May 12, 2022
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Nina Zeldes, a senior fellow at the center. We analyze scientific data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug or medical device companies, so I have no conflicts of interest.
Our statement today is based on our organization’s experience of working with thousands of patients and caregivers. We understand that patients and their parents urgently want new treatments for these terrible cancers and think they are willing to take almost any risks if a new treatment might possibly be effective, but they feel very differently when treatments do more harm than good. Of course, nothing is worse for a parent than making a medical decision that harms a child without providing meaningful benefits.
We agree with FDA’s statement in its memo that randomized trials “have a continued role in generating the evidence needed to improve treatment paradigms for patients with high-risk neuroblastoma, despite the challenges associated with enrolling sufficient numbers of patients in a timely fashion and the length of time needed to conduct the trials.” We note that the FDA points out that endpoints traditionally used to evaluate effectiveness of drugs for the first-line treatment of patients with high-risk neuroblastoma are event-free survival (typically defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy or death) and overall survival. These are the most appropriate endpoints for 2 reasons:
- Cancer treatments always have the potential of resulting in serious risks to quality of life. Parents of these children need as much information as possible when they decide what treatments to accept for their children. Any kind of surrogate endpoint that does not involve improved survival or improved quality of life has the potential to have risks that outweigh the benefits.
- Once a pediatric cancer treatment is approved, it can be very difficult if not impossible to conduct well controlled post-market studies to confirm whether the benefits outweigh the risks. Randomized trials with placebo are often impossible.
We acknowledge that researchers have emphasized the importance of identifying the most effective treatments to use during the induction phase of treatment in order to improve patient outcomes. It may be that end-of-induction response may predict event-free survival or overall survival, but that is not yet clear. In addition, the relationship between end-of-induction response and adverse events is also unknown. These are important to study, but meanwhile end-of-induction response is not an adequate endpoint for these very important treatments.
Clinical benefits should remain the key endpoints for approval decisions of these treatments. Surrogate endpoints that predict clinical benefits are not yet established and until they are, we are concerned about their use as secondary endpoints unless the primary endpoint is also met.