Notes of the American Society for Clinical Pharmacology and Therapeutics

MESSAGE FROM THE GOVERNMENT AFFAIRS COMMITTEE

There have been active discussions throughout Congress for many months on the issue of FDA Reform. The Government Affairs Committee (GAC) has followed these discussions and provided counsel and recommendations to Congressional staff and members of the Congress. The following is a status report effective February 22, 1996.

It is not at all clear that an FDA Reform Bill will be passed by the 104th Congress. The arguments for FDA Reform have been weakened by recent data indicating that the FDA has markedly reduced the time required to review new drugs and devices and the recently released report from the Government Accounting Office that con- cluded that there is no “drug lag” in the U.S. Nevertheless, several conservative organizations have recommended aggressive FDA Reform, and some include measures that would drastically weaken the FDA.

At this time (February 25th) the only Bill making any progress is the one sponsored by Senator Nancy Kassebaum, S1477. This Bill is much more moderate than the one expected to be discussed in the House. The Kassebaum Bill contains provisions from an earlier Bill sponsored by Senators Mack and Frist that lessens FDA regulation of dissemination of information on off-label indications. This Bill was discussed in hearings before the Labor and Commerce Subcommittee on February 21 and 22, 1996, and is expected to be revised in the next few weeks as the staff review the recommendations of those testifying in these hearings.

Several members of the GAC have participated in these discussions and even assisted in determining the substance of the legislation. Two members of the GAC (Drs. Peck and Woosley) testified in the hearings, and ASCPT’s policy statement on FDA Reform was included in the official record for the hearings. This policy was originally approved by the ASCPT’s Executive Committee on March 13, 1995, and a revised policy was reviewed on February 20, 1996. The text of the policy is appended to this report and indicates support for maintaining a strong and ade- quately funded FDA while encouraging thoughtful Reform. The Kassebaum Bill is complex and would make many changes in FDA. Some provisions would only codify policies that FDA has already adapted. For example, the Bill would enable FDA to contract out some of its NDA review process. Although this

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has been done in the past, it occurs less now that the FDA has the availability of user fees. The Bill would authorize FDA to accept one controlled trial as the standard for proof of efficacy instead of the usual two independent controlled trials. Again, FDA has accept- ed one trial as proof of efficacy on several occasions in the past. This report will address only those aspects of the Senate Bill that were discussed in the hearing and those that are most relevant to ASCPT.

The first day of hearings addressed, among many issues, the topic of shortening drug development time, including revitalization and modernization of the effi- cacy standards. The Bill, as currently drafted, would change the efficacy standard from two independent well-controlled trials (analyzed by intention-to-treat policy) to allow approval for a drug on the basis of one adequate and well-controlled clinical trial, accompa- nied by confirmatory evidence (derived from the entire knowledge base available from the drug’s development and the medical literature). Dr. Carl Peck testified in the hearings in support of this provision and modem- ization of the efficacy standard. In addition, the Bill would also establish a 4-6 month time frame for approval of new drugs: 4 months for priority drugs/devices and 6 months as the standard. There was general opposition to having a 4-6 month deadline for drug approval, and some noted that the availability of user fees has reduced the need for such deadlines. For those drugs already approved in another country, automatic approval would be granted after 30 days of FDA review (a list of acceptable countries would be established). There was very little support voiced for this provision of the Bill. The Bill would also allow the FDA to contract all or portions of the review process to outside organizations such as corporations. There was general agreement that the FDA should have the authority to contract out portions of NDA review that would not impair the agency’s evaluation of safety or efficacy. There was extensive discussion in favor of FDA asking expert consultant committees to review supplemental NDAs (new indications for marketed drugs).

On the second day of the hearings, the Senators focused on the Mack-Frist provisions that would

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allow drug/device manufacturers to disseminate copies of scientific articles from peer-reviewed journals that support efficacy of marketed drugs in unapproved indi- cations. The articles would have to be labeled to indi- cate that the indication has not been approved by the FDA, that the article was being provided by the manu- facturer and disclose any conflict of interest of the authors. Most of the testimony supported these provi- sions of the proposed legislation, although the FDA representatives and one witness expressed opposition. Much of the discussion concerned the need for a bal- anced independent source of information on drugs for physicians as recommended by ASCPT. Although not included in the current draft of the Bill, Dr. Woosley testified on how Centers for Education and Research in Therapeutics (CERT) could serve this role and also participate in evaluation of off-label indications for drugs and evaluate the safety of drugs early after mar- keting.

If anyone would care to have a summary of the Kassebaum Bill (S 1477) or a copy of the testimony by Drs. Peck or Woosley, they should contact Elaine Galasso at ASCPT. The GAC will continue to follow this process closely and encourages all ASCPT mem- bers to send their comments and suggestions to the Chair, Dr. Raymond Woosley, or any of the Committee members listed in the ASCPT Directory.

action, toxicology, clinical trial methodology, regula- tory law, biostatistics and epidemiology. Critically, none of these experts are likely to be completely free from conflict of interest as is the FDA staff Furthermore, to maintain quality, objectivity, and credibility, one cannot ask that the FDA simply sign off on the reviews peeormed by others, even .foreign national regulatory agencies.

In addition to maintenance of qualitv , maintenance of consistency of review is essential. Those with expe- rience in the drug development process appreciate the importance of the consistency and “level playing $eld” that is maintained by having one agency per- form the review. If the work were contracted to multi- ple organizations with variable experience and exper- tise, there would be loss of consistency that is essential

-for a development process that requires years of

advanced planning. Most importantly, the User Fee program has signi$cantly reduced the need for con-

tracting out NDA review and maintains the principles of freedom of conflict of interest and consistency of

review.

3. The FDA and industry should aggressively foster a “team” approach in which the FDA and industry work jointly to improve medical therapy and protect the public.

ASCPT’S RESOLUTIONS - February 22,1996 Whereas, the more than two thousand members of

the ASCPT are responsible for the evaluation and development of drug therapies, they have a unique per- spective on the need for FDA Reform and their exper- tise and perspective should be of value to the Congress. Therefore, ASCPT suggests the following principles to guide the Reform process: 1. The Food and Drug Administration should con- tinue to play its vital role serving the citizens of the USA through careful and expeditious review of new drugs and devices. ASCPT opposes abolition or weakening of the FDA, but strongly supports thoughtful reform. 2. ASCPT supports the FDA’s demonstrated ability to contract with qualified, non-FDA or outside organizations, portions of the review process that the Agency has concluded will not compromise public safety while facilitating the review process.

The FDA’s drug/device review activities should be distinguished from its enforcement activities in order to foster a mutually respectful and nonadversarial working relationship. FDA management should strongly support a personnel performance standard that aims to foster a “team” relationship between the medical reviewers and industry representatives. As called for by independent panels such as the Edwards Commission, the FDA has had earlier and more frequent meetings with industry and earlier involve- ment of the Advisory Committee members during the development of new drugs and devices. When possible and appropriate, consultants from the advisory com- mittees and the academic community should be added to the “team” responsible for ushering a drug or device through the review process. 4. Congress should create a forum for experts in drug development from the Agency, academia and the pharmaceutical industry to work together to conduct research and educational programs of mutual value to the industry and the public.

Those who favor the contracting of all drug and As the Moffet Center has been successful for the device review to commercial organizations fail to ,food industry, the FDA, industry and academia recognize the complex combination of scientific should collaborate to form a consortium that can talents that is required. Individual experts in acad- evaluate drugs for orphan indications, new uses

emia or private business usually do not have the for off-patent drugs, develop new approaches to requisite combined expertise in clinical drug prevention of adverse drug reactions, develop

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innovative methods for phase IV evaluation of drug safety, including methods to interrogate the Medwatch database. These research and educational programs are unlikely to be pursued by an individual company but can improve the eficiency and informativeness of the drug development process. 5. FDA’s standards of proof of efficacy and safe- ty should fully utilize modern methods of clinical pharmacology.

The FDA’s traditional requirement for two indepen- dent, empirical phase III controlled clinical eficacy trials of the to-be-marketed formulation and dosage, interpreted by intention-to-treat analysis, has not evolved to fully incorporate innovative methods of drug/device evaluation and data analysis. Significant advances have been made and state-of-the-art meth- ods in clinical pharmacology can now be usefully applied to the process of drug development and regu- latory review. As part of the FDA’s methodologic research program, methods such as the “learn- confirm” approach, modeling and Bayesian analysis should now be tested for their ability to facilitate drug development and, at the same time, maintain an acceptable margin of public safety.

The FDA has already demonstrated the value of approving drugs or devices on the basis of one ade- quate and well-controlled clinical trial, supple- mented by confirmatory evidence derived from the entire knowledge base available, including the medical literature. Broader, appropriate applica- tion of this standard, especially for supplemental indications, would improve the informativeness of drug development, save development time and con- serve scarce research resources. Further, the FDA should encourage innovative clinical trial designs and methods of analysis that employ modern con- cepts and techniques of clinical pharmacology and statistical modeling. 6. Physicians require better access to current, scientifically reliable and balanced informa- tion about drugs in order to make informed decisions for optimal treatment of their patients. Pharmaceutical and device compa- nies should be permitted to disseminate copies of peer-reviewed scientific articles that report scientifically sound clinical trials evaluating off-label indications for their products. They should be required to disclose their financial interests and the fact that the indication is not FDA approved. To address issues of relative efficacy and benefit of drugs, there should be a mechanism created to provide prescribing

physicians, health care professionals and the public unbiased information about the off- label utility of drugs. ASCPT has endorsed the creation of regional academic Centers for Education and Research in Therapeutics (CERT) for this purpose.

Limiting the dissemination of drug information to only those indications approved by the FDA has delayed the rapid implementation of proven effective therapies. However, FDA’s restrictions may have pre- vented treatment in cases where benefit is absent or where the drug is actually harmful. This function of the FDA has been considered to be necessary because our society does not have ready access to an indepen- dent source of information that can counter improper promotional claims. CERT operating in academic medical centers, could conduct the necessary research and educational programs to provide an independent evaluation of the relative merits of therapies. Furthermore, the ability of these Centers to carefully conduct early phase IV evaluations of drugs or devices would allay concerns about an expedited or accelerated approval process. 7. The FDA and industry have demonstrated their ability to work together to address regulatory bar- riers through FDA’s “IND reinvention” procedures to facilitate regulation of INDs for phase I studies in humans. The FDA should monitor this process to be sure that the new policies reverse the current trend in which these trials are being exported to other countries to avoid bureaucratic delays. 8. The FDA should retain access to user fees for drugs and biologics and this should be extended to devices.

This should continue to be subject to periodic review to ascertain that the original purpose of the user fees, that of demonstrable improvement in the timeliness of the new product review, is being fulfilled. 9. The FDA should continue its commitment to research.

There is a continued and important need for knowl- edge about the actions of generic drugs and their actions in special populations such as women, children and the elderly, and the unwanted effects of drugs. This information will not always be provided by the pharmaceutical industry. Furthermore, the FDA’s methodologic research in these areas is vital and should be expanded.

Raymond L. Woosley, MD, PhD Georgetown University Medical Center

Government Affairs Committee Chairperson