Article

Not long until the Joint Clinical Assessment begins: Will PICO anxiety become a reality?

  • Kim Joline Schmidt

    Kim Joline Schmidt, MSc

  • Mareike Konstanski

    Mareike Konstanski, MSc

  • Ruairi ODonnell

    Ruairi O'Donnell, PhD

In less than two months, the Joint Clinical Assessment will launch, ushering in a new era of collaborative evaluation across all 27 European Union Member States as they tackle the complexities of health technology assessment.
HTAQ

Are you ready?

The Joint Clinical Assessment (JCA) is set to commence in less than two months from now, marking three years since the European Union (EU) Health Technology Assessment Regulation (HTAR) came into effect in January 2022. Starting 12 January 2025, all cancer medicines and advanced therapy medicinal products (ATMPs) with new active substances for which an application for marketing authorisation is submitted to the European Medicines Agency (EMA) will undergo a JCA, in parallel to the regulatory process, involving all 27 EU Member States.

Recent developments

Scientific specifications of medicinal products

In June 2024, the HTA Coordination Group (HTACG) published scientific specifications of medicinal products to support manufacturers in determining whether a medicinal product shall be subject to JCA, including definitions of new active substance, cancer treatment, and ATMP, as summarised in Table 1. The specifications indicate that treatments that have already been approved in the EU prior to 2025 will not go through the JCA process for any subsequent indication unless major modifications have been made to the active substance. However, combination products that include both a new active substance and a previously approved substance will be subject to JCA, given that part of the combination is new, and the efficacy and safety of this combination specifically have not been previously assessed. In the future, all products that have been assessed via JCA will also be subject to JCA for any further indications.
Table 1. Definition of new active substance, cancer treatment, and ATMP according to the HTACG

New active substance

A new chemical, biological, or radiopharmaceutical active substance that:

  • has not previously been authorised in a medicinal product in the EU
  • is an isomer, a mixture of isomers, a complex or derivative or salt of a chemical substance previously authorised in the EU but differing significantly in properties with regard to safety and/or efficacy from that chemical substance previously authorised
  • is a biological substance previously authorised in the EU but differing significantly in properties with regard to safety and/or efficacy due to differences in molecular structure and/or nature of the source material and/or manufacturing process
  • is a radiopharmaceutical substance which is a radionuclide, or a ligand not previously authorised in a medicinal product in the EU, or the coupling mechanism to link the molecule and the radionuclide has not been authorised previously in the EU
Cancer treatment
  • Anti-neoplastic agents (including modulators and enhancers of anti-neoplastic activity) and adjuvant treatments against all malignant and borderline malignant neoplasms, following the current International Classification of Diseases for Oncology (ICD-O /1, /2, /3, /6, /9)
  • Note that the definition of anti-neoplastic treatment comprises chemotherapy, biologic therapies, hormonal agents used in hormonally responsive cancers, or therapies that increase the sensitivity of malignant cells to other anti-neoplastic treatments
  • Note that agents for treatment of side effects of cancer treatment or cancer-associated symptoms, diagnostic agents, and preventive agents do not fall under the mandatory scope of the JCA
ATMP
  • As defined in Regulation (EC) No 1394/2007 including gene therapy, somatic-cell therapy, and tissue-engineering products
  • Gene therapy medicines contain genes that lead to a therapeutic, prophylactic, or diagnostic effect
  • Somatic-cell therapy medicines contain cells or tissues that have been manipulated to change their biological characteristics, or cells or tissues not intended to be used for the same essential functions in the body; they can be used to cure, diagnose, or prevent diseases
  • Tissue-engineered medicines contain cells or tissues that have been modified to be used to repair, regenerate, or replace human tissue

Key: ATMP – advanced therapy medicinal product; EC – European Commission; EU – European Union; HTACG – Health Technology Assessment Coordination Group; ICD-O –International Classification of Diseases for Oncology; JCA – Joint Clinical Assessment.

 

Outstanding implementing acts and guidance documents

Although implementing acts and guidance documents have been intensively prepared by the European Commission and the HTACG during 2024, there are still some crucial documents outstanding for adoption. These include the three implementing acts regarding procedural rules for JCA of medical devices and procedural rules for Joint Scientific Consultation (JSC) of medicinal products and medical devices, which are all planned to be finalised by Q4 2024 (Table 2).
Table 2. Implementing acts to be adopted by 2025

Implementing act
Deadline
Status

Procedural rules for JCA of medicinal products

Q1–Q2 2024

Adopted 23 May 2024

Rules on cooperation by exchange of information with the EMA

Q3 2024

Adopted 18 October 2024

Procedural rules for the management of conflict of interest

Q3 2024

Adopted 25 October 2024

Procedural rules for JSC of medicinal products

Q3 2024

Final version in preparation, public consultation closed

Procedural rules for JSC of medical devices and IVD medical devices

Q4 2024

Public consultation open until 26 November 2024

Procedural rules for JCA of medical devices and IVD medical devices

Q4 2024

Planned

Key: EMA – European Medicines Agency; IVD – in vitro diagnostic; JCA – Joint Clinical Assessment; JSC – Joint Scientific Consultation.

Additionally, more than 10 guidance documents are currently in preparation and supposed to be published before the JCA comes into effect. Among these, the guidance describing the scientific methodology for the scoping process is particularly eagerly awaited by stakeholders since it is expected to complement previous preliminary guidance by EUnetHTA 21 on how this ‘first step’ of the JCA process, such as the definition of the PICO (population, intervention, comparator, outcome) for the JCA scope, will be conducted.

Initiation of the JCA process by the health technology developer

While details on the methodology of the scoping process are thus to be confirmed, the European Commission has recently provided instructions on how health technology developers (HTDs) should initiate the JCA process, stating that they need to declare in the EMA Letter of Intent (via the pre-submission request form) whether their application falls under the scope of the HTAR and, therefore, is subject to JCA. In addition, HTDs of agents falling under the JCA should also notify the HTACG by requesting access to the HTA IT platform to upload the EMA Letter of Intent. Details on documents to be submitted to the HTACG, timelines, and HTD involvement during the process have been specified in the first implementing act. (More information provided in a previous edition of HTA Quarterly here.)
shutterstock_1433546264 LR

PICO definition

The definition of the PICO in the scoping process has been one of the aspects most discussed since the implementation of the HTAR and remains one of the areas of greatest uncertainty. Stakeholders including EUnetHTA 21 and the European Federation of Pharmaceutical Industries and Associations (EFPIA) have conducted so-called PICO simulations to gather insights on the implications for the extent of the data to be presented in the JCA dossier and the likely impact on subsequent local market access submissions.
EUnetHTA 21 has published the results of a PICO simulation exercise for Pluvicto® (lutetium Lu 177 vipivotide tetraxetan), a radiopharmaceutical used to treat adults with metastatic castration-resistant prostate cancer (mCRPC). Further to this, Cencora has conducted an in-house PICO simulation of a hypothetical product—cenpicomab—for the same indication, extending the scope in terms of the number of Member States included and the time frame. PICOs were collected through an online survey with Cencora in-house market access experts located throughout the region and consolidated based on the EUnetHTA 21 scoping process practical guideline. See the comparison of approach and outcomes in Table 3.

Table 3. Comparison of PICO simulations in mCRPC by EUnetHTA 21 and Cencora

 
EUnetHTA 21
Cencora

Indication

Adult patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy

Number of Member States covered

8

(Countries not specified)

16

(Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, the Netherlands, Norway, Poland, Portugal, Spain, and Sweden)

Results (no.)

 

 

Populations

Full licensed population + 4 subpopulations

Full licensed population + 4 subpopulations

Intervention

Pluvicto

Cenpicomab

Comparators

6

12

Outcomes

21

20

(see Figure 1)

Consolidated PICOs

6, including 2 for the full licensed population

18, including 9 for the full licensed population (see Table 4)

Date of PICO survey

November 2022

May 2024

Key: no. – number; PICO – population, intervention, comparator, outcome.

The comparison of both simulations shows that including a broader range of Member States and extending the timeline to capture the most recently approved comparators may lead to a significant increase in consolidated PICOs to be considered for the JCA scope due to variations in clinical guidelines, treatment standards, and speed of market access of new medicines across EU countries.

Comparators

According to EUnetHTA 21’s practical guideline, every required comparator across the included countries results in a separate PICO for the assessment scope. Following this practical guideline, Cencora’s analysis led to a high number in PICOs for the full population driven by the requirement of five of the 16 countries (Germany, Ireland, Italy, Portugal, and Spain) to include all locally relevant comparators in the clinical assessment, covering a range of two comparators in Italy to seven comparators in Portugal. In contrast, three countries (Czech Republic, France, and the Netherlands) stated that assessment against one locally relevant comparator was sufficient, another country (Poland) stated that the relevant comparator would be selected based on the highest market share, and five countries (Belgium, Denmark, Finland, Norway, and Sweden) highlighted that the relevant treatment option would depend on the positioning of the product (i.e. the line of treatment) by the HTD. In Luxembourg, the assessment is based on the dossier submitted in the official ‘pays de provenance’ (i.e. country of origin, usually Belgium). In Greece, only one comparator was considered relevant for the assessment scope. Table 4 shows the identified PICOs for the full population of cenpicomab.

For the EUnetHTA 21 analysis, country-specific requirements have not been published, reflecting the scoping process in the framework of the JCA, where individual country responses will not be made available to HTDs.

Table 4. Consolidated PICOs for the full population for cenpicomab (hypothetical drug)

 

Comparators of interest for the full population for cenpicomab

Countries requesting each comparator
PICO 1

Abiraterone + prednisone/prednisolone

BE, DE, FI, FR, IE, LU, NL, NO, PT, SE
PICO 2

Best supportive care*

DE, DK, ES, FI, IE, NL, NO, SE
PICO 3

Cabazitaxel + prednisone/prednisolone*

BE, DE, DK, ES, FI, IE, IT, LU, NL, NO, PT, SE
PICO 4

Docetaxel + prednisone/prednisolone*

BE, DK, FI, IE, LU, NL, NO, PT, SE
PICO 5

Enzalutamide

BE, DE, DK, FI, FR, IE, LU, NL, NO, PT, SE
PICO 6

Lutetium (177Lu) vipivotide tetraxetan + androgen deprivation therapy*

BE, DE, FI, GR, IE, IT, NL, PO, PT
PICO 7

Olaparib*

DK, PT
PICO 8

Radium-223*

ES, FI, PO
PICO 9

Radium-223 + luteinizing hormone releasing hormone analogue*

PO, PT

Key: BE – Belgium; CZ – Czech Republic; DE – Germany; DK – Denmark; ES – Spain; FI – Finland; FR – France; GR – Greece; IE – Ireland; IT – Italy; LU – Luxembourg; NL – Netherlands; NO – Norway; PICO – population, intervention, comparator, outcome; PO – Poland; PT – Portugal; SE – Sweden.

Note: Countries in bold represent the countries the PICO was derived from due to the request for data against all identified comparators.
*Comparators also considered in PICOs for subpopulations (not presented here).

The possibility of extensive PICOs resulting from the scoping phase was confirmed in a recent EFPIA simulation for three authorised oncology treatments, including orphan and ATMP, which resulted in a large number of potential PICOs across seven countries, ranging from seven to 23 PICOs after consolidation.

Outcomes

In Cencora’s analysis, a total of 20 relevant clinical outcomes were identified for the assessment scope. The number and type of relevant outcomes differed between countries and ranged from two in the Netherlands to 19 in Ireland. Overall survival was the only outcome that was considered relevant by all assessed countries, followed by grade ≥3 adverse events (n=14) and radiological progression-free survival (n=13) (Figure 1). EUnetHTA 21’s simulation for Pluvicto® resulted in the same outcomes as Cencora’s simulation for cenpicomab, except one additional outcome (suspected unexpected serious adverse reactions) in EUnetHTA 21’s analysis.

Figure 1. Number of countries requesting data against specified clinical outcomes
htaq


Key: AE – adverse event; AESI – adverse event of special interest; EORTC-QLQ-C30 – European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (-Core, 30-item); EORTC-QLQ-PR25 – European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (-Prostate, 25-item); EQ-5D-5L – EuroQol-5 Dimension-5 Level; FACT-G – Functional Assessment of Cancer Therapy-General; FACT-P – Functional Assessment of Cancer Therapy-Prostate; PFS – progression-free survival; PSA – prostate-specific antigen.

Conclusions

The PICO simulations conducted consistently show that the number of consolidated PICOs heavily depends on the number of countries included as well as on the indication of the product under assessment, with a high number of PICOs expected in many oncology indications due to varying treatment landscapes and pathways. 
A pharmacist reviewing plans
While consolidated PICOs from Cencora’s analysis reflect all requirements from all assessed countries, it remains to be seen how the consolidation will be effectively conducted in practice; this will depend on whether all HTA bodies provide country-specific PICO information within the requested time frame. Many HTA bodies have expressed concerns with regard to the scoping process, including capacity issues and short timelines (especially for countries not yet defining PICOs in their local HTA process or not having any formal HTA process in place), the need to restructure the current processes due to the EU requirements, duplication of work when narrowing down extensive PICOs, and possible lack of engagement from key opinion leaders when testing local PICOs.
Once the assessment scope has been established, HTDs will be required to submit data for all PICOs defined by the HTACG or to justify any PICOs left unanswered. The complexity of addressing requirements from 27 Member States is causing anxiety across HTDs about unexpected research questions and the impact on downstream market access in Europe, including the need for additional analyses, like indirect treatment comparisons with comparators which are locally relevant but not covered in the pivotal clinical trials, speed of local market access, and implications for pricing based on the comparators included in the JCA. Furthermore, the ‘PICO anxiety’ could bear the risk of overemphasis on the needs of Europe compared to markets outside Europe and thereby drive an imbalance. HTDs are advised to conduct a comprehensive assessment of the comparator risk at the early evidence-planning stage, considering both European and global perspectives. 

With less than two months remaining until the JCA comes into effect, and with methodological guidance still pending, significant uncertainties persist for both the industry and HTA bodies regarding the scoping process, which forms the basis of the JCA. PICO exercises organised by the HTACG and involving various HTA bodies, as well as PICO simulations conducted by HTDs, are crucial for preparing key stakeholders for the upcoming JCA in terms of capability and internal strategy. However, it remains to be seen how these simulations will translate into the actual JCA and what impact the assessment will have on local market access. The EU HTA will function as a learning system during the initial JCAs, and the collaboration, effort, and feedback of all stakeholders will be essential to create an efficient system.

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Sources

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This article summarises Cencora’s understanding of the topic based on publicly available information at the time of writing (see listed sources) and the authors’ expertise in this area. Any recommendations provided in the article may not be applicable to all situations and do not constitute legal advice; readers should not rely on the article in making decisions related to the topics discussed.
 

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