FDA is moving towards potentially withdrawing, for the first time, a drug brought to market under the Subpart H accelerated approval mechanism.

Shire Pharmaceuticals, sponsor of the hypotension treatment ProAmatine (midodrine), and generic manufacturers of the drug received a ¹ letter from FDA Aug. 7 requesting completion of Phase IV efficacy studies.

"If those studies are not approved in a timely manner, that NDA (and all ANDAs referencing that NDA) will be subject to withdrawal," FDA states.

Shire acquired ProAmatine from Roberts Pharmacy in the late 90s, at which time three Phase IV efficacy studies were underway. In discussions with FDA before the sale, Roberts had been able to reduce the requirement to two trials, one of which, though completed, did not satisfy FDA standards, leading the trial to be listed as "delayed" in FDA's Phase IV database.

"We continue to have positive open dialog with FDA about potential steps for completing studies," Shire spokesman Mark Cabrey told "The Pink Sheet."

But it would appear as if financial incentives for Shire to complete Phase IV studies are slim because of competing market pressure from generics.

"The number of people benefiting from the brand ProAmatine is very small, primarily because of the generic versions that are available," Cabrey said.

In efforts to keep the drug on the market, generic sponsors also have the option of completing the Phase IV studies.

"Several holders of approved abbreviated applications for midodrine hydrochloride have considered whether to conduct the requisite studies," FDA's letter states.

When midodrine generics (of which there are currently five) became available in 2003, the number of patients using ProAmatine declined by about 80 percent, making it increasingly difficult to recruit patients for clinical studies.

In addition, because hypotension tends to affect a significant number of people with Parkinson's disease, some potential participants are already enrolled in other clinical studies.

According to FDA's database of Phase IV trials, Shire's study 404, which is "delayed," is a multi-center, double-blind, randomized, placebo-controlled, crossover study to assess the clinical benefit of midodrine in patients with moderate to severe neurogenic orthostatic hypotension. It replaces a previous study that was stopped because of poor enrollment and protocol trial design issues.

Historically, FDA has managed to keep drugs on the market despite poor results in Phase IV studies, such as Roche's HIV therapy Hivid (zalcitabine) and AstraZeneca's Iressa (gefitinib), which failed to demonstrate survival benefit for non-small cell lung cancer (² Also see "Iressa Gets Narrowed Indication Instead Of Withdrawal: New Model For FDA?" - Pink Sheet, 27 June, 2005., p. 18).

Hivid received a second-line indication, but was voluntarily discontinued by Roche in 2005. Iressa was limited to patients who had already shown a benefit from treatment. Sales of Iressa, which is still used by several hundred people, are declining, but AstraZeneca is continuing clinical development programs for the drug.

With Iressa, "FDA set up a de-facto type of withdrawal," Hyman, Phelps & McNamara attorney Kurt Karst said in an interview. As current Iressa patients become deceased, "the drug will not be able to be used anymore."

Amgen's Vectibix (panitumumab) also failed to show survival benefits in a Phase IIIb study (³ Also see "FDA Offers Possible Reasons For Vectibix Failure To Show Survival Benefit" - Pink Sheet, 2 April, 2007. p. 10). Amgen says Phase IV commitments for the product are progressing well, notably the registrational Phase III trial for second-line metastatic colorectal cancer. [Editor's note: The original version of this story incorrectly stated that the Phase IIIb trial was a Phase IV trial.]

Under the regs establishing FDA's accelerated approval mechanism, the NDA withdrawal process allows sponsors to request a hearing, which is followed by an advisory committee meeting and ultimately, a decision to withdraw or keep a drug on the market is made by the Commissioner.

FDA has not set a definite timeline for midodrine's sponsors to complete Phase IV studies; however, application holders have been asked to submit answers to several questions presented by the agency by Sept. 7.

The situation with midodrine illustrates some of the complexities FDA will face after the passage of the pending drug safety bill. The legislation is expected to give the agency stronger authority, in the form of fines, to require Phase IV studies of any product, but it will still face significant procedural hurdles in getting sponsors to act.

In the case of midodrine, FDA appears to be exploring the idea of giving sponsors an incentive for conducting the trials.

FDA's letter asked for input on legal and regulatory issues surrounding the completion of Subpart H trials by one or some of the generic sponsors. Apotex, Impax, Mylan and Sandoz market generics, and Upsher Smith markets the branded generic Orvaten .

Questions posed by FDA include: If more than one ANDA applicant completes the studies, are those studies eligible for three-year exclusivity? Would exclusivity depend on whether studies validate the use of a surrogate endpoint or change drug indications? Could multiple sponsors share exclusivity?

Finally, FDA asks, "If studies are completed and certain holders of approved ANDAs or the NDA holder does not cooperate, does FDA have the authority ... to withdraw approval of those applications?"

Coaxing sponsors of drugs granted accelerated approval is a challenge FDA may face again in the future. In addition to midodrine, there are six products granted accelerated approval that have Phase IV trials deemed "delayed" by FDA: Cell Therapeutic's Zevalin (ibritumomab), Eisai's Ontak (denileukin), ImClone's Erbitux (cetuximab), Novartis' Exjade (deferasirox), SmithKline Beecham's Bexxar (tositumomab) and Protherics' CroFab (crotalidae polyvalent immune fab, ovine).

- Carlene Olsen (c.olsen@elsevier.com)

Accelerated “De-proval”? FDA May Be Ready To Withdraw Subpart H Drug

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