Will the FDA provide more guidance or manage the process to share risk evaluation and mitigation strategies (REMS)?


Financier Worldwide Magazine

November 2013 Issue

November 2013 Issue

What the FDA will do to proactively manage the process to share Risk Evaluation and Mitigation Strategies (REMS) is a hot button topic that many in the pharmaceutical and biotechnology industry have been wondering, particularly as the FDA looks to standardise REMS. The Food and Drug Administration Amendments Act of 2007 (FDAAA) enacted on 27 September 2007, added REMS to the FDA’s arsenal to manage risks for certain drugs by requiring one or more strategies or elements to provide additional safe use of approved drug products, other than the drug product’s prescribing information and traditional labelling. Some REMS contain Elements to Assure Safe Use (ETASU), such as restricted distribution in particular pharmacies or hospital settings, special prescriber training, dispensing following evidence of safe-use conditions, or registries to track patients, prescribers or pharmacies. 

If the innovator’s drug includes ETASUs, FDAAA requires that innovator and generic versions use a single, shared REMS (SS REMS). FDAAA further provides that an innovator with an ETASU REMS cannot use any ETASU element to “block or delay approval” of an application approved as a 505(b)(2) new drug application (505(b)(2) NDA) or generic drug (abbreviated new drug application (ANDA)). Yet the FDA may waive this requirement if: (i) the FDA determines that the burden of creating an SS REMS between competitors outweighs the benefits; or (ii) an aspect of the ETASU is claimed by a patent, the patent has not expired, and the generic applicants have sought a licence but were unable to secure a licence. If waived, the generic applicants must use a comparable element to assure safe use of the product. The FDA has not issued regulations or guidance to explain this waiver process or how the innovator is expected to share its program, e.g., shared costs, information, risks or responsibilities. And only in August 2013, in response to a citizen petition, did the FDA outline a process for how sponsors may provide samples of their products with ETASU REMS to generic applicants – a process met with limited or no success in the past. 

As a potentially complicating factor, the Food and Drug Safety and Innovation Act of 2012 (FDASIA) modified the REMS system by allowing for modifications of a drug’s REMS without the need for the change to be tied to a specific assessment of the REMS. REMS assessments are required to be performed at 18 months, three years, and seven years after approval of the REMS unless modified by the FDA, so this could mean more REMS modifications. But, according to an Office of Inspector General Report issued in February 2013, entitled ‘FDA Lacks Comprehensive Data to Determine Whether Risk Evaluation and Mitigation Strategies Improve Drug Safety’, the FDA has received incomplete assessment information from REMS sponsors and audited only one REMS with ETASU since 2008. As a result, the FDA has little information to determine which ETASU elements are working and should be required in an SS REMS or in an innovator and comparable generic REMS, or whether a modified ETASU needs to be included. 

In practice, SS REMS generally have been successfully negotiated by the FDA only when the innovator’s REMS was not protected by a patent and the innovator’s and generic manufacturer’s products were already on the market, e.g., a class-wide REMS for extended-release and long-acting opioid analgesics first approved in July 2012. One historical pre-REMS shared risk management program with elements now deemed to be a REMS with ETASU is Accutane (isotretinoin). While the innovator had argued in a citizen petition that generic applicants needed to copy all elements of the risk management program, the FDA decided that the generic applicants need share only the “essential elements”.  And the innovator ultimately shared a risk management program that continued to evolve over time and later became a REMS. But more recently, the FDA said it would refer allegations of anticompetitive use of a REMS to the Federal Trade Commission (FTC), as the FDA did with the sponsor for Suboxone (buprenorphine hydrochloride / naloxone hydrochloride). In this case, the FDA also issued its first waiver of the SS REMS requirement for generic applicants, which formed their own shared REMS, Generic Buprenorphine Transmucosal Products for Opioid Dependence, which was approved in February 2013. 

In 2011, the FDA created a REMS Integration Initiative, and as part of its program has been seeking comments from stakeholders to review and improve REMS, including methods to standardise, assess the effectiveness of, and reduce the burden of REMS. The initiative has a report due in 2014, along with related guidance. Even before FDAAA and REMS, the FDA knew the problems associated with single, shared risk management programs, yet the FDA appears reluctant to issue guidance or initiate its notice-and-rulemaking authority to address the process for establishing an SS REMS. Instead, the FDA has left it to the innovator sponsor and interested generic applicants to work it out, and at times try to negotiate a resolution or permit a waiver, forwarding anticompetitive complaints to the FTC. Yet it is unclear what relief the FTC will provide, as it has not provided any decisions associated with earlier refusals to provide samples pursuant procedures described in the FDA’s recent citizen petition decision, nor the latest allegation of anticompetitive behaviour for the Suboxone REMS. 

It has been suggested in various citizen petitions, and most recently at an FDA Public Meeting Standardising and Evaluating Risk Evaluation and Mitigation Strategies on 25-26 July 2013, that the FDA needs to take a more proactive role in the SS REMS process. The FDA has been asked to either issue guidance or initiate notice-and-comment rulemaking to explain the FDA’s expectations for negotiating SS REMS, and incentives for sharing, e.g., reasonable shared control/access to data, development, maintenance, assessment, liability/insurance costs, and royalties/exclusivity. 

In addition, the FDA has been asked to explain the waiver process for SS REMS, including determining sanctions (other than referring the matter to the FTC) for failures to follow these procedures or provide samples pursuant to the FDA’s suggested procedures. As part of the REMS standardisation process, it has been further suggested that the FDA maintain a current, public database of REMS elements, in particular REMS with essential ETASU that must be shared or included in an alternative REMS alongside the innovator’s REMS. To the extent that assessment information is available for these REMS elements, it was suggested that the FDA provide such assessment information, so innovator and generic companies alike can use the information to develop new, shared, or alternative REMS programs alongside the innovator’s REMS. 

The FDA’s public docket to address these and other REMS standardising issues will remain open indefinitely, but the FDA asked for written comments by 16 September 2013 for inclusion in its 2014 REMS standardisation report.


Brian J. Malkin is a partner at Frommer Lawrence & Haug LLP. He can be contacted on +1 (202) 292 1530 or by email: bmalkin@flhlaw.com.

© Financier Worldwide


Brian J. Malkin

Frommer Lawrence & Haug LLP

©2001-2016 Financier Worldwide Ltd. All rights reserved.