AIDS TREATMENT NEWS #140, December 6, 1991
John S. James

What is new is that the White House is now putting its weight behind implementing some of the reforms -- which is the good news, and especially welcome since the AIDS community has long been asking for White House leadership in fighting the epidemic. The bad news is that the new proposals have become involved in a major non-medical controversy -- an ongoing bitter dispute involving charges of political abuse of the regulatory process, and questions of the relationship between the legislative and executive branches of government. Most of the Competitiveness Council proposals appear to be largely noncontroversial. But on some there will be different perspectives even within the AIDS community. We should accept different views as legitimate.

[Note: This article does not address the political background of this dispute -- such as the controversies involving the Council on Competitiveness, secret influence on the regulatory process, and political use of implementing regulations to nullify the intent of Congress. To cover these areas well would take us too far afield from the central focus on this newsletter. But we should be aware that these issues exist, because they color most of what is happening in the debate about FDA reform.]

The Council on Competitiveness Proposals

A ten-page fact sheet released on November 13 lists eleven specific reforms:

#1: Allow outside organizations to review certain new-drug applications, subject to FDA approval;

#2: Expand use of advisory committees, using them earlier than now in the drug-development process;

#3: Allow phase I trials to be approved by institutional review boards (IRBs), without necessarily having FDA review;

#4: Flexible interpretation of the efficacy standard. "FDA will make a deliberate effort to interpret the statutory requirement of efficacy in a manner that maximizes rather than limits a drug's potential for approval and takes into account the risks to human life and health that may result from delay of new treatments;"

#5: Accelerate development and approval of drugs which either (a) treat life-threatening, very serious, or seriously debilitating conditions (examples given are cancer, HIV disease, and cystic fibrosis), or (b) treat any condition which lacks satisfactory alternative therapy -- provided that "the drug's effectiveness can be measured by appropriate surrogate endpoints or other appropriate indicators of effectiveness."

#6: U. S. recognition of foreign approvals. "The Administration and the FDA will place high priority on achieving harmonization with other industrial countries that will enable the U. S. to recognize foreign approvals of drugs, in order too provide American patients with faster access to a broader variety of important therapies."

#7: Enhance computerization of new drug reviews.

#8: Classify all new-drug applications as either "routine" or "expedited," and review applications within each category in the order received. (This would replace the current system of six priority levels based on potential therapeutic benefit.)

#9: Use internal management systems to monitor the progress of each application submitted, and to reduce the use of clinical holds on investigational new drug (IND) applications.

10: Reduce product liability costs by Congressional passage of S. 640, which protects drug companies from punitive damage when their product has FDA approval. (They would still be liable for actual damages, despite FDA approval.)

11: Increase FDA staff and resources for new-drug review, (a) by directing all new expanded staff to drug approval until goals there are met, and (b) by "a concerted, one-time industry effort to pay for computerization for FDA through the use of the government's gift authority."

The Controversy

A November 13 letter to FDA Commissioner David Kessler from three members of Congress, all leading Democrats -- Edward M. Kennedy, Chairman, Senate Committee on Labor and Human Resources, John D. Dingell, Chairman, House Committee on Energy and Commerce, and Henry A. Waxman, Chairman, House Subcommittee on Health and the Environment -- strongly supported efforts to speed drugs for life-threatening conditions, but found serious problems in three of the eleven Council on Competitiveness proposals. Because of the importance of this issue, and the difficulty of summarizing the complex arguments briefly, we quote the letter in full:

"We have reviewed a summary of the report on the drug approval process issued today by the Vice President's Council on Competitiveness, and we are writing to express our serious concerns.

"We strongly support steps to expedite the approval of drugs for AIDS, and other life-threatening diseases and serious conditions. To the extent that the Council recommends expediting decisions on the approvals of these drugs while preserving the statutory requirement that there be substantial evidence of a drug's safety and efficacy, we would enthusiastically support those recommendations.

"Three proposals, however, raise particularly troubling questions. They are the proposals: (1) to allow private contractors to review the safety and efficacy of drugs proposed for FDA approval; (2) to move toward permitting the United States to accept foreign government approvals of drugs; and (3) to use private review boards in place of the FDA to evaluate animal studies before allowing an experimental drug to be used in the first stage of human testing.

"In our view, under these proposals, the FDA appears to be abdicating its statutory responsibility to make key decisions on the safety and efficacy of drugs. These proposals appear to be directed largely toward the development of drugs that are not designed to treat life- threatening diseases or other serious conditions. Unfortunately, they do not adequately account for the fact that the use of any prescription drug entails a risk of life-threatening adverse reactions. These risks will be compounded if decisions about safety and efficacy are delegated to private contractors or foreign governments.

"Respected experts are concerned that the proposals to use private contractors, foreign governments, and private review boards to make critical decisions currently made by the FDA are thinly veiled efforts to weaken the agency and would undermine the very purpose for which it was created and that it is uniquely qualified to fulfill -- the protection of the American public from unsafe and ineffective drugs. We are concerned, at a minimum, that the proposals will lead to inconsistent and uncertain standards for review and could permit commercial interests to override the objectivity that is essential in evaluating drugs.

"The proposals are particularly troubling in light of the Administration's historic refusal to request adequate funding for the FDA. In our view, the Administration should seek greater resources for the FDA rather than attempting to supplant it with less credible alternatives.

"We intend to make a thorough review and evaluation of the proposals as expeditiously as possible. While we are undertaking that evaluation, we respectfully request that you not take any action to implement the three recommendations that we have identified as being of particular concern.

"We look forward to receiving your prompt response to our request."

Comment

Here is our understanding of the issues behind the three points of controversy. More analysis, discussion, and debate is appropriate, but should not delay implementation of at least the noncontroversial parts of the proposals.

The most controversial recommendation seems to be #1, allowing the FDA to contract with private organizations to review certain new-drug applications. The reason for this proposal seems to be that due to government red tape, as well as salary scale, the FDA cannot hire enough physician/scientists to review the drug applications it receives. The major concern seems to be that allowing companies to contract with private organizations "to review their clinical data for a fee," as is proposed, could open a Pandora's box of potential abuses -- especially since these review companies would know that they would inevitably be judged by their clients (pharmaceutical companies) on their history of positive vs. negative reviews.

It may be fortunate that this most controversial recommendation may not be a major issue for persons with life- threatening diseases. For technical reasons, outside review would probably not be used for the most important drugs. What matters most is making sure that critical drugs do get evaluated quickly. Just how this work gets done may not be our issue.

Proposal #6, U. S. recognition of foreign approvals, is important because a number of critical drugs have been in widespread use abroad long before they were generally available in the U. S.; notable examples have included fluconazole, clarithromycin, and azithromycin. In addition, we are all affected by the cost of medical care, and duplication of expensive testing certainly adds to this cost.

This proposal calls for negotiating with selected countries to develop common standards for clinical trials, a common format for submission of drug-approval applications, common requirements for animal testing, and common manufacturing and inspection standards, as well as for country-by-country agreements to accept each other's drug approvals. The objection seems to arise because the United States has had the world's most meticulous standards for drug approvals; therefore, accepting others' approvals would seem to imply lowering standards. And yet it is widely recognized that the U. S. approval system has become too expensive and cumbersome; also, the world is rapidly moving toward more international commerce. In negotiation of international drug-approval standards, the U. S. will have much leverage to insist on high standards when they are supported by evidence -- and it can, of course, reject any proposed agreement not to its satisfaction.

Pilot Studies: The Need for Change

Proposal #3, to allow institutional review boards to approve most phase I trials, may ultimately be the most important of the eleven proposals. But the case against it is strong, and unfortunately the case for it has not been well stated by the Competitiveness Council. The text of the recommendation is:

"Reform No 3 -- Expanded Role for Institutional Review Boards

"FDA will immediately permit sponsors of new drugs to submit their applications for Investigational New Drugs (INDs) involving Phase I studies of patients for commercial drugs and all INDs for non-commercial drugs to the appropriate Institutional Review Board (IRB) for approval and will not require additional agency review.

"IRBs currently provide valuable assistance to investigators in the design and review of clinical studies, particularly in regard to ethical issues and informed consent.

"Pursuant to this reform the FDA will rely upon the IRB's expertise to allow sponsors to begin research in human subjects. At present, both FDA and the IRB must review such Investigational New Drugs (INDs).

"The expanded role for the IRBs will enable FDA to be less involved in the early stages of clinical research where a significant number of drug studies are discontinued. As a result FDA can focus its resources only on drugs that survive the early stages of investigation and appear to have potential as new therapies for human treatment. This reform will promote creativity in clinical research by eliminating regulatory constraints in the early phases of investigation."

Incidentally, this writer spoke recently with a researcher from Australia, which allows such IRB approval for phase I studies of drugs which are already approved for human use elsewhere, without additional review by their equivalent of the FDA. He told us that many IRBs were reluctant to get involved, since they were not experienced in evaluating the pharmacology and toxicology data on drugs. One had recently solved the problem by hiring a toxicologist to evaluate that information; the toxicologist wrote a letter to the IRB saying that he found no problem with the proposed trial.

It is easy to argue against this proposal. The FDA is far better qualified to evaluate early drug data and clinical-trial plans than IRBs, which are not set up for this purpose but rather an as ethical check, for protecting the volunteers in the trial. We suspect that pharmaceutical companies interested in getting their drugs approved would in almost all cases choose to go through the FDA, since otherwise their data would be unlikely to meet all of the FDA's standards and the company would be sent back to do the trial over again. In fact, a company with an important drug should consider meeting with the FDA even before its application for an IND (permission to test the drug in humans) is completed. The argument that letting IRBs approve phase I trials would save time for the FDA was not thought through -- especially since human lives can be at risk in these trials.

But the proposal is vitally important in allowing trials by smaller research groups without pharmaceutical support -- such as community-based organizations or university medical centers. Often these early trials would not be intended as a direct step toward drug approval, but rather to bring an important treatment possibility to the attention of the research mainstream.

Again and again we have seen promising AIDS treatments delayed for years before they get to the first human trials, because the cost of getting an IND, even for drugs already in common use abroad, is prohibitive for community-based or university organizations; required animal studies alone can cost hundreds of thousands of dollars. When a drug has no human data (from tests with the disease in question), it usually takes it several years to generate enough interest among corporate financial officials to meet the high hurdles now in place -- hurdles which make sense for routine, non- emergency drug development. If community organizations could legally do the first small pilot studies, then any drugs showing good indications of efficacy could move into mainstream research much more quickly. At present, such pilot studies must be done underground or not at all, and it is hard to fund underground studies and to get reliable and credible data from them.

Unlocking the research system to avoid shutting out community, physician, and university research organizations would also be important for pilot studies of drug combinations. Combination studies are notoriously difficult to negotiate when the drugs come from different companies, as is usually the case.

It could be argued that the right way to solve this problem is to get the national will to deal with AIDS as a major emergency -- instead of lowering the hurdles so that those who are interested can generate research by themselves, without serious mainstream support. But there is little sign of such national seriousness after ten years of the epidemic. We cannot wait indefinitely for it, but must pursue other promising approaches -- including opening up the research process to the creativity of smaller organizations.

And even aside from AIDS, our medical-research system is very poor at mobilizing the critically important early exploratory followup of practical opportunities (for potentially lifesaving treatment advances) as they present themselves. It usually takes years for even a completely sound idea to mobilize the commercial or professional momentum required to reach even a small pilot human trial. Those who do understand a new idea and are committed to it could carry it to credibility years ahead of today's system, which usually blocks all but well-financed corporate sponsors. Expeditious testing could greatly speed the most important practical medical advances, to the immense benefit of the public.

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