Item #15: Who Benefits from Clinical Trials?

By June 2004, the National Institutes of Health had registered 10,906 clinical trials in ninety countries. The size of these trials, which range from the hundreds to more than 10,000 people for a single study, creates a huge market for trial participants, who are motivated by different factors in different societies but generally by some combination of the promise of better health care, prenatal care, free “access” to drugs, and often—especially in the United States—cash payments. Participating doctors, whose patient-care profits have been dwindling in recent years because of insurance-company restrictions, beef up their incomes by recruiting patients.

Farber complains about the growth of clinical trials and claims that everyone profits except the subjects. She also implies that only the poor and disadvantaged are used as subjects.

No reference is supplied to support the view that subjects on the whole are not benefiting from clinical trials. Many well-off people participate in clinical trials. The claim that most subjects of clinical trials are put at greater risk than benefit is astonishing, and it certainly contradicts common sense. Not every clinical trial is conducted perfectly, particularly from the perspective of record-keeping. Some are poorly conducted, but the vast majority conform to strict, internationally accepted ethical guidelines and benefit the study subjects.

“There is a clear duty to provide assessment and explanation with appropriate reservations about the preliminary state of evidence and the fact that it may change with more data. This is an obligation all too often honored only in the breach, especially when the possibility of a new treatment, however remote, is present. Understandably, those afflicted with a serious illness and their families grasp desperately at any suggestion of cure or amelioration. They often listen selectively. They tend to filter out the negatives and overestimate the potential benefits. Such subjects are exceedingly vulnerable and exploitable, all of which sharpen the obligation to provide evidence with ethical circumspection.” [1].

“Patients died prematurely in two failed clinical trials at Seattle’s Fred Hutchinson Cancer Research Center - experiments using drugs in which the center and its doctors had a financial interest. The patients and their families were never told about those connections, nor were they fully and properly informed about the risks of the experiment.” [2]

Dr. Samuel Epstein noted in “The Politics of Cancer Revisited” (East Ridge Press, 1998) that “While entering a clinical trial may well sound attractive, particularly to patients with advanced cancer, the chances of any benefits are remote.” Dr. Ralph Moss, in testimony to the US Congressional Committee on Government Reform and Oversight, said “If you read the statements of the NCI [a branch of the NIH] they urgently appeal to cancer patients to join their clinical trials…However, as the President’s Commission for the Study of Ethical Problems in Medicine stated (in 1983), “Patients who are asked to participate in tests of new anticancer drugs” should “not be misled about the likelihood (or remoteness) of any therapeutic benefit they might derive.’ In fact there is little chance of therapeutic benefit to patients in such trials. Studies in both the United States and Japan have shown that only about 1% of patients in Phase I clinical trials have a complete response to the treatment, and only about 5% have any response at all.” And, just as in AIDS, the outcome known as “response” is just a surrogate marker, a shrinkage of a tumor by 50% or more sustained for at least a month, not an indication of a cure.

With AIDS it is very difficult to know if a trial is benefitting the patients because there is no placebo arm to the trials. Without such a control group it is impossible to distinguish between the adverse effects of the drugs and the progression of AIDS. Who gets to judge? Well, usually the researchers. The following remarks from three different studies illustrate how serious adverse events and deaths are trivialized or made to disappear by blaming them on HIV instead of one of the study drugs:

“Of the 59 serious adverse events reported in the first 56 days of life, those that occurred in four (1.4%) babies in the zidovudine group and in two (0.7%) babies in the nevirapine group were judged [our emphasis] to be possibly, but unlikely to be, related to study drug…Within the first 56 days of life, 22 babies had grade 3 anaemia (nine in the zidovudine group, 13 in the nevirapine group), with haemoglobin values ranging from 85–118 g/L. No case was judged to be serious or clinically important.” [3]

“Of the 217 clinical adverse events reported among children, most were [judged to be] due to a known cause unrelated to study drugs…16 children (4%) had major birth defects, including 4 cardiac malformation cases, 4 cases of polydactyly, 3 talipes cases, and 1 case each of congenital diaphragmatic hernia, hydronephrosis, imperforate anus, genu recurvatum with a suburethral cyst, and hypospadia. 1 child each had Down syndrome, Ito nevus, and sickle cell anemia” [4].

“There were 5 serious adverse events [out of 8 participants!] including two deaths in the infants in cohort 1 [Nevirapine to mother only]. Only one of the five serious adverse events was thought by the investigators to be possibly, but not likely study drug related…In cohort 2 [Nevirapine to mother and child] there were 7 serious adverse events [out of 13 participants], including 2 infant deaths, although none were [judged by the researchers to be] related to the study drug.” [5].

None of these trials had a placebo arm control group to the trial, so there is no way of knowing what caused the deaths and serious adverse events.

1. Pellegrino ED. The ethical use of evidence in biomedicine. Eval Health Prof. 1999 Mar; 22(1): 33-43.
2. Wilson D et al. Uninformed consent: what patients at ‘The Hutch’ weren’t told about the experiments in which they died. Seattle Times. 2001 Mar 11-15.
3. Guay LA et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet. 1999 Sep 4; 354(9181): 795-802.
4. Mandelbrot L et al. Lamivudine-Zidovudine Combination for Prevention of Maternal-Infant Transmission of HIV-1. JAMA. 2001 Apr 25; 285(16): 2083-93.
5. Musoke P et al. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS. 1999 Mar 11; 13(4): 479-86.