Analysis of risk evaluation and mitigation strategies for teratogenic drugs: Variation in primary and secondary prevention measures.

In an analysis of risk evaluation and mitigation strategies for teratogenic drugs, Ameet Sarpatwari, Beatrice Brown and Aaron Kesselheim explore the variation in primary and secondary prevention measures.

Risk evaluation and mitigation against flood danger in an arid environment. A case study (El Bayadh region, Algeria).

Floods are among the most serious and devastating phenomena of natural disasters. Cities adjacent to flood-prone areas in the last decades have played a major role in increasing the potential adverse effects of flood damage. This research study aims to evaluate and mitigate the risks of flood events in the El Bayadh region, which suffers from poor infrastructure and drained networks. To achieve this, it is necessary to evaluate rainfall intensities and their limits for durations from 0.167 to 24 h with return periods from 2 to 1000 years. Eight different frequency analysis distributions were fit to the historical rainfall data series over 43 years (1970-2012) using hypothesis-based goodness tests and information-based criteria. The most appropriate distributions were used to develop the rainfall intensity-duration-frequency (IDF) and flood risk-duration-frequency (RDF) curves for the study area. The results show that high-intensity rainfall values last for short durations, while high flood risk values last for intermediate durations. The results of the flood RDF curves can provide useful information for policy makers to make the right decisions regarding the effectiveness of the region's protection structures against future flood risks.

Implementation and Use of Risk Evaluation and Mitigation Strategies Programs in Practice: A Scoping Review of the Literature.

BACKGROUND: Risk Evaluation and Mitigation Strategy (REMS) programs intend to improve medication safety but can add significant administrative burdens to providers and health systems. Various stakeholders have made efforts to use technology to improve REMS programs. OBJECTIVES: The objective of this scoping review is to describe studies evaluating workflows, automation, or electronic data exchange related to REMS programs. METHODS: A literature search of PubMed, Embase, and Web of Science was performed for articles published between January 2007 and July 2021. Studies were identified using the relevant Medical Subject Headings terms and related keywords. Articles must have described a workflow change and measured the impact of the workflow change. RESULTS: Of 299 citations initially identified, 7 were included in the final review after removing duplicates and articles not meeting predefined inclusion criteria. Included studies consisted of three manuscripts and four conference abstracts. Electronic health record interventions, such as customized order sets and clinical decision support alerts, were the most common strategy reported. Other strategies included developing a portal to verify REMS enrollment, requiring prescribers to contact the dispensing pharmacy, provider education, and restrictions based on the provider specialty. One study evaluated automated data exchange for REMS program processes in a mock environment. Although only three studies reported baseline metrics for comparison, all studies noted an improvement or benefit to the implemented workflow process changes. CONCLUSION: There is limited evidence describing REMS workflows, automation, and electronic data exchange. Various strategies to address REMS program requirements were reported, but no studies described the use of data exchange standards in a real-world setting despite efforts by the Food and Drug Administration and other stakeholders. Additional efforts are needed to automate REMS programs.

Exploring the impact of mifepristone's risk evaluation and mitigation strategy (REMS) on the integration of medication abortion into US family medicine primary care clinics✰,✰✰.

OBJECTIVES: In 2000, the United States' Food and Drug Administration (FDA) approved mifepristone for medication abortion. In this article, we explore how the Risk Evaluation and Mitigation Strategy (REMS) criteria for mifepristone specifically impede family physicians' ability to provide medication abortion in primary care settings. STUDY DESIGN: We conducted 56 qualitative interviews with a national sample of family physicians across the US who were not opposed to abortion. We examined how the REMS criteria for mifepristone impact family physicians' ability to provide medication abortion. RESULTS: Of the 56 interviews conducted, 23 participants (41%) raised the REMS criteria as a barrier to providing medication abortion in primary care. These participants reported the REMS added a layer of bureaucratic complexity that made it difficult for family physicians to navigate, even when trained, to provide abortion care. These family physicians described 2 predominant ways the REMS impede their ability to provide medication abortion: (1) The REMS require substantial involvement of clinic administration, who can be unsupportive; (2) The complexity of navigating the REMS results in physicians and clinic administration in primary care viewing medication abortion as not worth the effort, since it is only a small component of services offered in primary care. CONCLUSION: Removing the REMS could simplify integration of medication abortion into primary care, which could meet patient preferences, improve access, and reduce abortion stigma. The FDA's revised REMS criteria may ease administrative burden but will likely maintain key barriers to integrating medication abortion into family physicians' practice. IMPLICATIONS: Our study highlights that the REMS criteria are barriers to family physicians' ability to integrate medication abortion into their primary care practices. The FDA's removal of in person dispensing criteria may provide some impetus for trained family physicians to integrate medication abortion into their scope of practice but the revised REMS criteria maintain key barriers to broader adoption.

Turalio risk evaluation and mitigation strategy for treatment of tenosynovial giant cell tumor: framework and experience.

For drugs with enhanced serious safety risks, Risk Evaluation and Mitigation Strategy (REMS) may be required. Pexidartinib is approved for treatment of adult symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Its approval was conditional on its prescription via a mandatory REMS due to serious and potentially fatal liver injury seen in clinical trials. Turalio® REMS aims to mitigate this risk by ensuring provider education on pexidartinib use and required REMS components, prescriber adherence to baseline and periodic monitoring, and enrolling patients in a registry to further assess safe use and acute, chronic and irreversible hepatotoxicity. Through Turalio REMS, benefits of treating patients with pexidartinib may be preserved.

For drugs with serious side effects, specific safety measures may be put in place to manage these serious side effects in the form of Risk Evaluation and Mitigation Strategy (REMS) programs. Pexidartinib (Turalio^®) is approved for treatment of adults who have symptoms of severe tenosynovial giant cell tumor or have limitations in function that do not improve with surgery. Turalio^® has an REMS program because liver injuries that can be serious or fatal were seen in Pexidartinib clinical trials. This program aims to decrease the seriousness of the liver injuries by assuring doctors and pharmacists are educated on how to use the drug, patients are advised of this potential risk and that baseline and periodic monitoring of patients are conducted.

Patient and Caregiver Experiences With and Perceptions of Risk Evaluation and Mitigation Strategy Programs With Elements to Assure Safe Use.

Importance: The US Food and Drug Administration (FDA) Amendments Act of 2007 authorized the FDA to impose safety requirements on drugs with important risks, such as prescriber certification or routine laboratory testing, to ensure that the benefits of use outweighed the risks. However, little is known about patient and caregiver experiences with these Risk Evaluation and Mitigation Strategy (REMS) programs with Elements to Assure Safe Use (ETASU). Objective: To understand patient and caregiver experiences with and perceptions of REMS programs with ETASU. Design, Setting, and Participants: This qualitative study included semistructured qualitative phone interviews conducted between 2016 and 2017, with initial analysis performed in 2017 and reanalysis performed in 2021. Adult patients prescribed natalizumab or sodium oxybate, adult patients or caregivers of adult patients prescribed vigabatrin, and adult female patients of reproductive age prescribed riociguat were included. Main Outcomes and Measures: Assessment of knowledge, decision-making, medication access, and perceptions of medical privacy. Results: Among 63 participants, 46 (73%) were female. Twenty-five participants (40%) had taken natalizumab, 10 (16%) riociguat, 15 (24%) sodium oxybate, and 10 (16%) vigabatrin. One participant had taken both natalizumab and vigabatrin; 4 (6%) were caregivers of patients using vigabatrin. Most participants expressed knowledge of REMS program requirements, but many lacked the insight that these requirements were part of an FDA-mandated special safety program and expressed difficulty understanding program education materials. REMS requirements made some participants more likely to initiate treatment. However, many reported burdens accessing medication, including the need to travel to certified prescribers or pharmacies. Manufacturer access to personal health information was also controversial, although some participants expressed an altruistic desire to assist others. Conclusions and Relevance: This qualitative study found that REMS programs with ETASU reassured patients and their caregivers about drug safety and helped support medication initiation. However, steps are needed to improve the quality of REMS educational materials, promote efficient medication access, and protect patient privacy.

Prenatal exposure to teratogenic medications in the era of Risk Evaluation and Mitigation Strategies.

BACKGROUND: Prevention of prenatal exposures to teratogenic drugs is a significant clinical and public health concern. With the enactment of the US Food and Drug Administration Amendments Act in 2007, the US Food and Drug Administration has begun to require manufacturers to implement Risk Evaluation and Mitigation Strategies to prevent prenatal exposures. Among 12 risk evaluation and mitigation strategy drugs, several had predecessor risk mitigation plans (eg, isotretinoin) and some were newly required (eg, mycophenolate). Only a small proportion of teratogenic drugs are currently subject to Risk Evaluation and Mitigation Strategies, and the extent of prenatal exposure to the universe of teratogenic drugs compared with drugs subject to Risk Evaluation and Mitigation Strategies is unknown. Moreover, the effectiveness of such advanced risk mitigation programs in preventing prenatal exposure is not clear. OBJECTIVE: This study aimed to characterize the epidemiology of prenatal exposures to definite and potential teratogens during the risk evaluation and mitigation strategy era. STUDY DESIGN: We constructed a time-series of pregnancies identified from a national private insurance claims database (IBM MarketScan) to estimate prenatal exposures to teratogenic drugs (2006-2017). Pregnancy outcomes, gestational age, and the onset of pregnancy were determined with previously validated algorithms. The Teratology Information Service and Clinical Pharmacology databases were used to identify drugs with definite (n=141) or potential (n=65) teratogenic effects, and drugs with debatable risks such as benzodiazepines, statins, tetracyclines, sex hormones, infertility treatments, and gonadotropin-releasing hormone analogs were excluded. We defined prenatal exposure as ≥1 prescription fill or medical encounter involving administration of drugs with a definite teratogenic risk (including 12 for which there is a "current or discontinued" risk evaluation and mitigation strategy) or a potential teratogenic risk. We evaluated secular trends and modeled the effects of age, preconception exposure, and state healthcare quality rankings on prenatal exposure, adjusting for demographic factors and clinical conditions. RESULTS: The cohort included 3,445,612 pregnancies (2,532,444 live deliveries). Prenatal exposures to definite teratogens decreased slightly during the study years from 1.86 to 1.24 per 100 pregnancies between 2006 and 2017, whereas exposure increased for potential teratogens from 3.40% to 5.33%. Prenatal exposure prevalences were higher during the first trimester and for pregnancies that ended in nonlive outcomes. Drugs subject to Risk Evaluation and Mitigation Strategies had low background utilization and contributed to a small proportion of prenatal exposures (15.1 per 100,000 pregnancies). We also observed fewer prenatal exposures to risk evaluation and mitigation strategy drugs among women of childbearing age who used these treatments (0.14% vs 0.36% for any definite teratogen). Age extremes and low state-level healthcare quality rankings were independent predictors of prenatal exposure. CONCLUSION: Fetuses in more than 1 in 16 pregnancies continued to be exposed to teratogenic drugs during the past decade. Drugs with Risk Evaluation and Mitigation Strategies imposed a small burden of prenatal exposure because of the low background utilization rates and lower pregnancy prevalence among women of childbearing age who used these drugs. Although the declining exposure rates to teratogenic drugs with definite risk are encouraging, the rising prenatal exposure to drugs with potential risk calls for more assessments. Future research is needed to elucidate the health outcomes of fetuses exposed to potential risk drugs, understand the effectiveness of risk evaluation and mitigation strategy programs, and prioritize teratogenic drugs for advanced risk mitigation.

A safe in-home disposal system with every opioid prescription? Food and Drug Administration is considering a potential new Risk Evaluation and Mitigation Strategy that could impact pharmacists.

Misuse of prescription opioids contributes to the ongoing crisis of opioid-related overdose and deaths in the United States. The failure of patients and caregivers to safely dispose of unused opioids contributes to the problems. In 2018, Public Law 115-271 provided U.S. Food and Drug Administration (FDA) authority to mandate a Risk Evaluation and Mitigation Strategy (REMS) for safe disposal packaging or safe disposal solutions for opioid analgesic medications. FDA has been collaborating with stakeholders to determine whether a new REMS is needed. A new or revised opioid REMS could substantially affect opioid packaging, pharmacist roles and services, and dispensing activities such as education, counseling, and product distribution. The pharmacy profession has provided limited input to FDA regarding a potential new or revised opioid REMS. In this commentary, we aim to (1) provide awareness and raise questions on pertinent issues regarding opioid use and safe home disposal, (2) offer considerations for regulators on needed research in the development and assessment of a new REMS, and (3) highlight actions for pharmacist engagement in patient care services to promote safe use and safe home disposal of opioids. Consideration of a potential mandate regarding enhanced safety packaging or safe disposal solutions for opioids presents opportunities to revisit professional roles and engage proactively with FDA and other stakeholders. We hope this commentary stimulates timely feedback by pharmacy leaders, researchers, and practitioners on whether and how options for safe home disposal of opioids should be included in a REMS in contemplation of potential benefits, unintended consequences, expanded professional roles, timeline, assessment of program effectiveness, and adequate compensation. We support a shared opioid REMS that funds the counseling of patients and caregivers on safe opioid use and safe home opioid disposal options and provides appropriate education and products to facilitate that disposal.

The Use of Real-World Data to Assess the Impact of Safety-Related Regulatory Interventions.

The regulation of medicines seeks to ensure the efficacy, safety, and quality of prescription and non-prescription medicines. Given that the conditions under which a medicine's benefits outweigh its risks are complex, it is essential that communications about the safe and effective use of medicines be clear and actionable. Assessing the impact of interventions to improve the safe and effective use of medicines is a developing area, and one in which real-world data are playing an increasingly important role. Although real-world data are commonly used to assess the impact of regulatory interventions, there are several areas where their use could be improved. Specific areas for improvement include assessing regulatory interventions across a wider range of medicines, rather than concentrating on a relatively few therapeutic areas; assessing more clinically relevant outcomes rather than relying on measures such as changes in the number of prescriptions, which may not always correlate with the desired impact; assessing the potential unintended or negative consequences of regulatory interventions; applying methods to address potential confounders; assessing long-term, rather than just short-term, impacts of an intervention; increasing the use of comparator groups, when feasible; and evaluating the impact of regulatory interventions from multiple dimensions, rather than from a single dimension. Expanded use of real-world data could inform some of these efforts, although data sources beyond administrative claims data will likely be necessary to achieve all these goals.

Proposta de categorização dos serviços de alimentação no Estado do Rio de Janeiro com foco no risco sanitário de doenças transmitidas por alimentos / Proposal for the categorization of food services in the State of Rio de Janeiro with a focus on the sanitary risk of foodborne diseases

A Categorização dos serviços de alimentação com foco no risco sanitário de Doenças Transmitidas por Alimentos no Brasil foi uma experiência pontual e exitosa com o Projeto de Categorização da Copa do Mundo FIFA® de 2014. Devido a Lei Federal de liberdade econômica nº13.874 de 20 de setembro de 2019, que classifica os serviços de alimentação como atividades de baixo risco, as Vigilâncias Sanitárias devem rever o planejamento de suas ações. O objetivo geral desse trabalho foi formular uma proposta para implantar o sistema de Categorização dos serviços de alimentação no Estado do Rio de Janeiro. Para isso foi realizada uma pesquisa aplicada com análise documental que derivou o desenvolvimento de produtos tecnológicos e inovadores. Elaborou-se um roteiro para auxiliar na escrita do ato normativo da Categorização de serviços de alimentação; uma planilha para facilitar o cálculo do risco sanitário; um guia e um vídeo orientativo para auxiliar o processo de implantação da Categorização dos serviços de alimentação. Os produtos desenvolvidos podem ser utilizados para a autoavaliação do serviço de alimentação e pelas Vigilâncias Sanitárias nas inspeções com foco no risco de Doenças Transmitidas por Alimentos. O resultado da Categorização será comunicado ao público consumidor informando a qualidade sanitária dos serviços de alimentação categorizados. A elaboração dessa proposta subsidia os estados e municípios para o processo de implantação da Categorização, bem como auxilia na mensuração do risco sanitário dos serviços de alimentação, planejamento das ações de Vigilância Sanitária com base no risco, valorização dos serviços de alimentação que investem nas Boas Práticas de Manipulação de Alimentos e comunicação da categoria ao consumidor para que faça uma escolha consciente.

Categorization of food services with a focus on the health risk of Foodborne Diseases was a sharp and successful experience during the 2014 FIFA® World Cup in Brazil. Due to the Federal Economic Freedom Act nº 13.874 of September 20, 2019, which classifies food actions by the Health Public Surveillance. The main idea of this project was to formulate a proposal to install The Categorization of food services in the state of Rio de Janeiro. Technological research was carried out with an analysis that resulted in the development of technological and innovative products. A script was created for the surveillance inspector to assist in the writing of the normative act of The Categorization for food services; a spreadsheet to make the calculation of Foodborne Diseases health risks easier; a guide and an orientation video were made on the process of installing The Categorization for food services and establishing the inspection score parameters. The developed products can be used for the self-evaluation of food services and by the Health Surveillance agents in their inspections, always focusing on the risk of Foodborne Diseases. The score of the Sanitary Inspection will be communicated to the consumer audience, informing the sanitary quality of the food service. This proposal sponsors the states and counties for the implementation process of The Categorization, as well as in the measurement of the sanitary risks of food services. The Sanitary Surveillance plan is based on health risks from Foodborne Diseases and the appreciation of food services that invest in Proper Food Handling Practices and the communication from the grade received on the sanitary inspection to the consumer so that they make an informed and smart decision about where they eat.

Olas de calor: guía para acciones basadas en la salud

En esta publicación se presenta un método integral para brindar apoyo a los Estados Miembros de la Organización Panamericana de la Salud (OPS) en la preparación para la respuesta a los riesgos para la salud relacionados con el calor en la Región de las Américas. Se basa en los documentos de alcance mundial de la Organización Mundial de la Salud y la Organización Meteorológica Mundial, así como en los métodos de preparación para hacer frente a desastres aplicados en todos los países de la Región. La presente publicación forma parte de un esfuerzo coordinado por la OPS para ayudar a los Estados Miembros a prepararse para hacer frente a múltiples amenazas e incluye el fortalecimiento de los sistemas de alerta temprana; la caracterización de la amenaza; la definición de los procedimientos de activación y desactivación, y la coordinación institucional. Abarca diferentes disciplinas y reconoce la importancia de la colaboración intersectorial para responder a los riesgos para la salud relacionados con el calor. Procura sensibilizar a las autoridades de salud pública acerca de los efectos del calor sobre la salud de la población de la Región de las Américas y de esa manera fortalecer la prestación de los servicios de salud.

Pragmatic applications of implementation science frameworks to regulatory science: an assessment of FDA Risk Evaluation and Mitigation Strategies (REMS) (2014-2018).

BACKGROUND: A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program for certain medications with serious safety concerns required by the U.S. Food and Drug Administration (FDA) of manufacturers to implement to help ensure the benefits of the medication outweigh its risks. FDA is encouraging "the research community to develop novel methods for assessing REMS," conveying the unmet need for a standardized evaluation method of these regulatory-mandated healthcare programs. The objective of this research is to evaluate FDA REMS assessment plans using established implementation science frameworks and identify opportunities for strengthening REMS evaluation. METHODS: A content analysis was conducted of publicly available assessment plans for all REMS programs (N = 23) approved 1/1/2014-12/31/2018 for new drug applications (NDAs) and biologics license applications (BLAs) requiring FDA-mandated Elements to Assure Safe Use (ETASU). Blinded reviewers critically appraised REMS assessment measures (n = 674) using three established implementation science frameworks: RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance); PRECEDE-PROCEED (Predisposing, Reinforcing, and Enabling Constructs in Educational/Environmental Diagnosis and Evaluation - Policy, Regulatory, and Organizational Constructs in Educational and Environmental Development); and CFIR (Consolidated Framework for Implementation Research). Framework constructs were mapped to REMS Assessment categories as defined by FDA Guidance for Industry to evaluate congruence. RESULTS: REMS assessment measures demonstrated strong congruence (> 90% mapping rate) with the evaluative constructs of RE-AIM, PRECEDE-PROCEED, and CFIR. Application of the frameworks revealed that REMS assessment measures heavily emphasize implementation and operations, focus less on health outcomes, and do not evaluate program context and design assumptions. CONCLUSIONS: Implementation science frameworks have utility for evaluating FDA-mandated drug safety programs including the selection of primary measures to determine whether REMS goals are being met and of secondary measures to evaluate contextual factors affecting REMS effectiveness in varying organizational settings.