FDA Wants Drug Withdrawn for Failure to Conduct Phase IV Studies- UPDATE: FDA Bows to Patients’ Concerns

FDA Phase IV Withdraw Approval

FDA Wants Phase IV Studies to Prove Effectiveness

(Original Post- UPDATE Below) The Food and Drug Administration proposed to withdraw approval of a drug treatment for low blood pressure. The drug is marketed as ProAmatine by Shire Development Inc. and as a generic by others called midodrine hydrochloride. FDA stated that “required post-approval studies that verify the clinical benefit of the drug have not been done.” This proposal takes place shortly after the Avandia advisory committee meeting sharply questioned the Phase IV study conducted by GlaxoSmithKline (GSK) called the Record study. It indicates that FDA is taking postmarketing studies much more seriously, both for safety and effectiveness. In a 2009 report by the Government Accountability Office (GAO) FDA was sharply criticized because of the number of postmarketing, or Phase IV, studies that had not been completed by the sponsors or had not been reviewed by FDA. THE GAO report said that FDA had never withdrawn a drug due to the failure to produce postmarket information. Now it looks like FDA will for the first time.

The FDA press release stated:

We’ve worked continuously with the drug companies to obtain additional data showing the drug’s clinical benefits to patients,” said Norman Stockbridge, M.D., director of the Division of Cardiovascular and Renal Drugs in the FDA’s Center for Drug Evaluation and Research. “Since the companies have not been able to provide evidence to confirm the drug’s benefit, the FDA is pursuing a withdrawal of the product.”

Midodrine hydrochloride was originally approved in 1996 with a fast track approval for drugs that treat serious or life-threatening conditions. The condition, orthostatic hypotension, can cause people to feel dizzy or feint when standing up due to the inability to maintain blood pressure in an upright position. FDA issued a Proposal to Withdraw Marketing Approval and Notice of Opportunity for a Hearing to the companies that manufacture midodrine hydrochloride citing the failure to provide Phase IV clinical studies since that approval. After 14 years, FDA wants documentation that the drug works for the labeled indication. FDA;s current leadership is showing that they can read a GAO report, something that many of their predecessors didn’t. The companies marketing midodrine hydrochloride have the opportunity to request a hearing to contest FDA’s proposed market withdrawal.

UPDATE: 4 September 2010: The New York Times in a report by Gardiner Harris, reports that FDA returns midodrine to the market due to patient concerns. There are no alternative therapies to midodrine.

Read the NY Times Article

GxP Perspectives: From the viewpoint of this blog, it is the responsibility of sponsors to supply FDA with required postmarket data to support their applications. I certainly want patients to have access to necessary therapies. However, I do not want FDA approving drugs using anecdotal evidence. This defeats the concept of “adequate and well-controlled trials.” Drug companies should follow through on their commitments to run Phase IV trials and submit reliable data to FDA.

UPDATE: 28 August 2010- Patient Perspective: Please read the comments for a different viewpoint, that of the mother of a patient with orthostatic hypotension (the 3rd comment). You can read about this in the blog: Suzanne’s World

Read the Press Release

Link for Products Receiving Accelerated Approvals

In news from GxP Perspectives: Read the updated article on the Form FDA 1572 in

Applied Clinical Trials

ALSO: Please join me on LinkedIn at:

GxP Perspectives LinkedIn Group

Special Notice: The Blog was published in the Journal of Diabetes Science & Technology on the topic of Supervisory Responsibilities of Investigators with my colleagues Ann Berenbaum and Patti Young.

Access the Abstract Here


4 Responses to FDA Wants Drug Withdrawn for Failure to Conduct Phase IV Studies- UPDATE: FDA Bows to Patients’ Concerns

  1. Christine Watters says:

    What is the industry perception of a Phase IV? Nearly every time I hear something about a study that raises eyebrows it turns out to be a Phase IV and everyone relaxes. My impression is that they are taken less seriously than the pre-marketing studies and that it is difficult to confirm anything from the data obtained. Is the FDA going to start examining how rigorous the studies are conducted or are they going to simply be happy that the studies were done?

    • GxP Perspectives says:

      In the case of Avandia they inspected three sites, the sponsor, and CRO. Form FDA 483s, Inspectional Observations, were given to the sponsor and perhaps the CRO. See the slides attached to Avandia advisory committee post. Anyway, I think FDA is taking it seriously.

  2. Unfortunately the collateral damage from this is falling on the people who take midodrine. My son has POTS. Midodrine made a big difference for him, hey he even barely passed 9th grade. 10th grade is not looking good if Midodrine is off the market.
    There is no concern about it’s safety. Shire had already told the FDA is was discontinuing it for business reasons. So the FDA is taking a symbolic action that will only take business from the generic manufacturers. Not to mention that it will help, Chelsea Therapeutics, which is finishing phase 3 trials on a new drug to treat orthostatic hypotension next month.

    • GxP Perspectives says:

      Suzanne- You make a very good point and I don’t think anyone wants to see “collateral damage.” I believe that FDA was called to task for not following through on post-approval commitments by pharma, which in the past they had not done. FDA does have programs of expanded access but I do not know if this will benefit your son as it applies to investigational drugs. I hope that you and your son’s physician can find the appropriate therapy for him. I am posting a link to your blog for readers to understand your views. Suzanne’s World

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