Effectiveness Of Risk Minimization Measures Research Articles

Comparing regulatory guidance on risk minimization/mitigation and the Reporting recommendation Intended for pharmaceutical Risk Minimization Evaluation Studies checklist.

The latest country-specific regulatory guidance for assessing effectiveness of risk minimization measures (RMM) strategies was identified across five continents-Africa (Egypt, South Africa), Asia (Australia, China, Japan, South Korea, Singapore), Europe (EU-27, United Kingdom), North America (Unites States, Canada) and South America (Brazil)-and compared to the Reporting recommendation Intended for pharmaceutical Risk Minimization Evaluation Studies (RIMES) checklist, developed to assess the quality of effectiveness evaluations and endorsed by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). RIMES checklist items address study hypothesis, participants, measures, statistical analysis and results. European Medical Agency (EMA) and Food and Drug Administration (FDA) guidance only partially aligned with RIMES, primarily for measures and results. In the absence of country-specific guidance, most countries recommended following EMA or FDA guidelines; Japan and South Africa mentioned the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH E2E) guideline; Brazil and China had no guidance/recommendations. Worldwide, there was a lack of RMM-specific guidance and, when guidance existed, they were not harmonized, and alignment with the RIMES checklist was limited.

Limitations Reported in Evaluating Effectiveness of Risk Minimization Measures in the EU during 2018-2021: A Qualitative Analysis of Industry-Sponsored Post-Authorization Safety Studies.

Marketing-authorization holders evaluate the effectiveness of risk minimization measures (RMM) for medicines through the conduct of post-authorization safety studies (PASS). Earlier studies show that concluding on RMM effectiveness is challenging. The aim of this study was to describe reported limitations associated with RMM effectiveness assessments of industry-sponsored PASS that did not render a conclusion. We conducted a thematic analysis of study limitations extracted from assessment reports and study reports finalized by the Pharmacovigilance Risk Assessment Committee between 2018 and 2021. In 39 (61.0%) of the PASS a conclusion on RMM effectiveness was drawn, where 25 (39.0%) PASS was inconclusive. Most PASS had a cross-sectional design with surveys as primary data sources (73.4% and 65.6% respectively). Four main themes emerged: (i) survey-specific limitations, (ii) limitations specifically related to secondary use of data, (iii) general limitations related to study design, and (iv) limitations not related to study design. In general, frequently reported limitations were survey-related, such as selection bias or information bias. Interestingly, well-known study limitations related to secondary use of data such as missing or misclassification of data were more often presented in inconclusive compared with conclusive PASS. Given that about 40% of PASS did not allow a conclusion on RMM effectiveness, our results suggest prioritization for strategies to mitigate limitations related to the secondary use of data at the protocol stage, for example, through feasibility assessments. Although many databases may have incomplete registration of some variables, feasibility testing prior to conducting a PASS could contribute to meeting study objectives and concluding on RMM effectiveness.

Review of Studies Evaluating Effectiveness of Risk Minimization Measures Assessed by the European Medicines Agency Between 2016 and 2021.

The European Medicines Agency (EMA) supervises medicines' safe and effective use throughout the product's life cycle by, for example, monitoring the implementation of risk minimization measures (RMMs). Limited information is available on factors associated with effectiveness of RMMs. This study reviews post-authorization safety studies (PASS) evaluating the effectiveness of RMMs assessed by the Pharmacovigilance Risk Assessment Committee (PRAC) between 2016 and 2021. PASS assessment reports finalized by PRAC between January 1, 2016, and December 31, 2021, were compiled from non-public EMA databases and PASS characteristics were extracted. Of the 93 PASS included, 62.4% aimed to measure healthcare professionals' awareness, knowledge, and behavior regarding RMMs. There were 67.7% of the 93 PASS that used primary data, 24.7% used secondary data sources, and 7.5% used both. A cross-sectional study design was most frequently applied (77.4%), followed by a cohort study design (29.0%). Nearly 40% of the included PASS did not render a conclusion on RMM effectiveness. Of the 60% that did render a conclusion, 82.1% were deemed effective. Only minor differences in characteristics were found when stratified by outcome (i.e., effective RMM, ineffective RMM, and no conclusion on RMM effectiveness). To conclude, 4 out of 10 PASS assessing impact of RMMs did not render a conclusion on RMM effectiveness. No clear differences in PASS characteristics were found in relation to their outcomes, indicating that additional research is needed to understand better the underlying reasons for PASS being inconclusive.

Impact of European Union label changes to avoid inadvertent use of medicinal products containing methotrexate for once-weekly administration: A survey amongst prescribers, pharmacists and patients on awareness, knowledge, and behaviour.

To determine the effectiveness of risk minimisation measures (RMM) to avoid inadvertent daily instead of weekly methotrexate (MTX) use, introduced by the European Medicines Agency (EMA) from 2019 onwards. Using a cross-sectional online survey in France, Greece, Germany, Poland, and Sweden in 2022, we assessed awareness, knowledge, and self-declared behaviour for respondents who prescribed, dispensed, or used once-weekly MTX in the last 3 months. Respondents' answers were considered as 'successful' with regards to RMM effectiveness (vs. unsuccessful) if they provided correct ('desirable') responses to 100% of questions regarding awareness and self-declared behaviour and correct responses to ≥80% of questions about knowledge. Per target population, an outcome was considered successful if achieved by ≥80% of respondents. Effectiveness of RMM was defined by ≥80% being successful on all outcomes. One-hundred-fifty-one prescribers, 150 pharmacists, and 150 patients completed the survey. Success rates were 56% (95% CI 48.0%-64.3%) for awareness, 42% (95% CI 34.4%-50.7%) for knowledge, and 31% (95% CI 23.8%-39.2%) for self-declared behaviour among prescribers, 18% (95% CI 12.8%-25.8%) for awareness, 7% (95% CI 3.7%-12.7%) for knowledge, and 50% (95% CI 41.7%-58.3%) for self-declared behaviour among pharmacists, and 29% (95% CI 21.6%-36.6%) for awareness, and 3% (95% CI 1.1%-7.6%) for knowledge among patients. Overall success was not attained by any target population. RMM were evaluated as not effective across outcomes of awareness, knowledge, and self-declared behaviour in prescribers, pharmacists, and patients. Findings suggested we need continued efforts for RMM across all target populations and across all outcomes.

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.

Cover Image, Volume 30, Issue 9

The cover image is based on the Review A review of the sampling methodology used in studies evaluating the effectiveness of risk minimisation measures in Europe by Laurence Sophie Jouaville et al., https://doi.org/10.1002/pds.5301.

A review of the sampling methodology used in studies evaluating the effectiveness of risk minimisation measures in Europe.

PurposeThis review aims to describe the sampling methodology used in studies assessing effectiveness of risk minimisation measures (RMMs) in the European Union.MethodsThe European Union electronic Register of Post‐Authorization Studies (EU PAS Register) was searched to identify studies that assessed the effectiveness of RMMs and recruited a target population of healthcare professionals (HCPs), sites or patients. Studies with both protocol and report were included and data was extracted from these documents to describe study characteristics and variables involved in the sampling methodology.ResultsOut of 1092 studies finalised between June 2017 and May 2019, 17 studies were eligible for review. Thirteen were surveys, three chart reviews and one combined both methodologies. All the 17 studies recruited HCPs/sites and 8 of them also recruited patients. The most common rationale for country sampling was market uptake (10/17), while for HCP/site sampling, it was representativeness of the prescribing practices (14/17). Only a minority of the studies (4/17) provided supporting evidence to inform this theoretical framework. HCP/site sampling frames were mainly network of physicians (5/17) or HCP databases (5/17), with only one study providing a detailed description of the sampling frame. HCPs were selected mainly using probabilistic sampling (10/17) and patients using non‐probabilistic sampling (6/8). Only a few studies compared participating with non‐participating HCPs/sites (5/17) and patients (3/8). Eight studies reported that their results were generalisable.ConclusionsOverall, the study documents provided insufficient details to understand the rationale behind the sampling decisions. More standardisation and guidance in reporting the sampling strategy and operational considerations applicable to these types of studies would support transparency and facilitate the evaluation of representativeness of the study results.

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.

Effectiveness of risk minimisation measures for valproate: A cross-sectional survey among physicians in Europe.

PurposeThis study evaluated the effectiveness of risk minimisation measures (RMMs) implemented following the 2014 referral for valproate in Europe.MethodsCross‐sectional survey was conducted over 2‐month period in 2016 among physicians who prescribed valproate in France, Germany, the United Kingdom, Spain and Sweden. The web‐based questionnaire included five endpoints to evaluate physicians' knowledge on (a) prescribing valproate only for epilepsy and bipolar disorder in women if other treatments were ineffective or not tolerated; (b) ensuring supervision by experienced physicians while treating these conditions; (c) considering alternative treatments for women planning pregnancy, regular review of treatment needs and re‐assessing the benefit–risk balance in women and girls reaching puberty; (d) informing patients about the risks of taking valproate during pregnancy and (e) advising women on effective contraception during their treatment.ResultsAmong 1153 physicians, 95.5% responded prescribing valproate for epilepsy and bipolar disorder in women only if other treatments are ineffective/not tolerated; 66.5% supervised while treatment; 76.6% considered alternative treatments for women planning pregnancy; 92.1% informed patients about the risks of taking valproate during pregnancy and 94.4% advised patients on the use of effective contraception during its treatment. Overall, 25.8% physicians recalled receiving both educational material (EM) and Dear Healthcare Professional Communication (DHPC). All endpoint rates were higher for physicians who acknowledged receipt of both DHPC and EM compared to physicians who did not receive them.ConclusionsAlthough results varied across geography and physician speciality, majority of physicians had good knowledge about the indication and safety aspects of prescribing and using valproate.

Effectiveness of Risk Minimization Measures for Fentanyl Buccal Tablet (FENTORA) in Canada: A Mixed-Methods Evaluation Using Surveys, Medical Chart Records and Web Surveillance.

Fentanyl buccal tablet (FBT), a potent opioid, was approved in Canada in 2013 for breakthrough pain in opioid-tolerant adult cancer patients. Additional risk minimization measures (aRMMs), consisting of communications to patients and healthcare providers (HCPs), were implemented from November 2014 through September 2015. The aim of this study was to assess the effectiveness of FBT aRMMs as measured by prescriber knowledge, understanding, and behavior regarding key safety concerns (off-label use, use in non-opioid-tolerant patients, misuse/abuse/diversion, and drug-drug interaction) and to evaluate illicit FBT use. The study included three components: (1) a knowledge and understanding (KAU) survey of FBT prescribers conducted in two waves: November 2016-February 2017 and April-September 2018; (2) a retrospective prescription study of medical records of patients treated with FBT by a subgroup of prescribers from the KAU survey; and (3) Web surveillance of illicit FBT use in Canada using the search term FENTORA (May 2014-September 2018). The aRMMs were considered effective if the lower bound of the 95% confidence interval indicated that at least 65% of respondents met or partly met the knowledge objective for each key safety concern. KAU survey: Of 46 eligible HCPs, 97.8% met or partly met the knowledge objective on use in breakthrough pain cancer patients, 97.8% on use in opioid-tolerant patients, 89.1% on dose and titration, 100% on abuse/addiction, and 58.7% on drug-drug interaction. Retrospective prescription study: Of 22 FBT-treated patients identified from 14 HCPs, 45.5% had cancer, 50.0% recorded a breakthrough pain indication, and 36.4% reported opioid tolerance; however, only 13.6% of patients were prescribed FBT according to the approved indication. Web surveillance: Of 932 FBT posts in Canada, only 40 (4.3%) mentioned illicit use. The aRMMs as measured by the prescriber KAU were effective for most key safety messages; however, not all key messages of the aRMMs were stringently followed in routine practice.

Use of real-world evidence in postmarketing medicines regulation in the European Union: a systematic assessment of European Medicines Agency referrals 2013–2017

ObjectivesTo assess the use, and evaluate the usefulness, of non-interventional studies and routinely collected healthcare data in postmarketing assessments conducted by the European Medicines Agency (EMA).DesignWe reviewed and systematically assessed...

Effectiveness of Risk Minimization Measures to Prevent Pregnancy Exposure to Mycophenolate-Containing Medicines in Europe.

In 2015, the European Medicines Agency (EMA) requested additional Risk Minimization Measures (RMM), consisting of a Direct Healthcare Professional Communication (DHPC), a Guide for Healthcare Professionals (HCPs), and a Guide for Patients, to prevent pregnancy exposure to mycophenolate-containing medicines. This study assessed the effectiveness of the additional RMM for any mycophenolate-containing medicine among prescribers of these products in Europe. A cross-sectional survey was conducted among prescribers of mycophenolate-containing medicines in five European countries via the administration of 19 questions checking knowledge levels for the key messages included in the additional RMM. Of 79,783 invitations sent to potential prescribers of mycophenolate-containing medicines, 295 HCPs accessed the survey, giving an overall response rate of 0.4% (range 0.1-8.6%). A total of 231 prescribers were included in the primary analysis. Knowledge levels for 15 questions was fair (50 to < 70%) to high (≥ 70%), and for 4 questions was poor (< 50%). Highest knowledge (≥ 75%) was for knowing that mycophenolate is contraindicated in women of childbearing potential not using highly effective contraception (80.3%) and that mycophenolate should not be routinely prescribed during pregnancy (77.5%). Lowest knowledge (≤ 30%) was for knowing that no specific mechanism of teratogenicity and mutagenicity has been identified for mycophenolate (23.4%). Less than half of HCPs reported receipt of the DHPC (42.5%) or were aware of the Guide for HCPs (32.1%) and Guide for Patients (29.7%). The most frequently reported primary source from which HCPs learned about these risks was the Summary of Product Characteristics (SmPC; 33.8%), while only 9.9% indicated the Guide for HCPs. Prescribers who participated in this survey appear to be reasonably well informed about the key messages of the RMM put in place in Europe for mycophenolate-containing medicines. The relatively high knowledge levels, in spite of the low proportion of HCPs reporting receipt of the additional RMM, suggest that the SmPC may be sufficiently informing prescribers about the pregnancy risks of mycophenolate-containing medicines and actions recommended to minimize pregnancy risk. Nevertheless, Roche in consultation with EMA will continue to distribute all additional RMM.

2324-PUB: Assessment of the Effectiveness of Risk Minimization Measures for Concentrated Insulin Lispro 200 Units/ml: A Multinational Study

This study evaluated the impact of additional risk minimization measures on healthcare professional (HCP) and patient understanding and behavior regarding the risk of hypoglycemia and/or hyperglycemia due to medication errors associated with administration of insulin lispro 200 units/ml (U-200) in U.S. and EU. The additional risk minimization measures for U-200 included a direct HCP letter, and a patient communication. Web and telephone cross-sectional surveys were administered to HCPs involved in the treatment and management of patients with diabetes who are aware of U-200, and adult patients with diabetes who have been prescribed U-200 in France, Germany, Sweden, and U.S. A total of 424 HCPs (278 in U.S., 146 in EU) and 307 patients (300 in U.S., 7 in EU) completed the surveys. Among HCPs, 46% (U.S.=56%, 95% CI=50%-62%; EU=27%, 95% CI=20%-35%) were aware U-200 is not approved for transfer to different insulin delivery device; however, HCPs knowledge of appropriate U-200 prescribing was high: 95% indicating correct strength on prescription (U.S.=98%, 95% CI=95%-99%; EU=91%, 95% CI=85%-95%); and 73% answered that dose conversion is not necessary when changing patients between insulin lispro strengths (U.S.=80%, 95% CI=75%-84%; EU=60%, 95% CI=51%-68%). The vast majority of patients in U.S. (97%, 95% CI=94%-99%) were aware that U-200 should only be injected using the prefilled pen in which it is supplied. In U.S., 78% (95% CI=73%-83%) of patients and 92% (95% CI=88%-95%) of HCPs indicated it is always necessary to carry a backup pen. In conclusion, this study showed in general that the additional risk minimization measures effectively communicated the key safety messages to the majority of HCPs. Patient recruitment in EU was challenging due to the stringent data protection regulations which makes the collection of meaningful pharmacovigilance-related data for patients in EU very difficult. Disclosure A.K. Ali: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. M. Ewing: Employee; Self; Eli Lilly and Company.

Are risk minimization measures for approved drugs in Europe effective? A systematic review

ABSTRACTObjectives: The effectiveness of risk minimization measures (RMMs) requires evaluation. This study aims to evaluate the results of cross-sectional surveys assessing the effectiveness of RMMs in Europe (EU RM Surveys) and review the regulatory consequences.Methods: The authors searched for study reports and manuscripts of completed EU RM surveys in the EU PAS Register, MEDLINE, and Google between 01/2011 and 01/2018. Regulatory responses were extracted from Assessment Reports. Random effects models to combine proportions were used.Results: Twenty-four EU RM surveys were identified. Twenty-three studies targeted health-care professionals (HCPs). The pre-specified sample size was reached in 52% of studies. HCP participation was 5% defined as completers/invited and 89% for completers/eligible. Receipt of materials was recalled by 60% of HCPs and 77% of items scored knowledge >60%. Eight studies targeted patients/caregivers. The pre-specified sample size was reached in only two. Participation was 93%, defined as completers/eligible. Materials were received by 50–80% of patients and read by over 90%. Patients only scored knowledge >60% in 38% of items. Further action was requested by regulators in 59% of studies.Conclusion: Surveys are necessary to evaluate many RMMs. Challenges remain in the design, conduct, and reporting of these studies which may benefit from the use of standard definitions and further guidance on reporting.EU PAS Register: http://www.encepp.eu/encepp/viewResource.htm?id=23435

A drug utilization study to evaluate effectiveness of risk minimization measures for trimetazidine in France, Hungary, Romania and Spain.

The approved indication for trimetazidine (TMZ) was restricted to "add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies" in 2012 by the Committee for Medicinal Products for Human Use (CHMP). TMZ was no longer indicated for ophthalmology and otolaryngology (ENT) indications. This drug utilization study analysed actual utilization of TMZ before and after the restriction on its indications to evaluate the effectiveness of risk minimization measures (RMM). This was a multi-national, cross-sectional, non-interventional drug utilization study using European databases: IMS Prescribing Insights (PI) for France and Spain, National Diagnostic Index (NDI) for Romania and National Prescription Audit (NPA) for Hungary. TMZ prescriptions issued by Ear-Nose-Throat (ENT) specialists, ophthalmologists, cardiologists and General Physicians (GPs)/others were analysed during the 24-month period before (reference period) and after RMM implementation (assessment period). During the assessment period, most of the TMZ prescriptions for ENT and ophthalmology indications (un-authorized indications) were made by GPs/others followed by ENT specialists, ophthalmologists and cardiologists in most of the countries. The proportion of TMZ prescriptions for ENT or ophthalmological indications after the restrictions on indication was reduced in Hungary (by 0.4%) and Spain (by 11.8%), remained the same in Romania and increased in France (by 3.7%). This study showed that a significant proportion of TMZ prescriptions was off-label for ENT or ophthalmological indications following the RMM implementation. More effective RMM strategies are required to reduce off-label prescriptions of TMZ.

Study design, process and outcome indicators of post‐authorization studies aimed at evaluating the effectiveness of risk minimization measures in the EU PAS Register

Risk minimization measures (RMMs) represent an essential tool for preventing the occurrence of safety-related outcomes. The evaluation of RMMs effectiveness is essential to prove their success and ensure protection of public health. The aim of this qualitative review was to assess the design, process and outcome indicators used for attesting successful implementation of RMMs. We searched the EU Post-Authorization Studies Register up to 30 June 2018 for studies having the scope defined as 'effectiveness evaluation'. Study titles and objectives were screened to select the ones evaluating the effectiveness of RMMs. We described and assessed the extent to which these studies aligned with Good Pharmacovigilance Practices guidelines recommendations. Out of 360 registered studies, we identified 35 studies on evaluation of RMMs effectiveness, 29 being eligible for review. Twenty-six studies evaluated additional RMMs, employed in case routine interventions are considered insufficient. All studies assessed process indicators, five also assessing outcome indicators, thus using a dual-evidence approach as recommended by the guidelines. However, none of the latter used a pre-post design, comparing the frequency of the adverse outcome before and after the implementation of RMMs. Behaviour and knowledge were the most often assessed process indicators. Outcome indicators included occurrence of adverse reactions, pregnancy, off-label use and medication errors. Only four studies had an established threshold, all for process indicators. Stricter adherence to existing recommendations would allow for a more robust design for reaching established endpoints for RMM effectiveness evaluation. It would also infer harmonization, facilitate review and further more detailed guidance on conducting these studies.

Evaluation of the effectiveness of risk minimization measures for trimetazidine: A cross sectional joint PASS survey among physicians in selected European countries.

In 2012, the Committee for Medicinal Products for Human Use (CHMP) restricted prescription of trimetazidine (TMZ) to "add-on therapy for patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line therapies." TMZ was no longer indicated for ophthalmology and otolaryngology. Risk minimization measure (RMM) was communicated to physicians. The survey presented here evaluated effectiveness of the RMM and assessed physicians knowledge and compliance with RMM. It also analyzed actual prescribing pattern of TMZ. A cross sectional, web-based survey was developed and conducted among prescribing physicians of TMZ across 12 European countries. Physicians' samples were weighted to account for the actual proportion of specialties within and across countries. Using weighted samples, data from 1123 physicians and 8332 prescriptions were analyzed. Most (74.0%) of the physicians assumed stable angina pectoris to be an indication for TMZ. Three quarter of (75.7%) of these physicians were aware of the approved indication. Vertigo (62.1%), tinnitus (42.5%), declined visual acuity, and visual field disturbances (45.1%) were also presumed to be approved indications for TMZ, and physicians actually prescribed for these indications. Only 29.8% of the physicians remembered receiving RMM communications regarding TMZ. Most (90.5%) of the physicians expressed their interest to know and comply with the safety communications. Of all prescriptions, 33.9% were issued for add-on therapy for patients with stable angina pectoris. RMM for TMZ prescription have been moderately effective. Improvement in physician's compliance with safety information of TMZ is necessary for patient's safety.

A review of studies evaluating the effectiveness of risk minimisation measures in Europe using the European Union electronic Register of Post-Authorization Studies.

PurposeAn important element of risk management is the planning and implementation of risk minimisation measures (RMMs) and the evaluation of their effectiveness by process or outcome indicators. The aim of this review is to summarize the characteristics of risk minimisation (RM) effectiveness studies in Europe and provide an overview of RMMs and their effectiveness.MethodsThis was a qualitative review of RM effectiveness studies in the European Union electronic Register of Post‐Authorization Studies (EU PAS Register); data extracted included study design, population, sample size, data sources, drug information, RMMs, study period, indicators, and their reported effectiveness.ResultsOf the 872 records in the EU PAS Register, 19 studies evaluating the effectiveness of RMMs were included. Eleven were cross‐sectional surveys and 8 used secondary data sources. Eighty‐nine percent (17/19) evaluated additional RMMs (used when routine RMMs are considered insufficient), and 36% (7/19) evaluated changes in routine RMMs (applicable to all medicinal products). A total of 42 effectiveness indicators were identified: 18 process and 24 outcomes. Half of the indicators (21/42) were successful; 2% (1/42) indicators were partially successful; 17% (7/42) indicators were inconclusive. Effectiveness of the remaining 31% (13/42) indicators could not be determined owing to limited information. The United Kingdom was the most frequent country for the conduct of RM effectiveness studies.ConclusionsMost of the included studies evaluated additional RMMs. Half of the effectiveness indicators (process and/or outcome) were reported as successful. This review provides evidence to support the development of future guidance on the effectiveness of RM in Europe.

Study Design and Evaluation of Risk Minimization Measures: A Review of Studies Submitted to the European Medicines Agency for Cardiovascular, Endocrinology, and Metabolic Drugs.

IntroductionStudies measuring the effectiveness of risk minimization measures (RMMs) submitted by pharmaceutical companies to the European Medicines Agency are part of the post-authorization regulatory requirements and represent an important source of data covering a range of medicinal products and safety-related issues. Their objectives, design, and the associated regulatory outcomes were reviewed, and conclusions were drawn that may support future progress in risk minimization evaluation.MethodsInformation was obtained from risk management plans, study protocols, clinical study reports, and assessment reports of 157 medicinal products authorized for cardiovascular, endocrinology, and metabolic indications. We selected observational studies measuring, as outcomes of interest, the relationship between the RMMs in place and (1) implementation measures, such as clinical knowledge or physicians` compliance to recommendations contained in the RMMs; and (2) occurrence or reduced severity of the adverse drug reactions for which the RMMs were required.ResultsOf 59 eligible studies (24 completed, 35 ongoing), 44 assessed implementation measures, whereas only 15 assessed safety outcomes (1 study as a single endpoint and 14 studies with other endpoints). Fifty-one studies used non-experimental designs and 25 studies employed electronic healthcare databases for analysis. Of the 24 completed studies, 17 were considered satisfactory and supported immediate regulatory decision making, 6 were considered inconclusive and required new evaluations, and 1 was terminated early because new safety restrictions were required, thereby necessitating a new evaluation. Compliance with agreed deadlines was considered acceptable in 21 of 24 completed studies; the average time for a submission was 37 months (standard deviation ± 17), with differences observed by type of data source employed.ConclusionsThree important gaps in the evaluation plans of RMMs were identified: lack of early feedback on implementation, limited evaluation of safety outcomes, and inability to provide information on the effectiveness from an integrated measurement of different elements of a set of risk minimization tools. More robust evidence is needed to advance regulatory science and support more rapid adjustment of risk minimization strategies as needed.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-017-0604-4) contains supplementary material, which is available to authorized users.

An Evaluation of the Effectiveness of Risk Minimization Measures for Tigecycline in the European Union

Risk minimization measures (RMM) were implemented from February 2011 in the European Union to address risks of superinfection, off-label use and lack of efficacy associated with tigecycline. The objective of this study was to evaluate RMM effectiveness by describing prescription patterns among adults and children treated with any dose of tigecycline for any indication pre- and post-RMM implementation; incidence proportions of superinfection and lack of efficacy among adults treated with approved doses of tigecycline for complicated intra-abdominal infection and complicated skin and soft tissue infection were also evaluated. This was an observational, retrospective chart-abstraction study, including charts from 777 patients (399 pre-RMM, 378 post-RMM) at 13 sites across Austria, Germany, Italy, Greece and the United Kingdom (UK). Potential superinfection and lack of efficacy cases among those using tigecycline for on-label indication, age, dose, and duration were adjudicated. The distribution of indications for tigecycline was analyzed overall (i.e. across both study periods) and stratified by study period. Numbers and incidence proportions of superinfection and lack of efficacy cases (potential and adjudicated) were calculated overall and by study period. Off-label use (indication or age) decreased from 54.2% [95% confidence interval (95% CI): 49.0, 59.3%] pre-RMM to 35.7% (95% CI 30.4, 41.2%) post-RMM. Overall, 45.7% (95% CI 41.9, 49.5%) of patients were prescribed tigecycline off-label; the most commonly reported off-label indications were characterized as “other” (25.5%), hospital acquired pneumonia (8.2%), other pneumonia (6.3%), bacteremia (5.2%) and diabetic foot infection (1.5%). Across study periods, incidence proportions of definite or probable superinfection and lack of efficacy in adults treated for approved indications, authorized treatment doses and duration were 4.5% (95% CI 2.1, 8.4%) and 5.5% (95% CI 2.8, 9.7%), respectively. Off-label use of tigecycline decreased following RMM implementation. Overall incidence proportions of definite or probable superinfection and lack of efficacy were low. EU PAS register number: EUPAS3674