Pill Pickle: Hypotension Drug Quandary Spotlights Tough FDA's Dilemma

Shelley Wood

August 26, 2010

August 26, 2010 (Philadelphia, Pennsylvania) — Last week's announcement from the FDA that it had requested drugmakers to withdraw midodrine hydrochloride is spotlighting a dilemma the regulatory agency must wrestle with as it faces calls to take a tougher stance on drug safety and efficacy while still meeting consumer demand--not just for new drugs, but old-timers too.

In the case of midodrine, that means a popular off-patent drug may disappear because the company in possession of the marketing paperwork no longer makes enough money from the product to justify further studies, while a handful of generics companies also making the drug are not inclined to fund the kind of research the FDA is asking for.

Midodrine was first approved in 1996 for the treatment of low blood pressure; nearly 15 years later, the FDA has said that the necessary postmarketing data needed to prove efficacy have not yet been supplied. Shire, which holds the new drug application (NDA) for the drug, branded as ProAmatine, says it completed the postmarketing studies the FDA asked for--but later deemed insufficient--and in a twist that may spell doom for the drug, now earns minimal revenues from its sales. Last year, Shire notified the FDA of its plans to withdraw the NDA September 30, 2010.

The Business Perspective

According to Shire spokesperson Matthew Cabrey, sales of ProAmatine represented just 1% of the total US midodrine sales last year, bringing in a meager $500 000 for the company. Five generics companies--Apotex, Impax, Mylan, Sandoz, and Upsher-Smith--are the ones presumably making money from midodrine sales, but if Shire withdraws the NDA, they will also be forced to yank their products.

According to Cabrey, Shire has worked for two years with the FDA and with the generics companies to find a way to jointly fund further studies and has explored selling or giving the NDA to another company. But any company taking over the NDA would then be saddled with meeting the FDA's request for further data. Impax, the only one of the five generics companies contacted by heartwire to respond, estimated that its drug's market share was recently reported to be in the high 30% range but that "sales of the product are very small in relation to share." An Impax spokesperson said he couldn't comment on any direction, if any, the company would take regarding this product.

"We [Shire] felt we had completed the postmarketing studies required, but the data that we submitted to FDA were deemed inconclusive, and [the agency] said we'd need additional data to show safety and efficacy," Cabrey said in an interview. "But we're not prepared to invest in more clinical trials at this time: from a business perspective, it doesn't make sense. From a consumer perspective, it would be better for the FDA to find a way to work this out."

A Rock and a Hard Place

Dr Robert Temple, deputy director for clinical science in the FDA's Center for Drug Evaluation and Research, told heartwire by email that the agency would like to see a future for the drug.

"For the same reasons we thought midodrine should be approved many years ago, we very much hope one of the sponsors--presumably a generics sponsor, as Shire has expressed a lack of interest in doing so--will conduct the studies needed to establish clinical benefit. We are prepared to advise on the conduct of these studies, as we have since approval, and we do not believe the studies will be difficult."

Existing studies of midodrine used surrogate end points, and the FDA is "legally and scientifically" required to show that the outcomes suggested by the surrogates actually translate into true clinical benefit, Temple said. But the fact remains that "very plausible surrogates have, in some very well-known cases, turned out not to provide the expected benefit."

Temple continued: "We obviously realize that people who feel they are benefiting from midodrine and their caregivers are concerned about the possibility that the drug would become unavailable or harder to get," Temple said. "We also know that people have been critical on occasion of the pace at which the required confirmatory studies following accelerated approval have been carried out. Both concerns are legitimate. But it should be possible at reasonable cost to gain the needed evidence, and we very much want that to occur."

Cabrey calls this "a tough situation for the FDA," a position echoed, less sympathetically, in theheart.org's forum, where readers are coming down hard on both Shire and the FDA for not finding a solution for their patients, with many asserting that midodrine is the only effective drug for orthostatic hypotension.

Temple himself acknowledges the dilemma. "There has always been a perceived tension between a tougher and more demanding FDA (fewer drugs and later approvals) and a more permissive FDA (more rapid and more approvals based on less secure evidence of benefit or greater risk)," he told heartwire . "We do not in fact have a 'toughness' policy. We try to be certain that drugs meet the legal standard for approval, recognizing that even 'science' has elements of judgment in it. We know perfectly well that when decisions are close, there can be dissatisfaction with any result."