REMS: Stakeholders seek flexibility in changing REMS vendors

Industry and patient groups are asking the US Food and Drug Administration (FDA) to take a flexible approach when reviewing changes that come with switching third-party vendors that provide services for Risk Evaluation and Mitigation Strategies (REMS), also known as REMS administrators. The groups argue that a restrictive approach could limit patient access to life-saving drugs.

The comments were made in response to a Federal Register notice in March 2023 that solicited comments on changes to third-party vendors for REMS systems to fulfill a requirement of the Consolidated Appropriations Act of 2023. Congress specifically tasked FDA with gathering feedback on the information applicants or REMS administrators should gather before developing and implementing a new REMS system, and what kinds of testing should be required before implementing a REMS system.

Concerns about the impact of changes to REMS systems on patient access flared up after changes to the iPLEDGE REMS system for the acne drug isotretinoin and the REMS program for the antipsychotic drug clozapine led to significant disruptions to patient access to both drugs. In both cases, FDA exercised its enforcement discretion to ease REMS requirements for the drugs to improve access; however, market factors such as major REMS administrators leaving the space continue to cause disruptions as new vendors come up to speed.

The public comment period closed on 21 July, and while some stakeholders supported greater oversight by the agency, most held the view that no two REMS systems are alike, and REMS administrators also vary greatly. With that in mind, most of the stakeholders that commented asked FDA to take a flexible approach to assessing changes to REMS vendors and to approach each REMS system on a case-by-case basis.

Feedback

The REMS Industry Consortium (RIC), which represents REMS administrators and manufacturers, said that drugmakers who participate in REMS systems are already facing major challenges in supplying their drugs, including essential drugs that are affected by shortages.

“It cannot be overemphasized that flexibility remains paramount in REMS program development and management, and the need for flexibility and ‘right-sizing’ an approach applies across the entire REMS system – from stakeholder feedback to pre-launch testing to timelines and metrics to measure success,” said RIC. “The decisions made today will directly impact all of this and it is therefore essential to proceed with full consideration of how requirements today will likely impact the marketplace of medicines tomorrow.”

Similarly, the Association for Accessible Medicine (AAM) said FDA should give applicants broad flexibility to make decisions when they need to change a REMS vendor. AAM noted that REMS participants must factor in several variables including a third-party vendor’s experience implementing the types of systems required by the REMS system and data migration to a new programs as well as the user interface and the cost of their services.

“Changing a REMS vendor is complicated and costly and has important implications for the long-term marketability of drug products covered by the REMS,” said AAM. “REMS vendors are selected with care from a limited pool of potential vendors, and that pool is shrinking as vendors have consolidated or left the market.

“The shrinking pool of vendors able to provide the necessary services can increase the costs for REMS participants, and for small generic companies these costs can be prohibitive, causing some to exit the market or withdraw pending abbreviated new drug applications (ANDA), ultimately compromising patient access to medicines,” the organization added.

When asked about stakeholder input that applicants and REMS administrators should obtain before developing and implementing a new REMS system, RIC said that “flexibility remains a paramount value” and especially when it comes to obtaining stakeholder feedback.

“While stakeholder feedback can be extremely valuable in certain circumstances, RIC strongly discourages a new requirement that would mandate stakeholder feedback before each REMS system is developed or implemented,” said the organization. “A formal collection of stakeholder feedback should be undertaken (in advance of a REMS system update taking effect) only when it is justified because meaningful input is expected on one or more key areas of inquiries.”

RIC argued that stakeholder input is already baked into the REMS system. For example, it said stakeholder input is gathered through Knowledge, Attitude, and Behavior (KAB) surveys, as well through direct feedback from sponsor field representatives, patients and healthcare provider advisory boards. The group said sponsors can also use various market research tools that inform them on how to manage their REMS programs.

RIC said its members understand that difference in perspectives from different stakeholders can be valuable but sponsors should have the discretion on how feedback is solicited.

“The ultimate objective is to achieve as much value as possible from such inquiries while avoiding feedback fatigue that can arise when the same stakeholders are called upon too often and without a compelling need to drive such outreach,” said RIC.

Contrasting RIC, drugmaker GSK told FDA stakeholder feedback is essential before implementing a new REMS system or when changing a REMS administrator. GSK is also a member of RIC.

"Early in the REMS development process, the REMS sponsor(s) should consult with impacted distribution channel entities (e.g. distributors, specialty pharmacies, retail pharmacies), healthcare systems, patient advocacy groups, prescribers, and health professional organizations to proactively identify possible challenges and barriers as well as ideal implementation timelines,” the drugmaker said.

Testing

Similarly, when asked to comment on whether the sponsor and/or REMS administrator should run tests before they change their REMS systems including user acceptance testing with stakeholders and evaluation of any unexpected impact on stakeholder workflow, RIC said there may not be a benefit to such testing in every case. The group said there are other approaches such as test case simulation scenarios or pilot program roll-out that may be effective in helping sponsors, in consultation with FDA, that may help assure stakeholders that the program changes will work.

RIC said that mandating one type of testing for every case is not the answer.

“Already, sponsors are faced with compressed timelines (sometimes due to involuntary substitutions of service providers (as was the case in 2021-2022)),” said the group. “In other instances, compressed timelines may result from FDA-defined priorities or preferences. Steps taken should therefore always be reasonably likely to yield actionable information or feedback to guide an expeditious roll-out of the new REMS (or REMS update).

“Ultimately, rigid standardization and uniformity in approach is not the answer,” the group added. “We need to strive for intelligent, thoughtful, well-reasoned approaches, and in the end, consistency and standardization should be embraced when, and only when, the objectives of safe, prompt access to REMS products is specifically and meaningfully advanced.”

AAM aligned with RIC and said while getting stakeholder input and testing different components of new REMS systems is a good idea in theory, they may be difficult to implement in practice.

“AAM recognizes that FDA has an interest in ensuring that REMS programs run smoothly, and recent experiences with the clozapine REMS and the iPLEDGE REMS modifications are illustrative of what can go wrong when program modifications are implemented,” said AAM. “The question is how to balance the need to provide REMS participants (i.e., sponsors) the flexibility to promptly make changes to a REMS when necessary with the need to ensure that the changes do not cause disruptions to the healthcare system.”

On the other hand, GSK said that user acceptance testing for impacted stakeholders is a reasonable approach to assess the impact the REMS system changes may have. To ensure minimal administrative burden for REMS stakeholders, the company said an assessment of REMS data flow and impact should be conducted before the new REMS system is implemented.

“If feasible, an automatic transfer of REMS data should be considered and employed,” GSK added. “Data validation should be performed to ensure quality of the migrated data. A phased approach to the implementation of the REMS Modification should be considered to avoid REMS system overload and support a seamless transition.”

The Healthcare Distribution Alliance (HDA) aligned with GSK and said it supports a requirement that the sponsor and/or REMS administrator develop a standardized testing methodology that can be used when any operational changes are made to the implementation system that especially affect wholesale distributors.

“If they intend to change their REMS system, the administrator and/or sponsor should test their daily, automated, provision of eligibility lists, and ensure they are provided in a standardized mode (i.e., SFTP Site) and file format (i.e., .CSV), to wholesale distributors to ensure a seamless transition with no disruption in the delivery of needed medicine to patients once the transition occurs,” the group said.

Timeline for changes

When asked about the amount of time stakeholders need to transition from one REMS system to another, HDA said they should be allowed at least 90 days to effectively implement significant changes to an existing REMS system.

“Based upon our members’ experiences with previous changes, 90 to 180 days is optimal to account for the time needed to build, test, and deploy the required technologies as well as process the required creation and integration work,” the group said.

The American Academy of Dermatology Association (AADA) said REMS administrators and drug sponsors should be given at least 12 months to allow for sufficient pilot testing of a new REMS system before they fully roll it out. This would also give ample time to prepare prescribers and patients to transition stakeholders from one REMS system to another REMS system, the group added.

Based on their experience with changing the REMS system for isotretinoin, AADA said dermatologists, pharmacists, and patients faced several challenges during the “rushed roll out” of the new iPLEDGE System which were implemented by the Isotretinoin Products Manufacturing Group (IPMG).

“Although IPMG notified prescribers of the system update in October 2021, prescribers were not given adequate time to prepare for a system shut down, patient and physician disenrollment in the program, and the extremely high call volume at the iPLEDGE help center,” said AADA. “Furthermore, IPMG did not share a rationale for modifications to the platform, solicit stakeholder input, or test any of the proposed changes with isotretinoin prescribers.

“Providing a mere two months' notice without soliciting any input from prescribers or conducting thorough testing of the proposed change is not enough time and is egregious,” the group added. “Not only were physicians ill-prepared to use the new system, IPMG was unable to handle the call volume from physicians, pharmacists, and patients requesting assistance. Furthermore, hundreds of patients were in jeopardy of losing access to vital treatments.”

Instead of a specific timeframe, RIC is asking for more flexibility because it said it is difficult to determine how much time stakeholders need to transition to a new REMS system as there are too many factors involved. The group also said in many instances, stakeholders don’t fully understand the amount of time they will need for the transition until the process has begun and all the stakeholders get involved.

“Stated simply, there can be no ‘one size fits all’ approach in REMS and this is especially true when factoring in a transition of service providers, especially for an already operational REMS program,” said RIC. “Because a limited pool of service providers typically handles much of the work needed for REMS to run smoothly, but how much any one particular service provider does varies widely from one REMS program to the next.”

Here, GSK agrees with RIC that the amount of time needed to transition stakeholders from one REMS system to another is highly variable based on the stakeholder and applicable technology. Factors such as availability of administrative staff to support the transition, incorporation of new workflows, and time to complete necessary REMS forms including new patient and prescriber enrollment and certification all play a role in the amount of time that will be needed for the transition for prescribers. Similarly, the company said pharmacies also have a slew of factors to consider when implementing new REMS systems.

“A phased approach to the implementation of the REMS Modification should be considered to mitigate transition burden and to support a seamless transition,” said GSK without being specific about any timelines.

The Angry Moms (TAM), a patient advocacy group, said it aims to end FDA restrictions on prescribing and dispensing clozapine and wrote to the agency with a slew of recommendations to curb its oversight of the antipsychotic drug. It said that the clozapine REMS has failed to improve safety for clozapine patients and more than 30 years of regulations has left the most seriously ill individuals in untreated. The group also said extreme testing requirements have created a faulty perception of the 'toxicity' of the drug and caused unwarranted fear among doctors, pharmacists and patients.

“The result of clozapine mis-regulation has been suicides, homicides, injuries, deterioration, suffering, and death,” said TAM. “These adverse events have gone unreported, undocumented, and unseen by an FDA- mandated program that rigidly, unreasonably, and myopically tracks a single patient characteristic while carelessly neglecting overall patient and caregiver safety.”

Among the recommendations made by TAM, 1,600 of its members wrote to FDA asking it to eliminate the REMS Dispense Authorization (RDA) process for the drug altogether and allow any pharmacy to fill any active clozapine prescription.

The group also asked FDA to expand the hospice option so other patients could be qualified under the definition and change it to the prescriber monitored option, so that the drug is considered appropriate for acute first-episode or treatment-resistant patients under 45, patients presenting a danger to self or others, patients at risk of suicide, gravely or acutely disabled patients, the prison population, patients for whom frequent blood tests would create significant risks to the treatment plan and patients who have been taking clozapine for more than two years without an occurrence of severe neutropenia.

REMS: Stakeholders seek flexibility in changing REMS vendors

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