Noncardiovascular Clinical Trials CRF

CSRC Cardiovascular Case Report Forms:

The CSRC has developed a set of targeted follow-up questions intended for use in clinical trials for noncardiovascular (non-CV) medical products. The purpose of these questions is to collect information on cardiovascular (CV) events that occur during non-CV outcome trials. Various stakeholders (members of industry, academia, and regulatory authorities) developed these forms to be streamlined and used by non-cardiologists. These forms are not intended for use in CV outcomes trials since there are other sources of targeted follow-up questions that are more detailed and designed for those particular studies.

Using Cardiovascular Case Report Forms (CV CRF) is optional; however, they should assist sponsors in optimizing the collection of serious and non-serious CV adverse events. In addition, there is no regulatory requirement for using these forms; rather the CSRC provides them to individuals and institutions involved with running clinical trials to encourage a consistent approach to information collection.

Imbalances in the frequency of CV events often occur in non-CV outcome trials. Although these trials may not be statistically powered to detect clinically meaningful differences in CV events, these imbalances, or potential "signals," can still lead to safety and/or regulatory concerns. These imbalances may be infrequent and not detected until late in a development program when sufficient patient exposures have occurred or when data are integrated across studies as part of a regulatory submission. At that time, it is often temporally too far removed from the event to go back to study sites and try to gather further information.

Additionally, in non-CV studies, investigators and medical monitors (who may not be cardiovascular experts) may not be as focused on these infrequent events or ask the necessary follow-up questions. Thus, lacking adequate information, proper evaluation and definitive adjudication cannot occur.

In order to collect information as temporally close to the event as possible, CV CRF forms are to be used during a study. The intention is that if a cardiac safety signal is detected at a later point, the appropriate information to interpret the cases will be available. By no means is the CSRC suggesting that all CV events require adjudication, but rather, if adjudication is needed, the information needed for post-hoc evaluation should be available in these forms.

Although collection of comprehensive information and source documentation regarding any adverse events should be sought, this is not necessarily possible or pragmatic in all settings. Instead, the goal for developing these forms was to balance the collection of the necessary elements needed for potential adjudication against the collection of overly detailed information which may not always be available in non-CV trials. Since the use of these forms is optional, sponsors can modify them in the manner that best suits their needs (adding or deleting items) for a particular study or patient population. These forms are intended to serve as a basis for a good targeted follow-up and are not proposed to be definitive, proscriptive, or comprehensive.

Mary Beth Sabol, MD (GSK)

John Finkle, MD (GSK)

Mitch Krucoff, MD (Duke University Medical Center)

Norman Stockbridge, MD, PhD (FDA)

Kaori Shinagawa, MD (PMDA)

Kenneth Mahaffey (Stanford University)

James Tcheng, MD (Duke University Medical Center)

Daniel Lenihan, MD (Vanderbilt)

Chiara Melloni, MD (Duke Clinical Research Institute

Thomas Todaro, MD, JD (Medpace)

Eric Michelson, MD (AstraZeneca)

Jiefen Munley, MD (AstraZeneca)

Judith Zander, MD (AstraZeneca)

Richard Oh, MD (Takeda)

Anupam Agarwal, MD, MPH (Gilead Sciences, Inc.)

 

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