John Concato

Real‐world evidence (RWE) derived from real‐world data (RWD) can complement randomized controlled trials (RCTs), yet the validity of RWD relative to RCT data remains insufficiently characterized. We obtained post hoc consent and linked individual participant data from the US‐based INVESTED trial (2016–2019) with Medicare fee‐for‐service claims (2012–2020) to validate demographic factors, baseline characteristics (using 183‐, 365‐, and 730‐day lookback periods) and outcomes, and to assess post‐trial events. Among 5260 trial participants, 126 were enrolled and eligible for linkage. Among 115 participants with demographic information available from Medicare enrollment files, agreement between RCT‐ and RWD‐based demographic factors was high: only one major age discrepancy, 100% agreement for sex, and an overall agreement of 0.89 for race. Participants with Medicare claims data ( n = 65) were older and more likely to be White compared with the overall RCT population. For the 365‐day lookback period, baseline comorbidities showed high sensitivity (median 0.80) and specificity (0.89), as did medication use (sensitivity 1.00, specificity 0.88). Lengthening the lookback period to 730 days increased sensitivity but decreased specificity, whereas shortening to 183 days decreased sensitivity but increased specificity. Clinical outcomes showed high specificity (0.88–0.94) but low sensitivity (0.18–0.50). Among those with Medicare coverage beyond the trial end date ( n = 45), 22% experienced cardiopulmonary, 18% cardiovascular, and 7% heart failure (HF) hospitalizations, highlighting the value of RWD for extending RCT evidence. Proactive planning of future RCT‐RWD linkage initiatives can improve the efficiency of linkage studies, leading to more actionable results.

The integration of molecular biology in medicine represents a remarkable achievement of modern science. Nonetheless, the success of molecular methods reshaped medicine's epistemology over time such that biological explanation came to mean explanation exclusively at the cellular or molecular level. This review argues that medicine committed a philosophical error—molecular investigation came to determine epistemic status, displacing person‐level clinical research as an entire domain of rigorous inquiry. Person‐level clinical research encompasses clinical observation, psychosocial and behavioral medicine, patient‐reported outcomes, and the biology of biography. Each tradition satisfies established criteria used to define foundational science. For example, KRAS mutation testing shares its epistemic structure with biographical constructs such as chronic neuroendocrine dysregulation and allostatic load. Both traditions identify specific activated pathways, predict therapeutic response, stratify patients into biologically distinct populations, and operate upstream of pharmacologic interactions. The biological significance of a pathway depends on the person‐level context in which it is activated. Two patients sharing the same mutation but carrying profoundly different neuroimmune histories, inflammatory set‐points, and stress exposure are not the same biological system. Precision medicine, as currently practiced, is often precise at the wrong level of analysis. Evidence supporting biography as mechanistically foundational has not been refuted; it was marginalized by self‐reinforcing institutional forces. Federal funding concentrated in molecular science created financial dependencies that transformed an epistemological preference into a structural imperative. Tenure structures systematically protected molecular faculty whereas clinical scientists were moved to contingent appointments. Successive generations of trainees oriented rationally toward the molecular model. The displacement of person‐level clinical research was not a scientific decision. It was a historical accident compounded by the financial and administrative architecture of modern academic medicine. Restoring this domain to foundational status is not a humanistic plea; it is a scientific corrective—and its costs, if deferred, are borne by patients.

BACKGROUND: Direct oral anticoagulants such as apixaban and rivaroxaban, have transformed the management of thromboembolic disorders. Randomized controlled trials were initiated in 2017 (COBRRA-VTE [Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism]) and 2021 (COBRRA-AF [Comparison of Bleeding Risk Between Rivaroxaban and Apixaban in Patients With Atrial Fibrillation]) to directly compare apixaban and rivaroxaban on the risk of bleeding in patients with venous thromboembolism (VTE) and atrial fibrillation (AF). We aimed to emulate the design and measurements of these ongoing trials and use US health care insurance claims data to predict their findings. METHODS: In cohort studies designed to emulate COBRRA-VTE (REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05264168) and COBRRA-AF (NCT05256797) in 3 US health care insurance claims databases (Medicare, Optum Clinformatics, Merative MarketScan), the risk of bleeding with apixaban was evaluated relative to the risk with rivaroxaban. Pretreatment confounding factors were adjusted for via 1:1 propensity score matching. The primary outcome was a composite of major bleeding and clinically relevant non-major bleeding (defined using International Classification of Diseases, Ninth Revision and Tenth Revision diagnosis codes) recorded in the inpatient setting. Results across databases were pooled using fixed-effects meta-analyses. Protocols were preregistered on ClinicalTrials.gov before inferential analyses were conducted. RESULTS: In the COBRRA-VTE emulation (N=14 023 matched pairs, mean age=67 years, 55% women), we observed a 31% decreased risk of bleeding for apixaban compared with rivaroxaban (incidence rate per 100 person-years: apixaban, 12.8; rivaroxaban, 19.1; hazard ratio, 0.69 [95% CI, 0.59–0.79]). For the COBRRA-AF emulation (N=176 990 matched pairs, mean age=74 years, 50% women), we similarly observed a 31% decreased risk for apixaban compared with rivaroxaban (incidence rate per 100 person-years: apixaban, 6.4; rivaroxaban, 9.2; hazard ratio, 0.69 [95% CI, 0.66–0.71]). CONCLUSIONS: In database studies that closely emulated the design and measurements of the COBRRA-VTE and COBRRA-AF trials, a substantially lower risk of bleeding with apixaban was observed, consistent with the results of COBRRA-VTE (published after completion of our analyses), and indirect comparisons from other trials.

Objective: Using national claims databases, we sought to emulate the design of the ongoing SEPRA trial and predict its findings, comparing the effects of once weekly semaglutide to SoC medications on glycemic control (A1C <7%) in type-2 diabetes mellitus (T2D). Research design and methods: Using Optum Clinformatics (July 2017 – May 2022), we identified a 1:1 propensity score-matched (PSM) cohort of adults with T2D on metformin monotherapy, who had recorded A1C and initiated either injectable semaglutide or SoC medications (dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, SUs, or glucagon-like peptide-1 agonists) and met eligibility criteria adapted from the SEPRA trial. The primary outcome was the proportion of patients achieving A1C <7%. The study protocol was preregistered ( NCT05577728 , ClinicalTrials.gov) before any etiologic analyses. Risk ratios and corresponding 95% CIs were estimated. Results: We identified 1,144 PSM pairs of injectable semaglutide and SoC initiators with balance in pre-exposure covariates. Semaglutide initiators were 30% (risk ratio (95% CI), 1.30 (1.16 to 1.45)) more likely to achieve glycemic control (A1C <7%) than those initiating SoC. Additionally, semaglutide initiators had a 1.3% reduction in A1C, compared with a 1.1% reduction in the SoC group. These results were consistent with interim results of the SEPRA trial, which were released after the protocol for our database study was preregistered. Conclusion: This claims database study, designed to predict the results of the SEPRA trial, found results consistent with interim trial results. Our findings support the notion that well-designed non-randomized studies using fit-for-purpose data can effectively complement pragmatic randomized controlled trials.

Advances in the availability and analysis of real‐world data (RWD) have enabled the generation of robust real‐world evidence (RWE) to support regulatory decision making by the US Food and Drug Administration. Realizing the full potential of RWE in a regulatory environment requires cross‐discipline expertise and collaboration to increase confidence in RWE‐based approaches. The FDA's Advancing RWE Program was established to address this need by providing a new option for regulatory interactions on RWE‐based approaches.

Improvements in the relevance and reliability of routinely collected clinical data and statistical methods to analyze the available data have enhanced the adoption of real‐world data (RWD) to generate real‐world evidence (RWE) for regulatory decision making of medical products. As part of the reauthorization of the Prescription Drug User Fee Act (PDUFA VII), the US Food and Drug Administration (FDA) committed to issuing annual reports describing such uses for drugs and biological products. The first report covered fiscal year (FY) 2023 and described two approvals based, at least in part, on RWE: tocilizumab (trade name Actemra) and lacosamide (trade name Vimpat). This article describes New Drug Applications and Biologics Licensing Applications approved by the Center for Drug Evaluation and Research (CDER) in FYs 2020–2022 with RWE that (1) contributed to substantial evidence of effectiveness or (2) provided safety data necessary for approval. RWE contributed to substantial evidence of effectiveness for the approval of applications for fosdenopterin (trade name Nulibry) and tacrolimus (trade name Prograf) in FY 2021 and abatacept (trade name Orencia), vosoritide (trade name Voxzogo), and alpelisib (trade name Vijoice) in FY 2022. No studies provided only safety data necessary for approval. The five approvals included six total studies that provided RWE pivotal for the applications approval. Four studies leveraged registry data, and two leveraged medical record data. In parallel with annual RWE public reporting under PDUFA VII, this report can inform interested parties regarding how RWD are used to generate RWE that can support regulatory decision making for medical products.

Real‐world evidence involving healthcare database studies is well established for making causal inferences in post‐market drug safety studies and methods, data, and research infrastructure for evaluating effectiveness have advanced in recent years. The rapidly expanding field of etiologic research using insurance claims and electronic health records databases is being evaluated for supporting effectiveness claims. One such use case to support regulatory decision‐making on effectiveness is for expanding indications beyond existing effectiveness claims. Confidence in the validity of findings from cohort studies conducted using databases (hereafter “database study”) to support indication expansions could be increased through a structured benchmarking process of an initial database study against RCT evidence followed by calibration of a subsequent database study based on differences in results observed in the initial RCT‐database pair. This paper proposes a benchmark, expand, and calibration (BenchExCal) approach to trial emulation and describes the design and process for evaluating the performance of the approach through both simulation studies; five planned empirical examples are also described. The project will provide insights regarding how a first‐stage benchmarking emulation of a completed trial for an existing indication can be used to calibrate, increase confidence, and improve interpretation of the results for a second‐stage emulation of a hypothetical trial that could potentially provide evidence for an expanded indication. Although the examples have been selected to provide a variety of learnings, five use cases do not address all clinical and data scenarios that may be encountered when seeking a supplemental indication for a marketed drug.

Understanding the potential for, and direction and magnitude of uncontrolled confounding is critical for generating informative real-world evidence. Many sensitivity analyses are available to assess robustness of study results to residual confounding, but it is unclear how researchers are using these methods. We conducted a systematic review of published active-comparator cohort studies of drugs or biologics to summarize use of sensitivity analyses aimed at assessing uncontrolled confounding from an unmeasured variable. We reviewed articles in 5 medical and 7 epidemiologic journals published between January 1, 2017, and June 30, 2022. We identified 158 active-comparator cohort studies: 76 from medical and 82 from epidemiologic journals. Residual, unmeasured, or uncontrolled confounding was noted as a potential concern in 93% of studies, but only 84 (53%) implemented at least 1 sensitivity analysis to assess uncontrolled confounding from an unmeasured variable. The most common analyses were E-values among medical journal articles (21%) and restriction on measured variables among epidemiologic journal articles (22%). Researchers must rigorously consider the role of residual confounding in their analyses and the best sensitivity analyses for assessing this potential bias. This article is part of a Special Collection on Pharmacoepidemiology.

Background: This report describes the U.S. Food and Drug Administration (FDA) experience in establishing a dedicated mailbox, and in publishing related guidance, to address concerns among interested parties regarding the conduct of clinical trials during the COVID-19 public health emergency (PHE). Methods: Six hundred and thirty-four mailbox inquiries were received from March 2020 through February 2022. Qualitative methods were used to provide a structured description of, and identify common themes among, these inquiries. Results: Most inquiries came from U.S.-based interested parties, including sponsors, industry trade associations, academic institutions, hospitals, clinics, research sites, trial participants, and individual persons. Approximately one-fifth of questions were related directly to COVID-19 (e.g., proposals for treatment); other inquiries were related to conduct of routine trial-related activities, and concerns were often focused on maintaining compliance with good clinical practice. In March 2020, FDA published a guidance titled Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency; the document was subsequently revised eight times based in part on issues raised in mailbox inquiries. Conclusions: The dedicated mailbox enabled expedited communication among invested parties during the COVID-19 PHE; FDA also provided updates of the aforementioned guidance. These efforts supported the continuance of ongoing trials and the initiation of new trials during the PHE in accordance with good clinical practice guidelines, thereby helping to ensure the safety of trial participants while maintaining the quality of trial data. By soliciting and responding to trial-related inquiries and addressing corresponding needs and concerns, FDA improved transparency and communication.