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REMS: The New Reality

Kuyler Doyle, Principal Consultant, Campbell Alliance Jay Jauregui, Senior Practice Executive, Trade and Distribution Practice Gary Tyson, Senior Vice President, Clinical Development and Medical Affairs Practices

The Food and Drug Administration Amendments Act (FDAAA) of 2007 ushered in an increase in regulatory authority for drug safety enhancement, including the power to require post-approval studies or clinical trials, label changes, or implementation of a Risk Evaluation and Mitigation Strategy (REMS). Since implementation, the number of products requiring REMS programs has continued to rise. Pharmaceutical and biotechnology companies are realizing that the new restrictions from REMS programs are a permanent part of the industry landscape and that they must adapt accordingly. This article highlights the challenges of the new regulatory restrictions, lists potential competitive advantages to these programs, and describes how organizations need to adjust to the evolving risk mitigation landscape.

Table 1 – Modern Risk Minimization Tools
Dates of Activity

2003 to 2007 Steps to achieve specific goals and objectives to minimize product risks, while preserving benefits FDA Premarketing Risk Assessment, Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, and Development and Use of Risk Minimization Action Plans, 2005 (finalized) Suggested

2007 to present


Steps to ensure that the benefits of the drug outweigh the risks



Key Documentation

Food and Drug Administration Amendments Act (FDAAA), 2007

History of Risk Minimization Programs
Withdrawals of several high profile drugs from the market elevated concerns about pharmaceutical product safety and increased public scrutiny of FDA practices. In response, Title IX of the FDAAA amended the Federal Food, Drug, and Cosmetic Act (FDCA) to authorize the FDA Secretary to require a REMS program on any product, pre- or post-marketing, if deemed necessary to ensure that the benefits of the drug outweigh its risks. Although this increased regulatory authority appears to be a paradigm shift, drug risk management has evolved over the course of several decades. The original FDCA of 1938 allowed drugs to be marketed once proven to be safe. However, birth defects associated with thalidomide in Europe and Canada during the late 1950s and early 1960s led to the passage of the Kefauver-Harris Amendments in 1962, requiring companies to demonstrate efficacy in addition to safety in order to be marketed. Since then, the FDA process of approval has been founded on a favorable benefit to risk ratio.

Impact on Manufacturers Non-Compliance Penalties



Fines and Possible Injunction

Throughout the evolution of risk management, special programs were instituted on a case by case basis for specific drugs as deemed necessary. Early examples emphasized the communication of risks to stakeholders. Initially, prescribers were the primary target of this information in the form of product labels, “Dear Healthcare Provider” letters, or black box warnings. Subsequently, drug makers were required to educate patients regarding product risks, initially in the 1970s through patient package inserts (PPI) that were first implemented with oral contraceptives, and in the late 1990s with mandatory medication guides for select drugs that were distributed to patients at the time of dispensing and included information required for safe and effective use. The FDA implemented its first program that restricted drug access in 1990 with the “no blood, 1

no drug” campaign for clozapine that required a patient blood count to test for agranulocytosis prior to dispensing. In 1998, the FDA approved the use of the teratogenic drug thalidomide, the very product that led to the increased burden of proof for market approval, to relieve complications from leprosy. Drug manufacturer Celgene developed a strict program called the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.®) in which only registered physicians could prescribe the drug, and then for only one month intervals. Further, pharmacist registration was required to dispense the product, women of childbearing age had to undergo mandatory pregnancy tests, and both men and women had to adhere to birth control methods. Subsequently,

the FDA now has the ability to mandate these restrictions based on the powers provided in the FDAAA amendment. which are required to be completed by 18 months. number of reported adverse events. All REMS must include a timetable for submission of program assessments. although there are also distinct differences (Table 1). and in the 7th year. Programs such as S. In response. should minimize the burden on the health care system and should be compatible with current distribution system ETASU options: Prescribers must have training or certification Pharmacies. practitioners. and in 7th year after REMS approval FDA may increase frequency of assessments or eliminate requirements after 3 years Assessment within 15 days for cause Medication guides are distributed to patients when drug is dispensed Patient package inserts may be required if they might help mitigate serious risks of the drug Necessary when FDA determines a plan may support implementation of an element of REMS May be through letters to healthcare providers or through professional societies about drug risks and safety protocols ETASU need to be commensurate with risk Must be posted publicly within 30 days of being imposed with an explanation of how elements will mitigate risk Will not be unduly burdensome on patient access (due to life threatening diseases or difficulty accessing healthcare) To the extent practicable.S.E.000 per violation on manufacturers for non-compliance. the FDA examines risks for serious side effects. potential for misuse of the drug. including pre-licensure. review.P. Communication Plan to Healthcare Professionals Access Elements to Assure Safe Use (ETASU) Implementation System 2 . or due to safety concerns arising from new data from phase 4 studies or literature reviews.P. program continues to be in use. by 3 years. The goal of the RiskMAP was to elevate the appropriate use of products and to decrease adverse events. While RiskMAPs were voluntary. including multiple myeloma. including the education of patients and physicians and restricted access. and can impose fines of up to $250.T. Following the Prescription Drug User Fee Act (PDUFA) and attempts at shortened review cycles. or healthcare settings that dispense the drug must be certified Drug must be dispensed only in certain healthcare settings Drug is dispensed to patients only with documentation of safe-use conditions. there were concerns about the marketing of products prior to being fully vetted as safe. and whether off-label usage needs to be minimized. and published final guidance for its Risk Minimization Action Plan (RiskMAP) in 2005. Post-approval Table 3 – Elements of REMS Element Assessments Timetable for Submission of Assessments of the REMS Description Required of all REMS Assess by 18 months. In fact. a post approval study. 3 years. and post-market. and to work to improve implementation Medication Guide or PPI Education Components of REMS Programs A REMS can be required of any manufacturer in all stages of development. such as laboratory test results Patients must be subjected to monitoring Patients must enroll in a registry May by required to monitor and evaluate implementation of ETASU elements by those responsible. or peer reviewed literature Pre-approval thalidomide has been found to be effective for other indications as well. and the S. many of the post-marketing elements that define REMS programs also made up RiskMAPs.REMS: The New Reality Table 2 – Consideration Factors for REMS Requirement Market Stage Factors Size of the population likely to use the drug Seriousness of the disease Expected benefit of the drug with respect to disease Expected duration of treatment Seriousness of known or potential adverse events related to the drug Whether drug is a new molecular entity New safety information deems a strategy is necessary to ensure the benefits outweigh the risks “New safety information” may be derived from a clinical trial. The other REMS elements vary at a level commensurate to the risk anticipated by the FDA. and may consist of education-based mandates or elements to ensure safe use (ETASU)(Table 3). and severity of the indication to be treated (Table 2). Sixteen accepted RiskMAPs were carried over and deemed approved REMS when the FDAAA went into effect in March of 2008. During the drug review process. REMS may be requested of products that are already on the market due to reports of adverse events via post-marketing surveillance.S.E. To determine if a REMS is needed. the FDA will consider the amount of information known on the product or drug class in relation to the size of the target population. treatment length. an adverse event report. helped pave the way for the modern era of risk minimization.T. the FDA established a new risk management system with PDUFA III in 2002.

In its simplest form. prescriber training or certification. medication guides. Due to the tens of millions of prescriptions written for opioid drugs each year. As perceived risk with the drug increases. In February 2009. can be a burden on prescribers when they include a patient-physician agreement to sign. but is required to have the most severe form of REMS where access is controlled due to evidence of increased ischemic cardiovascular events. This power has been exercised for fluoroquinolone antimicrobials. access is increasingly restricted to patients. it can also mandate REMS for entire drug classes. and administer. so these data will have to be tracked and analyzed. The more rigorous the REMS program becomes. or the need for a communication plan to healthcare providers. The drug Entereg® (Adolor and GSK) facilitates healing following bowel resection. implement. While most REMS programs required thus far have fallen into the “minimal” category and nearly 75% have required only medication guides (Figure 2). Even the lightest REMS requirements.Figure 1 – Four Tiers of REMS Complexity Less Severe Minimal Timetable for submission of assessments Medication guides or patient package inserts Specific package insert language Periodic adverse events reports and continuous monitoring More Severe Low Communication plan to disseminate safety information to healthcare providers Educational material packages Patient acknowledgement forms (e. duration of therapy limits) Implementation systems Educational elements can contain requirements for medication guide outreach. REMS generally fall into one of four tiers in severity (Figure 1).. there are also clear and significant costs associated with these programs. scheduled REMS assessments require sponsors to reveal that their program is effective.. Not only does the FDA have the power to require REMS for individual products. requiring label changes and medication guides. Other classes of drugs discussed as possibly requiring REMS are the erythropoietins.™) program. the new regulatory authority provided to the FDA certainly poses challenges to drug manufacturers and can obviously impact the bottom line (Table 3). Registries will also necessitate budgeting for full time employees or contractors to design. PPI.g. 3 In addition to revenue impact from a delayed launch. hospitals) Regular audits of prescribers and dispense locations Complex Patient screening Patient enrollment into registries Patient record audits (e. Challenges of REMS Although an increased focus on drug safety is a positive advancement. medication guides to satisfy REMS requirements add substantial costs for production and dissemination. The manufacturers established the Entereg Access Support and Education (E.A. As the requirements for REMS programs are still relatively new.E. REMS programs may further require approval of an implementation system to monitor and evaluate ETASU execution. Further. The additional paperwork associated with REMS can dissuade physicians from prescribing the product. antidepressants. understanding of risk) Follow-up surveys to assess the educational program Advanced Certification and training of prescribers Certification and training of pharmacists and site-of-service staff Recertification and product release approval at each dispense Limited distribution to only registered sites of service (e. they add an additional layer of preparation and uncertainty into the regulatory process for new drugs. and will require expenditures for software to manage and track confidential data.g. and drug distribution limited to certified pharmacies or healthcare settings. likely shrinking volume in sales. REMS that include limits to distribution or duration of therapy can lead . REMS negotiations can assign additional time to the approval process and lead to costly launch delays. ETASU include access restrictions via patient testing or screening for eligibility. complex REMS have also been employed. Maintaining patient and physician registries is not a trivial feat. Based upon the severity of the requirements.S. tumor necrosis factor blockers. Further.g. patient registry and tracking. the FDA notified manufacturers of opioid drugs that a class-wide REMS was in development. Also. botulinum toxins. and anti-epileptics.. implementing a REMS for this drug class will be a massive undertaking. The assessments need to demonstrate whether the ETASU are meeting their goals. the complexity of the REMS elevates accordingly. which restricts drug dispensing to only registered hospitals and tracks the patient to limit the duration of therapy. Effective training programs may need to be developed and employed for healthcare providers.

and are frequently willing to accept some risk for the potential benefits. helping to maintain sales while potentially reducing the risks associated with improper use. thereby reducing sales Establish a knowledgeable and dedicated group that can design effective REMS programs with the stakeholders in mind to minimize burden 4 . At the same time. and add an additional layer to the approval process Can lead to delay of launch . patients and physicians.REMS: The New Reality Figure 2 – Profile of Accepted REMS Programs 100% 80% 60% 40% 20% 0% MG Only MG + CP MG + ETASU + IS MG + CP + ETASU + IS CP + ETASU + IS to a reduction in revenue. REMS programs allow organizations to establish relationships via registries with two key stakeholders. Patients with indications that have high unmet needs desperately want new medications. Up-to-date patient registries allow active monitoring of drug usage. Data obtained from FDA website November. the FDA is allowing these medications to move forward by making sure the practitioner and patient fully comprehend correct use of the product as well as possible outcomes. a clearer understanding of proper usage of the drug can lead to increased adherence. MG = Medication Guide ETASU = Elements to Assure Safe Use CP = Communication Plan IS = Implementation System Note: n=89. Potential Advantages When properly planned and executed. 2009 Table 3 – REMS Challenges Challenge Regulatory Uncertainty Description REMS requirements are relatively new. First. thereby reducing revenue How to Prepare Proactively plan for REMS and communicate with regulatory officials during development Plan REMS programs early enough to avoid approval delays Integrate REMS planning into the organization and design SOP around the activities that emphasize efficiencies Design REMS programs that specifically match program activities with drug risk to minimize scale of the program Costs Associated with REMS Programs REMS programs will increase costs Tracking patient information will require management software and full time employees Paperwork Can Dissuade Healthcare Providers from Prescribing Increased REMS complexity expands the requirements for healthcare providers to track patients. REMS programs can also offer some potential advantages (Table 4). through its mandated programs to improve drug safety. making the product less commercially attractive to the manufacturer. REMS has provided the ability for the FDA to approve products that likely would have never made it to market. In requiring both the patients and physicians to be well versed with the risks associated with the products. amplifying workload More work for prescribers can dissuade drug use.

Although many view REMS that limit distribution as measures to restrict access. Pre-submission interactions with the FDA will allow discussions of drug safety profiles that could inform product managers regarding needs for appropriate REMS requirements. REMS registries provide an opportunity for companies to establish a connection with patients through personalized interactions regarding adherence and safe use or by setting up web portals for peers who are undergoing the same treatment and who are looking for relevant information regarding their disease and therapy. and the generic manufacturer is unsuccessful in obtaining a license to use aspects of the ETASU. Manufacturers should pursue pre-submission interactions with regulatory officials during the development process to limit late surprises that could impede launch. Interestingly. and execution of REMS. patient registries also share many aspects in common with health management or support programs developed for some specialty drugs. or source of revenue through license agreements. and 5 . thereby increasing adherence Keep stakeholder needs in mind when developing REMS programs When done effectively. Organizations must assess the impact of REMS activities on all stakeholders when developing potential REMS programs. A well designed REMS registry and information network can be an effective means of brand differentiation and could. thereby delaying entry into the market. and a novel REMS program could remain a barrier to entry.Table 4 – Potential REMS Advantages Advantage Ability to Market Drugs with Some Safety Risk Description REMS provides ability for FDA to approve products that likely would not have made it to market Requires patients and physicians to be fully aware of the drug and its risks How to Benefit Provides a means to fulfill unmet needs in the market Clearer understanding of safe use of the drug could lower risk and maximize benefit. When carried out effectively. as they may find the space less attractive due to the complex and costly programs. The formation of a knowledgeable and dedicated group to design effective and innovative REMS could afford organizations the ability to develop programs that set the bar for a drug class. organizations need to adopt a proactive outlook toward risk mitigation rather than a reactive one. the pursuit of novel programs that benefit patients and physicians while minimizing the paperwork burden could be beneficial. In a time when therapeutic areas are becoming increasingly crowded. How to Adapt Although Title IX of the FDAAA provides authority to ensure post-market drug safety. pharmaceutical companies need to alter their outlook. the new competitor must use a single. As REMS requirements could potentially be used for competitive advantages. such as patient screening algorithms. depending on the level of unmet need. This requires generic manufacturers to work with the innovator companies to establish the single system. Outlook To minimize the possibility of regulatory delays due to REMS negotiations. Further. these programs can build communities that foster brand loyalty. patients and physicians have options for their product of choice. Distinguishing factors within REMS programs will also come into play when class-wide REMS are required. there is likely to be increasingly less uncertainty surrounding the need for REMS requirements for new drugs. point of market differentiation. or request a waiver for this requirement if the burden of creating it outweighs the benefits. they could also in effect increase the lifecycle of a drug. can provide positive impact on the brand and the drug manufacturer Ability to Establish Relationships with Stakeholders REMS requirements for registration or training of patients and physicians provides an opportunity to establish a relationship with key stakeholders Complex REMS Could Lengthen Life Cycle Generic entrants are required to establish a single shared REMS system for ETASU unless burdensome or patented Access restrictions could make it difficult for generic manufacturers to obtain product for equivalency testing Develop a novel. as already seen with Celgene’s Revlimid®. preparation. and adverse events. Some companies have already filed patents for elements of their risk mitigation programs. Restrictive REMS hold the potential to stave off generic competition. The FDAAA states that upon generic entry. companies will be required to take a close look at safety issues earlier in the development process. As such. the limited product distribution imposed by REMS can make it difficult for generic competitors to acquire the drug in order to perform the comparative evaluations required for the abbreviated approval process. shared system of ETASU with the originator product. To adjust to the emerging risk mitigation environment. potentially allow for premium pricing to offset the costs of the program. Another potential to waive the single system requirement comes if the innovator company has active patents related to their novel risk mitigation plans. distinguishing REMS program that contains unique components with potential for intellectual property adherence.

planning. Analysis of FDA actions related to the prior negotiation and approval of REMS programs will help to plan proposals for pipeline products.REMS: The New Reality Preparation Since the development and negotiation of REMS programs can require a considerable amount of time. thereby keeping the scope of the program in check to control costs. the manufacturer should assume they will need a REMS program. Planning ahead will help alleviate the challenges associated with late stage design and negotiation of a complex REMS. sales.campbellalliance. This white paper is being offered as a background article in preparation for the public release in early 2010 of Campbell Alliance’s survey results regarding the “State of REMS Today. regulatory. companies will be able to capitalize on potential competitive advantages of a well-designed REMS.” The survey will provide a snapshot of how companies across the industry are currently planning and executing REMS programs. safety. A full appreciation of the impact of REMS requirements on key stakeholders is critical to the generation of programs to reduce risk while remaining commercially viable. Gary Tyson gtyson@campbellalliance. and vender partners must be established. To set up a time for us to share the results of this research. and implementation of programs. If clinical trials suggest that there may be some safety issues that the FDA will scrutinize. despite the associated challenges. be involved in REMS scenario planning for new products. organizations must also improve the ability to assess. Comprehension of the potential REMS triggers. Although committees that develop REMS programs will be cross-functional in nature. Through establishment of skill sets needed to understand and generate effective REMS programs. plan. Companies must accept this reality and adjust their organizations accordingly. companies need to initiate preparation for a REMS proposal early in new product planning. and early planning will help alleviate some of the challenges posed by a complex REMS and will help avoid costly delays to drug approval. marketing. and medical affairs functions need to Conclusion REMS is clearly part of the new landscape of the pharmaceutical industry. distribution. a permanent “home” for the management of activities must be established within the organization and a standard operating procedure (SOP) developed. a requirement to make REMS execution an efficient process. and implement programs by integrating them into the company DNA and making them part of a new routine. Marketing will need to determine how a proposed REMS program would likely affect the revenue forecast and commercial viability of a product. Note Execution As REMS programs appear to be a part of the permanent regulatory process. Efficiencies in REMS design and execution will further help provide credibility to the FDA that can facilitate future program negotiations and minimize costly delays. A means to monitor REMS effectiveness must also be generated. Companies must also define REMS activities that will be performed in-house versus outsourced. Clearly the clinical. including the ability for sales and medical affairs field teams to report back on prescriber sentiments towards requirements. Companies need to integrate REMS development as a permanent part of the organization and work to create a SOP that will allow for best practice development in the www. the program approval process. please contact Gary (888) 297-2001 6 . Inclusive discussions with internal stakeholders to define the SOP will define roles and responsibilities for REMS development and facilitate buy-in to the protocol. REMS should be designed to match associated risks of the drug with specific activities.