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Polypill: a 505(b)(2) candidate

FDA approved Novartis’ Exforge HCT on April 30, 2009 for the second-line treatment of hypertension.  Exforge, approved in 2007, contains the calcium channel blocker amlodipine and the angiotensin receptor blocker valsartan.  The new product adds to Exforge the well known diuretic HCTZ – hydrochlorothiazide.  The product was approved based on a single “8-week, multi-center, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of the combination of valsartan/HCTZ/amlodipine compared to valsartan/HCTZ, valsartan/amlodipine, and HCTZ/amlodipine in patients with moderate to severe hypertension.”  According to Novartis, the study included over 2,000 patients.

The media have dubbed tablet products containing more than 2 actives polypills.  For example, Dr. Reddy is developing a product containing 3 antihypertensives, a statin and aspirin and has recently reported results of a 2,000 subject phase 2 study in The Lancet (abstract only, pay for article).

To obtain approval for a polypill requires a multi-arm study, 1 + number of actives and maybe a placebo arm.  The goal depends on whether it is a 505(b)(1) or 505(b)(2).  That is, is the combination an extension of already approved combinations or known actives with existing indications?  If so, then the pivotal phase 3 study could be a non-inferiority trial.  These trials are certainly less expensive and take less time than a traditional 505(b)(1) phase 2 or 3 trial.  Indeed, they are much less cheaper in foreign countries.  For example, in a discussion of the Dr. Reddy phase 2 trials, the study lead investigator, Salim Yusuf, D.Phil., F.R.C.P.C.,  “estimated that the phase II trial conducted in India cost about $1 million, a drop in the bucket, he said, for a clinical trial.”

Thus, investors should examine other possible combination products that can be approved via the 505(b)(2) pathway that can have the study done in a  foreign country.