Some REMS programs may only require a medication guide to be distributed with each dispense that highlight safety information, such as relevant adverse events and risks associated with taking the product.
In the early 2000s, several products approved by the FDA were undergoing public scrutiny for serious and life-threatening adverse events (AEs). Vioxx, for example, was approved in 1999 as a painkiller effective in alleviating arthritis pain while causing fewer gastrointestinal problems compared with its competitors, such as naproxen.
After approval, however, follow on studies began to suggest that Vioxx may cause serious AEs, such as heart attacks and strokes with prevalence not observed in earlier clinical trials.1 Due to the health concerns that had arisen, Vioxx was taken off the market entirely in 2004.2 This product was available in the US market for 5 years and during that period is estimated to have caused approximately 60,000 deaths.3
At the time when Vioxx was removed from the market, other products such as Accutane, Tikosyn, Tracleer, and Plenaxis, also started to show severe AEs. The results being published on all of these high-risk drugs led to major concerns from the public and the FDA. To address these concerns, the FDA began to require manufacturers of certain high-risk products to develop and implement Risk Minimization Action Plans (RiskMAPs).
RiskMAPs created a framework for high-risk products to be monitored and controlled without having to take them off the market entirely. These programs required manufacturers to come up with a plan to educate health care providers and patients around the products’ risks, monitor possible AEs, and communicate data to the FDA showing that the drug was safe to keep it on the market.
For example, the FDA had required Accutane to create a RiskMAPs program because the product carries a high risk of causing severe birth defects if taken during pregnancy.4 In 2006, Roche introduced the iPLEDGE RiskMAP program for Accutane, which required physicians to go through an annual attestation and registration process.
Pharmacists also needed to undergo training to become a registered pharmacy able to dispense the product. Accutane prescriptions needed to be sent to pharmacies monthly and could only be filled within certain windows after physician-patient discussions.
Although Accutane developed relatively stringent guidelines for their proposed risk map, the published guidelines for RiskMAP programs were loosely outlined as to what was actually required by the manufacturers to launch and manage these programs. Different programs had different monitoring and reporting methods based on what the manufacturer felt would be an effective risk mitigation strategy, and the FDA reviewed these programs on a case-by-case basis.
In September 2007, the federal government introduced the Food and Drug Administration Amendments Act, which expanded the FDA’s authority. This legislation put a more comprehensive framework in place for manufacturers during the clinical trial process, allowed the FDA to require post-commercialization studies from manufacturers and enabled the agency to provide manufacturer guidance based on these post-approval results.
After 12 months, the FDA could review products for safety and efficacy and adjust package inserts based on this assessment. Additionally, the Food and Drug Administration Amendments Act allowed the FDA to require Risk Evaluation and Mitigation Strategy (REMS) programs for new and existing drugs.
These REMS programs were required for products with serious safety concerns, such as those previously mentioned. Sixteen products that had RiskMAPs transitioned to REMS programs after this act passed, including Accutane. Unlike RiskMAPs, however, these programs include specific guidance by the FDA and are generally more comprehensive than previously launched RiskMAP programs.
If the FDA determines that a product has high safety risk concerns, they will give manufacturers a 120-day notice to launch a REMS program. Initially, a manufacturer must submit a proposal to the FDA that includes details on how their REMS program will be managed.
Back-and-forth discussions generally occur between the manufacturer and the FDA after an initial proposal is submitted, and additional supporting documentation with supplemental background and supporting information is requested by the FDA. The submission must include the manufacturer’s stated goals of the REMS program and a timetable for submission but may also require a medication guide or patient package insert, a communication plan, and/or elements to assure safety use. Some REMS programs may only require a medication guide to be distributed with each dispense that highlight safety information, such as relevant AEs and risks associated with taking the product.
A communication plan may also be required that explains how the manufacture plans to train relevant health care professionals prescribing, dispensing, and providing counseling for their product. Physicians or pharmacists, for example, could be required to take trainings on the product and attest that they will comply with the specifications of the REMS program before they are permitted to prescribe or dispense.
For intravenous drugs, REMS programs may require point of administration training. Communication plans must lay out how the trainings will be documented and monitored.
For example, Accutane’s iPLEDGE program requires physicians or patients to login to an online portal every month and attest that they have had a conversation with the patient and both parties understand the risks associated with the product. The pharmacy then has to use an expiring code generated from this submission to dispense the product.
Elements to Assure Safe Use (ETASU), such as certification requirements, patient enrollment registries, and limited distribution plans for medication may also be required for some REMS programs. For rare disease and orphan products, patient enrollment registries are more common, as clinical data are far more limited in these types of populations.
The recently launched Novartis product Zolgensma, for example, requires a patient enrollment registry due to the ultra-rare population of spinal muscular atrophy.5 Limited distribution pharmacy network arrangements may also be required, which limit the size of the pharmacy networks.
Tracleer has a REMS program that limits the number of pharmacies in their network. A limited network may provide a more consistent patient experience with clinicians more familiar with the disease state and ensure consistent reporting of certain REMS program data elements. Each ETASU must have an implementation plan included in the manufacturer’s REMS proposal.
Lastly, REMS program submissions must include a timetable for submission. Assessments of REMS plans typically occur at 18 months, 3 years, and 7 years after approval. In some cases, the FDA may require more follow-up performance assessments based on the risk profile of the product. Assessment timetables can also be updated at any time based on the FDA’s risk assessment of new information.
Based on the above complexities involved with administering a REMS program and the data requirements outlined, products with REMS requirements are frequently dispensed by specialty pharmacies in limited networks. Many traditional pharmacies do not have ability to report on REMS appropriately and adhere to the FDA’s strict guidelines.
Specialty pharmacies use customized patient management systems to store data associated with REMS and then transmit this information to the manufacturer through a secure file transmission.
Specialty pharmacy network selection for REMS products is important for manufacturers, as penalties for failing to adhere to REMS programs may be severe. In addition to the possibility of pulling a drug from the market, according to the Chapter 53 of the FDA Guidance Documents, the “FDA may impose civil monetary penalties of up to $250,000 per violation of REMS requirements, not to exceed $1 million in a single proceeding (section 303(f)(4)(A)).”6
In 2017, Aegerion pled guilty for to failing to comply with an FDA-mandated REMS program for Juxtapid, a cholesterol drug for patients who have homozygous familial hypercholesterolemia (HoFH). Aegerion failed to give health care providers all necessary information regarding the clinical diagnosis of HoFH, violating their REMS program.
“By failing to follow the safety requirements that Aegerion had agreed to, the company put patients’ lives at risk and didn’t honor the safety commitments they made as a condition of gaining approval for their drug,” said Scott Gottlieb, MD, commissioner of the FDA in a press release. “This is unacceptable. We will continue to pursue those who skirt the law, and flout patient safety and other post-market commitments, using all of the enforcement tools available to us. Post-market safety requirements are a key element of the FDA’s public health protections and we will ensure that they are fulfilled.”7
Aegerion paid a criminal fine and forfeiture of $7.2 million for failing to comply with their REMS program.8 Manufacturers may fear that if a REMS program is deemed a requirement for their program from a competitive standpoint, however, the aim of these programs is to get more effective products on the market under watch by the FDA and to avoid unsafe product launches, such as Vioxx.
These programs allow for higher risk products to enter the market when there is a significant clinical benefit provided by a treatment for patients with significant unmet needs. If efficacy and safety of a product can be proven post-launch through other supplemental data provided to the FDA, REMS program requirements can be eliminated.
Interestingly, Tremeau Pharmaceuticals is now developing a generic form of Vioxx to treat severe joint pain in people with hemophilia. Some specialists such as Ellis Neufeld, MD, PhD, clinical director of hematology at St. Jude’s Children’s Research Hospital, feel that the removal of Vioxx deprived certain patients of important treatment.9
According to Neufeld, Vioxx prescribed off label was effective for patients with hemophilia who may not be able to take NSAIDS products such as ibuprofen, as these may lead to internal bleeding.4 Although a REMS program may be required if this product were to reach the market, the program may in fact give it the ability to enter the market when this was previously not possible, while also educating patients and caregivers of its potential risks.
About the Author
Gannon Vanscoy is the Director of Specialty Markets at RareMed Solutions, the nation’s first rare disease focused specialty pharmacy HUB. Gannon leads RareMed’s overall business development efforts and manages strategic partnerships across the company’s portfolio. Gannon began cultivating his expertise in rare and orphan disease states at PANTHERx Rare Pharmacy, where he participated in a rotational development program focused on hub services. Prior to working at PANTHERx Rare, Gannon served as a leader at a number of large multi-national banks, both in internal and client-facing roles.
Gannon earned his Bachelor of Business Administration degree from the University of Miami and is currently pursuing a Master of Pharmacy Business Administration (MPBA) from the University of Pittsburgh, a 12-month, executive-style graduate education program designed for working professionals striving to be tomorrow’s leaders in the business of medicines.