On September 30th, FDA issued its long awaited draft guidance, “Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments and Proposed REMS Modifications”. While much of this draft guidance is a codification of what’s already been happening in practice over the past two years, there are a few interesting surprises (depicted in bold below) for those working in the REMS space to contemplate. This is the second in an ongoing series of blog articles about this important document.
Our first article covered the background of FDAAA and REMS relative to RiskMAPs and those RiskMAPs deemed to be REMS, as well as an overview of a REMS submission. This second article addresses, in greater detail, the more concise “proposed REMS” component of the REMS document submission. The more expanded “REMS supporting document”, explaining the rationale for, and supporting information about, the proposed REMS being addressed in the next article.
The “proposed REMS” describes the goals of the REMS, the REMS elements proposed for inclusion, and a description of REMS assessment. All REMS educational materials are appended to the proposed REMS. A template can be found on the www.fda.gov website.
The proposed REMS document should either include the following sections or should include a statement that an element is not necessary
1. Goals – all REMS should state one or more goals and assessments should measure whether or not the goals are being met. Goals should target the achievement of a desired health outcome or understanding of the risks and be stated in a way that aims to achieve maximum risk reduction as a statement of the ideal outcome of the REMS. Each goal should be associated with one or more pragmatic and measurable objective that results in intermediate processes or behaviors that lead to achievement of the goal.
2. Description of Additional Potential REMS Elements – may include a Medication Guide and/or Patient Package Insert, Communication Plan, and Elements to Assure Safe Use with or without an Implementation System.
a. Medication Guide provides patient labeling when FDA determines a serious health concern exists, requiring distribution of patient information. One is required if patient labeling could prevent serious adverse effects, information could affect a patient’s decision to use or continue to use a product, and/or patient adherence to directions is critical for effectiveness. The Medication Guide must be available for distribution at the point of dispensing, and the REMS should describe how this distribution will occur. (It is notable here that FDA remains focused primarily on Medication Guides as the patient education tool, in contrast to a taking a more diverse approach to the education of health care providers).
b. Patient package insert may be required if FDA determines one will help mitigate risks. In most instances, only a Medication Guide is anticipated (rather than both a Medication Guide and a PPI) if patient labeling is required. Exceptions would include:
i. An editorial change to a pre-existing PPI
ii. Changes to how a product is used unless this mitigates a serious risk
c. Communication Plans provide information targeted to health care providers to support implementation of the REMS. This may include:
i. Letters to health care providers
ii. Information about REMS elements to encourage health care provider implementation, to explain safety management protocols, or to disseminate information through professional societies to healthcare providers about serious risks and protocols to assure safe use.
iii. If an NDA has been approved with a REMS communication plan and an ANDA is then approved, the FDA must undertake the communication plan. Neither the holder of the NDA nor the ANDA holder has to undertake a communication plan once an ANDA is approved. However, since many communication plan tools may fit under an element to assure safe use, both NDA and ANDA holders are required to implement such elements.
d. Elements to Assure Safe Use are intended to provide safe access to medication with serious risks that would otherwise not be available. To require such an element, FDA must determine that the drug can only be approved with such an element (or would be withdrawn without it) and that for a drug previously approved without such an element, other elements are insufficient. Elements to assure safe use may include attestations, enrollment forms, training materials, specified procedures, agreements, patient education, safety protocols, medical monitoring procedures, and data collection forms. Elements that may be included in a REMS include:
i. Health care providers who prescribe must have particular training, experience, and/or are certified. This may also require certification that training occurred or their attestation of experience or knowledge before they can enroll and are able to prescribe, with periodic recertification and reenrollment
ii. Pharmacies, practitioners, or settings that dispense are certified. This may also require certification of training or their attestation of experience or knowledge before they are enrolled and are able to dispense, with periodic recertification and reenrollment
iii. Medication is dispensed only in certain settings. This may also limit dispensing to specific healthcare settings, like hospitals or offices equipped to treat potential risks (e.g., serious allergic reactions)
iv. Medication is dispensed only to patients with documentation of safe use conditions. This may also include assuring patients have been counseled and signed an acknowledgement, have been provided materials and demonstrate understanding, and/or can receive drug only after authorized and verified by a pharmacy (e.g., checking lab test value, confirming physician qualification)
v. Patients using the drug are subject to certain monitoring. This may also include periodic lab test monitoring and/or patients re-contacting prescriber to confirm they are still appropriate and have not had a serious adverse event
vi. Each patient using the drug is enrolled in a registry. This element may be combined with and reinforce other elements to assure safe use. It can also be used to limit drug access to only enrolled patients, to collect important information about the patient, and/or to collect clinical data and allow case finding and follow up.
e. Implementation Systems support elements to assure safe use by monitoring and evaluating the implementation of such elements and informing the improvement of their implementation. This may also include a description of how applicable products are distributed, the certification of distributors to ensure delivery only to certified/specified pharmacies or settings, and/or to patients who meet certain criteria. Elements in a REMS may include:
i. A validated database of all certified entities to ensure certification or other requirements are met
ii. Periodic audits to ensure compliance with elements to assure safe use
iii. Periodic audits of distribution systems to confirm distribution only to authorized entities
f. Timetable for Submission of Assessment describes the proposed timetable for submitting assessments for NDAs and BLAs. For ANDAs, a timetable for submission of assessments is not required in a REMS. Some important aspects of REMS assessments include:
i. The minimum frequency of assessment submissions must be 18, 36 and 84 months, but assessments could be done more frequently and/or earlier, depending upon the risk.
ii. The interval and planned date of submission should be specified, with the end of the interval concluding no earlier than 60 days prior to the formal submission date.
iii. Modifications to the timetable may be made, based either on request or after the 36 month assessment, if the latter demonstrates that risks have been identified, assessed, and are being adequately managed.
In subsequent postings, we will be covering “Section IIIB – Content of the REMS Supporting Document”, “Section IV – REMS Assessment and Proposed REMS Modification Submissions”, and “Section V – Communicating with FDA Regarding REMS”.
Stay tuned…
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