FDA Issues NOOH Proposing to Withdraw All Midodrine HCl Approvals

By Kurt R. Karst –   

On August 16, 2010, FDA announced that the Agency plans to follow through on previous correspondence threatening to withdraw approval of all marketing applications for the Subpart H (accelerated approval) drug Midodrine HCl.  FDA also issued a Notice of Opportunity for a Hearing (“NOOH”) to application sponsors proposing withdrawal because of the failure to complete required postmarketing studies with due diligence (Docket No. FDA-2007-N-0475).

As we previously reported (here, here, and here), FDA approved PROAMATINE (midodrine hydrochloride) Tablets in September 1996 under the Agency’s Subpart H (accelerated approval; surrogate endpoint) regulations for the treatment of symptomatic orthostatic hypotension.  FDA also subsequently approved several 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.”  In September 2009, the Government Accountability Office (“GAO”) issued a report, titled “FDA Needs to Enhance Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints,” which found that  weaknesses in FDA’s monitoring and enforcement process have hampered the Agency’s ability to effectively oversee postmarketing studies conducted under FDA’s accelerated approval regulations.  The example used in the GAO report of a drug with uncompleted confirmatory studies is Midodrine HCl – the accelerated approval with the longest outstanding commitment.

An August 7, 2007 letter FDA sent to companies marketing approved versions of Midodrine HCL raised the possibility that generic sponsors might conduct the required confirmatory studies, and also raised the possibility of withdrawing approval for all Midodrine HCl applications if those studies are not conducted.  FDA stated in an August 2008 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.” 

FDA took an even more forceful tone in an August 2009 letter stating again that “[i]f an application or supplement containing studies that verify clinical benefit for midodrine hydrochloride is not approved in a timely manner as described herein, we will issue a [NOOH] on the Center’s proposal to withdraw the approval of the midodrine hydrochloride NDA (and all abbreviated NDAs (ANDAs) referencing that NDA) pursuant to 21 CFR §§ 314.530; 314.150, and 314.151,” but adding that the required studies must have “50% enrollment by April 12, 2010,”  “100% enrollment by June 12, 2010,” and that full study reports of the requested trials must be submitted “on or before October 12, 2010.”

According to FDA’s August 2010 NOOH letter:

No application holder has satisfied the requirements set forth in our letter of August 12, 2009.  Specifically, no application holder submitted documentation of IRB approval or statistical analysis plans for the two required studies on or before February 12, 2009, had 50 percent enrollment by April 12, 2010, or completed enrollment by June 12, 2010.  To our knowledge, the required studies are not currently being conducted. In light of the foregoing and consistent with our authority under applicable provisions of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 301 et seq.) and implementing regulations, we now propose to withdraw approval of NDA 19-815.  Upon withdrawal of NDA 19-815, FDA will also withdraw approval of all ANDAs that reference NDA 19-815.

The Midodrine HCl NDA holder has 15 days from receipt of FDA’s August 2010 letter to request a hearing and ANDA sponsors (which may participate in the hearing only as non-party participants) have 30 days to submit comments.  “If an ANDA holder has submitted timely comments but does not have an opportunity to participate in a hearing because a hearing is not held, the submitted comments will be considered by the Agency,” and FDA will issue “preliminary decision whether there are grounds to withdraw approval of the listed drug and the ANDAs.”  After that, FDA will accept comments and may “hold a limited oral hearing to resolve dispositive factual issues that cannot be resolved on the basis of written submissions,” and then issue a final decision.  FDA notes in the NOOH letter that:

If the Agency proceeds to withdraw approval of these products, any future use of midodrine HCI in the United States will require submission of an investigational new drug application to FDA. FDA will explore, as appropriate, continued availability of midodrine HCl under our regulations governing expanded access, 21 CFR part 312, subpart I.

The Midodrine HCl NOOH follows another FDA announcement from earlier this year that another Subpart H drug, MYLOTARG (gemtuzumab ozogamicin for Injection), would be voluntarily withdrawn from the market after a required postmarketing study failed to demonstrate clinical benefit.  The MYLOTARG withdrawal appears to have been the first instance in which a product granted accelerated approval was withdrawn from the market – either because a postmarketing study failed to verify clinical benefit or because of a sponsor’s failure to complete a required postmarketing study with due diligence.