Lawmakers' use of scientific evidence can be improved.

Core to the goal of scientific exploration is the opportunity to guide future decision-making. Yet, elected officials often miss opportunities to use science in their policymaking. This work reports on an experiment with the US Congress-evaluating the effects of a randomized, dual-population (i.e., researchers and congressional offices) outreach model for supporting legislative use of research evidence regarding child and family policy issues. In this experiment, we found that congressional offices randomized to the intervention reported greater value of research for understanding issues than the control group following implementation. More research use was also observed in legislation introduced by the intervention group. Further, we found that researchers randomized to the intervention advanced their own policy knowledge and engagement as well as reported benefits for their research following implementation.

Evidence Supporting the Value of Surgical Procedures: Can We Do Better?

There is an acknowledged need for higher-quality evidence to quantify the benefit of surgical procedures, yet not enough has been done to improve the evidence base. This lack of evidence can prevent fully informed decision-making, lead to unnecessary or even harmful treatment, and contribute to wasteful expenditures of scare health care resources. Barriers to evidence generation include not only the long-recognized technical difficulties and ethical challenges of conducting randomized surgical trials, but also legal challenges that limit incentives to conduct surgical research as well as market-based challenges that make it difficult for those funding surgical research to recoup investment costs. These legal and market dynamics differ substantially from those surrounding new drug or device development. Nevertheless, obstacles could be overcome and overall expenditures could be reduced if a share of federal health care agency budgets were reallocated to generating randomized trial data, standardizing outcome measures, and conducting observational studies analogous to those that have been facilitated for drugs via the Food and Drug Administration's Sentinel Initiative. Until better quality evidence is available, ethical principles require adequate disclosure of the limited evidence base supporting current surgical procedures.

European Medicines Agency's Priority Medicines Scheme at 2 Years: An Evaluation of Clinical Studies Supporting Eligible Drugs.

The Priority Medicines (PRIME) scheme was launched by the European Medicines Agency (EMA) in 2016 to expedite the development and approval of promising products targeting conditions with high unmet medical need. Manufacturers of PRIME drugs receive extensive regulatory advice on their trial designs. Until June 2018, the EMA granted PRIME status to 39 agents, evaluated in 138 studies (102 initiated before and 36 after PRIME eligibility). A third of the studies forming the basis of PRIME designation were randomized controlled trials, and a quarter of the studies were blinded. There was no statistically significant difference between trials initiated before and after PRIME designation in terms of randomized design and use of blinding. However, significantly more efficacy studies included a clinical end point after PRIME designation than before, and significantly fewer included surrogate measures alone. There were no statistically significant differences between the trial designs of PRIME and non-PRIME-designated products.

Issues, challenges, and the way forward in conducting clinical trials among neonates: investigators' perspective.

Clinical trials are essential to test the safety and efficacy of new treatments in any population. The paucity of drug trials especially in the neonatal population has led to the widespread use of unlicensed or off-label medications, exposing them to the risks of drug toxicity and ineffective treatment. Ethical and operational challenges are no longer considered valid excuses for not conducting drug trials in neonates. We recently participated in a combined phase-2 and phase-3 trial investigating a new indigenous goat lung surfactant extract (GLSE) for the treatment of respiratory distress syndrome (RDS) in preterm neonates. In this article, we share pertinent challenges faced by us during the trial to better inform and foster-positive discussion among drug developers, administrators, regulatory authorities, patient advocacy groups, and researchers. Also, we provide many tools developed for the GLSE trial that can be modified and used by prospective trialists.

Data Rich, Information Poor: Can We Use Electronic Health Records to Create a Learning Healthcare System for Pharmaceuticals?

Judicious use of real-world data (RWD) is expected to make all steps in the development and use of pharmaceuticals more effective and efficient, including research and development, regulatory decision making, health technology assessment, pricing, and reimbursement decisions and treatment. A "learning healthcare system" based on electronic health records and other routinely collected data will be required to harness the full potential of RWD to complement evidence based on randomized controlled trials. We describe and illustrate with examples the growing demand for a learning healthcare system; we contrast the exigencies of an efficient pharmaceutical ecosystem in the future with current deficiencies highlighted in recently published Organisation for Economic Co-operation and Development (OECD) reports; and we reflect on the steps necessary to enable the transition from healthcare data to actionable information. A coordinated effort from all stakeholders and international cooperation will be required to increase the speed of implementation of the learning healthcare system, to everybody's benefit.

Financial management of large, multi-center trials in a challenging funding milieu.

BACKGROUND: Randomized clinical trials that have public health implications but no or low potential for commercial gain are predominantly funded by governmental (e.g., National Institutes of Health (NIH)) and not-for-profit organizations. Our objective was to develop an alternative clinical trial site funding model for judicious allocation of declining public research funds. METHODS: In the Vitamin D and Type 2 Diabetes (D2d) study, an NIH-supported, large clinical trial testing the effect of vitamin D supplementation on incident diabetes in 2423 participants at high risk for diabetes, a hybrid financial management model for supporting collaborating clinical sites was developed and applied. The funding model employed two reimbursement components: Core (for study start-up and partial efforts throughout the study, ~40% of the total site budget), invoiced by sites, and Performance-Based Payments (for successful enrollment of participants and completion of follow-up visits, ~60% of the total site budget), automatically issued to the sites by the Coordinating Center based on actual recruitment and visits conducted. Underperforming sites transitioned to Performance-Based Payments only. RESULTS: Recruitment occurred from October 2013 through December 2016, requiring one additional year than the 2-year projection. Median enrollment at each site was 88 participants (range 29-318; 20 to 205% of the site target). At the end of year 1, study-wide recruitment was at 12% of the target (vs. 50% projected) and 12% of the total grant award was invested. The model constantly evaluated sites' needs and re-allocated resources to meet the study enrollment goal. If D2d had issued cost reimbursement subaward agreements and sites invoiced for their entire budget, 83% of the award would have been spent for all study activities over the first 4 years of the trial compared to 65% of the award spent (US$26M) under the hybrid model used by D2d. CONCLUSIONS: It is feasible to foster a hybrid financial management approach to steward limited available public funds for research in a dynamic and consistent way that does not compromise the trial's scientific integrity and ensures conservation of funds to complete recruitment and continue to follow up participants.

The More Things Change, the More They Stay the Same: A Study to Evaluate Compliance With Inclusion and Assessment of Women and Minorities in Randomized Controlled Trials.

PURPOSE: The National Institutes of Health (NIH) Revitalization Act of 1993 requires NIH-funded clinical trials to include women and minorities as participants and assess outcomes by sex and race or ethnicity. The objective of this study was to investigate current levels of compliance with these guidelines for inclusion, analysis, and reporting in NIH-funded randomized controlled trials (RCTs) and compare the results with those from 2009 and 2004, which the authors reported previously. METHOD: The authors identified 782 RCTs published in 14 leading U.S. medical journals in 2015 with a PubMed search. Of those, 142 were the primary report of an NIH-funded RCT, conducted in the United States, and eligible for analysis. The authors reviewed abstract, text, and tables of each eligible study as well as any follow-up published commentary to determine compliance with NIH guidelines. RESULTS: Thirty-five studies limited enrollment to one sex. The median enrollment of women in the remaining 107 studies was 46%, but 16 (15.0%) enrolled less than 30% women. Twenty-eight of the 107 (26%) reported at least one outcome by sex or explicitly included sex as a covariate in statistical analysis. Of the 142 studies, 19 (13.4%) analyzed or reported outcomes by race or ethnicity. There were no statistically significant changes in inclusion, analysis, or reporting by sex, race, or ethnicity compared with the previous studies. CONCLUSIONS: NIH policies have not resulted in significant increases in reporting results by sex, race, or ethnicity. The authors recommend strong journal policies to increase compliance with NIH policies.

Barriers to the conduct of randomised clinical trials within all disease areas.

BACKGROUND: Randomised clinical trials are key to advancing medical knowledge and to enhancing patient care, but major barriers to their conduct exist. The present paper presents some of these barriers. METHODS: We performed systematic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. RESULTS: The following barriers to randomised clinical trials were identified: inadequate knowledge of clinical research and trial methodology; lack of funding; excessive monitoring; restrictive privacy law and lack of transparency; complex regulatory requirements; and inadequate infrastructures. There is a need for more pragmatic randomised clinical trials conducted with low risks of systematic and random errors, and multinational cooperation is essential. CONCLUSIONS: The present paper presents major barriers to randomised clinical trials. It also underlines the value of using a pan-European-distributed infrastructure to help investigators overcome barriers for multi-country trials in any disease area.

Regulatory Considerations of Bioequivalence Studies for Oral Solid Dosage Forms in Japan.

Bioequivalence (BE) studies are used to infer the therapeutic equivalence of generic drug products to original drug products throughout the world. In BE studies, bioavailability (BA) should be compared between the original and generic drug products, with BA defined as the rate and extent of absorption of active pharmaceutical ingredients or active metabolites from a product into the systemic circulation. For most of BE studies conducted during generic drug development, BA comparisons are performed in single-dose studies. In Japan, the revised "Guideline for Bioequivalence Studies of Generic Products" was made available in 2012 by the Ministry of Health, Labour, and Welfare, and generic drug development is currently conducted based on this guideline. Similarly, the U.S. Food and Drug Administration and European Medicines Agency have published guidance and guideline on generic drug development. This article introduces the guideline on Japanese BE studies for oral solid dosage forms and the dissolution tests for the similarity and equivalence evaluation between the original and generic drug products. Additionally, we discuss some of the similarities and differences in guideline between Japan, the United States, and the European Union.

The Risks to Patient Privacy from Publishing Data from Clinical Anesthesia Studies.

In this article, we consider the privacy implications of posting data from small, randomized trials, observational studies, or case series in anesthesia from a few (e.g., 1-3) hospitals. Prior to publishing such data as supplemental digital content, the authors remove attributes that could be used to re-identify individuals, a process known as "anonymization." Posting health information that has been properly "de-identified" is assumed to pose no risks to patient privacy. Yet, computer scientists have demonstrated that this assumption is flawed. We consider various realistic scenarios of how the publication of such data could lead to breaches of patient privacy. Several examples of successful privacy attacks are reviewed, as well as the methods used. We survey the latest models and methods from computer science for protecting health information and their application to posting data from small anesthesia studies. To illustrate the vulnerability of such published data, we calculate the "population uniqueness" for patients undergoing one or more surgical procedures using data from the State of Texas. For a patient selected uniformly at random, the probability that an adversary could match this patient's record to a unique record in the state external database was 42.8% (SE < 0.1%). Despite the 42.8% being an unacceptably high level of risk, it underestimates the risk for patients from smaller states or provinces. We propose an editorial policy that greatly reduces the likelihood of a privacy breach, while supporting the goal of transparency of the research process.

Randomised trials in context: practical problems and social aspects of evidence-based medicine and policy.

Randomised trials can provide excellent evidence of treatment benefit in medicine. Over the last 50 years, they have been cemented in the regulatory requirements for the approval of new treatments. Randomised trials make up a large and seemingly high-quality proportion of the medical evidence-base. However, it has also been acknowledged that a distorted evidence-base places a severe limitation on the practice of evidence-based medicine (EBM). We describe four important ways in which the evidence from randomised trials is limited or partial: the problem of applying results, the problem of bias in the conduct of randomised trials, the problem of conducting the wrong trials and the problem of conducting the right trials the wrong way. These problems are not intrinsic to the method of randomised trials or the EBM philosophy of evidence; nevertheless, they are genuine problems that undermine the evidence that randomised trials provide for decision-making and therefore undermine EBM in practice. Finally, we discuss the social dimensions of these problems and how they highlight the indispensable role of judgement when generating and using evidence for medicine. This is the paradox of randomised trial evidence: the trials open up expert judgment to scrutiny, but this scrutiny in turn requires further expertise.

Logistic, ethical, and political dimensions of stepped wedge trials: critical review and case studies.

BACKGROUND: Three arguments are usually invoked in favour of stepped wedge cluster randomised controlled trials: the logistic convenience of implementing an intervention in phases, the ethical benefit of providing the intervention to all clusters, and the potential to enhance the social acceptability of cluster randomised controlled trials. Are these alleged benefits real? We explored the logistic, ethical, and political dimensions of stepped wedge trials using case studies of six recent evaluations. METHODS: We identified completed or ongoing stepped wedge evaluations using two systematic reviews. We then purposively selected six with a focus on public health in high, middle, and low-income settings. We interviewed their authors about the logistic, ethical, and social issues faced by their teams. Two authors reviewed interview transcripts, identified emerging issues through qualitative thematic analysis, reflected upon them in the context of the literature, and invited all participants to co-author the manuscript. RESULTS: Our analysis raises three main points. First, the phased implementation of interventions can alleviate problems linked to simultaneous roll-out, but also brings new challenges. Issues to consider include the feasibility of organising intervention activities according to a randomised sequence, estimating time lags in implementation and effects, and accommodating policy changes during the trial period. Second, stepped wedge trials, like parallel cluster trials, require equipoise: without it, randomising participants to a control condition, even for a short time, remains problematic. In stepped wedge trials, equipoise is likely to lie in the degree of effect, effectiveness in a specific operational milieu, and the balance of benefit and harm, including the social value of better evaluation. Third, the strongest arguments for a stepped wedge design are logistic and political rather than ethical. The design is advantageous when simultaneous roll-out is impractical and when it increases the acceptability of using counterfactuals. CONCLUSIONS: The logistic convenience of phased implementation is context-dependent, and may be vitiated by the additional requirements of phasing. The potential for stepped wedge trials to enhance the social acceptability of cluster randomised trials is real, but their ethical legitimacy still rests on demonstrating equipoise and its configuration for each research question and setting.