There is a compelling need to evaluate the real-world health effects of medical products outside of tightly controlled preapproval clinical trials. This is done through pharmacoepidemiology, which is ...the study of the health effects of medical products (including drugs, biologicals, and medical devices and diagnostics) in populations, often using nonrandomized designs. Recent developments in pharmacoepidemiology span changes in the focus of research questions, research designs, data used, and statistical analysis methods. Developments in these areas are thought to improve the value of the evidence produced by such studies, and are prompting greater use of real-world evidence to inform clinical, regulatory, and reimbursement decisions.
In a prospective meta-analysis (PMA), study selection criteria, hypotheses, and analyses are specified before the results of the studies related to the PMA research question are known, reducing many ...of the problems associated with a traditional (retrospective) meta-analysis. PMAs have many advantages: they can help reduce research waste and bias, and they are adaptive, efficient, and collaborative. Despite an increase in the number of health research articles labelled as PMAs, the methodology remains rare, novel, and often misunderstood. This paper provides detailed guidance on how to address the key elements for conducting a high quality PMA with a case study to illustrate each step.
Berlin and Golub talk about seeking out the best evidence that addresses prevention or treatment question. One dogma argues that it is the best-conducted randomized clinical trial (RCT) comprising ...patients similar to those seen by the clinician, reasoning that a well-done RCT mimics pure experimental conditions better than any other study design, hence minimizing the likelihood of confounding. A counter-argument is that the best evidence is a systematic review with meta-analysis, because this approach can integrate all of the relevant evidence and provide a more reliable answer than a single study, however well conducted.
Aims
Sodium glucose co‐transporter 2 inhibitors (SGLT2i) are indicated for treatment of type 2 diabetes mellitus (T2DM); some SGLT2i have reported cardiovascular benefit, and some have reported risk ...of below‐knee lower extremity (BKLE) amputation. This study examined the real‐world comparative effectiveness within the SGLT2i class and compared with non‐SGLT2i antihyperglycaemic agents.
Materials and methods
Data from 4 large US administrative claims databases were used to characterize risk and provide population‐level estimates of canagliflozin's effects on hospitalization for heart failure (HHF) and BKLE amputation vs other SGLT2i and non‐SGLT2i in T2DM patients. Comparative analyses using a propensity score–adjusted new‐user cohort design examined relative hazards of outcomes across all new users and a subpopulation with established cardiovascular disease.
Results
Across the 4 databases (142 800 new users of canagliflozin, 110 897 new users of other SGLT2i, 460 885 new users of non‐SGLT2i), the meta‐analytic hazard ratio estimate for HHF with canagliflozin vs non‐SGLT2i was 0.39 (95% CI, 0.26‐0.60) in the on‐treatment analysis. The estimate for BKLE amputation with canagliflozin vs non‐SGLT2i was 0.75 (95% CI, 0.40‐1.41) in the on‐treatment analysis and 1.01 (95% CI, 0.93‐1.10) in the intent‐to‐treat analysis. Effects in the subpopulation with established cardiovascular disease were similar for both outcomes. No consistent differences were observed between canagliflozin and other SGLT2i.
Conclusions
In this large comprehensive analysis, canagliflozin and other SGLT2i demonstrated HHF benefits consistent with clinical trial data, but showed no increased risk of BKLE amputation vs non‐SGLT2i. HHF and BKLE amputation results were similar in the subpopulation with established cardiovascular disease. This study helps further characterize the potential benefits and harms of SGLT2i in routine clinical practice to complement evidence from clinical trials and prior observational studies.
High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and ...quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.
In alignment with the International Council of Harmonization’s strategic goals, a public-private consortium has developed a structured template for planning and reporting on the implementation of ...real world evidence (RWE) studies of the safety and effectiveness of treatments. The template serves as a guiding tool for designing and conducting reproducible RWE studies; set clear expectations for transparent communication of RWE methods; reduce misinterpretation of prose that lacks specificity; allow reviewers to quickly orient and find key information; and facilitate reproducibility, validity assessment, and evidence synthesis. The template is intended for use with studies of the effectiveness and safety of medical products and is compatible with multiple study designs, data sources, reporting guidelines, checklists, and bias assessment tools.
IntroductionThe efficacy of pharmaceuticals is most often demonstrated by randomised controlled trials (RCTs); however, in some cases, regulatory applications lack RCT evidence.ObjectiveTo ...investigate the number and type of these approvals over the past 15 years by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).MethodsDrug approval data were downloaded from the EMA website and the ‘Drugs@FDA’ database for all decisions on pharmaceuticals published from 1 January 1999 to 8 May 2014. The details of eligible applications were extracted, including the therapeutic area, type of approval and review period.ResultsOver the period of the study, 76 unique indications were granted without RCT results (44 by the EMA and 60 by the FDA), demonstrating that a substantial number of treatments reach the market without undergoing an RCT. The majority was for haematological malignancies (34), with the next most common areas being oncology (15) and metabolic conditions (15). Of the applications made to both agencies with a comparable data package, the FDA granted more approvals (43/44 vs 35/44) and took less time to review products (8.7 vs 15.5 months). Products reached the market first in the USA in 30 of 34 cases (mean 13.1 months) due to companies making FDA submission before EMA submissions and faster FDA review time.DiscussionDespite the frequency with which approvals are granted without RCT results, there is no systematic monitoring of such treatments to confirm their effectiveness or consistency regarding when this form of evidence is appropriate. We recommend a more open debate on the role of marketing authorisations granted without RCT results, and the development of guidelines on what constitutes an acceptable data package for regulators.
Aims
To examine the incidence of amputation in patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose co‐transporter 2 (SGLT2) inhibitors overall, and canagliflozin specifically, ...compared with non‐SGLT2 inhibitor antihyperglycaemic agents (AHAs).
Materials and Methods
Patients with T2DM newly exposed to SGLT2 inhibitors or non‐SGLT2 inhibitor AHAs were identified using the Truven MarketScan database. The incidence of below‐knee lower extremity (BKLE) amputation was calculated for patients treated with SGLT2 inhibitors, canagliflozin, or non‐SGLT2 inhibitor AHAs. Patients newly exposed to canagliflozin and non‐SGLT2 inhibitor AHAs were matched 1:1 on propensity scores, and a Cox proportional hazards model was used for comparative analysis. Negative controls (outcomes not believed to be associated with any AHA) were used to calibrate P values.
Results
Between April 1, 2013 and October 31, 2016, 118 018 new users of SGLT2 inhibitors, including 73 024 of canagliflozin, and 226 623 new users of non‐SGLT2 inhibitor AHAs were identified. The crude incidence rates of BKLE amputation were 1.22, 1.26 and 1.87 events per 1000 person‐years with SGLT2 inhibitors, canagliflozin and non‐SGLT2 inhibitor AHAs, respectively. For the comparative analysis, 63 845 new users of canagliflozin were matched with 63 845 new users of non‐SGLT2 inhibitor AHAs, resulting in well‐balanced baseline covariates. The incidence rates of BKLE amputation were 1.18 and 1.12 events per 1000 person‐years with canagliflozin and non‐SGLT2 inhibitor AHAs, respectively; the hazard ratio was 0.98 (95% confidence interval 0.68–1.41; P = .92, calibrated P = .95).
Conclusions
This real‐world study observed no evidence of increased risk of BKLE amputation for new users of canagliflozin compared with non‐SGLT2 inhibitor AHAs in a broad population of patients with T2DM.
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