Thank you for the opportunity to speak today. My name is Dr. Megan Polanin, and I am a Senior Fellow at the National Center for Health Research. Our research center analyzes scientific and medical data and provides objective health information to patients, providers, and policymakers. We do not accept funding from the drug or medical device industry, so I have no conflicts of interest.
Patients with type 2 diabetes need safe and effective treatments to help them better manage the disease and reduce the risk of diabetes complications. We agree with the FDA’s assessment regarding semaglutide’s efficacy and safety data, but have several concerns that were not adequately addressed:
#1: While semaglutide met non-inferiority and superiority efficacy endpoints, there are clear differences between certain demographic subgroups. In placebo-controlled study 3623, the drug was less efficacious for participants of Hispanic ethnicity for both the .5mg and 1mg dose. In contrast, the drug was less efficacious for participants of non-White race for the 1 mg dose, but it is not clear which race, nationality, or ethnicity was driving this observed difference and whether any differences were observed specifically among patients within the U.S. In active-controlled trial 3625, which compared semaglutide to basal insulin, the .5 mg dose was less efficacious for men, and the 1 mg dose was less efficacious for patients over 65 years old. The predominance of younger patients across studies is concerning as complications of diabetes increase with age.
While these demographic comparisons are interesting, they do not provide the information that patients and physicians really need – or that the FDA really needs. Patients need to know if the benefits of this drug outweigh the risks for people like them. This would require separate analyses of these major subgroups to find out which types of patients are most likely to benefit. Because the sponsor has not provided these analyses, we have concerns about the generalizability of this drug’s efficacy and safety across subgroups.
American Indian/Alaska Native, Black, and Hispanic individuals have the highest prevalence of diabetes in the U.S.1 However, these groups are disproportionately underrepresented in these studies, and there are too few participants from these subgroups to draw conclusions about safety or efficacy.
#2: Outcomes in these studies are based on a biomarker, not a clinically meaningful endpoint important to patients such as living longer or quality of life. We know that glycemic control is controversial, especially for older patients. Low glucose levels can also put patients at serious risk. Let’s keep that in mind as we consider safety data.
#3: We agree with the FDA that diabetic retinopathy is a safety concern. Studies were not long enough to investigate whether these effects will decrease over time, and as noted in the FDA Ophthalmology Consult, the assessment of diabetic retinopathy was not properly standardized and was not based on meaningful clinical endpoints. A longer follow-up should be considered before the FDA makes a decision about this serious adverse event.
#4: Regarding cardiovascular safety, the sponsor has concluded that semaglutide risks are below the threshold of 1.8 and therefore non-inferior. One of the major goals of diabetes treatment is to protect against cardiovascular disease, and there is doubt about whether semaglutide does so for all patients. Although not statistically significant, the rates of cardiovascular death, hospitalization for unstable angina, and hospitalization for heart failure are worse for patients taking the drug. Moreover, major cardiovascular events are higher for women in these studies, and the sponsor has not studied the specific risks for women of color or women over 65 – groups at higher risk for diabetes. Currently it is unclear whether semaglutide should be considered safe for all women, and additional analyses should therefore be conducted before a decision is made about approval.
#5: Most adverse events were gastrointestinal, which is a risk with many diabetes drugs. GI events harm quality of life and can result in dehydration and acute kidney injury. One major question is whether patients who are not being monitored in clinical trials will be able to discontinue the drug before GI adverse events cause any serious damage.
In summary, we urge this Committee to recommend that the sponsor re-analyze the existing data to determine whether the benefits outweigh the risks for women of color, white women, men and women over 65, and other major demographic groups. We also recommend a longer follow-up of patients in the studies to determine safety, including appropriate evaluation of diabetic retinopathy. If there are too few patients in major subgroups to meaningfully evaluate risks and benefits, the sponsor should be required to add patients prior to FDA making a decision about approval. We urge this Committee to consider the safety and efficacy of semaglutide within demographic subgroups and not subject patients to uncertain risk.
Thank you for the opportunity to share our perspective.
References
- Centers for Disease Control and Prevention (CDC). National Diabetes Statistics Report, 2017: Estimates of Diabetes and Its Burden in the United States. Retrieved from https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf.
The Endocrinologic and and Metabolic Drugs Advisory Committee voted 16-0, with 1 abstention, in favor of approval of semaglutide. Read more about the meeting here.