REMS and Drug Development

How does the FDA’s risk approach affect new drugs?

By Pablo Garces, MD and Lynda Jacks, RN

The issue of risk versus benefit for marketed drugs has come under regulatory and public scrutiny due to well-publicized incidents in recent years involving the safety of marketed products. One important safety concern is the marketing of those drugs in which labeling alone is insufficient to ensure that the drug’s benefits will outweigh its risks. To ensure the benefits of such compounds continue to outweigh their risks following approval, the FDA has begun to implement Risk Evaluation and Mitigation Strategies (REMS) requirements, which may potentially impose new challenges during the drug development process.

In September of 2006, a report with significant impact was issued by the Institute of Medicine (IOM) of the National Academies, The Future of Drug Safety: Promoting and Protecting the Health of the Public, which made a series of recommendations for improvement to the FDA’s drug safety programs.¹

In response to growing pressures such as the IOM drug safety report, the FDA Amendments Act of 2007 (FDAAA) was passed by Congress on September 27, 2007. Title IX, Section 901 of this act authorizes the FDA, as of March 25, 2008, to require applicants — pharmaceuticals and biotechnology companies — to submit a proposed REMS as a component of NDAs, ANDAs and BLAs.² The FDA can also request a REMS at any time during the drug development lifecycle or after product approval.³

The FDAAA legislation is a culmination of ongoing safety initiatives. The FDA did not regulate post-approval measures on product information or drug marketing prior to 1970; it imposed labeling changes when needed, monitored the safety of drugs, at times required Phase IV clarification/ confirmatory studies, regulated the promotion of drugs, and withdrew drugs when new data showed that the risks outweighed the benefit.⁴

In 1970, Congress passed the Controlled Substances Act, which regulates the use and manufacture of certain products deemed by the FDA as having safety concerns. Subsequent measures included, in 1977, a requirement that all oral contraceptive packages contain patient package inserts, and in 1998, approval of a restricted access program for thalidomide for the treatment of lesions associated with erythema nodosum leprosum. In 2005, the FDA issued guidance on risk minimization action plans (RiskMAPs), considered the precursor to REMS.⁴

REMS consists of several components. The mandatory element is a Timetable for Submission of REMS assessments. Additional elements which may be required (discretionary) are: a Medication Guide, a Patient Package Insert, a Communication Plan to Health Care Providers, and Elements to Assure Safe Use (ETASU). ETASU may be required to mitigate the specific serious risk(s) listed in the labeling of the product when the drug has been shown to be effective, but is associated with a serious adverse event. ETASU may be required when an assessment and Medication Guide, Patient Package Insert, or Communication Plan are not sufficient to mitigate these risks. ETASU may include patient counseling and monitoring, patient data registries, a program for reporting SAEs, laboratory testing, and post-approval studies.

To determine the need for a REMS, the FDA considers the following:

• The population size likely to use the drug or biologic
• The seriousness of the disease to be treated
• The expected benefit with respect to the disease
• Duration of treatment
• The seriousness of known and/or potential adverse events
• The potential incidence of adverse events in the population likely to use the product
• Whether the drug is a new molecular entity³

Only 34 out of 200 REMS (17%) were actually imposed within the first year of the FDAAA legislation. According to Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research, 28 of the 34 REMS were implemented due to the need for a Medication Guide. Only four of the REMS involved the more complex ETASU. However, sponsors cannot assume that this low incidence of imposed REMS will continue, particularly for compounds in the opioid class. It is also possible that the recently installed Democratic administration may embrace the REMS model more robustly.⁵

To prepare for a possible REMS in order to meet approval and post-approval requirements, safety monitoring and risk minimization may require enhancement and carry over from the drug development phase on a continuum into the post-marketing phase.

Impact of REMS During Drug Development

Although the FDAAA legislation targets the post-marketing phases, clinical researchers in all stages of development may need to adopt an increasingly proactive stance in order to achieve approval of their compound. At a minimum, the FDA mandate should build awareness early in the drug development process of the potential need to formulate a REMS, in the event it becomes required for product approval or during clinical trials.

Pharmaceutical companies will need to address questions such as, “Based on our product type, which REMS components might be required for NDA approval? What study enhancements do we need to pursue to have the necessary data for potential REMS materials? At what point will we be able to identify whether the product’s risks outweigh its benefits?” Risk reduction should be undertaken with the following aspirations:

• Enhancing risk management during the development process may reduce issues or costly surprises in the post-marketing phase.
• An increase in pharmacovigilance during preclinical and clinical trials would provide a higher quality safety database, in order to prepare more substantial support for a NDA and a more substantial platform for post-approval safety analyses.
• Closer scrutiny of adverse events during the clinical trial process may ultimately better protect the public.
• Risk management strategies developed during the study trial process would assist in the design of a REMS plan, should one be found to be necessary, and in post-approval risk mitigation techniques.

Post-marketing safety monitoring should be taken into consideration during preclinical and Phase I – III clinical trial design. REMS requirements may potentially alter the development plan for new products and the methods in all stages of trials. Decisions regarding sample size, patient population, frequency of safety board reviews, dosing, and safety endpoints should be made with risk management in mind, which may cause sponsors to veer towards a more conservative approach. The natural questions during clinical trial design — “What are our objectives and what do we hope for in outcomes?” — will now more profoundly become, “How do we reach our objectives with sustainable outcomes within the context of long-term patient/public safety?”

Focused team discussions are instrumental in deciphering the risk management methods currently used, and those which should be improved. Examples of improvements could include imposing Drug-Induced Liver Injury guidelines, improving internal SAE reporting and review processes, increased use of Medical Monitors and/or pharmacovigilance staff, improvements in graphic displays and other communication tools, and increased frequency of on-site monitoring of AEs.

These analyses should provide an opportunity to modify study design to reduce risk, and assist in preparing the project team to address safety matters when they occur. Study design components that warrant examination include the frequency of visits and adverse event assessments, inclusion and exclusion criteria, the frequency and type of laboratory testing, the frequency and type of assessments, including ECGs, radiology studies, ultrasound, and biopsies, and timing of follow-up visits or addition of one or more follow-up visits.

The identification of early signs of potential risks (typically indicated by AEs reported during the study), could become a more integral part of the development process. It is important to remember that AE and SAE data collected during Phase I – III studies will become the foundation for the REMS Medication Guide — should one be needed — and the Patient Package Insert. Also, the Background section required in the REMS materials will encompass a discussion of the magnitude, severity, and frequency of the AEs, whether there are particular populations at risk, the background incidence of the risk in the population likely to use the product, and whether the AEs can be prevented or is reversible. Therefore, precise and thorough analysis of all safety issues will become crucial for the identification of potential risks, particularly in the event of abnormalities in liver function tests, renal clearance, or electrocardiographic studies. Products with suspected cardiac, liver or renal toxicity most likely will require a REMS with more than one component.

To perform these comprehensive safety analyses, additional clinical and administrative staff may be required, laboratory or other central reading vendor services may need to be augmented (e.g., lower level alerts for abnormalities, additional means of communicating results), or additional tracking mechanisms or databases may be needed. Trends discovered during medical monitoring of laboratory values may eventually be communicated as medical monitoring requirements in the REMS element, the Communication Plan to Health Care Providers.

Earlier risk determination during drug development may also translate into more frequent updating of safety reporting documents and interactions with study sites.

Once a potential risk is identified, or in the event of an identified toxicity, all essential information surrounding the event should be examined. Attempting to understand the mechanism of action of the toxicity is important, and could lead to the design of additional in vitro studies in human organs or cells. With REMS in mind as part of an NDA approval, the following may begin to occur in the event of toxicities:

1. companies may institute additional preclinical and clinical trials at lower doses, and
2. companies may institute stricter programs for monitoring and recovery.

In order to fully address laboratory abnormalities and/or toxicities during the course of the study, the following should occur: implementation of a plan for early detection, perform close monitoring of the subject and event sequelae, and implementation of a recovery plan.

Compounds that clearly demonstrate risks of toxicity or abuse, such as narcotic analgesics, will most likely require the ETASU component of REMS. Designing this component will require an added layer of complexity; therefore, from a planning perspective, it would be advantageous to obtain the FDA’s feedback on potential REMS requirements sooner rather than later.

With regards to planning, the FDA’s position is that a REMS should be discussed with the FDA at an early stage in drug development. For example, a REMS discussion could occur during an end of Phase II meeting. As Phase III begins, it should be noted that Phase III adverse event data could become the platform from which the risk/benefit ratio is examined and a primary factor in determining the need for a REMS. Although the number of exposures would be limited, Phase III trials could possibly serve as templates for some of the REMS components to be proven useful. Pharmaceutical companies should expect safety questions and recommendations to arise from the FDA, perhaps earlier in the drug development process, and more frequently.

The overall impact of a REMS may be increased costs during drug development, if more safety measures are implemented than would have been previously (e.g., initiation of additional trials, an increase in site budgets, increased data capture, or increased frequency of on-site monitoring). In-house or contract labor costs may also be incurred to design and produce the REMS.

Study costs will also increase if standard safety endpoints are expanded to include additional endpoints, which may not have been previously considered or expected. One example is the addition of laboratory assessments. Of all study components, safety endpoints are a primary target for enhancement in order to better prepare for a comprehensive safety database and data continuity from drug development to post-approval.

The FDA’s goal is to ensure that benefit vs. risk assessment continues as safety information is revealed in real-world product use. As a result of the FDAAA Title IX legislation, a shift in methodology should occur, from passive post-marketing surveillance to proactive, post-marketing pharmacovigilance, and this pharmacovigilance should be initiated and built upon during the clinical trial process, resulting in a data continuum. The burden therefore increases on pharmaceutical companies to apply comprehensive safety measures throughout the life cycle of the drug.

REMS requirements may and should propagate a more conservative attitude and approach towards patient safety. Companies should develop anticipatory thinking due to the potential need for a REMS. Not planning for REMS requirements could jeopardize a company’s multi-million-dollar product investment.

Preparing for a potential REMS may result in a more costly and intensive use of resources, primarily affecting medical and regulatory staff. The combination of planning, study design modification to reduce risks, and close/increased monitoring should produce a well-substantiated NDA, well-documented patient and health care provider materials, a solid AE data platform (to hopefully minimize post-approval surprises), a quality REMS design (should one be needed), and ultimately, an improvement in public safety.

References

1. Institute of Medicine. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, D.C.: Natl. Academies Press, 2006. http://www.iom.edu/Reports/2006/The-Future-of-Drug-Safety-Promoting-and-Protecting-the-Health-of-the-Public.aspx
2. U.S. Department of Health and Human Services. Food and Drug Administration Amendments Act (FDAAA) of 2007 (HR 3580), Federal Food, Drug and Cosmetic Act Chapter 5 Drugs and Devices. SEC. 505-1. [21 USC §355-1] Risk Evaluation and Mitigation Strategies. September 27.2007. http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsand Devices/ucm109090.htm. Accessed October 2009.
3. U.S. Department of Health and Human Services. Food and Drug Administration. Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications. September 2009.
4. U.S. Department of Health and Human Services. Food and Drug Administration Regulatory Information/Legislation. http://www.fda.gov/RegulatoryInformation/Legislation/ucm153119.htm. Accessed October 2009.
5. McCaughan M. Waking Up to REMS: Don’t Believe the Lack of Hype. The Regulation Policy Market Access Report. June 2009;3(21).

Pablo Garces is senior director Safety at inVentiv Health. Lynda Jacks is a medical writer at inVentiv Health.