Adaptive Learning of Drug Quality and Optimization of Patient Recruitment for Clinical Trials with Dropouts

2021 ◽  
Author(s):  
Zhili Tian ◽  
Weidong Han ◽  
Warren B. Powell
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Dynamic Programming ◽  
Value Function ◽  
Standard Treatment ◽  
Treatment Effectiveness ◽  
Interim Analyses ◽  
Clinical Trial Program ◽  
Patient Enrollment ◽  
The Value Function

Problem definition: Clinical trials are crucial to new drug development. This study investigates optimal patient enrollment in clinical trials with interim analyses, which are analyses of treatment responses from patients at intermediate points. Our model considers uncertainties in patient enrollment and drug treatment effectiveness. We consider the benefits of completing a trial early and the cost of accelerating a trial by maximizing the net present value of drug cumulative profit. Academic/practical relevance: Clinical trials frequently account for the largest cost in drug development, and patient enrollment is an important problem in trial management. Our study develops a dynamic program, accurately capturing the dynamics of the problem, to optimize patient enrollment while learning the treatment effectiveness of an investigated drug. Methodology: The model explicitly captures both the physical state (enrolled patients) and belief states about the effectiveness of the investigated drug and a standard treatment drug. Using Bayesian updates and dynamic programming, we establish monotonicity of the value function in state variables and characterize an optimal enrollment policy. We also introduce, for the first time, the use of backward approximate dynamic programming (ADP) for this problem class. We illustrate the findings using a clinical trial program from a leading firm. Our study performs sensitivity analyses of the input parameters on the optimal enrollment policy. Results: The value function is monotonic in cumulative patient enrollment and the average responses of treatment for the investigated drug and standard treatment drug. The optimal enrollment policy is nondecreasing in the average response from patients using the investigated drug and is nonincreasing in cumulative patient enrollment in periods between two successive interim analyses. The forward ADP algorithm (or backward ADP algorithm) exploiting the monotonicity of the value function reduced the run time from 1.5 months using the exact method to a day (or 20 minutes) within 4% of the exact method. Through an application to a leading firm’s clinical trial program, the study demonstrates that the firm can have a sizable gain of drug profit following the optimal policy that our model provides. Managerial implications: We developed a new model for improving the management of clinical trials. Our study provides insights of an optimal policy and insights into the sensitivity of value function to the dropout rate and prior probability distribution. A firm can have a sizable gain in the drug’s profit by managing its trials using the optimal policies and the properties of value function. We illustrated that firms can use the ADP algorithms to develop their patient enrollment strategies.

scholarly journals SO093LONGITUDINAL DATA ON TREATMENT DURATION AND COMPLIANCE FROM AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE CLINICAL TRIALS WITH TOLVAPTAN

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Xiaolei Zhou ◽  
Diana Garbinsky ◽  
John Ouyang ◽  
Eric Davenport ◽  
Indra Agarwal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Treatment Duration ◽  
Treatment Time ◽  
Treatment Compliance ◽  
Kidney Volume ◽  
Total Kidney Volume ◽  
Treatment Gaps ◽  
Clinical Trial Program

Abstract Background and Aims : Observation of impactful clinical outcomes in a clinical trial setting for ADPKD is challenging due to the life-long progressive nature of ADPKD and longer-term associated outcomes of interest in this population (e.g., renal function decline, cardiovascular events, and mortality). Since 2004, the tolvaptan (TOL) clinical trial program enrolled subjects in multiple clinical studies with the opportunity to enroll in subsequent clinical trials for treatment and outcomes evaluation. Method : Data from 6 ADPKD studies (protocols 156-04-250, 156-04-251, 156-06-260, 156-09-284, 156-09-290, 156-08-271) were pooled and evaluated over time for overall treatment duration, treatment time, and treatment gaps. Treatment duration for the individual clinical trials ranged from 1 week to up to 3 years. Results : Overall, 1,437 subjects received TOL in these ADPKD clinical trials. For these subjects, the mean overall treatment duration was 4.1 years (3.8 years on treatment) with a maximum of 9.7 years (9.0 years on treatment). In this cohort, 513 subjects (35.7%) received TOL treatment for more than 5 years. Mean treatment compliance was 94.1%. Overall, 723 subjects (50.3%) received TOL treatment in ≥2 trials, with a median treatment gap duration between trials of 0.1 years (maximum, 5.6 years). At least 7 years of follow-up data are available for estimated glomerular filtration rate in 241 subjects (mean at baseline, 78.6 mL/min/1.73m2) and for total kidney volume in 130 subjects (mean at baseline, 1,816.9 mL). Conclusion : This analysis provides longitudinal follow-up over an extended timeframe in a large number of subjects treated with TOL, with the greatest number of subjects being enrolled in clinical trials enriched for rapidly progressing ADPKD. Treatment compliance over years was reasonably good despite treatment gaps.

Adverse Reactions following Two Separate Intravascular Injections of Contrast Media in the Same Patient

1987 ◽  
Vol 28 (1) ◽  
pp. 93-97 ◽  
Author(s):  
E. E. Sogn ◽  
T. Ødegård ◽  
T. Haider ◽  
E. Andrew
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Contrast Media ◽  
Contrast Medium ◽  
Comparative Studies ◽  
Adverse Reactions ◽  
Northern Europe ◽  
Retrospective Design ◽  
Clinical Trial Program ◽  
Recurrence Frequency

Adverse reactions following contrast medium injections in 26 non-comparative and parallel trials were extracted from the iohexol vascular clinical trial program in Northern Europe. Six hundred and forty-one patients (13–88 years old) in whom information was available about a vascular contrast medium examination before the iohexol clinical trials were included, enabling a retrospective within patient comparison of adverse reactions. Iohexol gave a lower recurrence frequency (approximately 3.5 times) of reactions than ionic monomers in patients who previously experienced adverse reactions to vascular contrast media. In order to overcome some of the drawbacks with the present retrospective design, prospective comparative studies are recommended.

scholarly journals Prospective comparison of Bayesian and frequentist adaptive clinical trials : The SHADOW - SHINE project

2021 ◽  
Author(s):  
Kristine Broglio ◽  
William Meurer ◽  
Valerie Durkalski ◽  
Qi Pauls ◽  
Jason Connor ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Acute Stroke ◽  
Sample Size ◽  
Trial Design ◽  
Interim Analyses ◽  
Patient Level Data ◽  
Patient Level ◽  
Prospective Comparison ◽  
Level Data

Importance: Bayesian adaptive trial design has the potential to create more efficient clinical trials. However, one of the barriers to the uptake of Bayesian adaptive designs for confirmatory trials is limited experience with how they may perform compared to a frequentist design. Objective: Compare the performance of a Bayesian and a frequentist adaptive clinical trial design. Design: Prospective observational study comparing two trial designs using individual patient level data from a completed stroke trial, including the timing and order of enrollments and outcome ascertainment. The implemented frequentist design had group sequential boundaries for efficacy and futility interim analyses when 90-days post-randomization was met for 500, 700, 900, and 1,100 patients. The Bayesian alternative utilized predictive probability of trial success to govern early termination for efficacy and futility with a first interim analysis at 500 randomized patients, and subsequent interims after every 100 randomizations. Setting: Multi-center, acute stroke study conducted within a National Institutes of Health neurological emergencies clinical trials network. Participants: Patient level data from 1,151 patients randomized in a clinical trial comparing intensive insulin therapy to standard in acute stroke patients with hyperglycemia. Main Outcome(s) and Measure(s): Sample size at end of study. This was defined as the sample size at which each of the studies stopped accrual of patients. Results: As conducted, the frequentist design passed the futility boundary after 936 participants were randomized. Using the same sequence and timing of randomization and outcome data, the Bayesian alternative crossed the futility boundary about 3 months earlier after 800 participants were randomized. Conclusions and Relevance: Both trial designs stopped for futility prior to reaching the planned maximum sample size. In both cases, the clinical community and patients would benefit from learning the answer to the trial's primary question earlier. The common feature across the two designs was frequent interim analyses to stop early for efficacy or for futility. Differences between how this was implemented between the two trials resulted in the differences in early stopping.

scholarly journals Recommendations on the Clinical Trial Programme for Diabetes Medicines

2021 ◽  
Vol 11 (2) ◽  
pp. 94-103
Author(s):  
I. A. Proskurina ◽  
E. A. Petraneva ◽  
D. V. Goryachev
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Treatment Effectiveness ◽  
Clinical Trial Design ◽  
Public Health Problem ◽  
The Body ◽  
Noncommunicable Diseases ◽  
The European Union ◽  
Antidiabetic Therapy ◽  
Confirmatory Clinical Trials

Diabetes is a serious public health problem and one of the major chronic noncommunicable diseases. A lengthy stepwise treatment, and the need for an individualised approach to antidiabetic therapy, pose serious challenges for medicine developers. For all new hypoglycaemic medicines, there has been a centralised authorisation procedure in the European Union (EU) since 2005, which ensures a unified approach to efficacy and safety assessment. The aim of the study was to analyse current requirements for planning clinical trials of hypoglycaemic medicines containing new active substances (except for insulin products). The recommendations for diagnosis and treatment of type 2 diabetes, prepared by the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) in 2019, suggest a step-by-step approach to intensification of treatment to maintain glycaemic targets, which takes account of concomitant cardiovascular or other diseases, and clinical characteristics of patients. The analysis of EASD/ADA documents and scientific literature helped to develop recommendations on the basic principles of planning and conducting clinical trials at the final stages of hypoglycaemic medicine development. The paper describes new approaches to clinical trials, which allow for a more reliable assessment of the treatment effectiveness. The strategy for the assessment of therapeutic effect should be carefully planned, justified, and reflected in variables of interest, clinical trial design, and statistical analysis of the trial results. The main efficacy criterion in confirmatory clinical trials of hypoglycaemic medicines should be the demonstration of benefits in improving glycaemic control. The medicine’s effect on the body weight may be considered as a secondary endpoint. An essential requirement is confirmation of the medicines’ cardiovascular safety, while potential additional benefits are reduction or prevention of risks of cardiovascular disease development. The clinical trial protocol should provide definitions for intercurrent events and hypoglycaemia. A comprehensive safety study of a new hypoglycaemic medicine should involve identification of anticipated or known side effects characteristic of a particular pharmacological class. The provided recommendations may be helpful for medicine developers, and for experts who perform assessment of clinical trial programmes and regulatory submissions for hypoglycaemic medicines.           

Dynamic programming and feedback analysis of the two dimensional tidal dynamics system

2020 ◽  
Vol 26 ◽  
pp. 109
Author(s):  
Manil T. Mohan
Keyword(s):  
Optimal Control ◽  
Dynamic Programming ◽  
Jacobi Equation ◽  
Value Function ◽  
Two Dimensional ◽  
Tidal Dynamics ◽  
Infinite Dimensional ◽  
Bellman Principle ◽  
The Value Function ◽  
Hamilton Jacobi Equation

In this work, we consider the controlled two dimensional tidal dynamics equations in bounded domains. A distributed optimal control problem is formulated as the minimization of a suitable cost functional subject to the controlled 2D tidal dynamics equations. The existence of an optimal control is shown and the dynamic programming method for the optimal control of 2D tidal dynamics system is also described. We show that the feedback control can be obtained from the solution of an infinite dimensional Hamilton-Jacobi equation. The non-differentiability and lack of smoothness of the value function forced us to use the method of viscosity solutions to obtain a solution of the infinite dimensional Hamilton-Jacobi equation. The Bellman principle of optimality for the value function is also obtained. We show that a viscosity solution to the Hamilton-Jacobi equation can be used to derive the Pontryagin maximum principle, which give us the first order necessary conditions of optimality. Finally, we characterize the optimal control using the adjoint variable.

FDA analysis of patient enrollment by region in clinical trials for approved oncological indications.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2539-2539 ◽  
Author(s):  
Bindu Kanapuru ◽  
Harpreet Singh ◽  
Lola A. Fashoyin-Aje ◽  
Adrian Myers ◽  
Geoffrey Kim ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
North America ◽  
Global Scale ◽  
Malignant Solid Tumor ◽  
Trends Over Time ◽  
Clinical Trial Results ◽  
The Baltic ◽  
The Impact ◽  
Patient Enrollment

2539 Background: Clinical trials are increasingly conducted on a global scale in an effort to accelerate accrual. This analysis attempts to quantify and characterize participants in trials submitted to support approval of drugs for oncology indications by the region of enrollment. Methods: Demographic information was extracted for patients enrolled in clinical trials submitted to the FDA from 2005-2015. Only trials submitted to support approval for malignant solid tumor or hematology indications were included. Countries were grouped into regions for further analysis. A total of 178,024 patients with information regarding age and country were included in this analysis. Results: Forty five percent (80,460) of clinical trial participants were enrolled from Europe, 36% (63,958) from North America (includes U.S.A and Canada) and 8.4% (14,975) from Asia. Countries in Latin America, Middle East/Africa and the Baltic States/Russia enrolled the remainder 10.5% of the patients. Among 99,556 participants < 65 years of age; 38.7% (38,538) were enrolled from North America, 40.5% (40,362) from Europe, 9.7 % (9674) from Asia and 11% from the rest of the regions. Europe enrolled the highest number of cancer patients aged 65 years or older; 51.1% (40,098) compared to 32.4% (25,420) from North America and 6.8 % (5301) from Asia. Conclusions: Majority of patients enrolled into clinical trials submitted for oncology drug approvals were from regions other than North America, with highest number enrolled from Europe particularly in the older age group. While it is interesting to speculate, the reasons for differential enrollment of patients between Europe and North America and the impact of these findings on interpretation of clinical trial results need additional exploration. Analysis of trends over time may be useful to address this issue. [Table: see text]

scholarly journals COVID-19, SARS, MERS and Ebola: a comparative analysis registration of intervention clinical trials

2020 ◽  
Author(s):  
Yuxia Xiang ◽  
Zeyu Zhang ◽  
Chan Zeng ◽  
Zhanqing Hu ◽  
Yaxin Liu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Research ◽  
Clinical Trial Registry ◽  
Drug Intervention ◽  
Short Period ◽  
Epidemic Period ◽  
Virulent Virus ◽  
Intervention Trials ◽  
Clinical Trial Program

Abstract BackgroundCOVID-19 is a novel and highly virulent virus, which caused a rapid and massive onset of clinical trials in a short period of time.With the aim to obtain suggestions in the guidance on performing emergency clinical trials, and control this virus in China and other countries and for the prevention of the onset of other infectious viruses in the future.MethodsCOVID-19, SARS, MERS and Ebola clinical trials registered in the Chinese clinical trial registry and clinical trials.gov were collected and analyzed and intervention protocols were compared, focusing on the analysis and comparison of the drug used. The search period ended on February 24, 2020.ResultsThe number of the registered COVID-19 clinical trials was 295. Among 203 intervention trials, 78.3% (159) were drug clinical trials, in which 46.3% (94) used chemical drugs and biological agents, 32.0% (65) were performed using Traditional Chinese Medicine (TCM) and integrated traditional Chinese and western medicine.The 159 COVID-19 trials were designed and analyzed with the highest proportion of blank randomized controls [45.9% (73)], and placebo randomized trials [14.5% (23)]. The drug mostly used was Lopinavir/Ritonavir (15.1%). The sample size ranged from 10 to 100 in 52.8% (84) trials. The number of the registered SARS was 6, MERS 15, and Ebola 97. Among 3 MERS and 19 Ebola drug intervention clinical trials, MERS and Ebola were randomized, blind, and placebo-controlled drug clinical trials accounting for 100% (3) and 31.6% (6), respectively, while SARS were vaccine trials, without drug intervention clinical trials registered.ConclusionsCompared with the SARS in 2003, the awareness and capability of clinical research in China greatly improved. However, some of the COVID-19 clinical trials and drug selection performed are somewhat disordered, requiring greater attention to the needs, science assumptions, ethics and quality management of the clinical research. Thus, during the epidemic period, the country should deliver guidance on how to perform appropriate emergency clinical trials, design a scientifically based clinical trial program and focus on researching drugs or vaccines that have great potential.

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