Evaluating the impact of a Risk Evaluation and Mitigation Strategy with tolvaptan to monitor liver safety in patients with autosomal dominant polycystic kidney disease.

Background: On approval of JYNARQUE (tolvaptan) for use in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk for rapid progression, the US Food and Drug Administration required a Risk Evaluation and Mitigation Strategy (REMS) from the sponsor, which includes collection of post marketing liver safety data. Methods: This is a retrospective interim analysis of the ongoing REMS. The period evaluated was from REMS implementation (14 May 2018) at tolvaptan commercialization to the analysis cutoff date (23 February 2021). Patients were previously tolvaptan-naïve and initiated tolvaptan in the post marketing setting. Reports of possible severe drug-induced liver injury (DILI) were evaluated for severity based on the evidence obtained (e.g. liver enzyme levels, symptoms, diagnostic tests and event outcomes). The incidence of DILI was compared between the REMS and tolvaptan clinical trials in ADPKD. Results: Among 6711 REMS patients, 60 (0.9%) cases of possible severe DILI were reported, 4 of which were confirmed as serious and potentially fatal by the sponsor. One of these four patients met Hy's law criteria. In all four patients, liver enzymes normalized after tolvaptan discontinuation. The duration of tolvaptan exposure in the REMS is currently shorter than in completed clinical trials, but within this limitation, the incidence of possible severe DILI was lower in the REMS than in clinical trials (incidence rate ratio 0.587; P = .000411). Conclusions: In interim data on >6000 tolvaptan REMS patients, <1% experienced possible severe DILI. Monthly monitoring, as described in the tolvaptan prescribing information, enables the prompt detection of liver enzyme abnormalities and appropriate drug discontinuation.

A qualitative evaluation of patient and healthcare provider knowledge, attitudes, and behavior for safety and use of pexidartinib.

Aim: Pexidartinib is approved in the USA for the treatment of symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Due to risk of serious liver injury, a survey of patient and healthcare provider (HCP) knowledge, attitudes, and behavior (KAB) of the risks was required. Materials & methods: Prior to KAB survey execution, structured telephone interviews with 12 patients and 12 HCPs were conducted. Results: The interviews revealed that patients had difficulty with the complexity and wordiness of some of the questions, while HCPs noted that some questions were repetitive with terminology that was not self-explanatory. Of the 15 questions initially in the patient survey, nine were modified for survey inclusion. For the HCP survey, 10 of 18 questions were modified. Conclusion: Qualitative research prior to KAB surveys is recommended to improve comprehension and data quality.

Evaluation of patient/caregiver and healthcare provider knowledge, attitudes and behavior for safety and use of pexidartinib.

Aim: Pexidartinib was approved for the treatment of tenosynovial giant cell tumors with a required Risk Evaluation and Mitigation Strategy (REMS) to ensure its safe use. As required by the REMS, a survey was conducted to document the knowledge, attitudes and behavior (KAB) of patients/caregivers and healthcare providers (HCPs) regarding the risk of serious and potentially fatal liver injury due to pexidartinib, the need for liver testing prior to and during treatment and the need for patient counseling about this risk. Patients & methods: The KAB survey was conducted among 40 patients and 18 HCPs enrolled in the pexidartinib REMS. Results: Among patients, 87.5% demonstrated understanding of key risk message (KRM) 1 (risk of serious liver injury), 87.5% demonstrated understanding of KRM2 (liver testing requirement) and 77.5% demonstrated understanding of both KRMs. Among HCPs, 83.3% demonstrated understanding of KRM1, 88.9% demonstrated understanding of KRM2, 100% demonstrated understanding of KRM3 (patient counseling) and 83.3% demonstrated understanding of all three KRMs. Conclusion: The KAB surveys demonstrated that the educational goals of the pexidartinib REMS were being achieved.

Lay abstract Pexidartinib is a prescription medicine used to treat adults who have a tenosynovial giant cell tumor that is not likely to improve with surgery. Because of the risk of serious liver problems, pexidartinib is available only through a restricted program called a Risk Evaluation and Mitigation Strategy (REMS) that enrolls both patients and healthcare providers (HCPs). As part of the REMS, information is collected about their knowledge, attitudes and behavior (KAB) regarding the potential for pexidartinib to cause liver problems that may be severe and can lead to death. This KAB survey was conducted among 40 patients and 18 HCPs enrolled in the pexidartinib REMS. The results indicated that among patients, over three-quarters demonstrated understanding of the risk of serious liver injury and the need for regular liver testing. Among HCPs, 83.3­100% demonstrated understanding of the risk of serious liver injury, the need for regular liver testing and the requirement to counsel their patients about this risk. In conclusion, the KAB surveys demonstrated that the educational goals of the pexidartinib REMS were being achieved.

Knowledge and Understanding of the Safety and Efficacy Aspects of BRIDION® Among Canadian Anesthesiologists.

BACKGROUND: BRIDION® (sugammadex sodium) is an agent for the reversal of neuromuscular blockade (NMB) induced by rocuronium and vecuronium in general anesthesia. Following the approval of sugammadex in Canada (February 2016), Health Canada required a survey to assess the knowledge and understanding of the safety and efficacy aspects of sugammadex among anesthesiologists in Canada. OBJECTIVE: Our objective was to evaluate how well the anesthesiologists in Canada understood the safety and efficacy aspects of sugammadex. METHODS: A survey was implemented among anesthesiologists in Canada via internet/phone. The survey was organized to test the knowledge of anesthesiologists by utilizing 11 key questions regarding the safety and efficacy of sugammadex. Five additional safety questions that were not considered part of the key messages but were important concepts for anesthesiologists to know when administering sugammadex were also included. RESULTS: A total of 202 completed surveys were collected. Based on an a priori threshold of understanding of 75%, 9 out of 11 key messages scored at or above this threshold. The two messages that scored below this threshold involved (1) knowledge that sugammadex is not indicated for use in children aged < 18 years (71.8%; 95% confidence interval [CI] 65.0-77.9) and (2) that monitoring is required for recurrence of NMB after reversal with sugammadex (73.3%; 95% CI 66.6-79.2). Of the five additional safety questions, four had an understanding rate of ≥ 88.1%. One question scored 60.4%; this question covered the concept that sugammadex is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min), including those requiring dialysis. CONCLUSION: In general, the survey results suggested that anesthesiologists understood the use, safety, and efficacy of sugammadex for the reversal of moderate to deep NMB induced by rocuronium or vecuronium in adults undergoing surgery.

Patient Understanding of the Neuropsychiatric Risks Associated with Branded Bupropion Hydrochloride Products Used for Smoking Cessation.

BACKGROUND: Bupropion hydrochloride (Zyban) is an effective aid to smoking cessation; however, its use has previously been associated with neuropsychiatric adverse events. Here we report results of the patient Knowledge, Attitudes, and Behavior survey that forms part of the Year 7 Risk Evaluation and Mitigation Strategy (REMS) assessment for Zyban. OBJECTIVE: Assess participants' understanding of the neuropsychiatric risks associated with branded bupropion hydrochloride products that are used for smoking cessation, as described in the Medication Guides. METHODS: A cross-sectional study was conducted among patients ≥ 18 years of age, who had used or filled a prescription for branded bupropion hydrochloride for smoking cessation in the past 6 months. Participants were recruited through an online panel, pharmacy network, or by healthcare provider referral, and invited to complete a survey containing questions regarding the risks associated with the use of branded bupropion hydrochloride products, and whether they had received and read the Medication Guide. The study aimed for ≥ 80% of participants to respond correctly to each question regarding neuropsychiatric risks. RESULTS: From the 50,985 survey invitations distributed, 1017 participants responded, of whom 144 were eligible and 142 completed the survey. Over 80% of participants correctly responded to most neuropsychiatric risk questions. Approximately three-quarters of participants received the Medication Guide when they last filled their prescription, of whom over half read the Medication Guide at that time. CONCLUSIONS: Participants enrolled in this Year 7 REMS survey had good understanding of the neuropsychiatric risks associated with using branded bupropion hydrochloride products for smoking cessation.

Quantitative Testing of Prescriber Knowledge Regarding the Risks and Safe Use of Albiglutide.

BACKGROUND: The risk of pancreatitis and potential risk of medullary thyroid carcinoma associated with glucagon-like peptide-1 receptor agonists prompted the US Food and Drug Administration to require a Risk Evaluation and Mitigation Strategy for albiglutide, including education for prescribers and subsequent assessment of their knowledge of the risks and safe use of albiglutide via a quantitative survey. OBJECTIVE: The objective of this study was to assess prescribers' knowledge of the risks related to medullary thyroid carcinoma, pancreatitis, and the appropriate patient population for albiglutide. METHODS: Two Risk Evaluation and Mitigation Strategy surveys were conducted 18 months and 3 years after albiglutide was launched. Primary analyses evaluated correct response rates for each question. Secondary analyses evaluated the number of correct responses and the percentage of respondents scoring at/above the target comprehension thresholds (75% at 18 months; 80% at 3 years), which were selected based on discussion with the Food and Drug Administration and current standards for Risk Evaluation and Mitigation Strategy assessments, for each key risk message. RESULTS: The correct response rate for individual questions ranged from 68.2 to 97.9% (18-month survey) and from 69.4 to 98.1% (3-year survey). For the secondary analysis, 79.5, 86.7, and 86.7% of respondents in the 18-month survey answered ≥ 75% of the questions correctly and 70.8, 90.9, and 54.1% of respondents in the 3-year survey answered ≥ 80% of the questions correctly for key risk messages related to medullary thyroid carcinoma, pancreatitis, and appropriate patient population, respectively. CONCLUSIONS: Survey results indicated most, but not all, prescribers are knowledgeable regarding the risks and safe use of albiglutide. Additional education to address gaps in knowledge could further improve risk mitigation.

How can registries contribute to the development and evaluation of CNS therapeutics?

This article is based on the proceedings from a workshop held during the Autumn 2011 International Society for CNS Clinical Trials and Methodology (ISCTM) Conference in Amelia Island, Florida. The goal of the workshop was to establish preliminary steps in determining whether and how patient registries can augment clinical trials in the field of central nervous system therapeutics. Participants in the workshop first defined several different types of registries and then created a list of questions that should be addressed in order to determine how registries might be used. The workshop concluded with discussion on logistical and practical considerations regarding use of patient registries.

Assessment of mortality in patients enrolled in a risedronate clinical trial program: a retrospective cohort study.

Risedronate, a pyridinyl bisphosphonate, has been shown in large clinical trials to be effective in the prevention and treatment of osteoporosis. Analysis of safety data from these trials has shown that risedronate (2.5- and 5-mg doses) has an overall safety profile comparable to placebo during the course of the clinical trials. The clinical trials were powered appropriately to analyze the efficacy endpoints; however, patients were not systematically followed after completion of the clinical trials and therefore vital status for most of the patient cohort after the cessation of the clinical trials was unknown. In order to investigate further the safety profile of risedronate observed in the clinical trials database, we conducted a retrospective cohort mortality study among 7981 patients comprising the intent-to-treat population in three North American risedronate osteoporosis trials. No difference in all cause mortality was observed in patients receiving risedronate treatment compared with patients receiving placebo. There were also no differences between these groups in mortality due to all cancers, lung cancer, and gastrointestinal tract cancer. A trend toward lower cardiovascular mortality was observed in the risedronate groups compared with placebo; this difference was largely due to a significant reduction in stroke mortality in the active treatment groups. Follow-up mortality data in this retrospective cohort study demonstrate that treatment with risedronate has no effect on overall mortality rates.