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Biostatistics (Oxford, England) Apr 2019Previous estimates of drug development success rates rely on relatively small samples from databases curated by the pharmaceutical industry and are subject to potential...
Previous estimates of drug development success rates rely on relatively small samples from databases curated by the pharmaceutical industry and are subject to potential selection biases. Using a sample of 406 038 entries of clinical trial data for over 21 143 compounds from January 1, 2000 to October 31, 2015, we estimate aggregate clinical trial success rates and durations. We also compute disaggregated estimates across several trial features including disease type, clinical phase, industry or academic sponsor, biomarker presence, lead indication status, and time. In several cases, our results differ significantly in detail from widely cited statistics. For example, oncology has a 3.4% success rate in our sample vs. 5.1% in prior studies. However, after declining to 1.7% in 2012, this rate has improved to 2.5% and 8.3% in 2014 and 2015, respectively. In addition, trials that use biomarkers in patient-selection have higher overall success probabilities than trials without biomarkers.
Topics: Biomarkers; Clinical Trials as Topic; Databases, Factual; Drug Development; Humans; Models, Statistical; Outcome Assessment, Health Care
PubMed: 29394327
DOI: 10.1093/biostatistics/kxx069 -
BioMed Research International 2023Ciprofol is a novel compound that was independently developed in China. According to the Chinese product instructions approved by the China National Medical Products... (Review)
Review
Ciprofol is a novel compound that was independently developed in China. According to the Chinese product instructions approved by the China National Medical Products Administration and the information of official website, indications for ciprofol include sedation and anesthesia during the surgical/procedure of nontracheal intubation, induction and maintenance of general anesthesia, and sedation during intensive care. Ciprofol is a short-acting intravenous sedative based on the structural modification of propofol. Ciprofol has high efficacy, good selectivity, and fewer adverse reactions, indicating good clinical application potential. A series of clinical studies have been conducted to evaluate the sedative effect of ciprofol in various procedures and settings, including gastroscopy and colonoscopy, fiber-optic bronchoscopy, general anesthesia in elective surgeries, and mechanical ventilation in intensive care units. This review summarizes the chemical structure, pharmacodynamics, and pharmacokinetic properties of ciprofol. We also assessed the efficacy and safety of ciprofol by synthesizing the relevant clinical trial data.
Topics: Humans; Anesthesia, General; Anesthesia, Intravenous; Anesthetics, Intravenous; Critical Care; Hypnotics and Sedatives; Propofol; Clinical Trials as Topic
PubMed: 36714027
DOI: 10.1155/2023/7443226 -
Cancer Treatment Reviews Jun 2020When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and... (Review)
Review
When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab's initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies. In the past 15 years, our understanding of VEGF's role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive. Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Bevacizumab; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Randomized Controlled Trials as Topic
PubMed: 32335505
DOI: 10.1016/j.ctrv.2020.102017 -
The British Journal of General Practice... Jun 2000Aromatherapy is becoming increasingly popular; however there are few clear indications for its use. To systematically review the literature on aromatherapy in order to... (Review)
Review
Aromatherapy is becoming increasingly popular; however there are few clear indications for its use. To systematically review the literature on aromatherapy in order to discover whether any clinical indication may be recommended for its use, computerised literature searches were performed to retrieve all randomised controlled trials of aromatherapy from the following databases: MEDLINE, EMBASE, British Nursing Index, CISCOM, and AMED. The methodological quality of the trials was assessed using the Jadad score. All trials were evaluated independently by both authors and data were extracted in a pre-defined, standardised fashion. Twelve trials were located: six of them had no independent replication; six related to the relaxing effects of aromatherapy combined with massage. These studies suggest that aromatherapy massage has a mild, transient anxiolytic effect. Based on a critical assessment of the six studies relating to relaxation, the effects of aromatherapy are probably not strong enough for it to be considered for the treatment of anxiety. The hypothesis that it is effective for any other indication is not supported by the findings of rigorous clinical trials.
Topics: Anxiety; Aromatherapy; Clinical Trials as Topic; Humans; Massage; Oils, Volatile; Treatment Outcome
PubMed: 10962794
DOI: No ID Found -
Gerontology 2019Metformin is sometimes proposed to be an "anti-aging" drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial... (Review)
Review
Metformin is sometimes proposed to be an "anti-aging" drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for type 2 diabetics. Large prospective, placebo-controlled trials are planned, in pilot stage or running, to find a new use (or indication) for an aging population. As one of the metformin trials has "frailty" as its endpoint, similar to a trial with a plant-derived senolytic, the latter class of novel anti-aging drugs is briefly discussed. Concerns exist not only for vitamin B12 and B6 deficiencies, but also about whether there are adverse effects of metformin on individuals who try to remain healthy by maintaining cardiovascular fitness via exercise.
Topics: AMP-Activated Protein Kinase Kinases; Aging; Animals; Cellular Senescence; Clinical Trials as Topic; Electron Transport Complex I; Humans; Hypoglycemic Agents; Longevity; Metformin; Protein Kinases; Rejuvenation
PubMed: 31522175
DOI: 10.1159/000502257 -
Nature Reviews. Drug Discovery Mar 2021In the past 15 years, B cells have been rediscovered to be not merely bystanders but rather active participants in autoimmune aetiology. This has been fuelled in part by... (Review)
Review
In the past 15 years, B cells have been rediscovered to be not merely bystanders but rather active participants in autoimmune aetiology. This has been fuelled in part by the clinical success of B cell depletion therapies (BCDTs). Originally conceived as a method of eliminating cancerous B cells, BCDTs such as those targeting CD20, CD19 and BAFF are now used to treat autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis. The use of BCDTs in autoimmune disease has led to some surprises. For example, although antibody-secreting plasma cells are thought to have a negative pathogenic role in autoimmune disease, BCDT, even when it controls the disease, has limited impact on these cells and on antibody levels. In this Review, we update our understanding of B cell biology, review the results of clinical trials using BCDT in autoimmune indications, discuss hypotheses for the mechanism of action of BCDT and speculate on evolving strategies for targeting B cells beyond depletion.
Topics: Animals; Autoimmune Diseases; B-Lymphocytes; Clinical Trials as Topic; Humans; Lymphocyte Depletion
PubMed: 33324003
DOI: 10.1038/s41573-020-00092-2 -
Hepatology (Baltimore, Md.) Aug 2018Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide, and the progressive form of this condition, nonalcoholic... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide, and the progressive form of this condition, nonalcoholic steatohepatitis (NASH), has become one of the leading indications for liver transplantation. Despite intensive investigations, there are currently no United States Food and Drug Administration-approved therapies for treating NASH. A major barrier for drug development in NASH is that treatment response assessment continues to require liver biopsy, which is invasive and interpreted subjectively. Therefore, there is a major unmet need for developing noninvasive, objective, and quantitative biomarkers for diagnosis and assessment of treatment response. Emerging data support the use of magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) as a noninvasive, quantitative, and accurate measure of liver fat content to assess treatment response in early-phase NASH trials. In this review, we discuss the role and utility, including potential sample size reduction, of MRI-PDFF as a quantitative and noninvasive imaging-based biomarker in early-phase NASH trials. Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide. NAFLD can be broadly classified into two categories: nonalcoholic fatty liver, which has a minimal risk of progression to cirrhosis, and nonalcoholic steatohepatitis (NASH), the more progressive form of NAFLD, which has a significantly increased risk of progression to cirrhosis. Over the past two decades, NASH-related cirrhosis has become the second leading indication for liver transplantation in the United States. For these reasons, pharmacological therapy for NASH is needed urgently. Despite intensive investigations, there are currently no therapies for treating NASH that have been approved by the United States Food and Drug Administration..
Topics: Biomarkers; Clinical Trials as Topic; Humans; Intra-Abdominal Fat; Liver; Magnetic Resonance Imaging; Non-alcoholic Fatty Liver Disease
PubMed: 29356032
DOI: 10.1002/hep.29797 -
Arthritis Research & Therapy May 2019Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the... (Meta-Analysis)
Meta-Analysis
Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data.
BACKGROUND
Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS).
METHODS
The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab.
RESULTS
A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs.
CONCLUSIONS
Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.
Topics: Antibodies, Monoclonal, Humanized; Arthritis, Psoriatic; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Humans; Product Surveillance, Postmarketing; Psoriasis; Randomized Controlled Trials as Topic; Severity of Illness Index; Spondylitis, Ankylosing; Time Factors
PubMed: 31046809
DOI: 10.1186/s13075-019-1882-2 -
Circulation Mar 2021Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative...
BACKGROUND
Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications.
METHODS
We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication.
RESULTS
Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation.
CONCLUSIONS
Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.
Topics: Aged; Female; Humans; Male; Middle Aged; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic
PubMed: 33327727
DOI: 10.1161/CIRCULATIONAHA.120.051718 -
Alimentary Pharmacology & Therapeutics Aug 2018Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti-fibrotic therapies are available;...
BACKGROUND
Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti-fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD.
AIM
To standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Chron's disease.
METHODS
An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting.
RESULTS
Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre-stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post-prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24-48 weeks is considered the appropriate endpoint in pharmacological trials.
CONCLUSIONS
Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design.
Topics: Catheterization; Clinical Trials as Topic; Colon; Consensus; Constriction, Pathologic; Crohn Disease; Dilatation; Endoscopy; Expert Testimony; Fibrosis; Humans; Intestinal Obstruction; Intestine, Small; Practice Guidelines as Topic; Reference Standards
PubMed: 29920726
DOI: 10.1111/apt.14853