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From regulatory to reimbursement:
The evolving spectrum of how the EU4 and UK consider access to oncology treatments

Large inequality exists across Europe on patient access to new cancer treatments.1,2 The European Federation of Pharmaceutical Industries and Associations (EFPIA) oncology platform has recently identified several factors that cause delays in access to oncology medicines with value assessment criteria being a key barrier. 3
Despite an overarching agreement on the need to expedite the launch of promising oncology therapies, there is a disconnect between regulations and requirements of health technology assessment (HTA). In the last few years, approximately, two of three approvals granted by the European Commission (EC) for oncology therapies had no data available demonstrating controlled, statistically significant Overall Survival (OS) benefit.4,5 Although regulatory authorities accept clinical packages based on surrogate endpoints, non-randomized trials, etc., to inform risk/ benefit assessments, such data are not considered robust by European HTA bodies. As a result, misalignment between regulatory and HTA standards and among the different countries is an obstacle to patient access to critically important medications.
While this is true in many geographies, the variance across some major European markets on the evidentiary bar set by payers is particularly apparent. In this white paper, we examine the current “state of play” regarding new oncology medicines that are gaining market access in the EU4 and the UK. Our primary focus is to better understand how limitations in clinical data and disparities among European HTA bodies regarding the acceptable level of evidence impact market access. The purpose of this analysis is to provide insights into how value judgments can vary and how flexibility in approaches to managing uncertainty can lead to significantly different patient access to oncology therapies across European jurisdictions.
This is especially relevant given the current lack of consensus in evaluations and the planned adoption of the EUnetHTA joint clinical assessments (JCAs) framework by Q4 2024 for oncology medicines and advanced therapy medicinal products (ATMP s) and for all medicines by Q4 2029.6 Although the ambition of the consortium is to address the discrepancies in the assessment of therapies and set common standards on the level of acceptance of the clinical evidence package, the differences in the principles applied as well as the way innovations are viewed and approached across Europe makes this difficult.

Research Methodology

In the last 6 years (between January 2016 and December 2021), we reviewed 71 oncology therapies approved by the EC, excluding generics, biosimilars, hybrid medicinal products, and informed consent applications.7 We then assessed the market access status of these therapies across the EU4 and the UK (data collection cut off November 2022). Availability, HTA and time to market data was gathered from national HTA agencies and pricing and reimbursement (P&R) bodies.
We conducted an in-depth analysis of oncology therapies deemed not reimbursable in France (SMR -insufficient [SMR - Service Médical Rendu]) because French market access procedures require a clinical assessment of new therapies before prices can be negotiated. This excludes oncology therapies that have received SMR insufficient in only one indication or sub-group, which would still enable price negotiations with the Comité Economique des Produits de Santé (CEPS) based on the other indication(s) / sub-group(s). We then further reviewed the market access status of the oncology medicines with only SMR insufficient in France across four other key European countries (Germany, Italy, Spain, and the UK) to understand the different approaches used in neighboring markets and look for similarities and differences.

Research Findings

Current reimbursement landscape for oncology therapies: Setting context

Substantial inter-country variability is observed in availability and time to reimbursed access via standard reimbursement pathways across the EU4 and the UK. System structures are consistently the key drivers of differences.
Given implicit reimbursement with listing on the Lauer Taxe in Germany,8 the time to patient access is the quickest in Germany whereas the gap between regulatory and pricing approval is longer in France, Italy, Spain, and the UK9-12 (Table 1) due to local pricing, reimbursement, and HTA procedures. While the majority of EC-approved oncology therapies are launched in Germany (89%), the fewest therapies have completed price and reimbursement (P&R) procedures in France and Spain (56% and 59%, respectively).

Table 1: Availability and time to reimburse access for oncology therapies in the EU4 and the UK

Country Approved EC therapies - % of total approved (71) Average number of weeks to reimbursed access
France56% (n=40)77
Germany89% (n=63)16
Italy77% (n=55)76
Spain59% (n=42)79
UK (NICE)75% (n=53)61
Source: Market Access Trends of Pharmaceutical Products in the US, EU4, and UK (2016–2021). ISPOR
A closer look at therapies not available across countries (Figure 1) highlights that in France, 15% of oncology therapies approved by the EC in the last 6 years (11 of 71 approved) have been denied access because of insufficient clinical evidence (SMR insufficient) by the Haute Autorité de Santé (HAS) precluding any conversations about price. This is a much larger number than previously observed.13
Figure 1: Status of oncology therapies across the EU4/UK

Review of therapies denied access in France

No single underlying product characteristic explains the rationale for reimbursement denial in France (Table 2). The 11 therapies have different combinations of characteristics related to factors such as:
Regulatory pathway to approval (i.e., standard, conditional, exceptional)
Targeted indication (i.e., hematological malignancy, solid tumor)
Size of the treated population (only two had orphan drug designation) and
Size of marketing authorization holder (large and small pharmaceutical companies)

Table 2: Characterization of 11 oncology medicines with SMR insufficient

Generic name Brand name Therapeutic Area(s) Marketing Authorization Holder (MAH) EC approval date Regulatory approval pathway Orphan drug designation Previously included in early access program
neratinibNerlynxBreast NeoplasmsPuma Biotechnology B.V./Pierre Fabre31-Aug-18StandardNN
tivozanib hydrochloride monohydrateFotivdaRenal cell carcinoma (RCC)EUSA Pharma (UK) Limited24-Aug-17StandardNN
entrectinibRozlytrekCancer; Carcinoma, Non–Small-Cell Lung Cancer (NSCLC)Roche Registration GmbH31-Jul-20ConditionalNN
alpelisibPiqrayBreast NeoplasmsNovartis Europharm Ltd27-Jul-20StandardNY
polatuzumab vedotinPolivyLymphoma, B-cellRoche Registration GmbH16-Jan-20ConditionalODDY
padeliporfinTookadAdenocarcinoma of the prostateSTEBA Biotech S.A10-Nov-17StandardNN
amivantamabRybrevantCarcinoma, NSCLCJanssen–Cilag International N.V.9-Dec-21ConditionalNY
zanubrutinibBrukinsaWaldenstrom MacroglobulinemiaBeiGene Ireland Ltd22-Nov-21StandardN*Y
dostarlimabJemperliEndometrial NeoplasmsGlaxoSmithKline (Ireland) Limited21-Apr-21ConditionalNY
duvelisibCopiktraLeukemia, Lymphocytic, Chronic, B-cell; Lymphoma, FollicularSecura Bio Limited19-May-21StandardNN
tagraxofuspElzonrisLymphomaStemline Therapeutics B.V. (now part of Menarini)7-Jan-21ExceptionalODDY
*Orphan drug designation (ODD) withdrawn upon approval
A deeper analysis of HAS assessments underscores key concerns around clinical trial designs that are not considered reflective of best practice/standard of care in France, comparators that are misaligned with the targeted patient population, and immature data that cannot be objectively quantified (Table 3).13

Table 3: Rationale for SMR insufficient by HAS

Rationale # of assessments citing concern
Absence of robust comparative data when comparison possible or lack of relevant study comparator (mismatch with target patient group or not used in practice)9
Preliminary nature of data/absence of robust evidence of a benefit on a clinically relevant endpoint (no demonstration of Overall Survival (OS), Quality of Life (QOL) , or morbidity benefit)8
Poor safety/tolerability7
Patient selection (heterogenous population, low-risk population, etc.)4
Details with each assessment presented in appendix (Table 5)
Interestingly, six of the eleven therapies were previously included in the French early access program highlighting the potentially promising nature of the products. 14 Despite this, none of the products are currently available via standard reimbursement or early access routes. Reforms to the early access program that now require the HAS evaluation for inclusion in the L’autorisation d’accès précoce (AAP) may lead to more consistency in evaluations for both access pathways, but may result in fewer therapies becoming available via AAP; hence, further monitoring and tracking are required.
The HAS published a position paper in February 2023 setting out the general framework for assessments that presents situations where exceptions to standard rules could be justified depending on factors such as the level of unmet need (partially covered vs. not covered) and nature of innovation (e.g., disruptive/transformative vs incremental).15 The scrutiny of the clinical evidence package by the HAS, rigidity of data requirements, and the implications of launching with suboptimal trial designs or immature data in France could preclude reimbursement independently of price. This is not necessarily the case in other markets where different mechanisms could enable patient access.

Comparison across geographies

Recognizing how approaches differ across countries is crucial to better understanding how to navigate and finding solutions tailored to individual health systems. Of the eleven therapies not reimbursed in France because of limitations to clinical evidence package, seven are available and reimbursed in Germany and England, six in Italy, and five in Spain (Table 4). Contradictory outcomes in the HTA are not unusual; for example, entrectinib does not have a favorable HTA in most markets but is assigned innovative drug status in Italy. Inconsistencies in evaluations and outcomes are primarily driven by the systems’ procedures and assessment criteria.

Table 4: Status of selected oncology therapies with SMR insufficient across key European markets

Generic name Brand name Therapy area France Germany England Italy Spain
neratinibNerlynxBreast NeoplasmsSMR insufficientHint of minor added benefit - ReimbursedRecommended with restrictions and commercial arrangementNot innovativeClass C (not reimbursed)Reimbursed with restrictions
tivozanib hydrochloride monohydrateFotivdaRenal cell carcinoma (RCC)SMR insufficientNo added benefitReimbursedRecommended with restrictions and PASNot innovativeClass C (not reimbursed)Reimbursed as per label
entrectinibRozlytrekCancer; Carcinoma, Non-SmallCell LungSMR insufficientNo added benefitReimbursedCDF and managed access agreementFully innovative: Reimbursed (Class H)Not reimbursed
alpelisibPiqrayBreast NeoplasmsSMR insufficientNo / minor added benefitWithdrawnRecommended with restrictions and CAANot innovative: Reimbursed (Class H)Reimbursed with restrictions
polatuzumab vedotinPolivyLymphoma, B-CellSMR insufficientHint of nonquantifiable added benefitReimbursedRecommended with a CAANot innovative: Reimbursed (Class H)Reimbursed as per label
padeliporfinTookadAdenocarcinoma of the prostateSMR insufficientNo benefit assessment conducted (out of scope)- withdrawnNot recommendedNot innovative: Reimbursed (Class H)Not reimbursed
amivantamabRybrevantCarcinoma, Non-SmallCell LungSMR insufficientNo added benefitwithdrawnDraft not recommendedClass Cnn (not reimbursed); P&R procedure ongoingStudy or without financing request
zanubrutinibBrukinsaWaldenstrom MacroglobulinemiaSMR insufficientNo added benefitReimbursedRecommended with restrictions and CAANot innovative: Reimbursed (Class H)Reimbursed as per label
dostarlimabJemperliEndometrial NeoplasmsSMR insufficientNo added benefitReimbursedCDF and managed access agreementNot innovative: Reimbursed (Class H)Study or without financing request
duvelisibCopiktraLeukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, FollicularSMR insufficientNo added benefitwithdrawnTerminated appraisalswithdrawn evidence submissionsNot innovativeClass C (not reimbursed)Not available
tagraxofuspElzonrisLymphomaSMR insufficientHint of nonquantifiable added benefitreimbursedTerminatd appraisalsno evidence submission“Class Cnn (not reimbursed); P&R procedure ongoing”Not available
Not reimbursed
CAA: Commercial access agreement; PAS: Patient access scheme
Reimbursed with restrictions
The UK and Italy tend to be more accepting of immature data because of established funding paths such as the Cancer Drug Fund (England) and/or infrastructure for real-world data collection (Italy).10,12 Furthermore, both countries regularly seem to accept data limitations but negotiate significant confidential discounts in return for access in the face of uncertainty. For example, evaluation of Italian tender agreements suggests access to the six oncology medicines is based on an average discount of 52% (range: 40% to 69%), highlighting the aggressive nature of price negotiations when the clinical package is sub-optimal.
Spain is similar to the UK and Italy, however late submissions by manufacturers and economic constraints lead to protracted price negotiations and longer delays to access.10-12 This is illustrated by the fact that, besides the five drugs currently available, only two therapies have been denied reimbursement while the rest have not yet completed their evaluations.
The German system, on the other hand, sets listing and reimbursement prior to the HTA. However, stringent HTA, partial net price transparency, and the potential “domino effect” on pricing in other markets has resulted in four of the eleven therapies being withdrawn after launch. For instance, in August 2022, Janssen-Cilag decided to withdraw amivantamab following the Federal Joint Committee’s (G-BA) “no added benefit” assessment given the potential implications on net price.16 Recent revisions to AMNOG as per the SHI Finance Stabilization Act (effective November 2022) requiring “major/ considerable added benefit” to allow a premium price and applying a 20% mandatory discount to combination oncology therapies17 may lead to further market withdrawals in future.


While there is an ethical imperative to increase patient access to oncology therapies, the strong preference for comparative studies and mature data at approval on key survival metrics by payers pose a challenge for manufacturers. Different payer perspectives and expectations further increase complexity. Given the push for access, advances made in oncology to date, and investments in clinical trials, collaborative solutions are crucial to harmonize assessments and patient access across Europe.
As economic pressures on healthcare systems continue to intensify and budgets get squeezed further, the scrutiny of the clinical evidence package is only likely to increase. Monitoring the shifts across countries and understanding the commonalities and differences is the key to informing clinical development paths and designing optimal market access strategies.
As we have shown, the approach to dealing with these issues across the EU4 and the UK is not uniform. While there are similarities, there are also significant variations based on the approaches the systems take. Understanding these nuances as well as their impact is essential to understand how to best design clinical studies in order to gather the necessary evidence to achieve the market access, pricing, and reimbursement necessary to bring innovative medicines to market and remain commercially viable.
With the lack of agreed-upon common methodological guidelines, the applicability and acceptance of the EUnetHTA JCA are likely to be weak, increasing the administrative burden on manufacturers. Furthermore, given the absence of a centralized European fund for medicines and lack of legally binding nature of the JCA, there is a general skepticism on the adoption of such a report by stakeholders across multiple countries18 , especially if the entire EU membership is considered.
It is therefore crucial that the discussion takes the form of a collaborative, multi-stakeholder approach to outline the circumstances that could justify slimmer evidence packages and an acceptable evidence base at launch, mechanisms for the generation of real-world evidence, and the infrastructure for payment models that could enable patient access to innovation, pending the full demonstration of added clinical benefit. In the real world, as European regulatory and access reforms are introduced and the landscape evolves, these changes are likely to continue and be heavily influenced by local needs and standards.


Table 5: Rationale for SMR insufficient by HAS

Generic name Brand name Therapeutic Area(s) MAH Rationale for SMR insufficient
neratinibNerlynxBreast NeoplasmsPuma Biotechnology B.V./Pierre FabreAbsence of data capable of demonstrating the efficacy of neratinib, only data available in the MA indication derived from post hoc exploratory analyses in a subgroup of patients, poor safety profile of neratinib with increased grade 3 or 4 adverse events (inadequate level of evidence of the efficacy data and the significant toxicity)
tivozanib hydrochloride monohydrateFotivdaRenal cell carcinoma (RCC)EUSA Pharma (UK) LimitedAvailable data do not allow the impact in terms of morbidity and mortality to be quantified due to the profile of the patients included (70% in the first line) and of the comparator, unsuitable for the first line (mismatch between positioning and comparator)
entrectinibRozlytrekCancer; Carcinoma, NSCLCRoche Registration GmbHNSCLC: Preliminary nature of available data, absence of robust comparative data enabling assessment of the contribution of entrectinib in ROS1+ NSCLC compared to the available alternatives (chemotherapy or crizotinib), toxicity marked by incidence of serious AE. Solid tumours: preliminary nature of efficacy data and toxicity
alpelisibPiqrayBreast NeoplasmsNovartis Europharm LimitedStudy comparator not relevant; no demonstration of OS or QoL benefit and significant toxicity
polatuzumab vedotinPolivyLymphoma, B-CellRoche Registration GmbHPhase I/II multi-cohort trial including an exploratory randomized phase, lack of clinical relevance of the comparator, no OS, QoL, uncertainties around formulation and indirect comparison submitted
padeliporfinTookadAdenocarcinoma of the prostateSTEBA Biotech S.AExploratory results vs active surveillance, safety profile with serious AE, 10-year survival is 99% in low-risk cancer
amivantamabRybrevantCarcinoma, NSCLCJanssen-Cilag International N.V.Impossibility of determining the quantity of effect due to the absence of direct comparison and the methodological weakness of the indirect comparison. Preliminary data available from a cohort of the non-comparative phase I/II study in which a modest response rate was reported with moreover a fraction of patients included having a less aggressive disease, even indolent
zanubrutinibBrukinsaWaldenstrom MacroglobulinemiaBeiGene Ireland LtdInclusion in the study of a heterogeneous population of patients in terms of prognosis, absence of demonstrated superiority in terms of complete response or very good partial response compared with ibrutinib, PFS, PS, and QoL as exploratory secondary endpoints, uncertainty on tolerability profile
dostarlimabJemperliEndometrial NeoplasmsGlaxoSmithKline (Ireland) LimitedPreliminary Phase 1 non-comparative study when comparison is possible. Toxicity based on high incidence of serious AE
duvelisibCopiktraLeukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, FollicularSecura Bio LimitedCLL: Exclusion of patients having had prior treatment with aTKI or BCL-2 inhibitor considered SOC, inclusion of patients receiving a second-line therapy whereas the MA only validated for the third line of treatment, worrying safety data.

Refractory FL: primary endpoint not considered to be relevant at this stage of the disease; absence of comparison with the currently available treatments, despite this being feasible, worrying safety data
tagraxofusElzonrisLymphomaStemline Therapeutics B.V.Absence of comparative data, absence of robust evidence of a benefit on a clinically relevant endpoint, medical need partially met by available alternatives


EFPIA Patients W.A.I.T. Indicator 2021 Survey https://www.efpia.eu/media/676539/efpia-patient-wait-indicator_update-july-2022_final.pdf
Addressing challenges in access to oncology medicines: Analytical report 2020 https://health.ec.europa.eu/system/files/2020-04/access_oncologymedicines_rep_web_en_0.pdf
Absence of comparative survival data in health technology assessment of oncology therapies: A multi-stakeholder perspective on the current challenge, implications and potential solutions. Dolon 2023 https://dolon.com/wp-content/uploads/2023/01/Dolon-HTAiC-White-Paper.pdf
Kordecka A et al. Selection of endpoints in clinical trials: Trends in European marketing authorization practice in oncological indications. Value Health. 2019; 22:884-90 https://www.sciencedirect.com/science/article/pii/S1098301519301536
European public assessment reports (EPARs) https://www.ema.europa.eu/en/medicines/download-medicine-data
Official Journal of the French Republic (JORF): LegiFrance https://www.legifrance.gouv.fr/
National Institute for Health and Care Excellence NICE | The National Institute for Health and Care Excellence
Haute Autorité de santé https://www.has-sante.fr/
Agence nationale de sécurité du médicament et des produits de santé (ANSM) https://ansm.sante.fr/documents/reference/referentiel-des-specialites-en-acces-derogatoire
Doctrine de la commission de la transparence (CT) Principes d’évaluation de la CT relatifs aux médicaments en vue de leur accès au remboursement. Feb 2023 doctrine_ct.pdf (has-sante.fr)
SHI Financial Stabilization Act (GKV-FinStG) https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/
Implementation of the EU HTA Regulation needs directional correction. January 2023 https://www.vfa.de/de/wirtschaft-politik/euro-hta/positionpaper-eu-hta-vfa-bpi


Jack Mycka
Jack Mycka
Nekshan Dalal
Nekshan Dalal
Dr. Renato Dellamano
Dr. Renato Dellamano