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Lancet ; 395(10228): 986-997, 2020 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-32199486


Fewer than half of new drugs have data on their comparative benefits and harms against existing treatment options at the time of regulatory approval in Europe and the USA. Even when active-comparator trials exist, they might not produce meaningful data to inform decisions in clinical practice and health policy. The uncertainty associated with the paucity of well designed active-comparator trials has been compounded by legal and regulatory changes in Europe and the USA that have created a complex mix of expedited programmes aimed at facilitating faster access to new drugs. Comparative evidence generation is even sparser for medical devices. Some have argued that the current process for regulatory approval needs to generate more evidence that is useful for patients, clinicians, and payers in health-care systems. We propose a set of five key principles relevant to the European Medicines Agency, European medical device regulatory agencies, US Food and Drug Administration, as well as payers, that we believe will provide the necessary incentives for pharmaceutical and device companies to generate comparative data on drugs and devices and assure timely availability of evidence that is useful for decision making. First, labelling should routinely inform patients and clinicians whether comparative data exist on new products. Second, regulators should be more selective in their use of programmes that facilitate drug and device approvals on the basis of incomplete benefit and harm data. Third, regulators should encourage the conduct of randomised trials with active comparators. Fourth, regulators should use prospectively designed network meta-analyses based on existing and future randomised trials. Last, payers should use their policy levers and negotiating power to incentivise the generation of comparative evidence on new and existing drugs and devices, for example, by explicitly considering proven added benefit in pricing and payment decisions.

Aprovação de Equipamentos/normas , Aprovação de Drogas/métodos , Segurança de Equipamentos , Segurança , Biomarcadores Farmacológicos/análise , Tolerância a Medicamentos , Medicina Baseada em Evidências , Humanos , Estados Unidos , United States Food and Drug Administration
BMC Med Res Methodol ; 20(1): 41, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32103725


BACKGROUND: A Core Outcomes Set (COS) is an agreed minimum set of outcomes that should be reported in all clinical studies related to a specific condition. Using prostate cancer as a case study, we identified, summarized, and critically appraised published COS development studies and assessed the degree of overlap between them and selected real-world data (RWD) sources. METHODS: We conducted a scoping review of the Core Outcome Measures in Effectiveness Trials (COMET) Initiative database to identify all COS studies developed for prostate cancer. Several characteristics (i.e., study type, methods for consensus, type of participants, outcomes included in COS and corresponding measurement instruments, timing, and sources) were extracted from the studies; outcomes were classified according to a predefined 38-item taxonomy. The study methodology was assessed based on the recent COS-STAndards for Development (COS-STAD) recommendations. A 'mapping' exercise was conducted between the COS identified and RWD routinely collected in selected European countries. RESULTS: Eleven COS development studies published between 1995 and 2017 were retrieved, of which 8 were classified as 'COS for clinical trials and clinical research', 2 as 'COS for practice' and 1 as 'COS patient reported outcomes'. Recommended outcomes were mainly categorized into 'mortality and survival' (17%), 'outcomes related to neoplasm' (18%), and 'renal and urinary outcomes' (13%) with no relevant differences among COS study types. The studies generally fulfilled the criteria for the COS-STAD 'scope specification' domain but not the 'stakeholders involved' and 'consensus process' domains. About 72% overlap existed between COS and linked administrative data sources, with important gaps. Linking with patient registries improved coverage (85%), but was sometimes limited to smaller follow-up patient groups. CONCLUSIONS: This scoping review identified few COS development studies in prostate cancer, some quite dated and with a growing level of methodological quality over time. This study revealed promising overlap between COS and RWD sources, though with important limitations; linking established, national patient registries to administrative data provide the best means to additionally capture patient-reported and some clinical outcomes over time. Thus, increasing the combination of different data sources and the interoperability of systems to follow larger patient groups in RWD is required.

NPJ Digit Med ; 2: 17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31304365


Computational modelling has made significant progress towards clinical application in recent years. In addition to providing detailed diagnostic data, these methods have the potential to simulate patient-specific interventions and to predict their outcome. Our objective was to evaluate to which extent patient-specific modelling influences treatment decisions in coarctation of the aorta (CoA), a common congenital heart disease. We selected three cases with CoA, two of which had borderline indications for intervention according to current clinical guidelines. The third case was not indicated for intervention according to guidelines. For each case, we generated two separate datasets. First dataset included conventional diagnostic parameters (echocardiography and magnetic resonance imaging). In the second, we added modelled parameters (pressure fields). For the two cases with borderline indications for intervention, the second dataset also included pressure fields after virtual stenting simulations. All parameters were computed by modelling methods that were previously validated. In an online-administered, invitation-only survey, we randomized 178 paediatric cardiologists to view either conventional (control) or add-on modelling (experimental) datasets. Primary endpoint was the proportion of participants recommending different therapeutic options: (1) surgery or catheter lab (collectively, "intervention") or (2) no intervention (follow-up with or without medication). Availability of data from computational predictive modelling influenced therapeutic decision making in two of three cases. There was a statistically significant association between group assignment and the recommendation of an intervention for one borderline case and one non-borderline case: 94.3% vs. 72.2% (RR: 1.31, 95% CI: 1.14-1.50, p = 0.00) and 18.8% vs. 5.1% (RR: 3.09, 95% CI: 1.17-8.18, p = 0.01) of participants in the experimental and control groups respectively recommended an intervention. For the remaining case, there was no difference between the experimental and control group and the majority of participants recommended intervention. In sub-group analyses, findings were not affected by the experience level of participating cardiologists. Despite existing clinical guidelines, the therapy recommendations of the participating physicians were heterogeneous. Validated patient-specific computational modelling has the potential to influence treatment decisions. Future studies in broader areas are needed to evaluate whether differences in decisions result in improved outcomes (Trial Registration: NCT02700737).

BMJ Open ; 9(6): e027851, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31221887


INTRODUCTION: There are more people living with dementia in low- and middle-income countries (LMICs) than in high-income countries. Evidence-based interventions to improve the lives of people living with dementia and their carers are needed, but a systematic mapping of methodologically robust studies in LMICs and synthesis of the effectiveness of dementia interventions in these settings is missing. METHODS AND ANALYSIS: A systematic review and meta-analysis will be conducted to answer the question: Which dementia interventions were shown to be effective in LMICs and how do they compare to each other? Electronic database searches (MEDLINE, EMBASE, PsycINFO, CINAHL Plus, Global Health, WHO Global Index Medicus, Virtual Health Library, Cochrane CENTRAL, Social Care Online, BASE, MODEM Toolkit, Cochrane Database of Systematic Reviews) will be complemented by hand searching of reference lists and local knowledge of existing studies from an international network of researchers in dementia from LMICs. Studies will be eligible for inclusion if they were published between 2008 and 2018, conducted in LMICs and evaluated the effectiveness of a dementia intervention using a study design that supports causal inference of the treatment effect. We will include both randomised and non-randomised studies due to an anticipated low number of well-conducted randomised trials in LMICs and potentially greater external validity of non-randomised studies conducted in routine care settings. In addition to narrative synthesis of the interventions, feasibility of pairwise and network meta-analyses will be explored to obtain pooled effects of relative treatment effects. ETHICS AND DISSEMINATION: Secondary analysis of published studies, therefore no ethics approval required. Planned dissemination channels include a peer-reviewed publication as well as a website, DVD and evidence summaries. PROSPERO REGISTRATION NUMBER: CRD42018106206.

Front Cardiovasc Med ; 6: 43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31024935


Introduction: Exercise testing has become a diagnostic standard in the evaluation and management of heart disease. While different methods of exercise and pharmacological stress testing exist, only little is known about their comparability. We aimed to assess hemodynamic changes during dynamic exercise, isometric exercise, and dobutamine stress testing at different stress intensities in healthy subjects and patients with aortic stenosis (AS) and aortic coarctation (CoA). Methods: A systematic literature search (PROSPERO 2017:CRD42017078608) in MEDLINE of interventional trials was conducted to identify eligible studies providing evidence of changes in hemodynamic parameters under different stress conditions acquired by MRI or echocardiography. A random effects model was used to estimate pooled mean changes in hemodynamics. Results: One hundred and twenty-eight study arms with a total of 3,139 stress-examinations were included. In healthy subjects/(where available) in AS, pooled mean changes (95% CIs) during light dynamic stress were 31.78 (27.82-35.74) bpm in heart rate (HR) and 6.59 (2.58-10.61) ml in stroke volume (SV). Changes during light pharmacological stress were 13.71 (7.87-19.56)/14.0 (9.82-18.18) bpm in HR, and 5.47 (0.3-10.63)/8.0 (3.82-12.18) ml in SV. Changes during light isometric stress were 18.44 (10.74-26.14)/5.0 (-1.17-11.17) bpm in HR and -4.17 (-14.37-6.03)/-4.0 (-16.43-8.43) ml in SV. Changes during moderate dynamic stress were 49.57 (40.03-59.1)/46.45 (42.63-50.27) bpm in HR and 11.64 (5.87-17.42) ml in SV. During moderate pharmacological stress, changes in HR were 42.83 (36.94-48.72)/18.66 (2.38-34.93) bpm and in SV 6.29 (-2.0-14.58)/13.11 (7.99-18.23) ml. During high intensity dynamic stress changes in HR were 89.31 (81.46-97.17)/55.32 (47.31-63.33) bpm and in SV 21.31 (13.42-29.21)/-0.96 (-5.27-3.35) ml. During high pharmacological stress, changes in HR were 53.58 (36.53-70.64)/42.52 (32.77-52.28) bpm, and in SV 0.98 (-9.32-11.27)/14.06 (-1.62-29.74) ml. HR increase and age were inversely correlated at high stress intensities. In CoA, evidence was limited to single studies. Conclusion: This systematic review and meta-analysis presents pooled hemodynamic changes under light, moderate and high intensity exercise and pharmacological stress, while considering the potential influence of age. Despite limited availability of comparative studies, the reference values presented in this review allow estimation of the expected individual range of a circulatory response in healthy individuals and patients with AS and may contribute to future study planning and patient-specific models even when stress testing is contraindicated.

Br J Sports Med ; 53(14): 859-869, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30563873


OBJECTIVE: To compare the effect of exercise regimens and medications on systolic blood pressure (SBP). DATA SOURCES: Medline (via PubMed) and the Cochrane Library. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) of angiotensin-converting enzyme inhibitors (ACE-I), angiotensin-2 receptor blockers (ARBs), ß-blockers, calcium channel blockers (CCBs) and diuretics were identified from existing Cochrane reviews. A previously published meta-analysis of exercise interventions was updated to identify recent RCTs that tested the SBP-lowering effects of endurance, dynamic resistance, isometric resistance, and combined endurance and resistance exercise interventions (up to September 2018). DESIGN: Random-effects network meta-analysis. OUTCOME: Difference in mean change from baseline SBP between comparator treatments (change from baseline in one group minus that in the other group) and its 95% credible interval (95% CrI), measured in mmHg. RESULTS: We included a total of 391 RCTs, 197 of which evaluated exercise interventions (10 461 participants) and 194 evaluated antihypertensive medications (29 281 participants). No RCTs compared directly exercise against medications. While all medication trials included hypertensive populations, only 56 exercise trials included hypertensive participants (≥140 mmHg), corresponding to 3508 individuals. In a 10% random sample, risk of bias was higher in exercise RCTs, primarily due to lack of blinding and incomplete outcome data. In analyses that combined all populations, antihypertensive medications achieved higher reductions in baseline SBP compared with exercise interventions (mean difference -3.96 mmHg, 95% CrI -5.02 to -2.91). Compared with control, all types of exercise (including combination of endurance and resistance) and all classes of antihypertensive medications were effective in lowering baseline SBP. Among hypertensive populations, there were no detectable differences in the SBP-lowering effects of ACE-I, ARB, ß-blocker and diuretic medications when compared with endurance or dynamic resistance exercise. There was no detectable inconsistency between direct and indirect comparisons. Although there was evidence of small-study effects, this affected both medication and exercise trials. CONCLUSIONS: The effect of exercise interventions on SBP remains under-studied, especially among hypertensive populations. Our findings confirm modest but consistent reductions in SBP in many studied exercise interventions across all populations but individuals receiving medications generally achieved greater reductions than those following structured exercise regimens. Assuming equally reliable estimates, the SBP-lowering effect of exercise among hypertensive populations appears similar to that of commonly used antihypertensive medications. Generalisability of these findings to real-world clinical settings should be further evaluated.

Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Exercício Físico/fisiologia , Hipertensão/tratamento farmacológico , Hipertensão/prevenção & controle , Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Pressão Sanguínea/fisiologia , Bloqueadores dos Canais de Cálcio/administração & dosagem , Diuréticos/administração & dosagem , Humanos , Hipertensão/fisiopatologia , Metanálise em Rede