Joint Clinical Assessment in the EU: What Life Sciences Companies Need to Know

JCA Questions and Answers 

Here are some of the questions Trinity experts have been asked:  

Does the JCA process begin after the marketing authorization application is accepted? 

No. The JCA process initiates concurrently with EMA submission and operates largely in parallel with the EMA process. The JCA stipulates that the manufacturer should submit to the EU HTA secretariat the summary of product characteristics and clinical overview simultaneously with EMA submission. EMA will also inform that body of all new regulatory submissions that fall within JCA scope. This means that JCA strategy needs to be developed in advance of EMA submission; in fact, JCA planning should be underway well before lock-down of phase 3 trial design, to ensure evidence strategy is optimized for HTA purposes as well as regulatory purposes. 

Will manufacturers have to re-do the JCA submission if post CHMP-label is different from the anticipated label at submission? 

Potentially. Because the JCA evidence request (“scoping”) comes well before the CHMP label decision, there is some risk of the label being different from the expected label which is used to define that evidence request. The JCA report must be adopted within 30 days of the EMA marketing authorization, which leaves limited time to pivot. If the EMA label is narrower than anticipated, that decision will be based on subgroup data made available to EMA, so there is a good chance that the JCA assessors can work with a subset of the evidence the manufacturer has already submitted, based on the JCA scope. With that said, recent guidance from HTACG is that if the data submitted to JCA is not adequate to evaluate the evidence with respect to the label CHMP adopts, the JCA process may need to be begun again for that asset. 

Will JCA results dominate each member state’s HTA decision, especially when the assessors are the same as the member state? 

No. Member states retain the power to make pricing and reimbursement decisions for their own markets. Most member states consider information outside the scope of JCA in making those decisions (e.g., evidence on cost-effectiveness or budget impact – which are not within the scope of JCA). 

What are the implications of not addressing JCA’s PICO requests within the 90-day timeline? 

Unclear. In cases where a manufacturer fails to submit requested evidence, the JCA report will make a note of that. The impact on a given member state decision will be influenced by the relevance to that member state of the evidence in question, but it is reasonable to expect that member states will leverage in price negotiations evidence gaps identified publicly in the JCA report. 

Is there any chance for the EMA decision on a product to change post-JCA, considering the PICO requirements were not met? 

No. EMA has its own mandate, which is different from JCA (or any MS HTA or payer). EMA has to make a decision on whether a product has demonstrated safety and efficacy adequate to allow it to be marketed. HTAs and payers have to make decisions about value and whether to fund the product. With that said, it is interesting to speculate whether over the longer term, EMA’s own evidence requests may be influenced by the broader set of PICOs that JCA is likely to review. 

Will different member states have different evidence requirements under JCA? 

Yes. Within the JCA process itself, different member states are likely to ask for different PICOs. For many indications, differences in standard of care and even available therapies will lead to differences across member states in terms of the subpopulations in play and the comparators required for each subpopulation. In addition, different member states are likely to emphasize different outcomes, for example because of different perspectives on surrogate endpoints or their need for endpoints that speak to patient quality of life. At the national level, when it comes to the evidence that member states request in addition to the JCA output, there will of course also be country-specific requests for evidence that can support each market’s distinct approach to assessing value and thus price and reimbursement outcomes. 

Can EMA and JCA differ in their PICOs requirements? 

Yes. JCA’s PICOs requirements are developed based on input from all member states. Since PICOs requirements can vary considerably across EU member states, it is quite likely in indications with complex subpopulation structures and/or a broad set of therapeutic options that a different set of populations will be required for JCA than for EMA. For the same reason, JCA may ask for comparisons to a broader set of therapies than EMA does. In fact, it may require comparators in cases where EMA does not, since JCA assessment is an input into member states’ assessments of relative value. Finally, JCA may ask for outcomes that EMA does not require, for the same reason. 

Will JCA mean more demanding evidence standards?  

Yes. For example, JCA guidance on indirect treatment comparisons (ITCs) largely reflects the approach taken historically by IQWiG and G-BA, which is more demanding than a number of other national HTAs. This is important, because as noted above the expectation is that many products will require a large number of PICOs, driven in may cases by a large number of population/comparator combinations and thus a large number of ITCs. JCA guidance on ITCs is more demanding than a number of member states (e.g., Italy, Spain and France) with respect to, for example, more rigorous verification of similarity, homogeneity and consistency across trials used in ITCs, requiring conservative statistical approaches to manage uncertainty (e.g., random effects models rather than fixed effects models, using prediction intervals rather than confidence intervals) and a stronger mandate for anchored rather than unanchored ITCs. The JCA report which will inform all member states’ HTA assessments will thus reflect a higher evidence bar and may promulgate that higher bar more broadly across member states. For another example, JCA guidance aims to limit the use of surrogate endpoints, asking that countries’ PICOs requests include surrogate endpoints only “when absolutely necessary” and limit requests to validated surrogates in such cases. 

Will the JCA prefer, or require, pre-specified (vs. post-hoc) analyses? 

Pre-specified preferred. The HTA Coordination Group on JCA, which is responsible for managing and providing guidance on the JCA process, has released guidance on this aspect of evidence requirements. The guidance is that pre-specified analyses are preferred, on the grounds that they ensure transparency and methodological rigor. Post-hoc analyses may be accepted, but must be reported as such and justified.  

Does JCA guidance on statistical methodology for trial analysis differ from EMA’s? 

Yes. In some areas, EMA and JCA provide different guidance. This reflects the different purposes of the two bodies’ assessments. For example, EMA prescribes specific statistical methodologies that should be used to control false positives that can arise when multiple hypotheses are being tested at once (which is typical in a clinical trial). JCA asks for transparent reporting of the methods used but does not prescribe methods. Guidance on sensitivity analyses also reflects the two agencies’ different objectives. For EMA, sensitivity analyses focus on confirming robustness of primary efficacy results. For JCA, which is concerned with relative effectiveness assessments, sensitivity analysis must evaluate the impact of different methodologies on comparative effectiveness conclusions. 

What happens if we don’t submit a JCA dossier (for an asset that requires one)? 

Unclear. JCA has no built-in enforcement mechanism. For example, failure to submit a JCA dossier does not impact EMA decision-making. It is likely to impact country-level decision-making on pricing and reimbursement, but at this point it is not clear how most member states will react to such a situation. Germany’s G-BA has announced its proposed policy in case of an incompletely submitted, or late, JCA dossier submission. In such situations it will pause review for up to 90 days, after which it may request a full AMNOG review. Most member states have not yet announced policies of this kind, however. JCA is of course a moving target and if HTACG perceives that manufacturers are deliberately ignoring JCA’s requirements, that may provoke more stringent enforcement mechanisms. 

What does JCA mean for pricing? 

Unclear. There is no direct connection between JCA and pricing and reimbursement outcomes. JCA does not assess value, which remains the province of national HTAs/payers. However, as outlined above, the JCA’s assessment process may require both more evidence (via a broad set of PICOs – including, potentially, PICOs that the manufacturer has not planned for) and higher requirements for that evidence, than what is required of manufacturers at present. This means that the JCA report may provide member states with additional leverage in pricing negotiations with manufacturers. 

What does JCA mean for time to access across EU? 

Unclear. Enhancing speed to market and thus access to therapies across EU was one of the stated motivations for JCA, given the broad disparities that exist at present. However, it remains uncertain how member states will adapt their existing pricing and reimbursement approaches and thus how much potential JCA outputs create for acceleration of country-level access. In addition, manufacturer resource constraints, commercial priorities and strategic considerations, including international reference pricing, will also influence the timing of access across EU markets.