[Posted 08/16/2010]

AUDIENCE: Cardiology and Nephrology

ISSUE: FDA proposed to withdraw approval of the drug midodrine hydrochloride, used to treat the low blood pressure condition, orthostatic hypotension, because required post-approval studies that verify the clinical benefit of the drug have not been done. To date, neither the original manufacturer nor any generic manufacturer has demonstrated the drug’s clinical benefit, for example, by showing that use of the drug improved a patient’s ability to perform life activities.
BACKGROUND: The drug, marketed as ProAmatine by Shire Development Inc. and as a generic by others, was approved in 1996 under the FDA’s accelerated approval regulations for drugs that treat serious or life-threatening diseases. That approval required that the manufacturer verify clinical benefit to patients through post-approval studies. 
RECOMMENDATION: Patients who currently take this medication should not stop taking it and should consult their health care professional about other treatment options.

Midodrine

機轉：

Midodrine is a prodrug for desglymidodrine, the active metabolite. Desglymidodrine is an alpha ₁ -agonist, and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors. Desglymidodrine diffuses poorly across the blood-brain barrier, and is therefore not associated with effects on the central nervous system.

美國FDA近期發布有關含midodrine成分藥品之用藥資訊。該藥品主要作為治療血壓過低、直立性低血壓之用，因屬治療嚴重或危及生命疾病之藥品，故1996年美國FDA採快速核准方式，核准該藥品上市，惟上市後廠商仍須提供相關上市後試驗資料，以證明其臨床效益。惟至目前為止，廠商尚未能提供充分資料，證明該藥品之臨床效益，因此美國FDA建議將該藥品撤離市場，但仍保留給廠商提供進一步資料申訴之機會。
經查，衛生署核准含midodrine成分之製劑許可證僅1張，為衛署藥製字第045334號「"培力" 邁妥林錠」，核准適應症為「體質性血壓過低、直立性循環系統失統，病後、手術後及產後之血壓過低」。食品藥物管理局將函請該廠商提供相關試驗或研究資料，進行療效再評估作業，亦提醒正在服用該成分藥品之病患，不可任意停藥

持續更新資料：

[9/10/2010] Midodrine is a medication approved in 1996 under accelerated approval for the treatment of symptomatic orthostatic hypotension, a serious condition in which patients are unable to maintain their blood pressure while standing. Shire Pharmaceuticals is the sponsor of the innovator product, marketed as ProAmatine. Five generic drug manufacturers also make the medication.

FDA gave midodrine accelerated approval on the basis of studies demonstrating an improvement in blood pressure, and the company was obligated to conduct post-approval studies verifying actual clinical benefit to patients.

In the time since approval, the company has conducted several clinical studies of the drug, and literature regarding the efficacy of the product has been published, but the data submitted to the agency have not verified the clinical benefit that the drug was expected to have. Many patients and doctors, however, believe through experience that the medication does help patients substantially. We have also heard from several professional organizations that support the use of the product.

FDA has two goals with respect to midodrine: (1) to obtain high quality data on the effectiveness of the medication and (2) to maintain access for patients to the medication throughout this process.

FDA recently notified Shire and the generic manufacturers of the agency's proposal to withdraw product approval for midodrine. The FDA's proposed action was based on the lack of required post-marketing data confirming the clinical benefit of the drug.

A key point is that FDA's announcement did not represent the actual withdrawal of the medication from the market. It represented a step in the regulatory process – a step that reflects both the regulatory requirement for manufacturers to verify the clinical benefit of accelerated approval products and the agency's position that more data about the benefits of midodrine would help doctors and patients understand who can benefit from the drug and how best to use it.

Shire has requested a public hearing in response to FDA's proposal to withdraw midodrine. That hearing will provide an opportunity for the company to present the agency with data supporting the clinical benefit of the drug and for an advisory committee to review those data.

Since the agency notified the manufacturers of the proposed withdrawal of midodrine, we have heard from professional organizations, doctors, and patients about their concern about losing access to midodrine. We have also heard from organizations that have expressed interest in conducting the clinical studies necessary to establish effectiveness, as well as doctors and patients who support the conduct of such studies. FDA intends to work with Shire, the generic manufacturers, and other organizations to discuss the data that are necessary to establish the efficacy of midodrine. FDA will post this information in a public docket.

Midodrine remains approved and available in the marketplace. To reassure patients and their doctors, FDA has stated clearly that as the regulatory process moves forward, continued patient access to midodrine is a key agency priority.

FDA believes that its approach will serve both of its goals – getting the necessary efficacy data and maintaining patient access to the medication while it does so. It is critical to the success of the accelerated approval program that manufacturers of drugs that are marketed under that program perform the studies required to confirm whether the drugs really help people. Ultimately, patients will benefit from understanding more about available therapies and how they work to treat serious and life-threatening illnesses.

再次更新：2011/1/11

Midodrine Update: Opening of a public docket

[1/11/2011] The U.S. Food and Drug Administration (FDA) is announcing the opening of a public docket (FDA-2010-N-0637) to provide a forum to facilitate communication regarding the conduct of clinical trials needed to verify and describe the clinical benefit of midodrine hydrochloride (HCl). Since the approval of midodrine HCl under FDA's Accelerated Approval regulations, the company, Shire, has conducted several clinical studies of the drug, and literature regarding the efficacy of the product has been published, but the data submitted to the agency have not verified the clinical benefit that the drug was expected to have. FDA recognizes that existing and potential sponsors may wish to conduct the clinical trials needed to support continued marketing authorization of midodrine HCl.

To assist sponsors in planning and designing such trials we have provided a brief description of a recommended clinical trial design. The Federal Register notice invites interested parties to submit information to the docket such as any existing controlled studies that verify the clinical benefit of midodrine HCl when used to treat orthostatic hypotension. Physicians who treat orthostatic hypotension and patient organizations that would like to work with any sponsors of new clinical trials are invited to submit correspondence to the docket identifying themselves.

The docket will remain open for written or electronic submissions until July 11, 2011.