditions, is that a withdrawal or not? Denominator--what sample of drugs should be included? Biologics? Vaccines? Radiologicals? Annual vaccines? There's some ambiguity there. Third, the time period definition--what defines "pre-PDUFA" and "post-PDUFA?" Is it when drugs were approved? Or when drug applications were submitted? You can move these numbers around a fair bit. Because withdrawals are so relatively rare, you can move these numbers around quite a bit just by using calendar year versus fiscal year, and a variety of things like that. And one should bear that in mind. With that caveat, let me just mention three studies. [Slide.] One was a study published by the GAO, and focused only on chemical entities, not biologics. And although they didn't actually do the calculation, we used their numbers and calculated that there was no significant difference between those calendar years '86 to '92, versus '93 to 2000. There was an internal FDA analysis that was also put out. And, again, you can do a test on whether there was a significant difference in terms of approval dates pre- and post- PDUFA; withdrawal rates based on approval. Again, no significant difference. And we did a study of that, as well. Now, all these studies suffer from theproblem that there's differential time on themarket. Drugs approved before PDUFA have been on the market much longer, have had greater opportunity, if you will, to experience safety issues. And so what we did was do a survival analysis, which folks, I'm sure, in this audience, know very well, a Kaplan Meier curve. And I'd like you to look at two things here. Basically, the dark blue is the cumulative survival rate pre-PDUFA, and the more purple one is the post-PDUFA. Notice two things: the first thing is they tend to converge after about 12 years on the market. And, secondly, notice how--I mean, this graph kind of accentuates the difference because it starts at 97 percent, not zero percent--notice that drugs, at least in terms of calendar time, are now being withdrawn from the market more rapidly. Whether they're being more rapidly withdrawn in terms of exposure to patients is not clear, and is worthy of some examination. [Slide.] This slide just simply points out that drugs that were withdrawn from the market are now withdrawn much more rapidly; the mean of 2.4 months post-PDUFA, compared with 5.19 pre-PDUFA. [Slide.] Okay, let me switch to the second paper. As Dr. Kaitin and others have mentioned, while there's been an admirable success in reducing review times and approval times at the FDA, we can't say the thing about what's happened to clinical development times. These things haven't budged for 25 years; still about six years. And so what I did with some of my students at MIT is we decided to interview 50 senior R&D folks at a variety of biotech and pharma companies, as well as a few CROs, and we also interviewed eight senior staff members at the FDA. This was all done in the first half of last year, prior to Vioxx withdrawal and the anti-depressant hearings. It was pretty evenly divided between biotech and big pharma. And we asked them what can be done to make the clinical development time more efficient? Is the FDA a problem? Is the industry a problem? And basically we've written up these results at some length. Let me just talk about a few of the questions we asked. One was that we asked industry whether they thought FDA was doing a good job in terms of preventing unsafe drugs from coming to the market. There was general feeling by industry that the FDA was doing a good job of that. I would say the industry had "guarded respect" is probably the right choice of word to use. However industry also believed that in a number of cases there were significantly delayed review times that ultimately had a substantially negative impact on the public health. I might add that in this thing we didn't interview legal counsel or CEOs, or CFOs. This was senior R&D folks, who might have a different view than others. [Slide.] Now, more germane to this particular hearing, we also asked questions to both industry and the FDA: where would additional communications with the FDA be most valuable? And what was sort of interesting: industry believes that additional communications and interactions with the FDA would be very valuable across all phases of the development process, from pre-clinical IND to Phase I, Phase II, Phase III, and the actual NDA. By contrast, in four of these five stages, the FDA rated the value of additional interaction much lower--significantly lower--than industry. In one case, however--and I think it's a very notable case--the FDA and industry agreed that additional communication would be very valuable: that was early on in Phase II, particularly with respect to dosing issues. [Slide.] And much to our surprise, industry seemed to be willing to put their money where their mouth was, at least the R&D directors were. And industry interviews indicated that 'Our company would be willing to pay PDUFA type fees" particularly in Phase II. If you look at that, 80 percent--or 990 percent all together--were willing to pay more than $100,000 for additional contact with the FDA. The FDA working paper issued over the weekend indicated that, in fact, there have been a more meetings--I think they're called Class B meetings, in particular. And that suggests to us at least, on this project, that there might be some very fruitful discussions with industry and the FDA in terms of using additional user fee program to fund Phase II meetings. [Slide.] We had a number of recommendations that came out of that, as I just mentioned. Two of them were to institute better metrics and goals for development in exchange for PDUFA-like fees; increase interactions prior to Phase III, funded by user fees. I have a friend at Harvard University, Dan Carpenter, who's also just written recently suggesting that user fees might be tied to post-launch surveillance issues. We did not ask those questions in this survey, nor did we link user fees to DDMAC approvals of advertising content. But those are issues that might very fruitfully be discussed. [Slide.] Finally, we've done some additional work in this area that tries to monotize some of these benefits and costs of PDUFA. That's now in the peer-review process. If you want a copy of that paper, you can download it from te National Bureau of Economic Research. Thank you. MS. HENDERSON: Thank you very much, Dr. Berndt. Finally on this panel we have Dr. High Tilson. After retiring from GlaxoWellcome in 1996, Dr. Tilson joined the full time faculty of UNC School of Public Health in Chapel Hill where is a clinical professor of public health leadership, adjunct professor of epidemiology and health policy, and senior advisor to the dean. In addition, he is adjunct processor of social medicine at UNC; medicine at Duke; and pharmacy at UNC. He is an advisor to government andindustry in health outcomes, drug safety, and evidence-based health policy, including most recently public health preparedness. Of importance to the topic at hand today, Dr. Tilson chairs the National Steering Committee for the Centers for Education and Research on Therapeutics--the CERTs program. Dr. Tilson. DR. TILSON: Thanks, Madam Moderator. And, in fact, thank you for actually giving my talk. My reason for being here is to let you know that the Centers for Education and Research and Therapeutics--the CERTs--are here to help you. In fact, I have three very simple messages. The first is: the CERTs belong to the FDA, and the FDA needs to use them. The second is: the CERTs belong to the FDA, and the FDA needs to build them. And the third is: PDUFA provides an extraordinary opportunity for the FDA to leverage its work with the CERTs even more than it has up til now. It's wonderful that I get to be the last member of this panel, because I get to bring you a terrific success story. I'm very optimistic about what the CERTs have already been able to achieve, and the promise here, particularly in the face of renegotiating PDUFA, is quite extraordinary. The CERTs were part of the second regulatory revolution. If PDUFA was the first, then certainly the FDA Modernization Act--or FDAMA--was the second. And the CERTs were created by the FDA Modernization Act in 1997, specifically by act of Congress, to extend the public health role of the Food and Drug Administration through education and research, beyond simply the regulatory stick. While directed to the Food and Drug Administration, it is administered by AHRQ, through an extraordinary partnership between AHRQ and the Food and Drug Administration--more about that in just a second. We have seven centers out there already, with four more currently being considered, and shortly, I hope, to be approved and reported. And that gets us about halfway there to the total number of 22 which, at least our steering committee feels, the nation needs. There's an opportunity for PDUFA if there ever was one. We have almost 300 projects up and going. And if there was ever a success story, it was the public-private and public-public partnership that was part of the FDA Modernization Act mandate, with over 130 partners working with these seven centers. And over 200 peer-reviewed publications--obviously publications aren't the output; improved health is the output. And so one of our accountabilities is: so what? [Slide.] Let me just touch on the Congressional authorization. You my handout, and I don't plan to read this slide in any great detail, except to point out that in its wisdom, I must say added by Ray Woosley who is a member of our CERTs steering committee, the Chair of the Arizona CERT, and one of the inspirations for the CERTs movement, Congress realized that we have to have research in order to communicate more effectively, then we have to communicate more effectively and have research to document that we have done so, and provide the objective clinical information to all of those in the decision making system. Finally, of course, and quite critically, Congress also suggested that we have to have research on comparative effectiveness, cost-effectiveness, and safety of drugs, biologicals and devices--some of the things that a marketplace funded primarily by the research-based pharmaceutical industry simply can't and won't do by itself. And it represents a significant new role for the Food and Drug Administration, mandated by FDAMA, but not funded yet through PDUFA. [Slide.] The model for public-private partnerships is shown on the next slide. And again, without going to great detail, let me just point out that public-private partnerships are taken deadly seriously by the CERTs. We have a mechanism to review them and ensure the independence and trustworthiness of the academic process that gets brought to bear on this process, without turning our backs on industry, regulatory and commercial partners, who know more about the subject than we may, and certainly have a major stake. So creating the ground rules for this--the "neutral harbor," to use the term that's already on the table--was a critical objective for CERTs. And we created a vision statement to reflect that; namely, "to serve here as a trusted--"--with that as the operative term--"--a trusted national resource for all the people who are seeking to improve health through the best use of medical therapies. [Slide.] This organigram simply documents the points that I've made. The Food and Drug Administration work collaboratively with AHRQ to oversee this program. There is a coordinating center located at Duke, and seven centers which work collaboratively with the coordinating center, listed here, including Arizona CERT. And there should, of course, be a dotted line out there to the C-Path Initiative, which is one of the CERTs partners, co-located by and fostered through the University of Arizona; the University of Pennsylvania, Vanderbilt, University of Alabama at Birmingham, the University of North Carolina--go 'Heels!--and the HMO Research Network, as well as Duke University, a separate CERT. This entire process, however, is guided by a national steering committee, upon which the Food and Drug Administration, AHRQ, and the Centers for Disease Control all participate. There's also at-large public participation, most recently through the National Health Council, and before that, through the National Consumers League; and professional oversight, most recently through the American Nurses Association, and currently through the American Public Health Association. And big pharma has a seat at the steering committee table as well because, of course, they are essential partners in moving this forward. [Slide.] The next slide shows the inventory of centers, and I leave that to your reading. But suffice it to say: centers, in addition to be generalists in improving the nation's therapeutics, have their own areas of specific focus and expertise, ranging from infection control to addressing the problems of children. Incidentally, watch this space for the announcement for the next four CERTs which will include, among others, one in the long-neglected area of devices, and another critically needing advancing: that is the consumer perspective, particularly risk and benefit communication involving consumers. [Slide.] Well, all right. So what do the CERTs bring to this table? And why is this an item for PDUFA? Well, the answer is: the CERTs do research. And here is an inventory of the sorts of research the CERTs do: patterns of use; inappropriate, unsafe use; understanding risk management; documenting that risk management tools may or may not be effective, and how they might be effective; and particularly, of course, apropos of Steve Galson's critical comments, safety surveillance methodology, in partnership with the Food and Drug Administration. [Slide.] I list a couple of examples on the slides. And I don't want to go into them in any great detail. I just wanted to put some flesh on these bones, looking at something as important and expensive as transmyocardial revascularization, for example. To understand when it is used appropriately, and when it is not, will help the Centers for Medicaid and Medicare Research decide whether they do or don't wish to fund, and under what circumstances. So being a partner with CMS represents a critical dimension for the CERTs, as well as partnering with other Federal agencies. Here the possibility of monitoring patterns of use will help us to understand and learn from off-label use. Off-label use isn't good or bad. It's just off-label, and it represents use without the data available, and therefore a great opportunity for us to use PDUFA funds to learn from that experience. [Slide.] FDA is co-sponsoring some work with the CERTs that is extraordinarily important, I think, looking critically at the large automated population-based data sets out there. HMO Research Network is one of our seven CERTs, for example, and has the population of the sixth largest state in America of covered lives, for whom we have automated data of all prescription drugs, and all major medical outcomes. And yet we don't have a proper demonstration of their value in generating and documenting signals of possible adversity in drug use. Well, Food and Drug Administration is partnering with us to do so. And Ray Woosley pioneered the QT drugs registry, and from that a tremendous groups of learning opportunities, including curricula for medical education. [Slide.] CERTs are a convener. We've convened a series of think tanks, workshops. And it is said by many of our colleagues at the Food and Drug Administration who collaborated on five, looking at risk-management, its communication, assessment; working with media and the risk; balancing benefits against risk and so forth--that this thinking from these workshops and think tanks was instrumental in helping the Food and Drug Administration to develop its response to Congress for a program of guidance for risk management. [Slide.] All right. So here's the inventory of the things that I've said; represent things that Food and Drug Administration, as it contemplates PDUFA, particularly in the face of the drug safety work, which you already heard from Dr. Galson represents great progress, but a work in process, needing more work, might wish to pursue. Particularly here, the Food and Drug Administration has an extramural grants program to fund research in the development of methodologies and tapping into large automated population-based data bases, the so-called extramural program. Its external advisory board--I've sat on several of those study sections in my own jaded past--has recommended for years that that program is not simply underfunded, but it's underfunded by an order of magnitude; that is, a million dollars barely skims the surface; $10 million might help. And, of course, finding a partner to do the work with you; the partner who understands the use of population-based data and can work at arm's length as a trusted resource, represents the way forward, in my view, for PDUFA. And therefore, here's our critical path. It's working together. The CERTs are there. Use them. The CERTs are yours. Build them. The CERTs represent an opportunity for PDUFA. Fund them. Thank you. MS. HENDERSON: Thank you, Dr. Tilson, very much. We will now take a 10-minute break. I will ask all of you to be back in your seats by 10 minutes after 11. And I'd ask our third panel, which includes Dr. Cohen, Ms. Dorman, Dr. Sigal, and Ms. Ireland to be seated and ready to go at 11:10. Thanks a lot. [Off the record.] MS. HENDERSON: Back on the record. If you'd begin to return to your seats so we can get started. This panel is between you and lunch. [Pause.] Okay. If you'll take your seats, we'll get re-started. It may look like our FDA listening panel has emptied out. But, in fact, it's not true. Just for the information of the audience, some of our panelists have asked to move to the audience so they can see the slides for the presentations better. Panel III - Presentations by Patient Advocacy Groups MS. HENDERSON: We're going to change the order a little bit of this panel to accommodate Ellen Sigal's schedule. So we will move Dr. Sigal to the beginning, followed by Dr. Cohen, Ms. Dorman, and Ms. Ireland. And we will start with Ellen Sigal. Ellen Sigal, Ph.D., is founder and chairperson of Friends of Cancer Research, a Washington, D.C.-based nonprofit organization. Friends is dedicated to accelerating the nation's progress toward prevention and treatment of cancer by mobilizing public support for cancer-research funding, and providing education on key public policy issues. Dr. Sigal serves on the National Cancer Institute Board of Scientific Advisors, the National Institutes of Health's prestigious Director's Council of Public Representative, the National Institutes of Health Foundation Board, chairing its Public-Private Initiatives Committee, the American Society of Clinical Oncology Foundation Board, the American Association for Cancer Research Foundation Board, the Johns Hopkins Cancer Center Advisory Council, the Duke University Cancer Center Board of Overseers, and the Howard University Cancer Center Board of Visitors. So we are very pleased to have Dr. Sigal with us. DR. SIGAL: Good morning. And I'm sorry about leaving early, but I'm on the Board of Scientific Advisors of the National Cancer Institute, and there's a critical vote that I need to participate in. So I will try to be brief, and I will try not to be redundant, although some of my slides are redundant. But I will try. [Slide.] So why do we care, in the cancer community? That's pretty obvious. I mean, obviously, we have a million-three patients impacted every year on this; over 500,000 people dying every year of this disease. And, frankly, until many years ago, many of us in the advocacy and the research community didn't really focus on the FDA. It was a big black hole that was seen to be insurmountable, unintelligible, and frankly to many of us, dysfunctional. And frankly, there were a lot of bad drugs, and there not a lot of opportunities. So you know, that was the prevailing view. And a few years ago that changed. That changed. We thought that we really had a stake in the FDA, because we talk a lot about translational research, and you can't translate anything until you have better drugs, and more effective drugs. And so we started to work with the Agency in a very collaborative way. And now, rather than a black hole, they have become friends; people we care about. They're extremely, extremely important to the new generation of drugs, and to all cancer patients. So we have a major stake in the FDA. So we care a great deal. I'm not going to go over PDUFA. You all know about PDUFA. You know more about PDUFA than I do. You've heard about it today. Evaluating PDUFA is important. You know, I think that we're trying to, with the renewal of PDUFA, there's going to be a lot of metrics for evaluation. We heard some really good data today. By and large, it's very, very successful. And I think any of the critics that are going to complain about safety or compromising integrity are not going to be very happy, because the data shows the opposite. So PDUFA has been very, very good thing for the patient community, and certainly for the cancer community. And we are enthusiastic about the continuation of PDUFA and, frankly, the enhancement of PDUFA. [Slide.] You know, PDUFA has allowed the FDA to expand the user fees for the management. It's added staff. And, again, it's helped understand drugs' risk profile, which I'm going to talk about in a little bit. [Slide.] The safety issues are a very dramatic concern to the cancer community. This is something that we are very worried about, because we think that the cancer community can be more dramatically impacted on an overzealous of safety, or interpretation or understanding of safety, and therefore we often say: safety kills. And we mean that. I mean, we're very concerned about a new pipeline of new and better and targeted drugs that will really make a difference to the patient. And if we get so consumed with safety we, in fact, will lose many, many, many more patients from this disease than not monitoring safety. So it's extremely important for us. And we have patients from all ends of the spectrum; from people who have, you know, what can be a chronic disease, and people who have diagnosed with fatal disease. So clearly these issues are of significance. I mean, clearly, I'm going to tell you the obvious: no drug is 100 percent safe. And that we know about. And the public needs to understand that. As a matter of fact many of the nutriceuticals that people are taking in large quantities are not safe, as well. So they need to understand that. So obviously this issue between risk and benefit is very important. Intelligent design of trials. And if the speed and the certainty of drugs is really what we care about. We certainly understand that we need to monitor drugs; that we need safe and effective drugs. And particularly as our disease becomes, hopefully, a chronic disease, this is going to be even more important. So clearly, really, safety and efficacy are extremely important. [Slide.] There are things that can be done on safety. None of us would suggest that we're doing enough, or that we can't do better. But we need the resources to do that. We are very worried about overzealous regulation that would only deal with safety and create more bureaucracy and infrastructure and really not deal with efficacy. But we can certainly collect more data. We can enhance the Med Watch. We can increase the FDA's capacity to process and analyze adverse events and get that information to the public. But ultimately these decisions are between the patient and the doctor. And we don't want on-size-fits-all. It can't work for cancer, and it shouldn't work for cancer. We want these decisions. We want the information. And people are going to have to be informed about their choices on these drugs. [Slide.] Looking forward to PDUFA IV, clearly we talked about the safety of drugs. And I think that can enhance. And if we can really deal with the funding of FDA, and the funding of PDUFA, I think that that's going to be critical to the cancer community, and to the patients' receiving treatment or diagnostics. Funding is important. I'm going to talk about that a little more later on. But efforts to enhance safety systems should not compromise the timely approval of many patients facing life-altering disease. And this is the consistent message that I want to discuss. [Slide.] Adequate Resources--that's a huge concern. FDA is one of the most underfunded agencies in the Federal government. And I don't think people understand that. And I think people need to understand that. PDUFA isn't going to entirely fix it. As a matter of fact, it's a danger. We have to be very careful that we continue to fund what we're supposed to do for FDA, and fund the science, integrated the critical path, and to really fund the agency appropriately. And that's very important. That doesn't mean that we shouldn't continue to do PDUFA. We should enhance it. We should look for perhaps other funders other than the pharmaceutical agency, because I do think that even foundations and patient groups--there are other sources out there for funding and we should explore them. But we must continue continuing to appropriate the FDA and, frankly, enhancing that, because that's going to be important. And we really have to look at the critical path and the funding mechanisms for the critical path. Because if we don't integrate the science and fund the critical path, we're not going to get better and safer drugs to patients. So this is a very important issue. [Slide.] Finally, what's important to us is that our disease, or cancer, is changing. We have a lot more information. WE have better information. WE will have better drugs. They will be more targeted. They will get to the patients faster, we hope, and they will be more effective. So continuing the science, integrating the science, working collaboratively with the NIH, with the FDA, and with patient groups is critical to this. So we are very enthusiastic and, frankly, consumed with what happens at the FDA. Because what happens at the FDA impacts everyone who will be diagnosed with this disease, and everyone treated with a disease. And it's much more than just, you know, people who have final forms of cancer. We're talking about diagnostics, we're talking about a better class of drugs, targeted drugs. So this is really a new day for cancer. And if we're going to achieve the 2015 goals, and if we're going to really help cancer patients, the integration of science, safety, the funding is going to be critical to us. So we care a great deal about what happens, and we're very vested in it. You know, clearly a stronger FDA helps all of us. The predictability, the consistency of the application, greater efficiency. And frankly we need, in the patient community and the research community, to do a better job of advocating for the importance of this agency. I think a lot of people have really only talked about the science and the research. We just spend a lot of time talking about translational research, but not enough time about the entire spectrum, from early diagnosis to the importance of the interactions with the NIH and the FDA. As a matter of fact, when Mark McClelland came to the FDA, and Andy von Eschenbach, the first thing they did is this interagency task force between the National Cancer Institute and the FDA. And we encouraged that. We'd like to see advocacy groups and patient groups and industry and CMS as part of that, as well. So we want innovation. We want better science, and we care a lot about what's happening. And PDUFA IV is going to be on our radar screen. And the FDA is not a black box to us any more. Thank you. MS. HENDERSON: Thank you, Ellen. We'll let you set off to your vote. Our next speaker is Dr. Perry Cohen. Dr. Cohen is an active participant and leader on the national level in advocacy activities for Parkinson's issues. He is project director for the Parkinson's Pipeline Project, which he initiated to provide the patient's perspective to clinical researchers and sponsors of new therapies. Prior to diagnosis with Parkinson's disease in May of 1996, Dr. Cohen was a planning and evaluation consultant in the health industry for public health agencies, health insurance plans, and academic research centers. He has an M.S. and a Ph.D. in organizational development from MIT's Sloan School of Management, and a Bachelor's in Management Science and Math from Carnegie Mellon University. Please welcome Dr. Cohen. DR. COHEN: Thank you. And thank you for inviting me. As you introduced me, I am a Parkinson's patient and advocate, and I've had Parkinson's disease for 10 years now, and it gets worse. But I've been patient representative at FDA for Parkinson's since on a was on a deep brain stimulation advisory panel back in 2000. And in this role I learned some of the things that he last speaker just talked about, about the FDA. And I set up the Parkinson's Pipeline Project, which is a grass roots effort, to do everything we can do as patients to speed up and facilitate introduction of new treatments that are leading to cures. [Slide.] A little bit about Parkinson's Disease: briefly, in case you don't know, it's a chronic degenerative neurological condition, characterized by the loss of dopamine neurons. And dopamine is what controls movement. But it's interacting with other parts of the brain. The brain is very complicated, as you know. And there are cognitive and emotional symptoms, as well as autonomic system functioning, such as breathing and swallowing and some of the other aspects of Parkinson's. Parkinson's is known as a lower prevalence chronic disease by CDC, with somewhere under a million patients. It's far fewer than the bigger chronic diseases such as heart, cancer and diabetes. But it's similar to, like hundreds of other neurological diseases, which I think the next speaker will speak about some more. And collectively these numbers probably add up to a significant public health problem, which is only beginning to be recognized. And Parkinson's is on the vanguard on the last frontier of science: the brain and the central nervous system. And if the neuroscience meeting, which is downtown, which I have to go to later today, is any indication, we should be having more active discoveries and treatments in the future. Another thing about Parkinson's is: we have a pretty active advocacy movement. And there's a number of celebraties and prominent business people, as well. And just to let you know, for the advocates, there are a lot of people in the closet still who you'd be impressed to know have Parkinson's disease, and are starting to creep into the advocacy work. [Slide.] As far as treatments and cure goes, it's sort of a good news and bad news situation. First identified in 1817 by James Parkinson, the science and treatment has advanced compared to other central nervous system conditions. The good news is there are many effective treatments for Parkinson's. The bad news is the treatment may stop working after five or 10 years, and the side effects of some of these treatments are as bad as the symptoms. So we need more development. The good news is there's more known about Parkinson's than any other brain disease, and the recent big build-up in science has put us on a path toward better treatment and cures that are promised to be right around the corner. They've been telling us "five years" for the last 15 years. The bad news, however, is the pipeline, which we've been talking about today, 15 or 20 years or more--and I was quite impressed with that figure of neurological conditions, clinical pipeline average of 11 years. And I want some of the academics who spoke in the last panel to address that issue really quick. But in addition to the scientific issues, there are financial markets, and business strategies, and organizational politics, and people's careers, and publication schedules and all these other things that are in between us and the cures and treatments that we need. [Slide.] So, what do patients want? First: faster cures. Time is not neutral for someone with a serious or life-threatening illness. And we want to look beyond the review time. We want to look at the whole process; the whole process of drug development, and look for ways to do that. I've learned a lot at this session. These slides were obviously prepared in advance. I've learned a lot about what's being done. And I have to admit I was not fully aware of everything that was being done. And second, we want more emphasis on individual decision-making and choices--sort of echoing the last speaker. We need to recognize that the equation of risk-benefit tradeoff is different for each person, and there should be more flexibility for individuals to make their decisions, with advice and counsel of their own physician, or some expertise; but also with full information. And that's the key. Some of the safety problems, the coverup is worse than the problem. And third, we want greater participation in the process. We're not rats in a cage. Our experience is valid, and it's often not captured or considered. And I've been working with several companies, and this is true. [Slide.] Here's my naive view of what PDUFA has done--before I got here today; which is basically correct, but now I know a lot more. The PDUFA was established to reduce the length of time in reviews. There's extensive industry consultation, and FDA agrees to meet performance standards. And there's been little or no input from patients and consumers in the past legislation. [Slide.] So here's my view of the patient perspective on user fees, from the outside looking in. As I said: little information on the time frames, on the processes. It's a black box. The FDA processes are a black box. And even when you're involved with specific treatments, the proprietary information of the companies seem to be more important than the distribution of the scientific data. And when there are meetings, we don't even know when the meetings are being held, or if they're held, much less what goes on in them. There are a couple of simple observations I would like to make. The user fees are now greater than 50 percent of the FDA review costs, as was presented earlier. And this raises questions. Now, I don't believe this to be true, but it raises questions in the press and in the eye of the public, whether there's a lack of objectivity related to the rulings, based on this dependence on fees. So it behooves us, as advocates, to lobby for the FDA budget, just the way we lobby for the NIH budget, and with great success. So I'm not sure if the Agriculture Committee in the Congress has enough appreciation of what the FDA does. And, unlike the rest of the Health and Human Services Department, the FDA budget is handled by the Agriculture Committee, which came as a big surprise to me. Another little technical point is that the fees are only paid when the new drug application is submitted, yet the costs are distributed throughout the process. And that was pointed out earlier, as well. And by doing so, I think that maybe explains at least part of the reason why there are fewer applications. [Slide.] So we do we have for suggestions? My view is that we have an untapped resource, and there are new roles for patients. The Office of Special Health Initiatives, which included me and a number of other patient representatives and patient consultants, has been cultivating and advocacy group. And I think this is important for several reasons. First of all, when you have patients at the panel, that could counter the appearance of a bias towards industry if the patients are actively involved, because everybody says the bottom line is the patient's safety, and the patient's treatment. And if the patient is at the table, then you get that viewpoint expressed. [Slide.] Next, it needs to be a transparent process. Information about the process needs to be more public; when they're having meetings, what stage of the process they're in. Certainly, companies are allowed to have proprietary information, but if we knew what was coming down,if would give us something to have some hope for, and something where, if we were involved in the process more, we could contribute to. And I think the FDA should expand the excellent efforts of the Office of Special Health Initiatives to support community groups like the one that I work with, in education of the community about the regulatory process. [Slide.] So, just to summarize, this is our motto: "The missing ingredient in new therapy development is the voice of the patient." We're partners in clinical research. We're seeing input in risk and benefit judgments. And awe have created a research participants' "Bill of Rights," which sets a framework for collaboration in relationships between industry and researchers and patients. And PDUFA should recognize these roles. [Slide.] Now, a couple more suggestions. And this has been covered earlier quite a bit, so I'll go over it quickly. The entire pipeline should be examined for time savings. And system changes are necessary to achieve significant reductions in the duration of the pipeline, and the maintenance of the quality. These have been brought up in other talks quite strongly and I would agree with that. [Slide.] Business and science as usual is not sufficient. Though we have some leadership, the Critical Path Initiative, which has been mentioned quite a lot, the NIH translational research road map, they're talking the terms--the system's terms. And my training in management and organization and systems, it seems to me that they're talking the way to go. And "Faster Cures" is a program that starts looking at some of the assumptions in business-as-usual, and science-as-usual--like cycle times have been mentioned here; and turnaround times in getting the information back into the process from scientific research. [Slide.] And finally, I think my last suggestion is we should view the process in the continuous quality improvement paradigm. Rather than have one giant step to approve, which may make people be more cautious, I think we need a series of shorter steps of conditional approvals that expand the markets and the target audience for research in a more gradual way, and that way you could get some early approvals, particularly for those people who need access to potential life-saving treatments, as well as then continued maintenance of control of some of the bigger safety problems that might come up down the road. And that's all. Thank you. MS. HENDERSON: Thank you, Dr. Cohen. We very much want to hear the voice of the patient, and surely appreciate your input. Our next speaker is Dianne Dorman. Ms. Dorman currently serves as vice president for public policy for the