By Andrew Emmett
In 2007, Congress codified many established pharmaceutical risk management practices through the establishment of risk evaluation and mitigation strategies (REMS) under the Food and Drug Administration Amendments Act of 2007 (FDAAA). By definition, prescription drugs and biologics carry both benefits and risks that must be carefully evaluated and managed by patients, healthcare providers, regulators, and industry. Since the new REMS authorities became effective in March 2008, both the FDA and sponsors alike have gained valuable experience developing and implementing REMS programs, but many operational and procedural issues exist regarding ongoing implementation of the new REMS provisions.
To help address this concern, the FDA recently developed a draft guidance to provide additional information for industry on the processes for submitting, modifying, and assessing REMS programs. To maximize the effectiveness of REMS programs and reduce the potential for REMS to delay or restrict access to novel medicines and therapeutics, BIO (Biotechnology Industry Organization) believes that several important changes should be incorporated into the guidance.
The FDA and Sponsors Should Communicate About Potential REMS Requirements Early In The Review Process And On A Regular Basis
It is critical that the FDA and sponsors have a common understanding of how and when sponsors should communicate with the FDA regarding a potential REMS and how that discussion is integrated into the application review process. In general, the draft guidance addresses the question of what to do after a REMS is required, but does not address how the decision to require such a program is reached. It is important that sponsors understand when and how agreements are reached and what specific risk is to be mitigated.
The draft guidance should also more accurately address the timing of REMS discussions between sponsors and the FDA and how those discussions are integrated into the good review management principles and practices (GRMPs), established best practices, and key milestones for reviewing new drug or biologics marketing applications. For the REMS provisions to have their intended effect and to ensure a timely review and approval process, we recommend that the FDA integrate risk management considerations and discussions, including REMS, into the GRMPs early in the review process and not merely view it as an obligation for sponsors and the FDA to discuss at the end of a review.
When clinical data indicates a safety issue to be mitigated, or in some instances, for drugs in a class for which a previous active moiety has a REMS, sponsors and the FDA should be able to anticipate very early in development that a REMS will be expected should the drug be marketed. Both the FDA and the sponsor should discuss these issues early in the review process and be timely in the sharing of new safety information that may trigger a REMS program.
Additionally, it is important to note that most approved REMS consist of only communication-based risk management strategies rather than restricted distribution of the product, also known as Elements to Assure Safe Use (ETASU). As of March 2010, 108 REMS had been approved, of which 97 included only a medication guide or a medication guide with a communication plan. Only 11 were accompanied by ETASU elements. We believe the FDA should define a more streamlined program for these communication-only REMS programs that is consistent with the legal threshold and spirit of REMS, which is to impose substantial risk minimization only on products that would not otherwise be approved. Communication-only REMS should have more narrow goals and streamlined documentation and data collection.
The PostMarket Modification Process Should Facilitate Minor, Editorial, And Nonsubstantive Changes To REMS
The guidance addresses the important issue of how REMS programs should be modified in the postmarket time frame. However, we are concerned about the suggestion that all REMS modifications, regardless of whether they are substantive changes to the strategy or minor editorial changes to an implementing tool, must be submitted through the prior approval supplements process.
BIO believes this process will create unnecessary delays in mitigating emerging safety issues and create an administrative burden for the FDA and the industry when minor changes are needed. No matter how carefully the FDA and sponsor design a REMS, a sponsor will inevitably need to improve the selected tools over time to allow for effective implementation and best meet the plan’s goals. Sponsors need to have flexibility to make timely adjustments to REMS tools and should not be required to invest the substantial resources needed to conduct a REMS assessment for every minor nonsubstantive change. More importantly, the FDA’s limited resources should not be devoted to reviewing supplements making only minor changes to an implementing tool.
We recommend that the FDA clarify in the final guidance that the “approved REMS” consist of only the concise REMS document and the 10 REMS elements outlined in FDAAA. In turn, the agency should allow sponsors the ability to develop REMS tools that are consistent with the approved REMS and statutory elements. We suggest that the FDA should review and approve the REMS document governing the risk management strategy and that the sponsor should be charged with ensuring that all supporting REMS tools are fully consistent and compliant with the approved REMS document. The FDA could then exercise general oversight as warranted.
If the FDA does not agree with the above recommendation, then we suggest alternatively that the agency allow sponsors to make minor changes to approved REMS tools without obtaining prior approval from the agency through an administrative reporting process. Substantive modifications would continue to require prior approval supplements.
Assessing The Effectiveness Of REMS Programs And The Impact On The Healthcare Delivery System
To date, many of the discussions around REMS implementation have involved the FDA and drug manufacturers. Yet, REMS programs can impact the broader healthcare delivery system. Efforts to improve the efficiency of REMS administration will involve a wide range of stakeholders, including physicians, pharmacists, nurses, liability carriers, state licensing boards, and patients.
We recommend the FDA host a series of public workshops with public stakeholders to discuss the impact of REMS on the healthcare system and access to drugs. REMS and important questions of benefit/risk management touch many diverse stakeholders, and no single group will be able to resolve this issue alone. Full engagement and cooperation from healthcare professionals and other healthcare delivery system stakeholders is critical, and a public workshop can initiate a productive dialogue and foster a spirit of cooperation for the common good.
Despite the importance that other stakeholders play in administering REMS programs, we must also underscore that it is not appropriate to hold manufacturers responsible for the independent decisions or actions of third parties with respect to their drugs, even when those drugs are subject to REMS. The FDA, therefore, should not, as part of the REMS assessment process, hold sponsors accountable for these decisions and actions. There may, of course, be situations where a sponsor has information about third-party behavior. It is appropriate for REMS assessments to include whatever information is known to the sponsor about third-party decisions and behavior.
We hope that the draft guidance and future REMS guidances continue to identify common processes and best practices for agreeing upon REMS and appropriate risk management tools. We believe that as both the FDA and industry gain greater experience with the challenges and nuances of REMS, there will continue to be opportunities to share experience to refine and improve REMS-related processes and policies.
About The Author
Andrew Emmett is director for science and regulatory affairs at the Biotechnology Industry Organization (BIO). Mr. Emmett develops and implements strategic BIO responses to scientific and regulatory issues that affect the ability of BIO's human healthcare-focused companies to research and develop products and to bring these products to market.