Sham Studies and the Commercial IRBs that Approve Them, and Sham IRBs and the Government Department that Registers Them

We have occasionally posted about the activities of for-profit contract research organizations (CROs). These are commercial entities that conduct human research, including clinical trials for pharmaceutical, biotechnology and device companies. More clinical research is being done by such CROs rather than by academic investigators. CROs seem to operate under the radar of most physicians, academics, and policy makers, but sometimes stories surface that raise questions about them.

For example, we discussed the trials by SFBC International (now PharmaNet Development Group) in Miami that enrolled immigrants, often undocumented, under questionable circumstances and in Montreal that resulted in the transmission of active tuberculosis (see post here and links backward); and the trial by Parexel International in London that put most of its subjects in intensive care (see post here, with links backward). Last year, as we discussed here, two articles questioning the ethics of research done under the auspices of CRO appeared in two major medical journals.

In academia, human research is supposed to be overseen by institutional review boards (IRBs). Research done by CROs is also supposed to be overseen by IRBs, but the IRBs that do so are often also commercial. Despite concern that commercial IRBs may be tempted to lower their standards to get more business, commercial IRBs have flown even lower under the radar than have CROs. However, last week, a story appeared about how a "sting operation" tested one commercial IRB with amazing results. Here are excerpts from the article by Alicia Mundy in the Wall Street Journal,

The sting, detailed at a House Energy and Commerce Committee hearing Thursday, involved the creation of a fictitious company and a fake medical device, a surgical adhesive gel. The sham firm then applied to three for-profit oversight groups -- called institutional review boards, or IRBs -- for approval to begin a clinical trial using their adhesive on human subjects.

Two IRBs contacted by the GAO's sting operators -- Argus IRB of Arizona and Fox IRB of Illinois -- rejected the Adhesiabloc proposal because of unanswered safety questions.

'We realized it was a terrible risk for the patient … It is the worst thing I have ever seen,' an Argus IRB reviewer said, according to a slide shown at the hearing.

Coast IRB LLC of Colorado Springs, Colo., did approve a study for the fictitious adhesive gel, 'Adhesiabloc.'

The GAO also ran an experiment to see if the US Department of Health and Human Services (DHHS)would register a truly dubious commercial IRB

The committee, working with the Government Accountability Office, Congress's investigatory arm, named the CEO of the fake IRB Truper Dawg, after a staffer's three-legged dog, now deceased. Other fake names included 'April Phuls' and 'Timothy Wittless,' which lawmakers said should have signaled irregularities to HHS. The department registered the IRB.

On one hand, these anecdotes suggest, along with the stories discussed above, that CROs and the commercial IRBs that are supposed to oversee them deserve further scrutiny. Beyond that, one wonders if it is good for society for human research, including experiments involving drugs and devices, to be done by commercial firms dependent for their income on the companies that make these drugs and devices, overseen by other commercial firms also dependent on these same companies. The fundamental conflict is embodied by Coast IRB's self-description:

as an advocate and a catalyst for an ever-stronger pharmaceutical industry, ethically and economically.

which also

recognizes the vital importance of our role in protecting individuals in all clinical studies and in continuously raising the bar on professional standards.

How can the company be an "advocate" for the industry while simultaneously protecting the people exposed to the industry's still experimental drugs?

See also comments on the GoozNews blog.

The Clinical Trials "Torture Economy"

Two recent commentaries in major medical journals on the same topic failed to get the recognition they deserved. Both were about exploitation of the poor in clinical research, usually in Phase I drug trials conducted by contract research organizations (CROs), supervised by for-profit institutional review boards (IRBs), and both paid by pharmaceutical, biotechnology or device companies.

The first article was by Carl Elliott and Roberto Abadie. [ Elliott C, Abadie R. Exploiting a research underclass in phase I clinical trials. N Engl J Med 2008; 358: 2316-7. Link here.] Per Elliott and Abadie, the context is:

Over the past decade, clinical trials have moved from universities to private testing sites, the pressure to recruit subjects quickly has intensified, and ethical oversight has been outsourced to for-profit institutional review boards (IRBs). Payment to subjects has escalated, creating 'shadow economies' in cities throughout North America and elsewhere.

The authors then cited several misadventures that we have discussed on Health Care Renewal: the trials by SFBC International (now PharmaNet Development Group) in Miami that enrolled immigrants, often undocumented, under questionable circumstances and in Montreal that resulted in the transmission of active tuberculosis (see post here and links backward); and the trial by Parexel International in London that put most of the subjects in intensive care (see post here, with links backward).

Elliott and Abadie concluded "there are good reasons to believe that poor subjects are being exploited," and cited several justifications for this belief:

• "Poor people are less likely than wealthier ones to get access to the drugs in question." This "appears to contravene article 19 of the Declaration of Helsinki, which states that medical research is ethically justified only if there is a reasonable chance that the population in which it is conducted will benefit from the results."
• "The U.S. oversight system is not well equipped to monitor a highly competitive, market-based, multinational research industry." The Office for Human Research Protection "has no jurisdiction over privately sponsored studies," the US Food and Drug Administration (FDA) has insufficient funds to monitor all but a tiny minority of trials. The institutional review boards (IRBs) that are supposed to supervise trials are ill-equipped to protect against the sort of abuses that are likely. Furthermore, for-profit IRBs that are dependent on research sponsors for repeat business may be loathe to upset the apple-cart.
• "Most sponsors apparently do not provide free care or treatment when subjects are injured."

Elliott and Abadie observed that most subjects in such trials see their participation as a job, rather than as a voluntary activity to promote science and human welfare. As the authors point out, if so, it is a poorly paid, risky job with few benefits and protections. Their conclusion is troubling,

The result is what one Philadelphia trial subject describes as 'a mild torture economy.' 'You are not being paid to do something,' he explains. 'You are being paid to endure.'

The only addition I can make is not only does the treatment of some patients in such trials appear inhumane, it amounts to bad science. Results from "professional trial subjects," who are likely to conceal characteristics which might have excluded them from this line of work, who may undergo one trial while still recovering from the effects of a previous, undisclosed trial, and who may be prone not to follow study protocols likely will not generalize to the patients who might actually be candidates for the drugs and devices assessed.

An editorial in the American Journal of Medicine was based on an article by Carl Elliott on the same topic published in the New Yorker. [Alpert JS. Dealing with ethical conflicts in clinical research. Am J Med 2008; 121: 457. Link here.]

His main conclusions were:

The ethical failure of such activities is obvious. The Nuremburg and Helsinki codes, developed following the human experimental atrocities of World War II, strongly advocate for voluntary participation on the part of research subjects. The substantial sums of money paid to the human 'guinea pigs' described by Elliott clearly obfuscate any volunteerism on the part of the individuals involved in these clinical experiments.

Lives saved and disease suffering lessened at the expense of individuals who are lured and perhaps even coerced into clinical trial participation cannot be allowed to continue in an open and equitable democracy. Clearly, the article by Elliott should be widely disseminated among academic and community physicians and governmental authorities. The topic should be openly discussed leading to corrective actions. Steps must be taken in the near future to protect the lives and the civil rights of individuals participating in clinical research studies.

Despite this call, I found no news coverage, and so far, no public discussion of any kind of the issues raised by these articles.

I hope that the charges that many current trials violate international ethical standards might get some peoples' attention, and maybe even inspire some action. I am not optimistic that anything will be done too hastily. After all, a lot of people are benefiting financially by the current scandalous status quo. They will not give up their ill-gotten gains gracefully. But this "mild torture economy" signals the approaching moral bankruptcy of our current health care system.