2020 Vision For FDA's Sentinel: 'Systemic' Integration Of Surveillance Looms

The PDUFA VI user fee agreement negotiated by FDA and industry envisions the year 2020 as a critical milestone for FDA’s Sentinel active surveillance system: that is when the agency is committing to integrate Sentinel “into the human drug review program in a systematic, efficient and consistent way.”

The deadline is articulated via three specific deadlines outlined in Section I.K.1 of the "commitment letter" released by FDA for public comment on July 15. By the end of fiscal year 2020, FDA is committing to:

• Facilitate integration of Sentinel into the human drug review program in a systematic, efficient, and consistent way through staff development and by updating existing SOPPs and MAPPs, as needed;
• Develop a comprehensive training program for review staff (e.g., epidemiologists, statisticians, medical officers, clinical analysts, project managers, and other review team members) to ensure that staff have a working knowledge of Sentinel, can identify when Sentinel can inform important regulatory questions, and are able to consistently participate in use of Sentinel to evaluate safety issues; and
• Establish policies and procedures (MAPPs and SOPPs) to facilitate informing sponsors about the planned use of Sentinel to evaluate a safety signal involving their respective products.

The PDUFA VI discussion of Sentinel contrasts sharply with the comparable section in the PDUFA V agreement. There, the focus was framed as efforts to “determine the feasibility of using Sentinel to evaluate drug safety issues that may require regulatory action,” and the deliverables were items like workshops and pilot projects.

The new agreement, in fact, does not specifically call for FDA to continue its annual Sentinel update meetings, held in conjunction with Brookings for the first several years of the program and most recently with Duke-Margolis Center. (Also see "Sentinel’s “IMPACT” Beyond Safety: Anti-Coagulant Study Is Early Test" - Pink Sheet, 10 Mar, 2016.)

Instead, it explicitly calls for just one meeting, which is supposed to occur the year before the formal “integration” deadline:

By the end of FY 2019, FDA will hold or support a public meeting engaging stakeholders to discuss current and emerging Sentinel projects and seek stakeholder feedback and input regarding gaps in the current system to facilitate the further development of Sentinel and its system of Active Risk Identification and Analysis (ARIA).

The agreement includes a number of other statements about ongoing development of Sentinel, including commitments to expand its sources of data and core capabilities and steps to open up the capability for use by sponsors and/or the public – but those commitments are not tied to specific deadlines.

Collectively, the PDUFA VI goals serve as a a confirmation of Sentinel’s evolution from new, experimental safety tool to routine component of drug regulation. (Also see "Reality Check For Real World Data: FDA’s Sentinel Network Enters “Production” Stage" - Pink Sheet, 23 Mar, 2015.)

They also offer a potential timeline for the next frontier in the evolution of “Big Data” at FDA: the commitment to develop ways to use “real world evidence” to inform regulatory decisions – particularly as it relates to efficacy of new drugs. (FDA now refers to that aspect of Sentinel’s capability as Guardian.)

The scope of work outlined in that section of the commitment letter (Section I.I.6) reads more like the PDUFA V goals for Sentinel, with an emphasis on developing capabilities and soliciting regular input towards creating pilot projects. (Also see "PDUFA's 'Real-World' Journey Expected To Be Slow Walk" - Pink Sheet, 22 Jul, 2016.)

REMS Language Dropped, Sponsor Notification Emphasized

The discussion of Sentinel isn’t the only dramatic change when it comes to post-marketing safety issues in the PDUFA agreement letter.

By far the biggest change is the elimination of separate goals related to Risk Evaluation & Mitigation Strategy (REMS) standardization and integration activities. That topic was covered by its own section of the PDUFA V goal letter, with commitments for meetings and guidances throughout the five-year agreement.

In the PDUFA VI letter, the entire topic is covered in a single clause in the preamble to the post-marketing safety commitments section. “FDA will continue to uses user fee to enhance and modernize the current U.S. drug safety system,” the letter states, and then lists a number of ongoing activities, including “standardization and integration of REMS into the health care system.”

The PDUFA VI agreement does add a new area of commitments in post-marketing surveillance, related to communication with sponsors about emerging safety issues.

That language begins to address a long-standing concern of industry that has become more acute with the adoption of enhanced safety monitoring and communication by FDA in the past decade.

It is framed as a broad goal to assure “timely and effective evaluation and communication of postmarketing safety findings related to human drugs.” And the letter notes a broad commitment to support continued improvements in FDA’s “current processes that capture and track information, including enhancements to its information technology systems, as needed, in order to support the management and oversight of postmarketing drug safety issues.”

However, the more specific goals relate to FDA’s procedures for alerting sponsors to potential safety signals before any broader public notification.

Specifically, FDA agrees that, by the end of fiscal 2019, it will “update existing policies and procedures (MAPPs and SOPPs) concerning tracking postmarketing safety signals to include consistent and timely notification to a sponsor (1) when a serious safety signal involving a product is identified and (2) to the extent practicable, not less than 72 hours before public posting of a safety notice.”

That issue is also covered in FDA’s separate commitments for Sentinel. FDA commits that the internal MAPPs/SOPPs required by that scope of work “will address what types of evaluations and what information about the evaluations will be shared with sponsors, and the timing of such communications.”

FDA also commits to assess the impact of the Sentinel integration process and the updated communications policies by the end of PDUFA VI.

From the editors of the RPM Report.