NCHR’s Testimony on Carbetocin Nasal Spray for Hyperphagia in Prader Willi Syndrome

November 4, 2021.

NCHR Testimony before the FDA Advisory Committee on carbetocin nasal spray

for hyperphagia in Prader Willi Syndrome


I’m Dr. Diana Zuckerman, president of the National Center for Health Research.  Our nonprofit think tank scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products.

My perspective today is based on my training in clinical psychology, epidemiology and public health, and as a former faculty member and researcher at Yale and Harvard.  I also have a brother who was born with a serious disability, so that also affects my perspective. In my current position, I frequently testify about the safety and effectiveness of medical products, and have participated in more than 100 FDA Advisory Committee meetings over the years.

The testimony from family members in the Open Public Hearing was very compelling, and those experiences do not consistently support approval.  Unfortunately, the evidence provided by the sponsor today is among the worst I’ve ever seen, and would set a terrible precedent that would compromise the reputation of the FDA and the public’s confidence in FDA approval.

The sponsor and mothers have done an excellent job of explaining why hyperphagia is a terrible condition and families urgently need help to treat or manage it.  But that’s the point:  the treatment needs to work, and not make matters worse.  It is not appropriate for the sponsor to try to make this panel or the FDA feel guilty for expecting an appropriate level of scientific evidence.

We can see in the FDA Briefing Document the many ways that the FDA clearly told the sponsor what type of data they needed to provide to merit approval and that the sponsor repeatedly ignored that advice. The pandemic interfered with the study, but that is not the main problem – the studies had other serious inadequacies and that’s why they do NOT prove efficacy for this serious chronic condition.

None of us are asking for a perfect study.  We’re asking for a good study of an adequate number of patients studied for a reasonable amount of time, with clinically meaningful and statistically significant results – not one-sided at the .10 level.  And not a study that doesn’t control for Type 1 error.

The phase 2 study was only 2 weeks and only administered the higher dose. Of the only 38 patients randomized, 6 had major protocol violations, including being given the wrong drug.  All the patients were White, except 1, and only 14 were boys (that includes placebo patients)

The Phase 3 study was only 8 weeks long for the placebo controlled portion.

Neither of the two primary endpoints showed a statistically significant improvement, for the higher dose and the open label part of the study is not good science – for example, only 1 patient receiving the lower dose stayed in the study for a year.  If the drug worked, wouldn’t more patients stay in the study?

AEs leading to discontinuation were primarily psychiatric.  For the phase 2 trial, one child discontinued due to agitation, increased aggression, increased hyperphagia, and a broken bone.  Given that only 20 patients got the drug, that’s a 5% serious adverse event rate.

In the Phase 3 trial, once again 5% of patients taking the higher dose discontinued during the placebo-controlled period (in that case, due to impulsive behavior and tachycardia).

In the real world, will these psychiatric adverse events be dealt with adequately?  This morning, the sponsor also mentioned one child who started acting out sexually. That can be very serious.  Psychiatric adverse events are a real concern, given how desperate parents are to give the drug a chance to work.

If there is no proven benefit, these adverse events matter.

In conclusion, we agree with FDA criticisms of the evidence.  Families urgently need help, but the company should spend a few more months to establish whether this drug is effective and safe for more than 8 weeks – BEFORE FDA considers approving it. Meanwhile, we encourage the sponsor to facilitate free access to this experimental treatment through FDA’s expanded access program, which is a more appropriate than approval at this time.

Thank you for the opportunity to share my views today.



There is only one voting question:

Has the Applicant provided substantial evidence of effectiveness for carbetocin nasal spray (LV-101) in the treatment of hyperphagia associated with Prader Willi syndrome?


The vote was 1 Yes and 12 No.