Vitamin C and scar strength: analysis of a historical trial and implications for collagen-related pathologies.

A double-blind controlled trial initiated in 1944 has led to the common narrative that a 10-mg daily vitamin C intake is adequate to prevent and treat impaired wound healing, and by inference, other collagen-related diseases such as heart disease or stroke. The WHO relies on this narrative to set the recommended nutrient intake for vitamin C. This narrative, however, is based on what is known as the eyeball method of data assessment. The 1944 trial published individual participant data on scar strength providing an opportunity to statistically probe the validity of the 10-mg narrative, something which has not yet been done. The findings show that a vitamin C intake that averages to 10 mg/d over a mean follow-up of 11.5 mo was associated with a 42% weakened scar strength when compared with 80 mg vitamin C intake/d (P < 0.001). The observed dose-response curve between scar strength and vitamin C intake suggests that the daily vitamin C intake needed to prevent collagen-related pathologies is in the range recommended by the National Academy of Medicine and the European Food Safety Authority (75 to 110 mg/d), not the WHO recommendation (45 mg/d). The findings also show that a vitamin C intake that averages to 65 mg/d over a mean follow-up of 6.5 mo failed to restore the normal wound-healing capacity of vitamin C-depleted tissues; such tissues had a 49% weaker scar strength when compared with nondepleted tissues (P < 0.05). Thus, average daily vitamin C intakes ∼50% higher than the WHO recommends may fail to treat existing collagen-related pathologies. It is concluded that the prior lack of statistical analyses of a landmark trial may have led to a misleading narrative on the vitamin C needs for the prevention and treatment of collagen-related pathologies.

Breast cancer-The catalyst of contemporary trials design.

Surgical trials in breast cancer have catalyzed contemporary trial design for solid organ cancers and are a prime example of surgeons taking the lead in clinical trial design. Surgeons have lead trials that have improved patient outcomes and quality of life without sacrificing oncologic safety. We have evolved from radical mastectomy to breast conservation and sentinel node biopsy. Contemporary trial design in breast cancer now focus on personalizing care based on tumor genomics.

Melanoma trials that defined surgical management.

Treatment of regional lymph nodes in melanoma has been controversial for more than a century. A series of clinical trials evaluating elective lymph node dissection and then sentinel lymph node biopsy have helped define the current standard of care. These trials resulted in increasingly selective application of surgical intervention for regional lymph nodes in melanoma. First by focusing on optimal candidates for elective lymph node dissection and then by identifying patients through sentinel lymph node biopsy. The current standard of sentinel lymph node biopsy for appropriately selected patients and nodal observation for many patients, even with involved sentinel nodes is both more accurate in staging and much less morbid than what came before.

Melanoma trials that defined surgical management: Overview of trials that established NCCN margin guidelines.

Since the observation that clearance of all visible and microscopic tumors from cutaneous melanoma is critical to prevent a recurrence, wide surgical margins have been central to surgical dogma. In the last several decades, more conservative margin widths have been vigorously studied by surgical investigators to lessen wound complications, the need for reconstruction, and healthcare costs. This review summarizes surgeon-led clinical trials that define current guidelines and highlights the challenges to initiate and perform trials today.

Innovation and Tribulation in the History of Randomized Controlled Trials in Surgery.

Despite persistent critiques of the rigor of surgical research, surgeons have actually pursued careful empirical studies for centuries. Their work has enriched not only surgical science but also the development of evidencebased medicine. From conducting landmark controlled trials, to using statistics, alternate patient allocation, randomization, and sham controls, surgeons have long embraced innovative trial approaches and played important roles in the development of key methods of RCTs. However, historical contexts unique to surgery have shaped the implementation of RCTs in this field. Unlike the history of pharmaceuticals, in which substantial research funding has been devoted to testing new drugs before their approval, surgical trials have followed a different trajectory. New operations have repeatedly come into wide use in the absence of RCTs. On many occasions, when established procedures have become controversial, surgeons have then marshaled the resources to conduct RCTs reassessing the operations. Such trials have triggered powerful debates in which proponents of surgical RCTs battled against ingrained practices and preferences. In such cases, RCTs often were not decisive factors in determining the fate of surgical practices but supporting tools that followed and reflected changes in surgical judgment already underway. Surgical trialists also have encountered specific, recurring challenges, especially with the methodological and ethical complexity of blinded and sham-controlled trials. The history of surgical trials thus reveals major contributions from surgeons to the advancement of evidence-based medicine, as well as ongoing challenges. Strengthened and systematic trial support could advance the future of surgical RCTs.

Evolution of eligibility criteria for diffuse large B-cell lymphoma randomised controlled trials over 30 years.

Eligibility criteria for randomised control trials (RCT) in diffuse large B-cell lymphoma (DLBCL) may be becoming increasingly strict. In this analysis, 42 first-line phase III RCTs enrolling DLBCL patients since 1990 were identified from PubMed and clinicaltrials.gov. Changes in 31 individual eligibility criteria were assessed using three pre-defined eras [(1) 1993-2005; (2) 2006-2013; and (3) 2014-2020]. The presence of 15/31 criteria increased significantly over time, and the total number of criteria per study also increased over time [median Era 1: 14·5, interquartile range (IQR) 12·6-16·4; Era 2: 21, 18·8-23·3; Era 3: 23, 21-25; P < 0·001]. When each trial's eligibility criteria were applied to 215 consecutive patients from an institutional database treated between 2010 and 2020, a median of 57% (IQR 47-70) of patients were hypothetically eligible for trial enrolment. The median percentage of patients eligible was 68% (56-91), 54% (37-81) and 47% (38-82) for Era 1, 2 and 3 respectively (P = 0·004). Phase III front-line DLBCL trial criteria have become increasingly restrictive over the last three decades, resulting in a diminishing proportion of trial-eligible patients, with less than 50% of our patients eligible for modern-era studies. This potentially impacts generalisability of recent trial results and will likely limit recruitment to ongoing studies.

The methodological quality of 176,620 randomized controlled trials published between 1966 and 2018 reveals a positive trend but also an urgent need for improvement.

Many randomized controlled trials (RCTs) are biased and difficult to reproduce due to methodological flaws and poor reporting. There is increasing attention for responsible research practices and implementation of reporting guidelines, but whether these efforts have improved the methodological quality of RCTs (e.g., lower risk of bias) is unknown. We, therefore, mapped risk-of-bias trends over time in RCT publications in relation to journal and author characteristics. Meta-information of 176,620 RCTs published between 1966 and 2018 was extracted. The risk-of-bias probability (random sequence generation, allocation concealment, blinding of patients/personnel, and blinding of outcome assessment) was assessed using a risk-of-bias machine learning tool. This tool was simultaneously validated using 63,327 human risk-of-bias assessments obtained from 17,394 RCTs evaluated in the Cochrane Database of Systematic Reviews (CDSR). Moreover, RCT registration and CONSORT Statement reporting were assessed using automated searches. Publication characteristics included the number of authors, journal impact factor (JIF), and medical discipline. The annual number of published RCTs substantially increased over 4 decades, accompanied by increases in authors (5.2 to 7.8) and institutions (2.9 to 4.8). The risk of bias remained present in most RCTs but decreased over time for allocation concealment (63% to 51%), random sequence generation (57% to 36%), and blinding of outcome assessment (58% to 52%). Trial registration (37% to 47%) and the use of the CONSORT Statement (1% to 20%) also rapidly increased. In journals with a higher impact factor (>10), the risk of bias was consistently lower with higher levels of RCT registration and the use of the CONSORT Statement. Automated risk-of-bias predictions had accuracies above 70% for allocation concealment (70.7%), random sequence generation (72.1%), and blinding of patients/personnel (79.8%), but not for blinding of outcome assessment (62.7%). In conclusion, the likelihood of bias in RCTs has generally decreased over the last decades. This optimistic trend may be driven by increased knowledge augmented by mandatory trial registration and more stringent reporting guidelines and journal requirements. Nevertheless, relatively high probabilities of bias remain, particularly in journals with lower impact factors. This emphasizes that further improvement of RCT registration, conduct, and reporting is still urgently needed.

Better than nothing: A historical account of placebos and placebo effects from modern to contemporary medicine.

Throughout the history of medicine, multiple conceptions of "placebo" and "placebo effect" have often co-existed across different domains, and today the meaning of these concepts is still disputed. Against this background, this chapter provides a succinct account of the key events in the history of the concepts of "placebo," "placebo control," and "placebo effect." The first section reconstructs the etymology of the term "placebo" and its first introduction in medicine. The next sections provide an account of how placebos have been employed in both medical practice and scientific research in modern medicine. Later sections trace the emergence of the concepts of "placebo control" and "placebo effect" in the first half of the 20th century, from the first empirical studies investigating the effects of placebos up to the publication of Beecher's landmark article "The Powerful Placebo." Finally, the last two sections review the varieties of randomized, placebo-controlled trials (RCTs) in the second half of the 20th century, and the subsequent wave of empirical studies that, starting from the 1970s, have investigated the psychological, pharmacological and neurobiological mechanisms of placebo effects.

It Is Time to Reconsider Factorial Designs: How Bradford Hill and R. A. Fisher Shaped the Standard of Clinical Evidence.

OBJECTIVES: Could medical research and quality improvement studies be more productive with greater use of multifactor study designs? METHODS: Drawing on new primary sources and the literature, we examine the roles of A. Bradford Hill and Ronald A. Fisher in introducing the design of experiments in medicine. RESULTS: Hill did not create the randomized controlled trial, but he popularized the idea. His choice to set aside Fisher's advanced study designs shaped the development of clinical research and helped the single-treatment trial to become a methodological standard. CONCLUSIONS: Multifactor designs are not widely used in medicine despite their potential to make improvement initiatives and health services research more efficient and effective. Quality managers, health system leaders, and directors of research institutes could increase productivity and gain important insights by promoting a broader use of factorial designs to study multiple interventions simultaneously and to learn from interactions.

An FDA Review of Drug Development in Nonmetastatic Castration-resistant Prostate Cancer.

The FDA has approved three androgen receptor inhibitors-enzalutamide, apalutamide, and darolutamide-for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC.

Evolving primary and secondary endpoints in randomized controlled trials leading to approval of biologics and small molecules in IBD: an historical perspective.

Introduction: Therapeutic goals in inflammatory bowel diseases (IBD) have evolved, over the last decades, from clinical response to complete remission (clinical and endoscopic remission).Areas covered: Development of biologics and small molecules has been associated with the development of new endpoints in IBD trials that could not have been achieved in the pre-biologics era. Herein, we focus on evolving endpoints for approved biologics and small molecules. We searched for relevant publications using Medline/PubMed, Embase and the Cochrane Library from their inception to 1 July 2019.Expert opinion: Endpoints differ between induction (clinical and endoscopic response) and maintenance trials (clinical and endoscopic remission) because the goal is to evaluate the anti-inflammatory effect of a given drug during induction, whereas full disease control is the ultimate goal during the maintenance phase in order to change patients' life and disease course. Histological healing has recently emerged as a new co-primary endpoint in ulcerative colitis, and is now part of the definition of mucosal healing in these trials. Whether new endpoints such as transmural and radiologic healing could become an endpoint and replace endoscopy in Crohn's disease trials in the near future requires further investigation.