Practice Tip: FDA Issues Draft Guidance for REMS

Background

This section should provide a concise summary explaining the necessity of the proposed REMS and how the plan will verify that the benefits of the product outweigh the risks. In addition, the FDA provides that:

• An initial REMS for a previously approved product should describe the new safety information suggesting the need for the REMS;
• Detailed information about the risk to be minimized should be provided, and the following factors, which the FDA must consider in determining whether a REMS is necessary, should be addressed: the estimated size of the patient population; the seriousness of the disease or condition treated; the expected benefit of the product to the disease or condition; the duration of treatment; the risks and benefits of alternative therapies; and whether the drug is a new molecular entity; and
• Discussion of historical information about any successes and failures related to mitigating the risks for the specified product or similar products may be provided, as well as any information on relevant past experiences that would help in the development of the proposed REMS.

Goals

A summary of the rationale for the proposed goals of the REMS, describing how the elements will individually and collectively contribute, should be provided.

Supporting Information About Proposed REMS Elements

Describe why each element or tool was chosen for the proposed REMS and indicate how each tool contributes to the goals of the REMS. The FDA notes:

• Each method used to monitor and evaluate the implementation system should be discussed along with any plans to improve implementation.
• The rationale and supporting information for the proposed timetable should be provided, addressing each interval that each assessment will cover as well as the planned date for submission to the FDA.
• The applicant should give a thorough description of the available evidence, indicate whether any input was obtained from patient or health care interests, and discuss any feedback that was received regarding the feasibility of the proposed REMS.

Supporting Information with Elements to Assure Safe Use (ETASUs)

Proposed REMS that include ETASUs should include: 1) An explanation of how the ETASUs correspond to the specific serious risks listed in the labeling; 2) An explanation of how the ETASUs mitigate the observed serious risk; 3) Verification that the elements proposed are not unduly burdensome on patient access for patients with serious or life-threatening diseases or difficulty with access to health care; and 4) A description of how the ETASUs will minimize the burden on the health care delivery system, including discussion of any other drugs that pose similar risks to provide further information about the compatibility of proposed ETASUs with established health care delivery systems.

REMS Assessment Plan

REMS Assessments measure whether the goals are being met, and the proposed plan to assess the REMS should be fully explained in this section. Information should include the proposed evaluation methods, targeted values and time frames for each measure, the type of data collected and timing for data collection, and any applicable plans to assess unintended or unfavorable consequences. Plans to obtain information on the effectiveness of REMS elements to meet the stated goals or the need to modify the goals or the REMS elements should be included. The FDA requires that specific assessment instruments and methodology should be identified, and such information, once it is available, should be submitted to the FDA to update the REMS supporting documents at least 90 days before the assessments are conducted. In general, each assessment should contain sufficient detail to identify any need for changes to the REMS. In addition:

• For REMS that include an ETASU, the assessment must consider the extent to which the ETASUs are meeting the goal.
• For REMS with a MedGuide, the assessment should include a survey of the patients' understanding of the risks of the product, a report on periodic assessments of the distribution of the MedGuide, and a report on any failures as well as corrective actions to address non-compliance.

Required Postapproval Studies or Clinical Trials

The status of any post-approval study required or otherwise undertaken to investigate a safety issue must be included in the assessment. Specifically, the assessment must include the status of each clinical trial, the number of participants enrolled, the expected completion date, any difficulties encountered with completing the trial, and the clinical trial's registration information. A reference to the relevant information in the applicant's most recent annual report, with any updates since the report was prepared, may suffice to satisfy the requirement for information on the status of the post-approval study or clinical trial.

Other Relevant Information

This section should include information on positions within the applicant's company responsible for REMS policy, management, and implementation, with organizational charts, and any other information that is relevant to the proposed REMS.

REMS Assessment and Proposed Modifications of REMS

As noted above, REMS assessments must be submitted in accordance with the timetable included in the proposed REMS. Applicants may voluntarily submit assessments, and the FDA may also require additional REMS assessments. For example, the FDA may require an assessment when a supplemental application is submitted for a new indication for use or where the Agency determines that new safety or effectiveness information suggests that the assessment timetable requires modification or that a cause for withdrawal or suspension of the approved REMS exists.

After approval of the REMS, applicants may request proposed modifications to enhance or reduce the REMS requirements, including potential changes to any materials included as part of the REMS. Applicants may also ask for changes to the assessment timetable, including the elimination of any assessments after the three-year submission.

Proposed modifications should be submitted to the FDA using a new prior-approval supplemental application and may not be implemented until the FDA gives approval. Each proposed modification should include the new proposed REMS with the previous approved REMS, with all proposed modifications highlighted, along with an update to the REMS supporting document for the rationale and the impact of the changes on other REMS elements. The FDA intends to provide more detailed guidance on assessments and modifications to approved REMS in the future.

Communicating with the FDA About REMS

A proposed REMS may be submitted in the product's original drug application, a supplemental application, or as an amendment to an original or supplemental marketing application. The FDA specifically provides that:

• All supplemental applications that include a proposed REMS or for proposed modifications to an approved REMS should be submitted as prior-approval supplements;
• A proposed REMS submitted after approval, which is not associated with an existing supplemental application, should be filed as a new supplemental application;
• Although a REMS assessment alone, without a proposed modification, is not considered a supplemental application, REMS assessments with a proposed modification to the approved REMS may be submitted as either a new supplemental application or a related supplemental application, at the time of admission or as an amendment; and
• With few exceptions for those drugs not subject to Section 503(b) of the FDCA (e.g., non-prescription drugs) where the REMS includes only the timetable for the submission of assessments, a supplemental application for a new indication for use for a product with an approved REMS must include a REMS assessment and may propose modifications to the REMS.

A template for submissions of proposed REMS and proposed modifications of approved REMS is available on FDA's Web site at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm. The Agency requests that applicants also include electronic versions of the documents to facilitate processing. In addition, the REMS Guidance emphasizes that each submission, whether a proposed REMS application or REMS assessment, should provide identifying information to allow for tracking and provides detailed instructions for the labeling of each type of submission. The FDA notes that applicants may contact the regulatory project manager in the division assigned to the drug for questions, while the Director of the Division of Labeling and Program Support in the Office of Generic Drugs will be the primary contact for ANDA applicants.

Conclusion

For obvious commercial reasons, companies would prefer not to have to adopt a REMS program. However, if the FDA mandates such a program as a condition of approval or continued marketing, the FDA's draft guidance offers an outline for companies seeking to prepare a robust and quality system, which should help minimize product liability risk.

Alan G. Minsk, a member of this newsletter's Board of Editors, is a Partner and Leader of the Food and Drug Practice Team of Arnall Golden Gregory LLP. E-mail: [email protected]. Phone: 404-873-8690. Lanchi Nguyen is an associate of the firm in the Health Care and Life Sciences Practice Group.

The first part of this article discussed the background of REMS (Risk Evaluation and Mitigation Strategies) and provided a summary of the Draft Guidance, including the content and format of a proposed REMS submission. The conclusion of the article herein explains the second part of the procedure, including proposed modifications and communicating with the FDA.

Part Two: REMS Supporting Documentation

The REMS supporting documents should include a detailed explanation of the rationale for the proposed REMS, including how and when each REMS element will be implemented and the basis for the timeline, in addition to all supporting information for the REMS. The REMS Guidance notes that a template for the REMS supporting document is available on the FDA's Web site at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm. The FDA notes the documents should include the following sections listed as well as a table of contents:

Background

This section should provide a concise summary explaining the necessity of the proposed REMS and how the plan will verify that the benefits of the product outweigh the risks. In addition, the FDA provides that:

• An initial REMS for a previously approved product should describe the new safety information suggesting the need for the REMS;
• Detailed information about the risk to be minimized should be provided, and the following factors, which the FDA must consider in determining whether a REMS is necessary, should be addressed: the estimated size of the patient population; the seriousness of the disease or condition treated; the expected benefit of the product to the disease or condition; the duration of treatment; the risks and benefits of alternative therapies; and whether the drug is a new molecular entity; and
• Discussion of historical information about any successes and failures related to mitigating the risks for the specified product or similar products may be provided, as well as any information on relevant past experiences that would help in the development of the proposed REMS.

Goals

A summary of the rationale for the proposed goals of the REMS, describing how the elements will individually and collectively contribute, should be provided.

Supporting Information About Proposed REMS Elements

Describe why each element or tool was chosen for the proposed REMS and indicate how each tool contributes to the goals of the REMS. The FDA notes:

• Each method used to monitor and evaluate the implementation system should be discussed along with any plans to improve implementation.
• The rationale and supporting information for the proposed timetable should be provided, addressing each interval that each assessment will cover as well as the planned date for submission to the FDA.
• The applicant should give a thorough description of the available evidence, indicate whether any input was obtained from patient or health care interests, and discuss any feedback that was received regarding the feasibility of the proposed REMS.

Supporting Information with Elements to Assure Safe Use (ETASUs)

Proposed REMS that include ETASUs should include: 1) An explanation of how the ETASUs correspond to the specific serious risks listed in the labeling; 2) An explanation of how the ETASUs mitigate the observed serious risk; 3) Verification that the elements proposed are not unduly burdensome on patient access for patients with serious or life-threatening diseases or difficulty with access to health care; and 4) A description of how the ETASUs will minimize the burden on the health care delivery system, including discussion of any other drugs that pose similar risks to provide further information about the compatibility of proposed ETASUs with established health care delivery systems.

REMS Assessment Plan

REMS Assessments measure whether the goals are being met, and the proposed plan to assess the REMS should be fully explained in this section. Information should include the proposed evaluation methods, targeted values and time frames for each measure, the type of data collected and timing for data collection, and any applicable plans to assess unintended or unfavorable consequences. Plans to obtain information on the effectiveness of REMS elements to meet the stated goals or the need to modify the goals or the REMS elements should be included. The FDA requires that specific assessment instruments and methodology should be identified, and such information, once it is available, should be submitted to the FDA to update the REMS supporting documents at least 90 days before the assessments are conducted. In general, each assessment should contain sufficient detail to identify any need for changes to the REMS. In addition:

• For REMS that include an ETASU, the assessment must consider the extent to which the ETASUs are meeting the goal.
• For REMS with a MedGuide, the assessment should include a survey of the patients' understanding of the risks of the product, a report on periodic assessments of the distribution of the MedGuide, and a report on any failures as well as corrective actions to address non-compliance.

Required Postapproval Studies or Clinical Trials

The status of any post-approval study required or otherwise undertaken to investigate a safety issue must be included in the assessment. Specifically, the assessment must include the status of each clinical trial, the number of participants enrolled, the expected completion date, any difficulties encountered with completing the trial, and the clinical trial's registration information. A reference to the relevant information in the applicant's most recent annual report, with any updates since the report was prepared, may suffice to satisfy the requirement for information on the status of the post-approval study or clinical trial.

Other Relevant Information

This section should include information on positions within the applicant's company responsible for REMS policy, management, and implementation, with organizational charts, and any other information that is relevant to the proposed REMS.

REMS Assessment and Proposed Modifications of REMS

As noted above, REMS assessments must be submitted in accordance with the timetable included in the proposed REMS. Applicants may voluntarily submit assessments, and the FDA may also require additional REMS assessments. For example, the FDA may require an assessment when a supplemental application is submitted for a new indication for use or where the Agency determines that new safety or effectiveness information suggests that the assessment timetable requires modification or that a cause for withdrawal or suspension of the approved REMS exists.

After approval of the REMS, applicants may request proposed modifications to enhance or reduce the REMS requirements, including potential changes to any materials included as part of the REMS. Applicants may also ask for changes to the assessment timetable, including the elimination of any assessments after the three-year submission.

Proposed modifications should be submitted to the FDA using a new prior-approval supplemental application and may not be implemented until the FDA gives approval. Each proposed modification should include the new proposed REMS with the previous approved REMS, with all proposed modifications highlighted, along with an update to the REMS supporting document for the rationale and the impact of the changes on other REMS elements. The FDA intends to provide more detailed guidance on assessments and modifications to approved REMS in the future.

Communicating with the FDA About REMS

A proposed REMS may be submitted in the product's original drug application, a supplemental application, or as an amendment to an original or supplemental marketing application. The FDA specifically provides that:

• All supplemental applications that include a proposed REMS or for proposed modifications to an approved REMS should be submitted as prior-approval supplements;
• A proposed REMS submitted after approval, which is not associated with an existing supplemental application, should be filed as a new supplemental application;
• Although a REMS assessment alone, without a proposed modification, is not considered a supplemental application, REMS assessments with a proposed modification to the approved REMS may be submitted as either a new supplemental application or a related supplemental application, at the time of admission or as an amendment; and
• With few exceptions for those drugs not subject to Section 503(b) of the FDCA (e.g., non-prescription drugs) where the REMS includes only the timetable for the submission of assessments, a supplemental application for a new indication for use for a product with an approved REMS must include a REMS assessment and may propose modifications to the REMS.

A template for submissions of proposed REMS and proposed modifications of approved REMS is available on FDA's Web site at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm. The Agency requests that applicants also include electronic versions of the documents to facilitate processing. In addition, the REMS Guidance emphasizes that each submission, whether a proposed REMS application or REMS assessment, should provide identifying information to allow for tracking and provides detailed instructions for the labeling of each type of submission. The FDA notes that applicants may contact the regulatory project manager in the division assigned to the drug for questions, while the Director of the Division of Labeling and Program Support in the Office of Generic Drugs will be the primary contact for ANDA applicants.

Conclusion

For obvious commercial reasons, companies would prefer not to have to adopt a REMS program. However, if the FDA mandates such a program as a condition of approval or continued marketing, the FDA's draft guidance offers an outline for companies seeking to prepare a robust and quality system, which should help minimize product liability risk.

Alan G. Minsk, a member of this newsletter's Board of Editors, is a Partner and Leader of the Food and Drug Practice Team of Arnall Golden Gregory LLP. E-mail: [email protected]. Phone: 404-873-8690. Lanchi Nguyen is an associate of the firm in the Health Care and Life Sciences Practice Group.