Are You Ready for REMS (Risk Evaluation Mitigation Strategies)? Practical Recommendations for Managed Care An Overview for Pain Management

Transcription

1 Are You Ready for REMS (Risk Evaluation Mitigation Strategies)? Practical Recommendations for Managed Care An Overview for Pain Management Managed Care Policy and Processes for the Effective Implementation of a REMS Introduction On September 27, 2007, the President of the United States signed into law the Food and Drug Administration Amendments Act of 2007 (FDAAA). Within this statute was a new section of the Federal Food, Drug, and Cosmetic Act (FDCA) which authorizes the Food and Drug Administration (FDA) to require pharmaceutical manufacturers to submit a Risk Evaluation and Mitigation Strategy (REMS) if the FDA determines that a REMS is necessary to ensure that the benefits of a drug outweigh the risks of the drug. This applies to new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs). The law also authorizes the FDA to require a post approval REMS for products that did not initially require a REMS if new safety data suggest that a REMS is necessary to ensure that continued benefits of the drug outweigh the potential risks. In this case, once the holder of the approved covered application is notified by the FDA that a REMS is necessary, the holder must submit a proposed REMS within 120 days. A manufacturer may also voluntarily submit a proposed REMS without having been required to do so by the FDA if the manufacturer believes a REMS would help ensure the benefit of the product, while minimizing risks. 1 Prior to the FDAAA, the FDA utilized risk minimization action plans (RiskMAPs) for a small number of drug and biological products. The objective was similar to the later REMS, which was to minimize known risks of a product while preserving its benefits. For the majority of products, labeling and routine reporting requirements were sufficient. However, for this small group of drugs, RiskMAPs were required upon FDA approval. Subsequent to the FDAAA,

2 products that would have previously been approved with a RiskMAP are now approved with a REMS if requirements for a REMS are met. RiskMAP guidance currently only applies to products with existing RiskMAPs or to ANDAs for which the reference listed drug has a RiskMAP. 1 REMS include many potential components. Examples of strategies for managing risks associated with potentially harmful drugs include Medication Guides, patient package inserts, communication plans for healthcare professionals, and elements to assure safe use (ETASU). ETASU can include special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and use of patient registries. Implementation systems (eg, maintenance of a database of all certified pharmacies or prescribers) may also be requirements of ETASU. 1 The FDA requires Medication Guides (known as Med Guides ) and/or patient package inserts for prescription products when the agency determines that 2 : The drug is one for which patient labeling could help prevent serious adverse events The drug has serious risks relative to benefits that could affect a patient s decision to use, or continue to use, the product The instructions in the document are necessary to ensure the effective use of the product. Medication Guides are paper handouts developed by pharmaceutical manufacturers and approved by the FDA. Med Guides address issues that are specific to particular drugs and drug classes and they contain FDA approved information that can help patients avoid serious adverse events. Specific information must be included in Med Guides and a standard format must be followed. Appendix A lists the Code of Federal Regulations that pertains to Medication Guides. 3 2

3 Nearly every REMS requires the creation and distribution of a Med Guide. The FDA normally requires that the Med Guide be distributed to patients each time the medication is dispensed even in the inpatient setting. 1 New guidance (in draft form) concerning enforcement of Medication Guides was provided in February 2011, and is summarized as 2 : Inpatient Setting Outpatient when dispensed to healthcare professional for administration to patient (eg, clinic, infusion center) Outpatient when dispensed directly to patient or caregiver (eg, retail pharmacy, hospital ambulatory pharmacy) Patient or Patient s Agent Requests Medication Guide Must dispense Medication Guide Must dispense Medication Guide Must dispense Medication Guide Medication Guide Distributed Each Time Drug Dispensed FDA intends to exercise enforcement discretion; Medication Guide need not be dispensed FDA intends to exercise enforcement discretion; Medication Guide need not be dispensed Must dispense Medication Guide Medication Guide Distributed at Time of First Dispensing FDA intends to exercise enforcement discretion; Medication Guide need not be dispensed Must dispense Medication Guide Must dispense Medication Guide Medication Guide Distributed When Medication Guide Materially Changed FDA intends to exercise enforcement discretion; Medication Guide need not be dispensed Must dispense Medication Guide Must dispense Medication Guide A REMS may include a risk communication plan for healthcare providers. The communication plan may consist of "Dear Healthcare Provider" or "Dear Pharmacist" letters along with other outreach mechanisms, including dissemination of information through professional societies. A communication plan is the primary element of about 25% of FDA approved REMS programs, and "Dear Healthcare Professional" and "Dear Pharmacist" letters are the most common components of such plans. Twenty six REMS include specific elements to assure safe use, or ETASU, which can require healthcare professionals, including pharmacists, to complete special training before obtaining, prescribing, or dispensing the drug. Some of these REMS also involve a restricted distribution network. The FDA has statutory authority to require a so called implementation system for 3

4 ETASU to ensure that pharmacists and other healthcare providers are complying with those elements. 4 ETASU may include one or more of the following 5 : Healthcare providers who prescribe the drug are required to have particular training or experience, or special certification Pharmacies, practitioners, or healthcare settings that dispense the drug must be specially certified The drug can only be dispensed in certain healthcare settings (eg, hospitals) The drug may only be dispensed to patients with evidence of safe use conditions, such as certain laboratory test results Each patient using the drug is subject to monitoring Each patient using the drug is enrolled in a registry Approximately one third of the new molecular entities (NMEs) and biological products approved by the FDA since the beginning of 2010 have required a REMS to fulfill the agency's requirements for marketing the product. Through June 2010, the FDA approved a total of 51 new or revised REMS, most of which consisted of a printed Medication Guide, either alone or with other REMS components, according to data on the agency's Web site. Some also included a communication plan and fewer also included ETASU. Of those 51 REMS, 7 were for NMEs approved since the start of In all, the FDA has approved REMS for nearly 130 products since the provisions for the risk management programs went into effect in For a complete list, see 6 : forpatientsandproviders/ucm htm 4

5 Impact on Opioids and Pain Management The FDA sent letters to manufacturers of certain opioid drug products on February 6, 2009, indicating that these drugs would be required to have a REMS. The affected products included long acting and extended release brand and generic products with the active ingredients fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. 7 This list was updated on May 13, 2011, to also include buprenorphine. For the opioid products required to have a REMS, refer to Table According to the FDA, opioid drugs have a benefit for certain patients when used appropriately and are a necessary component of pain management. However, they have serious risks when used inappropriately. Prior to REMS, the FDA, drug manufacturers, and others took steps to prevent misuse and abuse of opioids. These actions included additional warnings in product labeling and extra communications to prescribers and patients. Despite these efforts, the misuse and abuse of opioids continue to rise. It is the belief of the FDA that REMS for opioids will reduce the risks of misuse and abuse while ensuring that patients with legitimate needs for pain management continue to have appropriate access to medications. 7 Table 1. Long acting and Extended release Opioid Products Required to Have REMS. 8 9 Brand Name Products Trade Name Generic Name Applicant/Sponsors 1 Duragesic Fentanyl Transdermal System Ortho McNeil Janssen 2 Palladone * Hydromorphone Hydrochloride Extended release Capsules Purdue Pharma 3 Dolophine Methadone Hydrochloride Tablets Roxane Laboratories 4 Avinza Morphine Sulfate Extended release Capsules King Pharmaceuticals 5 Kadian Capsules Morphine Sulfate Extended release Capsules Actavis 6 MS Contin Morphine Sulfate Controlled release Tablets Purdue Pharma 7 Oramorph Morphine Sulfate Sustained release Tablets Xanodyne Pharmaceuticals 8 Embeda * Morphine Sulfate and Naltrexone Extended release Capsules King Pharmaceuticals 9 OxyContin Oxycodone Hydrochloride Controlled release Tablets Purdue Pharma 10 Opana ER Oxymorphone Hydrochloride Extended release Tablets Endo Pharmaceuticals 11 Exalgo Hydromorphone Hydrochloride Extended release Tablets Mallinckrodt Inc. 12 Butrans Buprenorphine Transdermal System Purdue Pharma 5

6 Table 1 (cont). Long acting and Extended release Opioid Products Required to Have REMS. 8 9 Generic Products Drug Name Generic Name Applicant/Sponsors 1 Fentanyl Fentanyl Extended release Transdermal System Actavis 2 Fentanyl Fentanyl Extended release Transdermal System Lavipharm Laboratories 3 Fentanyl Fentanyl Extended release Transdermal System Mallinckrodt Inc. 4 Fentanyl Fentanyl Extended release Transdermal System Mylan Technologies 5 Fentanyl Fentanyl Extended release Transdermal System Noven Pharmaceuticals 6 Fentanyl Fentanyl Extended release Transdermal System Teva Pharmaceuticals 7 Fentanyl Fentanyl Extended release Transdermal System Watson Pharmaceuticals 8 Methadone Hydrochloride Methadone Hcl Tablets PHARMAnetwork 9 Methadone Hydrochloride Methadone Hcl Tablets Mallinckrodt Inc. 10 Methadone Hydrochloride Methadone Hcl Tablets Sandoz 11 Methadone Hydrochloride Methadone Hcl Oral Solution Roxane Laboratories 12 Methadone Hydrochloride Methadone Hcl Oral Solution VistaPharm 13 Morphine Sulfate Morphine Sulfate Extended release Tablets Endo Pharmaceuticals 14 Morphine Sulfate Morphine Sulfate Extended release Tablets KV Pharmaceutical Co. 15 Morphine Sulfate Morphine Sulfate Extended release Tablets Mallinckrodt Inc. 16 Morphine Sulfate Morphine Sulfate Extended release Tablets Watson Pharmaceuticals 17 Morphine Sulfate Morphine Sulfate Extended release Tablets Rhodes Pharmaceuticals 18 Oxycodone Hydrochloride Oxycodone Hcl Extended release Tablets Mallinckrodt Inc. 19 Oxycodone Hydrochloride Oxycodone Hcl Extended release Tablets Impax Laboratories 20 Oxycodone Hydrochloride Oxycodone Hcl Extended release Tablets Teva Pharmaceuticals 21 Oxycodone Hydrochloride Oxycodone Hcl Extended release Tablets Endo Pharmaceuticals 22 Oxymorphone Hydrochloride Oxymorphone Hcl Extended release Tablets Impax Laboratories 23 Oxymorphone Hydrochloride Oxymorphone Hcl Extended release Tablets Actavis *No longer marketed, but still approved Tentatively approved products In 2009, the American Pain Society (APS) published a position message from its president. At its 2008 mid year board meeting, the APS decided to assume the role of patient/prescriber advocate. The goal was to find a balance between limiting the risk of broad opioid availability with the potential unintended consequences of a REMS policy limiting access to opioids by patients who require these drugs as part of a comprehensive management plan. The Pain Care Forum (a broad based network representing patient advocates, nursing and physician 6

7 associations, and medical institutes), of which the APS is a member, also prepared a position letter that was sent to the FDA. The recommendations from these bodies were that 10 : 1. REMS should cover the entire class of opioid medications 2. There should be no registry requirements for patients using opioids included in the REMS 3. All implemented REMS components should be measurable and, when necessary, easily reversible 4. Demonstrated prescriber and dispenser knowledge concerning opioid pharmacology should be expected of all who seek Drug Enforcement Administration (DEA) licensure as a component of REMS 5. REMS education programs should be aimed at the public as well On October 19, 2010, the APS issued a statement saying that although the proposed REMS released by the FDA in June, 2010 did not fully meet APS's policies, we believe that these proposals were actionable initial public safeguards that fell within the FDA s limited jurisdiction. 11 Shortly thereafter, on December 9, 2010, the FDA announced at the FDA Centers for Medicare and Medicaid Services summit that the FDA s goal was to create plug and play REMS programs. 12 This reiterated the message in the letters sent to manufacturers of longacting opioids in This policy had largely been seen as not being stringent enough as it did not include immediate release opioids. On April 19, 2011, the FDA unveiled an updated plan for REMS related to opioids. The updated plan still only applies to long acting opioids since the FDA believes that long acting and extended release formulations of opioids carry unique risks that are not associated with immediate release opioids. 13 Interestingly, Abstral (immediate release fentanyl transmucosal tablets) was the first product to be approved using the new standardized REMS criteria. 12 The Abstral REMS program will be described later. The new FDA plan includes four key elements 13 : 1. Expanding state based prescription drug monitoring programs 7

8 2. Recommending convenient and environmentally responsible ways to remove unused medications from homes 3. Reducing the number of pill mills and rampant doctor shopping through law enforcement efforts 4. Supporting education for healthcare providers and patients Further information was provided by the Agency on April 20, Opioid REMS programs will focus on educating prescribers about proper pain management, patient selection and monitoring, and other aspects of opioid analgesic safety. The new REMS also requires prescribers to improve patient awareness about how to use opioids safely. The FDA wants opioid manufacturers to develop and make available patient education materials for use at point of care, and Medication Guides to be distributed by prescribers and with each product at pharmacies. 13 Manufacturers will be able to respond to the FDA with specific opioid REMS plans, but all risk reduction measures and education are expected to be implemented by early Implications for Managed Care The REMS implications for managed care organizations (MCOs) depend on the REMS and the MCO. Some REMS require that a drug be dispensed only in certain healthcare settings (eg, hospitals, certified and registered pharmacies, etc.). Other REMS may specifically prohibit dispensing of a drug in the hospital setting. Some REMS include ETASU for drugs with known serious risks that would otherwise be unavailable and health plans may play a vital role in coordinating these ETASU. 5 The restrictiveness of a REMS may impact the ability of a managed care organization to manage a drug or class of drugs. Providers may be less willing to prescribe an opioid that has a more robust certification requirement because of the added time and 8

9 burden associated. This would potentially impact plan market shares, rebates, and the cost of drugs within the category. For example, a plan might place a product with fewer or no REMS requirements in a preferred position subsequent to a contract negotiation, clinical review, and net cost evaluation. Additionally, if the provider is subject to multiple time consuming steps in order to prescribe a medication, he or she may instead choose to prescribe a less clinically appropriate or a more expensive medication because it is easier. It is therefore important that a plan include a discussion of applicable REMS and the potential impact on prescribing. It is also imperative that opioid REMS be consistent, so that non clinical or financial factors not determine utilization. Additionally, a plan that is part of an integrated delivery network may have different requirements than a pharmacy benefit manager (PBM). A PBM, for example, is typically only involved in benefit determination and payment of claims and would not necessarily be as directly impacted by certification and monitoring requirements. An integrated system (hospital and health plan) would be more impacted by prescriber status and certification requirements. The impact of these requirements would affect utilization as well as prescriber behavior and standing. 14 Therefore, plans and MCOs must be aware of REMS and understand the requirements so that the drug prescription and distribution process is appropriately managed from formulary determination to certification and dispensing. Developing REMS Best Practice Standards for System wide Success System Gaps and Barriers to Change Although there are critical gaps and barriers to overcome, the successful implementation of initial REMS programs will, over time, lead to quality improvements with future risk mitigation efforts. Ultimately, patients will be the beneficiaries of these interventions. However, it is still a 9

10 vital concern to balance the benefits and consequences of REMS, taking into account the steps required to operationalize this new model. Data from a population of 150 physicians indicate that practitioners do not know what is actually required of them when a drug has a Medication Guide or an ETASU as part of a REMS, and that there is inconsistency in the implementation of REMS programs. 14 In a recent survey of more than 2000 practicing pharmacists, 61% stated that risk management programs had a negative impact on their practices because the programs were confusing and carried excessive costs. In addition, there are current barriers to smooth implementation of this well meaning, patient safety directed initiative within the community based physician or pharmacist practice setting. These barriers include 15 : Increased time needed to fulfill REMS requirements by clinicians and pharmacists Burden of increased record keeping on administrative systems Disruption of process flow and professional relationship in order to integrate REMS requirements into patient provider interaction Varying complexity of REMS requirements, one size not fitting all, and new components emerging as safety concerns are uncovered with new agents in a drug class or new post marketing data The complexity of REMS, lack of a standardization in the requirements to fulfill REMS, considerations in deciding about how best to allocate limited resources to meet complex REMS requirements, and time needed to integrate processes involved in fulfilling REMS all support the need for a standardized approach to meeting REMS requirements as a best practice model. In an attempt to address the standardization issue, the FDA approved Abstral (immediaterelease fentanyl transmucosal tablets) on January 7, 2011, with a standardized REMS document, patient prescriber agreement, and enrollment form. The agency intends that the 10

11 standardized format be used for the development of REMS programs by all manufacturers seeking to market immediate release transmucosal fentanyl products. 12 Implementation of REMS for currently FDA approved opioids has yet to be addressed. There are also implications for MCOs, who need to address the aforementioned concerns to ensure that health plan affiliated physicians and pharmacists are prepared to participate in REMS. Incorporating REMS requirements into organizational policies and procedures involves not only consideration of general issues, but also consideration of specific drugs and drug classes. Documentation is the most important element to address. MCOs need to develop an overall approach for evaluating new drugs with safety concerns. Roles and responsibilities of various members of the healthcare team need to be defined so that they can educate patients and other healthcare providers about safety concerns and collect data to meet REMS requirements. Resources including medication information, procedures to follow when a new order is received, and record keeping requirements for REMS medications are elements that are needed for defined processes and procedures. For some medications, order sets should be created to ensure that REMS requirements for ETASU are fulfilled. 16 Lastly, one should remember the overarching goal of the REMS program: to mitigate risk and avoid adverse events for drugs with known potential safety issues where the scientific consensus affirms that the benefits of therapy outweigh the potential controllable risks. A coordinated effort by the entire healthcare team is needed to communicate effectively with patients about drugs with REMS requirements. Ventures to implement REMS requirements by MCOs can enhance drug safety, promote patient adherence to drug therapy, and improve overall patient health

12 Role of Managed Care Professionals Managed care professionals function in a variety of unique positions and settings. As such, they have different roles related to REMS based on their perspective and level within an organization as well as their degree of patient interaction and influence. Pharmacy Directors, Medical Directors, and Other MCO Administrators Pharmacy directors, medical directors, quality directors, and policy administrators from MCOs need to be aware of the REMS requirements that are applicable to a managed care setting. These healthcare decision makers are recommending policies and procedures for their insured populations and will be ensuring that the agreements with providers and healthcare facilities reflect the requirements for appropriately administering REMS. Pharmacy directors, medical directors, and other key administrators need to work to develop a community wide approach for drugs with REMS requirements. A system wide, multi disciplinary framework for the implementation of REMS initiatives in a managed care setting should be created and then shared with physician and pharmacist colleagues. This approach should take into consideration the many different REMS scenarios that address patient selection (based on the established safety criteria), patient education, and required record keeping. Although the safety criteria might vary depending on the drug, a standard framework is needed. For instance, a database can be created and posted on the Internet to facilitate sharing of REMS program information among collaborating plans. Collaborative efforts can help reduce the workload involved in meeting REMS requirements both for health plans and for their practitioners. The REMS requirements and ETASU should be integrated into the formulary evaluation process. Risk management personnel will also need to be involved in the evaluation of a REMS as part of the formulary evaluation process. 12

13 Managed Care affiliated Prescribers Prescribers affiliated with MCOs need information on the basics of the REMS regulatory process, including their role in REMS implementation. This may mean integrating new patient tests or monitoring, as well as new documentation requirements that address patient selection based on the established safety criteria, patient education, and required record keeping. It is vital that current patient communications be evaluated in order to implement the enhanced communications that are required with REMS. Prescribers should assess patients abilities to understand the requirements of REMS and, when working on an inpatient basis, the prescriber responsible for enrollment of patients should work with the pharmacy department to ensure that the drug will be available from a network provider who is also administering the appropriate REMS program. Furthermore, prescribers will need to understand any specific certification and monitoring requirements. Managed Care and Health system Pharmacists Pharmacists in a managed care setting are well suited to spearhead the implementation of REMS requirements in MCOs and other types of health systems because of their education, training, and experience. Pharmacy managers are responsible for ensuring the training of their respective staffs in the safe use of a specific drug. Requests for a drug should be approved by the pharmacy director or a drug use policy pharmacist. Orders should then be filled after verification of patient and physician enrollment in the manufacturer s REMS program if required, and patients should receive the Medication Guide before starting treatment and again with each dose if required. REMS requirements can also provide health system pharmacists with an opportunity and the impetus to conduct research on the safety outcomes resultant from drug therapy. Comparing safety measures before and after the implementation of a REMS can provide data to document 13

14 the impact of pharmacist efforts to meet REMS requirements. Evaluating outcomes measures that reflect safety is preferred to an assessment of process measures. Pharmacists have a responsibility to educate members of the pharmacy and therapeutics, medication safety, and other medication related committees and the pharmacy, medical, and nursing staffs about REMS requirements. A centralized pharmacy resource (ie, staff and infrastructure) should be established to coordinate REMS. As an example, this resource could be modeled after the investigational drug services provided by pharmacy departments, since many of the requirements are similar. Managed Care Health Plans MCOs cannot rely entirely on REMS to solve the problem of misuse and abuse of opioids. REMS do not necessarily impact member behavior (this is an area of unmet research need). Plans still need to monitor opioid prescribing and use. Additional monitoring tools can include restrictions (quantity limits, number of prescribers, number of dispensing pharmacies, limitations on ER use, etc.); case management; and collaboration with providers, drug manufacturers, states/regulatory bodies, guideline bodies, and advocacy groups. Plans are in the unique position of having prescribing information from all providers and pharmacies as long as they adjudicated the claims. This information should be used to augment provider education about member behavior if there is a pattern or suspicion of aberrant behavior. The general consensus is that pain is best treated by one educated and involved provider, and that medication use is best managed by one pharmacy. 17 Plan controls involving edits around number of providers allowed to prescribe at any one time, quantity limits for safety, etc., should positively impact appropriate utilization and support the goals of a REMS program as defined by the FDA. Plans also have the resources to offer case 14

15 management and access to behavioral health resources, if necessary, to improve outcomes. It would be worthwhile for states and governmental bodies to work more closely with MCOs because MCOs are in the position to more directly impact provider and member behavior. Drug manufacturers may also play an important role since they have data concerning certification and may have useful tools that can be used by plans. One example of a value added tool is Purdue Pharma s RxPatrol. 18 RxPatrol is a collaborative effort between industry and law enforcement designed to collect, collate, analyze, and disseminate pharmacy theft information. 18 Examples for the Successful Application of a REMS for Pain Management Examples of REMS Cited below are four examples of REMS: a REMS that includes ETASU (Onsolis FOCUS ); a REMS for OxyContin ; a REMS associated with an abuse resistant formulation (Embeda ) to evaluate any differences in requirements versus opioids not classified as abuse resistant; and the REMS for Abstral (the first FDA approved opioid using the standardized REMS for immediate release transmucosal fentanyl products). Onsolis 19 Meda Pharmaceuticals Inc. has developed a REMS program for Onsolis (fentanyl buccal soluble film) called FOCUS. The stated goal of the FOCUS program for Onsolis is to mitigate the risk of Onsolis overdose, abuse, addiction, and serious complications due to medication errors by: 1) helping to ensure proper patient selection; 2) reducing the risk of exposure to Onsolis in persons for whom it was not prescribed, including accidental exposure in children; and 3) training prescribers, pharmacists, and patients about proper dosing and administration. 15

16 The FOCUS program for Onsolis consists of a Medication Guide, which is dispensed with each prescription for Onsolis, a communication plan to physicians (a Dear Prescriber Letter), an ETASU, and an implementation system. The ETASU requires healthcare providers who prescribe Onsolis to be specially certified: To become certified, each prescriber must be enrolled in the FOCUS program. Prior to prescribing Onsolis, a prescriber must review the educational materials (and complete a knowledge assessment); complete, sign, and submit the Prescriber Enrollment Form; and receive notification of approval from the FOCUS program. Meda must maintain a database containing a list of all enrolled prescribers, and whether or not they are actively enrolled (prescriptions from prescribers who are not active can no longer be filled). Prescribers must be re educated following substantial changes to the FOCUS program or at least every 2 years. There are five materials for prescribers as part of the REMS: 1) Healthcare Professional Program Overview; 2) Prescriber Enrollment Form; 3) Web site Educational Materials; 4) Printed Educational Materials; and 5) Dear Prescriber Letter. The ETASU also states that Onsolis will only be dispensed by particular pharmacies that are specially certified: Meda must ensure that Onsolis be dispensed from certified pharmacies via a secure, traceable courier only. Onsolis is not available in retail pharmacies or hospitals. Pharmacies must be educated and enrolled in the FOCUS program to become certified. Specifics require that the pharmacist in charge review all of the educational materials; complete, sign, and submit the Pharmacy Enrollment Form; and receive notification of 16

17 approval from the FOCUS program. The Onsolis prescription process must follow certain steps: 1) Prescriber faxes prescription to the FOCUS program, 2) Prescriber sends the original hardcopy prescription to a FOCUS pharmacy via courier, and 3) Upon verification of accuracy and confirmation of enrollment, the FOCUS pharmacy dispenses Onsolis and delivers the medication directly to the patient via a secure, traceable courier that requires adult signature. Further, Meda must maintain a database containing all enrolled FOCUS pharmacies and their status (and ensure inactive pharmacies don t dispense Onsolis ). Pharmacies must also be re educated following substantial changes to the FOCUS program or at least every 2 years, and the same five materials that are required from prescribers are required by pharmacies as part of the REMS with the only difference being a Pharmacy Enrollment Form and a Dear Pharmacist Letter. The third and final component of the ETASU for Onsolis requires that it be dispensed to patients with evidence or other documentation of safe use conditions: Meda must ensure that each patient treated with Onsolis is counseled and enrolled in the FOCUS program. The counseling and enrollment process consists of: 1) the prescriber counsels the patient (the prescriber must distribute the Medication Guide); 2) both the prescriber and patient complete and sign the Patient Enrollment Form and the prescriber faxes it to the FOCUS program; and 17

18 3) the FOCUS program reviews the request and then counsels the patient using scripted interactions. Subsequently, the FOCUS program assigns each patient a unique identification number and maintains a list of all enrolled patients and their statuses. Patients remain active until a trigger for inactivation occurs or the enrollment period expires. Triggers for patient inactivation include: a prescription has not been filled for more than 3 months; the patient receives prescriptions for Onsolis from multiple prescribers within an overlapping time frame; the prescriber requests patient inactivation; the patient requests inactivation; or a report is received of patient misuse, abuse, or overdose of Onsolis. If an active patient transfers from one prescriber to another active prescriber, the patient and new prescriber must complete a new Patient Enrollment Form. An individual patient may have more than one current prescriber (eg, a pain specialist and general practitioner) as long as the prescriptions for Onsolis are not for the same time period of treatment. The REMS materials are the Patient Program Overview and the Patient Enrollment Form. Finally, Meda must manage an implementation system. Meda ensures that wholesalers and distributors of Onsolis are specially certified and enrolled in the FOCUS program. The wholesalers/distributors must review the program materials; complete, sign, and fax the Enrollment Form to the FOCUS program; and receive activation from the Program. Meda must also maintain a database of all enrolled FOCUS wholesalers/distributors and their statuses, and they must also be re educated following substantial changes to the FOCUS program or at least every 2 years. Meda must monitor the distribution of Onsolis to ensure that Onsolis is only shipped to active FOCUS pharmacies, and monitor the dispensing of Onsolis by active FOCUS pharmacies to ensure that only active patients are receiving Onsolis and only active 18

19 prescribers are prescribing Onsolis. Audits and evaluations are required to ensure that this procedure is followed. The concern from a managed care perspective is that such a highly restrictive REMS may discourage appropriate prescribing of Onsolis, making it less desirable to contractually work with Meda Pharmaceuticals. Also of concern is that secondary channels, such as buying on the street, may become more desirable to patients seeking to use Onsolis because it may actually be easier to obtain. If an MCO supports the use of Onsolis subsequent to clinical and financial valuation, the MCO should play an active role in disseminating information about the FOCUS program, specifically about certification requirements and mandatory patient educational materials. OxyContin 20 In contrast to the FOCUS program for Onsolis, the REMS for OxyContin simply consists of an education program. Similar to FOCUS, the stated goals of the OxyContin REMS are: 1) to inform patients and healthcare professionals about the potential for abuse, misuse, overdose, and addiction to OxyContin, and 2) to inform patients and healthcare professionals about the safe use of OxyContin. The Healthcare Provider training program component of the REMS consists of three steps. First, the prescriber should read the Dear Healthcare Professional Letter which describes the goals of the OxyContin REMS and is designed to convey and reinforce risks associated with OxyContin. Second, the prescriber should read the Healthcare Provider Training Guide which is designed to describe the potential risks of abuse, misuse, overdose, and addiction from exposure to OxyContin. Third, the prescriber needs to complete the Education Confirmation Form to acknowledge and verify their understanding of the safe use of OxyContin and to verify that they 19

20 have read the REMS education materials. The completed form may be returned via fax, , or mail. Completion of the form does not affect a healthcare practioner s ability to prescribe OxyContin. Initiatives that could be implemented by an MCO are the use of a point of service message reminding providers and pharmacies to review and complete the applicable letters and forms, newsletter articles summarizing the REMS requirements, and dissemination of the specified forms and letters. Embeda 21 The REMS for Embeda, an abuse resistant extended release formulation of morphine and naltrexone, consists of very simple educational materials. Included are a Dear Healthcare Professional Letter; a Dear Pharmacist Letter; Embeda prescribing information; Embeda Medication Guide; and questions about What to consider when prescribing Embeda. No action is required other than the expectation that the prescriber has read the Embeda materials and discussed them with the patient. The REMS does have the same goals of informing patients and providers about the potential for abuse, misuse, overdose, and addiction of the drug, and informing patients and providers about the safe use of the drug. Similar to the OxyContin initiatives, a managed care organization could utilize point of service messaging, newsletters, and dissemination of REMS information to improve awareness and appropriate utilization. Replication of the member education materials could be automated at time of dispensing from pharmacies by automatically including materials when a prescription is adjudicated and the label and supporting materials are printed. Abstral 12,22 Abstral (immediate release fentanyl sublingual tablets) is the first opioid product to be approved with the FDA s standardized format for immediate release transmucosal fentanyl products. Similar to the REMS for Onsolis, the goals of the Abstral REMS program are to 20

21 mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1) prescribing and dispensing Abstral only to appropriate patients, which includes use only in opioid tolerant patients; 2) preventing inappropriate conversion between fentanyl products; 3) preventing accidental exposure to children and others for whom it was not prescribed; and 4) educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose Prescribers are not eligible to prescribe Abstral for outpatient use unless they are enrolled in the Abstral REMS program after reviewing the prescriber educational materials (including the Full Prescribing Information) and successfully completing the knowledge assessment and enrollment form. Patients must complete a patient prescriber agreement before they can be prescribed Abstral (not required for inpatients). Outpatient pharmacies will not be eligible to purchase or dispense Abstral unless an authorized pharmacist has reviewed the Abstral REMS Education Program and successfully completed the knowledge assessment and enrollment form. Enrolled pharmacies can only dispense prescriptions for Abstral if the prescriber and pharmacy are enrolled and active and the patient has not been inactivated in the program. Inpatient Pharmacies will not be eligible to purchase or dispense Abstral unless an authorized pharmacist has reviewed the Abstral REMS Education Program and successfully completed the knowledge assessment and enrollment form. For inpatient use of Abstral, patient and prescriber enrollment in the Abstral REMS program is not required. Inpatient pharmacies may not dispense Abstral for outpatient use. Distributors enrolled in the program must verify current enrollment of the pharmacy in the Abstral REMS program before shipping Abstral. 21

22 ProStraken, the manufacturers of Abstral, have developed a reference library for Abstral consisting of resources for several healthcare stakeholders: General: Medication Guide, Full Prescribing Information, Frequently Asked Questions, educational materials, and knowledge assessment o The Medication Guide must be provided with all prescriptions Prescriber: Dear Healthcare Provider Letter, overview, enrollment form Outpatient pharmacies: Dear Outpatient Pharmacy Letter, overview, enrollment form Inpatient pharmacies: Dear Inpatient Pharmacy Letter, overview, enrollment form Patients and caregivers: Patient welcome Letter, overview, patient prescriber agreement Distributors: Dear Distributor Letter, enrollment form In order to participate in the REMS program; prescribers, inpatient pharmacies, and outpatient pharmacies must complete an on line educational program and be officially enrolled into the program. Similar to the Onsolis FOCUS program, if an MCO supports the use of Abstral subsequent to clinical and financial valuation, the MCO should play an active role in disseminating information about the REMS program, specifically about certification requirements and mandatory patient educational materials. The Abstral REMS program is accessible in terms of having PDF documents for presribers, pharmacies, and patients readily available. However, the program in total is not well described. Furthermore, even though this is the first standardized REMS approved by the FDA, it is only applicable to immediate release transmucosal fentanyl products. It has not been applied to other opioid products. 22

23 Case Study Managed Care Implementation of a REMS Health Plan XYZ is part of an integrated delivery network (IDN). Health Plan XYZ notices that utilization and costs of opioids are increasing across its membership. Upon further claims analysis, the Plan finds that there is a signficiant incidence of polypharmacy among the opioids, there is a high DACON (daily average consumption), and many members are using multiple prescribers and pharmacies to obtain and fill prescriptions for opioids medications. What can Health Plan XYZ do to address these issues? 1. Formulary management: a. Set appropriate quantity limits and polypharmacy edits b. Evaluate branded products for cost efficacy 2. Case manage: a. Develop drug contracts for patients using multiple pharmacies and prescribers requiring use of one prescriber and one pharmacy for opioids b. Assign case managers to high utilizers 3. Educate: a. Develop dissemination protocols for REMS programs i. Link appropriate REMS components to the MCO Web site (ie, Med Guide, letters, enrollment forms, etc.) b. Provide feedback to prescribers concerning utilization patterns 4. Coordinate with Network/System (applicable if plan part of IDN): a. Coordinate with inpatient pharmacies and prescribers concering REMS requirements b. Develop coordinatin of care protocols across system involving inpatient, outpatient, and ER components c. Assign a REMS coordinator 23

24 Summary The optimal approach to implementing requirements for REMS in a managed care setting is continuing to evolve. The key is understanding the process and the components of various REMS. This activity has attempted to describe the FDA policy, components, and purpose of REMS. Implications for MCOs and examples of REMS have been presented. MCOs can develop competencies in order to minimize the burden of these requirements while still helping to ensure the benefits outweigh the risks. Unfortunately, there is a certain level of inconsistency with REMS, especially within the opioid class of medication. The new FDA plan will hopefully standardize opioid REMS programs. MCOs can effectively allocate limited resources, integrate the processes involved in fulfilling REMS requirements, and define the collaborative roles of care team members so that medications are managed and used appropriately. MCOs should take an active role in the promulgation of REMS information and should advocate for more standardization in REMS programs. 24

25 References 1. Guidance for industry. Format and content of proposed risk evaluation and mitigation strategies (REMS), REMS assessments, and proposed REMS modifications. U.S. Food and Drug Administration Web site. [DRAFT GUIDANCE] M pdf. September Accessed May 31, Guidance for industry. Medication Guides Distribution requirements and inclusion in risk evaluation and mitigation strategies (REMS). U.S. Food and Drug Administration Web site. [DRAFT GUIDANCE] M pdf. February Accessed May 30, Code of Federal Regulations. Title 21: Food and Drugs. Part 208 Medication Guides for prescription drug products. Subpart B General requirements for a Medication Guide. 21 CFR Traynor K. Growth of REMS challenges FDA, stakeholders. Am J Health Syst Pharm. 2010;67(15): Questions and answers on the Federal Register notice on drugs and biological products deemed to have risk evaluation and mitigation strategies. U.S. Food and Drug Administration Web site. SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/ucm htm. Updated March 27, Accessed May 31, Approved risk evaluation and mitigation strategies (REMS). U.S. Food and Drug Administration Web site. /ucm htm. Accessed May 31, Background on opioid REMS. U.S. Food and Drug Administration Web site. Accessed May 31, Opioid products that may be required to have risk evaluation and mitigation strategies (REMS). U.S. Food and Drug Administration Web site. Accessed May 31, List of long acting and extended release opioid products required to have an opioid REMS. U.S. Food and Drug Administration Web site. 25

26 Updated May 13, Accessed May 30, Inturrisi CE. Speaking for you: APS develops and promulgates REMS position. American Pain Society Web site. Published Accessed May 31, American Pain Society (APS) policy related to FDA REMS decision, July 23 rd, American Pain Society Web site. Published October 19, Accessed May 30, Traynor K. First standardized REMS approved. Am J Health Syst Pharm. 2011;68(5): U.S. FDA releases long awaited opioid REMS. Pain Treatment Topics Web site. fda releases long awaited opioid.html. Published April 20, Accessed May 30, Hospital pharmacy directors, staff will need to know and handle REMS. Pharmacy News EU Web site. industry/dur hospital pharmacy directors staff willneed to know and handle rems. Published July 31, Accessed May 31, American Pharmacists Association. White paper on designing a risk evaluation and mitigation strategies (REMS) system to optimize the balance of patient access, medication safety, and impact on the health care system. J Am Pharm Assoc (2003). 2009;49(6): Shane R. Risk evaluation and mitigation strategies: impact on patients, health care providers, and health systems. Am J Health Syst Pharm. 2009;66(24 Suppl 7):S6 S Carollo K, ABC News Medical Unit. Pain Contracts: Would You Sign One to Get Treatment? ABC News Health Web site. pain contracts patientspioids/story?id= Published April 14, Accessed May 30, Rx Pattern Analysis Tracking Robberies and Other Losses Web site. Accessed January 11, Risk evaluation and mitigation strategy (REMS): FOCUS program for ONSOLIS. U.S. Food and Drug Administration Web site. July 13, Accessed May 31, Purdue Pharma L.P. OxyContin REMS Web site. Accessed May 31, King Pharmaceuticals, Inc. Embeda Web site. Accessed May 31, ProStrakan, Inc. Abstral REMS Web site. Accessed May 31,

27 Appendix A TITLE 21 F OOD AND DRUGS CHAPTER I FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER C--DRUGS: GENERAL PART 208 MEDICATION GUIDES FOR PRESCRIPTION DRUG PRODUCTS Subpart B--General Requirements for a Medication Guide Sec Content and format of a Medication Guide. (a) A Medication Guide shall meet all of the following conditions: (1) The Medication Guide shall be written in English, in nontechnical, understandable language, and shall not be promotional in tone or content. (2) The Medication Guide shall be scientifically accurate and shall be based on, and shall not conflict with, the approved professional labeling for the drug product under of this chapter, but the language of the Medication Guide need not be identical to the sections of approved labeling to which it corresponds. (3) The Medication Guide shall be specific and comprehensive. (4) The letter height or type size shall be no smaller than 10 points (1 point = inches) for all sections of the Medication Guide, except the manufacturer's name and address and the revision date. (5) The Medication Guide shall be legible and clearly presented. Where appropriate, the Medication Guide shall also use boxes, bold or underlined print, or other highlighting techniques to emphasize specific portions of the text. (6) The words "Medication Guide" shall appear prominently at the top of the first page of a Medication Guide. The verbatim statement "This Medication Guide has been approved by the U.S. Food and Drug Administration" shall appear at the bottom of a Medication Guide. (7) The brand and established or proper name of the drug product shall appear immediately below the words "Medication Guide." The established or proper name shall be no less than one-half the height of the brand name. (b) A Medication Guide shall contain those of the following headings relevant to the drug product and to the need for the Medication Guide in the specified order. Each heading shall contain the specific information as follows: (1) The brand name (e.g., the trademark or proprietary name), if any, and established or proper name. Those products not having an established or proper name shall be designated by their active ingredients. The Medication Guide shall include the phonetic spelling of either the brand name or the established name, whichever is used throughout the Medication Guide. (2) The heading, "What is the most important information I should know about (name of drug)?" followed by a statement describing the particular serious and significant public health concern that has created the need for the Medication 27