40. Medicine Safety Plans – RMP and REMS

In many countries, special medicine safety plans may be required as part of a medicine’s approval process and to retain its approved status. 

These plans are required as per: 

• The International Conference on Harmonisation’s (ICH) Harmonised Tripartite Guideline: Pharmacovigilance Planning—E2E.
• The European Medicines Agency’s (EMA) Guideline on Risk Management Systems for Medicinal Products for Human Use.
• EMA’s Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use.
• The U.S. Food and Drug Administration Amendments Act (FDAAA) and the FDA’s Guidance for Industry Format and Content for Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications.

The RMP (EU) and the REMS (USA) are now a standard part of pharmacovigilance planning.

Risk Management Plan (RMP):

In the EU, the RMP is a required part of the marketing authorization (MA) application for all products using the Centralized Authorization procedure (which is almost all new products). 

RMPs include information on:

• Safety profile of the medicine at that time in its life-cycle, either during preclinical testing, pre-approval clinical development, or pre-approval
• how its risks will be prevented or minimised in patients;
• plans for studies and other activities to gain more knowledge about the safety and efficacy of the medicine;
• measuring the effectiveness of risk-minimisation measures.

Pharmacovigilance and risk management activities that might be included in an RMP fall into two categories: 

Routine activities – which would generally be conducted for any medicine at the same stage of development where no special safety concerns have arisen. Routine risk management activities would include ensuring that suitable warnings are included with all product information and careful labeling and packaging of the medicine.

Additional activities designed to address identified safety concerns in the form of:

• Active surveillance (e.g., medical records reviews, patient or physician interviews, prescription event monitoring, data from disease or drug exposure registries).
• Epidemiology studies (retrospective or prospective).
• Further clinical studies (specific safety studies, larger studies over longer periods).
• Drug utilization studies (which describe how a drug is marketed, prescribed, and used in a specified population—often stratified by age, gender, concomitant medications, etc—and how these factors influence clinical, social, and economic outcomes). 

RMPs are continually modified and updated throughout the lifetime of the medicine as new information becomes available. Companies need to submit an updated RMP:

• at the request of EMA or an NCA;
• whenever the risk-management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit-risk profile or as a result of an important pharmacovigilance or risk-minimisation milestone being reached.

RMPs can only be submitted at the same time as the periodic safety update report (PSUR) if the change in the RMP comes as a consequence of the PSUR.

Risk Evaluation and Mitigation Strategy (REMS):

• A REMS is developed to help ensure that the benefits of a medicine outweigh its risks. 
• A REMS may be required by the FDA as part of the approval process for a new product, or for an approved product when new safety information emerges. 
• A REMS is a strategy to manage a known or potential serious risk associated with a medicine. Its purpose is to allow patients continued access to certain medicines for which there are safety concerns that may be managed through appropriate use. 

A REMS may also include one or more of:

• A Medication Guide. (This may also be a stand-alone requirement.)
• A patient package insert.
• A communication plan to disseminate information to health care providers in support of the strategy.
• Elements to Assure Safe Use (ETASUs) of the product, such as:
• > Special training or certification for health care professionals who prescribe or dispense the medicine.
• > Dispensing the medicine only in certain settings (e.g., in a hospital) or with evidence of safe use conditions (e.g., laboratory test results).
• > Monitoring or registration of each patient using the medicine.
• An implementation system for certain elements to ensure safe use.

Proposed revisions to an existing REMS may be submitted based on the results of assessments or when new safety information arises.