FDA panel: Randomized controlled trials should not be required for polypill approval

The FDA’s Cardiovascular and Renal Drugs Advisory Committee told the agency today that a randomized controlled trial should not be required for approval of a fixed-dose combination pill consisting of aspirin, a statin and at least one antihypertensive drug for secondary prevention of CVD.

While an application has not yet been submitted for such a combination, known as the polypill, the agency expects to receive at least one in the future, and research on its effects is ongoing. Proponents of the polypill say it will improve medication adherence, especially for patients who do not have access to regular CV care.

The agency asked the committee for input on whether outcome studies are necessary, who represents the appropriate target population, what the consequences would be if used outside the target population and what the sponsor of any application for marketing approval of a polypill would need to show in the application.

Observational studies recommended

Most panel members said that outcome studies should not be necessary because the effects of any components that would be used in a polypill are already known, but that postapproval observational studies might be a good idea.

“I don’t think we need a randomized, placebo-controlled, blinded trial for this,” panel member Stuart Rich, MD, of the University of Chicago Pritzker School of Medicine, said during the meeting. “I want to see observational studies in real-world settings. The data are compelling on the potential. The bigger issue is: how will we realize the potential and achieve it as best we can?”

While the FDA, in its briefing document prepared for the meeting, identified the likely target population as those who “cannot get the follow-up necessary for titration, for reasons that include geography, finances and patient preference,” committee members said the target population should include anyone who requires secondary prevention of CVD, has hypertension, has hyperlipidemia, and is able to tolerate all components of the polypill. Doctors will not be interested in identifying who is and is not likely to get follow-up for titration, they said.

Overutilization not a concern

Panel member Philip Sager, MD, of Stanford University School of Medicine, said that the FDA’s concerns about consequences for patients who could receive follow-up titration but instead take the polypill are unfounded.

“I’m not concerned about off-target use,” Sager said. “The bigger problem is underutilization.”

There was no consensus from the committee as to whether an application for approval of a polypill needed to show anything beyond the components’ potential for pharmacokinetic and pharmacodynamics interaction. Several members said that they did not think the panel needed to reconvene to advise on specific applications.

However, there was consensus that all components of a polypill must be in accordance with guideline-recommended dosages. For example, the committee recommended that any statin component consist of at least atorvastatin 40 mg or equivalent.

During a presentation at the meeting, Salim Yusuf, MD, DPhil, MRCP, professor of medicine and executive director of the Population Health Research Institute at McMaster University, Hamilton, Ontario, Canada, told the committee that there are at least five polypills in development, some of which are approved in other countries. Some form of the polypill is currently available in 14 countries, he added.

The FDA is not required to follow the advice of its advisory panels, but it usually does.

For more information:

CRDAC Clinical Briefing Document.

Disclosure: The members of the FDA’s Cardiovascular and Renal Drugs Advisory Committee report no relevant financial disclosures related to aspirin, statins or antihypertensive drugs for secondary prevention. They were not vetted with regard to conflicts relating to those drugs for primary prevention.