DSI Hits Hard on Human Subject Protection


The Division of Scientific Investigations (DSI) in FDA’s Center for Drug Evaluation and Research used to be something of a joke when it came to enforcement. In fact, in Fiscal Years 2005 and 2006 they failed to issue a single Warning Letter. Not one. Well, things have changed. In the article “Bimo Warning Letters for 2008” found on the page at the Blog Top I mention that DSI has started to issue Warning Letters for clinical trials. Now, DSI has issued three Warning Letters dated 2-3 March for some very serious violations of regulations protecting the rights, safety and welfare of participants in clinical trials. Although I have questioned some of DSI’s judgement in the past few years, all three are richly deserved. They are all sent to clinical investigators (the medical doctors conducting the research).

In the first Warning Letter the clinical investigator had three lapses in approval by an institutional review board (IRB), the longest lapse in approval was for five months. IRBs are the independent ethics committees that oversee clinical trials. Not having independent review of research is a very big no-no. The Warning Letter included a citation for consenting a participant, also referred to as a “subject,” first with an English language consent form and then later re-consenting the participant with a Spanish language informed consent form. This indicates that the participant was probably only fluent in Spanish. An informed consent form must be in the language used to provide informed consent to the participant. This is another essential right of people participating in clinical trials, the right to informed consent and to not participate if they so choose.

The second Warning Letter involved pediatric trials for Zemuron, a Schering Plough drug used in relaxing muscles during surgery and mechanical breathing. This time FDA cited the clinical investigator for failing to adequately supervise “individuals to whom you delegated study tasks…resulted in inadequate informed consent documentation…failed to obtain legally effective informed consent.” There were numerous problems at this study site that involved false signatures from the study coordinator (the clinical investigator’s primary assistant) and consent forms dated by study personnel instead of the study participant.

The third Warning Letter documented that all 18 participants who enrolled in the study “received study dug prior to your review and assessment of baseline laboratory results…were infused intravenously…” The clinical investigator (again, the medical doctor conducting the study) didn’t review the laboratory results from three to 20 days after infusing the investigational drug product. This is a big deal for three important reasons.

First, you never start a clinical trial before all requirements are met. Clinical trials are experiments, not the practice of medicine. Second, the clinical investigator was dealing with very ill patients. They were having IV drug infusions. He should have reviewed their lab results regardless if they were participating in a clinical trial.

Finally, and this is the first of two points I am trying to make in this post, the clinical investigator failed to establish a clinical baseline for the participants. This is an important concept for those of us who are involved in the conduct of clinical trials as our profession. There needs to be a clearly established clinical baseline, the medical condition of the participant when the study begins. And you really want to DOCUMENT the clinical baseline. This is important to determine if the drug is safe and effective.

The second point I would like to make is that it is very disturbing that clinical research in the United States is being conducted with these ethical violations. If you have read this far you probably know that there are problems with the conduct of clinical trials, with drug safety, and the entire new drug approval process. We know that FDA needs to improve its performance if it is to adequately protect the health of the American people. The question is what needs to be done.

I would like to suggest that putting more requirements on institutional review boards (IRBs), the ethical committees that oversee research, is not the way to go. Instead, I believe that we need to modernize the clinical trial regulations that came into being in the 1970s. In particular, I believe that we should make the Consolidated Good Clinical Practice Guidelines, ICH E6, into regulations, instead of a guidance document that cannot be legally enforced. This document was written with extensive input from FDA. It is the law in Europe, Canada, Japan, Australia, and many other countries. Our regulations are outdated and don’t give researchers the necessary oversight to ensure ethical clinical trials.

Unfortunately, over the years IRBs have been criticized for not providing the necessary oversight. This isn’t the responsibility of the IRBs, it is the responsibility of FDA. FDA needs to perform more effective inspections of clinical investigators and IRBs. However, FDA does not have the resources, and until now DSI did not have the will, to enforce protections for participants in clinical trials.

Currently IRBs are being investigated by a Congressional subcommittee chaired by Representative Bart Stupak. The investigation should be discussed at a hearing later this month. I think that they may be looking in the wrong place. There are two sets of regulations for IRBs in the U.S. which is confusing to many (FDA regulations and Department of Health and Human Services, 45 CFR 46). The regulations are enforced by two different federal agencies with different approaches. Out of date, conflicting regulations just don’t help very much.

In fact, the FDA “Compliance Program” for IRBs hasn’t been updated since 1994. It was due to be updated in 1997, 12 years ago. The compliance program is the blueprint for FDA field investigators to conduct an inspection. FDA has outdated regulations, field operations, and funding.

I am also posting E6, the combined guidance for Good Clinical Practice (GCP), and other ICH documents. Finally, I am posting the link for the outdated compliance program for the inspection of IRBs. It is high time that this document was updated. As always, I welcome your comments.

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