Better protection for whistleblowers, a national system of oversight for all clinical research, closer monitoring of informed consent procedures, tougher transparency provisions for contract research organisations and a less permissive approach to non-inferiority trials are among the reforms urgently needed to restore the credibility and safety of clinical trials in the US, a new report says.

According to Mark Cohen, co-author of the report and executive director of the Washington-based Government Accountability Project (GAP), the current US system for conducting and regulating clinical studies is “rife with conflicts of interest that put trial subjects at risk and produce suspect data on drug safety and efficacy”. To make matters worse, Cohen adds, federal oversight of the sector “is wholly inadequate”.

The GAP is a non-profit advocacy group that defends whistleblowers – among them David Graham, the Office of Drug Safety official who famously put the Food and Drug Administration’s (FDA) head on the block over Merck & Co’s Vioxx (rofecoxib). The Project’s ‘white paper’ on The ABCs of Drug Safety: Accountability, Balance, and Citizen Empowerment comes hard on the heels of a Congressional hearing that exposed serious flaws in the ethical review system for clinical research in the US.

The report suggests that deep-seated problems with drug safety stem partly from the FDA’s heavy reliance on industry user fees as federal support for the agency fails to keep pace with its needs. With this financial leverage, “drug companies have successfully pressured the FDA to greatly expedite the timetable for drug approvals, which results in a frequent rush for judgment about a product’s safety and efficacy”, it claims.

But the problems are also “structural to the FDA and to the conduct of clinical drug trials”, the report argues. For example, a study in 2003 found that around two thirds of academic medical centres held equity stakes in companies that sponsored research at those institutions.

Moreover, the law as it stands “promotes conflicted relations” between drug sponsors and the contract research organisations (CROs) and institutional review boards (IRBs) charged with ensuring the integrity of clinical trials and the safety of participants. Some CROs even hold shares in the very companies they serve, the report notes.

Too often, legislation designed to protect patients and clinical trial subjects is only “honoured in the breach”, the GAP maintains. And laws aimed at encouraging industry and government scientists to speak out about risky drugs and devices have failed to dispel a climate of fear about the consequences of whistleblowing.

The report’s recommendations include:

- Reforming statutory and common law provisions so that drug industry and government whistleblowers are properly protected.
- Congressional action to reinforce the recent US Supreme Court ruling in Wyeth v. Levine that personal injury lawsuits in state courts are not subject to federal pre-emption if the FDA approved the drug or medical device at issue.

- Extending federal regulation of clinical trials beyond those overseen by the FDA or the Department of Health and Human Services. According to the GAP report, many pre-Phase I, Phase IV and investigator-initiated trials are exempt from these controls, “leaving an estimated 40% of studies and over five million research participants uncovered each year”.
- Legislative reforms to ensure that IRBs “operate at arm’s length from drug sponsors and that IRB members are, themselves, free of compromising industry conflicts”.
- Launching pilot projects to determine whether the current IRB system provides genuine informed consent. The system in place “focuses almost exclusively on the review of consent forms” the report says. The law “does not require IRBs to regularly observe consent interviews or the conduct of study protocols. Instead, these critical processes are left to self-regulation by the investigators themselves”.
- Rather than undergoing either standard placebo-controlled or comparative studies, new medicines should be subject to three-arm clinical trials in which an investigational drug is tested both against a placebo and a comparator. This measure is aimed particularly at comparative non-inferiority trials, which lower the bar to approval of “common and lucrative” conditions such as ear infections – conditions that “almost always resolve on their own before the drugs are shown to have an actual impact”, the GAP asserts.