Heart Failure Trial Endpoints: Public Feedback on the Recent FDA Draft Guidance

The FDA recently released a draft guidance titled, “Treatment for Heart Failure: Endpoints for Drug Development.” This is a very informative document, since a main reason why FDA drafted it is to clear up a common misconception about the appropriate endpoints for chronic heart failure trials. The FDA noticed that, based on the prior approval history of marketed cardiac drugs, some stakeholders seem to believe that demonstration of improvements in mortality and morbidity (e.g., hospitalizations for heart failure) are required to support approval of a drug that’s intended to treat heart failure. However, in this draft guidance, FDA clarifies that this is not the case, since the FDA believes that a drug that improves symptoms or function in heart failure patients would not be required to improve survival or hospitalization rate to get approved. FDA clarifies further that if a drug leads to “substantial and persistent improvement in symptoms or function,” particularly for patients with advanced heart failure, FDA would even consider a small decrease in survival to be acceptable.

I’d encourage everyone to read the entire draft guidance, which is quite succinct, but some of the important information is:

· FDA states that mortality can serve as a primary efficacy endpoint or a safety endpoint for heart failure trials

· FDA lists the following factors that it generally considers in deciding whether additional pre- or post-approval assessment of a heart failure drug’s effects on mortality will be needed when improvement of symptoms or function serves as the basis for the drug’s approval:

o Mortality and other safety findings of pharmacologically similar drugs

o Planned duration of exposure

o Mortality and other safety findings of the drug in a closely related population in which at least a subset of the patients had heart failure or were at risk of heart failure

· FDA states that “improvements in symptoms (e.g., dyspnea, fatigue, edema) and/or function (e.g., walking, exercising, performing other activities of daily living)” can provide acceptable evidence of effectiveness for heart failure trials and provides some examples of endpoints

· FDA will consider whether novel measures of functional capacity and daily activity, such as accelerometry data, can provide evidence of effectiveness for a heart failure drug

· Considerations for quantifying hospitalizations as an assessment of morbidity are discussed

· The FDA points out that none of the current biomarkers have been validated as surrogate endpoints for clinical benefit in heart failure trials, but biomarkers can serve an important role in heart failure drug development, such as by providing prognostic information and assisting in dose selection

FDA is now asking for public feedback on this document before the FDA issues its final guidance. If you have a strong opinion one way or another about the content of this document, but you’ve never played a part in the FDA guidance process, now’s a good chance for your voice to be heard. From having been the Chair of a draft guidance finalization working group while I was a Medical Officer in FDA/CBER/OTAT, I can assure you that FDA takes all comments from the public into consideration. Some examples of the types of comments that FDA receives are: “the draft guidance provides good advice to sponsors,” “the endpoints recommended by the draft guidance are not stringent enough and therefore might allow ineffective products to get onto the market,” or “the draft guidance does not address some important issues and should include the following additional discussion. . .”

Even if your particular comment doesn’t make it into the Final Guidance, don’t be discouraged -- you can be certain that you played a role in the guidance finalization process, since FDA considered your feedback when they were finalizing the guidance. Just remember, FDA strongly encourages the public to become engaged in the guidance process, since FDA’s ultimate goal is to bring safe and effective drugs to the market for everyone’s benefit. To be sure that your feedback gets to the FDA on time, make sure that your comments are submitted by 08/27/2019. To view the draft guidance and the Federal Register announcement for the draft guidance, click on the following links:

https://www.fda.gov/media/128372/download

https://www.govinfo.gov/content/pkg/FR-2019-06-28/pdf/2019-13800.pdf

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