Oncology products and advanced therapy medicinal products (ATMPs), many of which treat rare diseases, are already within the scope of EU Joint Clinical Assessment (JCA). Additionally, all orphan medicinal products (OMPs) will be eligible for JCA from 2028. For manufacturers planning launches in rare indications, it’s therefore time to embed JCA considerations into global access strategies and evidence-generation planning. “PICO simulation” should be a central part of this work, to predict pan-EU HTA body expectations and ensure relevant populations, interventions, comparators, and outcomes (PICOs) are represented across the product’s evidence base.
The assessment scope for EU JCA will include all relevant parameters for assessment expressed as a series of “PICOs”. These will be identified in a PICO survey shared with all 27 Member States, with the results consolidated by the JCA (co-)assessors to capture all needs of Member States in as few PICOs as possible. However, based on different needs in different Member States, the number of collected PICOs could be very high (see our research), meaning that evidence generation activities will need to cover a broad range of PICOs. Additionally, the final PICO list will only be communicated to the manufacturer 100 days before the JCA dossier submission deadline, leaving little time for evidence generation and dossier development.
Companies will therefore need to simulate PICOs well in advance of receiving the final PICO scope from the JCA (co-)assessors: firstly, to inform appropriate evidence generation activities early on and secondly, to feed into early, proactive JCA dossier development.
PICO simulation is relevant at multiple stages in a product’s development pathway:
PICO simulation can identify the key questions a product’s evidence package should address, and therefore inform optimal trial design. It’s unlikely that a single trial will be able to cover all of the anticipated required PICOs, so companies may choose to prioritise which PICOs to address in the pivotal trial, with the remainder addressed through other evidence generation activities such as real-world data collection or indirect treatment comparisons (ITCs).
PICO simulation can help determine which trial analyses are needed and confirm if any additional, complementary data generation activities are needed; for example, if new patient sub-populations have been defined or if comparators have evolved since the previous simulation.
To ensure a strategy is in place for all likely PICOs and initiate JCA dossier development ahead of the final confirmation of PICOs from the JCA (co-)assessors (100 days from submission date).
Published PICO simulation exercises have found that clinical guidelines capture the majority of PICOs (see our research), and therefore for most conditions, prospectively examining guidelines is likely to provide a reasonably comprehensive assessment of likely PICOs. However, we often see a lot of regional variation in the management of rare diseases (particularly in “ultra” rare conditions), and there are typically only a handful of treatment guidelines available. The relevant comparator is often “best supportive care”’, and a wide range of different symptomatic treatments could fall into this category varying based on local preferences.
Investigating prior HTA submission scopes and discussing different Member State requirements with affiliates will also be useful activities for PICO simulations, particularly in well-trod disease areas, to identify the most relevant populations, comparators and outcomes. However, this approach relies on there being prior HTA appraisals in the disease area, and many rare disease products are launched as the first disease-modifying products in their therapy area. Other anticipated challenges for PICO simulation include:
Our recommendations for the manufacturers of treatments are as follows:
Achieving successful access in the rare diseases space has always required early, transparent and collaborative evidence generation planning and execution. This has only become more important with the introduction of EU JCA. By conducting robust PICO simulations at the right timepoints, leveraging learnings from well-considered literature reviews, taking HTA precedent from the most appropriate analogous indications, and by effectively engaging with colleagues, KOLs and patients, companies can proactively build strong evidence packages to support the best possible EU JCA submissions. Early preparation and careful collaboration are key!
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If you would like any further information or advice on the themes presented above, please get in touch, or visit our EU JCA page to learn how our expertise can benefit you. Issy Newell (Head of Rare Diseases) and Catherine Bunting (Expertise Director), created this article on behalf of Costello Medical. The views/opinions expressed are their own and do not necessarily reflect those of Costello Medical’s clients or affiliated partners.
