Persistent under-representation of female patients in United States trials of common vascular diseases from 2008 to 2020.

BACKGROUND: Women have been historically under-represented in vascular surgery and cardiovascular medicine trials. The rate and change in representation of women in trials of common vascular diseases over the last decade is not understood completely. METHODS: We used publicly available data from ClinicalTrials.gov to evaluate trials pertaining to carotid artery stenosis (CAS), peripheral arterial disease (PAD), thoracic and abdominal aortic aneurysms (TAA and AAA), and type B aortic dissections (TBAD) from 2008 to the present. We evaluated representation of women in these trials based on the participation-to-prevalence ratios (PPR), which are calculated by dividing the percentage of women among trial participants by the percentage of women in the disease population. Values of 0.8 to 1.2 reflect similar representation. RESULTS: The sex distribution was reported in all 97 trials, including 11 CAS trials, 68 PAD trials, 16 TAA/AAA trials, and 2 TBAD trials. The total number of participants in these trials was 41,622 and the median number of participants per trial was 150.5 (interquartile range [IQR], 50-252). The percentage of women in the disease population was 51.9% for CAS, 53.1% for PAD, 34.1% for TAA/AAA, and 30.9% for TBAD. Industry sources funded 76 of the trials (77.6%), and the Veterans Affairs Administration (n = 4 [4.1%]), unspecified university (n = 7 [7.1%]), and extramural sources (n = 11 [11.2%]) funded the remainder of the trials. The overall median PPR for all four diseases was 0.65 (IQR, 0.51-0.80). Women were under-represented for all four conditions studied (CAS, 0.73 [IQR, 0.62-0.96]; PAD, 0.65 [IQR, 0.53-0.77]; TAA/AAA, 0.59 [IQR, 0.38-1.20]; and TBAD, 0.74 [IQR, 0.65-0.84]). There was no significant difference in PPR among the diseases (P = .88). From 2008 to the present, there was no significant change in PPR values over time overall (r2 = 0.002; P = .70). When examined individually, PPR did not change significantly over time for any of the diseases studied (for each, r2 < 0.04; P > .45). The PPR did not vary significantly over time for any of the funding sources (for each, r2 < 0.85, P > .08). There was appropriate representation (PPR of 0.8-1.2) in a minority of trials for each disease except TBAD (CAS, 27.3%; PAD, 15.9%; TAA/AAA, 18.8%; and TBAD, 50%). Trials that were primarily funded from university sources had the highest median PPR (1.04; IQR, 0.21-1.27), followed by industry-funded (0.67; IQR, 0.54-0.81), and extramurally funded (0.60; IQR, 0.34-0.73). Studies funded by Veterans Affairs had the lowest PPR (0.02; IQR, 0.00-0.11; P = .004). CONCLUSIONS: Participation of women in US trials of common vascular diseases remains low and has not improved since 2008. Therefore, the generalizability of recent trial results to women with these vascular diseases remains unknown. An improved understanding of the underlying root causes for poor female trial participation, advocacy, and education are required to improve the generalizability of trial results for female vascular patients.

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.

High-Impact Clinical Studies That Fomented New Developments in Anesthesia: History of Achievements, 1966-2015.

The aim of this work is to identify the most influential initial clinical studies that fomented important developments in anesthesiology over the past 50 years. Studies fomenting new development can be selected using vastly different approaches and, therefore, might provide diverse outcomes. In the present work, two basic aspects of study assessments - the stage of development (eg, generation of idea, preclinical studies, clinical trials) and the method of selection (eg, committee vote, various types of citation analysis, method of finding the invention disclosure) - were chosen according to the following model. The stage of development: the initial clinical studies demonstrating the basic advantage of an innovation for providing anesthesia. The method: a combination of two factors - the study priority in terms of the time of its publication and the degree of its acknowledgement in the form of citation impact; the time of study publication was regarded as a primary factor, but only if the study's citation count was =/>20. The initial high-impact studies were selected for 16 drug-related topics (ketamine, isoflurane, etomidate, propofol, midazolam in anesthesia, vecuronium, alfentanil, atracurium, sevoflurane, sufentanil, rocuronium, desflurane, ropivacaine, remifentanil, dexmedetomidine in anesthesia, and sugammadex), and 9 technique-related topics (ultrasound-guided peripheral nerve block, capnography in anesthesia, target-controlled intravenous anesthesia, pulse oximetry in anesthesia, total intravenous anesthesia, transesophageal echocardiography in anesthesia, combined spinal-epidural anesthesia, and bispectral index). Twenty-five studies were designated the first high-impact studies (one for each topic); 16 are drug-related and 9 are technique-related. Half of the first high-impact studies had a citation count of =/>100, (range: 100 to 555). The citation count of the other half of high-impact studies did not reach the 100-citation threshold (range: 41 to 97). If a selected first high-impact study had a citation count <100, a next-on-timeline, additional study with citation count =/>100 was also selected; (range: 100 to 344). The present results show that an initial high-impact clinical study on a new development in anesthesiology can be determined and that related citations usually vary from one hundred to five hundred.

Changes in clinical trials of endocrine disorder and metabolism and nutrition disorder drugs in mainland China over 2010-2019.

With the improvements in relevant policies, laws, and regulations regarding drug clinical trials in China, the quantity and quality of drug clinical trials have gradually improved, and the development prospects of drug clinical trials for endocrine disorders and metabolism and nutrition disorders are promising. Based on information from the clinical trials from the online drug clinical trial registration platform of the National Medical Products Administration, we aimed to review and evaluate the development of clinical trials of drugs for endocrine disorders and metabolism and nutrition disorders in mainland China from 2010 to 2019, as well as the trends over time. A total of 861 trials were carried out on 254 types of drugs for endocrine disorders and metabolism and nutrition disorders, among which 531 (61.67%) involved endocrine disorders, and 330 (38.33%) addressed metabolism and nutrition disorders. The annual number of clinical trials has been increasing gradually, with a significant increase in 2017. Among them, the proportion of clinical trials with Chinese epidemiological characteristics was relatively large (Wu, Annual Report on Development Health Management and Health Industry in China, 2018). The largest number of trials were for diabetes drugs (55.63%), followed by trials of drugs for hyperlipidemia (19.4%) and those for hyperuricemia (7.9%). It was found that the geographical area of the leading units also showed obvious unevenness according to the analysis of the test unit data. Based on the statistics and evaluation of the data, comprehensive information is provided to support the cooperation of global pharmaceutical R&D companies and research units in China and the development of international multicenter clinical trials in China. This work additionally provides clinical trial units with a self-evaluation of scientific research competitiveness and hospital development strategies. At the same time, it provides a reference with basic data for sponsors and stakeholders in these trials to determine their development strategy goals.

Development and Clinical Applications of Antisense Oligonucleotide Gapmers.

DNA-like molecules called antisense oligonucleotides have opened new treatment possibilities for genetic diseases by offering a method of regulating gene expression. Antisense oligonucleotides are often used to suppress the expression of mutated genes which may interfere with essential downstream pathways. Since antisense oligonucleotides have been introduced for clinical use, different chemistries have been developed to further improve efficacy, potency, and safety. One such chemistry is a chimeric structure of a central block of deoxyribonucleotides flanked by sequences of modified nucleotides. Referred to as a gapmer, this chemistry produced promising results in the treatment of genetic diseases. Mipomersen and inotersen are examples of recent FDA-approved antisense oligonucleotide gapmers used for the treatment of familial hypercholesterolemia and hereditary transthyretin amyloidosis, respectively. In addition, volanesorsen was conditionally approved in the EU for the treatment of adult patients with familial chylomicronemia syndrome (FCS) in 2019. Many others are being tested in clinical trials or under preclinical development. This chapter will cover the development of mipomersen and inotersen in clinical trials, along with advancement in gapmer treatments for cancer, triglyceride-elevating genetic diseases, Huntington's disease, myotonic dystrophy, and prion diseases.

Decitabine/Cedazuridine: First Approval.

A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.

Vadadustat: First Approval.

Vadadustat (VAFSEO®) is a prolyl hydroxylase inhibitor being developed by Akebia Therapeutics, Inc. (Akebia) for the treatment of anaemia associated with chronic kidney disease (CKD). Akebia is collaborating with Mitsubishi Tanabe Pharma Corporation on the development and commercialization of vadadustat in Japan and with Otsuka Pharmaceutical Co. Ltd on the development and commercialization of vadadustat in the USA, the EU and certain other territories. The drug is approved in Japan for use in adult patients with anaemia associated with CKD and regulatory submissions are planned in the USA and the EU. This article summarizes the milestones in the development of vadadustat leading to this first approval.

Clinical trials and the origins of pharmaceutical fraud: Parke, Davis & Company, virtue epistemology, and the history of the fundamental antagonism.

This paper describes one possible origin point for fraudulent behavior within the American pharmaceutical industry. We argue that during the late nineteenth century therapeutic reformers sought to promote both laboratory science and increasingly systematized forms of clinical experiment as a new basis for therapeutic knowledge. This process was intertwined with a transformation in the ethical framework in which medical science took place, one in which monopoly status was replaced by clinical utility as the primary arbiter of pharmaceutical legitimacy. This new framework fundamentally altered the set of epistemic virtues-a phrase we draw from the philosophical field of virtue epistemology-considered necessary to conduct reliable scientific inquiry regarding drugs. In doing so, it also made possible new forms of fraud in which newly emergent epistemic virtues were violated. To make this argument, we focus on the efforts of Francis E. Stewart and George S. Davis of Parke, Davis & Company. Therapeutic reformers within the pharmaceutical industry, such as Stewart and Davis, were an important part of the broader normative and epistemic transformation we describe in that they sought to promote laboratory science and systematized clinical trials toward the twin goals of improving pharmaceutical science and promoting their own commercial interests. Yet, as we suggest, Parke, Davis & Company also serves as an example of a company that violated the very norms that Stewart and Davis helped introduce. We thus seek to describe one possible origin point for the widespread fraudulent practices that now characterize the pharmaceutical industry. We also seek to describe an origin point for why we conceptualize such practices as fraudulent in the first place.

Treatment of systemic necrotizing vasculitides: The 40-year experience of the French Vasculitis Study Group.

Treatment of vasculitides has benefited from the results of several prospective clinical trials focusing on the evaluation of new drugs, therapeutic strategies and adjuvant treatments. In the field of autoimmunity, vasculitides are the group of diseases for which the most important medical progress has been made, combining advances in understanding the pathogenetic mechanisms, classification of the various entities and willingness to evaluate treatments. Several international groups have been actively involved in these tasks. The French Vasculitis Study Group was the first to design and organize prospective trials in the field and to contribute to these medical advances. In this review, we analyze the different treatments and therapeutic strategies evaluated over the last few decades and, more precisely, the last 39 years by the French Vasculitis Study Group.