Additional Risk Minimisation Measures Research Articles

Effectiveness of Baricitinib Risk Minimization Activities in Patients With Rheumatoid Arthritis—A Cohort Study in Four Nordic Countries

ABSTRACTIntroductionBaricitinib received European Medicines Agency (EMA) approval for the treatment of moderate‐to‐severe active rheumatoid arthritis (RA) in 2017. Due to risks including serious infections, increased blood lipid parameters, and missing information regarding safety in pregnancy, additional risk minimization measures (aRMM) including healthcare professional educational material and a patient alert card were implemented to inform on the risks and actions to minimize risk such as the need to screen for tuberculosis and active viral hepatitis before starting baricitinib, monitoring of blood lipids and against use during pregnancy. The aim of the study is to report occurrences of infections, lipid level monitoring and pregnancies, in real world data, to gain insights into whether baricitinib is used in accordance with the aRMM.MethodsA descriptive observational cohort study, utilizing routinely collected data from the Swedish, Norwegian, Finnish, and Danish national registries, was carried out. RA patients initiating baricitinib treatment were identified in the periods 2017–19 (Sweden and Finland), 2017–20 (Norway) and 2017–21 (Denmark). Monitored events included pregnancies, cases of tuberculosis, viral hepatitis, and hyperlipidemia, as well as changes in statin prescriptions (including any of initiation, escalation, reduction or change of statin). Hyperlipidemia and statin use served as proxies for lipid level assessment.ResultsAmong 3908 patients initiating baricitinib (3373 person‐years exposure), eight pregnancies (1% of 815 women aged 18–50 years) potentially overlapped with treatment. During baricitinib treatment, there was a small number of prevalent cases of tuberculosis (less than three events), and a low prevalence of hepatitis (0.2%), and hyperlipidemia (0.5%), whereas 9.3% had start of or changes in statin prescription, indicating lipid level monitoring.ConclusionThe study's findings suggest that patients with RA are treated with baricitinib in accordance with the risk minimization recommendations, particularly concerning pregnancy and infection risks. However, the methods used for assessing lipid levels warrant further refinement for more accurate monitoring.

Evaluation of the Effectiveness of Additional Risk Minimization Measures for Ixazomib Citrate for Relapsed/Refractory Multiple Myeloma in Japan: A Web-Based Survey Among Pharmacists.

Ixazomib citrate (IXA) in combination with lenalidomide and dexamethasone (IRD therapy) has been approved for the treatment of relapsed or refractory multiple myeloma. In Japan, as these three drugs have different dosing schedules, dosing instructions for patients have been prepared and distributed to patients via healthcare professionals to promote an understanding of the appropriate dosing regimen, as an additional risk minimization measure (aRMM). This survey aimed to investigate whether the aRMM material is being utilized for the adequate use of IXA. A web-based questionnaire survey was conducted among in-hospital pharmacists in Japan who instructed patients on IXA dosing for IRD therapy. The primary endpoint was the proportion of pharmacists who provided patients with the contents of the aRMM material (i.e., how to take IXA). The secondary endpoints were the proportion of pharmacists who had obtained the aRMM material and the proportion of pharmacists who understood the importance of explaining how to take IXA to patients. Of the 330 pharmacists who completed the questionnaire, 93.0% answered that they had explained how to take IXA to patients. Of those who answered that they had explained how to take IXA, 33.2% responded that they had experience in using the aRMM material. In addition, 37.6% of the pharmacists answered that they had obtained the aRMM material. Moreover, 95.8% stated that they knew how to take IXA, and 90.3, 9.1, 0.3, and 0.3% of pharmacists answered that the importance of explaining how to take IXA was "very important," "probably important," "less important" and "not important," respectively. How to take IXA was explained to patients by pharmacists and the aRMM material was utilized at the time of the explanation, indicating that the aRMM material contributes to the promotion of the appropriate use of IXA.

A Sponsor's Perspective on the Contribution of Regulatory-Required Observational Post-Marketing Studies to Understanding Human Drug Product Benefit/Risk in Japan.

Following marketing authorization in Japan, for almost all new drugs or new indications, postmarketing studies (PMS) are a regulatory requirement. These PMS focus on accrual of a defined number of cases with data being collected for a predetermined period after approval to confirm efficacy/effectiveness, safety, and quality in the Japanese population. In contrast to other regions where PMS are only required to address a specific scientific uncertainty, in Japan, PMS are often required regardless of any specific scientific uncertainty, and therefore, their scientific value is unclear. To determine the contribution to the understanding of benefit/risk of PMS conducted by Pfizer in Japan over 2000-2020 for Pharmaceuticals and Medical Devices Agency (PMDA) reexamination. A retrospective analysis of all Pfizer Japan postmarketing studies (PMS) during 2000-2020 was performed. Available Pfizer clinical study reports (CSRs) and PMDA reexamination reports (RERs) were reviewed for key safety findings. The primary analysis was conducted on the subset of PMS that had both an English CSR and a discussion of that PMS in the relevant RER issued by the PMDA, which was subsequently translated into English by a professional translation vendor. Reexamination outcome is included in each RER and served to demonstrate the impact of the study of the benefit/risk profile of the drug. A total of 79 PMS for 43 different drug products across therapy areas enrolled a total of 98,035 patients. The 79 PMS comprised 34 general drug use investigation (GDUI) studies and 45 special investigation (SI) studies. The primary analysis involved 37 PMS with a CSR and RER available in English (40,470 patients); all of which were observational in design. For 31 of 37 PMS, the RER concluded the overall adverse drug reaction (ADR) rate in the PMS was nominally lower than in the phase 3 program. Unlabeled ADRs were reported in 28 of 37 PMS; however, no new safety concerns requiring regulatory action arose from any PMS. The PMDA did not require additional risk minimization measures for any of the 43 drug products studied in any of the 79 PMS assessed. Japan PMS data were consistent with prior global data with no evidence of clinically meaningful differences in safety in Japanese patients. In all cases, the reexamination outcome was category 1 ("usefulness is confirmed"). The reexamination process did not result in regulatory changes for any of the examined drugs. The Japan new-drug application (J-NDA) review and approval process, including implementation of the initial Japan product label, assures acceptable benefit/risk at the time of approval such that mandatory GDUI or SI studies for all products should be reconsidered. In the case of genuine scientific uncertainty to the extent that the benefit/risk of the product is not clear, a PMS is warranted.

Physician Awareness of the Safe Use of Cyproterone Acetate in Europe: A Survey on the Effectiveness of Additional Risk Minimization Measures.

Cyproterone acetate (CPA) is a synthetic progesterone derivative introduced in the 1970s and prescribed as antiandrogenic therapy for inoperable prostate cancer, sexual deviations in men, and signs of androgenization in women. In 2020, the CPA summary of product characteristics (SmPC)was revised to include an updated special warning and precaution about (1) the risk of meningioma with increasing cumulative dose and (2) contraindication in patients with meningioma or history of meningioma. A Direct Healthcare Professional Communication(DHPC) was distributed. The European Medicine Agency's Pharmacovigilance Risk Assessment Committee requested that marketing authorization holders in Europe conduct a survey to assess physicians' knowledge of the updated key safety information. The primary objective of this study was to measure physicians' awareness (i.e., did they receive and review the revised SmPC and DHPC) and level of knowledge and understanding of the key safety information pertaining to the restricted use of CPA monotherapy because of the risk of meningioma. This cross-sectional web-based survey was administered to dermatologists, endocrinologists, gynecologists, urologists, oncologists, psychiatrists, and general practitioners in France, Germany, Poland, Spain, and the Netherlands who had prescribed CPA monotherapy in the previous 12 months to assess awareness of the risk of meningioma associated with CPA monotherapy. Of the 613 physicians who participated, 85% correctly indicated that CPA monotherapy should be prescribed with the lowest effective dose, 75% correctly indicated that the risk of meningioma increases with increasing cumulative CPA monotherapy doses, and 73% correctly indicated that treatment with CPA-containing products must be stopped permanently if a patient is diagnosed with meningioma. Overall, 40% of physicians reported having received the DHPC, and 42% reported having received the revised SmPC. Despite low recall of receipt of the updated SmPC and DHPC, most physicians surveyed are aware of the meningioma risk and actions to mitigate the risk.

A Web-Based Survey of Patients Dispensed Viagra Connect® Behind the Counter in UK: An Evaluation of Effectiveness of Additional Risk Minimization Measures.

A national additional risk minimization measures (aRMMs) program was implemented to train pharmacists for safe supply of non-prescription Viagra Connect® (VC) to erectile dysfunction (ED) patients in United Kingdom (UK). A survey aimed to evaluate the effectiveness of aRMMs. A cross-sectional, web-based survey enrolled ED patients who purchased at least 1 supply of VC in UK, using a structured self-administered questionnaire. Patients were assessed for the suitability of VC and received appropriate advice from pharmacists. Descriptive statistics were used. The final sample had 297 patients, who reported that pharmacists inquired about blood pressure and heart comorbidities (91.9%), relevant illnesses (87.9%), medications (86.5%), ED diagnosis (82.2%), and were advised to consult their doctor regarding ED (51.2%). Furthermore, 85.5% of patients were advised on how to take VC correctly, 82.2% on possible side effects for which they might have to discontinue taking VC and consult their doctor, 80.1% on being informed that ED could be caused by underlying conditions. About 65.0% reported that they had visited (19.2%) or planned to visit (45.8%) their doctor. A majority (68.7%) also indicated that they had received advice on lifestyle modifications to manage their ED-related health risks. This survey provided a reasonable confirmation of the effectiveness of the VC aRMMs program and assurance that ED patients, when requesting and purchasing VC in UK pharmacies, are assessed appropriately for suitability of VC and receive the appropriate advice from pharmacists.

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.

Duration of Effectiveness Evaluation of Additional Risk Minimisation Measures for Centrally Authorised Medicinal Products in the EU Between 2012 and 2021.

In studies evaluating the effectiveness of additional risk minimisation measures (aRMMs), the need for speed must be properly balanced with the quality of the study. We assessed the duration of aRMM effectiveness evaluations, using additional pharmacovigilance activities, for centrally authorised medicinal products in the European Union. We established a cohort of medicinal products with aRMMs at marketing authorisation (MA) that were centrally authorised from July 2012-December 2021 using the European Public Assessment Reports. Evaluation studies were identified from the Risk Management Plans at the time of MA. Subsequently, we retrieved protocols, final study reports, Pharmacovigilance Risk Assessment Committee (PRAC) assessment reports, and PRAC minutes. We calculated the probability of completing an effectiveness evaluation within 60 months after MA using time-to-event analyses. Besides, we compared the planned final report with the actual final report date. We identified 134 medicinal products authorised with aRMMs, of which almost half (n = 63, 47.0%) had an effectiveness evaluation study. The probability of an evaluation for a medicinal product being completed within 60 months after MA was 20.7% (95% CI 6.8-32.6). Regarding study design, the probability of completing a study was higher for cross-sectional studies when compared to cohort studies (p = 0.002). Moreover, 81.0% of studies were delayed when compared to their planned final report date. The probability of completing an aRMM effectiveness evaluation at time for renewal of the MA was only one in five. Furthermore, estimates of the duration of studies around MA are too optimistic, with the majority being delayed.

Practical Considerations for the Implementation and Monitoring of Risk Minimisation Measures for High-Risk Teratogenic Medicines.

There is considerable societal interest in making medicines more affordable. A critical factor often inadequately considered early in the process of adding drugs to a company's product portfolio is that some products may require additional monitoring and complex, demanding and expensive additional risk minimisation measures (aRMMs). These aRMMs may have a sizeable impact on a company's commitment to that medicinal product throughout the product's entire life cycle. The teratogenic phthalimides were selected as an example of medicines that are recently being genericised and require a substantial commitment in terms of additional monitoring and aRMMs, most notably in the form of pregnancy prevention programmes (PPPs) with controlled distribution systems (CDSs). Implementing PPPs with CDSs is complex and demanding and encompasses all routine activities, aRMMs, local/regional Health Authority (HA) requirements, and commercialisation strategies. Considerations have been summarised that can support decision-making during due diligence processes, implementation and monitoring. Proactive, effective pharmacovigilance requires innovative, sustainable and flexible solutions to maintain high standards across the board. In particular, generic marketing authorisation holders operate with limited resources and may benefit appreciably from the following proposed suggestions and solutions such as early planning and preparation, knowledge-sharing, utilisation of new technologies and implementation of measures beyond HA-mandated requirements.

A cross‐sectional survey to evaluate prescribers' knowledge and understanding of safety messages following Dengvaxia® product information update

PurposeWe evaluated the effectiveness of additional risk minimisation measures (aRMMs; i.e., educational materials) distributed to prescribers to ensure that only individuals with evidence of prior dengue infection (PDI, i.e., dengue seropositive) would be vaccinated with the tetravalent dengue vaccine (CYD‐TDV; Dengvaxia®).MethodsA survey was conducted in 2020 among 300 CYD‐TDV prescribers in Brazil and Thailand to ascertain three success criteria: prescribers' awareness of the materials (receiving and reading them); knowledge of the key messages; and whether their self‐reported behaviour regarding practice‐related scenarios was aligned with the updated guidance.ResultsThe aRMMs were not generally effective as <80% of prescribers in both countries met two of the three predefined success criteria. In Brazil, 98.7% were aware of the aRMMs whereas in Thailand this criterion was fulfilled by 74.0%. Almost all prescribers knew that CYD‐TDV was recommended only in individuals with PDI (98.7% and 96.7% in Brazil and Thailand, respectively). In Brazil, where vaccination was restricted to those with a documented history of PDI, 11.3% considered that confirmation should be done through a blood test. More than 75% in both countries considered additional signs of dengue, as early warning signs, and not only those regarded as such by the 2009 WHO guidelines.ConclusionsThese results do not support that the aRMMs were effective as the predefined success criteria were not met. The use of reliable rapid diagnosis tests together with the revised prescribing information and educational materials will facilitate the implementation and compliance with pre‐vaccination screening for CYD‐TDV eligibility.

Chaos to Clarity: Pragmatic Approaches to Overcome Challenges for Successful Implementation of Additional Risk Minimisation Measures in the European Union and the UK by a Marketing Authorisation Holder.

Most national competent authorities issue guidance on the dissemination and implementation of additional risk minimisation measures (aRMMs), like the European Medicines Agency. However, national competent authorities guidance includes additional regulatory requirements, the reasons for which are unclear. The purpose of this study was to identify significant barriers to risk management implementation and methodological challenges encountered by local safety managers in the European Union and the UK owing to differences in country-specific regulations and regional national competent authorities guidance. The European Medicines Agency and national competent authorities guidance for each of the aRMM programme's formative components were compared. A survey was conducted to ascertain the challenges encountered by local safety managers throughout the implementation phases and the responses analysed. Twenty-seven national guidance documents were compared with the European Medicines Agency's guidance, and it was observed that national competent authorities provide additional aRMM dissemination and implementation parameters for the format and layout of aRMM, translation requirements, guidance on aRMM content, submission requirements, monitoring parameters and aRMM update requirements, among others. The survey was completed by 11 out of 21 local safety managers (52.38%). Eight local safety managers rated submission of an implementation plan as the most challenging aspect. Multiple national competent authorities requests, frequent updates, and delayed approval impacted planning and implementation, resulting in modifications and delays. Moreover, the study discovered that managing frequent version updates of digital aRMMs was challenging, and most national competent authorities neglected the post-implementation phase activities. Further, most local safety managers followed both the local and global processes to maintain documentation of aRMM implementation. It was evident that the European Medicines Agency and national competent authorities empower marketing authorisation holders to implement and disseminate aRMM materials tailored to their local healthcare settings. However, this poses a challenge for marketing authorisation holders because of a lack of clarity in guidance in executing an aRMM programme and an added burden of complying with both European Medicines Agency and national competent authority requirements.

A web-based survey of UK pharmacists to assess the effectiveness of Viagra Connect® additional risk minimisation measures

Background To support reclassification in the UK of sildenafil citrate (50 mg) from prescription-only medicine to a pharmacy medicine (P status) under the brand name “Viagra Connect®”, additional risk minimisation measures were implemented that included training materials and an optional checklist to assist community pharmacists in the safe supply of Viagra Connect® to suitable patients. Objective To evaluate the effectiveness of Viagra Connect® additional risk minimisation measures by assessing community pharmacists’ participation in training, their knowledge of key risk messages, and utilisation of the checklist. Setting A post-authorisation safety study implemented as a web-based survey, conducted in a representative population of UK community pharmacists. Method A random sample of community pharmacists who received at least 1 request to supply Viagra Connect® within the past 6 months completed an online questionnaire of 33 closed-ended questions/statements with multiple-choice responses. Data were summarised using descriptive statistics. Main outcome measure Knowledge of key risk messages and dispensing practices communicated in the additional risk minimisation measures. Results The survey was completed by 345 community pharmacists. Respondents displayed a high level of knowledge of key risk messages, with ≥80 % selecting correct answers for 43/51 items. Nearly all respondents (90.1 %) reported that the training materials were useful/very useful, and reported using the checklist at the point of supply (91.9 %). Counselling of patients who requested Viagra Connect® was generally considered a positive exercise. Conclusions The Viagra Connect® additional risk minimisation measures were effective for education of community pharmacists and to ensure safe supply of Viagra Connect® behind-the-counter to patients.

Impact of Changing Regulations and the Dynamic Nature of European Risk Management Plans for Human Medicines on the Lifecycle of Safety Concerns.

IntroductionThe European Risk Management Plan (EU-RMP) is a proactive planning tool for identification, characterisation and management of important risks and missing information throughout the lifecycle of a medicinal product. Over the past 15 years the EU-RMP has been a part of the pharmacovigilance practice in Europe, but there are no published studies assessing impact of the growing experience and evolving regulatory framework on the content and focus of the EU-RMP.ObjectivesThe objectives were to study the real-world impact of evolving pharmacovigilance guidelines on the proactive lifecycle management of important risks and missing information through EU-RMPs, and to further explore the impact of different resources on the management of the benefit-risk profile.MethodsA retrospective study based on the review of 64 EU-RMPs dated between 01 January 2006 and 01 October 2020 for seven human medicinal products for which Boehringer Ingelheim holds the Marketing Authorisation in the European Union. Data on the timing and rational behind changes (i.e., inclusion, reclassification, removal) to the safety concerns (Important Identified Risks, Important Potential Risks, Missing Information) and associated additional Pharmacovigilance activities and/or Risk Minimisation measures were collected and assessed.ResultsThe analysed EU-RMPs included a total of 197 safety concerns, 129 of which were removed and 19 were reclassified during the observation period. The implementation of the Guidelines on Good Pharmacovigilance Practices Module V in 2012 and Revision 2 in 2017 resulted in a noticeable decrease in the number of safety concerns. Clinical trial, non-clinical and routine post-marketing data were common sources that influenced the safety concern dynamics, and results from dedicated post-authorisation studies lead to the removal of 21 important risks and missing information. Many safety concerns were related to pharmacological class effect (n = 55) and target population characteristics (n = 37).ConclusionsThis study demonstrated that the growing knowledge regarding benefit-risk of approved products and the introduction of new or revised regulatory guidelines influenced the EU-RMP lifecycle of safety concerns, and moreover, the results emphasise that exchange of knowledge about the pharmacological class and target population between stakeholders are important for keeping an up-to-date understanding of a medicinal product’s safety profile. The aim of improving the efficiency of risk management has leveraged the accumulation of knowledge leading to revision of regulatory guidelines and increasingly, proactive Risk Management Plans focused on safety concerns that are important for patients and public health.

Digital Additional Risk Minimization Measures: An Exploratory Study Using Qualitative Feedback from Healthcare Professionals and Patients Across Six Countries.

BackgroundAdditional risk minimization measures (aRMMs) are required for some pharmaceutical products when routine risk minimization measures (i.e., product labeling) are deemed insufficient. Measures often include educational materials, such as paper brochures, leaflets, and/or alert cards that provide information to healthcare professionals and patients on the key risks associated with a product and risk minimization actions to take should particular signs or symptoms arise. Paper-based educational aRMMs have several limitations. They do not present information in an interactive manner, and their update and distribution can be costly and often complex. Measuring how effective they are in achieving their aims can also be difficult. Digital methods offer design and delivery flexibility, easier updating processes, opportunities to increase engagement with important information, as well possibilities for tracking distribution, receipt, and potentially understanding of the materials. Pharmaceutical companies have started to look to digital methods as an option for educational aRMMs, alongside paper materials.ObjectivesResearch into healthcare professionals and patient needs and preferences, as well as the general acceptability of digital educational options is needed to establish a baseline. This was an exploratory study intended to provide initial insights on the acceptability of digital aRMMs and to inform future research directions.MethodsDigital concepts for educational aRMMs, one for healthcare professionals and one for patients, were evaluated with 30 healthcare professionals and 20 patients in six countries through 1:1 Zoom calls, with responses recorded in a structured Qualtrics-based survey. Criteria for selecting the six countries included local familiarity with aRMMs as well as interest in and capability to deliver a potential digital aRMM program by the sponsoring company’s affiliate teams. Of the healthcare professionals, 19 were rheumatologists and 11 were dermatologists. 16 patients had rheumatologic (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis) conditions and four had atopic dermatitis. These conditions were chosen as they aligned to potential therapeutic areas where the sponsoring company may have the opportunity to use a digital aRMM. Participants were given an overview of the concept as well as the opportunity to interact with it directly via the “control screen” function in Zoom before questions were posed.ResultsThe results demonstrated that the majority of healthcare professionals (87%) and all patients interviewed would prefer website-based or app-based delivery, respectively, of aRMM information instead of, or alongside traditional paper-based approaches, with only 13% of healthcare professionals and no patients expressing a preference for paper-only communication.ConclusionsGiven new options offered by digital technology, its widespread use in many fields, and the importance of patient safety as a topic, there is an imperative for pharmaceutical companies and regulators to work together to establish a way forward for the use of digital options for aRMMs. This study is limited in its generalizability but offers some ideas for future research directions.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40290-021-00415-7.

Effectiveness of risk minimization measures for valproate: a drug utilization study based on implementation of a risk minimization programme in Europe, analysis of data from the UK

Objective Since 2014, valproate has not been recommended for use in girls and women of childbearing potential unless other treatments are ineffective or not tolerated. Risk minimization measures (RMMs) of valproate were implemented to reduce the potential risks of developmental disorders among pregnant women. A drug utilization study was carried out to assess the effectiveness of RMMs. Methods This was a multinational, non-interventional cohort study. For the UK, existing data from the Clinical Practice Research Datalink database were used. The primary study endpoint was a change in the proportion of valproate initiations preceded by other medications relevant for valproate indications before and after implementation of RMMs. Results The proportion of valproate initiations preceded by medications related to valproate indications increased after RMM implementation in incident female users in the UK from 66.4% to 72.4%. The proportion of incident prescriptions for epilepsy and bipolar disorder with prior medication related to valproate indications increased, from 36.2% to 44.1% and 72.9% to 77.8%, respectively. The incidence rate of valproate-exposed pregnancies decreased from 16.9 to 10.9 per 1000 person-years in the pre- and post-implementation periods, respectively. Conclusions Results from this study indicated some improvement in physician prescribing and a potential reduction in valproate-exposed pregnancies in the UK. Given only modest improvement has been achieved, additional RMMs were implemented in 2018.

Regulator-Requested Non-Interventional Postauthorization Safety and Effectiveness Studies for Oncology Drugs: A Systematic Review.

There has been a growing number of oncology drug approvals. Non-interventional postauthorization safety/effectives studies (PASSs/PAESs) aim to provide real-world evidence on the safety/effectiveness of oncology drugs postapproval. To understand the current landscape, a comprehensive search as of March 1, 2021, was conducted in major register/databases. We found that requested studies increased from 1 in 2006-2010 to 47 in 2016-2020. Of 78 total studies identified, 50 focused on safety/risk assessment (64.1%), 6 on effectiveness (7.7%), 3 on drug utilization (3.8%), 1 on disease epidemiology (1.3%), and 18 on effectiveness of additional risk minimization measures (23.1%). For safety/risk assessment studies, 58.9% focused on nonspecific end points (e.g., frequency of adverse events). For effectiveness studies, the leading primary outcome was overall survival. Overall, safety/risk assessment studies concerning nonspecific end points for vascular endothelial growth factor (receptor) inhibitors were most requested. Regarding data sources, though a majority (71.8%) used primary data collection, a growing proportion utilized secondary data sources. Among 23 studies with information available on study design, 10 (43.5%) were single-arm cohort studies, 9 (39.1%) were cross-sectional studies, 3 (13.1%) were comparative cohort studies, and 1 (4.3%) was a nested-case-control study. In conclusion, there was an increasing number of oncology-specific non-interventional PASSs/PAESs, with a majority on safety/risk assessment. Although most utilized primary data collection, there was an increasing use of secondary real-world data sources. Few conducted comparative analyses, and most used single-arm designs. Future efforts are needed to assess how findings of these studies would impact regulatory decisions and improve knowledge of toxicity for clinical/translational development.

Effectiveness of Additional Risk Minimization Measures for Atezolizumab in the European Union.

BackgroundA Guide for Healthcare Professionals (HCP Guide) and patient alert card (PAC) for atezolizumab as additional risk minimization measures for physicians were distributed to raise awareness and help in the detection and management of immune-related adverse drug reactions.ObjectivesThe main objective of this study was to assess the receipt, knowledge, and behaviors of physicians regarding the atezolizumab HCP Guide and PAC.MethodsA multi-country, one-wave, observational, cross-sectional, web-based, self-reported physician survey was conducted to assess the level of knowledge of key messages related to immune-related adverse drug reactions summarized in the atezolizumab HCP Guide and PAC among physicians (oncologists, pulmonologists, and urologists) prescribing atezolizumab in six European countries (Denmark, Germany, Italy, Spain, Sweden, and the UK). Responses regarding the receipt, understanding and use of the materials, and knowledge and behavior related to the HCP Guide and PAC are presented as percentages and continuous scores scaled out of 100 points, with corresponding 95% confidence intervals (CIs).ResultsAmong 313 physicians (255 oncologists, 30 pulmonologists, and 28 urologists), 77.4% received the HCP Guide and 74.2% the PAC. The HCP Guide was read by 71.3% of the 267 physicians who received the materials, and the mean usage score was 69.5 (95% CI 66.0–72.9), and 57.1% of physicians had scores ≥ 70. The HCP Guide was completely understood by 85.4% of physicians who had read it. Mean knowledge scores were 63.9 (95% CI 62.1–65.7) and 39.4% of physicians had correct knowledge scores ≥ 70. Mean knowledge scores were 66.8 (95% CI 64.9–68.7) for receipt of both the HCP Guide and PAC, 59.4 (95% CI 55.5–63.4) for one of the materials, and 60.8 (95% CI 55.4–66.2) for having received none of the materials. Mean behavior scores were 78.9 (95% CI 76.8–81.0), and 74.8% of physicians had behavior scores ≥ 70. The mean behavior score was 79.0 (95% CI 76.5–81.5) for those who received both the HCP Guide and PAC, 76.9 (95% CI 72.2–81.5) for receipt of one of the materials, and 81.5 (95% CI 75.0–88.0) for those who received none of the materials.ConclusionsThe study assessed the effectiveness of the atezolizumab additional risk minimization educational materials among physicians in six European countries, using process indicators. The educational materials reached over 70% of target physicians, 57.1% of whom reported using them. Knowledge and behavior related to immune-related adverse drug reactions for atezolizumab were no better in those who received the additional risk minimization educational materials. The results support the safe use of atezolizumab by these physician groups and contributed to the European Medicines Agency permitting removal of the HCP Guide.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40290-021-00407-7.

Patient Preferences for Rituximab Additional Risk Minimization Measures: Results From an International Online Survey.

ObjectivePatients’ opinions are essential in optimizing risk minimization measures (RMMs) because they bring their real-life experience of disease management and medicines’ use into the regulatory assessments. The aim of the survey launched in 2018 by the European Medicines Agency, in collaboration with the Pharmacovigilance Risk Assessment Committee, was to consult targeted patient groups treated with rituximab for nononcology indications to evaluate their preferences on how to receive information on progressive multifocal leukoencephalopathy and (serious) infections. Additional RMMs such as educational materials for physicians and patients including a patient alert card (PAC) and a patient brochure (PB) are in place to minimize these risks.MethodsA question-based online survey in English created on the EU-Survey platform and disseminated primarily via relevant European patient organizations.ResultsMost patients (47 of 61) had knowledge of these potential adverse effects. Mostly, they were informed by a healthcare professional. Both a PAC and a PB were supported as useful tools to raise awareness of these adverse effects and thus minimize the potential risks among patients. Where the participants had to choose only 1 of these educational materials, 43 of them preferred a PAC, a shorted description that is always held by the patient and reaches the relevant healthcare professional when needed.ConclusionsCollecting patients’ preferences supports periodic assessment of additional RMMs and increase transparency of regulatory processes. Considering the limitations of this initial survey, further investigation is needed to generalize the results into patients’ safety outcomes.

Evaluating the Effectiveness of Apixaban Additional Risk Minimisation Measures Using Surveys in Europe.

BackgroundApixaban (ELIQUIS®) is a direct oral anticoagulant authorised for multiple indications in the European Economic Area (EEA). Additional risk minimisation measures (aRMMs) to address the risk of bleeding include educational materials comprising a Prescriber Guide and Patient Alert Card.ObjectivesThis study evaluated effectiveness of the apixaban Prescriber Guide and Patient Alert Card in terms of healthcare professional (HCP) and patient knowledge of associated bleeding risk, as well as material distribution, utilisation and behaviour.MethodsThis non-interventional, cross-sectional study included online surveys in ten countries that represented a high proportion of apixaban usage in the EEA. The HCP source population was based on HCP lists used for communications about and distribution of the risk minimisation materials. Patient recruitment took place via HCPs. Study participants included HCPs involved in apixaban treatment and patients treated with apixaban (or their caregivers) for multiple indications. Data collection took place over an 18-month period between August 2015 and February 2017.ResultsSurvey responses from 385 HCPs and 125 patients/caregivers were analysed. HCP knowledge of bleeding risk included early recognition of symptoms requiring immediate contact with an HCP (96.1%), appropriate dosing (83.6%), contraindications (76.1%) and subpopulations at increased risk of bleeding complications (ranging from 63.5 to 85.9%). Patient knowledge included abnormal bleeding as an important side effect (71.2%), communicating risk factors to HCPs (76.8%) and recognition of potential bleeding symptoms (‘high’ knowledge levels 22.4%, ‘moderate’ knowledge levels 49.6%). Of 226 (58.7%) HCPs who recalled receiving/obtaining the Prescriber Guide, 97.8% read at least part of it and 74.8% had used it to assist patient discussions. Of 74 (59.2%) patients who were aware of the Patient Alert Card, 89.2% recalled receiving/obtaining a copy. When received, 90.9% of patients read the card at least once and 93.9% kept it with them at least some of the time.ConclusionsHCP and patient respondent knowledge of bleeding risk was satisfactory. Although not optimal, reach of the aRMMs was consistent with other studies. No modifications to aRMM content were required. To increase reach, the Prescriber Guide has been provided in an additional format as a web-based platform whilst the Patient Alert Card was included within product packaging.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40290-021-00380-1.

Effectiveness of risk minimisation measures for valproate: A drug utilisation study in Europe.

PurposeThe purpose of this study was to evaluate the effectiveness of the risk minimisation measures (RMMs) implemented in Europe in 2014 for valproate‐containing products to mitigate their risk during pregnancy and to characterise valproate prescribing patterns in women of childbearing potential (WCBP) before and after implementation of RMMs.MethodsA multinational cohort study based on existing data sources using a pre‐/post‐ design was performed in five European countries (France, Germany, Spain, Sweden, UK) in an outpatient setting. Effectiveness of RMMs was assessed by comparing the proportion of valproate initiations as second (or subsequent) line therapy before and after implementation of RMMs (primary outcome) with an increase in this proportion indicating success of RMMs. Overall use of valproate and incidence of pregnancies in WCBP were also examined.ResultsThe proportion of valproate initiations as second line therapy increased after implementation of RMMs in incident female users in Sweden (from 81.1%, 95% CI 79.9%‐82.3% to 84.5%, 95% CI 83.5%‐85.5%) and the UK (from 66.4%, 95% CI 64.5%‐68.3% to 72.4%, 95% CI 70.0%‐74.9%), it remained the same in Germany and Spain and decreased in France from 48.7% (95% CI 45.6%‐51.9%) to 40.6% (95% CI 37.6%‐43.7%). In Sweden and the UK, the incidence of pregnancies exposed to valproate decreased in the post‐implementation period: 8.0 vs 9.5 and 10.9 vs 16.9 per 1000 person‐years, respectively.ConclusionThe results on primary outcome of this study suggest limited effectiveness of the RMMs. Additional RMMs were implemented in 2018.

Additional risk minimisation measures for medicines approved in the EU

Additional risk minimisation measures for medicines approved in the EU