Will FDA and the Pharmaceutical Industry be Ready?
Carl C. Peck, M.D.
accompanied by
Raymond L. Woosley, M.D.
Center for Drug Development Science
Departments of Pharmacology and Medicine
Georgetown University Medical Center
Washington, D.C.
Reauthorization of the Prescription Drug User Fee Act and FDA Reform
Subcommittee on Health and Environment
Committee on Commerce
U.S. House of Representatives
Representative Michael Bilirakis, Subcommittee Chairman
We envision that clinical drug development could be accomplished efficiently and safely in less than 3 years in the very near future. However, "Reforms" are necessary in all sectors involved (pharmaceutical industry, FDA, and academia) in order to achieve this breakthrough.
The Collaboration on Drug Development Improvement (CDDI) comprises here-to-fore voluntary initiative among the three sectors that aims to identify approaches for substantially improving the development practices for new therapeutic agents. Consideration should be given to funding the CDDI initiative through the reauthorization of PDUFA or via Congressional appropriation.
The Prescription Drug Users Fee Act (PDUFA) has achieved its goals of predictable FDA review times. However, the unintended consequences of curtailed regulatory research in CDER and constrained professional development of its review scientists impeding adequate preparation for its role in future drug development and regulation.
A solution to the problem of dissemination of information on off-label uses of approved drugs would be the creation of academic Centers for Research and Education in Therapeutics (CERT) to provide unbiased information and needed research on off-label uses. CERT should be considered for funding via PDUFA or FDA appropriation.
Quantity and quality of evidence required to establish proof of effectiveness is inconsistently applied by FDA. FDAÕs recent draft clarifications of this explain the rationale for past and present policies but fall short of embracing the full breadth of modern scientific concepts and techniques of effectiveness demonstration. A new process for appeal and resolution of scientific disagreements between FDA and industrial or academic scientists is needed with mechanisms to guarantee no FDA retaliation against those who engage the process.
Reauthorization of PDUFA is an important opportunity to consider funding mechanisms for innovative programs (CDDI, CERT), critical FDA scientific staff activities (regulatory research at CDER and professional development), and key FDA reforms (evidentiary standards of effectiveness and dispute resolution).
Good afternoon Chairman Bilirakis and Members of the Subcommittee. I am honored to be invited to share my views regarding drug development and regulation, particularly on reauthorization of the Prescription Drug User Fee Act and FDA reform.
My name is Carl Peck. I am a physician trained in mathematics and chemistry, and Board Certified in Internal Medicine and Clinical Pharmacology. I direct the Center for Drug Development Science (CDDS) at Georgetown University Medical Center, where I am Professor of Pharmacology and Medicine. CDDS is an independent academic institution that maintains conflict-of-interest free collaborations with industry, government and other academic scientists. Prior to establishing the Georgetown Center in 1994, I served for 26 years in the U.S. Army Medical Research and Development Command and the U.S. Public Health Service. From 1987 to 1993 I was Director of FDAÕs Center for Drug Evaluation and Research, during which time I participated in the groundwork for implementation of the first Prescription Drug User Fee Act.
I founded the CDDS to advance the practices of drug development to vastly improve levels of informativeness and efficiency. We are achieving this through research, education and technical assistance programs. Coordinated by a small staff, our international network of academic, industry and regulatory scientists are identifying key opportunities for improvement of drug development programs. In order to maintain a practical focus, Center faculty, staff, and associates work directly with pharmaceutical developers in planning, analyzing and guiding actual drug development programs.
A CDDS Vision of Drug Development in the Near Future
We envision a very different paradigm for drug development than exists today. This paradigm will be dependent on conditions and incentives that favor innovation in scientific methods and management practices in evaluating new therapeutic agents. Our vision contrasts sharply with contemporary practices that involve tens to hundreds of clinical trials that may be flawed or have failed in design or performance, and excessive numbers of trial subjects, observations, and costs that require many years to accomplish. We propose a highly compressed, critically informative, efficient and economical development approach that entails two developmental scientific investigations and one clinical trial confirming effectiveness. These are:
1. Clinical Pharmacology in Normal Human Subjects or Mildly Ill Patients -- a comprehensive, exploratory clinical investigation in normal subjects or patients to determine a drugÕs actions in humans.
2. Clinical Pharmacology in Ill Patients -- a scientifically rigorous, proof-of-therapeutic- concept investigation in patients with a targeted disease that documents discovery of optimally safe and effective dosage.
3. Confirmatory Effectiveness Trial -- an unequivocal demonstration of effectiveness and safety in a multi-center (and possibly multi-national) clinical trial, with an adequate number of subjects receiving the new therapy under typical conditions of use.
A small number of developmental investigations, such as bioequivalence or drug interaction trials, may also be undertaken in conjunction with the three principle investigations. Using this approach, clinical drug development time from IND approval to NDA filing dates should be less than 3 years for most new drugs. Extensions beyond 3 years of clinical development might occur for confirmatory trials of new treatments for slowly progressing chronic diseases.
Much of the knowledge and technology for achieving this new paradigm is already available or is rapidly emerging. Modern clinical pharmacology enables discovery of what a patientÕs body does to an administered drug (pharmacokinetics) and what a drug does to a patientÕs body (pharmacodynamics). Clinical trial designs and data analysis techniques for confirmatory effectiveness testing are well known. CDDS is researching emerging technologies for facilitating improved drug development efficiency such as computer simulation of clinical trials.
To achieve this goal of an improved drug development process, all groups involved must work collaboratively. We believe that the CDDI initiative (described below) is an important pathway to this breakthrough in drug development practices.
Collaboration on Drug Development Improvement (CDDI)
On May 2, 1996, I presented my views to your subcommittee on whether it is possible to facilitate the development and approval of new drugs and biological products without compromising safety and effectiveness . I focused on the need for bold improvement in drug development practices, particularly in reducing the number of flawed, failed, or unnecessary human clinical trials. Citing the FDAÕs and the pharmaceutical industryÕs shared responsibility for improving drug development, I described a pathway for improvement using advances in drug development science, especially clinical pharmacology and statistical data analysis techniques for proving effectiveness. I predicted that streamlining and modernization of effectiveness testing methods could result in reductions in drug development times and more successful employment of human research subjects.
Following the Subcommittee Hearing on June 17-18, 1996, CDDS co-sponsored with FDA (CDER) and FDLI a public conference, "Drug Development: Who Knows Where the Time Goes?''. Participants were informed of the strengths and weaknesses of contemporary drug development practices by academic, industry and regulatory scientists. Significantly, attendees to the conference recommended that a formal collaboration among the three sectors be initiated with the goal of identifying approaches for substantially improving the development practices for new therapeutic agents.
Promptly following the conference, the Collaboration on Drug Development Improvement (CDDI) was founded. Driven by key scientists at CDER (especially Drs. Janet Woodcock and Roger Williams) and CDDS, the representation on the CDDI Steering Committee was broadened to include representatives from CBER, PhRMA, and BIO. The Steering Committee met on September 25 and December 5, 1996, to establish the purpose, scope, goals, and future actions. An issues identification meeting is planned for the near future to begin the real work of the CDDI. However, the lack of funding for this voluntary initiative is jeopardizing its ability to continue its programs. We recommend that your subcommittee consider PDUFA or Congressional appropriation as funding mechanisms for the CDDI initiative.
PDUFA: Accomplishments and Unintended Consequences
The Prescription Drug User Fee Act (PDUFA) is a great success. Since its implementation in 1993, to the credit of the leadership and scientific review staff of FDA and the new drug sponsors submitting high quality New Drug and Product License Applications (NDAs and PLAs), review times of priority and standard NDAs and PLAs have been reduced to 6 to 12 months. Moreover, the substantial review backlog has been eliminated. FDA is now properly attending to the processes and procedures necessary to meet review time standards. Congress, PhRMA, BIO, and FDA all deserve acknowledgment for their contributions to this landmark achievement.
However, there have been two unintended consequences of the restricted uses of PDUFA derived funds and application review time commitments (coupled with limited non- PDUFA operational resources): critical regulatory research in CDER, such as surveillance of adverse reactions, has been curtailed, and professional development of its scientific staff has been constrained. Because FDAÕs capacity to implement significant reforms to prepare for its advisory and regulatory roles in future drug development is critically impaired by these deficiencies, reauthorization of PDUFA should not be undertaken without their resolution.
Some FDA Reform Issues:
I. Dissemination of off-label uses of approved drugs and Centers for Research and Education in Research (CERT)
Physicians must have access to current, scientifically reliable and balanced information about drugs in order to make informed decisions for their patientÕs treatment. Pharmaceutical and device companies should be permitted to disseminate copies of peer-reviewed scientific articles that report scientifically sound clinical trials that have evaluated off-label indications for their products. The companies should be required to disclose their financial interests and that the indication is not FDA-approved, i.e. "off-label". However, dissemination of this information should be monitored by an independent bod prepared to respond to prescribing physicians, health care professionals and the public with balanced, unbiased information about the off-label uses of drugs.
The NationÕs academic medical centers have the medical, pharmacological, and educational expertise to teach practicing physicians, nurses, pharmacists and the public about drugs that are prescribed, administered, dispensed or purchased. A consortium of federally-authorized regional academically-based centers (CERT) has been proposed as a means to address this problem (Appendix 2). The consortium would be selected through a peer-review mechanism and would be affiliated with FDA so that activities will be coordinated at a national level. Each Center would include pharmacologists, clinical pharmacologists and clinical pharmacists, all conducting needed research and educational programs about the optimal use of medications. CERTs should include participation of scientists in the pharmaceutical industry; however, to ensure their objectivity, each CERT should be given independent funding. This independence that allows them to be credible advocates for optimal prescribing. These Centers also should conduct research that industry is unlikely to perform, such as the study of unprofitable off-label indications, and the use of medications in children, the elderly and other understudied populations. We recommend that your subcommittee consider PDUFA or directed appropriations to FDA as funding mechanisms for the CERT initiative.
II. Standards of Evidence of Effectiveness
As a result of the 1996 Senate and House Hearings on FDA reform the FDA Draft Guidance, "Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products" was published on March 13, 1997. Prompted by CDDS testimony on the redundant requirement in modern development programs for more than one confirmatory clinical trial to prove effectiveness, FDA scientists have prepared a comprehensive statement of the AgencyÕs current policies and views on the legal and scientific aspects of quantity and quality of evidence necessary to support effectiveness of new therapeutic agents. FDA deserves credit for its review and explication of its policies on this issue. Nevertheless, FDAÕs draft guidance falls short of embracing the full breadth of cutting edge, scientific concepts and techniques of effectiveness demonstration. CDDS is preparing a detailed critique of the draft guidance to be submitted to the Agency as a public comment.
III. Scientific Dispute Resolution and Appeals
Aside from many useful guidances and policy statements the Agency promulgates, there are and always will be disagreements over what constitutes sufficient quality and quantity of data to support FDAÕs conclusions about the safety and effectiveness of new therapies, as well as the investigations necessary to generate such data. Many new drugs for medical conditions with no available effective treatments are novel. The standards of evidence for these new therapeutic agents are sometimes arbitrarily established by the FDA reviewing division with insufficient input from external scientific experts. Currently, the only mechanism to resolve scientific disagreements about test methods, and what outcome measures and/or quantity of data are sufficient, is to bring the issues to the Division, Office or Center Directors. While FDAÕs standing advisory boards can be called upon to resolve such disputes, in practice many real or perceived disincentives and barriers mitigate this option. Drug developers fear retaliation and retribution when the FDA is not supported in the appeals resolution and often decline to enter into the existing appeals procedure.
To facilitate more efficient resolution of standards of evidence disputes, language could be included in PDUFA II that establishes a mechanism that involves external expert scientists in the IND phase of drug development to recommend to the FDA and the developer what quality or quantity of evidence should be generated to establish specific safety and/or effectiveness claims. At the request of the sponsoring company, the company and the agency jointly could create the expert panel to resolve disagreements. An administrative tracking mechanism should be established to ensure that companies that engage the dispute resolution procedure are not penalized in future interactions with FDA.
"Reform" of All Sectors Involved in Drug Development is Necessary
During the May 2, 1996, Subcommittee Hearing, I presented preliminary results of a pilot study of the contents and qualities of NDAs approved by FDA during 1994-1995, from which we concluded that vast improvements on contemporary drug development are warranted. At that time, our examination of data from 9 of the 52 approved NDAs indicated that contemporary drug development programs appeared to comprise large numbers of clinical trials (44-600+), many of which were not adjudged by FDA to be necessary or of high quality (9%-65%). We have recently expanded this pilot study to 24 NDAs. While our conclusions regarding improvability of drug development remain unchanged, the wide variability in content and quality of these successful programs may provide insights into pathways for improvement. For example, several NDAs were approved with fewer than 10 clinical trials, and FDA adjudged some of these programs to have few, if any, flawed or failed trials.
Thus, we remain convinced that all sectors involved in drug development can and should be "reformed." To be sure, many pharmaceutical firms have been reengineering their approaches to drug development toward fewer, more successful clinical trials. Nevertheless, inefficient and suboptimal practices persist in contemporary drug development, due in part to lack of carefully evaluated new approaches as well as to lack of receptivity of some (not all) FDA staff to newer and novel scientific methods. Although academia is increasingly involved in performance of clinical trials of new therapeutic agents, it has received few incentives to respond to the need to invent and investigate novel methodological approaches to scientific drug development.
Reauthorization of PDUFA is an important opportunity to consider funding mechanisms for innovative programs (CDDI, CERT), critical FDA scientific staff activities (regulatory research at CDER and professional development), and key FDA reforms (evidentiary standards of effectiveness and dispute resolution).
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