REMS, Risk and Reward

On Sept. 27, 2007, President George Bush signed into law the Food and Drug Administration Amendments Act of 2007 (commonly referred to as FDAAA), which amended the Federal Food, Drug, and Cosmetic Act (FDC Act). Newly created section 505-1 of the FDC Act authorizes the FDA to require certain types of marketing applications to include a REMS if the FDA determines that a REMS is necessary to assure the safe use of the drug, because of its inherent toxicity or potential harmfulness. 21 U.S.C. ' 355-1. This provision became effective on March 25, 2008. Due to space limitations, we will highlight only certain sections of the law.

A REMS program is a strategy to manage a known or potential serious risk associated with a drug or biological product. Some drug and biological products that previously were approved or licensed with risk minimization action plans, known as RiskMAPs, will now be considered to have a REMS program. 73 Fed. Reg. 16313. Elements to assure safe use may require:

• Health care providers who prescribe the drug have particular training or experience, or are specially certified;
• Pharmacies, practitioners, or health care settings that dispense the drug are specially certified;
• The drug is dispensed to patients only in certain health care settings, such as hospitals:
• The drug is dispensed to patients with evidence or other documentation of safe use conditions, such as laboratory test results;
• Each patient using the drug is subject to certain monitoring; or
• Each patient using the drug is enrolled in a registry.

21 U.S.C. ' 355-1(f)(3).

The opportunity to obtain training or certification for a drug should be made available to any willing providers at a reasonable cost, as approved by the Secretary of the Department of Health and Human Services. Id.

• During the new drug approval process, the FDA will determine whether a REMS is required. In evaluating whether to require a REMS, the FDA must consider: The estimated size of the population likely to use the drug involved;
• The seriousness of the disease or condition that is to be treated with the drug;
• The expected benefit of the drug with respect to such disease or condition;
• The expected or actual duration of treatment with the drug;
• The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug; and
• Whether the drug is a new molecular entity.

21 U.S.C. ' 355-1(a)(1).

If the FDA concludes a REMS is needed and notifies the drug sponsor of this decision, the sponsor of the application must submit a proposed REMS and it will be approved when the drug is approved. If a product is already approved, and the agency becomes aware of new safety information that suggests a REMS is necessary for that drug (i.e., to ensure that the drug's benefits outweighs its risks), it may require a REMS. 21 U.S.C. ' 355-1(a)(2). FDAAA defines “new safety information” as:

information derived from a clinical trial, an adverse event report, a post-approval study [ ], or peer-reviewed biomedical literature; data derived from the post market risk identification and analysis system [ ]; or other scientific data deemed appropriate by the Secretary about a serious risk or an unexpected serious risk associated with use of the drug that the Secretary has become aware of (that may be based on a new analysis of existing information) since the drug was approved, since the risk evaluation and mitigation strategy and mitigation strategy was required, or since the last assessment of the approved risk evaluation and mitigation strategy for the drug; or the effectiveness of the approved risk evaluation and mitigation strategy for the drug obtained since the last assessment of the strategy.

21 U.S.C. ' 355-1(b)(3).

The FDA will not approve a marketing application without a REMS, if required; the agency has issued Complete Response Letters in which sponsors were requested to submit a REMS proposal as a condition for approval.

All REMS must include a timetable for assessing their effectiveness. For a post-approval REMS, sponsors must submit a proposal within 120 days of receiving FDA notification that a REMS is required, and provide status reports at 18 months, three years and seven years after the REMS is approved. See, e.g., 21 U.S.C. ” 355-1(a)(2)(B) and 355-1(d). The FDA plans to issue developing REMS guidance for industry in the future.

The FDA can establish a REMS to mitigate a drug product's risks, even if the drug is effective but has serious risks. 21 U.S.C. ' 355-1(f)(1). The law requires the FDA to post a statement on its Web site within 30 days of imposing a REMS, which should explain how the strategy will mitigate the risk. Id. at ' 355-1(f)(2)(B). If the FDA imposes a REMS under this provision, it must make sure that the plan is commensurate with the risk involved, such as whether the strategy will be unduly burdensome on patient access to the drug. Id. at ' 355-1(f)(2)(C).

A responsible person may submit an assessment of, and modification to, a REMS at any time. 21 U.S.C. ' 355-1(g)(1). The law describes when assessments are required. Id. at ' 355-1(g)(2). The law also provides for dispute resolution. 21 U.S.C. ' 355-1(h)(4)-(5).

On March 27, 2008, the FDA identified a number of drugs and biological products that were approved or licensed with such safe use elements (e.g., required by regulation or otherwise agreed to by the sponsor) and considered to have a REMS. 73 Fed. Reg. 16313. To minimize risks, some products, for example, include a Medication Guide, a communication or educational plan for healthcare providers or patients. (However, the FDAAA notes that a drug will not be considered to have a REMS if it has only a Medication Guide, patient package insert, and/or communication plan. 21 U.S.C.
' 355-1(e)(2) and (e)(3).)

Since the enactment of FDAAA, the FDA has approved additional REMS programs, covering a wide variety of therapeutic areas. The specific restrictions vary among products. The agency has also notified manufacturers of certain marketed products that a REMS is required based upon new safety information. For example, on Feb. 6, 2009, the FDA notified sponsors of certain opioid drug products that they will be required to develop a REMS strategy. See, e.g., “A Guide to Safe Use of Pain Medicine,” FDA Consumer Health Information, Feb. 23, 2009.

In addition, the FDAAA requires that the FDA conduct regular, bi-weekly screening of its Adverse Event Reporting System database and post a quarterly report of any new safety information or potential signal of a serious risk. 21 U.S.C. ' 355(k)(5). Therefore, one can expect more REMS requests as the FDA analyzes the safety data relating to drugs on the market.

Penalties for violating REMS requirements can be costly, up to $250,000 per violation, or up to $1 million for all violations adjudicated in a single proceeding. In the case of a continuing violation, after the Secretary has provided written notice to the responsible person, the responsible person shall be subject to a civil monetary penalty of $250,000 for the first 30-day period, and such amount shall double for every 30-day period thereafter that the violation continues, up to $1 million for any 30-day period, but not to exceed $10 million for all such violations adjudicated in a single proceeding. 21 U.S.C. ' 333(f).

Discussion

A drug company, understandably, would prefer that the FDA not mandate a REMS for its product. The costs to implement such a system will result in increased costs for product distribution and marketing, whether to prepare specific communications tools, establish training systems for doctors, create monitoring or registry programs, or design limited dispensing procedures. In addition, mechanisms required to ensure the safe use of the product can negatively affect product sales, whether, for example, due to restrictions on product availability, or a physician's reluctance to prescribe with restrictions or additional responsibilities. REMS is not ideal from a marketing perspective, although it might be necessary to obtain FDA approval of the drug product.

In addition to potential negative distribution and marketing consequences, a REMS program might create an impression on the doctor, pharmacist, and patient that the specific drug product presents a higher safety risk than other products on the market that treat the same disease. Moreover, if an injury or adverse event arises, the product's need for a REMS might heighten its liability exposure and the risk of a lawsuit. That is, there is increased scrutiny because of the drug's risk profile.

The aforementioned concerns cannot be discounted and are real. Products with REMS present a different level of safety risk; otherwise, the FDA would not have required a particular REMS. However, it is important to recognize that, even if the FDA imposes such a program for a drug, it nevertheless has concluded that the product remains safe and effective and can be prescribed, albeit with some limitations. The FDA has the authority not to approve a product or, if the drug is already on the market, to recommend corrective action or even withdraw approval of the drug. The imposition of a REMS is a delicate balance, which allows a product to be sold because its benefits outweigh the risks, while establishing a system to minimize these risks.

It is also important to recognize that all drugs have inherent safety issues, which require warnings, contraindications, and precautions. REMS actually focuses on the evaluation of a product's risk profile early and often by communicating effectively these risks with health care professionals and patients. A REMS might actually help a drug company minimize, even if not completely eliminate, potential liability risks. Recent case law, which has been discussed in other editions of this newsletter, makes clear that preemption and an FDA approval might not immunize a company from liability exposure due to alleged injuries sustained by use of a particular drug, but a REMS program, if followed by the sponsor company, essentially becomes an additional safeguard and protective fence to maximize the product's safe use which, conversely, should help minimize risk.

Alan Minsk, a member of this newsletter's Board of Editors, is a Partner and Leader of the Food and Drug Practice Team at Arnall Golden Gregory LLP. Lanchi Nguyen is an associate in the firm's Food and Drug and Healthcare Practice Teams. They advise pharmaceutical and medical device companies on Food and Drug Administration-related legal and regulatory issues. Mr. Minsk can be reached at [email protected] or 404-873-8690, and Ms. Nguyen can be reached at [email protected] or 404-873-8520.

REMS, while not to be confused with R.E.M., the Athens, GA-based rock band, is becoming almost as ubiquitous and as influential on its respective audience. REMS, or Risk Evaluation and Mitigation Strategy, is a new tool that Congress provided the Food and Drug Administration to ensure the safe use of certain types of prescription drug products. REMS is an extension of Congress and the FDA's renewed emphasis on drug safety and proactive risk management. The FDA may require a drug manufacturer to include a REMS in its new drug application when the agency concludes this is necessary to ensure that the benefits of the drug outweigh its risks.

On first review, one might conclude drugs that require a REMS present an increased liability risk for drug manufacturers because of safety-related concerns. Perhaps, it will in a particular case. However, REMS, while potentially negatively affecting product sales, might actually help minimize liability risk, if the company follows the conditions described in the program.

Regulatory Overview of REMS

On Sept. 27, 2007, President George Bush signed into law the Food and Drug Administration Amendments Act of 2007 (commonly referred to as FDAAA), which amended the Federal Food, Drug, and Cosmetic Act (FDC Act). Newly created section 505-1 of the FDC Act authorizes the FDA to require certain types of marketing applications to include a REMS if the FDA determines that a REMS is necessary to assure the safe use of the drug, because of its inherent toxicity or potential harmfulness. 21 U.S.C. ' 355-1. This provision became effective on March 25, 2008. Due to space limitations, we will highlight only certain sections of the law.

A REMS program is a strategy to manage a known or potential serious risk associated with a drug or biological product. Some drug and biological products that previously were approved or licensed with risk minimization action plans, known as RiskMAPs, will now be considered to have a REMS program. 73 Fed. Reg. 16313. Elements to assure safe use may require:

• Health care providers who prescribe the drug have particular training or experience, or are specially certified;
• Pharmacies, practitioners, or health care settings that dispense the drug are specially certified;
• The drug is dispensed to patients only in certain health care settings, such as hospitals:
• The drug is dispensed to patients with evidence or other documentation of safe use conditions, such as laboratory test results;
• Each patient using the drug is subject to certain monitoring; or
• Each patient using the drug is enrolled in a registry.

21 U.S.C. ' 355-1(f)(3).

The opportunity to obtain training or certification for a drug should be made available to any willing providers at a reasonable cost, as approved by the Secretary of the Department of Health and Human Services. Id.

• During the new drug approval process, the FDA will determine whether a REMS is required. In evaluating whether to require a REMS, the FDA must consider: The estimated size of the population likely to use the drug involved;
• The seriousness of the disease or condition that is to be treated with the drug;
• The expected benefit of the drug with respect to such disease or condition;
• The expected or actual duration of treatment with the drug;
• The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug; and
• Whether the drug is a new molecular entity.

21 U.S.C. ' 355-1(a)(1).

If the FDA concludes a REMS is needed and notifies the drug sponsor of this decision, the sponsor of the application must submit a proposed REMS and it will be approved when the drug is approved. If a product is already approved, and the agency becomes aware of new safety information that suggests a REMS is necessary for that drug (i.e., to ensure that the drug's benefits outweighs its risks), it may require a REMS. 21 U.S.C. ' 355-1(a)(2). FDAAA defines “new safety information” as:

information derived from a clinical trial, an adverse event report, a post-approval study [ ], or peer-reviewed biomedical literature; data derived from the post market risk identification and analysis system [ ]; or other scientific data deemed appropriate by the Secretary about a serious risk or an unexpected serious risk associated with use of the drug that the Secretary has become aware of (that may be based on a new analysis of existing information) since the drug was approved, since the risk evaluation and mitigation strategy and mitigation strategy was required, or since the last assessment of the approved risk evaluation and mitigation strategy for the drug; or the effectiveness of the approved risk evaluation and mitigation strategy for the drug obtained since the last assessment of the strategy.

21 U.S.C. ' 355-1(b)(3).

The FDA will not approve a marketing application without a REMS, if required; the agency has issued Complete Response Letters in which sponsors were requested to submit a REMS proposal as a condition for approval.

All REMS must include a timetable for assessing their effectiveness. For a post-approval REMS, sponsors must submit a proposal within 120 days of receiving FDA notification that a REMS is required, and provide status reports at 18 months, three years and seven years after the REMS is approved. See, e.g., 21 U.S.C. ” 355-1(a)(2)(B) and 355-1(d). The FDA plans to issue developing REMS guidance for industry in the future.

The FDA can establish a REMS to mitigate a drug product's risks, even if the drug is effective but has serious risks. 21 U.S.C. ' 355-1(f)(1). The law requires the FDA to post a statement on its Web site within 30 days of imposing a REMS, which should explain how the strategy will mitigate the risk. Id. at ' 355-1(f)(2)(B). If the FDA imposes a REMS under this provision, it must make sure that the plan is commensurate with the risk involved, such as whether the strategy will be unduly burdensome on patient access to the drug. Id. at ' 355-1(f)(2)(C).

A responsible person may submit an assessment of, and modification to, a REMS at any time. 21 U.S.C. ' 355-1(g)(1). The law describes when assessments are required. Id. at ' 355-1(g)(2). The law also provides for dispute resolution. 21 U.S.C. ' 355-1(h)(4)-(5).

On March 27, 2008, the FDA identified a number of drugs and biological products that were approved or licensed with such safe use elements (e.g., required by regulation or otherwise agreed to by the sponsor) and considered to have a REMS. 73 Fed. Reg. 16313. To minimize risks, some products, for example, include a Medication Guide, a communication or educational plan for healthcare providers or patients. (However, the FDAAA notes that a drug will not be considered to have a REMS if it has only a Medication Guide, patient package insert, and/or communication plan. 21 U.S.C.
' 355-1(e)(2) and (e)(3).)

Since the enactment of FDAAA, the FDA has approved additional REMS programs, covering a wide variety of therapeutic areas. The specific restrictions vary among products. The agency has also notified manufacturers of certain marketed products that a REMS is required based upon new safety information. For example, on Feb. 6, 2009, the FDA notified sponsors of certain opioid drug products that they will be required to develop a REMS strategy. See, e.g., “A Guide to Safe Use of Pain Medicine,” FDA Consumer Health Information, Feb. 23, 2009.

In addition, the FDAAA requires that the FDA conduct regular, bi-weekly screening of its Adverse Event Reporting System database and post a quarterly report of any new safety information or potential signal of a serious risk. 21 U.S.C. ' 355(k)(5). Therefore, one can expect more REMS requests as the FDA analyzes the safety data relating to drugs on the market.

Penalties for violating REMS requirements can be costly, up to $250,000 per violation, or up to $1 million for all violations adjudicated in a single proceeding. In the case of a continuing violation, after the Secretary has provided written notice to the responsible person, the responsible person shall be subject to a civil monetary penalty of $250,000 for the first 30-day period, and such amount shall double for every 30-day period thereafter that the violation continues, up to $1 million for any 30-day period, but not to exceed $10 million for all such violations adjudicated in a single proceeding. 21 U.S.C. ' 333(f).

Discussion

A drug company, understandably, would prefer that the FDA not mandate a REMS for its product. The costs to implement such a system will result in increased costs for product distribution and marketing, whether to prepare specific communications tools, establish training systems for doctors, create monitoring or registry programs, or design limited dispensing procedures. In addition, mechanisms required to ensure the safe use of the product can negatively affect product sales, whether, for example, due to restrictions on product availability, or a physician's reluctance to prescribe with restrictions or additional responsibilities. REMS is not ideal from a marketing perspective, although it might be necessary to obtain FDA approval of the drug product.

In addition to potential negative distribution and marketing consequences, a REMS program might create an impression on the doctor, pharmacist, and patient that the specific drug product presents a higher safety risk than other products on the market that treat the same disease. Moreover, if an injury or adverse event arises, the product's need for a REMS might heighten its liability exposure and the risk of a lawsuit. That is, there is increased scrutiny because of the drug's risk profile.

The aforementioned concerns cannot be discounted and are real. Products with REMS present a different level of safety risk; otherwise, the FDA would not have required a particular REMS. However, it is important to recognize that, even if the FDA imposes such a program for a drug, it nevertheless has concluded that the product remains safe and effective and can be prescribed, albeit with some limitations. The FDA has the authority not to approve a product or, if the drug is already on the market, to recommend corrective action or even withdraw approval of the drug. The imposition of a REMS is a delicate balance, which allows a product to be sold because its benefits outweigh the risks, while establishing a system to minimize these risks.

It is also important to recognize that all drugs have inherent safety issues, which require warnings, contraindications, and precautions. REMS actually focuses on the evaluation of a product's risk profile early and often by communicating effectively these risks with health care professionals and patients. A REMS might actually help a drug company minimize, even if not completely eliminate, potential liability risks. Recent case law, which has been discussed in other editions of this newsletter, makes clear that preemption and an FDA approval might not immunize a company from liability exposure due to alleged injuries sustained by use of a particular drug, but a REMS program, if followed by the sponsor company, essentially becomes an additional safeguard and protective fence to maximize the product's safe use which, conversely, should help minimize risk.

Alan Minsk, a member of this newsletter's Board of Editors, is a Partner and Leader of the Food and Drug Practice Team at Arnall Golden Gregory LLP. Lanchi Nguyen is an associate in the firm's Food and Drug and Healthcare Practice Teams. They advise pharmaceutical and medical device companies on Food and Drug Administration-related legal and regulatory issues. Mr. Minsk can be reached at [email protected] or 404-873-8690, and Ms. Nguyen can be reached at [email protected] or 404-873-8520.