How to assess co-dependent technologies Dr Mira Pavlovic-Ganascia Deputy Director for HTA Haute Autorité de Santé France How to assess co-dependent technologies • Key words: – Harmonise, Synchronise, Co-ordinate • • • • • Concepts Development MAA process Assessment for reimbursement process Safety reporting (out of scope) 2 1 Co-dependent technologies Harmonise, synchronise, co-ordinate • Development: – Harmonise: • • • • Concepts, definitions, terminology Development requirements (regulatory, HTA) adequate for the intended use Synchronise the development of co-dependent technologies Synchronise and co-ordinate the process • • Industry HTA bodies and payers 3 Concepts, definitions, terminology HTA • Co-dependent technologies (PBAC, AU): health technologies are co-dependent if their use needs to be combined (either sequentially or simultaneously) to achieve or enhance the intended clinical effect of either technology – Mostly drug + test • Co-dependent products are products that depend on the use of a diagnostic test to meet their labelled safety and effectiveness claims (FDA) • Hybrid HT combine the characteristics of different HT in one entity – Drug + medical device (e.g. insulin pumps) – Procedure + drug + device 4 2 Development requirements depend on the type of HT • In hybrid HT, the most important part of hybrid HT drives development and assessment – Chondroselect: drug part most important • For co-dependent technologies, e.g. drug + diagnostic test, both are equally important – Development of IVDMD – Development of a drug – Co-development drug+IVDMD 5 Development requirements IVDMD Scientific basis Expression in diseased and non-diseased tissues Consistent relationship between IVDMD and condition Analytical performance = analytical validity ability of a test to measure accurately marker of interest early stage of development, before clinical trial Diagnostic performance = clinical validity = diagnostic accuracy accuracy with which a test predicts the presence (absence) of disease or a characteristic (able to adequately select/stratify patients) Specificity, sensitivity, NPV, PPV, Versus reference test if available; phase I-II clinical trials, single arm 6 3 Development requirements IVDMD Clinical utility = clinical usefulness likelihood that the test will lead to improved outcome with a given intervention by informing treatment decision clinical utility needs to be demonstrated in population that reflects clinical use phase III pivotal test-drug clinical trial (RCT): test-drug (cost)-effectiveness and safety vs adequate comparator if available RELEVANT FOR INTENDED USE 7 Development requirements Intended use • Predictive use: pre-treatment patient characteristic that determines if a patient is a good candidate for treatment with a specific product – Related to a particular therapeutic intervention • Identify patients who are most likely to benefit from a product • Exclude patients at increased risk for product-related serious adverse reactions • Monitor response to treatment – Drug effects compared in marker+ vs marker- patients (?) • Prognostic use – No intrinsic relation to specific intervention • Indicates natural history of a disease – Disease outcomes compared in marker+ and marker- patients 8 4 Development requirements for predictive use Unselected or enriched population? • Predictive claims for IVDMD rely upon understanding the effects of the drug in both marker+ and marker- patients (FDA, EMA) • Enrolment of enriched population only (marker+) acceptable (EMA) (enriched design): – If true predictive marker – if cut-off point established • Inclusion of marker- population will depend of the knowledge available ; justification necessary to include marker- patients if a benefit is not expected in this group • Case by case decisions – scientific advice/early dialogue useful 9 Drug+test Regulatory setting • Drug MAA: EMA • Test: NB – Conformity assessment procedure • Test: EMA – Diagnostic performance, cut-off values (in the context of clinical evidence) – Clinical utility • Consultation procedure between EMA and NB: planned 10 5 Drug+test HTA setting France: • Haute Autorité de Santé (HAS) • Unique HTA body for the assessment of all health technologies (drugs, MD, IVDMD, procedures) • Different committees – Drugs: CT – MD and IVDMD: CNEDIMTS – Procedures: CNEDIMTS, CEEPS 11 Drug+test HTA setting (France) HAS submission file request for drug and IVDMD available online (http://www.hassante.f r/portail/jcms/c1046750/depot-de-dossier-de-transparence) IVDMD: data to submit on • Intended use • CE marking dossier • Reference test? • Data on IVDMD from MAA file • Analytical validation data • Diagnostic performance data • Impact on the test on efficacy and safety of a drug (interaction test drug, target population, effect size, NNT) • Conditions of testing • Other possible use? 12 6 Drug+test HTA setting (France) • IVDMD and drug assessment done in parallel, not in combination • Positive reimbursement decision is not automatically extended to a diagnostic test • Two HT follow different routes: – Different HAS Committees: Transparency committee (drugs) and CNEDIMTS (IVDMD) – Different Sponsors (pharm company for drugs, another company for IVDMD, or healthcare professionals for in-house IVDMD) – Different timelines of assessment (longer for IVDMD, up to 1 year) – Different decision bodies (CEPS for drugs, UNCAM for IVDMD) 13 Drug+test HTA setting (France) • IVDMD reimbursement delayed as compared to a codeveloped drug – In-house tests, temporarily financed by different types of organisms, especially by INCA for cancer-related IVDMD, may bridge the gap • Final decision (UNCAM) based on HTA guidance given by HAS: – reimbursement of CE-marketed test – both CE-marketed and in-house test • No coordination between CEPS (drugs) and UNCAM (IVDMD) 14 7 Possible solutions Synchronise and co-ordinate the process • Before submission, (industry) – Different sponsors for drug and test • Different views • Different timelines – Same sponsor, different departments • Different indications requested for MD and for drug • After submission, (HTA bodies) – Independent committees – Different timelines – Different final decision bodies? 15 Synchronise and co-ordinate the process Before submission (industry) • Parallel EMA-HTA scientific advice • Early dialogues (EUnetHTA JA2, WP7) – between the industry and HTA bodies – to optimise co-development • Early contacts with regulatory and HTA bodies for procedural matters – EMA and NB – HTA and payers 16 8 Synchronise and co-ordinate the process After submission (France) HTA bodies and payers • Coordinate work of different committees • Coordinate decision bodies • Use innovation path (CED – art. 165.1.1) when possible • Plan, communicate… • Speed up… 17 References • • • • • • • • • • • Co-dependent and hybrid technologies. MSAC, PBAC, [email protected] In vitro companion diagnostic devices. FDA draft guidance, July 14, 2011 EMA/CHMP/641298/2008 EMA/CHMP/PGxWP/128435/2006 EMA/CPMP/EWP/1119/98/Rev.1 AHRQ Methods guide for medical tests reviews AHRQ Methods research report. Addressing Challenges in Genetic Test Evaluation European Commission Proposal for a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on in vitro diagnostic medical devices. COM(2012) 541 final Annexe au dossier type: actes associés à l’utilisation d’un médicament http://www.has-sante.fr/portail/jcms/c1046750/depotde-dossier-de-transparence R Simon. Per Med 2010;7(1):33-47 P Landais et al. Thérapie 2009;64(3):195-201 18 9