Is FDA Poised to Withdraw the First Subpart H Approval?

August 9, 2007

In December 1992, FDA promulgated final regulations under which the Agency will accelerate the approval of certain new drugs and biologics for serious or life-threatening illnesses, and when such products provide a meaningful therapeutic benefit to patients over existing treatments. These regulations, which are commonly referred to as “accelerated approval,” are located in Subpart H (21 C.F.R. § 314.500) of FDA’s drug regulations, and in Subpart E (21 C.F.R. § 601.40) of the Agency’s biologics regulations.  If a product meets these criteria, then FDA may grant marketing approval based: (1) on a demonstrated effect on a “surrogate endpoint” and a sponsor’s commitment to complete with “due diligence” the required postmarketing studies to demonstrate the product’s clinical benefits; or (2) on restrictions to assure safe use (that is, when FDA determines that a drug can be used safely only if distribution or use is modified or restricted, e.g., THALOMID (thalidomide)).  (In clinical trials, a “surrogate endpoint” is an alternative measurement of the symptoms of a disease or condition that are substituted for measurements of observable clinical symptoms.)   Importantly, FDA may expedite the withdrawal of approval of an application approved under the accelerated approval regulations if a sponsor “fails to perform the required postmarketing study with due diligence,” or if “[a] postmarketing clinical study fails to verify clinical benefit.”   

Since 1992, FDA has approved scores of applications under the Agency’s accelerated approval regulations –primarily for products with a demonstrated effect on a surrogate endpoint.  FDA has never, however, withdrawn approval of an application for a sponsor’s failure to complete a required postmarketing study with due diligence or because a postmarketing study failed to verify clinical benefit (under either Subpart H or Subpart E).  That may be changing.  (FDA could have pursued withdrawing approval of IRESSA (gefitinib) when the sponsor’s postmarketing study failed to verify clinical benefit.  Instead, FDA approved new labeling that limits IRESSA use to patients with cancer who are currently benefiting, or have previously benefited, from IRESSA treatment.)   

FDA approved Shire’s PROAMATINE (midodrine hydrochloride) Tablets under the Agency’s Subpart H (surrogate endpoint) regulations in September 1996 for the treatment of symptomatic orthostatic hypotension.  FDA also subsequently approved several generic versions of the drug.  The labeling for PROAMATINE includes the following warning: 

The indication for use of ProAmatine® in the treatment of symptomatic orthostatic hypotension is based primarily on a change in a surrogate marker of effectiveness, an increase in systolic blood pressure measured one minute after standing, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of ProAmatine®, principally improved ability to carry out activities of daily living, have not been verified.

To verify the drug’s clinical benefit to conclude that the drug is safe and effective, FDA required the sponsor of PROAMATINE to conduct certain Phase 4 studies.  According to FDA’s Postmarketing Study Commitments Database, the official status of the required postmarketing studies is “delayed.”  This makes PROAMATINE the accelerated approval with the longest outstanding commitment. 

On August 7, 2007, FDA sent a letter to companies marketing approved versions of midodrine hydrochloride.  The letter states: “To date, the holder of the midodrine hydrochloride [NDA] has failed to obtain approval for the required phase 4 studies verifying clinical benefit.  If those studies are not approved in a timely manner, that NDA (and all ANDAs referencing that NDA) will be subject to withdrawal . . . .”  It is unclear whether Shire plans to complete and obtain FDA’s approval of those studies.  If not, then FDA’s letter raises the possibility that companies currently marketing generic versions of midodrine hydrochloride might conduct those studies.  FDA’s letter states that “several holders of approved [ANDAs] for midodrine hydrochloride have considered whether to conduct the requisite studies and have requested FDA advice regarding the availability and potential scope of 3-year new clinical studies exclusivity if holders of approved midodrine applications were to collaboratively or individually complete the required post-marketing studies to verify clinical benefit for midodrine hydrochloride.”  FDA requests comment on several questions related to 3-year exclusivity and withdrawal of approval of certain applications, because the proposals to conduct the required midodrine hydrochloride postmarketing studies “raise issues of first impression and will affect more than one midodrine application holder.”