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FDA Intensifies Drive to Reduce REMS Burdens
Last August, Danielle Boyce brought her young son to a Pennsylvania hospital for brain surgery. The boy has catastrophic epilepsy and takes vigabatrin (Sabril, Lundbeck). Sabril is a prescription medicine used with other treatments in adults and children 10 years of age and older with refractory complex partial seizures and in babies 1 month to 2 years old with infantile spasms, if the possible benefits outweigh the possible risk of vision loss. Boyce’s son has infantile spasms. Because of the serious risk of vision loss associated with Sabril, the FDA, when it approved the drug, required Lundbeck to establish a risk evaluation and mitigation strategy (REMS).
Seventy-four pharmaceuticals have REMS attached, as do four classes of drugs; a list is available at the FDA’s website.1 All of those drugs provide major benefits, but they also have potentially devastating side effects, which is why the FDA requires a REMS as the price of approval. Some REMS require physicians, pharmacists, and patients to do relatively little to obtain access, often from a specialty pharmacy. Other REMS have elements to assure safe use (ETASU) attached, which require completion of such steps as certification, tests, paperwork, and other tasks before access to the drug is granted, often by a third-party REMS administrator engaged by the manufacturer. In the case of Sabril, that is the SHARE program.
When Boyce and her son arrived at the hospital, their supply of Sabril was dangerously low. However, the hospital was not allowed to dispense Sabril. “So we had to order more from the mail-order pharmacy, and someone had to go home, get the drug once it was delivered, and bring it back to the hospital, where we had to check it in,” Boyce explains. “But I wouldn’t give the hospital the whole supply for fear they would lose it and we wouldn’t be able to get any more. It really added to my stress. We hear this from families all the time.”
The difficulty some patients experience obtaining critical REMS drugs, whether at the hospital or in their homes, is just one of the criticisms that has buffeted the program since Congress authorized it in 2007. The stranglehold specialty pharmacies have on access is a continuing complaint from hospitals and even community pharmacies.
JoAnn Stubbings, BS Pharm, Assistant Director of Specialty Pharmacy Services at the University of Illinois Hospital and Health Sciences System, says the health care accrediting organization URAC has accredited her specialty pharmacy for its “closed loop workflow” system. That system employs clinical pharmacists for all sorts of tasks. “But we have been denied access to some drugs with REMS,” she says, meaning the pharmacy has to leave the patient’s electronic health record (EHR) and independently contact an outside specialty pharmacy that the manufacturer has designated. “That leads to fragmentation in the patient’s care and delay in getting the patient his or her medication,” she explains.
Even when hospital and retail pharmacists can obtain the drugs, those with ETASU complicate the dispensing process, forcing physicians and pharmacists to obtain certifications, make sure patients have gotten requisite tests, and complete numerous electronic tasks that cannot be done on their physician and pharmacy software, much less inside the patient’s EHR. Katie Stabi, PharmD, BCPS, Clinical Coordinator of Drug Use Policy and Compliance at University of Chicago Medicine, estimates it takes a hospital from three weeks to three months to implement a new REMS, including 160 hours of pharmacy workload.
The FDA has been holding public workshops over the past few years, at Congress’s insistence, and is slowly but surely working on solutions to some of those problems. The latest workshop took place for a day and a half in early October 2015.2 A couple of major agency initiatives are finally emerging and were discussed there, though in very broad strokes. Perhaps the most significant is a four-month pilot program that is about to end in which manufacturers with REMS have submitted the applicable documents to the agency in a format called structured product labeling (SPL). Manufacturers already submit labeling information in this format, but using it for REMS will give those documents a consistent format, allow them to be incorporated into EHRs, and greatly reduce the workflow burden on physicians and pharmacists. Another initiative earning praise from the pharmaceutical community is the FDA’s new website called REMS@FDA.
Congress required the FDA to establish a REMS program in 2007, replacing an earlier program called RiskMap. But REMS requirements can be confusing, with drug companies using different terminologies and sometimes mandating different requirements. “The lack of standardization of elements within the current REMS programs creates an unnecessary burden and practical impediment to their implementation,” says Melissa Schulman, Senior Vice President for Government and Public Affairs at CVS Health.
About half of currently approved REMS programs include ETASU. These especially prickly demands require significant outlays of time on the part of physicians and pharmacists. The REMS produced by Celgene for lenalidomide (Revlimid) is 100 pages long, for example.
The iPLEDGE program for isotretinoin, which treats severe recalcitrant nodular acne, is frequently cited as an example of how REMS programs should not work. There, pharmacies encounter challenges that include, but are not limited to, the recertification and retraining requirements for participating pharmacies; the need to access the iPLEDGE Web portal and interactive voice response system; and matching iPLEDGE patient identification numbers, says Michelle Cope, Director of State Public Policy for the National Association of Chain Drug Stores.
One REMS program is easier for pharmacists to fulfill than others: the transmucosal immediate-release fentanyl (TIRF) shared REMS. TIRF opioid agents include brand-name drugs Abstral (Galena Biopharma), Actiq and Fentora (Cephalon), Lazanda (Depomed Inc.), and Onsolis (BioDelivery Sciences International, Inc.). They are used to manage breakthrough pain in adults with cancer who routinely take other opioid pain medications around the clock. This was the first “class” REMS the FDA approved. In 2011, the FDA approved use of a “switch” to ensure compliance, allowing pharmacies to avoid going to a manufacturer or even the FDA website to obtain clarification or approval of the claim.
Michele Davidson, RPh, Manager of Pharmacy Technical Standards for Walgreens and Chairman of the Board of Trustees of the National Council for Prescription Drug Programs (NCPDP), says a TIRF prescription is filled via a normal NCPDP transaction within the retail pharmacy’s existing software dispensing system (which, unfortunately, does not work for hospital pharmacies, which use an X-12 standard when submitting claims). The retail pharmacy sends the claim to an intermediary (in the case of the TIRF REMS, a company called Relay Health), which in this system is called the “switch.” Relay acts as the REMS administrator. Relay takes the claim, does whatever edits are necessary, approves the claim, and then forwards the claim to the payer/processor before the claim is transmitted back to the pharmacy. All of this transpires in less than a second. The whole transaction is done within the pharmacy’s normal dispensing system. However, if the switch discovers that the physician didn’t do what he or she needed to do as part of his or her REMS responsibilities, the claim will be rejected and returned to the pharmacy. The pharmacist must then go back to the physician and correct the problem.
That is where SPL will come in—if it comes in (more on that later). With SPL, REMS approval is done within a physician’s e-prescribing system, so the prescription doesn’t go to the pharmacy until it is cleared by the REMS administrator. The pharmacy sees what the physician has done within the patient’s EHR. SPL would be an advantage over the “switch” process because in the latter case, pharmacies must build their own “alerts” specific to each REMS (so far only the TIRF REMS uses a switch) into their claims system. Every pharmacy has to do this on its own. “With SPL, those alerts can be integrated into everyone’s system in the same manner,” Davidson explains.
Who Should Dispense?
Simplifying and injecting uniformity into REMS, which the FDA is attempting to do with its SPL project, would not address the access issue. Specialty pharmacies and manufacturers believe there are good reasons to keep some REMS drugs—mostly those with ETASU—out of the hands of hospital and retail pharmacies. Schulman says the FDA should label some REMS drugs as “specialty only” so they are handled appropriately. CVS Health believes that the specialty pharmacies will fill gaps beyond the scope of the retail pharmacies, since they already dedicate the necessary educational and administrative time. REMS programs such as those developed by Celgene for Revlimid, Pomalyst (pomalidomide), and Thalomid (thalidomide) are not conducive to the retail environment and fit better in the specialty environment due to burdensome, time-consuming requirements, such as:
- Providing patient or caretaker consultation for every fill.
- Obtaining and maintaining confirmation and authorization numbers.
- Tracking each dispensing to adhere to quantity restrictions.
- Ensuring appropriate documentation is received.
Paul Sheehan, head of REMS for Celgene, puts it this way:
To satisfy this REMS obligation in a manner that optimizes both patient safety and access, Celgene has adopted a limited distribution network of specialty pharmacies, hospitals, and clinics that are authorized to dispense each of these three products. Including additional providers into the limited distribution networks could unnecessarily weaken the operation and effectiveness of our REMS and could make the certification, training, auditing, and monitoring requirements of the REMS infeasible.
FDA Efforts to Improve REMS
Although Congress authorized the REMS program in 2007, it took an additional significant step in 2012. In exchange for increasing user fees that drug companies pay to the agency, the FDA agreed, among other things, to measure the effectiveness of REMS, to continue to develop techniques to standardize REMS, and, with stakeholder input, to seek to integrate REMS into the existing and evolving health care system. The agency issued a report on its findings regarding REMS standardization in fall 2014 that unveiled four pilot projects:3
- Develop a report for stakeholders of findings, counseling processes, and tools that could serve as the basis for designing new tools and validating them in demonstration projects.
- Provide an analysis of time and resources required related to developing and using continuing education (CE) programs to conduct REMS-related training and/or communication.
- Investigate developing SPL for REMS content, including REMS documents, requirements, and materials.
- Allow stakeholders to compare requirements across REMS and minimize confusion associated with complying with multiple REMS programs.
The completion of these projects is especially important for pharmacists, who, the draft report acknowledged, bear most of the burden for assuring REMS requirements are met. The draft said:
FDA was advised that, in many organizations, primary responsibility for knowing the individual REMS requirements for prescribers, patients, and dispensers often falls to the pharmacist. Pharmacists noted they need to clearly understand who (prescribers, pharmacists, nurses, etc.) is accountable for each role or activity under a REMS. FDA heard that pharmacists often monitor individual health care provider responsibilities for REMS with ETASU elements, especially in inpatient health care settings. Some stakeholders expressed concern about the administrative burden that often falls upon the pharmacist to ensure appropriate REMS forms are completed.
Subsequent to that 2014 draft report, the FDA has made some headway in reducing the burden on pharmacists. One perceptible advance is the new REMS@FDA website. Dr. Stabi notes that pharmacists looking for guidance on particular aspects of a REMS can go to five different sources and sometimes get five different answers. These five are: REMS@FDA, the REMS document, the REMS full document, the enrollment form, and the REMS call center. These all provide information on what training and what level of knowledge a pharmacist must have before he or she can participate in a given REMS. “Pharmacists can face scenarios not addressed in the REMS document,” she explains. “What many pharmacists have found is that REMS representatives at a call center are not sure how to answer these questions and often provide answers that contradict what we find in the REMS document.” She says the new REMS@FDA website should be “the source of truth.”
While the new website is an advance and the pilot projects are in different stages of development, the FDA knows it needs to go further. That was the purpose of the public meeting held at the FDA offices in Maryland on October 5 and 6, 2015.2 The meeting was held so the agency could obtain information on improved strategies for evaluating and minimizing the burden of REMS on the health care delivery system to the extent practicable and their impact on patient access to the drugs covered by such programs.
Pharmacy Workload Reduction
One of the key targets for the FDA is integrating more functionality into REMS documents, particularly with regard to integrating them with EHRs, which, for the most part, is not possible today. SPL is a data standard used to capture and share structured information about drug products. SPL is maintained by Health Level Seven (HL7), a standards development organization that develops numerous standards for the transmission of information about health care and medical product regulation. The majority of information currently included in SPL, including general product information, the content of drug labeling, and registration and listing information, is entered by a sponsor and submitted to the FDA. As a result, the FDA does currently receive some information in the SPL format. HL7 published release 6 of the HL7 version 3 standard last February, and that allowed the FDA to start drafting what it calls “artifacts,” which included a structured prototype REMS, a controlled terminology/code set for key REMS concepts, and an implementation guide.
Those artifacts were at the center of the four-month pilot project started in November 2015 in which interested manufacturers submitted REMS data to the agency using SPL. For all REMS programs in the pilot, the REMS document was captured using standardized section headings. This information is captured in two places: a human-readable REMS summary and associated machine-readable data elements. Both the REMS summary and the data elements will capture four basic pieces of information about each requirement:
- Who is required to carry out the requirement. For example, a requirement may be carried out by the health care provider who prescribes the drug or dispenses it.
- What that individual is required to do. This could include a clinical activity, such as counseling a patient, or an administrative one, such as completing an enrollment form.
- When the activity must be carried out. For example, a REMS activity may need to be completed before a drug is prescribed or dispensed, or before a patient is able to receive the drug.
- References to REMS materials that may contain additional information about the requirement, such as forms and educational materials.
Adam Kroetsch, policy and information advisor at the FDA, says that once REMS are formatted in SPL, the REMS elements and requirements can be searched easily by a pharmacist on his or her pharmacy system. “The SPL format allows the REMS document to be interpreted by computer and within electronic health records,” he explains. The FDA had nine spots available for the pilot, and all nine were filled. Kroetsch declines to name the companies that participated. The nine REMS will apparently be “stored” in the DailyMed repository at the National Institutes of Health (
Some insurers integrate REMS data into EHRs on their own; Kaiser Permanente is one of the leaders. Kaiser Permanente has its own national specialty pharmacy with a specialty pharmacy information management system (SPIMS) that provides comprehensive functionality to link the pharmacy system to the EHR. If a patient is receiving a drug with REMS ETASU, SPIMS can issue system alerts to pharmacists (about required laboratory tests, refills, etc.). It can verify prescriber compliance and has added safety measures. The integration through the EHR provides assurance of fulfillment of REMS requirements to ensure patient safety—lab results, other medications taken, clinical factors, etc. The EHR can provide additional safeguards such as the ability to check progress notes, track electrocardiograms or other recommended measures, or view the REMS medication fills in the comprehensive medication lists consulted by other prescribers, emergency department staff, or other providers.
Jennifer M. Day, PharmD, Pharmacist Evidence Analyst and Strategist at Kaiser Permanente Drug Information Services, says the problem comes when Kaiser has to go to an outside specialty pharmacy to get a REMS drug. “The typical flow of clinical information between the pharmacist and the provider is interrupted and we lose key features of SPIMS design, such as those that improve safety, adherence, and data collection.”
While the NCPDP is working on a standard that would set the stage for e-prescribing systems to incorporate REMS in SPL, that standard needs to be broadened so that it can be used by hospital pharmacies, too, which use a rival standards group for their e-prescribing systems. The NCPDP has completed work on the NCPDP ePrescribing (SCRIPT) REMS transaction. Davidson expects it to be approved in February. “Once the standard is published, we can work with the FDA on how to get this standard adopted,” Davidson says. “We may need to tweak this standard for a broader group of stakeholders such as hospitals as we work with the FDA on developing a ‘common REMS platform,’ a new concept recently introduced by the FDA.”
Improvements are coming to the REMS program, some of which will make life easier for pharmacists. The question is how fast those changes will arrive and how far-reaching they will be. Those decisions rest with the manufacturers and then with the health information technology vendors. It may not be a good sign that none of the latter was at the FDA’s October 2015 workshop. A representative of Epic, a leading EHR vendor that has been active in the NCPDP, declined to comment on the FDA’s efforts. That is probably not encouraging either.
- Food and Drug Administration. Approved risk evaluation and mitigation strategies (REMS). Available at: https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm. Accessed January 7, 2016.
- Food and Drug Administration. Risk evaluation and mitigation strategies (REMS): understanding and evaluating their impact on the health care delivery system and patient access. December
152015;Available at: https://www.fda.gov/Drugs/NewsEvents/ucm441308.htm. Accessed January 7, 2016.
- Food and Drug Administration. Standardizing and evaluating risk evaluation and mitigation strategies (REMS). September 2014;Available at: https://www.fda.gov/media/89860/download. Accessed January 7, 2016.