Practice Tip: FDA Issues Draft Guidance for REMS

The FDA's initial guidance on REMS provides, to some extent, a blueprint to minimize potential liability risks, but companies should watch out for future REMS recommendations from the Agency on topics not addressed in detail in the current REMS Guidance, such as provisions related to Abbreviated New Drug Applications (ANDAs), REMS assessments, and proposed modifications to REMS, among others.

Background on REMS

In the October 2009 issue of LJN's Product Liability Law & Strategy, we discussed how a REMS program might actually help minimize a company's risk.

Section 901 of the Food and Drug Administration Amendments Act (FDAAA) amended the Federal Food, Drug, and Cosmetic Act (FDCA) to add Section 505-1, 21 U.S.C. ' 355-1, which allowed the FDA to require applicants to submit a proposed REMS as part of certain drug or biologics applications to ensure the benefits of the drug or biologic would outweigh the risks. (Section 505-1 for REMS only applies to “covered applications,” defined as new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs). FDAAA allows FDA to require REMS for generic drugs whose reference product has an approved REMS, which will be addressed in future guidance.) At this time, the REMS Guidance provides that ANDAs, based on a reference listed drug with a REMS, will be approved with any applicable elements of the REMS.) In addition, the FDA was authorized to require holders of applications approved without a REMS to submit a proposed REMS if the Agency became aware of new safety information indicating that such action would be necessary to protect the public health. Applicants may also voluntarily submit a proposed REMS for the Agency's approval. (Prior to enactment of the FDAAA, the FDA approved a limited number of drug and biological products, whose risk could not be managed by labeling and safety reporting requirements, by requiring risk minimization action plans (RiskMAPs). Much like REMS, RiskMAPs are a strategic safety program with specific goals and objectives for limiting the known risks of a product while preserving its benefits. The FDA anticipates that, where the statutory requirements for a REMS are met, REMS will replace the need for RiskMAPS, but the Agency also notes that RiskMAPs in place prior to the effective date of the FDAAA, but not replaced or included in a REMS, will remain effective. The FDAAA also provided for the small number of drugs and biologics approved prior to its effective date, with postmarketing restrictions on distribution or other Elements to Assure Safe Use to have an approved REMS.)

A drug is considered misbranded, under 502(y) of the FDCA, if the applicant or the holder of the approved application fails to comply with a requirement of the approved strategy. 21 U.S.C. ' 352(y). Violations of a REMS requirement can result in civil monetary penalties of up to $250,000 per violation, not to exceed $1 million in a single proceeding. 21 U.S.C. ' 333(f)(4)(a). Penalties significantly increase for violations continuing for more than 30 days after the FDA has provided notice of violation, doubling for the second 30-day period and any subsequent 30-day periods, up to $1 million per period and $10 million per proceeding. In addition, a product may not be introduced or delivered for introduction into interstate commerce if non-compliant with a REMS. 21 U.S.C. ' 355(p).

Summary of Draft Guidance

Content and Format of a Proposed REMS Submission

The REMS Guidance provides that a REMS submission include two parts: 1) a proposed REMS, the primary document describing the proposed goals and elements of the REMS; and 2) a REMS-supporting document, which explains the rationale for the content of the proposed REMS and provides additional information. Prior to approval, the FDA may require applicants to revise a proposed REMS to ensure that the product's benefits will outweigh the risks.

Part One: A Proposed REMS

A proposed REMS should include concise information on the goals and elements of the REMS and clearly describe the responsibilities of the applicant in implementation, with a date of implementation for each REMS element. All materials proposed to be included as part of the REMS (e.g., communication and education materials, Medication Guide, patient package insert, enrollment forms, prescriber and patient agreements) should be attached with the proposed REMS. A template REMS document may be accessed on the FDA's Web site at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm. Further, the FDA has confirmed that it will not review or require REMS in foreign languages.

A proposed REMS should contain the following elements or include a statement that the element is unnecessary:

Product and Contact Information ' The application number, proprietary and established names, dosage form, drug class according to the product label, and applicant's name and address. Contact information, including position titles, should be provided for persons responsible for the REMS policy, management, and implementation.

Goals ' All REMS should include a statement of one or more overall goals. If the REMS includes an Element To Assure Safe Use (ETASU), at least one goal must address mitigating a serious risk listed in the labeling of the drug, for which ETASUs are required. (In order to provide patients with safe access to drugs with known serious risks that would otherwise be unavailable, ETASUs must be put in place to mitigate a specific serious risk listed in the labeling of a product. Before requiring an ETASU, the FDA must determine that the product is effective but is associated with a serious adverse drug experience and can only be approved if the ETASU were required. If the product was initially approved without an ETASU, the FDA must also find that other possible elements of a REMS are not sufficient to mitigate the serious risk.) In general, a proposed REMS goal should focus on the achievement of particular health outcomes or increasing awareness of safety risks to target maximum risk reduction in absolute terms. For instance, examples of REMS goals are “Fetal exposures to Z drug should not occur” or “Patients on X drug should not also be prescribed Y drug.”

Additional Potential REMS Elements ' The development of a Medication Guide (MedGuide), Patient Package Insert (PPI), or Communication Plan may be required as one REMS element.

MedGuide ' A MedGuide may be required if: 1) patient labeling may help to prevent a serious adverse effect; 2) patient awareness of the serious risks of the product (relative to the benefits) could affect his or her decision for use or continued use; or 3) patient adherence to instructions for use is crucial to the product's effectiveness. If a MedGuide is required, the REMS should describe the mechanisms intended to be used for distribution.

PPI ' A PPI may be required to help mitigate a serious risk of the product. The FDA indicates that very few products will require both a MedGuide and a PPI, although a PPI may be converted to a MedGuide if the FDA finds that patient labeling must meet MedGuide requirements. Editorial changes to a PPI or changes related to use of a product will not trigger the need for conversion, unless the changes are to mitigate a serious risk, such as an overdose.

Communication Plan ' A communication plan may include sending letters or disseminating information about REMS elements to healthcare providers or professional societies to encourage REMS implementation or explain safety protocols. Notably, if an NDA-approved product with a REMS Communication Plan is the basis for a subsequent ANDA, the FDA must carry out the Communication Plan once the ANDA is approved, instead of the NDA or the ANDA holder. However, both the NDA and the ANDA holder will still be responsible for implementation of tools that were previously part of the Communication Plan which may be covered under an ETASU (e.g., training materials, specified procedures, patient/physician agreements, patient educational materials, safety protocols).

ETASUs ' The proposed REMS should describe any ETASUs and the tools designed to implement them and contain copies of all relevant materials as attachments. The categories of ETASUs include:

Health Care Providers Who Prescribe the Drug Have Particular Training or Experience, or Are Specially Certified ' Elements under this category may relate to certification, training, or attestation of specific experience or knowledge before a healthcare provider can be enrolled in a prescriptive program. The program may require periodic recertification and enrollment, and the opportunity to obtain training or certification must be available to any provider at a reasonable cost.

Pharmacies, Practitioners, or Health Care Settings That Dispense the Drug Are Specially Certified ' Elements under this category may require certification, training, or attestation of specific experience or knowledge before the pharmacy, practitioner, or health care setting can be enrolled in a prescriptive program. The program may require periodic recertification and enrollment, and the opportunity to obtain training or certification must be available to any provider at a reasonable cost.

The Drug Be Dispensed to Patients Only in Certain Health Care Settings, Such As Hospitals ' Elements under this category may include restrictions on dispensing the product to patients in specific settings. Examples of implementation include ensuring the drug is dispensed only to patients in hospitals that have met certain conditions or to physicians' offices equipped to treat any potential risks after administration of the drug.

The Drug Be Dispensed Only to Patients with Evidence of Other Documentation of Safe-Use Conditions, Such As Laboratory Test Results ' Elements under this category may include restrictions on dispensing the product to patients that meet specified criteria before exposure. Examples of implementation include counseling patients about risks and benefits or ensuring patients receive a drug only after specified authorization is obtained and verified by a pharmacy.

Each Patient Using the Drug Must Be Subject to Certain Monitoring ' Elements under this category may require that patients be monitored or that specific follow-up occur at specific times. Examples of implementation include having patients' lab tests monitored on a specified periodic basis or requiring that patients contact the prescriber periodically during and after treatment.

Each Patient Using the Drug Must Be Enrolled in a Registry ' Elements under this category may require that patients enroll in a program as part of the overall strategy to mitigate a specific serious risk listed in the product labeling. Use of the registry may be combined with other ETASUs, and drug access may be contingent on patient enrollment.

Implementation System ' The FDA may require an implementation system for any REMS, which include the ETASUs outlined above. The applicant would be expected to take reasonable steps to monitor, evaluate and improve the implementation of the ETASUs by other parties who are responsible for implementation, such as healthcare providers and pharmacists. The FDA may require a description of the product's distribution or the certification of wholesalers or distributors to ensure the product is dispensed only to appropriate parties.

Timetable for Submission of Assessment of the REMS ' A description of the proposed timetable for submission of REMS assessments for NDAs and BLAs is required, but the FDA does not require that REMS for ANDAs have a timetable at this time. FDA provides that:

1. At a minimum, each timetable must include assessments submitted by 18 months, by three years, and in the seventh year after the REMS is initially approved. Additional dates for assessments may be required as necessary, and factors influencing this determination include, among others, the estimated size of the patient population for the product, the seriousness of known or potential risks, and any knowledge about the effectiveness of the REMS elements to mitigate the risk

2. The 18-month and three-year requirement can be met by assessments submitted at specified, but earlier dates, and the dates specified must relate to the submission, not the performance, of the assessments.

3. The reporting interval for an assessment should conclude no earlier than 60 days before its submission date to facilitate the full inclusion of all available information.

The conclusion of this article will explain part two of the procedure, including proposed modifications to the REMS and communicating with the FDA.

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.

On Sept. 30, 2009, the Food and Drug Administration (FDA) issued a draft guidance for industry on better understanding and implementing Risk Evaluation and Mitigation Strategies (REMS), which the FDA requires for certain drugs or biologics when the Agency believes additional precautions are necessary to ensure that the benefits of a drug or biologic outweigh its risks. The FDA is placing increased reliance on its REMS authority and, as a result, REMS assessments and implementation have placed increased demands on time, money, and resources for sponsors and for physicians and hospitals.

The draft document, Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modification (“REMS Guidance“), reveals the Agency's current thinking on the format and content that manufacturers should use in developing proposed REMS.

The REMS Guidance focuses on three main points: 1) the content of a proposed REMS submission; 2) REMS assessment and modification of proposed REMS; and 3) communicating with FDA about REMS. In addition, it provides useful background information about REMS and RiskMaps and includes an example of a REMS for a fictitious product. This Bulletin summarizes the statutory REMS provision and highlights of the REMS Guidance.

The FDA's initial guidance on REMS provides, to some extent, a blueprint to minimize potential liability risks, but companies should watch out for future REMS recommendations from the Agency on topics not addressed in detail in the current REMS Guidance, such as provisions related to Abbreviated New Drug Applications (ANDAs), REMS assessments, and proposed modifications to REMS, among others.

Background on REMS

In the October 2009 issue of LJN's Product Liability Law & Strategy, we discussed how a REMS program might actually help minimize a company's risk.

Section 901 of the Food and Drug Administration Amendments Act (FDAAA) amended the Federal Food, Drug, and Cosmetic Act (FDCA) to add Section 505-1, 21 U.S.C. ' 355-1, which allowed the FDA to require applicants to submit a proposed REMS as part of certain drug or biologics applications to ensure the benefits of the drug or biologic would outweigh the risks. (Section 505-1 for REMS only applies to “covered applications,” defined as new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs). FDAAA allows FDA to require REMS for generic drugs whose reference product has an approved REMS, which will be addressed in future guidance.) At this time, the REMS Guidance provides that ANDAs, based on a reference listed drug with a REMS, will be approved with any applicable elements of the REMS.) In addition, the FDA was authorized to require holders of applications approved without a REMS to submit a proposed REMS if the Agency became aware of new safety information indicating that such action would be necessary to protect the public health. Applicants may also voluntarily submit a proposed REMS for the Agency's approval. (Prior to enactment of the FDAAA, the FDA approved a limited number of drug and biological products, whose risk could not be managed by labeling and safety reporting requirements, by requiring risk minimization action plans (RiskMAPs). Much like REMS, RiskMAPs are a strategic safety program with specific goals and objectives for limiting the known risks of a product while preserving its benefits. The FDA anticipates that, where the statutory requirements for a REMS are met, REMS will replace the need for RiskMAPS, but the Agency also notes that RiskMAPs in place prior to the effective date of the FDAAA, but not replaced or included in a REMS, will remain effective. The FDAAA also provided for the small number of drugs and biologics approved prior to its effective date, with postmarketing restrictions on distribution or other Elements to Assure Safe Use to have an approved REMS.)

A drug is considered misbranded, under 502(y) of the FDCA, if the applicant or the holder of the approved application fails to comply with a requirement of the approved strategy. 21 U.S.C. ' 352(y). Violations of a REMS requirement can result in civil monetary penalties of up to $250,000 per violation, not to exceed $1 million in a single proceeding. 21 U.S.C. ' 333(f)(4)(a). Penalties significantly increase for violations continuing for more than 30 days after the FDA has provided notice of violation, doubling for the second 30-day period and any subsequent 30-day periods, up to $1 million per period and $10 million per proceeding. In addition, a product may not be introduced or delivered for introduction into interstate commerce if non-compliant with a REMS. 21 U.S.C. ' 355(p).

Summary of Draft Guidance

Content and Format of a Proposed REMS Submission

The REMS Guidance provides that a REMS submission include two parts: 1) a proposed REMS, the primary document describing the proposed goals and elements of the REMS; and 2) a REMS-supporting document, which explains the rationale for the content of the proposed REMS and provides additional information. Prior to approval, the FDA may require applicants to revise a proposed REMS to ensure that the product's benefits will outweigh the risks.

Part One: A Proposed REMS

A proposed REMS should include concise information on the goals and elements of the REMS and clearly describe the responsibilities of the applicant in implementation, with a date of implementation for each REMS element. All materials proposed to be included as part of the REMS (e.g., communication and education materials, Medication Guide, patient package insert, enrollment forms, prescriber and patient agreements) should be attached with the proposed REMS. A template REMS document may be accessed on the FDA's Web site at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm. Further, the FDA has confirmed that it will not review or require REMS in foreign languages.

A proposed REMS should contain the following elements or include a statement that the element is unnecessary:

Product and Contact Information ' The application number, proprietary and established names, dosage form, drug class according to the product label, and applicant's name and address. Contact information, including position titles, should be provided for persons responsible for the REMS policy, management, and implementation.

Goals ' All REMS should include a statement of one or more overall goals. If the REMS includes an Element To Assure Safe Use (ETASU), at least one goal must address mitigating a serious risk listed in the labeling of the drug, for which ETASUs are required. (In order to provide patients with safe access to drugs with known serious risks that would otherwise be unavailable, ETASUs must be put in place to mitigate a specific serious risk listed in the labeling of a product. Before requiring an ETASU, the FDA must determine that the product is effective but is associated with a serious adverse drug experience and can only be approved if the ETASU were required. If the product was initially approved without an ETASU, the FDA must also find that other possible elements of a REMS are not sufficient to mitigate the serious risk.) In general, a proposed REMS goal should focus on the achievement of particular health outcomes or increasing awareness of safety risks to target maximum risk reduction in absolute terms. For instance, examples of REMS goals are “Fetal exposures to Z drug should not occur” or “Patients on X drug should not also be prescribed Y drug.”

Additional Potential REMS Elements ' The development of a Medication Guide (MedGuide), Patient Package Insert (PPI), or Communication Plan may be required as one REMS element.

MedGuide ' A MedGuide may be required if: 1) patient labeling may help to prevent a serious adverse effect; 2) patient awareness of the serious risks of the product (relative to the benefits) could affect his or her decision for use or continued use; or 3) patient adherence to instructions for use is crucial to the product's effectiveness. If a MedGuide is required, the REMS should describe the mechanisms intended to be used for distribution.

PPI ' A PPI may be required to help mitigate a serious risk of the product. The FDA indicates that very few products will require both a MedGuide and a PPI, although a PPI may be converted to a MedGuide if the FDA finds that patient labeling must meet MedGuide requirements. Editorial changes to a PPI or changes related to use of a product will not trigger the need for conversion, unless the changes are to mitigate a serious risk, such as an overdose.

Communication Plan ' A communication plan may include sending letters or disseminating information about REMS elements to healthcare providers or professional societies to encourage REMS implementation or explain safety protocols. Notably, if an NDA-approved product with a REMS Communication Plan is the basis for a subsequent ANDA, the FDA must carry out the Communication Plan once the ANDA is approved, instead of the NDA or the ANDA holder. However, both the NDA and the ANDA holder will still be responsible for implementation of tools that were previously part of the Communication Plan which may be covered under an ETASU (e.g., training materials, specified procedures, patient/physician agreements, patient educational materials, safety protocols).

ETASUs ' The proposed REMS should describe any ETASUs and the tools designed to implement them and contain copies of all relevant materials as attachments. The categories of ETASUs include:

Health Care Providers Who Prescribe the Drug Have Particular Training or Experience, or Are Specially Certified ' Elements under this category may relate to certification, training, or attestation of specific experience or knowledge before a healthcare provider can be enrolled in a prescriptive program. The program may require periodic recertification and enrollment, and the opportunity to obtain training or certification must be available to any provider at a reasonable cost.

Pharmacies, Practitioners, or Health Care Settings That Dispense the Drug Are Specially Certified ' Elements under this category may require certification, training, or attestation of specific experience or knowledge before the pharmacy, practitioner, or health care setting can be enrolled in a prescriptive program. The program may require periodic recertification and enrollment, and the opportunity to obtain training or certification must be available to any provider at a reasonable cost.

The Drug Be Dispensed to Patients Only in Certain Health Care Settings, Such As Hospitals ' Elements under this category may include restrictions on dispensing the product to patients in specific settings. Examples of implementation include ensuring the drug is dispensed only to patients in hospitals that have met certain conditions or to physicians' offices equipped to treat any potential risks after administration of the drug.

The Drug Be Dispensed Only to Patients with Evidence of Other Documentation of Safe-Use Conditions, Such As Laboratory Test Results ' Elements under this category may include restrictions on dispensing the product to patients that meet specified criteria before exposure. Examples of implementation include counseling patients about risks and benefits or ensuring patients receive a drug only after specified authorization is obtained and verified by a pharmacy.

Each Patient Using the Drug Must Be Subject to Certain Monitoring ' Elements under this category may require that patients be monitored or that specific follow-up occur at specific times. Examples of implementation include having patients' lab tests monitored on a specified periodic basis or requiring that patients contact the prescriber periodically during and after treatment.

Each Patient Using the Drug Must Be Enrolled in a Registry ' Elements under this category may require that patients enroll in a program as part of the overall strategy to mitigate a specific serious risk listed in the product labeling. Use of the registry may be combined with other ETASUs, and drug access may be contingent on patient enrollment.

Implementation System ' The FDA may require an implementation system for any REMS, which include the ETASUs outlined above. The applicant would be expected to take reasonable steps to monitor, evaluate and improve the implementation of the ETASUs by other parties who are responsible for implementation, such as healthcare providers and pharmacists. The FDA may require a description of the product's distribution or the certification of wholesalers or distributors to ensure the product is dispensed only to appropriate parties.

Timetable for Submission of Assessment of the REMS ' A description of the proposed timetable for submission of REMS assessments for NDAs and BLAs is required, but the FDA does not require that REMS for ANDAs have a timetable at this time. FDA provides that:

1. At a minimum, each timetable must include assessments submitted by 18 months, by three years, and in the seventh year after the REMS is initially approved. Additional dates for assessments may be required as necessary, and factors influencing this determination include, among others, the estimated size of the patient population for the product, the seriousness of known or potential risks, and any knowledge about the effectiveness of the REMS elements to mitigate the risk

2. The 18-month and three-year requirement can be met by assessments submitted at specified, but earlier dates, and the dates specified must relate to the submission, not the performance, of the assessments.

3. The reporting interval for an assessment should conclude no earlier than 60 days before its submission date to facilitate the full inclusion of all available information.

The conclusion of this article will explain part two of the procedure, including proposed modifications to the REMS and communicating with the FDA.

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.