FDA Warning Letter on Informed Consent

A new FDA Warning Letter shows the concern regarding the informed consent process that FDA has, along with most of us involved with clinical trials. This is a top FDA enforcement issue. However, are standard operating procedures (SOPs) the way to ensure GCP regulatory compliance at clinical trial sites?

informed consent

Informed Consent of Research

In a letter dated 28 January 2010 to a clinical investigator at the Women’s Hospital, affiliated with the University of Michigan Health System, FDA’s Division of Scientific Investigations (DSI) at the Center for Drug Evaluation & Research raise some serious concerns regarding the informed consent process in several clinical trials for Cystic Fibrosis (CF).

CF is a devastating inherited disease with a juvenile onset that attacks the lungs and digestive systems of about 30,000 juveniles and adults in the United States. The impact on families who have a child with CF is dramatic with the lives of the entire family changed forever as they take steps to care for their children. CF patients and their families meet my personal definition of a “vulnerable population.”

I believe that clinical trials studying CF need special protections for the young participants and their families.

That is why this FDA Warning Letter is so disturbing. These are not studies for male pattern baldness or another minor indication. They are for very sick children and young adults. Although the FDA citations seem a bit “technical” at first, it is very important that full disclosure of research is included in the informed consent process.

The Belmont Report

It is of particular concern that these studies took place at a very prominent health system; the Women’s Hospital is affiliated with the University of Michigan, Ann Arbor. The informed consent forms were IRB approved (the Warning Letter does not state which IRB). However, the informed consent of research study participants is a cornerstone of ethical research in the United States and much of the world. In 1979 the

Informed consent FDA

Informed consent is a process

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued the Belmont Report, the key document published by the United States Government on research ethics. The report states:

“Respect for persons incorporates at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.”

The violations documented by FDA include the failure to use language the sponsor requested to indicate a clear statement of research, a required element of informed consent (the sponsor requested changing the wording from “new drug” to “investigational or experimental drug”). In addition, the original approved informed consent form did not correctly state the purpose of the study originally stating the purpose was to see if the drug could “stop PA” (Pseudomonas aeruginosa). The wording should have been to “assess the safety and efficacy of a 28-day treatment… (to treat CF)” This is not a minor difference and there are more violations.

Standard Operating Procedures (SOPs)?

FDA warning letter informed consent

Shoud we require SOPs?

First, we need to clear: There are no regulatory requirements for SOPs at clinical sites. None. The clinical investigator offered some corrective actions that included writing SOPs about the informed consent process. FDA seemed to believe that SOP changes could be a satisfactory corrective action. They say:

“Your corrective actions to this finding included the development of new standard operating procedures (SOPs) including: ‘Completing the eResearch Application’ to ensure that a member of the study team reviewed the consistency of the information in the protocol, investigator’s brochure, consent document and the eResearch submission; ‘Responding to Monitoring Reports’ which required prompt response to any observations and a formal report to the IRB for further consideration; and ‘Obtaining Informed Consent’ which will prohibit handwritten statements on the informed consent form.”

FDA stated that the response was inadequate but later in the Warning Letter they say that another SOP would, “serve as corrective actions to prevent the recurrence of this finding” (to ensure that the investigations were conducted according to the investigational plans).

A Question of Training.

I have a different perspective. I think that the informed consent violations raise a genuine concern on how well the informed consent process and the principles of the Belmont Report are being taught to clinical investigators and IRB members involved in biomedical research at UM and the Women’s Hospital. To me, this

informed consent

GCP Training

is a question of being “qualified by training and experience,” and can’t be fixed with an SOP. For example, the primary method of training researchers at the University of Michigan, and a lot of other institutions, is through web-based training initiated by NIH. Web-based training is OK as a supplement to other training but ultimately a researcher needs to interact with others and have the opportunity to ask questions and be involved in problem solving discussions. Any reasonably bright individual is going to be able to breeze through a web-based training module and will retain very little.

We are placing a lot of administrative burdens and demands on both IRBs and clinical investigators. These demands take time and resources away from Good Clinical Practice. Investigators are being asked to sign and date reams of paper that could be delegated to the appropriate staff member. IRBs are asking for more and more documentation in an effort to comply with the requirements of FDA’s Bioresearch Monitoring program and other federal requirements. In fact, the University of Michigan had a simple checklist study halted because of bureaucratic interference. See this op/ed piece authored by the American Enterprise Institute, which accurately highlights some of the problems. I don’t agree very often with AEI but in this case they make a good point:


I would suggest that it is far more important to get “Back to Basics.” This includes research protocols that make sense and are practical in a clinical setting. It means emphasizing what is significant in protecting the rights, safety, and welfare of clinical trial participants (not the trivial). Finally it means ensuring that the data generated by a clinical trial can “stand alone” and be verified by regulatory authorities. Good, solid recordkeeping. I am not convinced that instituting SOPs at clinical research sites is the way to do this.

Here is a link to the Warning Letter:



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One Response to FDA Warning Letter on Informed Consent

  1. Shad Tod says:

    To-do lists are great for getting stuff complete and averting the coding slumps, imo. The great thing about them is you can change stuff round as required. If I am whirling my wheels on one task, I shift something easier to fulfill up to the top.

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