FDA Issues Comments Concerning Midodrine HCl Exclusivity Issues; Threatens to Withdraw First Subpart H Approval

August 18, 2008

As we previously reported, in August 2007, FDA issued a letter and started a docket requesting public comment on a variety of 3-year exclusivity issues concerning generic versions of Shire U.S. Inc.’s PROAMATINE (midodrine hydrochloride) Tablets.  FDA approved PROAMATINE in September 1996 under the Agency’s “accelerated approval” Subpart H (surrogate endpoint) regulations for the treatment of symptomatic orthostatic hypotension.  FDA also subsequently approved several Abbreviated New Drug Applications (“ANDAs”) for generic versions of the drug.  Approval under FDA’s accelerated approval regulations is conditioned on a sponsor’s commitment to timely complete the required postmarketing studies to demonstrate the product’s clinical benefits.  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.”  To date, Shire has not conducted the requisite studies to verify PROAMATINE’s clinical benefit.   

In March 2007, several ANDA holders met with FDA to discuss the studies needed to determine the clinical effectiveness of midodrine HCl. At that meeting, FDA reportedly raised the possibility of 3-year exclusivity for ANDA holders who complete the required postapproval studies, but noted that the issue had not yet been fully discussed among Agency officials.  FDA established a docket in August 2007 requesting public comment to assist the Agency in resolving those exclusivity issues.  Specifically, FDA requested comment on six questions:

1.         If the post-marketing studies have been previously required as a condition of continued approval of midodrine hydrochloride under subpart H and one or more ANDA applicants complete those studies, are those studies eligible for 3-year exclusivity?  Under what theory?

2.         Does the answer to #1 depend on whether the studies merely validate the use of the surrogate endpoint or change the indication or other condition of use for the approved drug product?

3.         Does the same result apply if the sponsor of the NDA, itself, completes phase 4 studies that were required as a condition of approval under subpart H?  Why or why not?

4.         If 3-year exclusivity is available for the required phase 4 studies and holders of approved ANDAs collaborate to conduct those studies, is there legal authority to permit them to share 3-year exclusivity?  If not, can the first applicant to obtain approval of its supplement selectively waive its 3-year exclusivity in favor of the other collaborators on the studies?

5.         Under the statute and applicable regulations, could a study be “conducted or sponsored by the applicant” as required for 3-year exclusivity if that applicant paid less than 50 percent of the costs of the study?  Why or why not?

6.         If studies are completed and certain holders of approved ANDAs or the NDA holder does not collaborate, does FDA have authority under section 505(e) of the FDC Act to withdraw approval of those applications?  Does FDA have such authority under any other statutory or regulatory provision?  Would notice and opportunity for hearing be required before withdrawal?

On August 18, 2008, FDA issued an uncharacteristically short letter commenting on the availability of 3-year exclusivity for a company that submits a supplement to its approved midodrine HCl application containing the results of postapproval studies verifying the clinical benefit of the drug.  According to the letter, companies will be eligible for 3-year exclusivity provided the statutory criteria are met.  Whether several companies may jointly sponsor the required clinical studies to qualify a single applicant for 3-year exclusivity (who may then waive that exclusivity in favor of other applicants) is an issue that FDA will not address until after approval of an application. 

As to FDA’s plans to seek expedited withdrawal of approved midodrine HCl applications, the Agency notes in the letter that “[i]f an application or supplement containing studies that verify clinical benefit for midodrine hydrochloride is not approved soon, we will issue a Notice of Opportunity for a Hearing on the Center’s proposal to withdraw the approval of the midodrine hydrochloride new drug application (NDA) (and all ANDAs referencing that NDA) pursuant to 21 CFR 314.530.”  Since the accelerated approval regulations were promulgated in 1992, FDA has approved scores of applications under those regulations based on 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. 

By Kurt R. Karst