Guest Column | December 5, 2017

CRS Lawsuit: Does FDA Guidance Require More Clarity?

By Roger Mills, M.D.

CRS Lawsuit: Does FDA Guidance Require More Clarity?

The recent announcement that the watchdog group Center for Responsible Science (CRS) has filed a lawsuit against the FDA has raised some concerns in the clinical research community. The lawsuit is regarding the denial of the group’s citizen petition, which was originally submitted in June 2014.

CRS’ argument in the petition centers around two points. First, the authors argue animal toxicology studies “are insufficiently predictive of human clinical or toxicological outcomes.” Second, they point out a phenomenon called “therapeutic misconception” and state, “Many drug trial participants not only fail to understand the risks involved in the clinical trial, but actually believe they will receive personal benefit from the research.” It further states, “In fact, for the vast majority of Phase I clinical trials no therapeutic benefit is expected, and in Phase II and III clinical trials such benefits are unlikely. The misconceptions that clinical trials subjects experience reflect a deficiency in the informed consent process1

Left unsaid are the obvious countervailing issues that compounds showing significant animal toxicity do not advance to human trials and that individuals who agree to participate in Phase 2 or 3 drug trials often have severe, advanced diseases that have been refractory to conventional treatment. 

On the other hand, if we look at the patient guidance provided by the FDA in its Informed Consent for Clinical Trials, it clearly states:

“As new medical products are being developed, no one knows for sure how well they will work, or what risks they will find. Clinical trials are used to answer questions such as:

  • Are new medical products safe enough to outweigh the risks related to the underlying condition?
  • How should the product be used? (for example, the best dose, frequency, or any special precautions necessary to avoid problems),
  • How effective is the medical product at relieving symptoms, treating or curing a condition?

“The main purpose of clinical trials is to ‘study’ new medical products in people. It is important for people who are considering participation in a clinical trial to understand their role, as a ‘subject of research’ and not as a patient.

“While research subjects may get personal treatment benefit from participating in a clinical trial, they must understand that they:

  • may not benefit from the clinical trial,
  • may be exposed to unknown risks,
  • are entering into a study that may be very different from the standard medical practices that they currently know.”2

The Institutional Review Board (IRB) process, including the review of informed consent documents, can vary from institution to institution. Indeed, both the FDA and Office for Human Research Protections (OHRP) encourage the use of a single, central IRB for multi-center trials. Nonetheless, the guidance the agency provides to investigators, IRBs, and sponsors is also unequivocal.  It states, “A clear statement that the clinical investigation involves research is important so prospective subjects are aware that, although preliminary data (bench, animal, pilot studies, literature) may exist, the purpose of their participation is primarily to contribute to research (for example, to evaluate the safety and effectiveness of the test article, to evaluate a different dose or route of administration of an approved drug, etc.) rather than to their own medical treatment” (italics added).3

As many investigators recognize, this comes back in a roundabout way to the concept of “materiality” that I discussed in my previous article. Exactly how the information above should be communicated varies in different circumstances.

CRS’ action emphasizes the increasing absolute number of subjects who have died while participating in clinical trials in recent years. As clinical scientists, we should ask, “Where are the denominator and the demographics for these data?”

We know there are 10,000 to 12,000 efficacy trials per year for serious and life-threatening conditions registered on The majority of trials (59 percent) test drugs. Fifty-two percent of all subjects are enrolled in Phase 3 trials, and 10 percent of all patients in clinical trials are involved in cardiovascular disease trials. 

I’ve been a sponsor’s study-responsible physician for Phase 1 studies, a site investigator for Phase 2, 3, and 4 studies, and deeply involved in cardiovascular drug safety for a large pharmaceutical company. The decision as to whether a serious adverse event, including mortality, should be classified as “treatment-related” is often complex, even after review of the source documents and discussions with the investigators.

In summary, no one can predict the outcome of the CRS lawsuit. However, given the clarity of the FDA’s guidances for patients and investigators and the large number of patients involved in clinical trials, I don’t think CRS can present a convincing argument that revision of the informed consent guidance is required or that such revision would somehow impact the small percentage of patients who, sadly, experience treatment-related mortality in clinical trials.



About The Author:

Roger Mills, M.D., is an academic cardiologist who recently retired from Janssen Research & Development, LLC. He has worked as a site investigator or study-responsible physician in all phases of clinical research from first-in-human trials to post-approval registries. He is now formally retired but remains active as a peer reviewer, consultant, and writer. His book Nesiritide: The Rise and Fall of Scios was recently named the Foreword INDIES 2016 Bronze Winner for science.