precision medicine and clinical trial design
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UNDERSTANDING UMBRELLA & BASKET TRIALS
CTO OCTOBER 2015
Precision Medicine and Adaptive Trial Design
Objectives
What is Precision Medicine?Adaptive Trial Design
Advantages/DisadvantagesUmbrella Trial Design
BATTLEBasket Trial Design
MATCHChallenges of New Trial Designs
Regulatory Operations
FDA
What is Precision Medicine?
Approach to deliver optimal patient outcomes by integrating clinical and molecular patient data to understand the biological basis of the disease
Guides selection of the most appropriate targeted therapy based on distinctive pt features and molecular features (such as specific biomarkers)
Optimize patient outcomes and provides favorable safety profiles
Precision Medicine
What does this mean?
Patients are receiving treatment that more specifically targets their tumor type based on biological characteristics such as biomarkers
Anticipated better outcomes overall
FROM EXCEPTION TO THE NORM
Precision Medicine Initiative
Precision Medicine Initiative
Goal is to revolutionize medicine and generate the scientific evidence needed to move the concept of precision medicine into every day clinical practice
Pres. Obama announced in early 2015 $215 million proposed investment for Presidential
2016 Budget Primary focus is cancer, but will expand to other
disease areas
NCI Involvement
Four broad focus areas of research: Expanding precision medicine clinical trials Overcoming drug resistance Developing new laboratory models for research Developing a National Cancer Knowledge System
Adapting Clinical Trial Design
Adaptive Trial Design
Allows researchers to analyze accumulating study data at prospective interim time points and to alter the course of a single patient’s study plan or trial itself
Ability to answer multiple questions Safety and efficacy How is drug best delivered? Who will get the most benefit from that drug?
Adaptive Trial Design
Design that uses accumulating data to decide on how to modify aspects of the study as it continues, without undermining the validity and integrity of the trial
Learn from the accumulating data and to apply what is learned as quickly as possible
Common Types of Trial Adaptations
Stopping early/extending accrual with a conclusion of either superiority or futility
Adaptively assigning doses to more efficiently assess the dose-outcome relationship
Dropping/Adding arms or dosesSeamless phases of drug development within a
single trialChanging proportion of patients randomized to
each armChanging accrual rate
Traditional vs Precision
Advantages
Potential to speed up the process of drug development
Allocate resources more efficiently without lowering scientific and regulatory standards
Potential to receive marketing approval for multiple indications from a single successful trial
Shorter clinical time lines than conventional approaches
A feasible way to conduct well powered trials in rare cancers
Disadvantages
Disadvantages Breaking the blind early can lead to problems with
dissemination of study results and the study population might change between the early and late stages of drug testing
Often less statistically efficient than fixed plans Regulators are very disturbed by changing scientific
hypotheses Statistical methods for the design and analysis are
technically and computationally more complex than those associated with conventional designs
COMBINING CLINICAL TRIALS WITH PRECISION MEDICINE AND ADAPTIVE DESIGN
Umbrellas and Baskets
Umbrella Trial: Study Design
Complicated trial design that has arms moving in and out
Can test impact of different drugs on different mutations in a single type of cancer
Main protocol with several phase II sub-protocols
Umbrella Trial: Study Design
Patients are enrolled onto main protocol and then tested for mutations
Based on results of test, patients are randomized to one of the sub-protocols
BATTLE Trial
4 treatment groups of single or combination therapy targeting specific pathways
Patients enrolled and tested for 11 biomarkers/marker groups Adaptively randomized to the treatment groups
BATTLE Trial (2006)
Findings EGFR mutations were predictive for erlotinib benefit Benefit in sorafenib-treated patients with wild-type
and mutant KRAS mutations
BATTLE-2 (NCI R01 Funded) Patients enrolled with either EGFR or KRAS mutations
were randomized to one of four directed single or combination treatments
Validation of the use of molecular and sequencing lab technology to better identify patients who would benefit from a specific target therapy
Basket Trial: Study Design
Each arm or “basket” is for a drug targeting a specific mutation across all cancer types
Allows researchers to examine response of patients by not only cancer type but what is the impact of the drug on patients as a group (mutation)
Downside: have to test large number of patients to find those who are eligible
Basket Trial: Stud Design
Benefits: Tests specific hypothesis of a biopathway and its
response to a particular drug Pilot data can be expanded to separate Phase II trial
for increased enrollment and statistical significance
NCI-MATCH Trial
Design: Master protocol with multiple phase II subprotocols Tumor biopsies to confirm genetic abnormalities that
a targeted drug exists for Treatment is assigned based on abnormality
Seeks to determine whether treating cancers according to molecular abnormalities will show evidence of effectiveness
NCI-MATCH
Unique DNA sequencing test, requires testing of large number of patients to find those eligible for study 4000 variants across 143 genes
Study design is able to detect inhibition of driver mutations in multiple tumor types Goal is to have 25% of 1000 patients have rare cancer
Patients can have 2 screening biopsies and 2 treatments per biopsy
WHAT ARE THE ROADBLOCKS AND REGULATORY ISSUES THAT CAN ARISE FROM THESE TYPES OF
TRIALS?
Issues and Concerns
Who Sponsors Adaptive Trials?
Collaborative effort NCI, FDA Numerous academic centers Pharma and laboratories
Operational Considerations
Enrollment rate/# of subsites openDrug supply/management: need plan to
manage supply for adaptations during the trial
Randomization systems need s to be developed with the data analysis system
Regulatory Issues
Privacy and data sharing b/c adaptive trial evolves as data is collected, limited
access is keyHow will confidentiality be maintained?
Clearly id’ed who will see what data and how information will be disseminated?
Maintenance of Good Clinical PracticeIncreased site monitoring for improved data
availability and data quality
Regulatory Issues
Documentation
Communication Plan to manage changes to study conduct and how to
communicate those changes within the team
Regulatory Issues
All adaptations need to be specified prior to initiation
Maintaining the study blind is important to the trial’s integrity.
How best to ensure adequate consentAdditional Start Up Costs
Integration of the process and information technology
FDA
Draft Guidance Documents: “Guidance for Industry Adaptive Design Clinical Trials
for Drugs and Biologics - Draft Guidance” (2010)
References
Semin Oncol Nurs 2014 May; 30(2): 109-116 Gaydos B, Anderson KM, Berry D, Burnham N, Chuang-Stein C, Dudinak J et
al. Good Practices for Adaptive Clinical Trials in Pharmaceutical Product Development. Drug Info J. 2009; 43: 539-556
Quinlan J, Gaydos B, Maca J, Krams M. Barriers and Opportunities for Implementation of Adaptive Design in Pharmaceutical Product Development. Clin Trials 2010. 7: 167-173
Berry DA. Adaptive Clnical Trials in Oncology. Nat Rev Clin Oncol 2012. 9: 199-207
Desmond-Hellmann S. Toward precision medicine: a new social contract? Sci Transl Med. 2012; 4: 129ed123
Berry DA, Herbst RS, Rubin, EH. Reports from the 2010 Clinical and Translational Cancer Research Think Tank Meeting: Design and Strategies for Personalized Therapy Trials. Clin Cancer Res; 2012 February; 18(3) 638-644
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