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Inferential reproducibility of therapeutic research: a registered report for a cross-sectional study of RCTs available on major data-sharing platforms

Inferential reproducibility of therapeutic research: a registered report for a cross-sectional study of RCTs available on major data-sharing platforms

Florian Naudet

Psychiatrist at CHU Rennes and Professor at Université de Rennes 1

12 May 2022

Ideally, the public and scientists feel more confident when the methods and results of scientific experiments can be reproduced. However, there are growing concerns about findings that cannot be reproduced. As a result, scientists have launched certain reproducibility initiatives. The existence and extent of reproducibility problems in the field of biomedical research is still unknown and few studies have attempted to answer the question. An empirical analysis suggests that only a small number of re-analyses of RCTs have been published to date; of these, only a minority were conducted by entirely independent authors, showing the limitations in the verification of findings and the lack of available data or metadata. Nevertheless, attempts to reproduce medical studies are often costly and difficult to perform. This is especially true for RCTs, although these studies are expensive and typically of major importance in providing information on health practices and policies.This independent reanalysis is carried out to estimate the reproducibility of the conclusions, which means that the objective is not necessarily to reproduce the same analytical methods or the same numerical results but to see whether, using only the original study protocol and data, it would be possible to find a clinically meaningful equivalence between the reanalysis and the original analysis. This study will include RCTs identified on 4 repositories. Eligible RCTs will be Phase III studies conducted in the field of therapeutics. 62 of these studies will be randomly sampled and analyzed.The results of this project are expected to have a direct impact on the medical community and patients as they are usually more confident and willing to participate in clinical research when they know that results of trials are reproducible. The project will inform decision-makers of the usefulness and feasibility of large-scale data-sharing policies. It will also give indications to clinicians about the strength of the evidence they rely on to treat patients in their day-to-day practice. This study will in the future trigger efforts to produce good-practice guidelines for data-sharing. Reports on RCTs are highly influential for clinical medicine and there is currently a growing interest in sharing their results; in addition, patients support data-sharing. In case of a divergent re-analysis, we will advise the authors or sponsors of the trial. Should exchanges with the authors prove impossible or not offer enough information to explain the reason for non-reproducibility, we will then inform the editors of the journals where the findings were published and/or the health authority in charge of the approval. The results will be published in a biomedical peer-reviewed journal. We have already submitted a registered report that has received in principal acceptance by Royal Society Open Science.Since reproducibility is an important property in the scientific process, good inferential reproducibility will probably be considered an important characteristic of a well-conducted study. By tackling data-sharing practices and their usefulness, we hope to enhance the awareness of scientists, editors,and funders towards these crucial, strategic issues and to advance the development of data sharing policies and practices that maximize the use of best research practices. We hope that our study will initiate RCT in a way that data sharing and reproducibility are calculated into the design from the beginning.This registered report is part of a wider project called “Reproducibility in Therapeutic Research”, funded by the French National Agency of Research and is part of the context of a growing interest in data sharing and reproducibility. Besides the proposed project, we will run parallel a project which aims to explore the reproducibility of trials used for decision-making on Marketing Authorizations for new medicines in the European Medicine Agency.

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Using Tiotropium (18 Mcg o.d.) as an Active Control in Japanese Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)" },{ "PostingID": 16159, "Title": "NOVARTIS-CRAD001Y2301", "Description": "A Randomized Double-Blind, Placebo-Controlled Study of Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole" },{ "PostingID": 19553, "Title": "GSK-208127/084 (HAB-084)", "Description": "An open, randomised study to compare the immunogenicity, safety and reactogenicity of SmithKline Beecham combined hepatitis A/hepatitis B vaccine Twinrix administered following a 2 dose schedule (0-6 mths) to that of Twinrix. Junior administered following a 3 dose schedule (0, 1, 6 months) in healthy volunteers aged 12-15 years" },{ "PostingID": 19836, "Title": "GSK-200147", "Description": "Safety and immunogenicity study of 2 formulations of GSK Biologicals’ varicella vaccines given as a 2-dose course in the second year of life." },{ "PostingID": 20113, "Title": "NOVARTIS-CBYM338B2203", "Description": "A randomized, double-blind, placebo-controlled, multicenter, parallel group, dose-finding, pivotal, Phase 2b/3 study to evaluate the efficacy, safety, and tolerability of intravenous BYM338 at 52 weeks on physical function, muscle strength, and mobility and additional long term safety up to 2 years in patients with sporadic inclusion body myositis" }]

Statistical Analysis Plan