The jury is still out on whether Shire’s hypotension drug ProAmatine (midodrine) will be the focus of the same type of public hearing recently held on the fate of Avastin’s metastatic breast cancer claim.

Genentech became the first company to contest the Center for Drug Evaluation and Research’s proposal to withdraw accelerated approval for a product or indication, requesting on Dec. 23, 2010 that the agency hold a public hearing on the MBC claim. That high-profile hearing was held on June 28-29, with the Oncologic Drugs Advisory Committee recommending the indication be withdrawn.

Shire’s request for a public hearing on CDER’s bid to remove ProAmatine and generic versions from the market predated Genentech’s request by several months but is still pending.

On Aug. 16, 2010, CDER notified Shire and five ANDA holders that it proposed to revoke accelerated approval of ProAmatine, and to withdraw generic approvals, because Shire failed to conduct post-marketing clinical trials that verify and describe the drug’s benefit in treating symptomatic orthostatic hypotension (Also see "FDA Begins Withdrawal For Midodrine Three Years After It First Threatened To End Approval" - Pink Sheet, 16 August, 2010.).

On Sept. 3, 2010, Shire filed a written request for a hearing, and it submitted a supporting data package several weeks later. However, there has been nothing entered in the public docket since October 2010, and FDA Commissioner Margaret Hamburg still has not decided whether a hearing should be granted.

FDA said it continues to review Shire’s request for a hearing. Shire said it is working with the agency to determine a pathway for keeping the drug available to the patients who need it.

The agency did take some action in January 2011, creating a separate public docket for comments related to midodrine clinical studies that would be needed to confirm clinical benefit. The docket included a memorandum from Division of Cardiovascular and Renal Products Director Norman Stockbridge describing the design of studies that FDA believes would be adequate.

The agency invited physicians and patient organizations that would like to work with sponsors on new clinical trials to submit correspondence to the docket. Although the docket remained open until July 11, no public submissions from any individual or group outside FDA have been entered to date.

Given the recent experience with Avastin, it seems unlikely that either the agency or midodrine product sponsors would be eager to go through the public hearing process, even for a considerably lower-profile drug.

The weeks leading up to the Avastin hearing were marked by increasingly bitter disputes between Genentech and CDER over the scope of the proceedings and the evidence that could be introduced.

There were moments of embarrassment for CDER, with Genentech making extensive use of statements in Office of Oncology Drug Products Director Richard Pazdur’s original 2008 approval memo for the MBC indication to try to undercut CDER’s current view that the claim should be withdrawn (Also see "Avastin Breast Cancer Approval Memo Comes Back To Haunt FDA’s Pazdur" - Pink Sheet, 18 July, 2011.).

Genentech also did not fair well: it wound up with a unanimously negative vote by ODAC on all four questions posed to it about Avastin’s efficacy, safety and whether the indication should remain on-label while the company conducts a new trial (Also see "Avastin’s Breast Cancer Claim: Will FDA’s Hamburg Take A Middle Road?" - Pink Sheet, 4 July, 2011.).

There also were administrative challenges for the agency, including delays in the public docketing of comments and hearing-related submissions by the parties. Hearing officer Karen Midthun twice reversed herself on earlier rulings, ultimately agreeing to allow a public comment period and the participation of a temporary voting member who served as the patient representative to ODAC (Also see "Less Than Half Of ODAC Members Will Participate In Avastin Hearing" - Pink Sheet, 23 June, 2011.).

In contrast to the Avastin and ProAmatine situations, which involve proposed withdrawal actions, ISTA Pharmaceuticals may soon seek a public hearing on CDER’s refusal to approve an sNDA for its ophthalmic Bromday (see related story, Also see "ISTA To Challenge FDA’s Refusal To Approve Bromday sNDA, Testing Little-Used Hearing Process" - Pink Sheet, 8 August, 2011.).

By Sue Sutter

Amid Avastin Noise, Shire Quietly Awaits Word On ProAmatine Public Hearing

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