Indegene
4Biosolutions Consulting
n June 2024, FDA expanded its Risk Evaluation and Mitigation Strategies (REMS) program for CAR T-cell therapies to include all six approved therapies, reducing the burden on healthcare providers by removing the requirement to report serious adverse events related to cytokine release syndrome (CRS) and neurological toxicities. At this same time, FDA modified the Opioid Analgesic REMS program to require manufacturers to provide pre-paid mail-back envelopes for safe disposal of unused opioids and updated the REMS for mifepristone to eliminate the in-person dispensing requirement, which allows certified pharmacies to dispense the medication directly to patients with a prescription.
The Changing Risk Evaluation and Mitigation Strategies (REMS) Environment
Isaac R. Rodriguez-Chavez (Global Forum): Would you please provide a general overview of how FDA’s REMS program (parts 1 and 2) has changed over the years, particularly during the past 5 to 10 years with respect to legislative trends (e.g., FDAAA), regulatory actions, and Elements to Assure Safe Use (ETASU) frequency? What are the principal drivers of these trends?
Siva Kumar Buddha: The evolution of the REMS program reflects a shift toward balancing patient safety with regulatory efficiency. Initially introduced under the 2007 FDA Amendments Act, REMS built upon earlier Risk Minimization Action Plans (RiskMAPs), which provided voluntary frameworks for mitigating medication risks. Over time, the FDA has refined REMS requirements to reduce administrative burden while maintaining stringent oversight for high-risk therapies. A key driver of this trend has been the need for regulatory agility, evidenced by the 2011 decision to remove REMS for drugs requiring only a Medication Guide. Contrary to concerns about loosening safety controls, this move allowed the FDA to concentrate resources on medications that necessitate more comprehensive risk mitigation strategies. The frequency of ETASU—which impose strict controls like prescriber certification and patient monitoring—has remained steady for the highest-risk medications, particularly in oncology, immunotherapy, and opioid management. However, the broader emphasis has shifted toward leveraging real-world evidence and digital platforms to enhance REMS effectiveness without creating undue burdens on healthcare providers. The FDA’s 2019 draft guidance on REMS Assessment: Planning and Reporting underscored this by encouraging innovative assessment methods, reinforcing that REMS should evolve in response to both clinical experience and technological advancements. Looking ahead, the integration of shared REMS programs and real-world data is likely to drive further refinements, ensuring that risk mitigation measures remain both practical and effective.
Global Forum: CAR T-Cell Therapy REMS Updates: What will be the impact of the REMS updates to CAR T-cell therapies (i.e., removal of required reporting of CRS and neurological toxicities) on healthcare providers and patient outcomes? How can one assure that safety signals are captured and resolved appropriately under this new framework?
Siva: In my mind, the FDA’s REMS updates for CAR T-cell therapies reflect confidence in established safety protocols while aiming to reduce administrative burdens on healthcare providers. The removal of mandatory reporting for cytokine release syndrome (CRS) and neurological toxicities acknowledges that clinicians are now well-equipped to manage these risks based on years of real-world experience. Providers will benefit from reduced documentation requirements which allow them to focus more on patient care. For patients, streamlined REMS processes could lead to faster access to treatment.
However, ensuring continued safety signal detection is critical. While mandatory CRS/neurotoxicity reporting is no longer required, robust post-marketing surveillance remains essential. Additionally, for example, FDA relaxed the requirement for treatment centers to maintain at least two doses of tocilizumab per patient to ensure readiness to manage severe CRS cases: Now, one dose must be available within 2 hours, with a second dose obtainable within 8 hours. In addition to tocilizumab, healthcare providers may consider other IL-6 inhibitors or cytokine-targeting therapies though supported by limited data as potential options for managing CRS or neurotoxicity in post-marketing settings.
Moving forward, a combination of decentralized data collection, advanced analytics, and proactive provider education will be key to identifying emerging risks while maintaining regulatory flexibility. This approach balances reduced burden with continued patient safety oversight.
GF: Opioid Analgesic REMS and Safe Disposal: Retooling Opioid Analgesic REMS programs with pre-paid mail-back envelopes for safe disposal of unused opioids came into effect on March 31, 2025. What are the operational rollout challenges of such a mail-back system? What synchronization from pharmaceutical companies, healthcare providers, and community organizations will reap the maximum advantage of this program in preventing misuse and diversion of opioids?
Siva: FDA’s enhancement to the Opioid Analgesic REMS (OA REMS) requiring manufacturers to provide pre-paid mail-back envelopes represents a significant step in combating opioid misuse and accidental exposure. By making safe disposal more accessible, this initiative aligns with broader public health efforts to reduce opioid-related harm. For healthcare providers, this update provides an opportunity to reinforce responsible opioid use and disposal, though its effectiveness will depend on patient awareness and engagement. From a pharmaceutical industry perspective, manufacturers will need to navigate logistical and financial challenges, including envelope distribution and the development of patient education materials.
One key concern is ensuring consistent patient participation, as disposal behaviors vary widely. Addressing this requires a coordinated effort: pharmacists emphasizing safe disposal at dispensing, manufacturers funding awareness campaigns, and integration with state drug take-back programs. The long-term success of this initiative will hinge on behavioral shifts, reducing leftover opioids in households, and limiting nonmedical use.
GF: Mifepristone REMS and Access: The recent mifepristone REMS update eliminates in-clinic dispensing. What is the impact of this update on patient access to mifepristone, especially for patients living in rural or underserved areas? How can this new dispensing model ensure that patients are counseled and assisted in accordance with best medical practices?
Siva: This update to the mifepristone REMS program is a major step in balancing access and safety. Removing the in-person dispensing requirement means more flexibility for both patients and providers, especially in areas where access to certified clinics was a challenge. At the same time, adding pharmacy certification ensures that dispensing remains controlled and that patients still receive the necessary counseling about how to safely use the medication. For healthcare providers, this reduces administrative hurdles while keeping essential safeguards in place. Of course, the responsibility now shifts more toward pharmacies, requiring them to stay compliant with REMS requirements. The key here is how well pharmacies adapt to these new responsibilities and whether patients continue to receive the right level of guidance. The FDA has kept the ETASU framework intact, so safety monitoring won’t be compromised, but its effectiveness will depend on strong implementation. Over time, we’ll see how this plays out in real-world settings, but overall, this move aligns with a broader effort to make REMS programs more efficient without sacrificing patient safety.
GF: Administrative Burden to Patients and Healthcare Providers: The complexity of the REMS program has been a well-known hurdle for patients and healthcare providers. Based on your analysis, what are the most significant pain points in each stakeholder group? What tangible measures can be implemented to limit the administrative and logistical burden without adversely affecting patient safety?
Siva: The biggest challenge with REMS is balancing safety with administrative efficiency. Providers face burdensome certification, reporting, and dispensing constraints, while patients struggle with access barriers like limited pharmacy availability and delays. While recent REMS modifications—such as those for CAR T-cell therapies and mifepristone—have streamlined certain aspects, other cases such as clozapine, where REMS was removed in favor of labeling cautions, still ensure safety without excessive oversight. Moving forward, integrating REMS into electronic health records (EHRs) could automate compliance, while AI-driven risk assessment can tailor oversight based on patient risk. A more dynamic, data-driven REMS model is key to maintaining safety while reducing unnecessary complexity for both stakeholders.
GF: Communication is a top priority in REMS programs. What communication strategies can be employed, in addition to electronic media and patient-friendly print materials, to promote patient understanding of REMS responsibilities and potential risks? Can these strategies be modified to target diverse patient populations with different levels of health literacy?
Siva: Effective REMS communication requires a multichannel, patient-centric approach integrating AI-powered chatbots, mobile apps with push notifications, and interactive dashboards for real-time adherence tracking. Telemedicine enhances access to remote counseling, while plain-language materials, icon-based risk visualizations, and multilingual video explainers address diverse health literacy levels. Personalized tools like wallet cards with QR codes, audio-based instructions, and community-driven train-the-trainer programs ensure inclusivity. Future-focused innovations, such as predictive analytics for proactive interventions, will further optimize patient engagement and compliance.
GF: Technology and REMS: How will technology advancements such as AI, machine learning, blockchain, or digital health technology improve the effectiveness and efficiency of REMS programs? What are the regulatory implications and risks to data privacy in applying such technology to REMS?
Siva: Oh, technology is evolving rapidly—we’re still digesting the impact of AI and ML, then came LLMs and GenAI, and now we’re already talking about how autonomous agents can transform the effectiveness, efficiency, and scalability of pharmacovigilance systems. Digital health tools, such as integrated clinical decision support and mobile applications, can streamline REMS compliance. Notably, the FDA’s collaboration with the MITRE Corporation and Duke-Margolis Center for Health Policy aims to embed REMS into clinical workflows and minimize disruptions for healthcare providers. However, these innovations must navigate data privacy risks, interoperability concerns, the need for standardized frameworks to ensure compliance, and other regulatory challenges. As technology evolves, balancing innovation with regulatory safeguards will be critical to optimizing REMS effectiveness.
GF: Assessing REMS Effectiveness: Can the performance of REMS programs be more critically assessed beyond compliance rates? What metrics and tools determine the impact of REMS on patient outcomes, drug adherence, and the drug benefit-risk profile? How would one use this data to continually refine REMS programs to ensure they are performing as intended?
Siva: To critically evaluate REMS effectiveness beyond compliance rates, a combination of process metrics, outcome metrics, and advanced analytics must be leveraged. Key metrics include patient adherence to REMS-mandated protocols, provider compliance with prescribing restrictions, and reduction in adverse events associated with the drug’s risk profile. Advanced methodologies such as real-world evidence (RWE), claims data analysis, and AI-driven predictive modeling can enhance assessment accuracy. Tools like FDA’s REMS Assessment Framework, Root Cause Analysis (RCA), and the RE-AIM model help identify gaps in implementation and patient safety impact. Additionally, longitudinal studies and patient-reported outcomes (PROs) can provide insight into the real-world impact on drug adherence and benefit-risk balance. Continuous monitoring, stakeholder feedback, and integration of machine learning-based risk stratification models can refine REMS strategies dynamically, ensuring they effectively mitigate risks while optimizing accessibility for patients.
GF: Global Perspectives: From a global pharmacovigilance perspective, in what ways do US REMS programs differ from risk management activities elsewhere around the world (e.g., the EU, Japan, China)? What international experiences could strengthen the design and implementation of REMS programs in the US?
Siva: The FDA’s REMS program differs from global risk management systems like the EMA’s Risk Management Plans (RMPs), Japan’s Post-Marketing Surveillance, and China’s pharmacovigilance frameworks in scope, flexibility, and patient engagement. REMS focuses on prescriber and patient education with tools like ETASU and medication guides, while RMPs emphasize real-world data collection through registry studies. Japan mandates long-term observational studies, and China employs centralized adverse event reporting.
Incorporating international best practices—such as integrating prospective studies, adopting quantitative risk-benefit analyses, and enhancing cross-border data sharing—could strengthen REMS in the US. Low- and middle-income countries often face challenges in implementing such structured pharmacovigilance frameworks due to resource constraints, limited regulatory infrastructure, and fragmented healthcare systems. The administrative and financial burden of adapting global risk management practices can strain these regions, making it essential to develop scalable, cost-effective approaches tailored to their needs. Aligning REMS with global standards while considering LMIC-specific constraints could improve drug safety and accessibility worldwide.
GF: What lies in the future for REMS programs within the next 5 to 10 years regarding new therapy developments on the horizon (e.g., gene therapy, individualized therapy), evolving regulator expectations, and technological advancements? What are some of the key future challenges and opportunities, and how can regulators and the pharmaceutical industry stay ahead of them?
Siva: Over the next 5 to 10 years, REMS programs will need to evolve alongside advancements in gene and individualized therapies, requiring specialized risk management strategies. Regulators may push for global harmonization, reducing administrative burdens while ensuring safety. AI-driven monitoring, blockchain for secure data tracking, and telehealth integration will enhance efficiency and patient adherence. Future REMS frameworks will shift from compliance-based models to outcome-driven approaches, focusing on hospitalization rates and long-term safety. However, challenges like complex therapy management, administrative burdens, and data privacy risks may persist, although to a lesser extent than at present. To stay ahead, regulators and pharmaceutical companies must embrace adaptive risk management, leverage real-world evidence, foster public-private collaborations, and streamline REMS through AI-powered automation and scalable cloud-based solutions, ensuring patient safety without operational inefficiencies.