December 14, 2022
I am Dr. Ealena Callender, Senior Fellow at The National Center for Health Research (NCHR). Our think tank conducts, analyzes, and scrutinizes research on a range of health issues with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.
Thank you for the opportunity to express our views today on the new drug application for omecamtiv mecarbil (OM) – which is indicated for the indication of reducing the risk of cardiovascular death and heart failure (HF) events in adults with symptomatic chronic heart failure with reduced ejection fraction (HFrEF).
As you consider whether the data indicate substantial evidence of efficacy, let’s think about the size of the study as well as the statistical significance. The phase 3 trial enrolled more than 8,000 patients. Since statistical significance is related to the number of patients studied, such a large trial would be expected to achieve a highly statistically significant treatment effect if the drug has a meaningful benefit. Although the trial did meet its prespecified primary endpoint – a composite of time to cardiovascular death or first heart failure event – the treatment effect was very small and only present in patients with severe heart failure. Given the small benefit for a limited group of patients, a second confirmatory study is needed to determine if the drug has meaningful benefits and, if so, for whom. It is also important to emphasize that the drug had no impact on any secondary outcomes, such as cardiovascular death or the Kansas City Cardiomopathy Questionnaire (KCCQ) score – which is a measure of heart failure symptoms, physical and social limitations and quality of life.
As you consider whether the benefits are likely to outweigh the risks, the main safety issue is cardiotoxicity, especially in patients with atrial fibrillation or atrial flutter. With such a small treatment effect, is any increased risk in cardiotoxicity acceptable? Also, the fact that the OM assay that the company would used is not FDA approved or cleared means that it was not evaluated by an objective third party. The CLIA program regulates labs that make these tests but not the tests themselves. Although the CLIA program regulates labs that make these lab-developed tests, CLIA does NOT evaluate or regulate the tests themselves. As a result, we agree with the FDA that we can’t be confident about the accuracy of the assay, therefore raising additional concerns about safety.
We respectfully encourage the advisory committee to require a confirmatory study before recommending approval of this new drug with significant risks and such a limited benefit.
The advisory committee voted 8 to 3 against approval.