FDA’s Sentinel Likely To Outpace Traditional Post-Market Studies, But Will It Replace Them?

Pilot project for overactive bladder drug Mybretriq raises questions as to how Sentinel will affect sponsor’s risk-monitoring obligations.

A Mini-Sentinel study examining the potential risk of acute myocardial infarction and/or stroke attributable to overactive balder drug Myrbetriq (mirabegron) should be complete before Astellas Pharma Inc.’s own post-market cardiovascular outcomes study – leaving questions about how the results may affect the firm’s study and how the Sentinel program might alter sponsor post-marketing obligations more broadly.

So far FDA has not provided much detail on how Sentinel, its soon-to-be-fully-enacted active pharmacovigilance system, will impact other post-marketing safety monitoring programs, but it seems logical that the outcome of a Sentinel study could prompt changes to – or potentially even the discontinuation of – an ongoing safety study.

Concerns about cardiovascular adverse events caused by Myebetriq were raised in the lead up to the drug’s approval in June 2012 because the highest approved dose produced heart rate and blood pressure increases in clinical trial patients.

As part of its approval, FDA required Astellas to conduct a long-term observational study looking at serious cardiovascular outcomes (Also see "Approval Of Astellas’ Myrbetriq Shows FDA’s Faith In Post-Marketing Studies" - Pink Sheet, 28 Jun, 2012.).

Now Mini-Sentinel, FDA’s working model of the full system, will conduct a prospective sequential surveillance to examine the potential risks of AMI and stroke attributable to the drug, according to a protocol posted for public comment May 1. Comments are due by May 15.

Short-term use of several drugs that increase HR and BP have been associated with an increased risk of acute MI and/or stroke, and the protocol says there is an interest in a prospective surveillance assessment to identify potential early signals of AMI and stroke with the use of Myrbetriq.

Mixed Messages From FDA

But it has been unclear exactly how the surveillance system, mandated by the FDA Amendments Act in 2007, will impact sponsors post-marketing safety monitoring requirements, including commitments to particular research such as Astellas’ CV outcomes study.

As FDA looks for a way to find an off-budget funding model for Sentinel, including encouraging industry to step up and take the lead, Center for Drug Evaluation and Research Director Janet Woodcock indicated last summer that the agency’s selling point to industry was the system could be used to do post-marketing observational studies much more cheaply and efficiently.

Besides some small projects in PDUFA V industry has not agreed to fund Sentinel through user fees (Also see "Selling Sentinel: FDA Highlights Vision For Broader Role For Data Network At Brookings" - Pink Sheet, 19 Aug, 2013.).

However, in previous years FDA has told industry that post-marketing commitment standards would not change as a result of Sentinel’s implementation and that Sentinel is envisioned to augment, not replace its existing post-marketing system (Also see "PDUFA V: Sentinel, Regulatory Science Upgrades Could Gain User Fee Funding" - Pink Sheet, 28 Feb, 2011.).

And in Astellas’ case, the description of the CV post-market study in Myrbetriq approval letter emphasizes that Sentinel “will not be sufficient to assess this serious risk.”

It’s unclear if FDA’s thinking could have changed since the drug’s 2012 approval given the agency’s experience with Mini-Sentinel.

The agency did not respond to questions about how Sentinel and traditional post-marketing commitments will affect one another, including how Mini-Sentinel’s surveillance of mirabegron, which appears poised to end before Astellas study, could modify or even eliminate Astellas’ requirement.

FDA also did not offer any information as to what the Astellas outcomes study might be able to reveal that the Mini-Sentinel project might not and vice-versa.

Astellas v. Mini-Sentinel

Astellas said the Mini-Sentinel study does not change its commitment to performing the post-marketing study outlined in the approval letter.

It’s difficult to compare the two studies in detail because a protocol for Astellas’ study was not available. A protocol was supposed to be submitted to FDA in March 2013, though none was available on clinicaltrials.gov and the company did not respond to a request for it.

The Mini-Sentinel assessment will utilize data beginning with the later of July 2012 or the first month in which a mirabegron dispensing appears in Mini-Sentinel’s distributed database of 153 million people.

The assessment will look at four cohorts – the primary analyses will focus on new users of mirabegron compared to new users of active comparator oxybutynin. Secondary analyses will focus on non-naïve uses of the drugs. Oxybutyin is the most commonly used overactive bladder therapy and is thought to be devoid of BP and HR effects, the Mini-Sentinel protocol says.

The surveillance will be done using Mini-Sentinel’s Prospective Routine Observational Monitoring Program Tool: Cohort Matching, better known as PROMPT Module 2. PROMPT can track new drugs as they enter the market, on an ongoing, semi-automated basis; the tool is designed to complement Mini-Sentinel’s ability to retrospectively measure exposure to products and then analyze specific outcomes.

PROMPT’s emphasis “is on signaling of potential excess risk rather than formal assessment of causal relationships,” according to Mini-Sentinel.

Acute MI is the primary outcome of interest, and stroke is the secondary outcome of interest, but they will be examined separately in the Min-Sentinel study.

Based on the criteria for stopping the sequential analysis, the longest the mirabegron Mini-Sentinel study should run once it begins is 24 months from the initial PROMPT 2 Module 2 analysis. The PROMPT Module 2 will run as soon as possible and not await accumulation of a critical mass of mirabegron use, the protocol says.

Though the 24-month timeline could be made longer or shorter based on information accrued by Mini-Sentiel and other data sources, it is likely the data will be run and the Mini-Sentinel project will conclude before Astellas finishes its post-market study.

Astellas’ data is likely to provide a more detailed look at the overall cardiovascular impact of the drug. Myrbetriq’s approval letter lists the post-market study as completing in July 2018.

The study, 1898-3, is required to be “a long-term observational study using electronic healthcare databases with appropriate linkages conducted in United States and European databases to evaluate the incidence of serious cardiovascular outcomes (both individual and composite outcomes) in patients administered Myrbetriq,” the approval letter states.