Risk Evaluation and Mitigation Strategy (REMS)
A Risk Evaluation and Mitigation Strategy (REMS) is a strategy to manage a known or potential serious risk associated with a drug or biological product. A REMS will be required if FDA finds that a REMS is necessary to ensure that the benefits of the drug or biological product outweigh the risks of the product, and FDA notifies the sponsor. A REMS can include a Medication Guide, Patient Package Insert, a communication plan, elements to assure safe use, and an implementation system, and must include a timetable for assessment of the REMS. Some drug and biological products that previously were approved/licensed with risk minimization action plans (RiskMAPs) will now be deemed to have REMS.
The decision to approve a drug is highly dependent on the answer to the following question: “Do the benefits of the drug outweigh the risks?” Both pharmaceutical manufacturers and the Food and Drug Administration (FDA) continually evaluate the potential benefits of a drug versus its potential risks. Many factors are taken into consideration, some of which include:
- Seriousness of the disease or condition to be treated
- Size of the patient population
- Expected benefit of the drug
- Expected duration of treatment
- Seriousness of the known or potential adverse events
These evaluations are performed not only prior to the approval of a new drug, but also throughout the entire life cycle of the drug. This serves as a means to continuously assess the safety and efficacy of existing drugs based on adverse event reports and results from post-marketing clinical studies.
Risk Minimization Action Plans (RiskMAPs)
After several products (e.g., Lotronex®, Rezulin®) were removed from the market because of safety concerns, the FDA came under increased scrutiny. FDA formed working groups that developed three risk management concept papers and draft guidances in May 2004. Final risk minimization guidances were issued in March 2005 to address safety monitoring and interventions:
- Premarketing Risk Assessment
- Development and Use of Risk Minimization Action Plans
- Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment
The guidance for RiskMAPs gave manufacturers specific direction about how to address product risk-related goals with tools or interventions to mitigate the risks and ensure strict adherence to product labeling. Products considered risky by the FDA were approved only if an appropriate RiskMAP was instituted by the manufacturer.
Despite Roche’s earlier efforts to communicate the risks associated with the use of Accutane® via the S.M.A.R.T. program, which included branded and generic products, product use among women of childbearing potential continued. This led to collaboration in 2006 among Roche, generic manufacturers, and the FDA to launch a shared RiskMAP program for isotretinoin – iPLEDGE.
Other examples of products with RiskMAPs included:
- Tikosyn® (dofetilide)
- Tracleer® (bosentan)
- Plenaxis® (abarelix)
Elements of these programs varied from the highest level of restricted distribution systems (e.g., performance-linked access systems) to educational materials to mitigate known or potential risks.
REMS
In September 2007, the Food and Drug Administration Amendments Act (FDAAA) was signed into law providing the FDA with expanded authority. Some of the new provisions gave FDA the authority to:
- Require post-approval studies or clinical trials to assess a known or serious risk, or to learn more about a hypothetical serious risk,
- Require that new safety information be added to the product labeling, and
- Require that companies submit Risk Evaluation and Mitigation Strategies (REMS) when deemed necessary to ensure that the product’s benefits outweigh the risks
FDA may now require REMS for any NDA, ANDA, or BLA at any stage of the product lifecycle. If the FDA requires a REMS, the manufacturer has 120 days to submit a proposed REMS if it is for a marketed drug. For a new drug, the manufacturer must include the proposed REMS as part of its New Drug Application (NDA) submission. Once approved, the REMS creates enforceable obligations for the manufacturer and the FDA.
The FDA requested that 16 selected products with current RiskMAPs transition into REMS by September 2008. Because of this expanded FDA authority beyond what was previously called RiskMAP, REMS have superseded the regulatory authority of RiskMAPs, making use of the term RiskMAP obsolete.
REMS Elements
Proposed REMS may contain any of the following elements:
- Medication Guide – Document written for patients highlighting important safety information about the drug; this document must be distributed by the pharmacist to every patient receiving the drug.
- Communication Plan – Plan to educate healthcare professionals on the safe and appropriate use of the drug and consists of tools and materials that will be disseminated to the appropriate stakeholders.
- Elements to Assure Safe Use (EASU) – These are strictly controlled systems or requirements put into place to enforce the appropriate use of a drug. Examples of EASUs include physician certification requirements in order to prescribe the drug, patient enrollment in a central registry, distribution of the drug restricted to certain specialty pharmacies, etc.
- Implementation Plan – A description of how certain EASUs will be implemented.
- Timetable for Submission of Assessments – The frequency of assessment of the REMS performance with regard to meeting the goal(s) and objective(s). FDA requires that assessments be conducted at 18 months, 3 years, and 7 years post-launch, at a minimum. Results of these evaluations must be reported to the FDA and will determine whether additional actions or modifications to the REMS program are required.
At this date, over 88 REMS have been approved by the FDA since the implementation of FDAAA. Final FDA guidance is anticipated by the end of 2009.
REMS Requirements
To assist manufacturers in developing REMS, the FDA has issued an outline of specific elements that should be included in the proposed document. The proposed REMS should be concise and specific and include the goal(s) along with the explicit components that will be developed to ensure that the drug will be used safely and appropriately.
The manufacturer should also describe how it intends to evaluate whether the REMS is meeting its goal(s) and objective(s) at various time points from the time of launch and beyond.
Failure to comply with FDA REMS requirements can render the company’s drug misbranded and result in substantial penalties (e.g., $250,000 to $1 MM cap per violation; $1 MM to $10 MM cap per proceeding).
- Check the following link For Approved Risk Evaluation and Mitigation Strategies (REMS) :
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Pre-exposer prophylaxis (PrEP)
Pre-exposure prophylaxis (PrEP) is any medical or public health procedure used before exposure to the disease causing agent, its purpose is to prevent, rather than treat or cure a disease. An example would be if a doctor gave a medication used to treat a disease to a healthy person who is not thought to have that disease, but is at risk for contracting it. More specifically, this practice is common with people who are about to travel from an area without Malaria to an area where malaria is a risk, and also it is being researched as a tool to prevent persons from contracting HIV. Pre-exposure prophylaxis can also refer to the aggressive use of vaccination, for example in an attempt to prevent Rabies in people such as laboratory workers who are high risk for being bitten by rabid animals.
Post-exposure prophylaxis (PEP)
Post-exposure prophylaxis (PEP) is any prophylactic treatment started immediately after exposure to a pathogen (such as a disease-causing virus), in order to prevent infection by the pathogen and the development of disease. PEP is commonly and very effectively used to prevent the outbreak of Rabies after a bite by a rabid animal. The treatment consists of repeated injections of Rabies vaccine and immunoglobulin. Tetanus post-exposure consists of 2 to 3 injections of tetanus vaccine and tetanus immunoglobulin, this treatment is also used in rabies post-exposure prophylaxis.
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