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Proposal 1323

Title of the Proposed Research

Detection of uninformative clinics during the trial of a new drug using statistical and machine learning techniques

Lead Researcher

Praveen Deorani

Affiliation

KKT Technology pte. Ltd.

Funding Source

Commercial organization: KKT Technology Pte. Ltd.

Potential Conflicts of Interest

Kevin Craig is a full-time employee and share-holder of Covance Clinical Development Services, a division of Laboratory Corporation Inc.

Data Sharing Agreement Date

21 October 2015

Lay Summary

Major Depressive Disorder (MDD) affects 350 million people worldwide and is now the world's second leading cause of disability [1]. Remission rates with standard therapies are 30-50% [2]. Despite the significant unmet need, no treatments with new mechanisms of action have been approved this century. Over the last ten years the probability of success for new MDD drugs entering human testing has been 7.2% [3]. Historically, for treatments that are known to be effective, up to 50% of clinical trials fail [4]. A key determinant of this failure is the high variability in subjective clinical ratings and large placebo response rates.

Our hypothesis is that poor quality endpoint data at a site level differs systematically from the general trial data, for example in variability, correlation between assessments or implausible placebo response trajectories generated in a given center. These systematic differences would allow detection of sites with poor quality data during the conduct of the trial. The aim of this study would be to develop a quantitative methodology to detect sites contributing poor quality data.

Blinded data from previous MDD trial will be divided into a training set and a test set to assess whether outlier sites can be detected and to determine the accuracy of such predictions. Our aim is to classify each recruitment center on an ongoing basis during patient accrual as informative or non-informative.

The detection of uninformative centers at an early stage could lead to more efficient drug testing as the noise level in the data due to placebo response could be controlled. This would mean more reliable results in a shorter time-frame, and with a smaller number of subjects. It is thus of great significance to find ways to recognize clinical centers which have a high probability of providing inaccurate data about the effect of drug and placebo.

References

[1] Ferrari et al. (2013) Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 2010. PLoS Med 10(11): e1001547. doi:10.1371/journal.pmed.1001547
[2] Sinyor M et al. (2010). The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial. Canadian J Psych 55 (3): 126–135.
[3] Hay M et al. (2014) Clinical development success rates for investigational drugs. Nature Biotech. 32(1) p40-51.
[4] Turner EH et al. (2008) Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 17;358(3):252-60.

Study Data Provided

Study LILLY-F1J-MC-HMAI: A Double-Blind, Placebo- and Clomipramine-Controlled Study of Duloxetine in Patients with Major Depression
Study LILLY-F1J-MC-HMAQ(A): Duloxetine Versus Placebo in the Treatment of Major Depression
Study LILLY-F1J-MC-HMAQ(B): Duloxetine Versus Placebo in the Treatment of Major Depression
Study LILLY-F1J-MC-HMAT(A): Duloxetine Versus Placebo and Paroxetine in the Acute Treatment of Major Depression
Study LILLY-F1J-MC-HMAT(B): Duloxetine Versus Placebo and Paroxetine in the Acute Treatment of Major Depression
Study LILLY-F1J-US-HMFS: Duloxetine Versus Placebo in Patients With Major Depressive Disorder (MDD): Assessment of Energy and Vitality in MDD
Study LILLY-F1J-MC-HMAY(B): Duloxetine Versus Placebo and Paroxetine in the Treatment of Major Depression
Study LILLY-F1J-MC-HMBH(A): Duloxetine Once-Daily Dosing Versus Placebo in the Acute Treatment of Major Depression
Study LILLY-F1J-MC-HMBH(B): Duloxetine Once-Daily Dosing Versus Placebo in the Acute Treatment of Major Depression
Study LILLY-F1J-US-HMCR: Duloxetine Versus Escitalopram and Placebo in the Treatment of Patients With Major Depression
Study LILLY-F1J-MC-HMAH: Duloxetine 20/30 mg vs. Placebo in Major Depression
Study LILLY-F1J-MC-HMCK: A Double-Blind, Efficacy and Safety Study of Duloxetine Versus Placebo in the Treatment of Children and Adolescents With Major Depressive Disorder
Study LILLY-F1J-MC-HMCL: A Double-Blind, Efficacy and Safety Study of Duloxetine Versus Placebo in the Treatment of Children and Adolescents With Major Depressive Disorder
Study LILLY-F1J-US-HMGR: A Phase 4, 8-week, Double-blind, Randomized, Placebo-controlled Study Evaluating the Efficacy of Duloxetine 60 mg Once Daily in Outpatients with Major Depressive Disorder and Associated Painful Physical Symptoms
Study LILLY-F1J-US-HMGU: Duloxetine Versus Placebo in the Acute Treatment of Patients With Major Depressive Disorder and Associated Painful Physical Symptoms
Study LILLY-F1J-MC-HMBV: Duloxetine Versus Placebo in the Treatment of Elderly Patients With Major Depressive Disorder
Study LILLY-F1J-US-HMCB: Duloxetine Once-Daily Dosing Versus Placebo in Patients With Major Depression and Pain

Statistical Analysis Plan

The statistical analysis plan will be added after the research is published.

Publication Citation

The publication citation will be added after the research is published.