Biomedical Politics (1991) / Chapter Skim
Currently Skimming:
Unproven AIDS Therapies: he Food and Drug Administration and ddI
Unproven AIDS Therapies: he Food and Drug Administration and ddI
Pages 9-42
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 9... ...
, of which all the federal agencies responding to AIDS are a part, including the Food and Drug Administration (FDA) , was, until late 1990, responsible for enforcement of a ban on immigration by homosexuals based on the determination that gays and lesbians are mentally ill even though the Jeffrey Levi is a Washington-based health policy consultant working with several groups on AIDS issues, including the National Gay and Lesbian Task Force, the Gay Men's Health Crisis, and the Institute of Medicine.
|
From page 10... ...
infection, occurred in a context of more general discussions within the AIDS scientific and activist communities about early access to experimental treatments for persons with AIDS that were to be offered on a "parallel track" with ongoing clinical trials. In effect, ddI became a prototype for early access before a model for implementing the broader parallel track program was developed or approved by the relevant government agencies.
|
From page 11... ...
In 1962, in reaction to the thalidomide scandal overseas, the Kefauver amendments to the Food, Drug, and Cosmetics Act resulted in a requirement that manufacturers demonstrate not only the safety of a drug but also its eff~cacy.5 This requirement led to far more complex clinical trials and the regulatory system that is the basis for today's drug approval process.
|
From page 12... ...
Although not required by regulation, there are generally three stages to the clinical trials process. During Phase I, initial safety studies are conducted, usually among a small number of healthy patients, with gradual increases in dosage to determine safe levels.
|
From page 13... ...
In a sense, the purpose of the regulations was to short-circuit the three clinical trials phases and, in the words of then FDA Commissioner Frank Young, "be able to reach a scientifically defensible decision to approve or disapprove marketing of drugs intended to improve the outcome in such diseases, based on the results of welldesigned Phase II controlled trials" (Young, 19891. Essentially, the new approach assumes that patients and physicians will use a different risk-benefit analysis for drugs to treat life-threatening illnesses and will be willing to use those drugs with less complete data than are usually available for approved drugs.
|
From page 14... ...
This concern was based on the assumption that if a drug were available outside of clinical trials, few people would enroll in randomized trials because there was no guarantee of actually receiving the drug in question.6 It is in this context with frustration over the length of time it took new drugs to move through the entire drug approval process and a feeling that existing mechanisms for early release of promising drugs were not being sufficiently employed—that AIDS activists began to call for a new mechanism for earlier release of AIDS drugs in the drug development process. This new mechanism is what became known as parallel track.
|
From page 15... ...
trials, this parallel track would make investigational AIDS drugs available to people with HIV disease who are ineligible for the drugs' clinical trials and have no reasonable treatment alternatives" (Eigo, 19891. As Eigo explains it, the parallel track concept grew out of the failure of existing mechanisms to "deliver drugs to people with serious or lifethreatening conditions who have no treatment alternative before full FDA marketing approval" (Eigo, 19891.
|
From page 16... ...
If patients did not see the clinical trials as their only means of obtaining a drug, it might be possible to conduct more efficient trials and have better patient compliance. Although there were hints from NIH officials at the Fifth International AIDS Conference in Montreal in early June 1989 that there might be more flexibility in NIH's position regarding earlier access, the formal declaration of a change of heart occurred in a speech given by Fauci in San Francisco later that month.
|
From page 17... ...
At the hearing, Mason presented an administration position on parallel track that was astonishingly similar in its broad outlines to that of the AIDS activist community. Said Mason, "As contemplated, the availability of investigational therapeutic agents through this mechanism would be limited to those persons for whom there are no satisfactory alternative drugs or therapies available to treat that stage of disease and who, for some reason, are not eligible for or not able to participate in a clinical trial" (Mason, 19891.
|
From page 18... ...
As discussions were held at the NAP O level regarding guidelines for the parallel track policy, the FDA, NIH, Bristol-Myers, and AIDS activists were negotiating protocols for the early release of ddI. In these talks everyone took pains to make it clear that the ddI package was not meant to be the prototype for parallel track.
|
From page 19... ...
In fact, they traced some of the difficulties in early access to Young's formalization of the treatment IND rules. This policy, they said, created false expectations among the AIDS activists and resulted in pressures to totally overhaul the system.
|
From page 20... ...
Scientists, on the other hand, pointed to the many instances, even in the context of the AIDS crisis, in which the popular perception that a drug worked simply was not borne out in clinical trials. In the end, the bureaucracy has supported, at least on its face, the parallel track concept.
|
From page 21... ...
Newton E Hyslop, Jr., a principal investigator for the TulaneLouisiana State University AIDS Clinical Trials Unit, told the Los Angeles Times that he was "concerned that the establishment of a parallel track process would affect the selection process for formal trials in a way that could bias the outcome because participants would no longer represent a statistically valid sample group" (Cimons, 19891.
|
From page 22... ...
The AIDS Activists The parallel track issue brought an unusual level of unanimity to the AIDS constituency. Although all elements in the community were supportive of expanded access to clinical trials, early release of drugs outside the research setting was an issue pushed initially by the ACT UP and Project Inform sector, which then brought along, in growing numbers, more of the mainstream groups.
|
From page 23... ...
Other consumer or patient interests were not well represented in the discussion, and it was assumed that the guidelines being developed for parallel track would be limited to AIDS drugs. But William Schultz, then with the Public Citizen Health Litigation Project, told the FDA's Anti-Infectives Advisory Committee, "I do not see how this can be formulated without talking about the impact on drugs for other diseases.
|
From page 24... ...
Once that was clear, according to the FDA, some form of early access or compassionate use proposal was immediately put on the table and supported by the FDA and the drug's sponsor, Bristol-Myers. The activist community seized on ddI after the June 1989 Fifth International AIDS Conference in Montreal, at which promising early data were presented.
|
From page 25... ...
Many activists felt the New York meeting marked a breakthrough in relations with Ellen Cooper, who led the FDA team in the ddI negotiations. They had arranged for community physicians to attend to introduce a real-world perspective, and the activists felt that this contact with the dilemmas facing physicians contributed to Cooper's more flexible approach.
|
From page 26... ...
· Third, an open safety protocol was permitted for those who had shown evidence of failing to respond to AZT. The criterion for access to both the treatment IND and the open safety protocol was the inaccessibility of clinical trials: either because the individual did not meet the entry criteria or because there was no geographically accessible trial for the individual to join.
|
From page 27... ...
Everyone involved in the early release decision was painfully aware of the criticisms of parallel track that it had the potential for undermining clinical trials, thus preventing clear answers as to the usefulness of a therapy. But what had not been considered was that enrollment in the treatment IND and the open safety protocol a relatively simple process of physicians contacting Bristol-Myers—would move much faster than enrollment of patients in the ACTG trials.
|
From page 28... ...
With so much riding on the success of this experiment, it is unfortunate that no objective system of evaluation has been established. Ex post facto review is possible, but the fact remains that the need for ongoing evaluation should have been recognized by those responsible for developing the early release program, if only to prevent evaluation by press comment.
|
From page 29... ...
It certainly generated good will and positive media coverage for Bristol-Myers, a stark contrast to the feelings among AIDS activists toward Burroughs Wellcome, the manufacturer of AZT. Burroughs is under almost constant attack from the very same activists for its pricing structure.
|
From page 30... ...
Commissioner Young, who was described by one activist as "tired of being out-Fauci-ed" in terms of favorable publicity among AIDS activists, wanted to use ddI as an example of how the FDA could make things work. He also saw the ddI case as an opportunity to vindicate his advocacy for the changes in the treatment IND regulations that allowed earlier release of drugs for life-threatening illnesses.
|
From page 31... ...
In his effort to gain support within the AIDS activist community, as well as out of sincere support for the concept, Fauci began something of which the ultimate outcome was not at all clear to him and whose far-reaching implications were probably not considered and thrashed out within NIH before the concept was introduced. This kind of process can be effective if one has faith that the events will play out as one would like them to.
|
From page 32... ...
The system may always have been open to this kind of input or may always have had this level of flexibility, as government and company officials often claimed; but in the case of ddI the activists achieved an unprecedented level of involvement by consumer and patient advocates in the drug regulation process, normally a very tightly held series of negotiations, and forced real-world considerations into the decision making of the regulators and the sponsor. Several fortunate political circumstances enhanced the activists' influence.
|
From page 33... ...
Young, for his part, pushed the FDA bureaucracy to move as quickly as possible on the ddI treatment IND so he could prove that he could make parallel track work before there was even a parallel track structure. In a sense, the strength of support
|
From page 34... ...
Yet no permanent mechanism currently exists to assure this level of involvement for future AIDS drugs or for drugs for any other disease. Ellen Cooper, who has often been perceived by many as an obstacle to just this kind of involvement, is one who believes that there is a need for all relevant participants to meet on a more formal basis.
|
From page 35... ...
But within the AIDS constituency, much of the pressure around early access to experimental drugs has, indeed, come from the gay community. More fundamental issues of access- to primary care and to clinical trials are also part of the AIDS constituency's agenda and have been pushed by the needs and advocacy of those minority and poverty community representatives active in the AIDS effort.
|
From page 36... ...
9. "Guidelines for the Parallel Track Program for AIDS and HIV-Related Treatments," memo to James Mason, M.D., Assistant Secretary for Health, August 17, 1989, from the AIDS Action Council, ACT UP/New York, ACT UP/ San Francisco, AIDS Project Los Angeles, American Association of Physicians for Human Rights, American Civil Liberties Union AIDS Project, American Foundation for AIDS Research, Community Research Alliance, Gay Men's Health Crisis, Human Rights Campaign Fund, Lambda Legal Defense and Education Fund, Mobilization Against AIDS, National Association of People with AIDS, National Gay and Lesbian Task Force, National Gay Rights Advocates, Project Inform, and San Francisco AIDS Foundation.
|
From page 37... ...
July 28, 1989. Quick release of AIDS drugs.
|
From page 38... ...
The first cases were exclusively male homosexuals; thereafter the syndrome was successively recognized in other population groups (transfusion recipients, hemophiliacs, intravenous (IV) drug users and their heterosexual partners, children born to infected mothers)
|
From page 39... ...
Although gay advocates do not speak with a single voice, many agree that RCTs are necessary to evaluate drug efficacy and safety. They share the concern of clinical investigators that the ability to obtain ddl outside of trials may markedly decrease enrollment in clinical trials.
|
From page 40... ...
The danger is less the confraternity of charlatans ready to peddle expensive nostrums to credulous patients than the risk that even nontoxic nostrums, through their illusory promise of ready cure at no discomfort, can lead to great harm by diverting patients from appropriate (but unpleasant) treatment protocols.
|
From page 41... ...
The case is an excellent example of the difficulties involved in attempting to achieve an appropriate balance between the needs of individuals (people with AIDS) , who desire access to an unproven therapy, and the needs of society, which must ensure proper testing of pharmaceutical products before they are made available for use outside of controlled clinical trials.
|
From page 42... ...
For example, the broader scientific community was not formally involved in the ddl decision and it is now beginning to question the apparent decision to move away from the "golcl standarcl" of randomized controlled clinical trials, particularly in light of reports of adverse reactions among individuals receiving the drug outside of clinical trials. The FDA has published aformal proposal to revise its rulesto permit the general application of the.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.