EU JOINT CLINICAL ASSESSMENT OF TOVORAFENIB: METHODOLOGICAL LEARNINGS FOR FUTURE ORPHAN DOSSIERS
Author(s)
Vijay D'Souza, PhD1, Alan Fleming, PhD1, Annete Njue, PhD1, Louise Hartley, PhD1, Patrick Hopkinson, MBA2, Caroline Ling, PhD1.
1RTI Health Solutions, Manchester, United Kingdom, 2PHTA Consulting, London, United Kingdom.
1RTI Health Solutions, Manchester, United Kingdom, 2PHTA Consulting, London, United Kingdom.
OBJECTIVES: To review and evaluate the tovorafenib JCA report to identify key learnings for evidence generation and dossier development for future JCA orphan submissions.
METHODS: We conducted a structured analysis of the published JCA report in June 2026 to identify methodological challenges related to PICO definition, evidence availability and identification, and indirect treatment comparisons (ITCs).
RESULTS: Of eight PICOs defined across three patient populations, six contained no comparative data and one was excluded by the assessors for abstract-only comparator evidence; only one MAIC was assessed. In terms of ITCs the following issues were identified: the PV/EM identification was insufficiently documented with three unadjustable confounders; both sensitivity scenarios increased risk of bias by using subsets of the base-case adjustment PV/EMs; the ITC SAP designated no primary analysis, rendering all p-values nominal; both unmeasured-confounding sensitivity tools were excluded because of a shifted null hypothesis without pre-specification, inappropriate odds-ratio approximations, and E-values using point estimates rather than confidence interval bounds contrary to cited good practice thereby downplaying unmeasured confounding. The HTD's post-hoc attempt to qualify its own submitted PFS ITC based on limitations in study comparability was not accepted. Although carer input was documented it was not clearly linked to assessment scope or conclusions, while several outcomes were unreported or omitted due to missing PICO 5 data or methodological issues.
CONCLUSIONS: Key learnings for future orphan submissions include the following: prospective ITC SAP must include hypothesis testing; PV/EM identification must be fully documented; sensitivity analyses should address uncertainty; and pivotal trial design should align with anticipated comparator studies. JCA may be more valuable when assessing medicines supported by large randomised controlled trials with head-to-head comparisons, established endpoints and accepted comparators. Applying the same comparative framework and methodological rigour to orphan drugs raises the likelihood of exposure to broad critique.
METHODS: We conducted a structured analysis of the published JCA report in June 2026 to identify methodological challenges related to PICO definition, evidence availability and identification, and indirect treatment comparisons (ITCs).
RESULTS: Of eight PICOs defined across three patient populations, six contained no comparative data and one was excluded by the assessors for abstract-only comparator evidence; only one MAIC was assessed. In terms of ITCs the following issues were identified: the PV/EM identification was insufficiently documented with three unadjustable confounders; both sensitivity scenarios increased risk of bias by using subsets of the base-case adjustment PV/EMs; the ITC SAP designated no primary analysis, rendering all p-values nominal; both unmeasured-confounding sensitivity tools were excluded because of a shifted null hypothesis without pre-specification, inappropriate odds-ratio approximations, and E-values using point estimates rather than confidence interval bounds contrary to cited good practice thereby downplaying unmeasured confounding. The HTD's post-hoc attempt to qualify its own submitted PFS ITC based on limitations in study comparability was not accepted. Although carer input was documented it was not clearly linked to assessment scope or conclusions, while several outcomes were unreported or omitted due to missing PICO 5 data or methodological issues.
CONCLUSIONS: Key learnings for future orphan submissions include the following: prospective ITC SAP must include hypothesis testing; PV/EM identification must be fully documented; sensitivity analyses should address uncertainty; and pivotal trial design should align with anticipated comparator studies. JCA may be more valuable when assessing medicines supported by large randomised controlled trials with head-to-head comparisons, established endpoints and accepted comparators. Applying the same comparative framework and methodological rigour to orphan drugs raises the likelihood of exposure to broad critique.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
P41
Topic
Health Technology Assessment, Medical Technologies, Methodological & Statistical Research
Topic Subcategory
Decision & Deliberative Processes
Disease
Oncology, Rare & Orphan Diseases