scholarly journals Clinical trials for cellular therapy products: conclusions reached by foreign regulatory bodies

2020 ◽  
Vol 22 (2) ◽  
pp. 139-150
Author(s):  
E. V. Melnikova ◽  
O. V. Merkulova ◽  
V. A. Merkulov
Keyword(s):  
Clinical Trials ◽  
Cellular Therapy ◽  
Genetic Diseases ◽  
The United States ◽  
Expert Assessment ◽  
Control Group ◽  
Number Of Patients ◽  
Historical Group ◽  
Regulatory Bodies ◽  
State Registration

Currently, the problem of adopting viable human cell-based drugs – biomedical cell products (BCPs) – in medical practice in the Russian Federation includes, among others, lack of experience in clinical trials for such drugs and insufficient expert assessment under the national state registration procedure. In global practice, by the beginning of 2020, there were over 30 cellular therapy products (human cellular- and tissue-based products) known to have undergone clinical trials for sales licenses from regulatory bodies in the United States, European Union, Japan, and South Korea. Most cellular therapy products are intended for treatment of severe orphan diseases and lifethreatening conditions that currently cannot be treated by traditional drugs or methods. The aim of this study is to analyze the global experience in clinical trials for cellular therapy products and also to examine conclusions reached by regulatory authorities with regards to issuance of sales licenses for the products. Particular attention was paid to clinical trials that subsequently led to granting of sales license (state registration). In reviewing such trials, we also focused on the types and number of clinical trials, the number of patients involved in the clinical trials, conclusions made by expert regulatory agencies on the efficacy, safety and risk/benefit ratio. Most of the products were approved for use based on uncontrolled phase II clinical trials. In the clinical trial, apart from the historical group and the placebo-controlled group, there was also a control group that received nothing. The number of patients in most clinical trials was limited, especially for drugs intended for treatment of rare genetic diseases, as well as drugs approved for use in Japan.

scholarly journals Design and analysis of a clinical trial using previous trials as historical control

2019 ◽  
Vol 16 (5) ◽  
pp. 531-538 ◽  
Author(s):  
David Alan Schoenfeld ◽  
Dianne M Finkelstein ◽  
Eric Macklin ◽  
Neta Zach ◽  
David L Ennist ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Sample Size ◽  
Standard Error ◽  
Controlled Trial ◽  
Sample Size Calculation ◽  
Control Group ◽  
Controlled Trials ◽  
Number Of Patients ◽  
Lateral Sclerosis

Background/AimsFor single arm trials, a treatment is evaluated by comparing an outcome estimate to historically reported outcome estimates. Such a historically controlled trial is often analyzed as if the estimates from previous trials were known without variation and there is no trial-to-trial variation in their estimands. We develop a test of treatment efficacy and sample size calculation for historically controlled trials that considers these sources of variation.MethodsWe fit a Bayesian hierarchical model, providing a sample from the posterior predictive distribution of the outcome estimand of a new trial, which, along with the standard error of the estimate, can be used to calculate the probability that the estimate exceeds a threshold. We then calculate criteria for statistical significance as a function of the standard error of the new trial and calculate sample size as a function of difference to be detected. We apply these methods to clinical trials for amyotrophic lateral sclerosis using data from the placebo groups of 16 trials.ResultsWe find that when attempting to detect the small to moderate effect sizes usually assumed in amyotrophic lateral sclerosis clinical trials, historically controlled trials would require a greater total number of patients than concurrently controlled trials, and only when an effect size is extraordinarily large is a historically controlled trial a reasonable alternative. We also show that utilizing patient level data for the prognostic covariates can reduce the sample size required for a historically controlled trial.ConclusionThis article quantifies when historically controlled trials would not provide any sample size advantage, despite dispensing with a control group.

Distribution and geographic accessibility of prostate cancer clinical trials in the United States.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 59-59 ◽  
Author(s):  
Matt D. Galsky ◽  
Asma Latif ◽  
Kristian D. Stensland ◽  
Erin L. Moshier ◽  
Russell McBride ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
United States ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Geographic Distribution ◽  
The United States ◽  
First Line ◽  
Trial Site ◽  
Lorenz Curves ◽  
Number Of Patients

59 Background: An extremely small proportion of patients with cancer in the United States (US) enroll in clinical trials. While several barriers to trial accrual have been described, the geographic distribution and accessibility of clinical trial sites has not been comprehensively explored. Methods: ClinicalTrials.gov was queried to identify all active US clinical trials exploring first-line therapies for metastatic prostate cancer (PCa) on 9/16/2012. We evaluated the geographic distribution of trial sites and determined the relationship between the number of sites and the number of patients with advanced PCa per county and evaluated heterogeneity using Lorenz curves. We also estimated the minimum driving distance required to access a clinical trial site from each ZIP code in the continguous US; a distance >30 miles was defined as high travel burden consistent with prior studies. Results: We identified 958 sites associated with 42 PCa clinical trials (Table). The geographic distribution of clinical trial sites was very inhomogeneous with several states having only 1-2 trial sites. Among 3185 US counties, 2,669 (83.8%) had no clinical trials available for first-line treatment of metastatic PCa. Counties with larger populations of patients with advanced PCa had significantly higher numbers of clinical trial sites. For every 100 additional patients with advanced PCa per county, the number of available trial sites increased by 21.0% (95% CI: 16.5-25.7%). However, Lorenz curves indicated a high degree of inequality in trial accessibility (Gini index 0.71). Approximately 31% of the US population resided >30 miles from a PCa trial site. Conclusions: Clinical trials sites are poorly accessible, geographically, to a large subset of US PCa patients, a finding that likely contributes to dismal accrual. Innovative solutions are required to address geographic barriers to access. [Table: see text]

scholarly journals Racial and Ethnic Enrollment Disparities and Demographic Reporting Requirements in Acute Leukemia Clinical Trials

2021 ◽  
Author(s):  
Andrew Hantel ◽  
Marlise R. Luskin ◽  
Jacqueline S Garcia ◽  
Wendy Stock ◽  
Daniel J DeAngelo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Native American ◽  
Acute Leukemia ◽  
Race And Ethnicity ◽  
Disease Incidence ◽  
The United States ◽  
Reporting Requirements ◽  
Number Of Patients ◽  
Hispanic Patients ◽  
Race Ethnicity

Data regarding racial and ethnic enrollment diversity for acute myeloid (AML) and lymphoid leukemia (ALL) clinical trials in the United States (US) are limited, and little is known about the effect of federal reporting requirements instituted in the late 2000s. We examined demographic data reporting and enrollment diversity for US ALL and AML trials from 2002-2017 as well as changes in reporting and diversity after reporting requirements were instituted. Of 223 AML and 97 ALL trials with results, 68 (30.5%) and 51 (52.6%) reported enrollment by both race and ethnicity. Among trials that reported race and ethnicity (AML N=6,554; ALL N=4,149), non-Hispanic (NH)-Black, NH-Native American, NH-Asian, and Hispanic patients had significantly lower enrollment compared to NH-white patients after adjusting for race-ethnic disease incidence (AML odds: 0.68, 0.31, 0.75, and 0.83; ALL: 0.74, 0.27, 0.67, and 0.64; all p≤0.01). The proportion of trials reporting race increased significantly after the reporting requirements (44.2 to 60.2%; p=0.02), but race-ethnicity reporting did not (34.8 to 38.6%; p=0.57). Reporting proportions by number of patients enrolled increased significantly after the reporting requirements (race: 51.7 to 72.7%, race-ethnicity: 39.5 to 45.4%; both p<0.001), and relative enrollment of NH-Black and Hispanic patients decreased (AML odds: 0.79 and 0.77; ALL: 0.35 and 0.25; both p≤0.01). These data suggest that demographic enrollment reporting for acute leukemia trials is suboptimal, changes in diversity after the reporting requirements may be due to additional enrollment disparities that were previously unreported, and enrollment diversification strategies specific to acute leukemia care delivery are needed.

Inhaled Nitric Oxide for Persistent Pulmonary Hypertension of the Newborn: Implications and Strategy for Future "High-Tech" Neonatal Clinical Trials

PEDIATRICS ◽  
1995 ◽  
Vol 96 (6) ◽  
pp. 1147-1151
Author(s):  
Ann R. Stark ◽  
Dennis Davidson
Keyword(s):  
Nitric Oxide ◽  
United States ◽  
Clinical Trials ◽  
Pulmonary Hypertension ◽  
The United States ◽  
Inhaled Nitric Oxide ◽  
Persistent Pulmonary Hypertension ◽  
High Tech ◽  
Widespread Application ◽  
Number Of Patients

Five large clinical trials are in progress in the United States and Canada examining the efficacy and safety of inhaled nitric oxide (iNO) for persistent pulmonary hypertension of the newborn (PPHN) and severe respiratory failure in near-term and term infants. A large trial in France that includes premature infants is also under way. Neonatologists have shown great interest in the use of iNO as a selective pulmonary vasodilator, but in the United States and perhaps elsewhere, widespread application of this treatment outside of study sites will have to await completion of clinical trials. At the current pace, we expect it will take several years to enroll an adequate number of patients to address relevant outcome end-points.

scholarly journals Mitochondrial Replacement Therapy: Let the Science Decide

2021 ◽  
pp. 345
Author(s):  
Sabrina Glavota
Keyword(s):  
United States ◽  
Clinical Trials ◽  
Replacement Therapy ◽  
Dna Sequences ◽  
Genetic Diseases ◽  
Mitochondrial Diseases ◽  
The United States ◽  
Vitro Fertilization ◽  
Mitochondrial Replacement Therapy

Mitochondrial replacement therapy (MRT) is an in vitro fertilization technique designed to prevent women who are carriers of mitochondrial diseases from passing on these heritable genetic diseases to their children. It is an innovative assisted reproductive technology that is only legal in a small number of countries. The United States has essentially stagnated all opportunities for research and clinical trials on MRT through a rider in H.R.2029 – Consolidated Appropriations Act, 2016. The rider bans clinical trials on all therapies in which a human embryo is intentionally altered to include a heritable genetic modification. This note argues that the rider should be amended to permit therapies such as MRT, which do not create artificial DNA sequences, while continuing to prohibit clinical trials on germline therapies that modify the sequence of a gene. MRT is distinct from the types of therapies that Congress intended to ban through the rider. Amending the rider would not automatically approve MRT trials, but rather allow the FDA to evaluate investigational new drug applications and determine whether individual trials may proceed. Without proper FDA oversight, carriers of mitochondrial diseases are denied access to a therapy that provides them with benefits they cannot enjoy by any other means, and researchers may look abroad to conduct the therapy illegally or dangerously. Further, the United States can look to other countries such as the United Kingdom as a model for how to proceed with research and trials on MRT in an ethical manner.

Prescreening to Increase Therapeutic Oncology Trial Enrollment at the Largest Public Hospital in the United States

2021 ◽  
Author(s):  
Jennifer Wu ◽  
Amin Yakubov ◽  
Maher Abdul-Hay ◽  
Erica Love ◽  
Gianna Kroening ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Low Income ◽  
Underserved Populations ◽  
The United States ◽  
Public Health Care ◽  
Tumor Board ◽  
Cancer Center ◽  
Therapeutic Trial ◽  
Improvement Program ◽  
Number Of Patients

PURPOSE: The recruitment of underserved patients into therapeutic oncology trials is imperative. The National Institutes of Health mandates the inclusion of minorities in clinical research, although their participation remains under-represented. Institutions have used data mining to match patients to clinical trials. In a public health care system, such expensive tools are unavailable. METHODS: The NYU Clinical Trials Office implemented a quality improvement program at Bellevue Hospital Cancer Center to increase therapeutic trial enrollment. Patients are screened through the electronic medical record, tumor board conferences, and the cancer registry. Our analysis evaluated two variables: number of patients identified and those enrolled into clinical trials. RESULTS: Two years before the program, there were 31 patients enrolled. For a period of 24 months (July 2017 to July 2019), we identified 255 patients, of whom 143 (56.1%) were enrolled. Of those enrolled, 121 (84.6%) received treatment, and 22 (15%) were screen failures. Fifty-five (38.5%) were referred to NYU Perlmutter Cancer Center for therapy. Of the total enrollees, 64% were female, 56% were non-White, and overall median age was 55 years (range: 33-88 years). Our participants spoke 16 different languages, and 57% were non–English-speaking. We enrolled patients into eight different disease categories, with 38% recruited to breast cancer trials. Eighty-three percent of our patients reside in low-income areas, with 62% in both low-income and Health Professional Shortage Areas. CONCLUSION: Prescreening at Bellevue has led to a 4.6-fold increase in patient enrollment to clinical trials. Future research into using prescreening programs at public institutions may improve access to clinical trials for underserved populations.

Oncology medical home: Payer return on investment (ROI).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e17582-e17582
Author(s):  
Winston Wong ◽  
Joseph Cooper ◽  
Daniel Winn ◽  
Tim Olson ◽  
Ram Swarup Trehan ◽  
...  
Keyword(s):  
Emergency Room ◽  
Medical Home ◽  
Hospital Admissions ◽  
Financial Incentive ◽  
The United States ◽  
Control Group ◽  
Total Risk ◽  
Home Program ◽  
Adjusted Cost ◽  
Number Of Patients

e17582 Background: CareFirst BlueCross BlueShield (CFBCBS) partnered with Cardinal Health Specialty Solutions (CHSS) to launch the first cancer clinical pathway in the United States in August 2008. Due to the early success of the program with regard to savings and physician participation and compliance, CFBCBS and CHSS piloted an oncology medical home program in January 2011 with the hope of further decreasing cancer care costs while continuing consistency and quality of care. We analyzed payer ROI after year +1 of the medical home program. Methods: The medical home program offered a new physician reimbursement model that shifted the source of revenue from margin on drug sales to cognitive services allowing physicians to focus on optimal patient care without the financial incentive to prescribe chemotherapy. Physicians were encouraged to commit to an intensive continuous quality improvement (CQI) program, which included an end-of-life initiative and a post chemotherapy nurse call-back program that would lower costs by decreasing emergency room and hospital admissions. Physicians participating in the first CFBCBS pathway program were eligible to join the medical home program; physicians who chose not to join made up the control group. Data were collected from April 2010 to March 2012. Medical home ROI was calculated by subtracting the total weighted cost per patient for the medical home group from the total risk-adjusted cost per patient for the control group multiplied by the total number of patients in the medical home program. Results: Fourteen practices (31 physicians, 478 patients) joined the medical home program. The control group was comprised of 39 practices (103 physicians, 2031 patients). Total weighted cost per patient for the medical home program for year +1 was $26,702. Risk-adjusted cost per patient for the control group for year +1 was $30,670. The medical home program provided a gross savings of $2,016,868 compared to the first CFBCBS pathways program. Conclusions: Significant savings can be achieved in a provider group already compliant with a mature pathways program. A CQI program can directly and favorably impact patient outcomes and ROI via presumed reduction in emergency room and hospital admissions.

Cardiac Arrest Research Methods

1993 ◽  
Vol 8 (S1) ◽  
pp. S41-S44
Author(s):  
Terence D. Valenzuela ◽  
W. Douglas Weaver
Keyword(s):  
United States ◽  
Clinical Trials ◽  
Quality Assurance ◽  
Cardiac Arrest ◽  
Medical Condition ◽  
Prehospital Care ◽  
The United States ◽  
Control Group ◽  
Research Questions ◽  
Hospital Cardiac Arrest

Determining the variables that influence survival in the treatment of cardiac arrest is important as both a research and a quality assurance tool. Out-of-hospital cardiac arrest remains the only medical condition in which it has been determined rigorously that prehospital care affects survival. Thus, it uniquely is suited to outcome-based research and quality assurance studies. After approximately 20 years of study, the determinants of survival after cardiac arrest are well-known; however, a plethora of fascinating research questions remain to be addressed.The prevalence of out-of-hospital cardiac arrest seems to be decreasing. In the Seattle area, there are 30% fewer cases than there were ten years ago. This parallels the overall decline in mortality from ischemic heart disease in the United States in the last thirty years. There also has been a change in the profile of cardiac arrest victims, with today's arrestee several years older than the victim of fifteen years ago. Thus, when one performs comparative clinical trials, the control group of today is very different from the historical control of ten or fifteen years ago.

scholarly journals Mouth-rinses and SARS-CoV-2 viral load in saliva: A living systematic review

2021 ◽  
Author(s):  
Akram Hernández-Vásquez ◽  
Antonio Barrenechea-Pulache ◽  
Daniel Comandé ◽  
Diego Azañedo
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Viral Load ◽  
Randomized Clinical Trials ◽  
Risk Of Bias ◽  
Control Group ◽  
Sterile Water ◽  
Eligibility Criteria ◽  
Mouth Rinses ◽  
Number Of Patients

ABSTRACTObjectiveTo conduct a living systematic review of the clinical evidence regarding the effect of different mouth-rinses on the viral load of SARS-CoV-2 in the saliva of infected patients. The viral load in aerosols, the duration of the reduction in viral load, viral clearance, SARS-CoV-2 cellular infectivity, and salivary cytokine profiles were also evaluated.Materials and methodsThis study was reported using the PRISMA guidelines. An electronic search was conducted in seven databases and in preprint repositories. We included human clinical trials that evaluated the effect of mouth-rinses with antiseptic substances on the viral load of SARS-CoV-2 in the saliva of children or adults that tested positive for SARS-CoV-2 using reverse transcriptase polymerase chain reaction (RT-PCR). Risk of bias was assessed using the ROBINS-I tool. PROSPERO registration number CRD42021240561.ResultsFour studies matching eligibility criteria were selected for evaluation (n=32 participants). Study participants underwent oral rinses with hydrogen peroxide (H2O2) at 1 %, povidone–iodine (PI) at 0.5% or 1%, chlorhexidine gluconate (CHX) at 0.2% or 0.12% or cetylpyridinium chloride (CPC) at 0.075%. Only one study included a control group with sterile water. Three of the studies identified a significant reduction in viral load up to 3, 4, and 6 hours after the use of mouthwashes with PI, CHX, and CPC or PI vs. sterile water, respectively, while one study did not identify a significant reduction in viral load after the use of H2O2 rinses.ConclusionsAccording to the present systematic review, the effect of the use of mouth-rinses on SARS-CoV-2 viral load in the saliva of COVID-19 patients remains uncertain. This is mainly due to the limited number of patients included and a high risk of bias present in the studies analyzed. Evidence from well-designed randomized clinical trials is required for further and more objective evaluation of this effect.

scholarly journals PHYSIOLOGICAL EFFICIENCY OF DRINKS FROM FENUGREEK SEEDS

2021 ◽  
Vol 39 (3) ◽  
pp. 105-114
Author(s):  
PRYTULSKA Nataliia ◽  
MOTUZKA Yuliia ◽  
KOSHELNYK Anna
Keyword(s):  
Clinical Trials ◽  
The Body ◽  
Control Group ◽  
Emotional States ◽  
Duration Of Treatment ◽  
Fenugreek Seeds ◽  
Endocrine Diseases ◽  
Physiological Efficiency ◽  
Number Of Patients ◽  
Therapeutic Diets

Background. Today, diabetes is one of the most common diseases with a steady upward trend. In particular in Ukraine it ranks 2nd among endocrine diseases in the number of patients. The annual growth of such patients averages 9.8–11 %. In the treatment of endocrine diseases, dietary nutrition aimed at normalizing metabolismis of great importance. It is recommended to add to the diet special, func­tionally-oriented foods based on biologically valuable raw materials. The aim of the workis to determine the physiological efficiency of drinks from fenugreek seeds. Materials and methods. The physiological effects of fenugreek seed drinks were determined from clinical trials involving 54 patients with type II diabetes and 40 patients diagnosed with pre-diabetes. Two groups of 32 patients who did not consume the product were also selected. Biochemical methods were used to assess the effect of the product on the correction of condition of patients according to the indicators of the general condition of patients, the indicator of the level of glucose and cholesterol in the blood.The assessment of physical and psycho-emotional states was conducted by a survey. Drink is a plant-based milk analogue from the fenugreek seeds is presented in a ready-to-drink form.Depending on the disease and the condition of the body, participants in clinical trials drank the developed drink daily at 200–400 cm3/day (1–2 times a day at 200 cm3) for 30–60 days together with an individually prescribed treatment package. Results. It was found that patients who consumed a drink of fenugreek seeds in addition to the main diet had a faster normalization of blood glucose levels, more pronounced improvement in physical condition, as well as a reduction in the overall duration of treatment than patients in the control group. There was an improvement in lipid metabolism in patients of both study groups who drank a plant-based milk analogue from fenugreek seeds, and patients have noted that consumption of the developed drink helped to improve the condition of the gastrointestinal tract.This can be explained by the large number of galactomannans in the fenugreek seeds, which promote the secretion of mucous substances during the production of the drink. Conclusion. The new plant-based milk analogue from fenugreek seeds helps to normalize blood sugar and cholesterol levels, and therefore can be recommended for use in dietary and therapeutic diets of people with diabetes and atherosclerosis during treatment and recovery. Taking into accountthe properties of fenugreek seeds, the developed product can be recommended to protect the organs of the gastrointestinal tract in these diseases and in general to normalize metabolism.

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