Accelerated Approval: Midodrine Experience Shows Regulatory Challenge US FDA Faces With Makena
Executive Summary
The orthostatic hypotension treatment midodrine has been on the market for more than 20 years despite the failure of postmarketing studies to confirm clinical benefit; an advisory committee soon will weigh the future of AMAG’s preterm birth drug Makena, which failed its confirmatory trial required as a condition of accelerated approval.
Unresolved questions about the clinical efficacy of a hypotension drug that received accelerated approval 23 years ago highlight the challenges the US Food and Drug Administration and its external advisors will face in weighing whether AMAG Pharmaceuticals Inc.'s preterm birth drug Makena should remain on the market despite failure to confirm clinical benefit.
On 29 October, the FDA will convene its Bone, Reproductive and Urologic Drugs Advisory Committee to consider the continued availability of Makena (hydroxyprogesterone caproate injection, also known as 17P), an accelerated approval drug for which the required confirmatory trial failed to demonstrate a statistically significant treatment difference on two co-primary endpoints. (Also see "Makena’s Accelerated Approval Will Hang In Balance At US FDA Panel Meeting In October" - Pink Sheet, 23 Sep, 2019.)
The midodrine experience shows what can happen when a drug for an underserved condition makes it onto the market via the accelerated approval pathway, and how problematic removal can be when confirmatory trials fail.
The meeting is expected to raise a host of complexities in deciding whether Makena and its generics should stay on the market – pitting the integrity of the accelerated approval system against the potential removal of the only FDA-approved version of a drug that has been widely compounded and used to prevent preterm birth.
Makena will mark yet another test of the agency’s accelerated approval pathway, which allows drugs to reach market on the basis of a surrogate or intermediate clinical endpoint reasonably likely to predict clinical benefit. Such approval is conditioned upon verification of clinical benefit in postmarketing confirmatory trials and, as in the case of Makena, such studies do not always pan out as regulators and sponsors had hoped.
Indeed, the Makena discussion could bring new attention to accelerated approval drugs that have lingered on the market for years despite the failure of postmarketing studies to confirm clinical benefit.
One such drug is Shire PLC’s ProAmatine (midodrine), first approved in 1996 but which the agency still acknowledges has yet to verify clinical benefit despite several postmarketing studies.
The experience of midodrine, which currently is available only in generic form, shows what can happen when a drug for an underserved condition makes it onto the market via the accelerated approval pathway, and how problematic removal of such drugs can be when their confirmatory trials fail.
Withdrawal Proposal Put On Hold
ProAmatine holds accelerated approval for treatment of symptomatic orthostatic hypotension. Approval was based on trials demonstrating that the drug increased one-minute standing systolic blood pressure, a surrogate marker considered likely to correspond to a clinical benefit.
Shire acquired the NDA in 2000 and completed two postmarketing confirmatory trials, but the FDA’s Center for Drug Evaluation and Research deemed the studies insufficient to confirm clinical benefit.
In August 2010, CDER formally proposed to withdraw ProAmatine’s approval and gave Shire an opportunity to request a hearing. However, the agency’s withdrawal proposal triggered concerns from professional organizations, doctors and patients regarding the possible loss of access to what they viewed as an effective treatment for orthostatic hypotension.
Although Shire requested a hearing on the withdrawal proposal, no hearing was held because, in 2011, CDER and the company reached an agreement for the sponsor to conduct two new randomized, placebo-controlled trials to investigate midodrine’s clinical benefit in patients with symptomatic orthostatic hypotension. (Also see "Not The Next Avastin? Plan For New ProAmatine Studies Would Negate Shire’s Withdrawal Hearing Request" - Pink Sheet, 19 Dec, 2011.)
The original target date for submission of the study results was September 2014; the agency and Shire subsequently agreed to push that timeline back to March 2015.
Continued Interest By ANDA Sponsors
While Shire (which recently was acquired by Takeda Pharmaceutical Co. Ltd.) still holds the new drug application, it has not manufactured or marketed ProAmatine since 2010. Nevertheless, midodrine generics remain available, and the FDA’s “Orange Book” lists seven companies holding abbreviated new drug application approval for midodrine products that are not discontinued.
There remains interest in bringing new generic formulations to market.
In a May citizen petition, Alembic Pharmaceuticals Ltd. said it intended to submit an ANDA for midodrine and requested the agency make a “prompt determination” that withdrawal of ProAmatine, the reference listed drug, was for reasons other than safety or efficacy.
In a 22 October Federal Register notice, the FDA said it has concluded that ProAmatine 2.5mg, 5mg and 10mg tablets were not withdrawn from sale for reasons of safety or effectiveness, and this determination allows the agency to approve ANDAs referencing these products.
The notice acknowledges that ProAmatine came to market under the accelerated approval pathway, and Shire was required to conduct postapproval studies to verify clinical benefit. The clinical benefit of ProAmatine “remains subject to verification,” the notice states.
This statement is notable because it suggests the agency has not accepted as confirmatory evidence of clinical benefit the results of Shire’s two most recent postmarketing studies conducted to satisfy the 2011 agreement with CDER.
FDA documents indicate that Shire submitted the study results to the agency in March 2015.
Although Shire submitted results from the two new midodrine studies in March 2015, the FDA says the drug’s clinical benefit “remains subject to verification.”
In a February 2017 supplemental approval letter for changes to the Warnings, Precautions and How Supplied sections of ProAmatine labeling, the FDA stated: “We remind you that your supplement submitted March 30, 2015 containing the results of studies intended to address the requirements under 21 CFR 314.510 to verify and describe clinical benefit of midodrine remains under review by the agency. Approval of this labeling supplement does not constitute an agency decision on the adequacy of those studies to verify clinical benefit.”
The FDA said it was not able to respond to various questions from the Pink Sheet about the regulatory status of midodrine or Shire’s postmarketing studies.
Takeda also did not respond to questions about the postmarketing studies or midodrine’s regulatory status.
A Win On One Study, A Miss On The Other
Information on ClinicalTrials.gov about Shire’s two most recent postmarketing studies suggests that one study met its primary endpoint, while the other did not.
The former was a randomized, placebo-controlled crossover trial to assess midodrine’s efficacy on symptoms of orthostatic hypotension caused by being on a tilt table. The study enrolled 24 patients with severe symptomatic orthostatic hypotension who were on a stable dose of midodrine for at least three months.
The primary outcome measure was time to onset of syncope/near syncope while on tilt table at one hour post-dose. After a 30-minute supine period, the table was tilted from 0-90º within 30 seconds and maintained in that position for 45 minutes or until endpoint. Subjects were monitored for near-syncopal symptoms, and a report of such symptoms ended the test. If the investigator observed that the subject was about to lose consciousness, that also constituted an endpoint.
The study was completed in June 2013. Midodrine was associated with a 521-second improvement in time to onset of syncope relative to placebo, a statistically significant benefit. (p= 0.0131)
The results of the study were published in the journal of Clinical Autonomic Research in 2016, with the authors concluding that midodrine is a “well-tolerated and clinically effective treatment for symptomatic orthostatic hypotension.”
The second study was a randomized withdrawal, placebo-controlled, parallel group study that investigated the clinical benefit of midodrine in 67 patients with severe symptomatic orthostatic hypotension who were on a stable dose of midodrine for at least three months.
The primary outcome measure was the percent of subjects who failed to maintain a response 30 minutes post-dose on day 16, the day on which subjects were randomized to continue their midodrine dose or placebo. Failure to maintain a response was defined as any randomized subject that met the following criteria:
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The Orthostatic Hypotension Symptom Assessment (OHSA) Item 1 score increased by >4 points compared to baseline. OHSA Item 1 is a dizziness scale that is scored on a range from 0 (no dizziness) to 10 (severe dizziness). A lower score indicates less severe symptoms.
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There was an increase in the number of syncopal/near syncopal events or severity of events within 15 minutes of standing compared to those observed at baseline.
The study was completed in November 2013. The results posted on ClinicalTrials.gov suggest midodrine failed to demonstrate a statistically significant benefit (p=0.3145), although the drug appears to have shown a numerical advantage over placebo.
Dearth Of FDA-Approved Treatments
As is the case with Makena, removal of midodrine from the market could create a void in approved pharmacologic treatments, something the agency surely is reluctant to do.
The only other drug approved for orthostatic hypotension, Lundbeck Inc.’s Northera (droxidopa), also came through the accelerated approval pathway and its clinical benefit has yet to be confirmed in postmarketing trials.
Droxidopa received accelerated approval in February 2014 for the treatment of orthostatic dizziness, lightheadedness or the “feeling that you are about to black out” in adult patients with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure (Parkinson's disease, multiple system atrophy and pure autonomic failure), dopamine beta-hydroxylase deficiency and non-diabetic autonomic neuropathy. (Also see "Chelsea’s Northera Clears FDA But With A Confirmatory Trial Requirement" - Pink Sheet, 19 Feb, 2014.)
The indication statement notes that effectiveness beyond two weeks of treatment has not been demonstrated. Like midodrine, droxidopa also carries a boxed warning on the risk of supine hypertension.
The droxidopa approval letter included a postmarketing requirement for a clinical trial to assess the sustained effects of therapy, with the final study report due by April 2021.
The FDA does not consider drugs approved under accelerated approval to be “available therapy” for purposes of expedited regulatory programs unless clinical benefit has been verified by postmarketing studies. (Also see "Accelerated Approval Conversion Could Mean ‘Breakthrough’ Loss" - Pink Sheet, 11 May, 2015.)