GLOBAL REGISTRATION STRATEGIES: Therapeutic Product (TP) and the Companion Diagnostic (CDx) Erin Pedalino Regulatory Affairs International MSD
Unique Role as CDx Regulatory Liaison at a Therapeutic Product Company
Unique Role as CDx Regulatory Liaison at a Therapeutic Product Company Regulatory link to CDx partners on rest of world (ROW) registrations Understand and drive synchronization in regulatory strategy for TP and CDx
Global Diagnostic Regulatory Landscape Regulatory Requirements Varied & Evolving - Limited - Developing/Changing - Complex Including in-country technical testing and clinical testing
Roles of Partners Therapeutic Product Company Responsibilities TP registration activities Provides required TP information for CDx dossier Diagnostic Company Responsibilities CDx registration activities Provides required CDx information for TP dossier Provides TP strategy/ approval timelines to the diagnostic partner in order to enable proper planning Joint activities span all phases of product lifecycle (e.g. preclinical, registration, commercialization)
TP and CDx Label Examples TP - Indication and Usage CDx - Intended Use US Accelerated Approval Label for 2L NSCLC KEYTRUDA is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA [see Clinical Studies (14.2)]. For in vitro diagnostic use. PD-L1 IHC 22C3 pharmdx is a qualitative immunohistochemical assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3 intended for use in the detection of PD-L1 protein in formalin-fixed, paraffinembedded (FFPE) non-small cell lung cancer (NSCLC) tissue using EnVision FLEX visualization system on Autostainer Link 48. PD-L1 protein expression is determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining. The specimen should be considered PD-L1 positive if TPS 50% of the viable tumor cells exhibit membrane staining at any intensity. PD-L1 IHC 22C3 pharmdx is indicated as an aid in identifying NSCLC patients for treatment with KEYTRUDA (pembrolizumab).
TP and CDx Label Examples TP - Indication and Usage For in vitro diagnostic use. CDx - Intended Use US Full Approval Label for 1L and 2L NSCLC KEYTRUDA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) 50%)] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)]. KEYTRUDA is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA [see Clinical Studies (14.2)]. PD-L1 IHC 22C3 pharmdx is a qualitative immunohistochemical assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3 intended for use in the detection of PD-L1 protein in formalin-fixed, paraffinembedded (FFPE) non-small cell lung cancer (NSCLC) tissue using EnVision FLEX visualization system on Autostainer Link 48. PD-L1 protein expression is determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The specimen should be considered to have PD-L1 expression if TPS 1% and high PD-L1 expression if TPS 50%. PD-L1 IHC 22C3 pharmdx is indicated as an aid in identifying NSCLC patients for treatment with KEYTRUDA (pembrolizumab). See the KEYTRUDA product label for expression cutoff values guiding therapy in specific clinical circumstances.
TP and CDx Label Examples EU SmPC 1L and 2L NSCLC TP - Indication and Usage KEYTRUDA as monotherapy is indicated for the firstline treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a 1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA. Patients with NSCLC should be selected for treatment based on the tumour expression of PD-L1 confirmed by a validated test (see section 5.1). For in vitro diagnostic use. CDx - Intended Use PD-L1 IHC 22C3 pharmdx is a qualitative immunohistochemical assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3 intended for use in the detection of PD-L1 protein in formalin-fixed, paraffinembedded (FFPE) non-small cell lung cancer (NSCLC) tissue using EnVision FLEX visualization system on Autostainer Link 48. PD-L1 protein expression is determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. PD-L1 IHC 22C3 pharmdx is indicated as an aid in identifying NSCLC patients for treatment with KEYTRUDA (pembrolizumab). See the KEYTRUDA product label for expression cutoff values guiding therapy in specific clinical circumstances.
Regulatory Considerations Affecting Registration Timelines CDx submissions in many countries must wait until after reference agency approval - US Certificate for Foreign Government (CFG) Separate divisions of Health Authorities review CDx and TP applications - Coordination of TP / CDx reviews often difficult or impossible - Agency review timelines may differ between TP and CDx Drug filing approach drives CDx submission strategy - Different clinical studies designs may influence filing plans - Alignment between drug and CDx needed
Footprint Gap Analysis Identification of Rest of World countries in scope during initial contract phase Regulatory & commercialization capabilities Strong Partnership Best Practices - Timely communication of TP submission timelines and strategy required from TP partner to Dx partner - Trust allows for constructive and professional handling of issues - Global direction with support and input from regional and country colleagues
Regulatory Best Practices CDx international registration strategy built off TP strategy Submission planning team across companies Tracking mechanism Regulatory and Commercial partnership The different regulatory requirements can pose challenges when it comes to the development of therapeutics and companion diagnostics that are intended to be marketed on a global scale. N A Meadows, A Morrison, D A Brindley, A Schuh & R W Barker An evaluation of regulatory and commercial barriers to stratified medicine development and adoption The Pharmacogenomics Journal (2015) 15
Country Examples Latin America EMEA Asia Pacific Mexico Reference Country Approval Russia Local Technical and Clinical Testing South Korea CDx Specific Regulations
Mexico Requirements to Register a CDx - Reference country approval (e.g. US approval) - Local representation - Registration dossier and associated ancillary documents
Russia Complex and Lengthy Registration Process for CDx - IVDs regulated as medical devices - Preparation of documents, local testing, review: + 24 months - Evolving regulations - Local technical testing and clinical testing required Local testing must be performed in government accredited laboratory - Point for Consideration - Do these laboratories have correct instrumentation?
Two phase review - Phase 1 Russia Review of technical file and local testing report At end of this phase scope of clinical testing known - Phase 2 Clinical testing review Close collaboration of TP and Dx partner Global, regional, local
South Korea Guideline for Approval and Evaluation of In Vitro Companion Diagnostic Devices, October 2015 - Reference source to define CDx and provide details of requirements for registration - Simultaneous approval of TP and CDx (in case of novel TP and CDx) - Class according to Regulations on Product Classification of Medical Device and Class by Product Class I-IV based on risk - CDx class III - Guidelines on information to be submitted on both analytical performance and clinical performance
Keys to Success Country specific understanding of the regulatory requirements Collaboration between TP and CDx partners - Aligned regulatory strategies and submission plans Initial registration is just the beginning
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