A Blueprint to Develop a Companion Diagnostic Assay, Jeff Allen, PhD

A Blueprint to Develop a Companion
Diagnostic Assay
Jeff Allen, PhD
Executive Director, Friends of Cancer Research
Draft Guidance for Industry and FDA Staff: In Vitro
Companion Diagnostic Devices
July 2011
• Goals:
– Define IVD companion diagnostic devices
– Clarify the need for FDA oversight and approval for safe and effective use
– Provide direction for both industry and FDA staff on possible developmental
pathways and the approval requirements for labeling of therapies that require
IVD companion diagnostic devices
• Guiding Principle: “Ideally a therapeutic and its corresponding IVD
companion diagnostic device would be developed contemporaneously
with the clinical performance and clinical significance of the IVD
companion diagnostic device established using data from the clinical
development program of the corresponding therapeutic product”
A Blueprint to Develop a Companion Diagnostic Assay
• Goals: Address key issues not raised in the 2011 Guidance Document and
propose approaches for drug-Dx co-development that introduce flexibility
and options in today’s drug development
– Development strategy for Dx-selected populations
– Defining selected population given Phase III data
– Multi-marker diagnostic development
• Guiding Principle: Although the different types of diagnostics used to
identify the patient population will face different issues and requirements
for analytical validation, with some biomarkers and assays being more
challenging for co-development than others, the core principles regarding
clinical validation and clinical utility will be similar.
A Blueprint to Develop a Companion Diagnostic Assay
Workgroup 1- A Blueprint for Future Drug/Diagnostic Co-development
Rich Buller, Vice President of Translational Oncology, Pfizer, Inc.
Liz Mansfield, Director of Personalized Medicine, U.S. Food and Drug Administration (FDA)
Rick Pazdur, Director of the Office of Hematology and Oncology Products, U.S. Food and Drug Administration (FDA)
Nancy Roach, Chair, Fight Colorectal Cancer
Howard Scher, Chief, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center
Rich Simon, Chief, Biometric Research Branch, National Cancer Institute (NCI)
Jane Fridlyand, Senior Statistical Scientist, Genentech (SSF)
Workgroup 2- Creating an Environment for Personalized Medicine
Keith Flaherty, Director of Developmental Therapeutics, Cancer Center, Massachusetts General Hospital
Pat Mahaffy, President and CEO, Clovis Oncology, Inc.
Vince Miller, Senior Vice President, Clinical Development, Foundation Medicine
Jeff Roche, Medical Officer, Center for Medicare and Medicaid Services (CMS)
Jeff Shuren, Director Center for Devices and Radiation Health, U.S. Food and Drug Administration (FDA)
Deb Rasmussen, Global Head of Regulatory Affairs, Janssen Diagnostics
Janet Woodcock, Director Center for Drug Evaluation and Research, U.S. Food and Drug Administration (FDA)
Development Strategy for Dx-Selected Populations
In general, development decisions are guided by the aim to maximize exposure of
patients who are likely to benefit from a drug and minimize exposure of patients
who are not, or who are at increased risk for serious adverse events.
Proposed decision-making strategy for determining whether and how evaluation
of diagnostically negative patients could be undertaken
Analytical performance of the diagnostic assay must have been characterized
before it is used in any clinical registration trial
If not, evaluation of marker-positive patients only is not possible, and an all-comers trial design must
be used
Factors that influence evaluation of marker-negative patients
Provides support for
restricting efficacy evaluation
to Dx-selected patients only
Key Factors and their categories
Evidence supporting clear definition of
diagnostically selected population
Mechanism of action (MOA)
Pre-clinical efficacy
Compelling evidence supporting
threshold for definition of Dx-positive
population (e.g., mutation; complete
loss of expression; high-level
Threshold for Dx-positive population
uncertain (e.g., continuous or ordinal
Dx marker is an immediate drug target
or a measure of activation of a pathway
of the drug target.
Dx marker is less clearly related to drug
Dx has high sensitivity and specificity for
drug activity.
Dx has high sensitivity and lower
specificity for drug activity.
Class effect (i.e., knowledge of behavior Established class effect in Dx selected
of existing drugs with similar
MOA/multiple MOAs (or
First in Class (FIC).
targets)/chemical structure or known
pharmacological effects)
If an all-comer approach was chosen: Recommended Phase III
evaluation of Dx-negative patients, given Phase II outcome and
the biomarker type
Observed Clinical
Risk-Benefit in Phase
II (or Phase I if no
Phase II)
Clinically meaningful
benefit/risk in Dxselected patients;
benefit/risk in Dxnegative patients
Clinically meaningful
benefit/risk in Dxselected patients; no
clinically meaningful
benefit/risk in Dxnegative patients
(a) Clear binary
definition of Dxpositive population
(e.g., mutation,
complete loss of
expression, highlevel amplification)
No additional efficacy
evaluation should be
required of Dx-negative
No or very limited
evaluation of Dxnegative patients
(b) Threshold for Dxpositive population
uncertain (e.g.,
continuous or
ordinal biomarker
such as RT-PCR
expression or IHC)
Limited safety
assessment of the
patients with the
biomarker value
borderline with the
proposed Dx threshold,
dependent on severity
of detriment
benefit/risk in all
biomarker shows
better benefit in
Fully assess
benefit/risk in allcomers
If there is concern
with the strength of
the marker/outcome
relationship, gated or
full benefit/risk
evaluation of Dxnegative patients to
define best threshold
Development Strategy for Dx-Selected Populations
• Staged clinical development
• could be appropriate in cases where the treatment is expected to have
activity in marker-positive patients
• Biomarker information in label when Phase III trial is not
diagnostically restricted
• When restricted to test-positive, labeling is straight forward
• When (+) and (-) are included a pre-specified analysis plan is needed
and labeling can be more difficult
– One approach might stipulate that such inclusion could be considered provided the
following conditions are met:
• Pre-specified primary endpoints are met (e.g., Dx-positive and all-comers).
• Clinically meaningful difference in benefit estimate between Dx-positive and Dxnegative patients with no observed detriment in Dx-negative patients.
Defining the Dx-Selected Population given
Phase III Data
• Situations in which sponsor may need to re-define the Dxselected patients
– Readjusting the threshold on the biomarker prospectively specified in the trial
– Evaluating the Phase III trial with regard to a biomarker not specified in the
• Proposal for planned threshold re-adjustment
• Timing of threshold pre-specification for primary analysis
• New marker specification after trial initiation or completion
Multi-marker Diagnostic Development
Several biomarkers may be necessary to identify the patients likely to benefit from
a therapy
For composite biomarkers such as scores that combine gene expression values, it is
the score that is the biomarker that is used and that must be validated
For the case of gene mutations, if the sponsor is proposing to use as a biomarker
the presence of any mutation of the gene or any of a pre-specified set of
mutations, then it is that composite biomarker which must be validated in the
Phase III trial.
Provided there is appropriate pre-clinical evidence and scientific rationale, clinical
validation of each biomarker separately should not be required; rather, it should
be sufficient to validate the combination of markers, essentially treating the pool
of biomarkers as one
DNA Sequencing and Companion Diagnostics
• Next-generation sequencing (NGS) and screening platforms have multiple
advantages over the current single-test, single-drug paradigm
• Sponsors could obtain an Investigational Device Exemption (IDE) for the
entire platform prior to the start of clinical testing.
• The presence of a particular predictive biomarker in the platform could
enable the entire platform to be adequate for selecting patients
• If the new drug demonstrated acceptable clinical benefit, the biomarker
could be reviewed and given FDA clearance for diagnostic use, along with
approval for the drug
• Much like composite assays, if the platform used multi-markers for
selection, the platform should not require separate clinical validation for
each component
Breakthrough Therapies
Advancing Breakthrough Therapies for
Patients Act of 2012
– Senators Bennet (D-CO) Hatch (R-UT)
and Burr (R-NC)
– Representatives DeGette (D-CO) and
Bilbray (R-CA)
• Breakthrough Therapy Designation
– Expedite drug development process for
products that show remarkable clinical
activity early
– Minimize the number of patients exposed to
a potentially less efficacious treatment
A Blueprint for Drug/Diagnostic Co-development: Breakthrough Therapies
September 6, 2013
• A forum to bring together researchers, sponsors, advocates and regulators
to discuss the recognized opportunities and challenges associated with
contemporaneous development of drugs and diagnostics, with a focus on
how development of the diagnostic component can also be expedited in
the instance of a Breakthrough Therapy designation.
Forum Goals
• Identify data elements that are essential for analytical validation that need
to be prioritized early in development
• Propose potential modifications for data elements that could be
postponed until the post-market setting
Supplementary Slides
CNB/CLIA Biomarker
Biomarker A
(Interim PFS)
Biomarker Β
(Interim PFS)
Biomarker C
(Interim PFS)
Biomarker D
(Interim PFS)
TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib
Courtesy of: Vali Papadimitrakopoulou
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