Recruitment failure and futility were the most common reasons for discontinuation of clinical drug trials. Results of a nationwide inception cohort study in the Netherlands

Objectives The objective of the study was to identify the reasons for discontinuation of clinical drug trials and to evaluate whether efficacy-related discontinuations were adequately planned in the trial protocol. Study Design and Setting All clinical drug trials in the Netherlands, reviewed by institutional review boards in 2007, were followed until December 2015. Data were obtained through the database of the Dutch competent authority (Central Committee on Research Involving Human Subjects [CCMO]) and a questionnaire to the principal investigators. Reasons for trial discontinuation were the primary outcome of the study. Three reasons for discontinuation were analyzed separately: all cause, recruitment failure, and efficacy related (when an interim analysis had demonstrated futility or superiority). Among the efficacy-related discontinuations, we examined whether the data monitoring committee, the stopping rule, and the moment of the interim analysis in the trial progress were specified in the trial protocol. Results Of the 574 trials, 102 (17.8%) were discontinued. The most common reasons were recruitment failure (33 of 574; 5.7%) and solely efficacy related (30 of 574; 5.2%). Of the efficacy-related discontinuations, 10 of 30 (33.3%) of the trial protocols reported all three aspects in the trial protocol, and 20 of 30 (66.7%) reported at least one aspect in the trial protocol. Conclusion One out of five clinical drug trials is discontinued before the planned trial end, with recruitment failure and futility as the most common reasons. The target sample size of trials should be feasible, and interim analyses should be adequately described in trial protocols

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

Renal function of MDR-TB patients treated with kanamycin regimens or concomitantly with antiretroviral agents

SETTING: To compare renal insufficiency among mul-tidrug-resistant tuberculosis (MDR-TB) patients treated with kanamycin (KM) based regimens and those treated concomitantly with tenofovir disoproxil fumarate (TDF) or other antiretroviral therapy (ART) regimens in Namibia. DESIGN: Retrospective review of the treatment records and laboratory tests of patients initiated on MDR-TB treatment (January–December 2014). The glomerular filtration rates (eGFR) estimated pre- and post-treatment were compared using the analysis of variance test. Renal insufficiency was defined as an eGFR of,60 ml/ min/1.73 m2. Use of KM or TDF and association with renal insufficiency was assessed using Kaplan-Meier plots and Cox proportional hazards analysis. RESULTS: The baseline mean eGFR for the three groups was similar (P ¼ 0.24): 139.3 6 25.6 ml/min for the KM group (n ¼ 68), 131.1 6 25.7 ml/min for the KMþTDF group (n ¼ 44) and 134.2634.4 ml/min for the KMþOther group (n ¼ 23). After 8 months, the values had declined significantly to respectively 104.8 6 37.5 ml/min (P, 0.001), 101.5 6 38.3 ml/min (P, 0.001) and 111.5 6 41.7 ml/min (P ¼ 0.01). Co-treatment with KMþART was associated with an increased risk of renal insufficiency (hazard ratio [HR] 1.8, 95%CI 0.7–4.1, P ¼ 0.20 for KMþTDF, and HR 3.5, 95%CI 1.4–8.2, P ¼ 0.005 for KMþOther ART). CONCLUSION: Renal function declined at a similar rate in MDR-TB patients treated with KM-based regimens compared with patients treated concomitantly with TDF-based or other ART. The risk of renal insufficiency was greater for patients on ART

Linking market authorizations of medicines with disease burden in South Africa

Background: Sub-Saharan Africa is going through an epidemiological transition, including an impressive increase in non-communicable diseases. The introduction of medicines has not kept pace with the needs in developing countries. The objectives of this study were to (i) examine the correlation between the number of medicine approvals and disease burden and (ii) compare approval timelines of medicines with disease burden in South Africa in the period 2012–2017. Methods: The dataset was compiled from publicly available data on medicines registered in South Africa between 2012 and 2017. A correlation analysis was conducted to determine the level of alignment between the number and nature of medicines registered, as determined by the WHO ATC Classification and the Lancet Global Burden of Disease data. Median registration timelines were determined to assess whether medicines for diseases of higher burden were registered faster. Results: A total of 3059 registered medicines were included in the study, including 2779 generic medicines, 267 new chemical entities and 13 vaccines. There was a high level of alignment between the number of medicines registered to treat diseases with higher disease burden levels more effectively, except for lower respiratory tract infections and HIV/AIDS which showed less medicines registered as compared to expectations based on disease burden, respectively. HIV/AIDS showed a lower level of correlation with a much higher disease burden compared to number of medicines registered, but simultaneously also a much shorter median registration timeline (32 months) compared to the other disease areas. Conclusions: There was generally a high level of alignment between disease burden and number of medicines authorised, except for HIV/AIDS and lower respiratory tract infections. Regulatory authorities should continue to consider burden of disease data to ensure that public health needs are met

Balancing individual benefits and risks of warfarin in patients with atrial fibrillation

Background: Anticoagulation with warfarin reduces the risk of ischaemic stroke in patients with atrial fibrillation (AF) but may increase the risk of bleeding. A positive benefit-risk balance in the overall AF population has been well established, but hardly studied on an individual level. Objectives: To estimate benefits and risks of warfarin treatment for the individual and identify characteristics determining the benefit-risk balance. Methods: The study cohort consisted of patients with AF exposed to warfarin in the Clinical Practice Research Datalink (CPRD). Outcomes of interest were ischaemic stroke, transient ischaemic attack, haemorrhagic stroke and major bleed. The probability of an outcome dur-ing exposure was estimated with a Cox proportional hazard model. Attributable risks for each outcome were estimated using the individual probabilities and relative rates of warfarin effects (based on meta-analyses of trials). Each outcome was weighted by 1-year mortality. The individual net benefit was calculated as the weighted sum of benefits minus adverse effects and then characterized as being less favourable (net benefit 1.5). Logistic regression was used to identify characteristics that explained a less favourable net benefit. Results: The study population included 33,772 patients with AF exposed to warfarin. The mean net benefit was 1.17 (SD 16.0) ischaemic stroke cases or equivalent prevented. Characteristics that were associated with a less favourable benefit-risk balance were age > 85 years (OR 2.82, 95% CI 2.37-3.36), presence of congestive heart failure (OR 2.67, 2.27-3.14), cancer (OR 2.51, 2.19-2.88), minor bleed (OR 2.68, 2.25- 3.18) and renal insufficiency (OR 3.30, 2.37-4.60). Hypertension (OR 0.41, 0.36-0.46) and vascular disease (OR 0.16, 0.13-0.19) were associated with a favourable benefit-risk balance. Conclusions: We confirmed that the net benefit of warfarin for the overall AF population is positive. However, there is a large variation of benefit-risk balance across this population for individual patients

ACE-REMMERS VERGROTEN HET RISICO OP HYPOGLYKEMIE BIJ DIABETICI

Objective. To determine the association of hypoglycaemia in diabetic patients with the use of ACE inhibitors. Design. Nested case control study. Setting. Six medium sized Dutch cities (300.000 inhabitants). Method. Using data in the Dutch PHARMO system (1986-1992) 94 diabetic patients treated with insulin or with oral antidiabetic drugs, who had been admitted to hospital with hypoglycaemia, were identified. From the same cohort 654 control patients were selected at random. Results. With adjustment for a wide range of potential confounding factors, hypoglycaemia was significantly associated with current use of ACE inhibitors (odds ratio: 2.8 (95% CI 1.4-5.7)). Both among users of insulin and users of oral antidiabetic drugs, use of ACE inhibitors was significantly associated with an increased risk of hospital admission for hypoglycaemia (2.8 (1.2-6.4) and 4.1 (1.4-12.2), respectively). It was estimated that about 13.8% of all admissions for hypoglycaemia in diabetic patients were due to the use of ACE inhibitors. Conclusion. Although the use of ACE inhibitors for hypertension in diabetic patients has advantages over the use of other antihypertensive drugs, one should be aware of the increased risk of hypoglycaemia