Friday, April 18, 2008

Another Example of Manipulation of Clinical Research (Vioxx Department)

We have posted frequently about manipulation of clinical research by those with vested interests in having the research turn out a certain way. (Try clicking on the label "manipulating clinical research" below.) A recent JAMA article, companion to the article on ghost writing and guest authorship which we have already discussed, provided another vivid example of the manipulation of clinical research. [Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: a case study based on documents from rofecoxib litigation. JAMA 2008; 299: 1813-1817. Link here.]

Basically, the article was a case-study of how mortality results of trials of rofecoxib (Vioxx, by Merck, now off the market) were reported. The article focused on two clinical trials, 078 and 091, and compared results reported in publications, reported to the FDA, from the commercial sponsor's own analysis, and from an independent analysis of the original data done by an author of the JAMA article.

Our major interest is the manipulation of research as reported in the clinical literature (because published results are what are most available to physicians, other health professionals, and patients to provide evidence used in clinical decision making). So we will focus on these results.

Here is how the published reports of these trials discussed mortality (quoting from the JAMA article), first for study 078:

'A total of 39 deaths occurred in patients who were taking study treatment or from fatal adverse events that started within 14 days of the last dose (24 or 3.3% for rofecoxib and 15 or 2.1% for placebo). . . . There were an additional 22 deaths in the off-drug period (17 in patients assigned to rofecoxib and five in patients assigned to placebo); 12 of these (11 in the rofecoxib group and one in the placebo group) occurred more than 48 weeks after treatment discontinuation.' The report also states: 'In addition to evaluating efficacy, the present study provided important placebo-controlled data on the safety of rofecoxib 25 mg over periods of up to 4 years in an elderly population. . . . Rofecoxib was generally well tolerated by the elderly patients in the study, consistent with results from prior clinical studies in osteoarthritis (Langman et al, 1999; Reicin et al, 2002) and AD (Reines et al, 2004). The overall incidence of adverse experiences, serious adverse experiences, and discontinuations due to adverse experiences were [sic] similar or only slightly increased for rofecoxib vs placebo.' The overall impression created by this report, for which 8 of 11 authors are employees of the sponsor, is that rofecoxib was 'generally well tolerated.'

And for trial 091:

'There were no drug-related deaths during the study. Non-drug related deaths occurred in 11 patients (9 in the rofecoxib group and 2 in the placebo group) while taking study treatment or within 14 days of the last dose.' Deaths that may have occurred more than 14 days after the last dose were not reported. Regarding safety, the authors conclude that 'Rofecoxib was generally well tolerated by the elderly patients in our study, which is consistent with results from previous clinical trials in patients with osteoarthritis.'

Note that the reports both mentioned that there were more deaths in the group of patients who took rofecoxib, but did not analyze these results for statistical significance, and found no importance in these results.

Here are the results of the sponsor's own intention to treat analysis, which was done in 2001, and not sent to the FDA until 2003.

Study Rofecoxib Mortality Placebo Mortality Hazard Ratio (95% CI)
091 13/346 3/346 4.43 (1.26-15.53)
078 21/723 9/732 2.55 (1.17-5.56)

Note that in both trials the death rates were statistically significantly higher for patients taking rofecoxib compared to placebo.

And the JAMA author's independent analysis of data combined from both trials showed a total mortality of 57/1069 for patients treated with rofecoxib, 29/1074 for those on placebo, and a hazard ratio of 2.13 (1.36-3.33).

Thus, it appears that the two published trial reports minimized the drug's apparent relationship to mortality by failing to do an intention-to-treat analysis, and in fact failing to do any analysis of the mortality data.

This is just the latest (but certainly one of the better publicized) examples of how commercial sponsors of clinical research may manipulate the design, implementation, analysis, and/or dissemination of results of studies to further their vested interests.

This is bad for patients because clinical decisions supposedly based on apparently the best data from clinical research may be distorted by such manipulation.

This manipulation also betrays the trust of research subjects who volunteered to participate thinking that the results of the research were meant to further science and patient care. Instead, the manipulation of clinical research means that its results may really mainly further the marketing of the sponsors' products or services.

As the JAMA authors concluded,

The findings from this case study suggest that additional protections for human research participants, including new approaches for the conduct, oversight, and reporting of industry-sponsored trials, are necessary. A clinical trials system in which sponsors fund the trials that are conducted by independent investigators would provide additional protections.

In my humble opinion, continuing revelations about suppression and manipulation of clinical research suggest that all such research ought to be done by truly independent investigators who have no financial or other entanglements with organizations with vested interests in the research turning out a certain way.


InformaticsMD said...

Perhaps these findings explain why I was unable to get involved in anything related to clinical trials when I was at Merck, and was rejected (sometimes rudely) when seeking rehire after the 11/2003 layoffs into such domains, such as adverse events and drug safety surveillance.

My 2000 "hiring justification" memo (p1 here and p2 here) specifically mentioned I was a highly ethical person (p 2), OK for running a research library under the watchful eye of nonbiomedical IT personnel, I guess, but perhaps deemed a potential "troublemaker" with regard to trials data.

One can only wonder if the designation of "ethical" actually harmed my employment opportunities.

-- SS

Anonymous said...

Not investigating the obvious increased death rate, not only does a disservice to those who participated in the study, but raises the potential impact on those, who in good faith, took this drug after it was released.

What is truly shocking is the low value placed on human life. These studies showed a marked increase in mortality, but this was ignored, in an effort to bring a product to market.

Steve Lucas