Lessons From 2013 FDA Warning Letters to Investigators

The beginning of a new year is a great time to look back and reflect on possible improvements for the year to come. If you’re a clinical researcher looking for inspiration, then look no further than the Food and Drug Administration’s 2013 List of Warning Letters Issued to Clinical Investigators.  In this blog post, we’ll summarize the key themes contained in the warning letters and provide some suggestions to help you stay off the list in the coming year.

By far the most common issue found in FDA warning letters to clinical investigators was a “failure to ensure that the investigation was conducted according to the investigational plan.” While the details vary, we noted several recurring issues, including:

  • Inclusion of individuals that did not meet the inclusion criteria
  • Continuation of individuals that should have been removed from the study
  • Errors in performance of study procedures
  • Errors in dosing
  • Errors documenting the issues and subsequent corrective actions

FDA Warning Letter Summary Graphic

It’s probably no surprise that many of these errors were likely rooted in communication problems between the investigator and protocol’s sponsor. Indeed, time and again we noted warning letters indicating the investigators thought they were properly following the protocol at the time the errors were made. For example, the FDA found that investigators misunderstood how to use scales required by the protocol, how to perform screening exams, how to collect data on protocol-required worksheets, and how to define therapeutic response. According to the FDA’s letters, these errors lead researchers to inappropriately include or continue participants in clinical studies.

Similarly, the FDA found that investigators misunderstood what information the protocol required to be recorded and how much discretion an investigator had in assigning individuals to a given study treatment.  This resulted, said the FDA, in investigators who made errors performing procedures and dosing participants.

On the whole, warning letters do not indicate that investigators lacked oversight. Rather, investigators had not clearly understood the protocols to begin with. This ultimately makes it impossible to comply with the protocol.

 How Can Sponsors and CROs Improve Communication with Investigators?

communication_headpuzzle-[Converted]Upon reflection, it is clear that better communication would have mitigated many of the issues that drew the FDA’s unwanted attention. First and foremost, making the protocol as clear as possible is essential. Investigator trainings should cover how the protocol defines terms, how to apply required scales, and how to use tools (such as worksheets) that are required by the protocol. Sponsors and CROs should develop resources to help investigators correctly follow the protocol. For example, providing investigators with a document that defines key terms and highlights key points about a particular scale or procedure will help reinforce the learning objectives taught in training.

Once a site has begun enrolling, close monitoring is critical. The FDA recommends a risk-based monitoring approach, as opposed to a one size fits all framework. The monitoring plan should be specific to the protocol and the sponsor and/or CRO need to work with monitors to ensure they understand areas of greater risk.

Checking to ensure that subjects have been appropriately enrolled is important throughout the research but it is especially important to ensure that there are no errors enrolling the first subjects. Errors made during initial enrollment may indicate the investigator does not understand the inclusion/exclusion criteria. Such misunderstanding of the criteria can put subjects’ safety in jeopardy and compromise the integrity of study data. To effectively minimize these risks, sponsors and CROs must identify enrollment errors early and, when found, retrain investigators quickly.

When enrollment errors are identified across several sites, a proactive approach to re-training on a wider scale is important. It is likely that similar issues will come up at other sites. It should be expected that issues with the protocol (such as ambiguity or inconsistencies) will not come to light until it is put into practice.

 Training Beyond the Protocol-Research Conduct

The FDA warning letters identify  a few issues not related to the protocol, but rather the investigators’ lack of understanding of critical requirements when conducting clinical investigations.

In some instances, investigators consented individuals after they had undergone study procedures. This is an often reported error to the IRB as well, and speaks to the need to address this issue as part of protocol training. During training, investigators should be reminded why it is important to obtain consent prior to initiating  research. Moreover, they should be given specific guidance as to when to obtain consent for the research at hand. Often, investigators conduct screening procedures prior to obtaining consent. However, investigators must clearly understand that conducting any study procedures, including screening procedures, prior to obtaining consent is not acceptable.

training-Keyboard-shutterstock_140098876In other instances, the FDA found that investigators misunderstood how much discretion they had in treating subjects. More often than not, this issue arises when investigators blur the lines between the function of research versus treatment.  To avoid this problem, sponsors and CROs must emphasize the importance of adhering to the protocol as a means of protecting subject safety and maintaining data integrity. This is a point worth reiterating in training and may need greater emphasis depending on the nature of the study and the patient population.

Finally, any discussion about expectations should address the fact that investigators are ultimately responsible for the conduct of the research at the site. Likewise, investigators should be advised to refer regularly to the protocol and other resources, particularly in the early implementation of the study. They should also be encouraged to contact the sponsor or CRO with questions or concerns about the protocol instead of moving forward when they are unclear about how to proceed.

In reviewing these letters it is encouraging to see that many of the issues noted by the FDA are preventable. With the goal of preventing these types of errors in 2014, now is the time to think through ways to improve communication with investigators in order to avoid misunderstandings. Moreover, consider ways to assist investigators and provide them with resources when protocol questions arise. This is a critical component of effectively executing any study. The monitoring plan should identify aspects of the protocol that present risk in terms of adherence. Plans for mitigation need to be in place for these. It is also important to quickly respond to issues identified after the study has begun.


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