HRS, FDA express views over proposed midodrine withdrawal

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In response to a letter from the Heart Rhythm Society (HRS) regarding the FDA's proposal to withdraw approval of the hypotension drug midodrine hydrochloride, the agency said there will be a public hearing for the drug manufacturer to present evidence of the medication's clinical benefit. The date has not been announced.

In addition, the letter, dated Oct. 4, said, "The FDA would soon announce in the Federal Register the opening of a public docket that will serve as a forum to facilitate communication regarding the conduct of clinical trials needed to verify and describe the clinical benefit of midodrine when used to treat symptomatic orthostatic hypotension."

The FDA on Aug. 16 proposed withdrawing approval of midodrine because neither the original manufacturer nor any generic manufacturer had provided data on the drug's clinical benefit.

The drug, marketed as ProAmatine by Shire Development and as a generic by others, was approved in 1996 under the FDA's accelerated approval regulations for drugs that treat serious or life-threatening diseases.

Under this process, a drug company may obtain approval based upon a surrogate endpoint. A surrogate endpoint is a clinical marker, such as a positive effect on blood pressure, believed to predict actual clinical benefits such as improved survival or decreased severity of the disease.

That approval required the manufacturer to verify clinical benefit to patients through post-approval studies.

Recognizing the need to ensure drug safety and for companies to comply with post-market drug approval requirements, the HRS stated in its Aug. 24 letter that the FDA has not identified any safety or effectiveness problems with midodrine. Taking the drug off the market would "negatively affect the care of approximately 100,000 patients who are currently receiving this drug," the HRS said.

In its response, the FDA clarified that its announcement "does not represent actual withdrawal of the medication from the market," but is a necessary regulatory step that "reflects both the requirement that manufacturers of midodrine verify the clinical benefit of accelerated approval products and the agency's position that more data are needed about the actual benefits of midodrine."

The FDA said the drug will remain available to patients as it works to obtain the data.

HRS informed the FDA that electrophysiologists prescribe midodrine because it has "substantial effectiveness in the treatment of some patients who are seriously disabled by autonomic dysfunction and hypotension," as well as for patients with other clinical conditions.

There are few alternative therapies "except those with higher side effect profiles," according to the HRS letter.

The FDA said that the drug's manufacturer had conducted clinical studies, and other studies have been published in the medical literature. "The data submitted to the agency, however, have not verified the clinical benefit that the drug was expected to have."

Continuing, the letter said, "Because of the absence, after a very long time, of the required data confirming clinical benefit, the FDA recently notified the current manufacturers [of the proposal] to withdraw approval of the drug."