FDA Drug Approval: Major Reform Considered

A behind-the-scenes effort to reform the Federal drug- approval process has recently become public through an
editorial in The Wall Street Journal (August 2), and a major article in The New York Times (August 7).
The effort, spearheaded by Vice President George Bush and his Presidential Task Force on Regulatory Relief, apparently seeks the following changes:
* Regulatory hurdles could vary with the severity of the disease. For example, a treatment for AIDS, cancer, or
Alzheimer's disease could be approved more quickly than a new cold remedy or sleeping pill.
* For life-threatening diseases, the current "phase III" testing (large-scale efficacy trials) could be eliminated. This phase takes the longest, yet it contributes the least since the great majority of drugs which begin phase III are eventually approved (after several more years) for marketing. These drugs have already been proved safe in phase I, and probably effective in phase II.
* The FDA would be allowed to require a "phase IV", or post-marketing monitoring of the drug. This step is important because one of the current obstacles to earlier approval is that once approval is given, the FDA loses control of the drug and the company has no further incentive to complete its research. Instituting phase IV could allow the FDA to let patients get the drug while the research continued.
(The importance of finishing the research is illustrated by the problems in surgery, where new procedures do not need to prove efficacy. Some experts believe that a large fraction of operations are unnecessary, and that some accepted procedures may not be effective or do more harm than good. The issue isn't whether drugs should prove efficacy, but whether drugs that probably work should be denied to patients in an emergency, pending lengthy, final proof.)
* The FDA would also work more closely with companies during phase I and phase II, to design trials which could lead quickly to approval, and avoid the need to redo trials because of ambiguities in the results.

Comment

These reforms could be very important--or they could fail, in many ways. The AIDS community must be vigilant to see that the needs of persons with life-threatening illnesses are addressed.
The forces which wrecked previous reform attempts like the "treatment IND" could sabotage this one too. A process as complex and delicate as drug approval inevitably leaves room for obstructionism. Could the proposed reforms deal with the depth of problems which have occurred?
Time and again the AIDS drugs closest to approval have had extraordinary bad luck:
* Going into the recent Stockholm conference, the only drug close to approval was Imreg-1. Four days later it was so vilified by exaggerated criticism that the researchers were terrified of loss of their professional reputations. Criticism
of the research design was legitimate. But the crowd lost the perspective to ask whether, even if all the criticism were
true, the drug still should be available to patients.
* A year and a half ago, ribavirin was closest to approval. Early release of questionable data led not only to justified criticism, but to extraordinary vilification of leading researchers who were completely innocent of wrongdoing.
* Imuthiol (DTC) looks good in every way. But the U.S. trial results on which U.S. approval depends are being kept secret, for about a year, pending the completion of the last straggling arms of the multicentered trial. Apparently the developers feared that what happened to ribavirin could happen to them if they did not wait for full completion. What they are doing makes sense if the existence of an emergency is ignored.
* DHPG (ganciclovir), the only accessible treatment for AIDS-related blindness, got caught in regulatory limbo long ago because after compassionate use in thousands of cases everybody knew that it worked--and that scientific trials to "prove" it worked would require deliberately letting people go blind. When the FDA acted against this drug, apparently to punish the company for not doing the scientific trials, other compassionate-use treatments such as fluconazole for
cryptococcal meningitis suddenly became less available. It is well known that the FDA does not like compassionate use for AIDS drugs.
The common factor in each of the cases above is that the drugs were close to approval. All were threats to AZT, which takes in more money than anything else in AIDS, and therefore has more clout.
The corporations victimized by these abuses seldom dare to speak out, for fear of retribution not only against the drug in question, but against their non-AIDS drugs as well. Government agencies will not speak out. Researchers dare not, for doing so would damage their career prospects with almost any potential employer, public or private. Funded AIDS organizations have feared loss of funding if they speak about treatments not already approved by the FDA. In short, no major institutions nor any of their employees can tell the public what is wrong--which is why these problems were not recognized, addressed, and corrected long ago.
For these reasons we are only cautiously optimistic about the proposed reforms. The AIDS community must be cautious about fine print which could destroy the goal of faster approval--such as the rumored proposal to start the reform by moving all AIDS drugs back to phase I, requiring that all the trials be redone.
In particular we should note whether the new policy has written standards specifying the conditions under which a drug
can be released. The "treatment IND" system had no such standards, meaning that drug companies set their course depending on their reading of internal FDA politics. The real decisions were made privately, with public scrutiny excluded.
The U.S. drug-approval process was deliberately designed to be impervious to outside pressures and influences. Clearly a case can be made for setting up the system that way; for otherwise, powerful companies could buy or pressure their way to approvals not medically justified. But this system has also resisted scrutiny and challenge of the ill-concealed, de facto public policy decision to write off those already ill or infected with HIV.
The FDA is not the whole problem. The NIH, and private drug companies, have done no better. Few major drug companies even have an antiviral program. Almost all of the ballyhooed business interest in AIDS research concerns only new tests or other non-treatment products--and much of the rest is stock manipulation.
The fundamental problem has been a pervasive lack of political will to save the lives of people with AIDS. During
the last year we have seen the beginning development of this political will. But still it must overcome the legacy of
previous years--the inertia of legions of officials and professionals less inclined to do the job than to argue why it can't be done.
Ultimately this battle will be won; this country will not sit still while hundreds of thousands die from public neglect.
The question is how long victory will take, and that depends on the effort we bring to the struggle.
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