Lawrence Grylack, MD

The Food and Drug Administration Amendments Act (FDAAA) of 2007 provided new regulatory authority to require sponsors to develop and comply with risk evaluation and mitigation strategies (REMS). The REMS requirements in FDAAA built on previous experience with risk management programs and the Guidance for Industry—Development and Use of Risk Minimization Action Plans (March 2005). 

Determinations about a REMS requirement are made jointly by the Office of New Drugs (OND) and the Office of Surveillance and Epidemiology (OSE). The factors that the FDA considers (mandated by FDAAA) for requiring a REMS include: target population in terms of seriousness of disease and numbers of patients likely to use the product; whether the product is a new molecular entity (NME); the expected benefit and duration of treatment; and the potential seriousness of the documented or potential adverse events associated with the use of the product. Additional safety considerations in determining a REMS requirement include the potential reversibility of the adverse event, and whether this risk can be managed adequately through a defined intervention. Although the FDA evaluates products on a singular basis, they have been more likely to request a REMS for a product that is within a class of products that are recognized to have a common risk (e.g., extended release, long-acting opioids). On the other hand, the FDA has not been granted the authority to require one REMS for a specific drug class.

The potential timing for REMS submissions are during the pre-approval and the post-approval periods. During the pre-approval period, a REMS may be submitted prospectively on the part of a sponsor, or upon request by the FDA. In the latter situation, a formal notification will be sent to the sponsor, which should include rationale for submitting the REMS and the timeframe for submission. Sponsors are encouraged to submit the REMS as early in the review process as possible, so as not to take the risk of delay of approval and marketing. Also, early submission allows for adequate time for modification, if necessary. Keep in mind that the FDA has the authority to prevent marketing if an approved REMS does not exist. Specifically, issuance of a Complete Response letter will be done if the proposed or requested REMS has not been submitted and approved. The post-approval REMS requirement is similar to other post-marketing safety requirements. If new safety information becomes available, then the FDA may require a REMS to be submitted and approved. Otherwise the same criteria that are used by the FDA to make this determination in pre-approval are applied in the post-approval period.

 One hundred and fifty REMS have been approved as of October 13, 2010. These have been for products that were the focus of both New Drug Applications (NDAs) as well as Biologic License Applications (BLAs). Approximately two-thirds of the approved REMS contain only a medication guide. The remainder required additional elements such as elements to assure safe use (ETASU), communication plan and implementation system. Less than 25% of the REMS have a communication plan as the primary element, and less than 10% have the ETASU as the primary element. Despite these other elements being required, rarely was a medication guide not required. Associated with the FDAAA legislation, approximately 300 post-marketing requirements have been issued. In addition, approximately 40 label changes have been recommended. These have typically been recommended for classes of products. REMS may also be modified, and between 10% and 15% have undergone revision.  

Based on the experience to date, the FDA has recognized that it still faces ongoing challenges in terms of meeting its goals in the REMS arena. Although the FDA is bound by the statutory requirements that exist with regard to REMS, evolution of process and policy is still ongoing. With regard to process, continued evaluation of what criteria are being used to request a REMS, and what elements are required in the REMS continues to be evaluated, both for the pre-and post-approval periods. Furthermore, integrating the REMS process into the basic PDUFA review timeline is a challenge, and the discussion of a REMS within the primary review division may not be a priority and not occur until late in the review process.

 From a REMS assessment perspective, there are no well-defined criteria for determining whether a REMS is meeting its stated objectives and goals, and no formal guidance exists to address REMS assessments. A draft guidance was issued in September 2009 on the format and content of proposed REMS, REMS assessments, and proposed modifications. The docket was open to comment until the end of August of this year and the comments are currently under review.  

As would be expected, there has been response to REMS requirements from various individual sponsors, healthcare practitioners, consumers, product dispensers (e.g. pharmacists) and organizations representing these various stakeholders. A public meeting was held at the FDA during July of this year for the purpose of allowing these stakeholders to express their views and have the FDA representatives respond. Some of the main issues that were raised at the meeting included:  

 Increasing the number and variety of REMS with different requirements makes it difficult for the sponsor to make decisions on whether to submit a REMS prospectively.
 

Writing, submitting, implementing a REMS creates a disruption in the standard processes and timelines for the sponsor.
 

Lack of financial compensation for compliance with REMS requirements.
 

Stakeholders, other than the sponsors, feel that they should have more prospective input to the REMS process, rather than being told what they need to do once the REMS has been instituted. One of the impediments is confidentiality of information that has yet to be reviewed by the FDA. 
 

Claims that REMS exert an adverse influence on patient access to the product (e.g. delay in treatment and lack of participation by product prescribers and dispensers due to increased burdens of time, work and financial expense).

 In summary, the REMS era is well underway, with many being submitted and approved. Experience to date has provided some insight to the criteria for submitting a REMS, and the elements required. The experience has also elicited feedback from various non-governmental stakeholders, and further definition and guidance on various aspects of REMS is ongoing within the FDA. 

Following are recommendations for sponsors to consider:

  Determine the need for a REMS early in the review process.
 

  Look at precedent (e.g., for class of product in terms of potential for abuse, misuse, overdose, addiction, or teratogenicity)
 

 Take other factors into consideration such as: expected duration of treatment, seriousness and frequency of known or potential adverse events, whether the risk has been fully characterized, and the reversibility of the adverse event.
 

 Support the REMS plan with Phase III trial data if available.
 

 Test aspects of the REMS plan pre-approval in order to make implementation as time- and cost-efficient as possible
 

Note: Dr. Grylack, Principal Consultant, PAREXEL Consulting, served as Medical Officer in the Division of Pediatric Drug Development in the Office of Counterterrorism and Pediatric Drug Development, and the Division of Pulmonary and Allergy Drug Products at the FDA Center for Drug Evaluation and Research (CDER).

Lawrence Grylack, MD

Articles

Regulatory Update on Risk Evaluation and Mitigation Strategies (REMS)