September 10th, 2014
FDA Advisory Panel Offers Cautious Support for Polypill
The controversial polypill took one step closer to reaching the U.S. market after receiving a mostly positive reception from the FDA’s Cardiovascular and Renal Drugs Advisory Committee on Wednesday. The idea for the polypill– which in this case would be composed of aspirin, a statin, and one or more blood pressure drugs– has been kicking around for more than a decade and has attracted considerable doses of support as well as skepticism.
An all-star group of cardiology leaders– including Sir Nicholas Wald, Salim Yusuf, Suzanne Oparil, Sidney Smith, and Clyde Yancy– helped provide the spoonful of sugar that helped the committee swallow the polypill. The FDA also eased the way by limiting the discussion to the use of the polypill for secondary prevention in people who have already had an MI or a stroke.
The more difficult discussion about the polypill for primary prevention use was put off for another day, though panel members and even FDA leaders couldn’t help occasionally commenting on the primary prevention question. Most panelists seemed to agree that the argument for secondary prevention was more straightforward than the argument for primary prevention. Panelist Philip Sager said that the main problem in secondary prevention is that the drugs that would be contained in a polypill are now being underutilized, not overutilized.
The committee generally agreed with the FDA’s proposed indication for use in patients who need the drugs to prevent recurrent events but are unlikely to be closely and carefully monitored by a physician. “We believe there are patients in the USA for whom cardiovascular prevention therapy is appropriate but who cannot get the follow-up necessary for titration, for reasons that include geography, finances, and patient preference,” the FDA wrote in its briefing documents for the committee. “We are asking then whether people who are not, for whatever reason, going to receive regular follow-up are better off on some reasonable doses of drugs for secondary prevention of cardiovascular disease, rather than none, even if they are not getting what is believed to be optimal care.”
The prevailing view was that the polypill was not better than standard care or was not intended to replace standard care but that it could be used where adherence is a problem and when physicians are able to treat a patient but are unable to monitor their care. The FDA’s Robert Temple said that the FDA hopes that fixed-dose combination drugs, including the polypill, can improve adherence, but that the FDA has previously not insisted that improved adherence be demonstrated.
In general the panel was not impressed by research specifically examining the polypill, but this was not a source of major concern since all the individual components of the polypill have been studied in considerable detail. The panelists did not see a strong need for phase 3 or outcome trials with the polypill, but they expressed lots of interest in trials that could look at the effect of the polypill on adherence or that would monitor or assess possible safety issues related to the polypill.
Panel member James De Lemos provided the following comment on the meeting:
The tenor of the discussion was generally quite positive with caveats that some members wanted to see more safety and real world effectiveness data. Others, including myself felt like the FDA’s stated path to approval limited to pharmacokinetic and dynamic studies would be sufficient for regulatory approval, given how much we already know about the individual components that are already used in combination routinely. There would remain lots to learn about in whom and how these fixed dose combinations should be used, but this may best be handled via health services research after market approval. We did not go into much detail about which drugs and doses would make up the ideal polypill.
Salim Yusuf viewed the panel as a positive development:
It is a positive move that the FDA has taken the initiative to discuss possible regulatory pathways for the availability and approval of polypills in the USA. Even in the USA, there are major gaps in treatments of proven, inexpensive and safe drugs in high risk individuals and the polypill can help bridge this gap.
And Sanjay Kaul offered his perspective:
While the current evidence is not strongly supportive of the polypill hypothesis in the setting of secondary prevention, it is sufficient enough to get a favorable consideration from the FDA. It will, however, have to fulfill the regulatory requirement of demonstrating bioequivalence and therapeutic equivalence to exclude the possibility of a pharmacokinetic or pharmacodynamic interaction. The safety issues can be addressed in a phase IV study post approval. In my opinion, the high expectations generated by rosy predictions derived from modeling exercises more than a decade ago will have to be recalibrated.