How a little-known drug posed a big FDA dilemma

There are orphan drugs and then there is midodrine, which no one really wants - except the patients it helps.

The drug is a thorn to the U.S. Food and Drug Administration and unprofitable for Shire Pharmaceuticals Inc., which manufactured it for a decade, creating an odd predicament for both.

Orphan drugs are those that treat life-threatening diseases affecting fewer than 200,000 people. Patients with symptomatic orthostatic hypotension (SOH) have episodes of low blood pressure and use midodrine to avoid passing out, which can be bad. Falling can be worse.

Such drugs are often approved without the usual time-consuming clinical trials. But once the drug is on the market, companies are still required to conduct trials to gauge efficacy and safety. And that is where the dispute arose and has existed at least since 2005.

The FDA sort of threatened to pull the plug on midodrine unless Shire completed high-quality trials at a faster-than-normal pace.

Shire, which is based in Ireland and has U.S. headquarters in Wayne, was willing to conduct trials, but at its own pace, and was willing to let the FDA try to pull the drug off the market. But FDA rules say a public hearing is needed to do that and the FDA didn't want to do that.

The latest phase of the standoff went on for more than a year, but a tentative, interim solution was announced late last week. Shire and the FDA's Center for Drug Evaluation and Research agreed on a plan for a new set of clinical trials to be completed in 2014. FDA Commissioner Margaret Hamburg has to approve the plan.

"The time frame outlined in the proposal for additional clinical trials is consistent with Shire's original request and we are appreciative that we have come to agreement with CDER on this path forward," Jeffrey Jonas, senior vice president of research and development for Shire, said in a statement.

The FDA declined to comment, pending Hamburg's decision.

The FDA gave fast-track approval in 1996 to midodrine, which has the brand name ProAmatine. Shire acquired the drug in 2000 by purchasing the company that developed it, completed the follow-up trials, and submitted the results to the FDA in 2005. In the FDA's opinion, however, the trials did not show that the drug provided enough benefit to offset the side effects.

However, 15 years of patient experience told a sufficiently different story, with patients and doctors saying that it was a lifesaver and that there was no alternative. Doctors from the American College of Cardiology and the Mayo Clinic were among those who implored the FDA not to pull midodrine from the market.

The doctors recognized that the FDA was in a difficult spot.

If the FDA pulled midodrine, patients who found success with the drug would be without treatment. But if it left the drug on the market without its passing the standard tests, the FDA would be open to criticism from two angles.

Patients who did have problems with side effects could say the FDA was negligent. Drugmakers could also say they wanted similar treatment to Shire.

The quirky thing here is that Shire insists it no longer makes a dime in profit from midodrine. Five generic companies - Impax Laboratories Inc., Sandoz Inc., Mylan Pharmaceuticals, Upshur-Smith Laboratories Inc., and Apotex Corp. - entered the market in 2003 once Shire's patent exclusivity expired. By 2010, the profits had evaporated, so Shire stopped manufacturing, distributing and selling the drug.

But as the holder of the original new drug application, Shire is responsible for regulatory compliance and those follow-up trials, which will cost $15 million to $20 million, according to a spokesman.

Perhaps the final irony is that Shire will have to buy the pills for the trials from the generic companies.