1. How do you determine if a REMS is needed during product development?
A REMS should be considered when risk mitigation efforts are required beyond product labeling and routine pharmacovigilance. The types of REMS as defined by the FDA are inclusive of a Medication Guide only REMS (patient labeling), education and outreach to HCP through a Communication Plan, and Elements to Assure Safe Use (ETASU). Most REMS with ETASU also include an implementation system, which allows the Sponsor to monitor and evaluate those in the healthcare system who are responsible for implementing ETASU measures. All REMS must include a Timetable for Submission of Assessments. Any REMS may have one or more of these features.
Decisions regarding risk management are always made on a case-by-case basis, but several considerations are common. Some key considerations in these decisions are:
Nature and rate of known risks versus benefits: Comparing the characteristics of the product’s adverse effects and benefits will clarify whether risk management actions could improve the product’s benefit-risk balance. The characteristics to be weighed might include the (1) type, magnitude, and frequency of risks and benefits; (2) populations at greatest risk and/or those likely to derive the most benefit; (3) existence of treatment alternatives and their risks and benefits; and (4) reversibility of adverse events observed.
Preventability of adverse effects: Serious adverse effects that can be minimized or avoided by preventive measures around drug prescribing are the preferred candidates for risk management.
Probability of benefit: If factors are identified that can predict effectiveness, a risk management plan could help encourage appropriate use to increase benefits relative to known risks.
Anticipating the likelihood of a REMS and the potential scope of the program is the first step in the REMS planning process. Currently, there are no set rules or direct guidance for when the FDA might impose a REMS. There are, however, a few considerations published by the FDA that drive their decision making process. Manufacturers need to make early determinations about the probability of a REMS for their product by trying to predict the approval pathway imposed by the FDA. This can be a difficult task and much like reading a REMS crystal ball, however analysis of all approved REMS in the marketplace will provide insight. In September 2016, FDA issued a draft Guidance document outlining the factors that are important to consider in determining if a REMS is needed, FDA’s Application of Statutory Factors in Determining When a REMS is Necessary.1 FDAAA requires FDA to consider these six factors in making a decision about whether to require a REMS and what type of REMS should be put in place.
2. Who from your organization needs to be at the REMS design table?
A REMS team should be cross-functional, and have as its objective to make recommendations to senior management about the need for a REMS and the level of risk mitigation that is needed. Sponsor companies vary in terms of which functional area or department leads the REMS development and implementation.
In UBC’s experience, we find that either the PV/Epidemiology Group or Regulatory lead REMS planning, although a REMS can be driven by Clinical Development. Any model may work, however; it is generally preferable to have a representative other than Clinical Development take the lead since this group will be heavily involved in the final stages of NDA/BLA preparation at the time that the strategy for the REMS and the documents need to be prepared.
The REMS team should be lead, if possible, by someone from the United States, with a liaison to any working groups in Europe who are preparing an MAA. It is also important to coordinate any risk minimization activities proposed in the REMS or the RMP. Although the specific activities may differ, the level of seriousness of the risk(s) and the degree of complexity of the risk mitigation should be consistent.
3. How do you align the products commercial strategy with the REMS?
A significant omission that UBC has often encountered when working with cross-functional REMS teams at the sponsor company, is not including commercial representation, or bringing them in late in the planning process. It is critical to know how the product will be distributed to be sure that the REMS is aligned with the distribution strategy.
The REMS strategy typically has more flexibility than the distribution strategy. The REMS should not dictate the distribution strategy, but rather the distribution strategy dictates the REMS. Allowing the REMS to dictate the distribution strategy could impact the commercial viability of the product. Commercial objectives take into consideration other factors such as allowing prescribers and patients to access the product through the same or similar distribution channels as equivalent or similar products. The REMS team must understand the overall distribution strategy under consideration. For example, will the product be dispensed via specialty pharmacies or provided by specialty distributors? If so, then how many of each will be utilized to support the prescriber and patient volumes anticipated for this product? Will prescribers function in a “buy and bill” capacity for this product? Will hospitals/infusion centers or other sites of care order product and stock it in their pharmacies, or will the orders be on a named patient basis?
4. What are the appropriate metrics to assess your REMS?
Metrics should be established for all categories relevant to the REMS and they should be feasible to collect and report upon!
In one of the two recent FDA guidance documents, Planning and Reporting Guidance for Industry2, the FDA provided examples of metrics that should be considered, by category (e.g. Program Outreach and Communication, Program Implementation and Operations, Knowledge, Safe use Behaviors and Health Outcomes and/or Surrogates of Health Outcomes) for all assessment categories.
Complementary data sources that provide qualitative and quantitative information about the REMS are encouraged. Examples include REMS data, of course, as well as survey data, drug utilization data, post-marketing and adverse event data, observational/epidemiology data, data from root cause analysis, and data from stakeholder outreach.
5. Can you implement a REMS in your organization or should you plan to outsource?
One advantage in using a third party is the experience factor. An experienced third party, UBC, for example, has developed many REMS, and has reviewed countless others, therefore has had exposure to strategies familiar to and agreed upon by FDA for other products.
Since FDAAA, of the over 275 products that have had a REMS, many have been designed and managed outside of a Sponsor company. Often Sponsor companies hire companies like UBC to design and implement the REMS. It is best to bring a third party into the REMS discussions early. Using a third party can begin as a consultative process whereby UBC and the Sponsor Company collaborate on proposed REMS. The REMS may be a contingency plan, if the FDA should request a REMS during their review or if the sponsor company knows a REMS is required prior to NDA/BLA submission. At the time of operationalizing the REMS, the communication between the external vendor and the Sponsor company follows a typical clinical project plan, i.e., creating document repositories, holding regularly scheduled meetings, collecting operational metrics and other evaluation data, and developing the FDA Assessment Reports with the Sponsor’s review and approval.
In some instances, a Sponsor company may take the lead on developing the REMS and REMS Supporting Document. In many of those cases, they often hire a third party to review and validate their approach prior to FDA submission. The development of REMS tools is often also part of the agreement and generally led by the third party. Typically, in this hybrid model, the graphic support and final formatting is assumed by the third party over 75% of the time.
In summary, partnering with an experienced third party such as UBC for risk management will alleviate a Sponsor’s burden. UBC will guide manufacturers in meeting FDA requirements to develop a REMS appropriate to mitigate the risks.
For more information on UBC’s REMS services, click here.