Presentation on theme: "A Blueprint to Develop a Companion Diagnostic Assay"— Presentation transcript:
1A Blueprint to Develop a Companion Diagnostic Assay Jeff Allen, PhDExecutive Director, Friends of Cancer Research1
2Draft Guidance for Industry and FDA Staff: In Vitro Companion Diagnostic Devices July 2011 Goals:Define IVD companion diagnostic devicesClarify the need for FDA oversight and approval for safe and effective useProvide direction for both industry and FDA staff on possible developmental pathways and the approval requirements for labeling of therapies that require IVD companion diagnostic devicesGuiding 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”
3A 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 developmentDevelopment strategy for Dx-selected populationsDefining selected population given Phase III dataMulti-marker diagnostic developmentGuiding 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.
4A Blueprint to Develop a Companion Diagnostic Assay Workgroup 1- A Blueprint for Future Drug/Diagnostic Co-developmentRich 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 CancerHoward Scher, Chief, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer CenterRich Simon, Chief, Biometric Research Branch, National Cancer Institute (NCI)Jane Fridlyand, Senior Statistical Scientist, Genentech (SSF)Workgroup 2- Creating an Environment for Personalized MedicineKeith Flaherty, Director of Developmental Therapeutics, Cancer Center, Massachusetts General HospitalPat Mahaffy, President and CEO, Clovis Oncology, Inc. Vince Miller, Senior Vice President, Clinical Development, Foundation MedicineJeff 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 DiagnosticsJanet Woodcock, Director Center for Drug Evaluation and Research, U.S. Food and Drug Administration (FDA)
5Development 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 undertakenAnalytical performance of the diagnostic assay must have been characterized before it is used in any clinical registration trialIf not, evaluation of marker-positive patients only is not possible, and an all-comers trial design must be used
6Factors that influence evaluation of marker-negative patients Key Factors and their categoriesProvides support for restricting efficacy evaluation to Dx-selected patients onlyEvidence supporting clear definition of diagnostically selected populationCompelling evidence supporting threshold for definition of Dx-positive population (e.g., mutation; complete loss of expression; high-level amplification).YesThreshold for Dx-positive population uncertain (e.g., continuous or ordinal biomarker).NoMechanism of action (MOA)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 target.Pre-clinical efficacy(in-vitro/in-vivo)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 of existing drugs with similar MOA/multiple MOAs (or targets)/chemical structure or known pharmacological effects)Established class effect in Dx selected populations.First in Class (FIC).
7If an all-comer approach was chosen: Recommended Phase III evaluation of Dx-negative patients, given Phase II outcome and the biomarker typeObserved Clinical Risk-Benefit in Phase II (or Phase I if no Phase II)Clinically meaningful benefit/risk in Dx- selected patients; detrimental benefit/risk in Dx-negative patientsClinically meaningful benefit/risk in Dx- selected patients; no clinically meaningful benefit/risk in Dx-negative patientsClinically meaningful benefit/risk in all patients; biomarker shows better benefit in Dx-selected patientsDx-selected population definition(a) Clear binary definition of Dx-positive population (e.g., mutation, complete loss of expression, high-level amplification)No additional efficacy evaluation should be required of Dx-negative patientsNo or very limited benefit/risk evaluation of Dx-negative patientsFully assess benefit/risk in all-comers(b) Threshold for Dx-positive 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 detrimentIf there is concern with the strength of the marker/outcome relationship, gated or full benefit/risk evaluation of Dx-negative patients to define best threshold
8Development Strategy for Dx-Selected Populations Staged clinical developmentcould be appropriate in cases where the treatment is expected to have activity in marker-positive patientsBiomarker information in label when Phase III trial is not diagnostically restrictedWhen restricted to test-positive, labeling is straight forwardWhen (+) and (-) are included a pre-specified analysis plan is needed and labeling can be more difficultOne 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 Dx- negative patients with no observed detriment in Dx-negative patients.
9Defining the Dx-Selected Population given Phase III Data Situations in which sponsor may need to re-define the Dx-selected patientsReadjusting the threshold on the biomarker prospectively specified in the trialEvaluating the Phase III trial with regard to a biomarker not specified in the protocolProposal for planned threshold re-adjustmentTiming of threshold pre-specification for primary analysisNew marker specification after trial initiation or completion
10Multi-marker Diagnostic Development Several biomarkers may be necessary to identify the patients likely to benefit from a therapyFor 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 validatedFor 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
11DNA Sequencing and Companion Diagnostics Next-generation sequencing (NGS) and screening platforms have multiple advantages over the current single-test, single-drug paradigmSponsors 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 patientsIf the new drug demonstrated acceptable clinical benefit, the biomarker could be reviewed and given FDA clearance for diagnostic use, along with approval for the drugMuch like composite assays, if the platform used multi-markers for selection, the platform should not require separate clinical validation for each component
12Breakthrough Therapies Advancing Breakthrough Therapies for Patients Act of 2012Senators Bennet (D-CO) Hatch (R-UT) and Burr (R-NC)Representatives DeGette (D-CO) and Bilbray (R-CA)Breakthrough Therapy DesignationExpedite drug development process for products that show remarkable clinical activity earlyMinimize the number of patients exposed to a potentially less efficacious treatment
13A 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 GoalsIdentify data elements that are essential for analytical validation that need to be prioritized early in developmentPropose potential modifications for data elements that could be postponed until the post-market setting