Key Takeaways
- The European Commission has published simulated exercises to demonstrate the types of questions, known as PICOs, companies will be asked during joint clinical assessments.
- These will play a key role in the new EU Health Technology Assessment Regulation, but the exercises come with some caveats such as a lack of methodological explanation.
- Experts explain how companies can use the exercises to prepare for the PICO process and outline other information crucial to successfully answering PICOs.
EU-level joint clinical assessments (JCAs), which began applying to advanced therapies and oncology products from 12 January under the new Health Technology Assessment (HTA) Regulation, will involve companies answering questions in their dossiers known as PICOs (population, intervention, comparator, outcomes).
The European Commission released six PICO exercises on 3 February, three of which relate to pharmaceutical products. The exercises are effectively simulated responses to PICO surveys, which were carried out in spring 2024 by the JCA subgroup.
Ruairi O’Donnell, HTA lead at the pharmaceutical services provider Cencora, formerly known as AmerisourceBergen, told the Pink Sheet that the exercises were “useful,” but outlined an “important caveat to any interpretation” of them.
The exercises were performed to help the commission develop its guidance on the JCA process, and therefore are “not reflective of the final adopted guidance,” he said.
However, the exercises “are tools [EU authorities] were using to pressure test during the development process,” and are “one of the closest simulations to what we will see in practice,” O’Donnell explained.
“I think they’re important to look at, unfortunately, there isn’t a lot of detail in how these were done,” he continued, adding that he would have preferred a report describing the methods and providing some color to the smaller judgments made.
JCAs, which have been introduced in the EU under the HTA Regulation ((EU) 2021/2282), are similar to relative clinical efficacy assessments that individual member state authorities carry out at the national level. JCAs will be conducted at an EU-level and member states will be obliged to consider them in their pricing and reimbursement decision-making.
Consolidation A Critical Step
One of the key pieces of information that is missing from the PICO exercises relates to how the consolidation of questions from EU member states will work in practice.
Under the JCA process, each EU member state will have the opportunity to set out their needs in the form of PICOs, which would then be consolidated by assessors to minimize duplication as much as possible.
The consolidation process is a “critical step” in terms of making the PICOs gathered more manageable for companies to answer in their dossiers, O’Donnell said, but the exercises published by the commission do not include an explanation about this process.
Nonetheless, he said it was still “very instructive” for manufacturers to study the exercises and look at the range of PICOs the companies used in the exercises conducted.
Another important part of the PICO exercises for manufacturers is analyzing what would represent a subpopulation in a clinical context, something that would drive a full PICO, versus a subgroup analysis, which would require an additional analysis such as an effect modifier, according to O’Donnell.
“As I know from talking to clients, there’s been lots of debate and thinking being done to make sure we’re clean and clear in our thinking about how you differentiate between these two. Because sometimes it’s not crystal clear, depending on the disease state, what represents a subpopulation versus a subgroup,” he explained.
Not All PICOs Addressable
O’Donnell said that the PICO exercises had also “validated” the expectation of the industry that they would be dealing with 10-15 PICOs, rather than four to six, a figure that was shared towards the start of the HTA Regulation journey.
However, he said that companies should “differentiate” between what is an addressable, or analyzable PICO, compared to the number of PICOs in total. While all PICOs need an answer in the dossier, manufacturers will not necessarily have the evidence base to answer each with a strong statistical analysis.
Herbert Altmann, Cencora’s vice president for pan-European market access and healthcare consulting, told the Pink Sheet during the same discussion that member states could request off-label comparator products as well as specific subgroups.
“You cannot just ignore PICOs which are not covered by a clinical trial, you have to explain why the clinical trial does not do that, or why it [doesn’t include a certain] comparator,” he said.
In a previous Pink Sheet article, O’Donnell and Altmann explained in more detail how companies can respond to unanswerable PICOs.
The co-chair of the JCA subgroup has also stated that companies should not leave PICO responses blank, but said they could provide a justification if a PICO could not be answered using data.
About The PICO Exercises
Of the three products to undergo a PICO exercise, two were for anti-cancer treatments while one was for a one-time gene therapy for hemophilia B.
The products used were:
- AstraZeneca’s anti-PDL1 cancer drug Imfinzi (durvalumab) for the first line treatment of adults with advanced or unresectable hepatocellular carcinoma (HCC).
- Bristol-Myers Squibb’s KRAS-inhibitor Krazati (adagrasib) for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation and disease progression after at least one prior systemic therapy.
- CSL Behring’s gene therapy Hemgenix (etranacogene dezaparvovec) for the treatment of severe and moderately severe hemophilia B (congenital Factor IX deficiency) in adult patients without a history of Factor IX inhibitors.
Imfinzi and Krazati both had a total of 13 PICOs, while Hemgenix had seven. The PICOs ranged in terms of the specific effectiveness and safety analysis that was requested for each patient population.
During the same interview, O’Donnell and Altmann explained how increased transparency under the JCA process could result in information that a company considers to be commercially sensitive ending up in the public domain.