A Polypill in the US? FDA Panel Debates Possibility

September 11, 2014

SILVER SPRING, MD – It has taken more than 11 years since Sir Nicholas Wald and Dr Malcolm Law (University of London, UK) first introduced the concept of a polypill, a fixed-dose combination tablet that would likely feature aspirin, a statin, and one or two antihypertensive agents, but the "paradigm-shifting" treatment strategy gained a small foothold on the climb toward approval when a Food and Drug Administration (FDA) advisory committee cautiously supported its availability and use among select patients.

Yesterday's meeting of the Cardiovascular and Renal Drugs Advisory Committee did not include a yes-or-no vote on approval, and no one multidrug combination was looked at; rather, the panel explored the potential usefulness of a polypill strategy to reduce the risk of cardiovascular death, nonfatal MI, and nonfatal stroke in patients with a history of cardiovascular disease.

The nature of the discussion suggested that most panel members felt the proposal to market a fixed-dose combination tablet for secondary prevention would be welcomed for at-risk patients who are unlikely to receive adequate follow-up needed for dose titration. As the FDA noted in its own briefing documents, there are secondary-prevention patients in the US who don't return to the physician's office because they live too far away, can't afford to make the trip, or simply don't wish come back.

For panel member Dr Philip Sager (Stanford University School of Medicine, CA), the polypill is a major advance with big implications for secondary prevention. "The way I see it is that this could have major public-health benefits," he said. "I think the lowest-hanging fruit are those individuals who don't have very good access to care or have only intermittent interaction with healthcare providers and aren't getting therapy now."

Dr Stuart Rich (University of Chicago, IL) also said there is a role for the polypill in secondary prevention, but the concept of approving a fixed-dose combination represents real change for the FDA. "We've been buying into appropriately personalized medicine, really focusing on the right dose and the right patient, and now we're going back to one size fits all and accepting good rather than perfect," said Rich. "The issue I see is not one of efficacy, nor is it one of safety, but rather one of adherence, which has not really been the charge of the agency in the past. So you're asking us to address the issue of adherence."

The challenge of simply getting patients to take their prescribed medications is compounded by fact that prevention is a tough field, he said. Patients don't see the reward of taking their tablets.

What About Patients With Hypertension?

One expert in hypertension, Dr John Flack (Wayne State University School of Medicine, Detroit, MI), likes the concept of the polypill, saying he thinks it might be used in noncompliant patients or even those who have already achieved adequate cholesterol and blood-pressure control with individual agents. In a subset of these patients, a polypill might be more convenient. While physicians won't need to titrate, he said a range of doses will be needed to ensure patients are receiving adequate treatment. "On the other hand, if you've got a polypill and you need another blood-pressure drug, you can add it," said Flack. "There's nothing to prevent you from doing that."

For Flack, the "tough animal" is still going to be blood pressure. Although one or two antihypertensive agents would be included in the polypill, hard-to-treat patients often require more drugs or higher doses. "You can throw a statin at somebody, get them on 10 mg of atorvastatin, and you have a pretty good chance of getting a good response. On the flip side, blood pressure is not that way. A three-drug polypill, with an evidence-based diuretic, like 15 mg of chlorthalidone, really minimizes the difficulty practitioners have in putting together effective combination antihypertensive therapy."

Sager had similar concerns about blood pressure. "I would encourage thinking about higher doses with more aggressive blood-pressure lowering," he said. "I wouldn't want people to be put on [the polypill] that are having frequent and very good interactions with healthcare providers and see them never get their blood pressure brought to goal."

Throughout the daylong meeting, some panel members did express concern about the polypill. One skeptic was Dr Julia Lewis (Vanderbilt University School of Medicine, Nashville, TN), who said she is not overwhelmed by the studies testing the polypill concept. Even the safety data, she said, are limited.

"I think we have to be careful," said Lewis. "This is a huge paradigm shift. I think the FDA's responsibility, in my opinion, extends beyond just saying these drugs don't react pharmacokinetically, because the reality is that [the polypill] is going to have an effect on our public's health. You can think of lots of unintended consequences within our healthcare system where if someone is told to stop their aspirin they stop their entire pill. All of a sudden their blood pressure is 210/120 mm Hg and they have a stroke."

AHA Not on Board Just Yet

Dr Niteesh Choudhry (Brigham and Women's Hospital, Boston, MA), who was not part of the advisory committee but who spoke on behalf of the American Heart Association (AHA), noted that just 30% to 50% of post-MI patients are taking their medications 12 to 15 months after hospital discharge. While he said the polypill holds promise, there are several remaining questions. It is not definitively known if the polypill is as effective as the individual agents, if it would be safe in clinical practice, and whether or not the inability to titrate would pose a problem, said Choudhry.

While the AHA would like to see a large-scale, randomized clinical trial testing of the polypill in the relevant population—one that was adequately powered, of sufficient duration, and with "clinically meaningful" end points—panel members, for the most part, did not think such a trial would be necessary. They felt the individual components of the polypill—aspirin, a statin, and at least one antihypertensive medication, or possibly two—have been sufficiently tested in other studies and are frequently used in combination. Many of the committee members were comfortable with the FDA requirement of pharmacokinetic and pharmacodynamic studies showing the polypill was equivalent to other available single-pill options and that the components of the polypill didn't interact with each other.

The FDA session focused exclusively on secondary-prevention patients but they did touch on the larger elephant in the room occasionally. Some proponents of the polypill have suggested the combination can also be used in primary prevention, such as in high-risk patients, while others have even pushed for its use in everybody older than 50 years old, regardless of their cardiovascular risk factors. Dr Salim Yusuf (McMaster University, Hamilton, ON), an advocate of the polypill for many years, doesn't think that every 50-year-old should receive the polypill just yet, although he does think that might be closer to the right approach.

The polypill, said Yusuf, can simplify the treatment process and reduces costs. "Remember, each step in titration is a visit to the doctor. It's a fee paid to the doctor. It's time off from work. It's parking fees and driving. All that adds to the cost. So titration now is a barrier. We need to think if we have simple, safe drugs, how can we get patients to a reasonably effective dose? We need a health approach that simplifies things. The polypill is part of the delivery strategy under these circumstances. It's not a new drug."

There are currently a number of clinical trials, including TIPS-3 , HOPE-3 , and Poly-Iran , assessing the viability of the polypill for the reduction of cardiovascular outcomes, while others are looking at the effect of the strategy on adherence and other surrogate end points.

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