Robert M. Califf's research while affiliated with University of California, San Francisco and other places
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Publications (807)
Importance
Randomized clinical trials (RCTs) are critical in advancing patient care, yet conducting such large-scale trials requires tremendous resources and coordination. Clinical site start-up performance metrics can provide insight into opportunities for improved trial efficiency but have not been well described.
Objective
To measure the start-...
The economic, social, and political challenges facing rural areas in the US have implications for the entire country. Even though rural-urban disparities in mortality from such diseases as chronic lung disease and cardiovascular disease have been described,¹,2 less is known about recent trends in rural-urban differences in age-adjusted mortality ra...
Introduction
In the 2016 U.S. Presidential election, voters in communities with recent stagnation or decline in life expectancy were more likely to vote for the Republican candidate than in prior Presidential elections. We aimed to assess the association between change in life expectancy and voting patterns in the 2020 Presidential election.
Metho...
The laws and policies for informed consent and other aspects of participant safety in clinical trials receive considerable attention. Equally important are laws designed to ensure that trial participation advances medical science—because this potential benefit is what makes even the smallest set of risks acceptable. The Food and Drug Administration...
Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real-world evidence (RWE) in the evaluation of new treatments or products. RWE studies often rely on real-world data (RWD), including data extracted from healthcare records or data captured by mobile phones or...
Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real‐world evidence (RWE) in the evaluation of new treatments or products. Real‐world clinical trials or pragmatic trials often differ from traditional clinical trials in the use of open‐label or nonblinded tr...
Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real‐world evidence (RWE) in the evaluation of new treatments or products. The RWE label has been used to refer to a variety of departures from the methods of traditional randomized controlled trials. Recogniz...
The randomized controlled trial (RCT) is the gold standard for evaluating the causal effects of medications. Limitations of RCTs have led to increasing interst in using real‐world evidence (RWE) to augment RCT evidence and inform decision‐making on medications. Although RWE can be either randomized or nonrandomized, nonrandomized RWE can capitalize...
Introduction
In the 2016 U.S. Presidential election, voters in communities with recent stagnation or decline in life expectancy were more likely to vote for the Republican candidate than in prior Presidential elections. We aimed to assess the association between change in life expectancy and voting patterns in 2018 U.S. House of Representative elec...
Background:
Prior analyses suggest an association between formula-based plasma volume (PV) estimates and outcomes in heart failure (HF). We assessed the association between estimated PV status by the Duarte-ePV and Kaplan Hakim (KH-ePVS) formulas, and in-hospital and postdischarge clinical outcomes, in the ASCEND-HF trial.
Methods and results:
T...
Importance:
Adherence to the Consolidated Standards of Reporting Trials (CONSORT) for randomized clinical trials is associated with improvingquality because inadequate reporting in randomized clinical trials may complicate the interpretation and the application of findings to clinical care.
Objective:
To evaluate an automated reporting checklist...
Objective:
To estimate using the UK Prospective Diabetes Study Outcomes Model Version 2 (UKPDS-OM2) the impact of delaying type 2 diabetes onset on costs and quality-adjusted life expectancy using trial participants who developed diabetes in the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) study.
Research...
Concerns about the external validity of traditional randomized clinical trials (RCTs), together with the widespread availability of real-world data and advanced data analytic tools, have led to claims that common sense and clinical observation, rather than RCTs, should be the preferred method to generate evidence to support clinical decision-making...
Amid the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, substantial effort is being directed toward mining databases and publishing case series and reports that may provide insights into the epidemiology and clinical management of coronavirus disease 2019 (COVID-19). However, there is growing concern about whether attempts t...
The pipeline of new cardiovascular drugs is relatively limited compared with many other clinical areas. Challenges causing lagging drug innovation include the duration and expense of cardiovascular clinical trials needed for regulatory evaluation and approvals, which generally must demonstrate noninferiority to existing standards of care and measur...
Emerging data science techniques of predictive analytics expand the quality and quantity of complex data relevant to human health and provide opportunities for understanding and control of conditions such as heart, lung, blood, and sleep disorders. To realize these opportunities, the information sources, the data science tools that use the informat...
Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a “digital clinical trial...
Wide variation in cardiovascular disease age-adjusted mortality rates (AAMRs) has been noted among counties in the US.¹ Rural residents experience higher death rates compared with residents of urban areas, particularly from potentially preventable causes.² We examined temporal trends in cardiovascular disease AAMRs overall and across subgroups stra...
Background
Clinical guideline documents reflect the evidence supporting clinical practice, but few recommendations in cardiovascular guidelines are supported by evidence from randomized controlled trials (RCTs), the highest level of evidence. Incentives for generating evidence from RCTs differ by topic of guideline recommendation, and it is uncerta...
Understanding and addressing the unique health needs of people residing in rural America is critical to the American Heart Association’s pursuit of a world with longer, healthier lives. Improving the health of rural populations is consistent with the American Heart Association’s commitment to health equity and its focus on social determinants of he...
The availability of large datasets from multiple sources [e.g. registries, biobanks, electronic health records (EHRs), claims or billing databases, implantable devices, wearable sensors, and mobile apps], coupled with advances in computing and analytic technologies, have provided new opportunities for conducting innovative health research. Equally,...
Responding to concerns about the potential for increased risk of adverse cardiovascular (CV) outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the U.S. Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceut...
Project management expertise is employed across many professional sectors, including clinical research organizations, to ensure that efforts undertaken by the organization are completed on time and according to specifications and are capable of achieving the needed impact. Increasingly, project leaders (PLs) who possess this expertise are being emp...
The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical tri...
In Reply We agree with Dr Cohen and colleagues that any solution to the escalation of drug pricing must support continuing innovation and drug development. Unfortunately, their critique presents a set of false choices that offers no remedy to the problem that a growing number of patients are experiencing serious health consequences from inability t...
Background:
Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes.
Methods:
We performed a retrospective stu...
Project management expertise is employed across many professional sectors, including clinical research organizations, to ensure that efforts undertaken by the organization are completed on time and according to specifications and are capable of achieving the needed impact. Increasingly, project leaders (PLs) who possess this expertise are being emp...
Background:
Cluster-randomized trials (CRTs) are being increasingly used to test a range of interventions, including medical interventions commonly used in clinical practice. Policies created by the NIH and the Food and Drug Administration (FDA) require the reporting of demographics and the examination of demographic heterogeneity of treatment eff...
Background
Addition of ezetimibe to statin therapy reduces the risk of recurrent cardiovascular (CV) events in patients with prior acute coronary syndrome (ACS). The role of biomarkers in identifying subsets of patients who may derive greater clinical benefit with ezetimibe is unknown.
Objectives
This study sought to evaluate the role of establish...
Importance
Limited evidence is available regarding the benefit and hazard of higher-intensity treatment to lower lipid levels among patients 75 years or older. As a result, guideline recommendations differ for this age group compared with younger patients.
Objective
To determine the effect on outcomes and risks of combination ezetimibe and simvast...
Although the sharing of misleading information is likely as old as humanity, an unfortunate concomitant of the current digital environment is the amplification and accelerated spread of medical misinformation.¹,2 Growing distrust of medical professionals is causing some people to eschew drugs that have been proven effective, such as statins for hyp...
Individual-level baseline covariate imbalance could happen more frequently in cluster randomized trials, and may influence the observed treatment effect. Using computer and real-data simulations, this paper quantifies the extent and impact of covariate imbalance on the estimated treatment effect for both continuous and binary outcomes, and relates...
Skin cancer is the most common malignancy in the United States and is estimated to affect more than 3.3 million individuals each year.¹ Photoprotection, including sunscreen use for areas of skin not covered by sun protective clothing or shade, aims to reduce exposure to UV radiation, likely the main risk factor for the development of skin cancer.
US drug costs have reached unacceptable and unsustainable levels. Evidence shows that “financial toxicity” arising from drug costs and other medical expenses is reducing financial security for many families¹ and prompting difficult choices, as patients defer or forgo therapies they cannot afford.² In stark contrast, comparable countries negotiate d...
Importance
Clinical decisions are ideally based on evidence generated from multiple randomized controlled trials (RCTs) evaluating clinical outcomes, but historically, few clinical guideline recommendations have been based entirely on this type of evidence.
Objective
To determine the class and level of evidence (LOE) supporting current major cardi...
Background:
Although cholesterol-lowering medications can reduce the risk of recurrent cardiovascular events, premature discontinuation limits effectiveness. Discontinuation rates have not been systematically reported for lipid-lowering trials.
Methods and results:
We evaluated medication discontinuation in IMPROVE-IT (Improved Reduction of Outc...
In Reply It is promising that institutes such as the NHGRI have chosen to invest in projects addressing the return of individual research results, as Dr Kaufman and colleagues highlight. Conducting rigorous research to answer the “what, when, and how” to return these results is important to move the field forward.¹ Although some extant literature e...
Background:
Globalization of clinical trials fosters inclusion of higher and lower income countries, but the influence of enrolling country income level on heart failure trial performance is unclear. This study sought to evaluate associations between enrolling country income level, acute heart failure patient profile, protocol completion, and tria...
Background:
Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarcti...
The number of persons with heart failure has continued to rise over the last several years. Approximately one-half of those living with heart failure have heart failure with preserved ejection fraction, but critical unsolved questions remain across the spectrum of basic, translational, clinical, and population research in heart failure with preserv...
The natural history of patients hospitalized for acute coronary syndrome (ACS) with pre-existing versus (vs) de novo heart failure (HF) has not been previously reported over an extended duration of follow-up. The IMPROVE-IT trial enrolled 18,144 patients hospitalized for ACS and randomized them to combination simvastatin (40 mg)/ezetimibe (10 mg) v...
Research data may be of great utility to study participants and their clinicians in understanding and managing the health of patients who participate in research, depending on the clinical context and nature of results. In addition, increasing amounts of digital data are generated by commercial health products, such as accelerometers and smart watc...
How is it possible that, despite staggering growth in spending on health care, the United States ranks in the middle of economically developed countries in health status¹ and has now experienced its second consecutive year² of decreases in life expectancy? Just as vexing, the declines in both relative and absolute status compared with international...
Biomarkers are critical to the rational development of medical therapeutics, but significant confusion persists regarding fundamental definitions and concepts involved in their use in research and clinical practice, particularly in the fields of chronic disease and nutrition. Clarification of the definitions of different biomarkers and a better und...
The current heart failure clinical trial environment is strained by increasing complexity and cost, regulatory requirements, competing demands on stakeholders, implementation challenges, and decreasing patient and investigator participation. To begin the process of developing potentially effective strategies and tactics, stakeholders including pati...
In this issue of JAMA Internal Medicine, Fralick and colleagues¹ create a straw man to demonstrate that observational treatment comparisons could be useful for expanding indications for medical products. The authors modeled the Ongoing Telmisartan Alone and in Combination with Ramipril Global End-point Trial (ONTARGET),² which compared the angioten...
When people use medical products, they generally expect that the benefits of doing so will outweigh the risks in terms of living longer, feeling better, or improving their functional status. However, most drugs and biologics and many medical devices that enter early evaluation in humans are found either to have no benefit or to have risks that outw...
Few physicians consider cosmetics and related products relevant to their professional lives. Cosmetics, of course, are used to alter the body’s appearance, not its actual structure or function. However, the distinction between substances that only alter bodily appearance or aesthetics and medicinal compounds that affect the body’s structure or heal...
Percutaneous treatment of valvular heart disease is a modern miracle. A decade ago, it was inconceivable to all but a few visionary inventors that a catheter–based approach could be used to replace a cardiac valve, thus eliminating the need for a thoracotomy with all of its associated costs, inconvenience, and potential for major adverse outcomes....
In recent years, there has been increased recognition of the critical need to improve dietary habits of the general U.S. population as the number of adults with obesity has grown in tandem with the burden of diseases influenced by diet. There is a direct relationship among obesity and hypertension,
Cigarette smoking ranks among the most devastating, but modifiable, risk factors for cardiovascular disease. Of the more than 20 million premature deaths caused by smoking and secondhand smoke since the first Surgeon General’s Report on Smoking and Health was published in 1964, nearly 7.8 million
Medication nonadherence, a major problem in cardiovascular disease (CVD), contributes yearly to approximately 125,000 preventable deaths, which is partly attributable to only about one-half of CVD patients consistently taking prescribed life-saving medications. Current interest has focused on how labeling and education influence adherence. This pap...
The US Food and Drug Administration’s (FDA’s) independent evaluation of medical products for safety and effectiveness prior to granting approval for marketing or new labeled indications is fundamental to assuring the public and clinicians that marketed products have a positive balance of benefit to risk when used according to labeling. Ever since t...
Therapeutics known as combination products because they combine drug, device, and/or biologic elements can offer important advantages relative to single-modality products. However, regulatory policy in this arena has lagged relative to increases in product submissions and complexity of these products. In this article, we describe how the US Food an...
Federal health agency leaders describe plans to develop infrastructure for generating high-quality evidence to improve care. They argue that it will be necessary to embed research in clinical care, create interoperable research data networks, and apply new research methods.
The FDA is developing guidance on the use of “real-world evidence” — health care information from atypical sources, including electronic health records, billing databases, and product and disease registries — to assess the safety and effectiveness of drugs and devices.
To ensure that the emerging field of stem-cell therapy fulfills its promise to patients, we must first understand its risks and benefits and develop therapeutic approaches based on sound science. That requires a commitment to the principles of evidence generation.
Before a medical product can be widely used in the United States, it generally must first be approved or cleared for marketing by the US Food and Drug Administration (FDA). Then, payers such as the Centers for Medicare & Medicaid Services (CMS) must decide whether the product merits coverage and payment. Because the statutes governing these agencie...
Cardiovascular medicine has led the drive for creativity and innovation with a culture that has been at the forefront of evidence generation. However, we are functioning at only a fraction of our evidence generation capacity. Despite the leadership of cardiovascular medicine, very few guideline recommendations are supported by high levels of eviden...
The National, Heart, Lung, and Blood Institute convened a Think Tank meeting to obtain insight and recommendations regarding the objectives and design of the next generation of research aimed at reducing health inequities in the United States. The panel recommended several specific actions, including: 1) embrace broad and inclusive research themes;...
Federal regulatory frameworks governing medical products are designed to (1) provide evidence that a product benefits patients when used as intended and should be available despite accompanying risks and (2) ensure timely access to needed therapies and diagnostics. Historically, policy makers and product developers have viewed these objectives as b...
Congenital heart disease (CHD) is the most common birth defect, affecting about 0.8% of live births. Advances in recent decades have allowed >85% of children with CHD to survive to adulthood, creating a growing population of adults with CHD. Little information exists regarding survival, demographics, late outcomes, and comorbidities in this emergin...
This Viewpoint describes the rationale behind an FDA and NIH effort to develop a glossary of common terms and definitions for biomarkers and surrogate endpoints.Biomarkers, surrogate endpoints, and clinical outcome assessments provide an essential set of tools needed to translate scientific concepts into diagnostic and therapeutic approaches and te...
Data S1. End point event definitions.
Background
Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions.
Methods and Results
In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atr...
We at the Food and Drug Administration (FDA) continue to be deeply concerned about the growing epidemic of opioid abuse, addiction, and overdose - an epidemic directly related to the increasingly widespread misuse of powerful opioid pain medications. As the federal agency charged with ensuring that the drugs used by the U.S. public are both effecti...
Unlabelled:
Non-ST-segment myocardial infarction (NSTEMI) can be complicated by high-degree atrioventricular (AV) block, asystole, or electromechanical dissociation (EMD), but these events are not well characterized in the contemporary era. This analysis assesses the incidence of and factors associated with these dysrhythmias in acute NSTEMIs.
Me...
Objective:
Inflammation in response to oxidized lipoproteins is thought to play a key role in acute coronary syndromes (ACS), but the pattern of immune activation has not been fully characterized. We sought to perform detailed phenotypic and functional analysis of CD8 T lymphocytes from patients presenting with ACS to determine activation patterns...
Background
A 1.5‐day interactive forum was convened to discuss critical issues in the acquisition, analysis, and sharing of data in the field of cardiovascular and stroke science. The discussion will serve as the foundation for the American Heart Association's (AHA's) near‐term and future strategies in the Big Data area. The concepts evolving from...
This Viewpoint discusses the conceptual framework of the Precision Medicine Initiative that could lead to improved health by more effectively matching medical products to the needs and preferences of patients and care partners.The complex tasks of developing, evaluating, and determining the appropriate use of medical technologies occur in an evolvi...
Objectives:
This study sought to determine the relationship of KIM-1 levels with adverse clinical outcomes in acute decompensated heart failure (ADHF).
Background:
Kidney injury molecule (KIM)-1 is a biomarker expressed by the nephron in acute tubular injury, and is a sensitive and specific marker for early acute kidney injury. Although commonly...
Human research projects must have a scientifically valid study design, analytic plan, and be operationally feasible in order to be successfully completed and thus to have translational impact. To ensure this, institutions that conduct clinical research should have a scientific review process prior to submission to the Institutional Review Committee...
Biomedicine has entered a transformative era, one in which advances in mechanistic biology, bioengineering, data management, and health policy promise to deliver unprecedented benefits for public health, such as precision and preventive medicine, theranostic imaging techniques, and mobile health.
The FDA has recommended a pathway to expedite completion of studies to ensure that new sunscreen ingredients are safe and effective. A renewed commitment to collaboration on high-quality studies could lead to breakthroughs in melanoma prevention.
Background:
Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known.
Methods:
We conducted a double-blind, randomized tria...
Diuretic unresponsiveness often occurs during hospital admission for acute heart failure (AHF) and is associated with adverse outcome. This study aims to investigate determinants, clinical outcome, and the effects of nesiritide on diuretic response early after admission for AHF.
Diuretic response, defined as weight loss per 40 mg of furosemide or e...
Despite the global burden of cardiovascular disease, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas. The reasons for this trend are multifactorial, but of primary concern is the high cost of conducting cardiovascular outcome trials in the curre...
The Food and Drug Administration Amendments Act (FDAAA) mandates timely reporting of results of applicable clinical trials to ClinicalTrials.gov. We characterized the proportion of applicable clinical trials with publicly available results and determined independent factors associated with the reporting of results.
Using an algorithm based on input...
Recent developments have highlighted the challenges facing cardiovascular clinical research in global contemporary practice, particularly in North America, including shifting priorities for drug development targets, increasing regulatory requirements, and expensive operational approaches for conducting randomized clinical trials. Nonetheless, emerg...
Objective: The Durham Diabetes Coalition (DDC) was established in response to escalating rates of disability and death related to type 2 diabetes mellitus, particularly among racial/ethnic minorities and persons of low socioeconomic status in Durham County, North Carolina. We describe a community-based demonstration project, informed by a geographi...
Citations
... The generation of new evidence in medicine and improvement in patient care are hampered by inefficient and laborious processes [1,2]. Most evidence is gathered through stand-alone research projects that are costly and time-consuming, and are conducted in an artificial research setting with a selected sample of patients. ...
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... Appliqués dans des conditions d'utilisation maximale pendant 4 jours consécutifs, ces composés ont atteint des taux sanguins qui excédaient les limites recommandées dans les lignes directrices de la FDA 45 . Les investigateurs ont de plus noté de longues demivies pour chacun de ces ingrédients, donnant à penser que l'utilisation régulière des écrans solaires pourrait entraîner une accumulation dans l'organisme 46 . Une étude de suivi a confirmé ces observations 47 . ...
... There was no interaction between the presence of HF (5% of the total population) and the benefits observed with the addition of ezetimibe to statin therapy. In a recent post-hoc analysis of the IMPROVE-IT, subjects enrolled were divided into 3 groups: pre-existing HF, de novo HF, and no HF [84]. After adjusting for potential confounders, a history of pre-existing or de novo HF was independently associated with increased risk of death and hospitalizations for HF, further confirming the highest overall risk of HF associated with post-MI [84]. ...
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... older trial participants' rationale for discontinuing study drugs may aid trial investigators in developing effective strategies for maintaining participants in their allocated study arm [13]. Despite the importance and complexity of this area, few studies have investigated the underlying factors contributing to this phenomenon [14]. ...
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... This study used a geographic information system (GIS) to estimate diabetes burden at the school district level. Although it has been used in various diabetes studies using different geographic scales (Geraghty et al., 2010;Spratt et al., 2015), GIS analysis using school district boundaries has not been used to target diabetes prevention at schools to our knowledge. Given the high rate of diabetes prevalence and deaths related to diabetes as well as the importance of intervening early at schools, this study aimed to analyse whether diabetes-related deaths can be used as a proxy for the diabetes burden at the school district level to target for schoolbased diabetes prevention interventions. ...
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... Each year in the US, over 550,000 individuals are newly diagnosed with HF dysbiotic microbiome, hyperlipidemia, obesity, and diabetes (4-6). However, the medical community has traditionally focused on pharmacotherapy and devices and not on nutrition in both the primary and secondary prevention of HF (7,8). ...
... High-quality comparative-effectiveness research is made complex by the growing burden of administrative requirements, frequent operational inefficiencies, and large sample sizes required to detect treatment effects in heterogeneous patient populations [1][2][3][4]. As comparative effectiveness research grows, strategies to streamline components of contemporary randomized controlled trials (RCT) will be needed to deliver simpler, faster, and more impactful research [5]. ...
... The revised AKTN activities ( Table 2) were assessed for their pragmatism across the trial portfolio using a method inspired by the PRECIS-2 tool [14]; there is scope for further pragmatism in trial delivery (Fig. 3b) and monitoring (Fig. 3a). The lessons learned from COVID-19 will mean more weight will be given to innovative and simplified delivery of trial assessments and data acquisition [15] when designing trials to enable trials to continue during future health emergencies (Fig. 4). New trial budgets will include provision for devices, data and additional resources to facilitate remote trial activities and web-based training. ...
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... Those alternatives could include cluster-level randomization, stepped-wedge designs, non-randomized comparisons to contemporaneous controls (21,22), or single-arm comparisons to historical controls. Each step on this gradient from patient-level randomization to completely naturalistic non-randomized comparison may increase the risk that inference will be biased by unmeasured confounding (23). Any RWE study may depart from traditional clinical trial methods on any or all of these three dimensions: real-world data, real-world treatment, or real-world treatment assignment. ...
... However, this research reflects the perception, demonstrated in other studies, that the mandate of RECs is to review ethics-related aspects, less the validity of the methodology and/or research tools (Suzuki & Sato, 2016). Some believe that reviewing the scientific rigor is an important and increasingly required element of IRB review of research proposals (Suter & Suter, 2017) holding that weak or flawed research design that cannot achieve research aim imposes risk and burdens to research participants with little or no knowledge or social benefit and as such represents unethical research (Selker et al., 2015). Yet, previous studies reveal a controversy among REC members as to whether the scientific merit of the proposals which they review should be good enough or that it should be as good as possible. ...
