The Office of the Inspector General (OIG) for the Department of Health and Human Services (HHS) released a report, which asserts that the Food and Drug Administration (FDA) is not receiving crucial information from pharmaceutical manufactures regarding Risk Evaluation and Mitigation Strategies (REMS). OIG also released a podcast explaining the report.
The Federal Food, Drug, and Cosmetic Act (FDCA), as amended by the Food and Drug Administration Amendments Act of 2007 and the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA), authorizes FDA to require REMS for certain drugs and biological products to assure that their benefits outweigh their risks. REMS are structured plans to manage specific risks of drugs that are effective but associated with known or potential risks (e.g., death, injury) that, without REMS, may outweigh benefits.
When FDA requires a REMS, the drug manufacturer (i.e., sponsor) must develop, implement, and assess it. FDA reviews and approves each REMS. FDA has the authority to, among other things, deem a drug misbranded or impose civil monetary penalties on sponsors that violate approved REMS. However, FDA does not have the authority to take enforcement actions against sponsors that do not include all information requested in FDA assessment plans. If FDA does not have comprehensive data to monitor the performance of REMS, it cannot ensure that the public is provided maximum protection from a drug’s known or potential risks.
Consequently, OIG found that nearly half of sponsor assessments for the 49 REMS it reviewed did not include all information requested in FDA assessment plans, and 10 were not submitted to FDA within required timeframes. OIG also reported that FDA had not identified reliable methods to assess the effectiveness of REMS. In addition, while FDA determined that 7 of 49 REMS were meeting all of their goals, 21 were not. Further, FDA has completed the federally required evaluation for 1 of 32 drugs with ETASUs since program inception. Therefore, OIG asserted that FDA has limited data to demonstrate that the remaining REMS with ETASUs effectively ensure safe use of drugs or meet statutory requirements to minimize burdens on patients and the health care system. Finally, FDA’s assessment review times exceeded its goal of 60 days for all but one sponsor assessment, which reduces sponsors’ time to make suggested changes before submitting subsequent assessments. These findings raised concerns for OIG “about the overall effectiveness of the REMS program.”
To address these concerns, OIG made seven recommendations:
- Develop and implement a plan to identify, develop, validate, and assess REMS components
- Identify REMS that are not meeting their goals and take appropriate actions to protect the public health
- Evaluate the ETASUs of one REMS each year as required by Federal law
- Identify incomplete sponsor assessments and work with sponsors to obtain missing information
- Clarify expectations for sponsors’ assessments in FDA assessment plans
- Seek legislative authority to enforce FDA assessment plans
- Ensure that assessment reviews are timely
FDA concurred with six of the recommendations. For the remaining recommendation, to seek legislative authority to make FDA assessment plans enforceable, FDA did not state whether it concurred or did not concur. However, FDA agreed that this recommendation should be considered if another opportunity arises to pursue legislative changes to the statutory provisions that describe the requirements for REMS assessments. Below is a more in-depth summary of the OIG Report.
A drug may be deemed to be misbranded if it is subject to a REMS and the sponsor fails to comply with a requirement of the REMS. Misbranded drugs may not be introduced into, delivered, or received into interstate commerce. Sponsors that violate REMS requirements may be subject to civil monetary penalties of up to $250,000 per violation. Civil monetary penalties are not to exceed $1 million in a single proceeding. Civil monetary penalties may increase to $10 million for continued violations. Additionally, a sponsor may not introduce or deliver for introduction into interstate commerce an approved drug if a REMS is required for the drug and the sponsor fails to maintain compliance with the requirements of the approved REMS or with other requirements.
FDA approved 199 REMS between 2008 and 2011, 99 of which were still required in 2012. Each REMS includes one or more overall goals to achieve a particular safety-related health outcome or understanding by patients and/or health care providers of a drug’s risks. Examples of REMS goals include preventing fetal exposure to a drug and informing prescribers, patients, and pharmacists of the serious risks and safe-use conditions for a drug.
REMS include one or more strategies to provide additional safety in the usage of certain drugs. For example, REMS may require sponsors to create additional safety information for patients or to ensure that health care providers that prescribe the drug are specially certified.
For brand-name drugs, each REMS must include a timetable for sponsors to submit REMS assessments. The standard timetable requires sponsors to submit assessments of REMS’ effectiveness by 18 months, 3 years, and 7 years after approval of the REMS. FDA may require sponsors to submit assessments at different intervals specified in the REMS or eliminate the timetable after 3 years if it determines that a drug’s risks have been adequately identified and assessed and are being adequately managed.
FDA may require one or more of the following components in addition to the timetable for assessments: medication guide or patient package insert, a communication plan, or elements to assure safe use (ETASU). FDA determines which of these additional components to require according to a drug’s risks.
Medication Guides and Patient Package Inserts. Medication guides are paper handouts that include FDA-approved information about the safe and effective use of a drug. Medication guides are not unique to REMS; FDA oversees their content and format under separate regulations and may require them without requiring a REMS. Some REMS may require patient package inserts, which also contain drug safety information, in addition to medication guides.
Communication Plans. Communication plans describe how sponsors will inform health care providers about a drug’s risks and/or the components of a REMS. These plans may describe how a sponsor will send letters to health care providers and disseminate information through professional societies about a drug’s risks.
ETASUs. FDA may require ETASUs for drugs that are associated with a serious adverse drug experience if, without the ETASUs, FDA would not approve the drug or would withdraw the drug’s approval. If drugs were initially approved without ETASUs, FDA must determine that other REMS components are not sufficient to mitigate risks before it requires ETASUs. FDA can require one or more of the following ETASUs:
- health care providers who prescribe the drug have certain training, experience, or certification;
- pharmacies, practitioners, and/or other health care settings that dispense the drug are specially certified;
- the drug is dispensed only in certain health care settings (e.g., hospitals, appropriately equipped physicians’ offices);
- the drug is dispensed only to patients with evidence or documentation (e.g., laboratory test results, signed acknowledgement of risks) that they can safely use the drug;
- each patient using the drug is subject to monitoring (e.g., patients must periodically contact the prescriber or undergo laboratory tests); and
- each patient using the drug is enrolled in a registry.
Each ETASU must (1) correspond to the specific serious risk listed in the labeling of a drug; (2) considering such risk, not be unduly burdensome on patient access to a drug, particularly considering patients with serious or life-threatening conditions and patients who have difficulty accessing health care; and (3) to the extent practicable, minimize the burden on the health care delivery system. When FDA requires certain ETASUs, the REMS may also include an implementation system.
Sponsors may use implementation systems to take reasonable steps to monitor, evaluate, and improve the implementation of ETASUs. Examples of implementation systems include requiring sponsors to conduct periodic audits of health care settings that use the drug or to maintain a database of all certified entities to ensure that certification requirements are met.
REMS components are not exclusive. For example, REMS that require ETASUs generally also require a communication plan and/or a medication guide. FDA refers to three types of REMS according to the most intensive (i.e., primary) required component: medication guide, communication plan, and ETASU REMS.
Criteria for Requiring REMS and Approval Process
FDA may require a REMS before approving an application to market a drug (i.e., preapproval REMS) or after a drug is on the market (i.e., postapproval REMS). FDA must consider the following factors to determine whether a preapproval REMS is necessary:
- the estimated size of the population likely to use the drug,
- the seriousness of the disease or condition that the drug treats,
- the expected benefit of the drug,
- the duration of treatment,
- the seriousness of any known or potential adverse events related to the drug and the background incidence (i.e., frequency) of these events in the population likely to use the drug, and
- whether the drug is a new molecular entity.
FDA may require a postapproval REMS if it becomes aware of new safety information after a drug is on the market and determines that a REMS is necessary to ensure that the benefits of the drug outweigh the risks. For example, FDA required a postapproval REMS for the drug Wellbutrin in response to reports of suicide-related events in patients using the drug for smoking cessation.
When FDA requires a REMS, it notifies the drug’s sponsor in a REMS notification letter. The REMS notification letter instructs the sponsor to submit a proposed REMS containing the components FDA determines are necessary. FDA reviews the proposed REMS and approves it after an interactive process with the sponsor. After FDA approves a proposed REMS, it notifies the drug’s sponsor in a REMS approval letter.
FDA works with sponsors to develop an FDA assessment plan for each REMS, which is included in the REMS approval letter. Assessment plans describe the information that FDA requests sponsors to collect to complete a valid assessment of whether a REMS is meeting its goals. For example, FDA may request that a sponsor’s assessment include the number of patients enrolled in a user registry or an evaluation of patients’ understanding of a drug’s risks.
Sponsors’ Assessments of REMS
Sponsors of brand-name drugs must submit their assessments of REMS for FDA’s review according to the timetable in the approved REMS. FDCA requires FDA to review sponsors’ assessments but does not require FDA to perform its own assessments of each REMS. FDA may require sponsors to submit an additional assessment if one is needed to evaluate whether the REMS should be modified. Sponsors may also submit voluntary assessments of REMS at any time. Sponsors’ assessments must include information required by FDCA and should also include information requested in FDA assessment plans.
Requirements for Sponsors’ Assessments. Assessments of REMS with ETASUs were required to include an evaluation of the extent to which each ETASU is meeting the goal stated in the REMS in addition to complying with the approved timetable. Under current amendments to FDCA, all REMS assessments must include, with respect to each goal of the REMS, an assessment of the extent to which REMS are meeting the goals or of whether the goals or REMS should be modified. FDCA does not require sponsors to include additional information about the effectiveness of REMS in assessments. FDA may take enforcement actions (e.g., deem a drug misbranded, impose civil monetary penalties) if sponsors fail to meet the assessment requirements outlined in FDCA. However, FDA does not have authority to take enforcement actions if sponsors’ assessments do not include information requested in FDA assessment plans.
FDA’s Reviews of Sponsors’Assessments. Multidisciplinary teams made up of staff in FDA’s Division of Risk Management within the Office of Surveillance and Epidemiology, the respective drug review division(s) in the Office of New Drugs, and the Office of Compliance review sponsors’ REMS assessments. Staff in the Division of Risk Management complete review memorandums that summarize the teams’ findings. The teams review assessments for completeness and determine whether REMS are meeting their goals or whether modifications to the REMS or FDA assessment plans are required. A Division of Risk Management review memorandum documents whether a sponsor’s assessment (1) is complete, (2) indicates the REMS is meeting its goals or needs modifications, and (3) identifies any deficiencies that may affect a REMS’s ability to mitigate risks.
The Office of Compliance also completes review memorandums, which document whether sponsors submit complete assessments according to the approved timetable. However, the Office of Compliance defers the analysis of assessment data and of whether REMS are meeting their goals to the Division of Risk Management.
FDCA requires FDA to promptly review sponsors’ assessments. Although FDA does not define “promptly,” FDA officials indicated that their goal is to complete all assessment reviews within 60 days of submission if it does not discuss REMS modifications with sponsors.
The FDCA requires FDA to evaluate the ETASUs of at least one REMS each year to determine whether the ETASUs (1) assure safe use of the drug; (2) are unduly burdensome on patient access to the drug; and (3) to the extent practicable, minimize the burden on the health care delivery system. In 2008, FDA issued a 5-year plan (2008–2012) to enhance and modernize its drug safety activities. In the 5-year plan, FDA states that it will develop a plan to identify, develop, validate, and assess the effectiveness of REMS components.
OIG Review and Study
Of the 199 approved REMS, 119 required medication guides only and 48 required communication plans. For drugs with the most serious risks, FDA approved 32 REMS with ETASUs. These drugs would not be approved or their approval would be withdrawn without the ETASUs. Of the 199 approved REMS, FDA approved 74 preapproval REMS in response to information in drug applications. The remaining 125 postapproval REMS were required in response to new safety information discovered after the drugs were already on the market or for drugs with ETASUs already in effect before REMS program initiation.
According to the approved timetable in each REMS, 57 REMS required sponsors to submit at least 1 assessment by December 31, 2011. FDA provided review memorandums for 49 of these REMS. Of these 49 REMS, 11 required medication guides only, 19 required communication plans, and 19 required ETASUs.
FDA assessment plans request sponsors to submit specific information to enable FDA to determine whether REMS are meeting their goals. FDA reviewed 49 sponsor assessments as of December 31, 2011. Almost half (23 of 49) of the sponsor assessments did not include all of the information requested in FDA assessment plans.
For example, one sponsor did not include the number of pharmacies that were deauthorized to dispense the drug because of noncompliance with the REMS, as requested in the assessment plan. The same sponsor also did not include the amount of the drug shipped to health care providers compared to actual patient orders, as requested. In review memorandums for the 23 assessments that did not include information requested in assessment plans, reviewers recommended that FDA notify the sponsors of 6 that their assessments were incomplete. FDA review memorandums for the remaining 17 assessments did not indicate that FDA no longer requested sponsors to submit the missing information.
Sponsors and health care providers have expressed concerns about the challenges associated with collecting data on the compliance of third parties (e.g., patients, pharmacies, drug distributors). Specifically, concerns about patient confidentiality and the lack of a standardized format for sponsor assessments may contribute to the lack of data in some assessments. FDA does not have authority to take enforcement actions against sponsors that do not include requested information in their REMS assessments.
Some items requested in FDA assessment plans are also required by Federal law. An assessment of the extent to which the ETASUs met the goal stated in the approved REMS was required by Federal law, but was missing from seven assessments.
Further, 10 of 49 of sponsor assessments were not submitted to FDA by the dates specified in the approved timetables, as required by FDCA. These assessments were submitted between 3 and 70 days after the dates specified in the timetables, with a median of 17 days. FDA has the authority to take enforcement actions against sponsors that do not meet Federal requirements for REMS assessments. However, since program inception in 2008, FDA has not done so.
Using limited information in sponsor assessments, FDA determined that 7 of the 49 REMS OIG reviewed were meeting all of their goals and that 21 were not. FDA review memorandums indicated that FDA could not determine whether 17 REMS were meeting all of their goals. FDA review memorandums did not contain statements regarding whether the remaining four REMS were meeting all of their goals.
FDA determined that 1 of 19 REMS with ETASUs, which are required for the riskiest drugs, was meeting all of its goals. In review memorandums, FDA reviewers stated that eight REMS with ETASUs were not meeting all goals and that they could not determine whether eight others were meeting all goals. FDA did not determine whether two REMS with ETASUs were meeting their goals.
FDA most often determined that REMS were not meeting their goals because of deficiencies in patient and prescriber awareness of drug risks: When FDA determined that REMS were not meeting all of their goals, it most often identified deficiencies related to patient awareness of risks (14 of 21 assessments) and/or prescriber awareness of risks (12 of 21 assessments). For example, because a survey showed that patients had a low understanding of key risk messages, FDA determined that one REMS was not meeting its goal to inform patients of a drug’s risks. FDA discussed REMS modifications with sponsors for 16 of the 21 REMS it determined were not meeting all of their goals. FDA did not discuss REMS modifications with sponsors of the remaining five REMS it determined were not meeting their goals.
FDA most often determined that REMS were not meeting their goals because of deficiencies in patient and prescriber awareness of drug risks: When FDA determined that REMS were not meeting all of their goals, it most often identified deficiencies related to patient awareness of risks (14 of 21 assessments) and/or prescriber awareness of risks (12 of 21 assessments). For example, because a survey showed that patients had a low understanding of key risk messages, FDA determined that one REMS was not meeting its goal to inform patients of a drug’s risks. FDA discussed REMS modifications with sponsors for 16 of the 21 REMS it determined were not meeting all of their goals.
FDA did not discuss REMS modifications with sponsors of the remaining five REMS it determined were not meeting their goals. Additionally, FDA has not met the Federal requirement to evaluate the ETASUs of one REMS each year. Further, FDA has identified limitations in methods used to evaluate the effectiveness of REMS.
FDA has evaluated the ETASUs of one REMS since program inception in 2008: Between 2008 and 2011, FDA approved 32 REMS with ETASUs to address drugs with the most serious risks. As of December 31, 2011, FDA had completed an evaluation for one drug with an ETASU. On December 1, 2011, FDA’s Drug Safety and Risk Management Advisory Committee met to evaluate the ETASUs of isotretinoin. At the meeting, FDA and stakeholders discussed the impact of the isotretinoin REMS on patients and the health care delivery system. FDA and industry representatives noted several challenges associated with completing the required evaluation, including the lack of baseline (pre-REMS) utilization data and the inability to account for changes in utilization because of factors not related to the REMS.
FDA stated that it had not formally evaluated a REMS with ETASUs in the first 3 years of the REMS program because it was focused on developing REMS and implementing the program. Additionally, FDA stated that REMS must be implemented for a sufficient period of time before they can be properly evaluated. Because FDA has completed this evaluation for just 1 of 32 drugs with ETASUs, it has limited data to demonstrate that the remaining REMS with ETASUs effectively ensure safe use of drugs or meet statutory requirements to minimize burdens on patients and the health care system.
FDA has identified limitations with using survey data to assess REMS: FDA often requests that sponsors include results of surveys regarding patients’ and/or health care providers’ knowledge of risks in REMS assessments. FDA made such requests in each of the 49 sponsor assessments OIG reviewed. Of these 49 sponsor assessments, 40 included survey data in response to this request and 9 did not. However, in a White Paper issued in June 2012, FDA identified several limitations in some sponsors’ surveys. These included sample sizes too small to draw conclusions, survey populations that do not reflect the demographics of the target population, bias caused by convenience samples, and the lack of objective standards to measure knowledge of risks. FDA states that because of these limitations, surveys may not always be the best method for assessing the effectiveness of REMS educational components.
FDA’s assessment review times exceeded its 60-day goal for all but one sponsor assessment: FDCA requires FDA to promptly review sponsor assessments. Although FDA does not define “promptly,” FDA officials indicated that their goal is to complete all assessment reviews within 60 days of a sponsor’s assessment submission if FDA does not discuss REMS modifications with sponsors. FDA did not discuss REMS modifications with sponsors for 29 of the 49 sponsor assessments OIG reviewed. FDA’s assessment review times exceeded 60 days for 28 of these 29 sponsor assessments. FDA’s average assessment review time was 73 days and the median review time was 69 days. Reviews of three sponsor assessments were completed at least 120 days after the sponsor submitted them. If FDA does not review sponsor assessments in a timely manner, sponsors may have limited time to implement suggested changes to a REMS before submitting the next assessment.
Recommendations and FDA/HHS Response
1. Develop and implement a plan to identify, develop, validate, and assess REMS components: This plan should fulfill FDA’s commitment in its 5-year plan and outline ways that FDA will assess the effectiveness of REMS beyond reviewing sponsors’ assessments. FDA should also identify and implement reliable methods to assess the effectiveness of REMS. FDA should decrease its reliance on survey data in sponsors’ assessments and work with sponsors and health care providers to develop more accurate evaluation methods. Additionally, FDA should continue to hold discussions with stakeholders, similar to the public meetings held in 2010 and 2012, about the issues and challenges associated with assessing the effectiveness of REMS components.
FDA noted that the REMS Integration Initiative will include contributions from key stakeholders on the development, implementation, and effectiveness of REMS tools. Specifically, Peter Lurie, MD, MPH, FDA’s Acting Associate Commissioner for Policy and Planning, further elaborated on this Initiative, the goals of which include:
- Developing guidance on how to apply the statutory criteria to determine when a REMS is required
- Improved standardization and assessment of REMS; and
- Improved integration of REMS into the existing and evolving healthcare system
To support the initiative, FDA will incorporate input from stakeholders on issues and challenges associated with development, implementation and assessment of REMS. In addition, Lurie noted that CDER’s REMS Integration Steering Committee (RISC) oversees activities of three subordinate work groups whose deliverables fulfill commitments FDA has made under FDASIA. He noted the following:
- The Policy Work Group is currently developing a draft guidance to provide more information about how FDA applies the statutory criteria to determine whether REMS is necessary and expects publication by September 2013
- The Design and Standardization Work Group is leading efforts to identify best practices to incorporate into REMS design, as well as appropratie ways to standardize REMS tools and integrate REMS into the healthcare delivery system. The group will solicit input within the next year and expects to have a report by December 2013
- The Evaluation Work Group is leading FDA’s efforts to develop an evidence-based approach to assessing the effectiveness and burden of REMS. The group plans to obtain additional input and publish a draft guidance on evaluation methodologies by September 2014
Finally, by March 2015, FDA intends to publish a report on what it has learned about REMS through the efforts of these groups.
2. Identify REMS that are not meeting their goals and take appropriate actions to protect the public health: FDA should consistently discuss potential REMS modifications with sponsors when it determines that a REMS is not meeting its goals. FDA should work with sponsors to determine the most appropriate modifications to address the REMS’ deficiencies. If a REMS undergoes multiple modifications and continues not to meet its goals, FDA should consider removing the drug from the market. If FDA cannot determine whether a REMS is meeting its goals, it should work with sponsors to obtain any additional information that it needs to make this determination. FDA should not wait until it reviews the next sponsor assessment to determine whether a REMS is meeting its goals.
FDA stated that it has worked and will continue to work with sponsors to determine the best response when it determines that a REMS is not meeting its goals. Additionally, FDA stated that it plans to develop draft guidance concerning how to write REMS goals and the metrics for determining whether these goals have been met.
3. Evaluate the ETASUs of one REMS each year as required by Federal law: FDA should determine whether the ETASUs (1) assure safe use of the drug; (2) are unduly burdensome on patient access to the drug; and (3) to the extent practicable, minimize the burden on the health care delivery system. FDA fulfilled this requirement for the first time in 2011 and should continue to conduct formal evaluations of at least one REMS with ETASUs each year. Through these evaluations, FDA can determine how effective various ETASUs are, whether ETASUs cause barriers to patient access, and which ETASUs are the most burdensome for health care providers. Evaluations would also inform FDA’s decisions about the most effective ETASUs for mitigating specific risks. FDA should use this information to change or eliminate any ETASUs that are both burdensome and ineffective in assuring safe use of a drug.
FDA acknowledged its insufficient experience in evaluating REMS and insufficient assessment data available; however, the agency noted that it discussed certain REMS with ETASUs at various advisory committees prior to 2011.
4. Identify incomplete sponsor assessments and work with sponsors to obtain missing information: FDA should consistently notify sponsors that their assessments are incomplete and request that sponsors provide the missing information as soon as possible. FDA should also work with sponsors to obtain the missing information.
FDA stated that it has worked and will continue to work with sponsors to obtain information missing from assessments if that information is necessary to determine whether a REMS is meeting its goals. If FDA determines that the information is not necessary to determine whether a REMS is meeting its goals, it will reevaluate the need for the information.
5. Clarify expectations for sponsors’ assessments in FDA assessment plans: FDA should make assessment plans as specific as possible to ensure that data included in sponsors’ assessments will enable FDA to determine whether REMS are meeting their goals. For example, FDA should specify sample sizes needed to complete valid surveys. FDA should use assessment plans to establish quality standards for data to be submitted in sponsors’ assessments. If FDA cannot determine whether a REMS is meeting its goals because of the quality of data in a sponsor’s assessment, it should notify the sponsor of this concern and, if necessary, clarify data standards for future assessments.
FDA stated that it is committed to holding public workshops to gather stakeholder input. FDA plans to issue draft guidance on methodologies for assessing whether REMS are meeting are their goals and the impact of REMS on patient access and burden on the health care system. Additionally, FDA noted that it has reviewed and will continue to review proposed assessment protocols if sponsors submit them prior to initiating the REMS assessment.
6. Seek legislative authority to enforce FDA assessment plans: FDA currently does not have authority to take enforcement actions when sponsors do not submit all information requested in assessment plans. FDA should work with the appropriate stakeholders to seek legislative authority to enforce assessment plans. This would allow FDA to take regulatory actions when a sponsor’s assessment did not include all items requested in the FDA assessment plan. Further, enforcement authority should encourage sponsors to submit the amount and quality of information FDA needs to determine whether REMS effectively mitigate risks.
7. Ensure that assessment reviews are timely: FDCA requires FDA to promptly review sponsor assessments. FDA officials indicated that their goal is to complete all assessment reviews within 60 days of sponsors’ assessment submissions if FDA does not discuss REMS modifications with sponsors. Since FDA set this goal, some FDCA provisions regarding the review of sponsors’ assessments have changed because of FDASIA. If FDA chooses to change this goal of 60 days, it should define “promptly” as it pertains to reviewing sponsor assessments and complete assessment reviews within this timeframe. FDA should identify ways to complete assessment reviews within its goal of 60 days or the newly established timeframe. This would allow time for informed discussions with sponsors about REMS modifications, if necessary. This would also enable sponsors to make timely changes to REMS and/or REMS assessments in response to FDA’s review. To maximize review resources, FDA could prioritize assessment reviews for REMS with ETASUs as these REMS are required for drugs with the most serious risks and generally require more frequent assessments.
FDA stated that it is examining the internal assessment review process for ways to improve the timeliness of FDA assessment reviews.