Bulletin of Experimental Treatments for AIDS, No. 26; September 1995
Ronald Baker, PhD

In June 1995, BETA reviewed 3 documents that address FDA reform: the Clinton/Gore proposals, a bill introduced by Representative Ron Wyden and the "FDA Reform Principles" endorsed by several AIDS community groups. A statement on FDA reform supported by a coalition of community AIDS organizations appears on page 45 of this issue of BETA.

Reviewed below is a recently released "concept paper" on FDA reform from Republican Senator Nancy Kassebaum of Kansas. Senator Kassebaum chairs the powerful Senate Committee on Labor and Human Resources, whose recommendations will strongly influence full Senate action on FDA reform. Massachusetts Democratic Senator Edward Kennedy also sits on the Senate Labor committee, along with 6 other Democrats and 9 Republicans. Entitled "The FDA Performance and Accountability Act of 1995," the Kassebaum concept paper outlines her priorities for Congressional legislation on FDA reform.

FDA Mission and Accountability

Senator Kassebaum proposes to radically change the mission statement of FDA by adding the "promotion" of the public health to its current mission of "protecting" the public from unsafe or ineffective products: "The mission of FDA is to promote and protect the health of the American people by:

* facilitating the rapid and efficient development and availability of safe and effective products; * protecting the public from the dissemination of unsafe or ineffective products; * enforcing applicable statues and regulations in a timely, fair, consistent and decisive manner."

Commentary

The proposed new mission of FDA is not just to protect Americans from harmful drugs but also to create broader access to promising new medications and products. Many patient groups agree with such a change in FDA mandate to enhance the agency's role in working proactively for patient and other consumer interests.

Performance Review Panel

Equally aggressive is Kassebaum's proposal to create a permanent panel of experts within the office of the Sec-retary of Health and Human Services. The panel consists of researchers, physicians, health policy experts, industry representatives and members of patient advocacy groups. In consulation with the Commissioner of FDA, the panel develops quantifiable performance standards for the agency's review of medical and food products. The performance standards become the basis of a required annual report by the Commissioner to the Secretary and to Congress.

The Performance Review Panel reviews and comments on the Commissioner's annual report and recommends any changes in statute or FDA policies, procedures and organization that it deems appropriate.

Commentary:

If implemented, this statute would make the FDA Commissioner accountable to a panel that represents those most affected by FDA policies and procedures. Patient groups would have significant, direct input into decisions concerning FDA policy. In addition, the proposed panel would have an opportunity each year to propose changes to improve the agency's performance.

Industry Advisory Council

The proposal directs the Commissioner to establish a permanent council with the function to facilitate and improve communication between the agency and the regulated industries and to foster continued technological innovation in partnership with the regulated industries.

Commentary:

It is important to create a more collegial relationship between FDA regulators and those whom they regulate, starting at the earliest point through the final stages of approval in the drug development process. Such an approach will foster speedier reviews, because many concerns will be addressed long before submission of the New Drug Application (NDA).

Expedited Access to Products for Seriously Ill Patients

The proposal codifies (makes into law) the current methods FDA uses to provide access to unapproved therapies for serious and life-threatening illnesses. The Commissioner will ensure that these options are made available consistently across all FDA centers and divisions.

Commentary:

This proposal seeks to assure that the 12 divisions of FDA operate with uniform philosophies and processes in their review of drugs and products.

Under Kassebaum's proposal, manufacturers could charge for drugs or products made available under FDA's Treatment Investigational New Drug (TIND) programs, as long as these products are for a serious or life-threatening condition. The amount charged could not exceed recovery costs for manufacture, research, development and handling. Product sponsors could disseminate information about the product to medical associations, but may not advertise it, and in all communications must state that the product is experimental and not proven safe and effective.

Current FDA policy mandates that manufacturers provide free drug to patients enrolled in TIND programs, which are experimental studies. The current policy is a sound one that is in the best interests of patients. Expedited Approval of New Drugs and Devices

Kassebaum proposes that manufacturers be allowed to submit a request for an expedited review ("accelerated approval") of a drug or device to treat serious or life-threatening conditions. FDA must approve or disapprove the application within 30 days of submission of the request. If FDA finds that the risk from the product is not greater than the risk from the disease and there is promise of efficacy, FDA will grant an expedited review. Approval of a product by the European Medicines Evaluation Agency (or the equivalent agency in England) would provide sufficient evidence that the risk from the product is not greater than the risk from the illness.

If the agency grants an expedited review, Kassebaum proposes that FDA have up to 180 days (6 months) to either approve or disapprove the product. Further, if disapproved, FDA must show cause why the product risk is greater than the disease risk. Finally, the manufacturer must agree in writing to conduct post-marketing studies to determine the clinical benefit of the product.

Commentary:

It is in the public interest for FDA to significantly reduce the amount of time it takes to review drugs, especially drugs or products for life-threatening conditions. The Kassebaum proposal does not address this serious problem.

Many AIDS groups favor 2 changes in regulations regarding expedited review of these types of drugs or products:

* FDA Advisory Committees meet and make a recommendation on approval within 45 days following submission of the New Drug Application (NDA); * Final FDA action on approval is made within 45 days following the FDA Advisory Committee's recommendation.

Adoption of this policy would reduce the FDA review period by 90 days for products for life-threatening illnesses. Individuals facing immediately life-threatening illness would have a reasonable opportunity to benefit from a promising experimental treatment.

Use of Outside Expertise

Almost everyone involved with FDA reform believes that the agency could make more and better use of outside experts to review NDA, in part or entirely. The Prescription Drug User Fee Act of 1992, which imposed fees on manufacturers for filing each NDA, was intended to allow FDA to hire hundreds of new reviewers. This should enable the agency to eliminate backlogs and deal quickly with new filings. With the $56,284,000 allocated by the act for an additional 700 reviewers, action on NDA for drugs for life-threatening illnesses should go much more quickly than it presently does.

Summary Data

Kassebaum proposes that applications for the approval of all new drugs and products include summary reports of studies on safety and effectiveness, certified for accuracy by the applicant. Applicants for NDA will not be required to include primary data tabulations, case reports or other detailed tabulations on human and animal studies. However, such data must be maintained by the applicant and be immediately available to FDA on request.

Commentary:

Adoption of this proposal by FDA would significantly decrease the amount of time required for the agency to review a new drug. The suggestion to use "summary data" for approval of NDA comes from various interest groups: patients, activists and industry. It makes eminent sense to substitute certified summaries of data for the voluminous NDA materials (100,000 or more pages per application) now required by the agency.

Good Manufacturing Practices

Prior approval by FDA would not be required for minor manufacturing changes unless these changes affect formulation, bioequivalence or performance (for devices).

Commentary:

In addition to these changes, others have proposed "Good Regulatory Practices" for FDA that will help the agency to detect and correct incompetence or obstructionism by FDA staff. Such a program, endorsed by FDA administration, is apparently already underway at the agency.

Use of Institutional Review Boards

The Kassebaum proposal allows Phase I and Phase II investigations not associated with a product approval to begin following approval by an Institutional Review Board (IRB) and notification to FDA of that approval. FDA would set standards for and certify IRB for this purpose. FDA could issue a "clinical hold" on such research, but these holds would be subject to review and reporting requirements. Strengthening the Advisory Committees

Kassebaum proposes giving FDA Advisory Committees authority to modify the agenda developed for them by the agency. Advisory Committees will include a non-voting industry representative and a non-voting public representative. Individuals will be permitted to sit on more than one Advisory Committee. FDA officials responsible for product approval will approve or disapprove the committee's recommendation within 60 days of its action and notify the applicant of the reasons for their decision.

Commentary:

It would be more to the advantage of consumers to have patient representation on these committees rather than public representation. The patient representative should be drawn from the affected community, e.g., people with HIV infection would serve on committees reviewing AIDS drugs, cancer patients would join cancer drug Advisory Committees, etc.

Resolving Disputes

Kassebaum proposes establishing an "Ombudsman Office" and requiring that all FDA divisions and offices be notified of the functions of that office and the procedures for enlisting assistance from the ombudsman.

Kassebaum also proposes a system for internal appeals of decisions by individual reviewers. A sponsor who has exhausted the internal appeals process has the right to appeal to the appropriate Advisory Committee. If the committee concurs with the FDA decision, then no further appeal is permitted. If the committee agrees with the sponsor, the director of that particular FDA center reviews the issue and within 30 days notifies the applicant of the decision.

Commentary:

An impartial appeals process is needed at the agency. The process now in place is biased against the sponsor, and rather than fight a battle they won't win, most sponsors simply comply with the FDA position without complaining too loudly.

Information about Unapproved Uses of Approved Products (Off-Label Use)

The Kassebaum proposal permits product sponsors to disseminate medical texts, articles from peer-reviewed, scientific publications, presentations from scientific meetings, and extracts of such materials. Such materials may not be prepared by or for the product sponsor and must disclose prominently that the materials contain information about uses of the product not approved by FDA.

Commentary:

It is in the best interests of patients, clinicians and researchers to have rapid access to important new information about products that have been approved for one purpose, but may have other, significant uses, as described in scientific papers and presentations. Access to such information may be critical to the health of individuals or groups of patients. Barriers to the free flow of information between researchers, clinicians and the patient population are out of place in our society. However, it is appropriate that product sponsors not promote such information as scientific fact nor represent the "off-label" use as FDA-approved.

Approval Standard for New Drugs

The Kassebaum bill seeks to clarify that product approval by FDA requires completion of only a single clinical (human) study.

Commentary:

There is some confusion among FDA staff, within industry and among patient groups regarding FDA's minimal requirement for approval of a new drug or product. A careful look at existing regulations reveals that FDA policy requires only "one adequate and well-controlled" clinical study as the basis for seeking marketing approval. For example, FDA could approve a drug based on the results of a Phase II study, rather than requiring Phase III and Phase IV trials that add years to the approval process. Such an expedited process seems especially appropriate for the approval of drugs for seriously debilitating or life-threatening conditions.

In fairness to FDA, the agency has already taken steps to improve its review processes for drugs and products, most recently for AIDS drugs. But in spite of good intentions, the process of bringing a drug to market has doubled in length over the past 30 years to an average of 14-16 years! This has occurred in the face of rapid advances in medical science that, in general, have made drugs much safer than they were in the past.

One unwanted result of the slowing of the drug development and approval process is an enormous increase in the cost of developing a new drug. If FDA reform can decrease the cost of drug development by speeding up the process, it will be an attractive incentive to manufacturers to continue to look for breakthrough products for life-threatening illnesses that will not generate big profits. Without such incentives, manufacturers may abandon their search for drugs for difficult-to-treat conditions such as AIDS and cancer. Sadly, some large and small companies have already done so.

Conclusion

For patients facing life-threatening illnesses for which no suitable approved treatments exist, there are 2 critically important issues to be addressed by any serious FDA reform proposal: (1) speeding the pace of drug research and development and (2) broadening access to promising new therapies at earlier stages of development.

Patients and consumers certainly will not benefit from reform efforts that seek only to promote the financial interests of the pharmaceutical, biotechnology and medical product industries. But industry and consumers share many of the same reform objectives, including the following:

* faster drug development and approval; * reduction of the costs for drug development; * expedited patient access to drugs for serious and life-threatening conditions; * patient community representation on Advisory Committees; * use of Summary Data for FDA review of drugs or products granted expedited reviews (accelerated approval review); * information dissemination concerning off-label use of approved drugs; and * creation of an impartial and expeditious appeals process.

It is not unthinkable that FDA management will consider the reform proposals that address these concerns and decide to implement them. For patients and consumers, such an "internal" reform of FDA may be the most effective and efficient method to accomplish their priorities.

It is difficult to know what is the appropriate role of Congress in changing the mission of FDA and its regulatory policies regarding drug development. Politics and medicine usually do not mix well.

But if the agency itself does not adequately address the most pressing concerns of both industry and patient groups, Congress may seize the opportunity to legislate changes at FDA. Congressional action on FDA reform may take a back seat to other priorities outlined in the "Contract with America." For this reason, the Congressional debate on specific FDA reform legislation could be postponed until 1996.

In considering FDA reform legislation, let us hope that Congress will place paramount importance on the best interests of patients and consumers while also appropriately addressing the legitimate concerns of the pharmaceutical, biotechnolgy and medical product industries.

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Copyright © 1995 - Bulletin of Experimental Treatments for AIDS (BETA). Reproduced with permission. BETA is published four times a year by the San Francisco AIDS Foundation. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. Call 415.487.8060; FAX: 415.487.8069. Mailing Address: P.O. Box 426182, San Francisco, CA 94142-6182.  beta@sfaf.org  http://www.sfaf.org/beta.html