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While the coronavirus disease 2019 (COVID-19) pandemic continues to present global challenges, sufficient time has passed to reflect on lessons learned and use those insights to inform policy and approaches to prepare for the next pandemic. In May 2022, the Duke Clinical Research Institute convened a think tank with thought leaders from academia, clinical practice, the pharmaceutical industry, patient advocacy, the National Institutes of Health, the US Food and Drug Administration, and the Centers for Disease Control and Prevention to share, firsthand, expert knowledge of the insights gained from the COVID-19 pandemic and how this acquired knowledge can help inform the next pandemic response. The think tank focused on pandemic preparedness, therapeutics, vaccines, and challenges related to clinical trial design and scale-up during the early phase of a pandemic. Based on the multi-faceted discussions, we outline 10 key steps to an improved and equitable pandemic response., Competing Interests: Potential conflicts of interest. A. F. H. reports contracts with Pfizer and Merck and consulting fees from Merck. B. L. is an employee of and owns stock in Moderna and reports support for travel to a meeting from Moderna. C. W. W. reports consulting fees from Arena Pharmaceuticals, BioFire, FHI Clinical, Giner, Karius, and SeLux Diagnostics; grants or contracts (paid to institution) from Defense Advanced Research Projects Agency, National Institutes of Health (NIH)-Antibacterial Resistance Leadership Group/National Institute of Allergy and Infectious Diseases/NIH Vaccine and Treatment Evaluation Units/National Institute of Mental Health/National Institute of General Medical Sciences, Sanofi, Najit, the Centers for Disease Control and Prevention (CDC), Patient-Centered Outcomes Research, United States Army Medical Research Acquisition Activity, Department of Defence, Abbott, and Pfizer; support for attending meetings and/or travel from the American Society for Microbiology (ASM); participation on a data and safety monitoring board (DSMB) or advisory board for IDbyDNA, Janssen, Regeneron, Roche Molecular Sciences; a leadership or fiduciary role for ASM and the American Society of Tropical Medicine and Hygiene; being employed by Duke University, Durham Veterans Affairs Hospital, Biomeme, and Equity/Founder of Predigen, Inc; and planned, issued, or pending patents for biomarkers for the molecular classification of bacterial infection, methods to diagnose and treat acute respiratory infections, gene expression signatures useful to predict or diagnose sepsis and methods of using the same, host-based molecular signatures of human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 (coronavirus disease 2019 [COVID-19]), methods of identifying infectious disease and assays for identifying infectious disease, and nasopharyngeal protein biomarkers of acute respiratory virus infection and methods of using same. H. C. and S. C. B. are employees of and hold or may hold stock in AstraZeneca. J. W. reports being an employee of and owns stock/stock options in and received equipment, materials, drugs, medical writing, gifts, and other services from Johnson & Johnson and, as CMO, has been deposed in litigation; patents issued that do not relate to the current article (available on request); and a role on the Brooklyn College Cancer Center Advisory Board, a Brooklyn College Foundation Trustee, and on the Fellowships at Auschwitz for the Study of Professional Ethics, Academic Committee. J. R. D. is an employee and shareholder in Eli Lilly and Company. L. H. C. reports consulting fees from Regeneron for the NFL Players Association and grants or contracts from NIH for PCORI. L. S. reports stock/stock options in Novartis. L. R. is an employee of and owns stock/stock options in and received support for attending meetings and/or travel from Bayer AG. M. S. reports consulting fees from AbbVie, Assembly Bio, Antios, Arbutus, Gilead Sciences, Precision Bio, and GSK for scientific advisory boards and participation on a DSMB for Gilead Sciences and AbbVie and a role as editor of the Journal Viral Hepatitis. O. V. is an employee of Boehringer Ingelheim. P. P. has a patent pending for sotrovimab and is an employee and shareholder of Vir Biotechnology. S. N. reports consulting fees from Pardes Biosciences, Theratechnologies, and Silverback Therapeutics; stock/stock options in Vir Biotechnology; grants or contracts (paid to institution) from Gilead Sciences and AbbVie; participation on an advisory board for Vir Biotechnology, a DSMB for Personal Health Insights, Inc; and serving on an event adjudication committee for Bristol–Myers Squibb/PRA. M. A. M. reports consulting fees from Abcam; stock/stock options in Grid Therapeutics; a role as an advisory board member for GSK Belimumab Pregnancy Registry; and funding to Duke from NIAD (U01 AI151378): Centers for Research in Emerging Infectious Disease (CREID) Network Coordinating Center, HHS 75N93019C00050: Duke Collaborative Influenza Vaccine Innovation Centers (CIVICs) A: Vaccine Center, HHS 75N93019C00054: Duke CIVICs C: Clinical Core, U19 AI144177: A Global Syphilis Vaccine Targeting Outer Membrane Proteins Of Treponema pallidum, 2P01 AI089618: Structure-Function Analysis Of Infection- And Vaccine-Induced B Cell Repertoires. S. E. T. reports royalties from UptoDate; grants or contracts (paid to institution) from the CDC; payment or honoraria (to author) from the Infectious Disease Society of America (IDSA) and Emerson Hospital; support from DCRI to attend the meeting upon which this article was based. L. R. B. is involved in human immunodeficiency virus (HIV) and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network, COVID Vaccine Prevention Network, International AIDS Vaccine Initiative, Crucell/Janssen, Moderna, Military HIV Research Program, the Gates Foundation, and Harvard Medical School. reports participation on a DSMB for NIH and AMDAC Committee for the FDA (research funded by the NIH, Welcome Trust, and the Gates Foundation). R. T. G. reports a leadership or fiduciary role on the NIH COVID Treatment Guidelines Panel and IDSA COVID Treatment Guidelines Panel. R. G. reports grants (to institution) from NIH/NIAID, book chapter royalties from Elsevier, and section editor royalties from UpToDate. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

In late 2018, the Food and Drug Administration (FDA) outlined a framework for evaluating the possible use of real-world evidence (RWE) to support regulatory decision-making. This framework was created to facilitate studies that would generate high-quality RWE, including pragmatic clinical trials (PCTs), which are randomized trials designed to inform clinical or policy decisions by assessing the real-world effectiveness of an intervention. There is general agreement among experts that the use of existing healthcare and patient-generated data holds promise for making randomized trials more efficient, less costly, and more generalizable. Yet the benefits of relying on real-world data sources must be weighed against difficulties with ensuring data integrity and completeness. Additionally, appropriately monitoring patient safety in randomized trials of new drugs using healthcare system data that might not be available in real time can be quite difficult. Recognizing that these and other concerns are critical to the development and acceptability of PCTs, a group of stakeholders from academia, industry, professional organizations, regulatory bodies, government agencies, and patient advocates discussed a path forward for PCT growth and sustainability at a think tank meeting entitled "Monitoring and Analyzing Data from Pragmatic Streamlined Randomized Clinical Trials," which took place in January 2019 (Washington, DC). The goals of this meeting were to: (1) evaluate study design and methodological options specific to PCTs that have the potential to yield high-quality evidence; (2) discuss best practices to ensure data quality in PCTs; and (3) identify appropriate methods for study monitoring. Proceedings from the think tank meeting are summarized in this manuscript.

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 trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

Competing Interests: Conflict-of-Interest Disclosures: Dr. Antman is conducting a clinical trial with Daiichi Sankyo. Dr. Califf serves on the corporate board for Cytokinetics and is board chair of the People-Centered Research Foundation. He receives consulting fees from Merck, Biogen, Genentech, Eli Lilly, and Boehringer Ingelheim, and is employed as an advisor by Verily Life Sciences (Alphabet). Dr. Ingelfinger is salaried deputy editor of the New England Journal of Medicine. Dr. Krumholz is chair of the Cardiac Scientific Advisory Board for UnitedHealth; participant on the Life Sciences Board for IBM Watson Health; member of the Advisory Board for Element Science; member of the Physician Advisory board for Aetna; member of Advisory Board for Facebook; and owns Hugo, a personal health information platform. Dr. Peterson is a consultant for Abiomed; Amgen, Inc.; AstraZeneca; Bayer AG; Janssen Pharmaceuticals; Livongo; and Sanofi-Aventis. Dr. Peterson receives research funding in grants partially funded by Amarin; American College of Cardiology; American Heart Association; Amgen, Inc.; AstraZeneca; Baseline Study, LLC; Bayer AG; Eli Lilly & Company; Genentech; Janssen Pharmaceuticals; Merck & Co.; Novartis; Reflexion Health; Regeneron; Sanofi-Aventis; and the Society of Thoracic Surgeons. Dr. Ross recieved support through a research grant from Medtronic, Johnson & Johnson, Blue Cross-Blue Shield Association, and the Laura and John Arnold Foundation. Dr. Waldstreicher is an employee of Johnson & Johnson and a former employee of Merck & Co. Dr. Wang receives research funding in grants partially funded by Novartis Pharmaceuticals, Boehringer Ingelheim, and Johnson & Johnson. Dr. Zarin serves as a consultant for the National Library of Medicine.

Background: Janssen Research & Development, LLC, part of the Janssen pharmaceutical companies of Johnson & Johnson, and NYU School of Medicine partnered to establish the Compassionate Use Advisory Committee (CompAC) to evaluate the use of an independent, external, expert committee in ensuring transparent, fair, beneficent, evidence-based, and patient-focused compassionate access to investigational medicines, a public health challenge that has been an ongoing issue for over 3 decades., Methods: To this end, NYU School of Medicine was responsible for the formation, member selection, and operation of CompAC, consisting of physicians, ethicists, and patient advocates, under Johnson & Johnson's sponsorship., Results: A pilot was successfully run using CompAC to provide recommendations on compassionate use access to a Johnson & Johnson oncology investigational asset called daratumumab., Conclusion: This innovative model provides a framework that can be emulated by the industry globally.

The Yale University Open Data Access (YODA) Project has facilitated access to clinical trial data since 2013. The purpose of this article is to provide an overview of the Project, describe key decisions that were made when establishing data sharing policies, and suggest how our experience and the experiences of our first two data generator partners, Medtronic, Inc. and Johnson & Johnson, can be used to enhance other ongoing or future initiatives.

Background: Sharing data from clinical trials could assist with the advancement of science and medicine, potentially providing a better understanding of both the benefits and risks of medicines and other treatments. Sharing data also allows for questions to be addressed at the meta-analysis level that cannot be addressed within individual studies., Purpose: In this article, we offer some practical recommendations that will allow researchers to readily combine datasets from different studies and sources, thereby enabling meta-analyses that could have significant impact on advancing medicine., Methods: The authors relied on their collective experience in the conduct and reporting of clinical trials to define the areas of potential concern related to responsible sharing of clinical trial data. We conducted a review of the literature and engaged in an iterative consensus-building process., Results: To further the goal of responsible sharing of clinical trial data, collaboration on a consistent set of data standards and methods across both industry and academia is sorely needed. Protection of participant privacy is a paramount principle. The additional questions of who maintains, funds, and oversees databases of participant-level data will be important to resolve. Requiring researchers to register their requests for participant-level data and to provide details of their intended research would allow others to evaluate the proposed research plan, consistent with the principles of science and transparency., Limitations: The recommendations represent the views of the individual authors. We recognize that other approaches to data sharing that have been advocated are also based on sound ethical and scientific principles.

Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.

Purpose: We determined the effect of long-term treatment with finasteride on the incidence of acute urinary retention (AUR) and benign prostatic hyperplasia (BPH) related surgery in men with BPH., Materials and Methods: The Proscar (Merck and Co., Inc., Whitehouse Station, New Jersey) Long-Term Efficacy and Safety Study (PLESS) was comprised of 3040 men with enlarged prostates, moderate to severe symptomatic BPH and no clinical evidence of prostate cancer. Patients were randomized to placebo or 5 mg finasteride daily for 4 years. Of the 3016 randomized patients with available efficacy data 62% completed the original 4-year study (1006 on finasteride and 891 on placebo) and 89% of these (908 from the original finasteride arm and 785 from the placebo arm) continued in a 2-year open extension on finasteride. Followup was attempted in discontinued patients. Complete 6-year outcomes data, including 6-year followup in 770 men who had discontinued treatment during years 1 to 6, were available for 2463 (82%) of the 3016 originally randomized patients., Results: For patients on continuous finasteride treatment the decrease in incidence of AUR and/or BPH related surgery in the 4-year base study was sustained during the open extension. In patients who were switched from placebo to finasteride in the extension, the incidence of AUR and/or BPH related surgery was similar to that in the continuous finasteride arm., Conclusions: The 6-year data from PLESS confirmed and further extended the findings from the original 4-year trial, demonstrating that finasteride treatment led to a sustained decrease in the incidence of AUR and/or BPH related surgery in men with BPH and enlarged prostates.

Objectives: To examine the effect of finasteride on serum testosterone in men with benign prostatic hyperplasia (BPH)., Methods: The Proscar Long-Term Efficacy and Safety Study (PLESS) was a 4-year trial comparing the safety and efficacy of finasteride 5 mg with placebo in 3040 men with moderate to severe symptomatic BPH and enlarged prostates. PLESS included the prospective measurement of annual serum testosterone in a randomly selected subset of patients comprising approximately 10% of the randomized population (n = 301)., Results: Finasteride treatment led to a modest, but significant (P <0.001), increase relative to placebo in serum testosterone, with this increase greatest in patients who had low baseline testosterone levels. The larger testosterone increases seen in finasteride-treated patients in the lower baseline testosterone tertiles were associated with significant mean reductions relative to placebo at year 4 in body mass index (BMI), ranging from 0.6 to 0.8 kg/m2. No statistically significant between-group difference was found in BMI in the upper testosterone tertile. The sexual adverse experience profiles for finasteride and placebo were similar across the baseline testosterone cohorts examined., Conclusions: Finasteride treatment led to a generally modest increase relative to placebo in serum testosterone, with the greatest increases occurring in men with low baseline testosterone levels. The physiologic significance of these changes in men with low baseline testosterone levels is unclear, but the associated reduction in BMI is intriguing and may be related, because BMI is known to be negatively correlated with serum testosterone levels in men.

Objectives: To summarize the 6-year clinical trial data with finasteride. Benign prostatic hyperplasia is a chronic and progressive disease and therefore assessment of long-term safety and efficacy is important., Methods: The North American and International Phase III Finasteride trials enrolled symptomatic men with enlarged prostate glands. The initial 1-year placebo-controlled study was followed by a 5-year open-label extension. In total, 6-year finasteride data were available in 487 patients originally randomized to finasteride, and 5-year data were available on 238 patients originally randomized to placebo., Results: After 6 years of treatment with finasteride 5 mg, the mean quasi-American Urological Association Symptom Score improved by 4.0 points, the median prostate volume decreased by 24%, and the mean maximal urinary flow rate increased by 2.9 mL/s (P <0.001 for all parameters). Long-term finasteride treatment was well tolerated, with a low incidence of drug-related sexual adverse events occurring during the first year and even fewer occurrences during the 5-year open extension., Conclusions: Treatment with finasteride leads to durable improvement in urinary tract symptoms, flow rate, and prostate volume, with no increase in the prevalence of drug-related adverse events over time.

Objectives: To evaluate the incidence and resolution of sexual adverse experiences (AEs) in men with benign prostatic hyperplasia treated with finasteride 5 mg compared with placebo., Methods: The Proscar Long-term Efficacy and Safety Study (PLESS) was a 4-year, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of finasteride 5 mg in 3040 men, aged 45 to 78 years, with symptomatic benign prostatic hyperplasia, enlarged prostates, and no evidence of prostate cancer. Patients completed a questionnaire at screening regarding their history of sexual dysfunction. During treatment, spontaneously self-reported sexual AEs were recorded., Results: At screening, 46% of patients in each treatment group reported some history of sexual dysfunction. During year 1 of the study, 15% of finasteride-treated patients and 7% of placebo-treated patients had sexual AEs that were considered drug related by the investigator (P <0.001). During years 2 to 4, no between-group difference was noted in the incidence of new sexual AEs (7% in each group). The drug-related sexual AE profile for finasteride was similar for men with or without a history of sexual dysfunction. Sexual AEs resolved while continuing therapy in 12% of finasteride patients and 19% of placebo patients. Only 4% of finasteride and 2% of placebo patients discontinued the study because of sexual AEs. In men who discontinued with a sexual AE, 50% and 41% experienced resolution of their sexual AE after discontinuing finasteride or placebo therapy, respectively., Conclusions: Compared with placebo, men treated with finasteride experienced new drug-related sexual AEs with an increased incidence only during the first year of therapy.

Objectives: To assess the utility of voiding and filling symptom subscores in predicting features of benign prostatic hyperplasia (BPH) progression, including acute urinary retention (AUR) and prostate surgery., Methods: The Proscar Long-term Efficacy and Safety Study (PLESS) was a 4-year study designed to evaluate the effects of finasteride versus placebo in men with lower urinary tract symptoms (LUTS), clinical evidence of BPH, and no evidence of prostate cancer. A self-administered questionnaire was employed to quantify LUTS at baseline. Receiver operating characteristics (ROC) curves were used to assess baseline characteristics from patients treated with placebo as predictors of outcomes. The characteristics assessed included the overall symptom score (Quasi-AUA SI), separate voiding and filling subscores, prostate volume (PV) and serum prostate-specific antigen (PSA) levels., Results: PV and PSA were superior to the symptom scores at predicting episodes of spontaneous AUR and all types of AUR. The Quasi-AUA SI and the filling and voiding subscores were effective at predicting progression to surgery; however, PSA was more effective at predicting this outcome. To better evaluate symptoms as predictors of surgery, patients who experienced a preceding episode of AUR were excluded from the surgery analysis. In the absence of preceding AUR, the best predictors of future surgery were the Quasi-AUA SI and the filling subscore., Conclusions: Among men with LUTS, clinical BPH and no history of AUR, the overall symptom score and storage subscore are useful parameters to aid clinicians in identifying patients at risk for future prostate surgery. PV and PSA were the best predictors of AUR, while PSA was the best predictor of prostate surgery (for all indications).

In this double-blind, randomized, placebo-controlled study, normally cycling women (n = 86) with elevated low density lipoprotein cholesterol (LDL-C) levels were studied over six menstrual cycles. At the end of the screening phase, participants received placebo for the second menstrual cycle and subsequently were randomized to receive either placebo or simvastatin (40 mg/d) for the next four cycles. The second and sixth menstrual cycles were considered baseline and treatment cycles, respectively. Participants kept a menstrual diary throughout the study and provided daily first-void urine samples during cycles 2 and 6. Urine samples were assayed for LH and pregnanediol glucuronide (PdG). The primary end point was change in luteal phase duration as defined by the day of the urinary LH peak to the day preceding the onset of menstruation. Treatment with simvastatin (40 mg/d) effectively lowered LDL-C by 34.3% (P < 0.001). Simvastatin was generally well tolerated, and no meaningful difference in adverse event profile was observed between treatment groups. Compared with the placebo group, simvastatin did not have clinically relevant effects on luteal phase duration, peak PdG concentration, or integrated luteal phase PdG concentration. The results of this study demonstrate that treatment of healthy premenopausal women for approximately 4 months with simvastatin (40 mg/d) lowers LDL-C without adversely affecting reproductive gonadal function. Simvastatin should not be used during pregnancy or by nursing mothers.

Purpose: We determine the effect of long-term suppression of dihydrotestosterone with finasteride, a specific type II 5alpha-reductase inhibitor, on bone mineral density., Materials and Methods: As part of a large (3,040 cases) 4-year, double-blind, placebo controlled trial designed to assess the long-term effects of finasteride in men with benign prostatic hyperplasia, 157 men 46 to 76 years old who were randomized to receive either 5 mg. finasteride or placebo underwent dual energy x-ray absorptiometry of the lumbar spine at baseline and at years 2, 3 and 4., Results: Of 117 patients who had a baseline measurement and at least 1 additional measurement during the study baseline mean plus or minus standard deviation bone mineral density values were 1.12 +/- 0.17 gm./cm.2 in the finasteride group (63) and 1.10 +/- 0.17 gm./cm.2 in the placebo group (54). After 4 years bone mineral density was not different between treatment groups (finasteride 1.14 +/- 0.17 gm./cm.2 and placebo 1.13 +/- 0.18 gm./cm.2). Similar results were obtained for the 33 finasteride and 25 placebo treated patients who completed the study with year 4 bone mineral density measurements., Conclusions: These data demonstrate that long-term inhibition of type II 5alpha-reductase with finasteride does not adversely affect bone mineral density.