US regulators have set in motion wheels to remove Shire’s veteran hypotension drug ProAmatine from the market, because the firm has failed to carry out additional post-marketing studies to verify the drug’s effect.

For the first time ever, the US Food and Drug Administration has kicked off the process to withdraw approval of a drug that was granted under its accelerated process because of a manufacturer’s failure to comply with the conditions.

Under the accelerated approval process, companies can obtain regulatory clearance to market a drug for serious or life-threatening conditions based upon a surrogate endpoint, i.e. a clinical marker that is believed to predict actual clinical benefits, but following approval they must conduct additional trials to confirm the drug’s benefit.

ProAmatime (midodrine hydrochloride) was granted an accelerated approval 14 years ago for the treatment of orthostatic hypotension, in which patients are unable to maintain blood pressure in the upright position and so become dizzy or faint when they stand up, and is now also sold in various generic forms.

But, to date, neither Shire nor any generic manufacturer has demonstrated the drug’s clinical benefit, for example, by showing that use of the drug improved a patient’s ability to perform life activities, and therefore the FDA is pursuing a withdrawal of the product, explained Norman Stockbridge, director of the Division of Cardiovascular and Renal Drugs in the FDA’s Center for Drug Evaluation and Research.

The agency has now issued a Proposal to Withdraw Marketing Approval and a Notice of Opportunity for a Hearing to the companies manufacturing midodrine and if, after considering any relevant submissions, the FDA believes withdrawal of approval is warranted, then all midodrine products, including the generics sold by Apotex, Impax Laboratories, Mylan, Sandoz and Upsher-Smith Laboratories, will be removed from the market.

The FDA has come under fire in the past for a relatively relaxed attitude towards policing post-marketing studies required under the accelerated approvals process, but its actions with ProAmatime may be a signal that the agency is taking a much harder-line on ensuring that its conditions are adhered to.

Shire now has 15 days to request a hearing to object to the FDA’s proposal, and one company watching developments very closely will be Chelsea Therapeutics, whose most advanced candidate is Droxidopa, an orally active synthetic precursor of norepinephrine being developed for neurogenic orthostatic hypotension.