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.

Regulatory and operational challenges in conducting Asian International Academic Trial for expanding the indications of cancer drugs.

There are many differences between Asian regions in terms of the regulatory requirements and operational procedures in conducting international academic clinical trials for the approval of new drugs. The National Cancer Center Hospital in Japan has launched an international investigator-initiated registration-directed trial (IIRDT) in Japan, Korea, Taiwan, and Singapore, aiming at obtaining pharmaceutical approval in participating regions. Differences in regulatory and operational procedures were identified while coordinating the trial. In Japan, regulatory authority reviews should be performed after approval by institutional review boards for IIRDT, whereas in other regions these can be done in parallel. There were disparities in Good Manufacturing Practice-related documents between regions. Several differences were found regarding investigational product (IP) management, specifically concerning labeling, import/export procedures, and customs clearance costs. On the other hand, safety reporting procedures were relatively well-harmonized in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH-E2A). Regions also differed in per-patient costs, due to varying regulations for academic registration-directed trials. In conclusion, the observed differences among Asian regions should be harmonized to facilitate international academic trials in Asia and thus resolve unmet patient needs worldwide. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? International clinical trials have become common because they make it possible to accrue patients faster and obtain new drug approval in wider areas. However, pharmaceutical regulatory differences hinder the efficient conduct of international clinical trials, especially in academia. WHAT QUESTION DID THIS STUDY ADDRESS? We conducted an academic international clinical trial on new drug applications in four Asian countries and clarified pharmaceutical regulatory differences and operational difficulties. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study identified differences between countries in terms of regulatory affairs, institutional review board (IRB) review processes, investigational new drug (IND) dossiers, investigational product (IP) management procedures, and clinical trial costs, while safety reporting procedures were relatively harmonized. Japan utilizes investigator-initiated registration-directed trials, an advanced regulatory system for new drug application by academia, but the other countries do not. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Harmonization of pharmaceutical regulations and trial initiation procedures, and regulatory reform of clinical trial costs are important to accelerate academic international clinical trials for new drug applications.

An under-represented and underserved population in trials: methodological, structural, and systemic barriers to the inclusion of adults lacking capacity to consent.

BACKGROUND: There is increasing international recognition that populations included in trials should adequately represent the population treated in clinical practice; however, adults who lack the capacity to provide informed consent are frequently excluded from trials. Addressing the under-representation of groups such as those with impaired capacity to consent is essential to develop effective interventions and provide these groups with the opportunity to benefit from evidence-based care. While the spotlight has been on ensuring only appropriate and justifiable exclusion criteria are used in trials, barriers to the inclusion of adults lacking capacity are multifactorial and complex, and addressing their under-representation will require more than merely widening eligibility criteria. This commentary draws on the literature exploring the inclusion of adults lacking the capacity to consent in research and a number of recent studies to describe the methodological, structural, and systemic factors that have been identified. MAIN TEXT: A number of potentially modifiable factors contributing to the under-representation of adults lacking the capacity to consent in trials have been identified. In addition to restrictive eligibility criteria, methodological issues include developing appropriate interventions and outcome measures for populations with impaired capacity. Structurally determined factors include the resource-intensive nature of these trials, the requirement for more appropriate research infrastructure, and a lack of interventions to inform and support proxy decision-makers. Systemic factors include the complexities of the legal frameworks, the challenges of ethical review processes, and paternalistic attitudes towards protecting adults with incapacity from the perceived harms of research. CONCLUSIONS: Measures needed to address under-representation include greater scrutiny of exclusion criteria by those reviewing study proposals, providing education and training for personnel who design, conduct, and review research, ensuring greater consistency in the reviews undertaken by research ethics committees, and extending processes for advance planning to include prospectively appointing a proxy for research and documenting preferences about research participation. Negative societal and professional attitudes towards the inclusion of adults with impaired capacity in research should also be addressed, and the development of trials that are more person-centred should be encouraged. Further work to conceptualise under-representation in trials for such populations may also be helpful.

Confronting the Multidimensional Challenges of Research in the Context of Emerging Infectious Diseases in Brazil: The Example of Yellow Fever.

In the most recent Brazilian yellow fever (YF) outbreak, a group of clinicians and researchers initiated in mid-January 2018 a considerable effort to develop a multicenter randomized controlled clinical trial to evaluate the effect of sofosbuvir on YF viremia and clinical outcomes (Brazilian Clinical Trials Registry: RBR-93dp9n). The approval of this protocol had urgency given the seasonal/short-lived pattern of YF transmission, large number of human cases, and epidemic transmission at the outskirts of a large urban center. However, many intricacies in the research regulatory and ethical submission systems in Brazil were indomitable even under such pressing conditions. By April 2018, we had enrolled 29 patients for a target sample size of 90 participants. Had enrollment been initiated 3 weeks earlier, an additional 31 patients could have been enrolled, reaching the prespecified sample size for the interim analysis. This recent experience highlights the urgent need to improve local preparedness for research in the setting of explosive outbreaks, as has been seen in the last few years in different countries.

Participants' written informed consent in low-risk pragmatic clinical trials with medicines.

Introduction: An important gap within modern medicine is the lack of enough comparative effectiveness research of marketed medicines. Low-risk pragmatic randomized controlled trials (pRCTs) are those conducted resembling usual clinical practice that poses no or minimal incremental risk compared with normal clinical practice.Areas covered: This review addresses one important hurdle in the conduct of low-risk pRCTs: the need to seek participants' written informed consent.Expert opinion: The CIOMS ethical guidelines consider that any research that (a) would not be feasible or practicable to carry out without the waiver or modification, (b) has important social value, and (c) poses no more than minimal risks to participants, and that is approved by the relevant research ethics committee, could be conducted without participants' consent. It is clear that these provisions are applicable to some low-risk RCTs. Recently a research on the EU-CTR registry showed that only 2% of all ongoing phase 4 RCTs could have fulfilled the CIOMS provisions following the investigators' assessment. The EU clinical trial regulation - and that of other jurisdictions - should be debated on the suitableness of the conduct with an alteration or waiver of participants' consent of those low-risk pRCTs that fulfill the three CIOMS provisions.

Master Protocol Trial Design for Efficient and Rational Evaluation of Novel Therapeutic Oncology Devices.

Historically, the gold standard for evaluation of cancer therapeutics, including medical devices, has been the randomized clinical trial. Although high-quality clinical data are essential for safe and judicious use of therapeutic oncology devices, class II devices require only preclinical data for US Food and Drug Administration approval and are often not rigorously evaluated prior to widespread uptake. Herein, we review master protocol design in medical oncology and its application to therapeutic oncology devices, using examples from radiation oncology. Unique challenges of clinical testing of radiation oncology devices (RODs) include patient and treatment heterogeneity, lack of funding for trials by industry and health-care payers, and operator dependence. To address these challenges, we propose the use of master protocols to optimize regulatory, financial, administrative, quality assurance, and statistical efficiency of trials evaluating RODs. These device-specific master protocols can be extrapolated to other devices and encompass multiple substudies with the same design, statistical considerations, logistics, and infrastructure. As a practical example, we outline our phase I and II master protocol trial of stereotactic magnetic resonance imaging-guided adaptive radiotherapy, which to the best of our knowledge is the first master protocol trial to test a ROD. Development of more efficient clinical trials is needed to promote thorough evaluation of therapeutic oncology devices, including RODs, in a resource-limited environment, allowing more practical and rapid identification of the most valuable advances in our field.

Nonrandomized Real-World Evidence to Support Regulatory Decision Making: Process for a Randomized Trial Replication Project.

Recent legislation mandates that the US Food and Drug Administration issue guidance regarding when real-world evidence (RWE) could be used to support regulatory decision making. Although RWE could come from randomized or nonrandomized designs, there are significant concerns about the validity of RWE assessing medication effectiveness based on nonrandomized designs. We propose an initiative using healthcare claims data to assess the ability of nonrandomized RWE to provide results that are comparable with those from randomized controlled trials (RCTs). We selected 40 RCTs, and we estimate that approximately 30 attempted replications will be completed after feasibility analyses. We designed an implementation process to ensure that each attempted replication is consistent, transparent, and reproducible. This initiative is the first to systematically evaluate the ability of nonrandomized RWE to replicate multiple RCTs using a structured process. Results from this study should provide insight on the strengths and limitations of using nonrandomized RWE from claims for regulatory decision making.

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.

Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1 randomized clinical trial as an example.

Regulatory guidelines describe the use of estimands in designing and conducting clinical trials. Estimands ensure alignment of the objectives with the design, conduct and analysis of a trial. An estimand is defined by four inter-related attributes: the population of interest, the variable (endpoint) of interest, the way intercurrent events are handled and the population level summary. A trial may employ multiple estimands to evaluate treatment effects from different perspectives in order to address different scientific questions. As estimands may be an unfamiliar concept for many clinicians treating diabetes, this paper reviews the estimand concept and uses the PIONEER 1 phase 3a clinical trial, which investigated the efficacy and safety of oral semaglutide vs placebo, as an example of the way in which estimands can be implemented and interpreted. In the PIONEER 1 trial, two estimands were employed for each efficacy endpoint and were labelled as: (a) the treatment policy estimand, used to assess the treatment effect regardless of use of rescue medication or discontinuation of trial product, and provides a broad perspective of the treatment effect in the population of patients with type 2 diabetes in clinical practice; and (b) the trial product estimand, used to assess the treatment effect if all patients had continued to use trial product for the planned duration of the trial without rescue medication, thereby providing information on the anticipated treatment effect of the medication. Both approaches are complementary to understanding the effect of the studied treatments.

A limited number of medicines pragmatic trials had potential for waived informed consent following the 2016 CIOMS ethical guidelines.

OBJECTIVES: European regulations do not allow modification or waiver of informed consent for medicines randomized controlled trials (RCTs) where the three 2016 Council for International Organizations of Medical Sciences (CIOMS) provisions are met (consent would be impractical or unfeasible, yet the trial would have high social value and pose no or minimal risk to participants). We aimed to identify whether any such trials of medicines were being conducted in Europe. STUDY DESIGN AND SETTING: This is a survey of all phase 4 "ongoing" RCTs on the EU clinical trial register between July 1, 2016 and June 30, 2018, to identify those with potentially high levels of pragmatism. Trials that were excluded were as follows: those conducted on rare diseases; conducted on healthy volunteers (except those assessing vaccines); masked (single-, double-blind) trials; single-center trials; those where one could expect to lead patients to prefer one intervention over the other; and miscellaneous reasons. The degree of pragmatism of the RCTs was self-assessed by trials' investigators by means of the PRECIS-2 tool. Investigators of those trials considered to be highly pragmatic assessed the fulfillment of the three CIOMS provisions. Seven patients assessed the social value of the RCTs. Finally, 33 members of 11 research ethics committees (RECs) assessed the social value of the trials and whether they posed no more than minimal risk to participants. Investigators, patients, and REC members assessed the fulfillment of the CIOMS provisions as "yes," "not sure" or "no." RESULTS: Of the 638 phase 4 trials, 420 were RCTs, and 21 of these (5%) were candidates to be pragmatic. Investigators of 15 of these 21 RCTs self-assessed their trial's degree of pragmatism: 14 were highly pragmatic. Of these 14, eight fulfilled the three CIOMS provisions. Assessments by patients and RECs were inconsistent for several trials. CONCLUSIONS: We found few low-risk participant-level pragmatic RCTs that could be suitable for modified or waived participants' informed consent. European regulators should consider amending the current regulation and encouraging the conduct of such trials.

Objecting to experiments that compare two unobjectionable policies or treatments.

Randomized experiments have enormous potential to improve human welfare in many domains, including healthcare, education, finance, and public policy. However, such "A/B tests" are often criticized on ethical grounds even as similar, untested interventions are implemented without objection. We find robust evidence across 16 studies of 5,873 participants from three diverse populations spanning nine domains-from healthcare to autonomous vehicle design to poverty reduction-that people frequently rate A/B tests designed to establish the comparative effectiveness of two policies or treatments as inappropriate even when universally implementing either A or B, untested, is seen as appropriate. This "A/B effect" is as strong among those with higher educational attainment and science literacy and among relevant professionals. It persists even when there is no reason to prefer A to B and even when recipients are treated unequally and randomly in all conditions (A, B, and A/B). Several remaining explanations for the effect-a belief that consent is required to impose a policy on half of a population but not on the entire population; an aversion to controlled but not to uncontrolled experiments; and a proxy form of the illusion of knowledge (according to which randomized evaluations are unnecessary because experts already do or should know "what works")-appear to contribute to the effect, but none dominates or fully accounts for it. We conclude that rigorously evaluating policies or treatments via pragmatic randomized trials may provoke greater objection than simply implementing those same policies or treatments untested.

Research involving adults lacking capacity to consent: a content analysis of participant information sheets for consultees and legal representatives in England and Wales.

BACKGROUND: Research involving adults who lack the capacity to provide informed consent can be challenging. In England and Wales there are legal provisions for consulting with others who know the person with impaired capacity. The role of the 'proxy' (or 'surrogate') is to advise researchers about the person's wishes and feelings or to provide consent on the person's behalf for a clinical trial of a medicine. Information about the study is usually provided to the proxy; however, little information is available to proxies about their role, or the appropriate legal and ethical basis for their decision, to help inform their decision-making. The aim of this study was to analyse the written information that is provided to consultees and legal representatives. METHODS: Studies including adults lacking capacity to consent which utilised consultees or legal representatives were identified using the UK Clinical Trials Gateway database. A representative sample (n = 30) were randomly selected. Information sheets and other study documents provided to proxies were obtained, and relevant content was extracted. Content analysis was conducted through four stages: decontextualisation of the unit of analysis, recontextualisation, categorisation, and compilation. The data were summarised narratively according to each theme and category. RESULTS: Considerable variation was found in the written information sheets provided to proxies. Most directed proxies to consider the wishes and feelings of the person who lacked capacity and to consult with others during the decision-making process. However, a small number of studies extended the scope of the proxy's role to consider the person's suitability or eligibility for the study. Particular discrepancies were found in information provided to those acting as consultees or legal representatives in a professional, as opposed to a personal, capacity. Incorrect uses of terminology were frequently found, and a small number of studies inaccurately interpreted the law. CONCLUSIONS: Despite undergoing ethical review, study documents lacked essential information, incorrectly used terminology, and conflated professionals' clinical and representation roles. Future recommendations include ensuring proxies are provided with adequate and accurate information which complies with the legal frameworks. Further research is needed to explore the information and decision-making needs of those acting as consultees and legal representatives.

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.