Item #37: Are Clinical Trials Improving with Time?

AZT was approved in record time, but that record didn’t stand for long. In 1991, the FDA approved another DNA chain terminator, ddI, without even the pretense of a controlled study. Anti-HIV drugs such as Crixivan were approved in as little as six weeks, and cast as a triumph of AIDS activism. This pattern of jettisoning standard experimental controls has continued up to the present, as the HIVNET affair amply demonstrates, and has characterized not only research into new drugs designed to exterminate HIV but the more fundamental questions at the root of AIDS research.

Farber states in relation to clinical trials “This pattern of jettisoning standard experimental controls has continued up to the present ... ”.

On the contrary, clinical trials are more closely scrutinised than before and, as a result, their scientific and ethical qualities are ever-improving. More needs to be done to improve the separation of clinical trials from those with a financial interest in their outcome, but this does not mean that clinical trials are a cesspit of corrupted science.

We agree with the Gallo document that “More needs to be done to improve the separation of clinical trials from those with a financial interest in their outcome”. Farber did not claim that standards for clinical trials were getting worse over time, but does illustrate that standards for AIDS drug trials are very low.

Financial conflicts of interest are one of the worst problems, and there are numerous papers, from a variety of medical research fields, indicating that this has a big impact on results, almost always in favor of new drugs approval:

• “Authors who supported the use of calcium-channel antagonists were significantly more likely than neutral or critical authors to have financial relationships with manufacturers...(96% vs. 60% and 37%, respectively).” [1]
• “The conclusions of review articles are strongly associated with the affiliations of their authors...original research articles that acknowledge sponsorship from the pharmaceutical industry, the chemical industry, or the tobacco industry tend to draw pro-industry conclusions...94% of reviews by tobacco industry-affiliated authors concluded that passive smoking is not harmful, compared with 13% of reviews by authors without tobacco industry affiliations...we identified only 1 review written by an author without any known tobacco industry affiliations that concluded that passive smoking is not harmful to health” [2]
• “Significantly more articles with drug company support (98%; 39 of 40) than without drug company support (79%; 89 of 112) had outcomes favoring the drug of interest” [3]
• “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” [4]
• “The 181 peer-reviewed journals examined by the research team published 61,134 original research items in 1997. Of the original research items, the number that contained at least one positive disclosure [as opposed to a declaration of ‘no financial interests’] of an author’s personal financial interests related to the publication was 327 (0.5%)…low rates of personal financial disclosures are either a result of low rates of financial interest (nothing to disclose) or poor compliance among authors to the journals’ COI policies. Based on the previously mentioned pilot study, higher disclosure rates in the template journals, and the growth of commercialization in the biomedical sciences, we believe that poor compliance is the more likely explanation for low disclosure rates in most journals with COI policies.” [5]
• “unfortunately, even when an investigator has had substantial input into trial design and data interpretation, the results of the finished trial may be buried rather than published if they are unfavorable to the sponsor’s product. Such issues are not theoretical” [6]
• “Approximately 1/4 of investigators have industry affiliations, and roughly 2/3 of academic institutions hold equity in start-ups that sponsor research performed at the same institutions. Eight articles, which together evaluated 1140 original studies, assessed the relation between industry sponsorship and outcome in original research. Aggregating the results of these articles showed a statistically significant association between industry sponsorship and pro-industry conclusions (pooled Mantel-Haenszel odds ratio, 3.60; 95% confidence interval, 2.63-4.91). Industry sponsorship was also associated with restrictions on publication and data sharing. The approach to managing financial conflicts varied substantially across academic institutions and peer-reviewed journals.” [7]
• “The experimental drug was recommended as treatment of choice in 16% of trials funded by nonprofit organizations, 30% of trials not reporting funding, 35% of trials funded by both nonprofit and for-profit organizations, and 51% of trials funded by for-profit organizations.” [8]

1. Stelfox HT et al. Conflict of interest in the debate over calcium-channel antagonists. N Engl J Med. 1998 Jan 8; 338(2): 101-6.
2. Barnes DE et al. Why review articles on the health effects of passive smoking reach different conclusions. JAMA. 1998 May 20; 279(19): 1566-70.
3. Cho MK et al. The quality of drug studies published in symposium proceedings. Ann Intern Med. 1996; 124: 485-9.
4. 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.
5. Krimsky S et al. Conflict of interest policies in science and medical journals: editorial practices and author disclosures. Sci Eng Ethics. 2001 Apr; 7(2).
6. Davidoff F et al. Sponsorship, authorship, and accountability. N Engl J Med. 2001 Sep 13; 345(11): 825-7.
7. Bekelman JE et al. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. 2003 Jan 22-29; 289(4): 454-65.
8. Als-Nielsen B et al. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA. 2003 Aug 20; 290(7): 921-8.