Risk Evaluation And Mitigation Strategy Research Articles

Utilization of long-acting injectable monthly depot buprenorphine for opioid use disorder (OUD) in Kentucky, before and after COVID-19 related buprenorphine access policy changes

IntroductionLong-acting injectable buprenorphine (LAI-bup) formulations have advantages over transmucosal buprenorphine (TM-bup), but barriers may limit their utilization. Several policies shifted during the COVID-19 pandemic to promote buprenorphine access. The federal government expanded telemedicine treatment for opioid use disorder and Kentucky (KY) Medicaid lifted prior authorization requirements (PAs) for LAI-bup (i.e., Sublocade®). This retrospective cohort study evaluated changes in LAI-bup access, utilization, and retention before and after these policy changes in KY. MethodsIndividual-level TM-bup and LAI-bup dispensing record data from KY's prescription drug monitoring program examined LAI-bup utilization and retention, without a >30-day gap in coverage, for patients starting a new episode of LAI-bup treatment. Two key time periods were examined: pre-policy changes (Apr 1, 2019 – Dec 31, 2019) and post-policy changes (Apr 1, 2020 – Dec 31, 2020). Data on PA requests among Medicaid managed care organizations and availability of LAI-bup Risk Evaluation and Mitigation Strategy (REMS)-certified pharmacies were also obtained. A multivariable Cox proportional hazard regression model analysis compared pre- versus post-policy period treatment discontinuation. ResultsThe number of patients initiating LAI-bup increased from 211 to 481 over the two periods. By the end of the post-policy period, 24.3 % of eligible patients were retained on LAI-bup, versus 12.5 % in the pre-policy change period. The adjusted hazard ratio, comparing discontinuation during the post- versus pre-policy change periods, was 0.70 (95 % confidence interval: 0.55–0.89). There were also more REMS-certified pharmacies and providers in the post-policy change period. ConclusionsLAI-bup access, utilization, and retention increased after several policy changes.

Development of Cell and Gene Therapies for Clinical Use in the US and EU: Summary of Regulatory Guidelines.

Recent decades have seen advancements in the management and treatment of difficult-- to-treat diseases such as cancer. A special class of therapeutics called cell and gene therapy has been introduced in the past 10 years. Cell and gene therapy products have strengthened the treatment options for life-threatening diseases with unmet clinical needs and also provided the possibility of a potential cure for the disease in some of the patients. Cell and gene therapy products are gaining recognition, and the interest in clinical development of cell and gene therapy products is increasing. Moreover, as the class of cell and gene therapy products is relatively new, there is a limited regulatory experience in the development, and the developers of the cell and gene therapy products can often be puzzled with an array of questions on regulations. The current review intends to provide a basic understanding of regulatory guidelines from the FDA and EMA that are applicable to cell and gene therapy products. Essentials such as which office is responsible for the evaluation of applications, which regulatory class/pathway is appropriate for development, and what are the quality, nonclinical and clinical studies that are needed to support the application are discussed in the article. In addition, a summary of regulatory designations and the post-approval requirements, such as Risk Evaluation and Mitigation Strategies (REMS) and long-term follow- up, is included in the article. Developers (referred to as 'sponsors' in this article) of cell and gene therapies can use the respective guidance documents and other specific review articles cited in this review for detailed information on the topics.

Assessment of the U.S. Food and Drug Administration's risk evaluation and mitigation strategy (REMS) for prasugrel (EFFIENT): A narrative review

BackgroundPrasugrel, first approved in 2009, was subject to a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) to mitigate the risk of bleeding associated with its use. MethodsWe performed a narrative review of FDA documents obtained through a Freedom of Information Act request. Document classification and primary evidence extraction was performed by three authors (TM, JC, and SL). ResultsThe prasugrel REMS consists of a medication guide and a communication plan. Assessment of the REMS was via patient and clinician surveys. 1560 patients were invited to participate and 212 individuals (13.6 %) completed the survey. Rates of awareness among respondents varied across key messages and were highest for those examining the risks of premature discontinuation (96 % and 88 % of respondents), while lower for those regarding the importance of perioperative discontinuation (66 %) and contraindications posed by a history of stroke (16 %) or transient ischemic attack (17 %). Of the 6000 clinicians invited to participate in the survey, 201 (3.4 %) agreed to take part. Four of 11 key risk messages did not meet prespecified acceptable levels of comprehension. No prespecified levels of patient or provider knowledge were required for the retirement of the REMS, which took place on March 23, 2012 based on the sponsor's request. ConclusionsThe prasugrel REMS consisted of passive educational materials whose adequacy was evaluated using highly limited, one-time, cross-sectional surveys. Our assessment adds to evidence suggesting the importance of improving the quality and impact of the FDA's post-approval activities to maximize drug safety.

Pharmacist dispensing of mifepristone: An opinion of the Women's Health Practice and Research Network of the American College of Clinical Pharmacy

AbstractA rising percentage of patients are electing medication abortion over procedural abortion for increased safety and privacy. Access to medication abortion is essential healthcare, but many Americans face unsurmountable barriers when pursuing this option. This has been in large part due to unnecessary restrictions imposed by the United States Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) for mifepristone, used in combination with misoprostol for medication abortion. Moreover, many states have imposed additional restrictions on abortion, further impeding access to care. Since its original approval in 2000, mifepristone can only be prescribed by certified prescribers. Until recently, mifepristone could only be dispensed by certified prescribers, whereby more accessible community and mail‐order pharmacies were prohibited from dispensing mifepristone. During the Coronavirus disease 2019 public health emergency, there was a temporary allowance for certified prescribers to utilize mail or mail‐order pharmacies to deliver medications to patients. In January 2023, the FDA approved modifications to the mifepristone REMS to allow certified pharmacies to dispense the medication. Given the established safety and effectiveness of mifepristone, the evidence supports its distribution via pharmacies and leveraging pharmacists to expand medication abortion access. Pharmacists are one of the most widely accessible healthcare providers and their responsibility centers on patient and medication safety and improving health outcomes. This article, an opinion of the American College of Clinical Pharmacy Women's Health Practice and Research Network, adds the voice of members of the pharmacy profession to the collective efforts to ensure access to medication abortion, including pharmacist dispensing of mifepristone. We encourage pharmacists to embrace this fresh opportunity to provide medication abortion care in their communities.

Phase 1 Study of Autologous Sirpα-Low Macrophages (SIRPant-M) Administered By Intratumoral Injection Alone or in Combination with External-Beam Radiotherapy in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma (NCT05967416)

Background and Significance. While a sentinel role of macrophages in channeling immune responses has long been recognized, the opportunity to harvest, harness and deploy macrophages for therapeutic potential has been underappreciated clinically. Most currently marketed and development-stage cell therapies target a single tumor-associated antigen, permitting activation of resistance and tumor escape mechanisms that frequently lead to relapse. High rates of CRS and neurotoxicity (ICANS) associated with CAR-T therapies complicate usage, with associated product labeling that includes a Risk Evaluation and Mitigation Strategy (REMS), mandating hospitalization and post-therapy monitoring with attendant administrative burden that precludes widespread use in community-based settings. Moreover, many subtypes of lymphoma (NHL) lack a readily druggable target. The current first-in-human Phase 1 study advances a novel paradigm in cell-therapy, deploying SIRPα-depleted activated macrophages, manufactured from an autologous mononuclear apheresis (SIRPant-M). In the context of macrophages, SIRPα acts as a strong negative regulator of (i) phagocytosis and (ii) productive pro-inflammatory T cell stimulation; therefore abrogation of SIRPα-activity serves as a necessary precondition for robust neo-antigen-specific anti-tumor responses. Requiring no genetic modification, in pre-clinical models these SIRPα-depleted macrophages orchestrated an immune response that targets multiple individual-specific and tumor-unique neo-antigens in parallel. SIRPant-M elicits a multi-pronged polyclonal immune response that transforms the tumor microenvironment (TME) by fostering a pro-inflammatory milieu that provides for unencumbered and orchestrated targeting of cancer cells via both cellular and humoral effector mechanisms. Manufactured and subsequently frozen as 3 aliquots from a single apheresis, activation of macrophages is brought about by conditioning the macrophages during ex vivo culture with a proprietary cytokine cocktail (PhagoAct™) with the added effect of modulating activity of SIRPα. This combination of product attributes permits the same cell product to have potential clinical applications in both solid tumor and hematologic malignancies. While this initial Phase 1 study administers the macrophages by intra-tumoral injection (ITI), subsequent studies aim to explore IV-dosing. Study design, methods and patients. This is a multicenter open-label Phase 1 study of SIRPant-M monotherapy, with sequential cohorts receiving low [90×10 6] and high [300×10 6] ITI cell doses. Cell product is administered alone or combined with focal external-beam radiotherapy (XRT). Each cell dose is administered in 3 ITI-fractions on days 1, 3, and 5 over 1 cycle. Upon confirmation of safety as a single agent, subsequent cohorts receive cell product concurrent with focally directed radiation in three 2.5 Gy fractions (7.5 Gy total). The primary end point, Dose Limiting Toxicity, is assessed over 30 days and dose escalation is gated by a standard 3+3 dose escalation design, overseen by a Safety Monitoring Committee. The enrollment target is 12-24 DLT-evaluable patients. The study enrolls an “all comers” B- and T-cell NHL population, including systemic and cutaneous histologies (CTCL), with relapsed or progressive disease following a minimum of 2- but no maximum number of prior therapies. Minimum age is 18, with no upper age limit. Prior CAR-T, bi-specific antibody and/or autologous/allogeneic transplant is allowed after recovery from treatment-related AEs. Patients must not receive immuno-suppression for GVHD and must have at least 1 target lesion that is 1.5 to 5 cm in diameter and accessible for safe ITI, ECOG ≤ 2, life expectancy > 3 months, renal/hepatic/coagulation parameters and blood counts that are standard for Phase 1 studies at baseline. Secondary and Exploratory Endpoints. Tumor response, including abscopal response, is evaluated by Lugano criteria or other Workgroup criteria as appropriate for the tumor type at the end of the DLT-period (Day 30), Week 12 and per SOC thereafter. Serial blood samples and a tumor biopsy before and 16 days after treatment are collected for multi-parameter analyte detection including pro-inflammatory cytokines, multiplex flow cytometry, scRNA sequencing, and ctDNA analysis to investigate pharmacodynamics and mechanism of action.

“Defining the Optimal Post-CART Monitoring Period in Recipients of Axicabtagene Ciloleucel and Tisagenlecleucel”

Background: Rigorous monitoring for approximately 4 weeks after chimeric antigen receptor T-cell therapy (CART) is mandated due the potentially fatal toxicity risks of cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndromes (ICANS) during this period, and to allow early appropriate interventions. The US Food and Drug Administration implemented the Risk Evaluation and Mitigation Strategy (REMS) program for approved CART that mandates patients remain within the proximity of the authorized treating center for the monitoring period. The physical and financial burden of stringent monitoring may pose a barrier to CART access, especially for minorities and patients from rural areas and low-income groups. Therefore, evaluating the optimal duration of monitoring and causes of non-relapse mortality (NRM) is an area of unmet need. We evaluated safety outcomes for commercial axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) recipients. Methods: Patients (pts) ≥ 18 yrs who received an axi-cel or tisa-cel infusion for large B-cell lymphoma between April 2016 and July 2022 at nine academic US medical centers were identified from the Cell Therapy Consortium registry. Descriptive analysis was used to report outcomes. NRM was death due to causes other than disease progression. New-onset CRS and ICANS were reported as a percentage of pts at risk (alive with no prior CRS/ICANS). Results: A total of 374 pts were included with 216 (58%) receiving axi-cel, and 158 (42%) tisa-cel. Demographics are in Table 1. Median follow-up was 12.4 mo (0.3-58) Safety: Any grade CRS occurred in 63% pts, more common in axi-cel recipients (80%) compared to tisa-cel (41%), p<0.0001. During week 1 (Day 0-7), new-onset CRS occurred in 60.4% of the total population including 75.4% of axi-cel and 39.8% of tisa-cel recipients. New CRS onset in week 2 (Day 8-14) was seen in 6.1% of pts (15.4% axi-cel vs 1% tisa-cel). There was no new onset CRS in Week 3 or beyond. The median time to CRS onset was 3 days (0-13). (Figure 1) Unresolved CRS beyond Day 14 occurred in 7.2% (8.7% of axi-cel vs 3.1% of tisa-cel recipients), of which only 1.7% of pts (all axi-cel recipients) had unresolved CRS beyond Day 28. The median time to resolution was 4 days (IQR 25-75%: 2-7). 98.3% of CRS resolved by Day 28. Any grade ICANS was seen in 35% of pts, more common in axi-cel (52%) compared to tisa-cel (10%), p<0.0001. During Week 1, new-onset ICANS was seen in 27% of of the total population including 40.7% of axi-cel and 8.2% of tisa-cel recipients. New ICANS in week 2 was seen in 9.5% of pts (18.8% of axi-cel vs 2.8% of tisa-cel recipients). During week 3, new-onset ICANS occurred in only 1 tisa-cel recipient (0.4%). There were no new cases in week 4 and beyond. The median time to ICANS onset was 5 days (1-21). Unresolved or ongoing ICANS beyond Day 14 occurred in 32.8% of pts (34.8% of axi-cel: vs 18.7% of tisa-cel recipients), and beyond Day 28 in 7% of pts (7.1% of axi-cel vs 6.3% of tisa-cel recipients). The median time to ICANS resolution was 12 days (IQR 25-75%: 9-16). 93% of ICANS resolved by Day 28. Toxicity Management: Tocilizumab was utilized in 47% of pts (axi-cel 62% vs tisa-cel 26%) and 33% of pts received steroids (axi-cel 50% vs 10% tisa-cel) for management of CART-related toxicities. Other Complications: Infectious complications from Day 0-28 were seen in 18.5% of the total population and more commonly in axi-cel (22%) compared to tisa-cel (13.9%) recipients, p=0.006. Grade ≥4 neutropenia from Day 0-28 days was seen in 66% of the total population (81% axi-cel vs 46% tisa-cel). 82% of the total population did not have Grade ≥4 neutropenia beyond Week 2, and 93% had no Grade ≥4 neutropenia beyond Week 4. NRM: Day 0-28 NRM included 4 deaths (3 related to ICANS and 1 infection), and Day 29-90 NRM included 7 deaths (3 infections, 1 ICANS, 1 cardiac, 2 other). Conclusions: This large multicenter retrospective analysis evaluates patterns of CRS, ICANS, and NRM in recipients of axi-cel and tisa-cel. While NRM is mainly due to infections and ICANS, our study suggests that beyond 2 weeks following CART infusion, the incidence of new onset CRS and ICANS is low. This data supports further investigation into individualized monitoring strategies for stable patients. A flexible monitoring period may help to decrease the financial and physical burden for patients and make CART more accessible and feasible, especially for those with limited socioeconomic support.

A Real-World Evidence Review of Post-Marketing Safety and Compliance with Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) in the US

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic condition characterized by complement-mediated, life-threatening hemolysis and thrombosis which are associated with significant impacts on health-related quality of life (HRQoL). Pegcetacoplan is the first targeted complement component 3 (C3) therapy approved for adults with PNH (US) and adults with PNH plus anemia despite receiving a complement component 5 inhibitor (C5i) for ≥3 months (EU). In clinical trials including patients with PNH who were C5i-experienced or -naive, pegcetacoplan significantly improved levels of hemoglobin (Hb) and lactate dehydrogenase (LDH) and reduced transfusion burden. Pegcetacoplan had a favorable safety profile in parent studies and an ongoing long-term, rollover, open-label extension study (NCT03531255). Compliance with pegcetacoplan treatment was high across all clinical studies. In the US real-world OPERA and Adelphi PNH Disease Specific Programme™ (DSP) patient-reported outcomes (PRO) studies, improvements in levels of Hb and LDH, along with self-reported fatigue and cognitive outcomes, were observed. Pegcetacoplan treatment also led to reductions in the frequency and severity of PNH symptoms (including shortness of breath and fatigue) and improvements in social, physical, and emotional HRQoL domains in the US real-world Voice of the Patient PRO study. Further, both patient and physician satisfaction with pegcetacoplan treatment was high in the Adelphi PNH DSP study. However, to date, compliance and safety with pegcetacoplan treatment in the real-world setting have not been described. The objective of this real-world evidence review study was to evaluate compliance and safety with pegcetacoplan treatment in patients with PNH in the US post-marketing setting. Methods: Post-marketing data from the US, including the number of patients who received pegcetacoplan and reported safety events, were collected and analyzed from the pegcetacoplan Risk Evaluation and Mitigation Strategies (REMS) program which controls the distribution of pegcetacoplan and the pharmacovigilance safety database through May 13, 2023. Treatment compliance was calculated as the proportion of days a patient had the drug in possession, divided by the total number of days of follow-up, using central pharmacy prescription refill data. Thrombosis (a leading cause of death in patients with PNH prior to the availability of complement inhibitors) and meningococcal infections (a potential risk with complement inhibitors) were safety events of interest. To reduce the risk of serious meningococcal infections, clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae; N meningitidis types A, C, W, Y, and B; and Haemophilus influenzae type B before starting treatment with pegcetacoplan. If pegcetacoplan treatment must be initiated before vaccination, the US label mandates prophylactic antibiotic use. In this study, the rates of thrombosis and meningococcal infection per 100 patient-years were estimated based on the total number of thrombosis and meningococcal infection events reported in the REMS program. Results: As of May 13, 2023, the cumulative pegcetacoplan exposure was 273.10 patient-years in the US post-marketing setting. Based on prescription refill data, compliance with pegcetacoplan treatment was ~98%. There were 2 confirmed thrombotic events reported and the incidence of thrombotic events was 0.73 events/100 patient-years in 273.10 patient-years. Similar to clinical trials, no meningococcal infections were reported in the US post-marketing setting. Conclusions: The high compliance rate and favorable safety profile of pegcetacoplan in the US post-marketing setting were consistent with clinical trial observations. These data, coupled with the effectiveness on hematologic parameters and improvements in symptoms and HRQoL reported in pegcetacoplan real-world PRO studies, support a positive benefit:risk profile for pegcetacoplan in the real-world setting.

Industry Review of Best Practices for Risk Management of Drug-Induced Liver Injury from Development to Real-World Use.

The relative treatment benefit of a drug for patients during development, marketing authorization review, or after approval includes an assessment of the risk of drug-induced liver injury (DILI). In this article, the Pharmacovigilance and Risk Mitigation Working Group of the IQ-DILI Initiative launched in June 2016 within the International Consortium for Innovation and Quality in Pharmaceutical Development presents and reviews three key topics for essential risk management activities to identify, characterize, monitor, mitigate, and communicate DILI risk associated with small molecules during drug development. The three topics are: (1) Current best practices for characterizing the DILI phenotype and the severity and incidence of DILI in the treatment population, including DILI identification, prediction and recovery. (2) Characterization of the relative treatment benefit for patients who will be exposed to a drug and the attendant risk of DILI in conjunction with existing global risk mitigation strategies. (3) Implementation of risk mitigation strategies during drug development highlighting patient factors, healthcare settings and site of product administration, and prescriber and healthcare provider factors. Industry guidance is provided for assessing whether the product labeling is sufficient to minimize the risk of DILI or whether a United States Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) or European Medicines Agency (EMA) Risk Management Plan (RMP) with additional Risk Minimization Measures (aRMM) is needed.

Supporting patients in the transition to the revised pexidartinib dosing regimen: perspectives from the multidisciplinary clinical and allied health professional team

Pexidartinib is a colony-stimulating factor-1 receptor inhibitor approved in the United States for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Because of the risk of severe and potentially fatal hepatotoxicity, pexidartinib is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. Pexidartinib pharmacokinetics are influenced by the fat content of meals: compared with the fasted state, consuming a high-fat meal with pexidartinib increases pexidartinib absorption by 100%; a low-fat meal increases absorption by approximately 60%. Pexidartinib was initially authorized to be taken at 800 mg/day on an empty stomach; therefore, if this same dose of pexidartinib is taken with food, there is a risk of overexposure and potential toxicity. To reduce the risk of hepatotoxicity and improve patient compliance, pexidartinib has undergone a revised dosing regimen, from 800 mg/day (400 mg twice daily) fasted to 500 mg/day (250 mg twice daily) with a low-fat meal (approximately 11–14 g of total fat). The objective of this report is to educate clinical and allied health professionals on the revised dosing regimen and the importance of patient compliance with a low-fat meal. Healthcare professionals need to understand the rationale for the switch from pexidartinib dosing on an empty stomach to dosing with a low-fat meal and how meal composition and timing influence pharmacokinetics. Finally, we provide guidance for the healthcare team of prescribing providers, nurses, pharmacists, and dietitians who are caring for patients with TGCT on pexidartinib. It is important for healthcare providers to deliver consistent messaging on the low-fat meal requirement and help patients fit pexidartinib into their regular meal schedules. Consulting a dietitian may be helpful for patients, especially those with complex dietary needs. We provide an overview of the roles and responsibilities of each healthcare professional and outline steps to best support patients, including key questions and answers related to the revised dosing regimen. This report provides the information necessary to guide the multidisciplinary team caring for patients with TGCT and to support them through the pexidartinib dosing regimen change.

Evolution of Cross-Sectional Survey Protocol Quality Over Time: A Case Series of Index U.S. REMS Knowledge Survey Protocols (2007-2020).

Surveys are commonly used to assess effectiveness of FDA-required risk evaluation and mitigation strategies (REMS) for drugs and biologics in the United States. The aim of this study was to assess the scientific rigor of REMS knowledge survey protocols submitted to FDA and compare protocols before and after FDA's 2012 public workshop and 2019 draft guidance. A content analysis of index survey protocols submitted to FDA (2007-2020) for single-product REMS with elements to assure safe use (39 programs, 78 protocols) was conducted. Each protocol was scored against 52 core essential elements (CEE), abstracted from FDA's guidance and grouped into six domains: study objective (n=5), study design (n=18), survey instrument (n=9), participant recruitment (n=7), survey administration (n=9), and statistical analysis plan (n=4). Scores were collected by time periods: (A) Oct 2007 to Jul 2012; (B) Aug 2012 to Feb 2019; (C) Mar 2019 to Dec 2020; and compared using logistic generalized linear mixed models adjusting for domain, survey population, vendor, program, and protocol. There were 30 (38.5%), 40 (51.3%), and 8 (10.3%) protocols submitted in time period A, B, and C, respectively. Adjusted marginal means of elements present (on the probability scale) by time period were 0.5816 (SE = 0.0242), 0.6429 (SE = 0.0229), and 0.7543 (SE = 0.0394). The likelihood of missing a CEE declined over time (adjusted p-value = 0.0094, time period A vs C). The statistical analysis plan domain had the most improvement; study design remained the weakest domain with the scientific justification CEE particularly underrepresented. The rigor of REMS knowledge survey protocols improved over time consistent with FDA's efforts to advance regulatory science, but gaps remain.

Provision of ambrisentan from a health-system specialty pharmacy affiliated with a pulmonary hypertension Center of Comprehensive Care.

This descriptive report describes the process used to obtain access to providing ambrisentan from a health-system specialty pharmacy (HSSP) affiliated with a pulmonary hypertension Center of Comprehensive Care, develop a pulmonary arterial hypertension (PAH) care team at the HSSP, and characterize medication adherence and access metrics. PAH is a rare disease treated with several specialty medications requiring intensive monitoring. Historically, specialty medications used to treat PAH have been provided by only select specialty pharmacies due to restricted drug distribution channels. It is recommended that patients with PAH receive their care at centers with expertise in the diagnosis and management of this disorder, but the HSSPs at these expert centers are unable to provide specialty PAH medications. The current care model for PAH leads to patients receiving their medical and pharmaceutical care from separate entities. This descriptive report describes a multidisciplinary team's approach to gaining access to providing ambrisentan and developing a disease state care team within an established HSSP. After implementing this service, specialty pharmacy metrics were assessed, including proportion of days covered (PDC), time to first fill, patient contact rate, Risk Evaluation and Mitigation Strategy (REMS) program compliance, time to prior authorization (PA) approval, rate of optimal adherence (PDC of >80%), and PA renewal rate, to demonstrate a proof-of-concept HSSP model for PAH. In this model, the HSSP was able to demonstrate high-quality specialty pharmacy metrics with regard to medication adherence, medication access, and REMS program compliance. The development of a PAH care team to provide ambrisentan at an existing HSSP was associated with high adherence rates, efficient and reliable medication access, and REMS program compliance.

Gender disparities in isotretinoin prescribing patterns for pediatric patients before and during practice changes introduced by the COVID-19 pandemic.

Isotretinoin is a systemic therapy approved for acne and has historically required lab monitoring in addition to adherence to the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) given the medication's teratogenic effects. The COVID-19 pandemic resulted in the expansion of telemedicine, acceptance of remote pregnancy tests, and relaxation of lab monitoring practices. A retrospective review of 142 pediatric patients was conducted, and multivariate linear regression was performed to examine differences in prescribing patterns pre-COVID and during COVID. Backward elimination identified gender and the interaction between acne severity and number of systemic treatments tried before isotretinoin as significant factors associated with increased number of visits to isotretinoin initiation, with females requiring more visits before starting isotretinoin at every acne severity level and even after accounting for systemic treatments previously tried. While the changes catalyzed by the pandemic may have improved visit-related burdens for patients and caregivers, female patients with acne continue to be delayed in receiving isotretinoin even when adjusting for acne severity and systemic treatments trialed, underscoring persistent gender disparities in prescribing practices for isotretinoin.

Mifepristone use for early pregnancy loss: A qualitative study of barriers and facilitators among OB/GYNS in Massachusetts, USA.

Early pregnancy loss (EPL) affects 1 million patients in the United States (US) annually, but integration of mifepristone into EPL care may be complicated by regulatory barriers, practice-related factors, and abortion stigma. We conducted qualitative, semi-structured interviews among obstetrician-gynecologists in independent practice in Massachusetts, US on mifepristone use for EPL. We recruited participants via professional networks and purposively sampled for mifepristone use, practice type, time in practice, and geographic location within Massachusetts until we reached thematic saturation. We analyzed interviews using inductive and deductive coding under a thematic analysis framework to identify facilitators of and barriers to mifepristone use. We interviewed 19 obstetrician-gynecologists; 12 had used mifepristone for EPL and 7 had not. Participants were in private practice (n = 12), academic practice (n = 6), or worked at a federally qualified health center (n = 1). Seven had fellowship training, including four in complex family planning. The most common facilitators of mifepristone use for EPL were access to the expertise or protocols of local-regional experts, leadership from a "champion," prior experience with abortion care, and hospital capacity constraints during the COVID-19 pandemic. The most common barriers were related to the Mifepristone Risk Evaluation and Mitigation Strategy (REMS) Program imposed by the US Food and Drug Administration (FDA). Additionally, mifepristone's affiliation with abortion was a barrier to its use in EPL for some obstetrician-gynecologists. The FDA Mifepristone REMS Program presents substantial barriers to obstetrician-gynecologists incorporating mifepristone into their EPL care.

The Importance of Gender-Neutral Terminology in Risk Evaluation and Mitigation Strategy Programs: A Call to Action.

The use of risk evaluation and mitigation strategy (REMS) programs is frequently required for prescriptions with potentially teratogenic effects, especially in the field of dermatology. Among these REMS programs, the most well-known example is isotretinoin, an oral retinoid that uses the iPLEDGE system. iPLEDGE has strict regulations and a lengthy approval process, and until recently, patients were grouped into 3 categories: male, female, or female of reproductive potential. This strict grouping has posed problems in the medical community, especially for gender-diverse individuals where their perceived gender conflates with their assigned grouping causing patient-specific distress. The distinction between gender-a multifactorial perception of identity-and biological sex is addressed under new iPLEDGE guidelines. Dermatologists now register patients under one of 2 categories: patients who can become pregnant and those who cannot become pregnant. This change simultaneously improves the accessibility to isotretinoin among gender-diverse individuals, while limiting prescription barriers. Despite initial success being limited due to lengthy system conversions, a registration process based on reproductive potential ultimately enhances iPLEDGE's goal to prevent potential birth defects. We propose that other REMS programs follow the standard set by the iPLEDGE system, including those for the medications thalidomide, acitretin, and mycophenolate mofetil, all of which currently have a similar taxonomy to that of the old iPLEDGE system. Implementing the standardization of gender-neutral terminology can maximize enrollment and minimize distress. Current and ongoing refinement of iPLEDGE and other REMS is needed to build protocols solely around the prevention of birth defects without regard to sex or gender.

Patients prefer free drug disposal options delivered by pharmacists at the point of care: Results of a decision tree analysis of a national factorial vignette panel survey.

Unused opioid medication in the home increases risk of medication diversion, misuse, and unintended harm. The United States Federal Food and Drug Administration is currently considering the implementation of a risk evaluation and mitigation strategy (REMS) program that would require US pharmacists to provide drug disposal products with opioid prescriptions. Still, little is known about consumer preference for drug disposal method. The objective of this study was to identify product and program characteristics associated with consumer preference for at-home drug disposal products. A 2x2x3x3 full-factorial design was employed to text-based vignettes representing opioid analgesic disposal scenarios. Each vignette varied on four characteristics: product cost (free vs paid), ease of use (a mail back envelope, bringing medication to a takeback site, and an at-home drug deactivation pouch), potential environmental impact (incineration), and point of access (pharmacy, community organization, and prescriber). Of the 36 possible vignettes, 12 were removed as they represented a non-realistic combination of vignette characteristics. The remaining 24 were administered to a panel of patients with controlled-substance use in the past six-months. Decision tree modeling and general linear mixed (GLM) models were used sequentially to identify product characteristics associated with patient drug preferences RESULTS: A total of 1,006 participants completed all vignette drug disposal scenarios. Regression tree analysis found that the most important predictor of use was cost followed by ease of access and product design. GLM showed that takeback programs offered at a pharmacy were the most preferred disposal option followed by at-home products (mailed envelope or deactivation system) dispensed with the prescription. Programs that provide disposal resources directly to the patient at no cost with their prescription are likely to optimize willingness to dispose. Findings support the FDA's plan for a REMS program requiring pharmacies to distribute mail-back envelopes to patients when dispensed opioids.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Mid-Cycle Communications.

The United States Food and Drug Administration (FDA) implemented "the Program" in 2012 to promote greater transparency and increased communication between the FDA and applicants of New Molecular Entity (NME) New Drug Applications (NDA) and original Biologics License Applications (BLA). We examined 128 publicly available NME NDA and original BLA approval packages reviewed and approved under the Program with the goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor. This research found that the timing of communications between FDA and the Sponsor through the Mid-Cycle Communication (MCC) was consistent with the 21st-century Desk Reference Guide (DRG); 90% of internal FDA Mid-Cycle Meetings, MCCs with the applicant, and corresponding issuance of MCC minutes were within the target date. The content and format of the MCC were also consistent with the DRG and across disciplines. Almost all MCCs reviewed included a discussion on significant review issues, including major safety concerns. FDA's preliminary opinion on the necessity of a Risk Evaluation and Mitigation Strategy (REMS), which was predictive of REMS requirement at approval. The FDA's MCC comment on advisory committee meeting plans was highly predictive; if the MCC indicated an AC was planned, an AC meeting was held 91% of the time. With respect to the MCC, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the review of a NME NDA or original BLA.

SMI Adviser to Bring Hands-On Learning to Annual Meeting

SMI Adviser to Bring Hands-On Learning to Annual Meeting

346 Post-marketing Liver Safety Data from 4 Years of the Tolvaptan Risk Evaluation and Mitigation Strategy (REMS) in the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

346 Post-marketing Liver Safety Data from 4 Years of the Tolvaptan Risk Evaluation and Mitigation Strategy (REMS) in the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Assessment of the Risk Evaluation and Mitigation Strategy (REMS) for Phentermine-Topiramate to Prevent Exposure During Pregnancy.

The U.S. Food and Drug Administration approved phentermine-topiramate for obesity in 2012 and required a Risk Evaluation and Mitigation Strategy (REMS) to prevent prenatal exposure. No such requirement was introduced for topiramate. To evaluate the rate of prenatal exposure, contraceptive use, and pregnancy testing among patients with phentermine-topiramate compared with topiramate or other antiobesity medications (AOMs). Retrospective cohort study. Nationwide health insurance claims database. Females aged 12 to 55 years with no infertility diagnosis or sterilization procedure. Patients with other indications for topiramate were excluded to identify a cohort that was likely treated for obesity. Patients initiated use of phentermine-topiramate, topiramate, or an AOM (liraglutide, lorcaserin, or bupropion-naltrexone). Pregnancy at treatment initiation, conception during treatment, contraceptive use, and pregnancy testing outcomes were ascertained. Measurable confounders were adjusted for, and extensive sensitivity analyses were done. A total of 156280 treatment episodes were observed. Adjusted prevalence of pregnancy at treatment initiation was 0.9 versus 1.6 per 1000 episodes (prevalence ratio, 0.54 [95% CI, 0.31 to 0.95]) for phentermine-topiramate versus topiramate. The incidence rate of conception during treatment was 9.1 versus 15.0 per 1000 person-years (rate ratio, 0.61 [CI, 0.40 to 0.91]) for phentermine-topiramate versus topiramate. Both outcomes were similarly lower for phentermine-topiramate compared with AOM. Prenatal exposure was marginally lower in topiramate users compared with AOM users. Approximately 20% of patients in all cohorts had at least 50% of treatment days covered by contraceptives. Few patients had pregnancy tests before treatment (≤5%), but this was more common among phentermine-topiramate users. Outcome misclassification; unmeasured confounding due to lack of prescriber data to account for possible clustering and spillover effects. Prenatal exposure seemed to be significantly lower among phentermine-topiramate users under the REMS. Pregnancy testing and contraceptive use appeared to be inadequate for all groups, which deserves attention to prevent the remaining potential exposures. None.

Oral buprenorphine utilization, concomitant benzodiazepines and opioid analgesics, and payment source: Trends from 2015 to 2019

IntroductionThis study describes utilization patterns of oral buprenorphine products indicated for the treatment of opioid use disorder with a focus on patterns consistent with prescribing guidelines and the safe use conditions during induction and maintenance treatment outlined by the Risk Evaluation and Mitigation Strategy (REMS) Program, including trends over time. MethodsUsing an anonymized longitudinal patient-level dataset that captures information on medical and pharmacy claims in the United States (October 1, 2014 through March 31, 2020), buprenorphine prescriptions, days' supply, and daily dose were described overall and stratified by induction (month 1) vs. maintenance (month 2–6) treatment, along with duration of concomitant benzodiazepines or opioid analgesics. ResultsOverall, there were 1.5 million buprenorphine treatment episodes initiated between January 1, 2015 to September 30, 2019 (2015: 258,899; 2019: 351,378). Treatment episodes included an average of 6.8 buprenorphine prescriptions (standard deviation [SD] = 6.7), 16.8 days' supply per prescription (SD = 10.5), 94.2 total days' supply per treatment episode (SD = 71.4), and a mean daily dose of 13.6 mg (SD = 6.3), with the number of prescriptions and total days' supply per treatment episode declining over the study period. There was a lower mean number of days' supply per prescription in the first month of treatment compared to months 2–6 (month 1: 15.8 [SD = 11.0]; month 2–6: 19.0 [SD = 10.1]) and daily dose per prescription (month 1: 13.3 mg [SD = 6.4]; months 2–6: 14.3 mg [SD = 6.2]), and a higher mean number of prescriptions per month (month 1: 2.5 per month [SD = 1.7]; months 2–6: 1.8 per month [SD = 1.2]). From 2015 to 2019, there appeared to be a shift in payer mix, with increases in Medicaid/Medicare and declines in cash and commercial insurance. Concomitant benzodiazepine and opioid analgesic use declined over time; in 2019, 16.6 % and 14.3 % of treatment episodes had any concomitant benzodiazepine or opioid analgesic, respectively, and <5 % had chronic (>90 overlapping days) concomitant use (3.0 % and 0.4 %, respectively). ConclusionsThe number of oral buprenorphine treatment episodes increased over the study period, and prescribing was generally consistent with the REMS and other treatment guidelines. There was a decline in concomitant buprenorphine and benzodiazepine or opioid analgesics, and chronic concomitant use was rare.