The Social Impact of AIDS in the United States (1993) / Chapter Skim
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4 Clinical Research and Drug Regulation
4 Clinical Research and Drug Regulation
Pages 80-116
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From page 80... ...
Debate about the ethics and scientific validity of clinical trials occurs not only among physicians, statisticians, and ethicists, but also among patients, activists, and politicians. AIDS has opened the arena of clinical investigation the organization, ethics, and politics of research to media and public scrutiny.
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From page 81... ...
Randomized clinical trials experiments in which human subjects are randomly assigned to experimental and nonexperimental (control) groups for purposes of comparison - offer re
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From page 82... ...
As biostatisticians have recognized, the development of randomized clinical trials was perhaps the most important methodologic advance associated with the scientific basis of therapeutics (Zelen, 1990~. Despite these advantages, randomized clinical trials did not immediately become the basic rule of clinical investigation.
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From page 83... ...
In Salk's mind, the research he had already conducted demonstrated the effectiveness of the vaccine; to conduct a full-fledged randomized trial, he concluded, would be merely a "fetish of orthodoxy" and would lead to more new and unnecessary cases of paralytic polio among the group receiving the placebo. Other researchers countered that without a full randomized clinical trial the
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From page 84... ...
The difficult ethical considerations that attend randomized clinical trials remain a critical part of the debate concerning "therapeutic research," a term used to denote research conducted on subjects who, it is hoped, will benefit from the experimental preparation. When are randomized trials justified?
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From page 85... ...
As late as the early 1960s, randomized clinical trials continued to be the exception rather than the rule .
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From page 86... ...
Generally, randomized clinical trials are divided into three phases: phase I trials typically assess data on safety; phase II trials evaluate efficacy; and
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From page 87... ...
In the view of the pharmaceutical industry, which typically bears the costs of clinical trials, the Kefauver-Harris amendments raised the cost of researching, developing, and marketing new products. In the face of the AIDS epidemic, FDA's policies of cautious protection came under fire.
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From page 88... ...
In the midst of the AIDS epidemic, when access to clinical trials has become a bitterly contested question, it is worth remembering that only a short time ago the focus of discussion was the protection of research subjects from potentially dangerous experimental protocols. What the regulatory process had failed to recognize was that in certain specific situations individuals might be eager to have access to experimental drugs even if their safety and efficacy had yet to be proven by scientific criteria.
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From page 89... ...
Since that time, there have been several changes that reflect, if not characterize, a shift away from "medical paternalism": a growing skepticism by patients of medical and scientific authority; a deeper commitment to disclosure and consent by physicians; the legal codification of informed consent, as well as clearer promulgation of patients' "rights"; and the establishrr~ent of institutional mechanisms, such as internal review boards to protect human subjects. All these developments reflected significant charge in the general practice of medicine and the nature of clinical investigation (Katz, 1984; Faden and Beauchamp, 1986)
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From page 90... ...
Indeed, it was the sudden marked increase in requests for a drug long used to treat PCP, pentamidine, that provided one of the first pieces of evidence that AIDS was an epidemic disease. Frustration that PCP and other complications in AIDS patients were not amenable to conventional therapies led to a host of alternative approaches, including vitamins, holistic therapies, and imported, non-FDA-approved drugs.
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From page 91... ...
The experience with suramin again appeared to validate the preeminence of orthodox clinical trials. The Emergence of AZT In the winter of 1985-1986, preliminary studies of a previously discarded anticancer agent, zidovudine (AZT)
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From page 92... ...
, became increasingly visible, and the primary federal mechanism for the conduct of clinical trials, the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases, expanded rapidly. Advocacy by grassroots organizations in the gay community had been strong almost from the beginning of the epidemic.
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From page 93... ...
Despite these changes, which permitted patients a greater degree of personal choice in deciding which drugs to take, activists charged that the FDA interpreted the 1987 regulations too conservatively, only approving drugs for which phase II trials were completed or nearly completed, as a bridge between trials and FDA approval. Activists pushed for the creation of a novel mechanism to widen patient access, a concept that came to be called the "parallel track." The parallel track concept was loosely modeled on an approach to clinical trials common in Europe to obtain definitive information about treatment efficay.
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From page 94... ...
New York's ACT-UP, which had become increasingly knowledgeable and sophisticated about drug approval, did the most to popularize this concept. The first public discussion of the parallel track concept occurred in April 1988 under the leadership of the AIDS Clinical Trials Group.
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From page 95... ...
Thus, in the space of a very few years, radical changes in drug regulation have occurred, and for the first time, they have been due not to public reaction to a fatal drug toxicity, but to strong consumer activism by a group of affected patients and their advocates. The Integration of Activists in the Clinical Trials Process As activists achieved success in altering the regulation of drugs from 1987 to 1989, they began to turn their attention to the actual design and conduct of clinical trials, criticizing what they perceived as the failure of the AIDS Clinical Trials Group to test and deliver effective therapies rapidly.
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From page 96... ...
Several individual trial sites (called AIDS clinical trial units) formed local community advisory boards to provide two-way communication of issues and concerns.
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From page 97... ...
The CCG has come to play an active role in the ACTG: two positions on the ACTG Executive Committee are allotted to the CCG, and CCG members serve on each of the core committees. The CCG also works closely with the individual AIDS Clinical Trials Units (ACTUs)
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From page 98... ...
For a brief time, the AIDS Clinical Trials Group considered requiring that pharmaceutical companies virtually hand over promising drugs they wanted put into the group's trials, but in 1990 the pendulum seemed to swing back to individual companies' dictating many of the details of drug design and monitoring. Thus, it is likely that multiple experimental studies will continue to be conducted concurrently.
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From page 99... ...
Who Performs Clinical Trials Clinical trials have been traditionally performed almost exclusively in tertiary care (specialized teaching or research) hospitals and clinics by academic physicians.
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From page 100... ...
; the availability of specialized laboratory testing and nursing personnel trained in the requirements of research; and the availability of people to constitute an institutional review board to provide approval and oversight of the study and ensure proper protection of subjects. The first significant changes in the traditional approach to clinical trials resulted from the large expansion in clinical research funded through the National Cancer Institute.
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From page 101... ...
Almost from the beginning of the AIDS epidemic, patient advocacy groups took on the role of medical advisers through the creation of patient information newsletters (Steinbrook and Lo, 1990; Bishop, 1991~. In San Francisco, AIDS Treatment News began appearing in May 1986 and grew from a biweekly column in a local gay newspaper to a newsletter with a circulation of about 5,000 (James, 19891.
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From page 102... ...
Activists have also become researchers in other less dramatic ways. As noted above, activist representatives now sit on many major scientific committees, including the Executive Committee of the AIDS Clinical Trials Group and several AIDS clinical trial units have community advisory boards.
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From page 103... ...
Monitoring of toxicity due to an experimental drug is therefore difficult because observed side effects may be due to medications other than the experimental agent or because of interactions with that agent. The use of definitive outcomes in AIDS research to determine drug efficacy is becoming increasingly problematic.
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From page 104... ...
Some have argued that at least among African Americans, distrust of the medical system is so high and the collective memory of clinical trial abuses (as in the Tuskegee syphilis study) so strong that many people are actively opposed to participation
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From page 105... ...
It has proven difficult to obtain consent for enrolling such children in trials (Martin and Sacks, 19901. Yet the natural history of HIV disease in children differs appreciably from that in adults, which is an argument for earlier and fuller trials involving children.
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From page 106... ...
The protocol for this study (the so-called AIDS Clinical Trials Group protocol 076) has been the subject of more debate and controversy than that for any other AIDS trial; that 2-year debate illustrates the changing climate regarding treating pregnant women with experimental therapies.
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From page 107... ...
To meet concerns that in this protocol, and others, decisions regarding the treatment of women were not being addressed by those qualified to make them, a working group composed of obstetrician-gynecologists, internists, and pediatricians was established within the AIDS Clinical Trials Group. The working group has since been raised to the level of a full scientific committee and presumably will be consulted regarding all studies in which pregnant women will be enrolled.
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From page 108... ...
Whether it will have far-reaching effects on how decisions are made regarding the use of experimental or standard therapies with pregnant women with other diseases is unclear, but given that the entire area of research in women's health is undergoing dramatic evolution, it is likely that developments regarding AIDS will be scrutinized and considered as possible models. Dissemination of Information Peer-Reviewed Reporting of Clinical Research Dissemination of information regarding research results has traditionally occurred first through peer-reviewed scientific and medical publications.
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From page 109... ...
Similar announcements in the past 5 years have included information concerning a protective effect of corticosteroids for spinal cord injury, a news conference to announce an unexpected mor tality from two widely used antiarrhythmic drugs in a large clinical trial, and announcements of termination of a clinical trial of AZT versus a placebo in delaying the progression to AIDS among HIV-positive asymptomatic subjects. Such announcements have been criticized, however, as not providing sufficient information to permit physicians and patients to proceed with clinical care, for which they would want to have detailed information, such as drug dosage, drug side effects and interactions, and any caveats concerning the applicability of the results to types of patients other than those included in the trial.
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From page 110... ...
It is likely that continued refinements, large and small, will be proposed that will alter the process of research review and dissemination. Because of the large number of AIDSrelated clinical studies, including clinical trials, and the urgency of AIDS research, it is likely that much of the debate and change will take place in the context of the epidemic.
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From page 111... ...
First, not since randomized clinical trials became the orthodox mode of clinical investigation had the most basic approaches and assumptions regarding research methodologies been open to searching critique in the context of an epidemic disease. AIDS has led to a fundamental reconsideration of basic methodologies for establishing the efficacy and safety of pharmaceuticals.
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From page 112... ...
Moreover, it seems likely that the new methodologic approaches will not be limited to AIDS investigations, but, rather, will be diffused to other research fields. Although randomized clinical trials continue to offer significant scientific advantages for the evaluation of new drugs, it seems likely that in the context of AIDS, alternative approaches to clinical investigation will be proposed and evaluated in the years ahead.
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From page 113... ...
(1976) The ethics of experimentation with human subjects.
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From page 114... ...
Controlled Clinical Trials 11:80-87. Gross, J
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From page 115... ...
The Impact of Randomized Clinical Trials on Health Policy and Medical Practice: Background Paper. Washington, D.C.: U.S.
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From page 116... ...
Ho (1988) The role of community advisory committees in clinical trials of anti-HIV agents.
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