CV Risk Assessment For All Obesity Drugs Seems Inevitable Pre-Approval Requirement
This article was originally published in The Pink Sheet Daily
Executive Summary
FDA’s Endocrinologic and Metabolic Drugs Advisory Committee March 29 voted 17-6 that all obesity drugs should be vetted for cardiovascular risk, but some could rely on a meta-analysis rather than an outcomes trial.
Sponsors would have to rule out a certain level of cardiovascular risk for all obesity drugs through a CV outcomes trial, or a meta-analysis of Phase II and III major adverse cardiovascular events data, if FDA follows the March 29 recommendation of its Endocrinologic and Metabolic Drugs Advisory Committee.
The panel voted 17 to 6 in favor of such studies for drugs without a theoretic risk or signal for CV harm. FDA told the committee that for drugs with a signal, a CV outcomes trial (CVOT) will be necessary prior to approval.
During an explanation of their yes votes, 13 committee members said the assessment for drugs without a signal could occur in a two-stage process, with one assessment pre-approval and the second post-approval. In asking for input on the question, FDA said a two-step process would involve two different non-inferiority margins.
That is the approach FDA takes in diabetes drug guidance, which several panel members suggested as a model for obesity CV evaluation.
The agency recommends a meta-analysis of MACE results from Phase II and III trials for all diabetes therapies, and a full CVOT pre-approval if the meta-analysis does not rule out an 80% or higher increased risk of MACE, meaning that the upper bound of the 95% confidence interval for the estimated risk ratio must be below 1.8. If the upper bound of the two-sided 95% CI for the risk ratio is between 1.3 and 1.8, a CVOT must be conducted post-approval and demonstrate an upper bound of less than 1.3 (Also see "FDA Diabetes Guidance Encourages Enrollment Of Sicker Patients" - Pink Sheet, 17 Dec, 2008.).
Conducting a meta-analysis would be less onerous than a CVOT, but as outlined in the diabetes guidance, entails prospective design of the Phase II and III trials to facilitate collective assessment of the data and requires prospective adjudication of cardiovascular events.
The size of the potentially affected population and the poor track record of weight-loss drugs with regard to cardiovascular safety influenced the vote in favor of assessing even therapies that don’t have a signal.
Safety trials usually are not required when there is no signal, Erica Brittain, National Institute of Allergy and Infectious Diseases conceded, “but obesity drugs are going to be used by very large populations.”
Patients will number “tens of millions of people … and we can’t guarantee the drugs will be used exactly the way that the label authorizes their use,” Peter Savage, National Institute of Diabetes and Digestive and Kidney Diseases, explained.
As to studying drugs without a safety signal, Sanjay Kaul, Cedar Sinai Medical Center, Los Angeles, suggested that “given the checkered history of weight-loss drugs, I think it’s better to be prudent and err on the side of caution”
The most recent obesity drug to fall to safety issues is Meridia (sibutramine), which Abbott Laboratories Inc. withdrew from the U.S. market in 2010 at FDA’s request because the SCOUT post-market study found a 16% higher relative risk for major adverse cardiac events in older overweight and obese individuals taking the drug compared to those receiving placebo (Also see "REMS Cannot Save Abbott's Obesity Drug Meridia In Face Of Cardiovascular Issues" - Pink Sheet, 8 Oct, 2010.).
Several panel members objected to the studies because of the possible chilling effect on obesity drug development. If sponsors must spend money on a CV outcomes trials, it could take funds away from early stage development projects that could produce better therapies, Ellen Seely, Harvard, noted.
CV trials also could be looking at the wrong adverse events, she said. They “may give a false assurance of safety because we don’t know that the side effects of these drugs are going to be cardiovascular.” The safety issue may be “related to mood, suicidal ideation. It may be cancer risk, and we’re dedicating the company’s funds now to looking at the cardiovasculoar risk which may not be the primary one.”
In an earlier discussion of the two-stage approach to CV evaluation for drugs with a signal, panel members indicated it is a reasonable option because it would provide an early risk assessment with a minimum delay to market for drugs that meet the initial safety criteria.
The panel also provided FDA with input on the pros and cons of enriching clinical trials with patients at higher risk for CV events and a variety of trial design parameters, including the primary endpoint and primary analysis population.