Regulatory, health technology assessment and company interactions: the current landscape and future ecosystem for drug development, review and reimbursement.

BACKGROUND: Multi-stakeholder interactions have evolved at product and policy levels. There is a need to assess the current and future landscape of interactions between companies, and regulatory and HTA agencies to address challenges and identify areas for improvement. OBJECTIVES: The aims of this study were to review the current interactions within and across regulatory and HTA agencies, and companies' experiences in engaging in these activities; to assess the added value of interactions as well as limitations; to explore the future ecosystem for stakeholder interactions. METHOD: Three separate questionnaires were developed for companies, regulators and HTA agencies, respectively, to assess their experiences and perceptions. The responses were analyzed using descriptive statistics and discussed at a multi-stakeholder workshop. Key outcomes from the surveys and workshop discussion were reported. RESULTS: All seven regulators and seven HTA agencies in the survey indicated that they had stakeholder interactions. More formal collaboration occurred with regulators compared with HTA agencies. All nine companies have taken early advice but indicated the need for future prioritization. Success indicators can be built at the product and therapy levels, with the added value of faster patient access. Four principles were proposed for the future ecosystem: separate remit and functions between regulators and HTA; align processes; converge evidence requirements where possible; increase transparency. CONCLUSIONS: This research brought together regulators, HTA agencies, companies to examine how they interact with one another. We propose measures of value and make recommendations on future evolution to enable better evidence generation and improve regulatory and HTA decision-making.

Pre-approval and post-approval availability of evidence and clinical benefit of conditionally approved cancer drugs in Europe: A comparison with standard approved cancer drugs.

AIMS: Cancer drugs are increasingly approved through expedited regulatory pathways including the European conditional marketing authorization (CMA). Whether, when taking CMA post-approval confirmatory trials into account, the level of evidence and clinical benefit between CMA and standard approved (SMA) drugs differs remains unknown. METHODS: We identified all CMA cancer indications converted to SMA in 2006-2020 and compared these to similar SMA indications with regard to pivotal trial and CMA post-approval confirmatory trial design, outcomes and demonstrated clinical benefit (per the European Society for Medical Oncology Magnitude of Clinical Benefit Scale). We tested for differences in clinical benefit and whether substantial clinical benefit was demonstrated. To account for the clinical benefit of unconverted CMA indications, we performed sensitivity analyses. RESULTS: We included 15 SMA and 15 converted CMA cancer indications (17 remained unconverted). Approval of 11 SMA (73%) and four CMA indications (27%) was supported by a controlled trial. Improved overall survival (OS) was demonstrated for four SMA indications (27%). Improved quality of life (QoL) was demonstrated for three SMA (20%) and one CMA indication(s) (7%). Of subsequent CMA post-approval confirmatory trials, 11 were controlled (79%), one demonstrated improved OS (7%) and five improved QoL (36%). After conversion, CMA indications were associated with similar clinical benefit (P = .31) and substantial clinical benefit as SMA indications (risk ratio 1.4, 95% confidence interval 0.57-3.4). CONCLUSION: While CMA cancer indications are initially associated with less comprehensive evidence than SMA indications, levels of evidence and clinical benefit are similar after conversion from CMA to SMA.

Key Considerations in the Health Technology Assessment of Advanced Therapy Medicinal Products in Scotland, The Netherlands, and England.

OBJECTIVES: Advanced therapy medicinal products (ATMPs) are highly innovative therapies. Their costs and uncertain value claims have raised concerns among health technology assessment (HTA) bodies and payers. Little is known about how underlying considerations in HTA of ATMPs shape assessment and reimbursement recommendations. We aim to identify and assess key considerations that played a role in HTA of ATMPs underlying reimbursement recommendations. METHODS: A review of HTA reports was conducted of all authorized ATMPs in Scotland, The Netherlands, and England. Considerations were extracted and categorized into EUnetHTA Core Model domains. Per jurisdiction, considerations were aggregated and key considerations identified (defined as occurring in >1/assessment per jurisdiction). A narrative analysis was conducted comparing key considerations between jurisdictions and different reimbursement recommendations. RESULTS: We identified 15 ATMPs and 18 HTA reports. In The Netherlands and England most key considerations were identified in clinical effectiveness (EFF) and cost- and economic effectiveness (ECO) domains. In Scotland, the social aspects domain yielded most key considerations, followed by ECO and EFF. More uncertainty in evidence and assessment outcomes was accepted when orphan or end-of-life criteria were applied. A higher percentage of considerations supporting recommendations were identified for products with positive recommendations compared with restricted and negative recommendations. CONCLUSIONS: This is the first empirical review of HTA's using the EUnetHTA Core Model to identify and structure key considerations retrospectively. It provides insights in supporting and opposing considerations for reimbursement of individual products and differences between jurisdictions. Besides the EFF and ECO domain, the social, ethical, and legal domains seem to bear considerable weight in assessment of ATMPs.

Impact of medicine shortages on patients - a framework and application in the Netherlands.

BACKGROUND: Medicine shortages are often described in plain numbers, suggesting all shortages have a uniform impact. However, some shortages have a direct and serious effect on patients and need a prompt reaction from stakeholders. This study aims to create a broad framework to assess the impact of a shortage. METHOD: We identified high impact shortages and selected exemplary shortages which we considered our learning cases. From five learning cases, we identified elements that had a potentially profound impact on one or more of these cases. We tested data saturation on the elements with another five test cases. Based on these elements, we created a framework to assess impact of shortages on patients and presented practical examples how to rate these different elements. Subsequently, we visualised the impact of these five learning cases on patients in radar charts. RESULTS: The five elements which we identified as potentially having a large impact were 1) alternative product, 2) disease, 3) susceptibility, 4) costs and 5) number of patients affected. The five learning cases rated high on different elements, leading to diverse and sometimes even opposite patterns of impact. CONCLUSION: We created a framework for assessing the impact of a medicine shortage on patients by means of five key elements. By rating these elements, an indication of the impact can be obtained.

Addressing uncertainty in relative effectiveness assessments by HTA organizations.

This study outlines the ways in which different health technology assessment (HTA) organizations deal with uncertainty in relative effectiveness assessments (REAs), using the GRADE framework as a common reference. Guidelines regarding REA and uncertainty assessment methods and three most recent HTA reports (as of April 2020) of seven HTA organizations in Germany, England and Wales, France, the Netherlands, Europe (EUnetHTA), the USA, and Canada were included. First, it was analyzed how each organization addressed uncertainty on the following levels of evidence: (i) individual studies, (ii) body of evidence for one outcome, (iii) body of evidence across all outcomes, and (iv) added net benefit. Second, the extent to which HTA organizations considered the eight domains of certainty of evidence defined by GRADE was assessed. For individual studies, checklists were the most common approach to express uncertainty (4/7 organizations). Uncertainty in the body of evidence for all outcomes and in added benefit was combined in a single conclusion by five organizations. All organizations reported on at least 4/5 downgrading domains of GRADE, while the three upgrading domains were reported less. The operationalization of the assessment of multiple domains was unclear due to vague or absent guidelines. HTA organizations consider most domains of the GRADE framework, but approaches to assess uncertainty within REAs on different levels of evidence differ substantially between organizations. More alignment and guidance on the best methods to deal with uncertainty within HTA could lead to more clarity for stakeholders and to more aligned reimbursement recommendations.

Estimation of manufacturing development costs of cell-based therapies: a feasibility study.

BACKGROUND AIMS: Cell-based therapies (CBTs) provide opportunities to treat rare and high-burden diseases. Manufacturing development of these innovative products is said to be complex and costly. However, little research is available providing insight into resource use and cost drivers. Therefore, this study aimed to assess the feasibility of estimating the cost of manufacturing development of two cell-based therapy case studies using a CBT cost framework specifically designed for small-scale cell-based therapies. METHODS: A retrospective costing study was conducted in which the cost of developing an adoptive immunotherapy of Epstein-Barr virus-specific cytotoxic T lymphocytes (CTLs) and a pluripotent stem cell (PSC) master cell bank was estimated. Manufacturing development was defined as products advancing from technology readiness level 3 to 6. The study was conducted in a Scottish facility. Development steps were recreated via developer focus groups. Data were collected from facility administrative and financial records and developer interviews. RESULTS: Application of the manufacturing cost framework to retrospectively estimate the manufacturing design cost of two case studies in one Scottish facility appeared feasible. Manufacturing development cost was estimated at £1,201,016 for CTLs and £494,456 for PSCs. Most costs were accrued in the facility domain (56% and 51%), followed by personnel (20% and 32%), materials (19% and 15%) and equipment (4% and 2%). CONCLUSIONS: Based on this study, it seems feasible to retrospectively estimate resources consumed in manufacturing development of cell-based therapies. This fosters inclusion of cost in the formulation and dissemination of best practices to facilitate early and sustainable patient access and inform future cost-conscious manufacturing design decisions.

Early Cost-Effectiveness of Onasemnogene Abeparvovec-xioi (Zolgensma) and Nusinersen (Spinraza) Treatment for Spinal Muscular Atrophy I in The Netherlands With Relapse Scenarios.

OBJECTIVES: Onasemnogene Abeparvovec-xioi (AVXS-101) is a gene therapy intended for curative treatment of spinal muscular atrophy (SMA) with an expected price of around €2 000 000. The goal of this study is to perform a cost-effectiveness analysis of treatment of SMA I patients with AVXS-101 in The Netherlands including relapse scenarios. METHODS: An individual-based state-transition model was used to model treatment effect and survival of SMA I patients treated with AVXS-101, nusinersen and best supportive care (BSC). The model included five health states: three health states according to SMA types, one for permanent ventilation and one for death. Deterministic and probabilistic sensitivity analyses were performed. Effects of relapsing to lower health states in the years following treatment was explored. RESULTS: The base-case incremental cost-effectiveness ratio (ICER) for AVXS-101 versus BSC is €138 875/QALY, and €53 447/QALY for AVXS-101 versus nusinersen. If patients relapse within 10 years after treatment with AVXS-101, the ICER can increase up to 6-fold, with effects diminishing thereafter. Only relapses occurring later than 50 years after treatment have a negligible effect on the ICER. To comply with Dutch willingness-to-pay reference values, the price of AVXS-101 must decrease to €680 000. CONCLUSIONS: Based on this model, treatment with AVXS-101 is unlikely to be cost-effective under Dutch willingness-to-pay reference values. Uncertainty regarding the long-term curative properties of AVXS-101 can result in multiplication of the ICER. Decision-makers are advised to appropriately balance these uncertainties against the price they are willing to pay now.

Advanced therapy medicinal product manufacturing under the hospital exemption and other exemption pathways in seven European Union countries.

BACKGROUND AIMS: As part of the advanced therapy medicinal product (ATMP) regulation, the hospital exemption (HE) was enacted to accommodate manufacturing of custom-made ATMPs for treatment purposes in the European Union (EU). However, how the HE pathway has been used in practice is largely unknown. METHODS: Using a survey and interviews, we provide the product characteristics, scale and motivation for ATMP manufacturing under HE and other, non-ATMP-specific exemption pathways in seven European countries. RESULTS: Results show that ATMPs were manufactured under HE by public facilities located in Finland, Germany, Italy and the Netherlands, which enabled availability of a modest number of ATMPs (n = 12) between 2009 and 2017. These ATMPs were shown to have close proximity to clinical practice, and manufacturing was primarily motivated by clinical needs and clinical experience. Public facilities used HE when patients could not obtain treatment in ongoing or future trials. Regulatory aspects motivated (Finland, Italy, the Netherlands) or limited (Belgium, Germany) HE utilization, whereas financial resources generally limited HE utilization by public facilities. Public facilities manufactured other ATMPs (n = 11) under named patient use (NPU) between 2015 and 2017 and used NPU in a similar fashion as HE. The scale of manufacturing under HE over 9 years was shown to be rather limited in comparison to manufacturing under NPU over 3 years. In Germany, ATMPs were mainly manufactured by facilities of private companies under HE. CONCLUSIONS: The HE enables availability of ATMPs with close proximity to clinical practice. Yet in some countries, HE provisions limit utilization, whereas commercial developments could be undermined by private HE licenses in Germany. Transparency through a public EU-wide registry and guidance for distinguishing between ATMPs that are or are not commercially viable as well as public-private engagements are needed to optimize the use of the HE pathway and regulatory pathways for commercial development in a complementary fashion.

What does cell therapy manufacturing cost? A framework and methodology to facilitate academic and other small-scale cell therapy manufacturing costings.

BACKGROUND AIMS: Recent technical and clinical advances with cell-based therapies (CBTs) hold great promise in the treatment of patients with rare diseases and those with high unmet medical need. Currently the majority of CBTs are developed and manufactured in specialized academic facilities. Due to small scale, unique characteristics and specific supply chain, CBT manufacturing is considered costly compared to more conventional medicinal products. As a result, biomedical researchers and clinicians are increasingly faced with cost considerations in CBT development. The objective of this research was to develop a costing framework and methodology for academic and other small-scale facilities that manufacture cell-based therapies. METHODS: We conducted an international multi-center costing study in four facilities in Europe using eight CBTs as case studies. This study includes costs from cell or tissue procurement to release of final product for clinical use. First, via interviews with research scientists, clinicians, biomedical scientists, pharmacists and technicians, we designed a high-level costing framework. Next, we developed a more detailed uniform methodology to allocate cost items. Costs were divided into steps (tissue procurement, manufacturing and fill-finish). The steps were each subdivided into cost categories (materials, equipment, personnel and facility), and each category was broken down into facility running (fixed) costs and operational (variable) costs. The methodology was tested via the case studies and validated in developer interviews. Costs are expressed in 2018 euros (€). RESULTS: The framework and methodology were applicable across facilities and proved sensitive to differences in product and facility characteristics. Case study cost estimates ranged between €23 033 and €190 799 Euros per batch, with batch yield varying between 1 and 88 doses. The cost estimations revealed hidden costs to developers and provided insights into cost drivers to help design manufacturing best practices. CONCLUSIONS: This framework and methodology provide step-by-step guidance to estimate manufacturing costs specifically for cell-based therapies manufactured in academic and other small-scale enterprises. The framework and methodology can be used to inform and plan cost-conscious strategies for CBTs.

Efficacy gap between phase II and subsequent phase III studies in oncology.

AIMS: There is a trend for more flexibility in timing of evidence generation in relation to marketing authorization, including the option to complete phase III trials after authorization or not at all. This paper investigated the relation between phase II and III clinical trial efficacy in oncology. METHODS: All oncology drugs approved by the European Medicines Agency (2007-2016) were included. Phase II and phase III trials were matched based on indication and treatment and patient characteristics. Reported objective response rates (ORR), median progression-free survival (PFS) and median overall survival (OS) were analysed through weighted mixed-effects regression with previous treatment, treatment regimen, blinding, randomization, marketing authorization type and cancer type as covariates. RESULTS: A total of 81 phase II-III matches were identified including 252 trials. Mean (standard deviation) weighted difference (phase III minus II) was -4.2% (17.4) for ORR, 2.1 (6.7) months for PFS and -0.3 (5.1) months for OS, indicating very small average differences between phases. Differences varied substantially between individual indications: from -46.6% to 47.3% for ORR, from -5.3 to 35.9 months for PFS and from -13.3 to 10.8 months for OS. All covariates except blinding were associated with differences in effect sizes for at least 1 outcome. CONCLUSIONS: The lack of marked average differences between phases may encourage decision-makers to regard the quality of design and total body of evidence instead of differentiating between phases of clinical development. The large variability emphasizes that replication of study findings remains essential to confirm efficacy of oncology drugs and discern variables associated with demonstrated effects.

A Review of Methodological Considerations for Economic Evaluations of Gene Therapies and Their Application in Literature.

OBJECTIVES: To identify methodological considerations discussed in literature addressing economic evaluations (EEs) of gene therapies (GTs). Additionally, we assessed if these considerations are applied in published GT EEs to increase understanding and explore impact. METHODS: First a peer-reviewed literature review was performed to identify research addressing methodological considerations of GT EEs until August 2019. Identified considerations were grouped in themes using thematic content analysis. A second literature search was conducted in which we identified published evaluations. The EE quality of reporting was assessed using Consolidated Health Economic Evaluation Reporting Standards. RESULTS: The first literature search yielded 13 articles discussing methodological considerations. The second search provided 12 EEs. Considerations identified were payment models, definition of perspectives, addressing uncertainty, data extrapolation, discount rates, novel value elements, and use of indirect and surrogate endpoints. All EEs scored satisfactory to good according to Consolidated Health Economic Evaluation Reporting Standards. Regarding methodological application, we found 1 methodological element (payment models) was applied in 2 base cases. Scenarios explored alternative perspectives, survival assumptions, and extrapolation methods in 10 EEs. CONCLUSIONS: Although EE quality of reporting was considered good, their informativeness for health technology assessment and decision makers seemed limited owing to many uncertainties. We suggest accepted EE methods can broadly be applied to GTs, but few elements may need adjustment. Further research and multi-stakeholder consensus is needed to determine appropriateness and application of individual methodological considerations. For now, we recommend including scenario analyses to explore impact of methodological choices and (clinical) uncertainties. This study contributes to better understanding of perceived appropriate evaluation of GTs and informs best modeling practices.

Differences in Health Technology Assessment Recommendations Among European Jurisdictions: The Role of Practice Variations.

BACKGROUND: Health technology assessment (HTA) plays an important role in reimbursement decision-making in many countries, but recommendations vary widely throughout jurisdictions, even for the same drug. This variation may be due to differences in the weighing of evidence or differences in the processes or procedures, which are known as HTA practices. OBJECTIVE: To provide insight into the effects of differences in practices on interpretation of intercountry differences in HTA recommendations for conditionally approved drugs. METHODS: HTA recommendations for conditionally approved drugs (N = 27) up until June 2017 from England/Wales, France, Germany, the Netherlands, and Scotland were included. Recommendations and practice characteristics were extracted from these five jurisdictions and this data was validated. The effect of nonsubmissions, resubmissions, and reassessments; cost-effectiveness assessments; and price negotiations on changes in the percentage of negative recommendations and the interpretation of intercountry differences in HTA outcomes were analyzed using Fisher exact tests. RESULTS: The inclusion of cost-effectiveness assessments led to significant increases in the proportion of negative recommendations in England/Wales (from 4% to 50%, P<.01) and Scotland (from 21% to 71%, P<.01). The subsequent inclusion of price negotiations led to significant reductions in the proportion of negative recommendations in England/Wales (from 50% to 14%, P<.01), France (from 31% to 3%, P=.012), and Germany (from 34% to 0%, P<.01). Results indicated that the inclusion of nonsubmissions and resubmissions might affect Scottish negative HTA recommendations (from 7% to 21%), but this effect was not significant. No significant effects were observed in the Netherlands, possibly owing to sample size. CONCLUSION: Variations in HTA practices between international jurisdictions can have a substantial and significant impact on conclusions about recommendations by HTA bodies, as exemplified in this cohort of conditionally approved products. Studies comparing international HTA recommendations should carefully consider possible practice variations between jurisdictions.

Prescribing patterns and compliance with World Health Organization recommendations for the management of severe malaria: a modified cohort event monitoring study in public health facilities in Ghana and Uganda.

BACKGROUND: Injectable artesunate (AS) is the World Health Organization (WHO) recommended medication for the treatment of severe malaria followed with an oral artemisinin-based combination therapy (ACT). There are few studies indicating how physicians prescribe injectable AS, injectable quinine (Q) or injectable artemether (AR) and ACT for severe malaria. This study was undertaken to evaluate prescription compliance to the WHO recommendation in 8 public health facilities in Ghana and Uganda. This was a modified cohort event monitoring study involving patients who were administered with injectable anti-malarial for treatment of presumed or confirmed severe malaria. Patients prescribed at least one dose of injectable artesunate, artemether or quinine qualified to enrol in the study. Patients were recruited at inpatient facilities and followed up in the hospital, by phone or at home. Following WHO recommendations, patients are to be prescribed 3 doses of injectable AS, Q or AR for at least 24 h followed with oral ACT. Compliance rate was estimated as the number of patient prescriptions that met the WHO recommendation for treatment of severe malaria divided by the total number of patients who completed the study by end of follow up. Log-binomial regression model was used to identify predictors for compliance. Based on the literature and limitations of available data from the patients' record, the diagnosis results, age, gender, weight, and country were considered as potential predictors of prescriber adherence to the WHO recommendations. RESULTS: A total of 1191 patients completed the study, of which 93% were prescribed injectable AS, 3.1% (injectable AR or Q) with 32.5% prescribed follow-on oral ACT and 26% on concomitant antibiotics. 391 (32.8%) were in Ghana and 800 (67.2%) in Uganda. There were 582 (48.9%) women. The median age was 3.9 years (IQR = 2, 9) and median weight was 13 kg (IQR = 10, 20). Of the 1191 patients, 329 of the prescriptions complied with the WHO recommendation (compliance rate = 27.6%; 95% CI = [25.2, 30.2]). Diagnostic results (Adjusted prevalence ratio (aPR) = 4.56; 95% = [3.42, 6.08]; p < 0.0001) and weight (20 + kg vs < 10 kg: aPR = 0.65; 95% = [0.44, 0.96]; p = 0.015) were identified as factors independently associated with compliance. CONCLUSION: Injectable AS is the most commonly prescribed medicine in the management of severe malaria in Ghana and Uganda. However, adherence to the WHO recommendation of at least 3 doses of injectable anti-malarial in 24 h followed by a full course of ACT is low, at less than 30%.

Post-marketing dosing changes in the label of biologicals.

AIM: The aim of this study was to evaluate post-marketing label changes in dosing information of biologicals. METHODS: Biologicals authorized between 2007 and 2014 by the European Medicines Agency (EMA) were included and followed up from marketing authorization until 31 December 2016 or date of withdrawal of the marketing authorization. The primary outcome of the study was defined as label change in dosing information for the initially approved indication. Incidence of changes, type of change and mean time to change were assessed. As a secondary outcome, label changes in dosing information for extended indications were assessed. RESULTS: A total of 71 biologicals were included. Dosing information in the label changed for the initial indication during follow-up for eight products (11%). In one of the eight products the change concerned an increase in dose. Also, a change in dosing frequency was identified in three products, for one product a recommendation was added that therapy could be initiated with or without a loading dose, and for one product the minimum dose was removed and a maximum dose was added. For the remaining product the dose was decreased due to safety issues. For 30 products (42%) the indication was extended at least once. No changes in dosing information were observed for the extended indications (n = 59) during follow-up. CONCLUSIONS: This study showed that in 11% of the biologicals, the dosing for the initial indication in the label was changed. In contrast to small molecules, the dose was rarely reduced for safety reasons.

Unmet Medical Need: An Introduction to Definitions and Stakeholder Perceptions.

BACKGROUND: Despite increasing informal and formal use of unmet medical need (UMN) in drug development, regulation, and assessment, there is no insight into its definitions in use. This study aims to provide insight into the current definitions in use and to provide a starting point for a multi-stakeholder discussion on alignment. METHODS: A scoping and a gray literature review were performed to locate definitions of UMN in literature and on stakeholder websites. These definitions were categorized and then discussed among the multi-stakeholder author group via semistructured group discussions and open session workshops with a broader stakeholder audience. Issues with the formation of a common definition and mechanisms for use were discussed. RESULTS: The reviews yielded 16 definitions. Differences were evident, but all included 1 or more of the following elements: (adequacy of) available treatments (16 of 16: 100%), disease severity or burden (6 of 16: 38%), and patient population size (1 of 16: 6%). The stakeholder discussions led to a suggestion for a definition including the first 2 items and, depending on context, population size. The discussions also showed that quantification of UMN is highly dependent on the scope and the value framework in which it is used based on different stakeholder preferences and responsibilities. CONCLUSION: We encourage stakeholders that want to promote alignment on the concept of UMN to prospectively discuss the scope in which they want to apply the concept, what elements they find important for consideration in each case, and how they would measure UMN within the broader regulatory or value framework applicable.

The accuracy of date of death recording in the Clinical Practice Research Datalink GOLD database in England compared with the Office for National Statistics death registrations.

PURPOSE: It is not clear whether all deaths are recorded in the Clinical Practice Research Datalink (CPRD) or how accurate a recorded date of death is. Individual-level linkage with national data from the Office for National Statistics (ONS) and Hospital Episode Statistics (HES) in England offers the opportunity to compare death information across different data sources. METHODS: Age-standardised mortality rates (ASMRs) standardised to the European Standard Population (ESP) 2013 for CPRD were compared with figures published by the ONS, and crude mortality rates were calculated for a sample population with individual linkage between CPRD, ONS, and HES data. Agreement on the fact of death between CPRD and ONS was assessed and presented over time from 1998 to 2013. RESULTS: There were 33 997 patients with a record of death in the ONS data; 33 389 (98.2%) of these were also identified in CPRD. Exact agreement on the death date between CPRD and the ONS was 69.7% across the whole study period, increasing from 53.4% in 1998 to 78.0% in 2013. By 2013, 98.8% of deaths were in agreement within ±30 days. CONCLUSIONS: For censoring follow-up and calculating mortality rates, CPRD data are likely to be sufficient, as a delay in death recording of up to 1 month is unlikely to impact results significantly. Where the exact date of death or the cause is important, it may be advisable to include the individually linked death registration data from the ONS.

Potentially inappropriate medications with risk of cardiovascular adverse events in the elderly: A systematic review of tools addressing inappropriate prescribing.

WHAT IS KNOWN AND OBJECTIVE: In the last decades, many lists have been developed to screen for inappropriate prescribing. However, information on which potentially inappropriate medications (PIMs) could increase the cardiovascular risk in the elderly is not objectively presented. This review aimed to identify and quantify those PIMs by extracting information from published PIM-lists. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA), a systematic review of PIM-lists was conducted. The search strategy was run in PubMed, MEDLINE and Google Scholar (1991-09/2017). All PIMs described in those lists were extracted and stratified by their potential cardiovascular risk (including major adverse cardiovascular events-MACE). The number of times each PIM was reported on those lists was also assessed. RESULTS AND DISCUSSION: We identified 724 papers, and 24 were retained. From those, a total of 17 PIMs to be avoided by the elderly and 21 drug-disease interactions were retrieved. The reporting of PIMs with risk of cardiovascular adverse events was 15.3%, whereas the reporting of those with MACE risk was 7.2%. PIMs most frequently described were tricyclic antidepressants (TCAs; 12/24), centrally acting antiadrenergic agents (11/24), NSAIDs (7/24), antiarrhythmics (Class I and III; 6/24), peripherally acting antiadrenergic agents (6/24) and antithrombotic agents (5/24). Most frequently described PIMs with MACE risk were NSAIDs (7/24), antiarrhythmics (Class I and III) (7/24), selective calcium channel blockers with vascular effects (6/24) and antipsychotics (4/24). WHAT IS NEW AND CONCLUSION: Data suggest that PIM-lists focus mainly on common adverse events and often poorly describe the potential consequence for MACE occurrence. This systematic review could help healthcare professionals in the identification and deprescribing of these medicines in older patients with high cardiovascular risk during medication review.

Precision medicine in diabetes and diabetic kidney disease: Regulatory considerations.

Over the past 15 years, three new classes of drugs, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium glucose cotransporter-2 (SGLT-2) inhibitors have been approved to treat type 2 diabetes based on effects on glycemic control. Although large randomized controlled trials have played an important role in characterizing the efficacy and safety of these agents on a population level, questions remain about how best to individualize therapy and target the "right" medicine to the "right" patient. In contrast, few medicines have been approved to treat diabetic kidney disease and initiatives have been launched on both sides of the Atlantic to facilitate the development of effective personalized medicines for the treatment of diabetic kidney disease. Increasingly, "omics," imaging and other biomarkers will be used to match patients with therapies to which they are likely to respond best. This review addresses regulatory considerations related to precision medicine, draws lessons learned from other therapeutic areas and discusses efforts undertaken by the European (EMA) and United States (FDA) to facilitate the development of such therapies. Moving forward, an integrated approach that makes use of predictive preclinical models, innovative trial designs, observational "real-world" data and novel statistical methodologies will likely be needed to complement inherently smaller RCTs conducted in more selected populations. Patient involvement will also be critical. Regulatory agencies are ready to engage in such approaches.

Increased risk of all-cause mortality associated with domperidone use in Parkinson's patients: a population-based cohort study in the UK.

AIMS: Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson's disease (PD) and is linked to an increased risk of mortality. We sought to examine the risk of all-cause mortality associated with domperidone exposure in PD. METHODS: We conducted a cohort study using data from the Clinical Practice Research Datalink database (1987-2011). The first recorded PD diagnosis defined index date. Time-dependent Cox proportional hazards models estimated hazard ratios (HRs) of all-cause mortality associated with domperidone use. PD patients were stratified by domperidone use (current/recent/past), with never used as the referent. Current domperidone users were stratified by daily dose, domperidone duration and other anti-Parkinson's medications. A secondary analysis compared PD patients to matched (1:1) non-PD patients. RESULTS: A total of 5114 PD patients were identified. Current use of domperidone among PD patients was associated with a two-fold increase in all-cause mortality (HRadj  = 2.00, 95% confidence interval [CI]: 1.64-2.45), as compared to patients never exposed to domperidone. All-cause mortality risk was highest in those starting domperidone in the previous month [HRadj  = 2.97, 95% CI: 2.06-4.27]. When compared to matched non-PD patients, PD was associated with a 43% increased risk of all-cause mortality, yet this increased to a 2.4-fold increased risk among PD patients currently using domperidone. CONCLUSION: Current use of domperidone was associated with a two-fold increased mortality risk in PD patients, as compared to PD patients that never used domperidone. The risk is highest in the first month of use and does not appear to be attributable to PD alone.

Comparing safety information of biosimilars with their originators: a cross-sectional analysis of European risk management plans.

BACKGROUND AND AIMS: Biosimilars have been available in the European Union (EU) since 2006. However, their uptake in routine care is heterogeneous across countries. The aim of the present study was to compare the safety information of biosimilars and their originators based on the information in the European risk management plan (RMP). METHODS: A cross-sectional analysis on publicly available regulatory documents (RMPs and Summaries of Product Characteristics) of biosimilars and corresponding originators up to 1 November 2015 was performed. The safety concerns were extracted and merged into general safety concerns, and clinical relevance was assessed. The frequency of safety concerns and the representation of these safety concerns per general safety concern were assessed by either comparing RMPs of biosimilars and originators (if available for both) or comparing RMPs with the Summary of Product Characteristics of the originator. RESULTS: Nineteen biosimilars and six originators were included. Overall, 55 general safety concerns (12 low, 21 medium and 22 highly clinically relevant) were identified. For all active substances, except for infliximab, no or only one difference was found in the listed general safety concerns. Comparison of regulatory documents for infliximab identified three medium clinically relevant general safety concerns more for infliximab biosimilars and two general safety concerns more for its originator. CONCLUSION: Based on publicly available information filed for regulatory purposes, no substantial differences were observed in the reporting of safety information for biosimilars and related originators. A direct comparison between biosimilars and related originators through formal postmarketing studies is needed to evaluate specific safety issues emerging during the products' life cycle.