Heather Morel

The FDAA Act of 2007 empowered the FDA to require Risk Evaluation and Mitigation Strategies (REMS) for new and existing pharmaceutical products. After the first programs were introduced in 2008, REMS have now become an established part of the pharmaceutical landscape. As of February 2010, FDA has approved 93 REMS programs in therapeutic areas ranging from cancer, analgesia, infection, and even single use bowel preparation products for colorectal procedures. It seems that no therapeutic area—whether its primary care or specialty, chronic or single dose treatments&mdash;will be untouched by REMS. 

While almost 90% of these REMS have required only a healthcare professional communication plan and patient medications guide, some REMS require ETASUs (Elements to Assure Safe Use). These elements are far more interventional in nature and include components such as prescriber or patient registration, controlled distribution, and other tools. Although all REMS have the potential to improve safety, programs with ETASUs are most likely to have unintended consequences on healthcare stakeholders. 

	In recent months, many healthcare stakeholders have expressed concern over REMS. The American Pain Society, Kaiser Permanente, and American Society of Community Oncology have all made recommendations on how REMS could be implemented in order to minimize the impact on healthcare providers and patients. “We run the risk of serious unintended consequences to people living with chronic pain in the effort to prevent misuse and abuse of these important medications. It would be of great concern if the REMS led healthcare providers to prescribe drugs not encumbered by the REMS,” wrote Dr Sid Schnoll, Clinical Professor, Medical College of Virginia, Virginia Commonwealth University, in a recent Medical News article on the planned class-wide opioid REMS. 

Kaiser Permanente filed a Citizen’s Petition on December 22, 2009, asking FDA to seek public input from patients or healthcare providers before implementing REMS. Kaiser is concerned that REMS with ETASUs may increase burden on healthcare providers and drive up costs, resulting in avoidance of essential drug use. 

	FDA explicitly states in its guidance document (August 2009) that the agency seeks to avoid what they term “unintended consequences” of REMS programs in their quest for improving drug safety. Nevertheless, FDA is not involved in designing the details of REMS processes—this responsibility falls on the pharmaceutical industry and biotech manufacturers who must ensure execution of their REMS while trying minimize the unintentional impact on stakeholders and access. Also, FDA does not usually have any direct regulatory interaction over many of the stakeholders (e.g., pharmacies) that are directly affected by REMS programs. 

Stakeholders have identified some key, unintended outcomes resulting from REMS: 

“Squeezing” or restricting drug use with a REMS for certain products results in expanded prescribing of alternate, less desirable agents—also known as the “balloon effect.” 

Impeding patient access to medications by adding additional steps or limited distribution. For example, a pharmacy may need to verify that a prescriber is registered in a REMS database thus increasing the number of patients who do not initiate or lapse on therapy. 

Increased, uncompensated costs to healthcare providers in meeting REMS requirements, such as added paperwork or additional counseling. 

Altering the efficient existing workflow with REMS requirements and imposing additional reporting requirements, or recordkeeping for audit purposes. 

	The goal of pharmaceutical manufacturers of REMS programs should be to preserve safety goals without creating obstacles or excess work for healthcare providers. In order to accomplish this goal, manufacturers should view REMS from the user’s viewpoint—what is the usual flow of practice activities? Where, when, and how are decisions about therapy made? How and when do patients access medications? What processes of automation and technology are used and could be leveraged by a REMS system? The order and types of processes employed may differ in various healthcare settings. 

	Stakeholder workflow is not a factor independent of the actual number or type of additional restrictions or steps required by a REMS—rather, it is a measure of how much the REMS requirements force deviation from the usual routine and systems that the healthcare provider typically uses. For example, a REMS program that requires a pharmacist to access Web-based systems, as opposed to their usual pharmacy dispensing system has a negative impact on stakeholder workflow. In other cases, a physician who does not use electronic medical records (EMR) for patients at all may paradoxically find a paper-based system is less intrusive, since it integrates into existing workflow. For the same reasons, healthcare providers find that there are coordination and tracking challenges if REMS programs require recordkeeping or tracking of patients outside of their usual processes. Therefore, manufacturers should consider the various steps that occur in a REMS from the decision to prescribe a medication to the point-of-dispensing and examine the potential obstacles and solutions for each. A brief analysis follows. 

	In some REMS programs, pharmaceutical and biotech manufacturers must implement educational programs, which provide prescribing physicians with information on the risks of the product prior to ever starting any patients on therapy. These educational interventions often have a knowledge test that a potential prescriber must periodically complete and pass prior to be a verified and eligible prescriber. This educational process has happened for decades but never before has FDA and, by extension, the manufacturer been as prescriptive as to how, when, and in what exact format the education must take place. The workflow of pre-prescribing has been disrupted, though in this case, it is likely the intention of FDA to have risk information accepted and attested to by providers prior to prescribing.

	In general, pre-prescribing education is a one-time event in a REMS program; so healthcare providers find this to be one of the less cumbersome elements. Nevertheless, there are ways of improving the interaction:

	• Ensure a smooth, high-quality process with clear, transparent communication around the expectations, feedback, steps in the process as well multiple options for providers.

	• Technology may be useful in helping prescribers keep track of their enrollment status. Since programs require periodic re-certification over time and prescribers will enroll in multiple programs, the technological solutions that allow practices to track of multiple registrations will be helpful.

	Once the pre-prescribing stages of REMS are complete, a provider begins selecting patients based on the balance of potential benefit and risks. With REMS programs, there are new steps required at therapy initiation to ensure that patients have adequate information about the risks of the product. These educational discussions have been ongoing between physicians and other clinical providers for years but now FDA has once again become prescriptive and focused on consistent, documented delivery of risk messages.

	• The concept of “certified counseling” is something that is being explored with pharmaceutical manufacturers. Clearly, the prescriber must be involved in risk conversations, but may be able to permit staff that has been trained on the specific REMS elements to assist. These conversations may be possible by phone. While FDA has, in our experience, not always been supportive of interactive voice response (IVR) systems, we believe that a well-designed system can attain safety goals and remove some of the more repetitive elements of risk communication with patients. One must also recognize that while the written information in medication guides is relatively easy to develop, REMS programs often require that the prescriber ensures that the patient reviews and attests to understanding its content — often a more involved process than it sounds. Focusing on ensuring patient comprehension is key.

3. PATIENT THERAPY MAINTENANCE AND FOLLOW-UP 

	Providers must now work with their patients to comply with ETASUs that are required on an ongoing basis. Various data may need to be provided to the manufacturers, or specific diagnostic and therapeutic interventions completed based on evaluations of patients’ status, examination, and test results. Patients may need to comply with periodic clinical counseling calls to understand and detect risk signals in the population and provide opportunities for early intervention.

	More than any other area, integration with existing healthcare-provider systems offers an opportunity to make REMS programs easier in patient therapy and follow-up:

	• Physicians—Many community practices have yet to adopt EMR, e-prescribing, or electronic connectivity for laboratory and other test results. However, EMR has the potential to allow automation of many ETASUs, such as prescriber or patient enrollments. The marketplace will await REMS specific applications that are embedded in EMRs.

	• Pharmacies—Unlike physicians, all pharmacies are connected and routinely use electronic systems to manage their own workflow, patient records, and connectivity with payers. Furthermore, multiple pharmacies, whatever their location, are linked to payers through nationwide switch systems. As a result, during dispensing of prescriptions, it is relatively easy and non-disruptive to introduce REMS controls that allow pharmacists to obtain online verification of the eligibility of prescribers, which is fully integrated into routine pharmacist workflow. REMS providers, including McKesson Relay Health, are developing this approach for high-volume, retail-pharmacy dispensed drugs.

	• Wholesalers—Electronic exchange of information has been used for a variety of purposes in the wholesaling industry. Verification of REMS requirements (like registration status of a clinic, hospital, or physician office) can occur electronically, limiting the impact on the typical workflow for a distributer. 

REMS usability is a key element to success

	As REMS become more common in the near future, pharmaceutical and biotechnology companies must invest in developing internal expertise in the forecasting for REMS, design of REMS, program management, and change processes. Unfortunately, the penalty is high for pharmaceutical companies that do not take this approach. The biggest fear that pharmaceutical manufacturers have regarding REMS programs is the potential to limit or shrink their franchise. A REMS program that neglects to consider usability in the hands of healthcare providers and stakeholders incurs this risk. 

Other trends that pharmaceutical manufacturers should consider are: 

• Healthcare providers and patients want the FDA to develop a more transparent process to disseminate the data and lessons from existing REMS programs. Their rationale is that FDA needs to give more timely feedback on success and failures, in order to react and rapidly process iterative improvements, or even eliminate certain REMS programs or components if no incremental benefit is observed.

	• Pharmaceutical manufacturers need to go wide and deep to obtain an in-depth perspective from providers that will be affected. The challenge for industry is to balance the feedback from providers with the need to create a program that FDA will approve. While pharmaceutical manufacturers are accountable to FDA, they must constantly focus on usability to ensure success. PC 

Articles

REMS programs need to address stakeholder usability

Smoothing the Path to Drug Safety

	The advent of the Risk Evaluation and Mitigation Strategies (REMS) era has fundamentally changed the way many new drugs are launched and safety risks are monitored post-launch. Successful design and implementation of complex REMS programs requires pharmaceutical and biotechnology manufacturers to approach commercialization with uncharted processes and considerations. Planning early for a possible REMS mandate, bringing together key internal stakeholders, securing an experienced vendor to implement the REMS, and seeking ways to realize efficiencies by linking safety and reimbursement programs are all critical factors that influence commercialization strategies and ultimately, REMS program success.

	While the vast majority of REMS programs approved in 2008 required only the distribution of a medication guide and assessing patients’ receipt and understanding of the guide, a shift in program complexity is occurring. Many REMS currently in development are more stringent than their predecessors, and several include Elements to Assure Safe Use (ETASU). All REMS programs are designed to manage a known and potentially serious risk associated with a drug or biologic, but those programs involving ETASU are the most complex and may involve physician certification, patient enrollment, ongoing collection of patient data and controlled distribution. These programs impact commercialization most significantly and have far reaching implications for the way drugs reach hospitals, physician offices, pharmacies and patients.

	What should a manufacturer do to prepare for a possible REMS mandate?

	Anticipating the likelihood of a REMS mandate and the potential scope of the program is an important first step in the planning process.

	Although the first REMS were mandated by the Food and Drug Administration (FDA) just 16 months ago, early trends, patterns and indicators have emerged. In 2008, two-thirds of new biologic [1] and specialty drug [2] approvals were required to have a REMS as part of their commercialization plan. In addition, drugs with certain risk profiles are more likely to have a REMS than those with less-serious potential side effects. Several drugs with risks related to teratogenicity, cardiac problems, hematologic risks, liver dysfunction and new or worsened malignancies have required a REMS program. Products that treat serious or life-threatening diseases or those that meet a previously unmet medical need may also have an increased likelihood of requiring a risk management plan. Further, commercialized drugs and biologics with emergent adverse-event data accounted for almost 50% of REMS approved last year—a further indication that any drug is subject to REMS if the risk profile is deemed significant.[3] Manufacturers should look closely at such trends and make early determinations about the probability of a REMS mandate for their pipeline agents.

	Getting the right people “around the table” for planning and development is critical.

	When the first complex REMS programs were mandated in early 2008, manufacturers were entering entirely new territory and were faced with many critical questions. How will REMS impact our existing commercialization strategy? How should we organize internally for success? What departments should be involved, and what role does each play? While many manufacturers continue to struggle with these questions upon learning that the FDA has mandated a REMS for their product, others have begun to organize for REMS success by implementing various organizational strategies.

	When unexpectedly faced with a REMS involving patient enrollment, physician enrollment, institution enrollment and controlled distribution in 2008, a biologic manufacturer approached McKesson to help design the program, prepare required supporting documents for the FDA, assist with conversations with the FDA and implement the program. While McKesson was preparing to operationalize the REMS, the manufacturer began to organize internally to not only meet the needs that this REMS required, but to establish enterprise-wide processes and designate personnel who would be accountable for preparing REMS for their pipeline products, should it become necessary.

	A lesson quickly learned during this process was that a cross-functional team to assist with the development and ongoing support of a REMS must be assembled, and representatives from regulatory, legal, brand, managed markets, technology, training, distribution and clinical research must have a seat at the REMS table. Further, gaining commitment from all levels of the organization to support the REMS was important to facilitate program design and the development of commercialization strategies.

	For manufacturers with pipeline products whose risk profiles suggest the likelihood of a REMS, creating a dedicated team to manage existing and future risk management programs may make sense. Regardless of the approach or structure, past lessons have shown that effective internal organization and resourcing for REMS are key factors for commercialization success.

	Developing a risk management plan before mandated by the FDA may be a wise strategy.

	As REMS become more common and manufacturers face the possibility of several months of drug launch delays when notified of an unexpected REMS requirement, many are planning early and preparing a risk management plan as an “insurance policy” in the event that the FDA requires it at the time of launch or post-commercialization. In some cases, organizations are implementing risk management programs at the time of launch, regardless of whether the FDA mandates it, to ensure patient safety and avoid preventable adverse events.

	Planning early and developing a risk management plan prior to New Drug Application (NDA) submission allows manufacturers the time needed to consider the impact REMS would have on commercialization and prepare strategies to effectively balance risk and access. This approach also affords the opportunity to organize internally and create a cross-functional team to support risk management activities, as well as prepare a timeline and budget to support the REMS

	Partnering with an experienced vendor that has implemented and managed complex REMS and can support all components of the program is highly beneficial.

	No two REMS programs are alike. Each approved REMS has a unique design and methodology for meeting FDA requirements, just as the drugs they support have distinct risk profiles that must be effectively managed. As Fig. 1 demonstrates, a REMS can be as restrictive as a controlled distribution model with patient, physician and institution enrollment and the ongoing collection of patient data or as simple as the distribution of a medication guide.

	Determining whether the REMS will be designed and managed in-house or whether the organization will outsource the REMS to a vendor is one of the most important decisions a manufacturer must make. Although a small number of pharmaceutical and biologic manufacturers are organized to manage less restrictive REMS programs in-house, the vast majority are not structured to manage the more complex components often required by the FDA. Further, while a REMS may start with the straightforward distribution of medication guide, the requirements of the program could potentially expand if new risk or adverse-event data emerge or if the program is not meeting its goals.

	When outsourcing the development and implementation of a REMS, manufacturers must carefully select the most appropriate vendor to manage the programs’ unique requirements. A careful evaluation of potential partners’ capabilities and experience is critical. Fig. 2 highlights the most important questions manufacturers should consider when selecting a REMS vendor.

Step 5: Linking REMS and Reimbursement Programs

	Evaluating opportunities to link safety and access programs may help ease the burden on physician offices and create cost efficiencies.

	One of the primary concerns associated with REMS programs is the additional work required of physician offices. Physician enrollment in REMS programs and completion of the required physician certifications or trainings takes time away from patients and creates a hurdle for appropriate drug adoption. Manufacturers can ease the burden on physicians by integrating REMS and reimbursement initiatives.

	As described, biologics and specialty drugs are the most likely REMS candidates. Due to these products’ high costs and out-of-pocket spending requirements, patients taking these drugs are most in need of reimbursement assistance. Typically, the burden is on the physician’s office to seek and obtain prior authorizations, benefits approval and reimbursement assistance for their patients. If these same physicians are also required to enroll in a REMS for the same drug, manufacturers can create a single point of contact through which both reimbursement and REMS needs can be managed simultaneously. This approach helps minimize the administrative workload required for physician practices to safely prescribe, administer and obtain reimbursement on behalf of the patient. Selecting a vendor that has experience managing both REMS and reimbursement programs may also create process and cost efficiencies for manufacturers by leveraging a single framework and system to manage both programs.

	REMS are perhaps the most significant change to U.S. drug regulation in many years. With risk management plans becoming more common and complex, planning early for a possible REMS mandate has never been more critical as manufacturers are facing significant and costly drug launch delays if unprepared. Bringing together key stakeholders within the organization throughout the program development phase and gaining support from all levels of the organization is crucial. Creating a single point-of-contact for both REMS and reimbursement programs can help minimize the burden on physicians’ offices and potentially increase adoption of the product. Manufacturers should also carefully select a vendor with broad assets and proven capabilities to help guide them through the program design and FDA submission process, as well as implement the spectrum of program components. REMS is here to stay, and now is the time to embrace risk management planning as an integral part of the commercialization process. PC

	1 Smith, L. “The REMS Report Card: FDA Using New Tools for One-Third of New Drugs in First Six Months,” The Pink Sheet, November 10, 2008.

	Heather Morel is VP and GM of Reimbursement & Access Services for McKesson Specialty Care Solutions, a business unit of McKesson. She leads the development and execution of reimbursement strategies and support services, patient assistance programs (PAPs), REMS programs and other patient- and physician-focused initiatives. With more than 18 years of experience in healthcare reimbursement and marketing, Morel is a nationally recognized expert in developing reimbursement strategies for pharmaceutical, biotechnology, medical device and diagnostic firms. Morel earned a bachelor’s degree in political science from Pennsylvania State University and an MBA from Arizona State University.

	Regina Murphy manages McKesson Specialty Care Solutions’ Risk Evaluation and Mitigation Strategies (REMS) program offering for pharmaceutical and biologic manufacturers. Murphy is responsible for initiating and directing external strategic partnerships, as well as for developing internal collaborations to support REMS solutions. Previously, she worked at McKesson on reimbursement strategies, was a project manager at Boston University’s School of Public Health, and an associate at Medimetrix Consulting. Murphy received her bachelor’s degree from Yale University and her MBA in Health Care Management from Boston University.

Five steps to take when the duty for developing Risk Evaluation and Mitigation Strategies (REMS) is imposed on commercial operations