# Impact of Early Access Reform on Oncology Innovation in France: Approvals, Patients, and Costs

Tess Martin, Catherine Rioufol, Bertrand Favier, Nicolas Martelli, Isabelle

Madelaine, Christos Chouaid, Isabelle Borget

► To cite this version:

Tess Martin, Catherine Rioufol, Bertrand Favier, Nicolas Martelli, Isabelle Madelaine, et al. Impact of Early Access Reform on Oncology Innovation in France: Approvals, Patients, and Costs. BioDrugs, 2024, 38 (3), pp.465-475. 10.1007/s40259-024-00658-1. hal-04684216

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1 Impact of Early Access Reform on Oncology Innovation in France: Approvals, Patients, and

Costs

2
3
Tess Martin¹, ², Catherine Rioufol³, ⁴, Bertrand Favier⁵, Nicolas Martelli¹, ², Isabelle Madelaine⁶,

4 Christos Chouaid<sup>7,8</sup>, Isabelle Borget<sup>9,10</sup>

5 Affiliations:

6 ¹Pharmacy Department, Georges Pompidou European Hospital, AP-HP, 20 Rue Leblanc, 75015, Paris,

7 France.

8 ²Paris-Saclay University, GRADES, Faculty of Pharmacy, 17 Av. des Sciences, 91400 Orsay, France.

9 ³Pharmacy Department, Lyon Sud Hospital, Hospices Civils de Lyon, Lyon, France.

10 ⁴EA3738, CICLY, UCBL1, Lyon, France

11 ⁵Centre Léon Bérard, Pharmacy Department, 28 rue Laennec, 69008 Lyon, France

12 ⁶Pharmacy Department, Saint-Louis Hospital, AP-HP, 1 avenue Vellefaux 75010 Paris, France, Vice

13 president of Société Française de Pharmacie Oncologique (SFPO)

14 ⁷Service de Pneumologie, CHI Créteil,

15 ⁸Inserm U955, UPEC, IMRB, Créteil France

16 ⁹Gustave Roussy, Biostatistics and Epidemiology Office, Université Paris-Saclay, Villejuif, France

17 ¹⁰Inserm, Université Paris-Saclay, CESP U1018, Oncostat, labeled Ligue Contre le Cancer, Villejuif,

18 France

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20 **Corresponding author**: Tess Martin

21 Paris-Saclay University, GRADES, Faculty of Pharmacy, 17 Av. des Sciences, 91400 Orsay, France.

22 Tel: +33156092575

23 E-mail: tess.martin@universite-paris-saclay.fr

24 **Short Title**: Impact of Early Access Reform on Oncology Innovation in France

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**Acknowledgments:** The authors would like to thank the following individuals for their expertise and
assistance in building the study database: Emilie Nohet and Ilan Moralli.

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**Conflicts of interests:** All authors certify that they have no affiliations with or involvement in any
organization or entity with any financial interest or non-financial interest in the subject matter or
materials discussed in this manuscript.
Abstract

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Background

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An ambitious reform of the Early Access (EA) process was set up in July 2021 in France, aiming to simplify

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procedures and accelerate access of innovative drugs.

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Objective

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This study analyzes the characteristics of oncology drug approvals through the EA process, and its impact in real-

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life data for oncology patients.

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Methods

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The number and characteristics of EA demands concerning oncology drugs submitted to the National Health

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Authority (HAS) were reviewed until December 31, 2022. A longitudinal retrospective study on patients treated

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with an EA oncology drug between January 1, 2019, and December 31, 2022 was also performed using the French

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Nationwide claims database (SNDS) to assess the impact of the reform in number of indications, patients and

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costs.

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Results

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Among 110 published decisions, HAS granted 88 (80%) EA indications within 70 days of assessment on average,

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including 46 (52%) in oncology (67% in solid tumors and 33% in hematological malignancies). Approved

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indications were mostly supported by randomized phase III trials (67%), whereas refused EA relied more on non-

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randomised (57%) trials. Overall survival was the primary endpoint of 28% of EA approvals versus none of denied

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EA. In the SNDS data, the annual number of patients with cancer treated with an EA drug increased from 3,137

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patients in 2019 to 18,341 in 2022 (+484%), whereas the number of indications rose from 12 to 62, mainly in

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oncohematology (n=17), lung (n=12), digestive (n=9) and breast cancer (n=9). Reimbursement costs for EA

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treatments surged from €42 to €526 million (+1159%).

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Conclusion

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The French EA reform contributed to enabling rapid access to innovations in a wide range of indications for

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oncology patients. However, the findings highlight ongoing challenges in financial sustainability, warranting

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continued evaluation and adjustments.

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The French EA reform contributed to enabling rapid access to innovations in a wide range of indications for

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oncology patients. However, the findings highlight ongoing challenges in financial sustainability, warranting

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continued evaluation and adjustments.

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Key points:

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• The early access reform in France has enabled rapid access to innovation, particularly for oncology drugs.

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61 • Approved oncology drugs are mostly supported by high-level evidence studies (phase III trials) with mature overall survival data provided.

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62 • The reform also led to a significant increase in the annual number of patients treated and reimbursement costs.

64 • The reform also led to a significant increase in the annual number of patients treated and reimbursement costs.
# MAIN TEXT

## 1. INTRODUCTION

Cancer is a major public health concern. In 2020, there were 2.7 million new cases in the European Union (EU) countries, leading to 1.3 million deaths [1]. Cancer-related deaths are expected to rise by over 24% by 2035, making it the leading cause of death [2], even with therapeutic innovations.

Drugs innovations, as targeted therapies, immunotherapies or CAR-T cells, have represented a significant breakthrough in the treatment of advanced cancer, significantly improving overall survival and patient's quality of life [3,4]. However, the process of reimbursement and drug pricing has become much more complex and prolonged, taking 503 days on average after the EMA approval in France [5]. Since then, access to medicines in the EU has been accelerated, largely encouraged by the 'Europe's beating cancer' plan [6], and various schemes have emerged [7], such as the PRIME (priority medicines) programme for medicines to address unmet needs [8].

Early access programs (EAPs) are designed to provide patients access to medicines before their marketing authorization (MA) or during the national reimbursement & pricing process. In 1994, France was pioneer by implementing an EAP framework called authorization for temporary use (ATU) [9]. Due to successive modifications over time, the ATU system became however increasingly complex with six different pathways [10].
Concomitantly, expenditures related to innovative drugs (including those in ATU program) continued to rise significantly in France, exhibiting an annual growth rate of 54% between 2019 and 2022. Among these, oncology drugs have seen their costs more than triple over the past three years [11].

In July 2021, an ambitious reform of the French early access (EA) system was thus implemented with three main objectives: to simplify and harmonize procedures for EA to innovative drugs, allow patients faster access to drugs, and guarantee financial sustainability for the healthcare system [12]. Two pathways now exist: authorization for early access (AEA) and authorization for compassionate use (ACU). AEA concerns drugs in specific indications, aiming at treating serious, rare or desabilitating disease, when all the following criteria are met: (i) in exceptional circumstances, (ii) no appropriate treatment exists, (iii) treatment cannot be postponed, (iv) efficacy and safety of the drug are highly presumed according to clinical trials and (v) the drug is presumed innovative in regards to a possible clinically meaningful comparator. AEA is applicable both to drugs in "Pre-MA" EA (before MA by EMA) or in "Post-MA" EA (MA is approved by EMA that not yet reimbursed/priced) [13]. Conversely, ACU allows, the use of drugs without MA indications in France to treat severe or rare diseases when there is no appropriate treatment available, the patient cannot be enrolled in a clinical trial, and the implementation of treatment cannot be delayed. This applies to drugs not intended for registration or marketing. For example, EA has been granted for
therapeutic innovations such as CAR T cell therapy and antibody drug conjugates for severe solid tumors and hematologic malignancies. Additionally, compassionate use has been granted for certain drugs already on the market but lacking marketing authorization for specific indications, such as dapsone for the treatment of autoimmune bullous dermatosis.

The reform also changes the procedure pathway: whereas ATU was only regulated by the French Medicines Agency (ANSM, Agence nationale de sécurité du médicament et des produits de santé), the National Health Authority (HAS, Haute Autorité de Santé) is now also involved in AEA decisions. ANSM and HAS are expected to deliver a common decision within 90 days to allow patients prompt access to drugs. Regarding financing for EA pathway, the drug is provided to hospitals at a price freely fixed by the manufacturer and communicated to the Economic Committee for Healthcare Products (CEPS). However, two types of rebates are applied afterwards: annual rebates based on the net invoiced turnover to hospitals, following a progressive scale set by decree. These rebates can be increased if the manufacturer fails to adhere to the terms of the early access agreement. Additionally, there are "unwinding" rebates based on the final negotiated price with the CEPS.

At the European level, various models of early access to medicines have also emerged. Spain regulates EAPs under Royal Decree 1015/2009, mainly nominal-based but with some cohort-based options like compassionate use. The UK's Early Access to Medicines Scheme (EAMS) covers pre-MA drugs for all trial-eligible patients, offered as either nominal or cohort-based. In Italy, multiple lists oversee early access and off-label use, including Law 648/96, Well-Established Use, and the 5% Fund. While Italy has shown generosity in implementing EAPs, it faces challenges due to mixed approaches combining early access with off-label use. The comparative study of these different early access systems has led researchers to consider the French EA reform as a potential model for harmonizing different European EAP.[7,13,14]. However, there is currently insufficient data assessing the impact in terms of drug approvals and number of treated patients in France, and no economic data is available since the EA reform[7,15,16]. This study aims to review the first 18 months of the reform, focusing on oncology (including hematological malignancies) drugs following an AEA decision. The objectives were to analyse the characteristics of oncology drug approvals through the new AEA process and to evaluate the impact of the reform in real-life, in terms of number of indications, number of treated patients and costs, using the nationwide claims database.

## 2.MATERIAL AND METHODS

The present study follows a two-step approach. First, it used the National Health Authority data to identify and analyse the characteristics (number, acceptance rate, delay for decision, tumor type, methodological issues of the
trial) of the AEA demands related to oncology drugs since the reform (July 1, 2021). Secondly, a longitudinal study using data from the French Nationwide claims reimbursement database (SNDS) from 2019 to 2022 was performed to evaluate the impact of the AEA reform in real-life conditions, in terms of number of drugs/indications used, number of patients treated and reimbursement costs.

## 2.1 Number and characteristics of drug demands to the AEA pathway

All the AEA demands submitted to the HAS since the reform (July 1, 2021) until December 31, 2022 were identified and reviewed. Given that HAS is now responsible for AEA decisions, all the information's regarding the corresponding demands are now available on the HAS website[17]. It included information regarding the drug, the claimed indication, the eligibility criteria to AEA program, the pivotal data supporting the demand, the decision (approval/failure) and its reasons, and the submission and decision dates. Note that these dossiers are presented by indication (rather than by drug), as authorization and reimbursement occur on a per-indication basis.

For oncology (solid tumors and hematological malignancies) indications, we collected the drug's name, therapeutic class (using WHO Anatomical Therapeutic Chemical classification[18]), the decision, and the time between submission and decision. Data related on the methodology of the main trial supporting the EA demand (phase, design, comparator, primary endpoint, presence of overall survival (OS) data and OS maturity if provided) were also collected and compared between approval and failure decisions. Combination therapies that submitted two similar demands were counted as a single one (n=4). Three demands for indication renewals with no significant modification were excluded, as well as one demand concerning an antidote (glucarpidase), considering it has no anti-tumor effect. Figure 1 presents the flowchart of the selected demands.

## 2.2 Real-word data on patients receiving an EA drug

The second part of our analysis aimed to quantify the impact of the AEA reform in real life conditions, regarding the number of drugs (or indications) administered, the number of patients treated by an EAE drug and their costs in France. To do that, we performed an observational retrospective longitudinal study using the nationwide claims database (SNDS) between January 1, 2019, and December 31, 2022. The SNDS database contains claims data for more than 99% of the French population, covering both hospital and community care and both the public and private sectors[19]. The SNDS uses a unique and anonymous patient identifier, so that individual patients can be followed over their lifetime. Regarding medicines, ATU/AE treatments administered or delivered at hospital are documented into the MEDATU/MEDAPAC database, including information on the drug code (UCD, unite
commune de dispensation), the indication code<fnref n="1" />, the anonymous patient identifier, the month and year of delivery and the reimbursement cost from the French National Health Insurance's perspective (in €), before discounts are applied. For each indication code identified, the molecule's name, reimbursement dates under ATU/EA pathway, therapeutic area and anatomical location can be retrieved using a Ministry of Health file[10].

All ATU/EA drug deliveries between 1 January 2019 and 31 December 2022 corresponding to solid tumours and haematological malignancies indications were extracted from the MEDATU/MEDAPAC databases. Analysis was restricted to indications included in the AEA pathway (from 07/01/2021 to 12/31/2022) and certain ATU indications (cohort ATU, "post-ATU," indication extension ATU, and direct access post-MAA, which later merged to become AEA status, during the period from 01/01/2019 to 06/30/2021), excluding ACU indications.

For the selected indications, the number of indications used, the number of (prevalent) patients treated and the costs were calculated monthly and annually, and presented both globally and by tumor localisation.

Of note, the sum of the number of patients treated monthly is not equal to the number of patients treated annually, since patients are generally treated over several months.

Statistics were descriptive. Data from the HAS website were collected in Excel® (Microsoft Office 2016), whereas analyses from the SNDS data were conducted using SAS® software version 9.4.

## 3. RESULTS

### 3.1 Characteristics of drugs and demands approved under the AEA reform

By December 31, 2022, 130 demands for AEA have been submitted by manufacturers to the HAS. Among the 110 decisions published, 54 (49%) concerned oncology indications (67% in solid tumors and 33% in haematological malignancies). Across all therapeutic areas, the HAS has granted 88 (80%) positive access decisions, while the acceptance rate for oncology/hematological malignancies indications is 85%. Oncology drugs that were approved and their indication are listed in Supplementary Table 1. Another point is the speed in decisions, as HAS and ANSM have rendered them within 70 days on average [range: 47-113], and in less than 90 days in 87% of cases.

Regarding therapeutic classes, 21 (46%) approvals concerned monoclonal antibodies and antibody-drug conjugates drugs, 7 (15%) concerned protein kinase inhibitors (16%) and 6 (13%) concerned CAR-T cells agents. The methodological characteristics of the trials supporting the EA decisions are presented on Table 1, according to AEA status (n=39) or denied (n=7). Granted AEA were mostly supported by phase III trials (67%) that

<footnote n="1">¹ A code provided by the French ministry used to label the drug under ATU/EA pathway in an authorized indication.</footnote>
included a randomisation (69%), whereas refused AEA were mainly phase I or II trials (58%), mostly non-
comparative (43%). The notion of comparator is important, as 51% of granted AEA had a clinically relevant
comparator<fnref n="2" />. But trials *versus* placebo or supportive care were also accepted in 18% of cases, in accordance with
the HAS methodological guide[21] that accepts them when justified, particularly for rare diseases or when no
treatment exists. Regarding primary (or co-primary) endpoint, they were distributed among overall survival (OS,
28%), progression free survival (PFS, 28%), overall response rate (ORR, 28%) or another endpoint (23%) for
granted demands. OS was also explored as secondary endpoint in 25 (64%) of granted cases. Conversely, primary
endpoints were mostly ORR (71%) or other endpoints (29%) but never OS or PFS for denied demands. To date,
all demands having mature OS data (41% of cases) in a comparative trial were accepted, meaning that OS data
remain a major endpoint, including for the EA process. For the 7 denied demands, the HAS considered that an
appropriate treatment already existed in the indication (6/7), or/and that the drug was not presumed innovative
(5/7).

## 3.2Evolution of the number of indications, patients and cost for AEA oncology drugs

The figure 2 presents the evolution of the number of distinct ATU/EA indications of oncology drugs used in real-
world practice from 2019 to 2022, by trimester. It showed that the number of indications strongly increased over
the period, ranging from 12 ATU indications (7 for solid cancers and 5 for hematological malignancies) in 2019
to 62 EA indications in 2022, predominantly in hematological malignancies (n=17), lung cancer (n=12), digestive
cancer (n=9) and breast cancer (n=9). This may be explained by multiple extension of indications (like CAR-T
cells in multiple myeloma or pembrolizumab in 4 indications (2 in breast, 1 in pancreatic and 1 in cervical cancers),
the arrival of new therapeutic classes (2 indications for the trastuzumab deruxtecan in breast cancer and in digestive
cancer or teclistamab), or the pursuit of treatment under EA reform.

As a possible consequence, the annual number of patients with cancer who were treated with an AEA drug strongly
increased from 3,137 patients in 2019 to 18,341 in 2022 (+484%). The figure 3 shows the evolution of the number
of patients treated by an AEA drug in France, by month and by tumor localization. It reveals that the number of
patients treated monthly with an oncology AEA treatment has risen steadily, being multiplied by 20 over the

<footnote n="2">² According to the definition of HAS transparency committee's doctrine, a clinically relevant comparator may be a medicinal product (active substance or placebo, with or without MA), a medical device, a procedure or any other non-medicinal therapy (or diagnostic method). It plays the same role in the therapeutic strategy as the new medicinal product and is aimed at the same patients. [20]</footnote>
period, from 326 in Jan 2019 to 6,800 in Dec 2022. It mainly concerned patients treated for breast (from 68 to 2,877 patients, +4131%) or lung cancers (from 84 to 650 patients, +674%). New localizations have also emerged like digestive and urological cancers, with 866 and 619 patients in December 2022, respectively. Hematologic oncology, which represented approximately half of the treated patients in January 2019 (168 patients), saw a sevenfold increase in its number of patients (1251 patients in December 2022) and represents only 18% of patients treated with an EA oncologic drug at the end of the study period.
Reimbursement costs also increase significantly, from 42 to 526 million (M) between 2019 and 2022 (+1159%).
In 2022, the higher reimbursement costs concerned treatments for hematological malignancies (180 M€), breast cancer (159 M€), urology (68 M€), and lung cancer (64 M€). Figure 4 shows the evolution of monthly reimbursement costs for AEA drugs in France by tumor localization.

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With 88 indications approved within 18 months, the French early access reform has allowed rapid access to innovations with a high level of evidence and a regulatory simplification of the previous EA systems. More than half of approvals concerned oncology indications, predominantly for solid tumors, notably targeted kinase-inhibitors and immunotherapy. The same trend is found in the US where roughly one-quarter of accelerated-approved drugs are precision medicines for treating solid tumors since 1992[22]. This trend highlights the fact that specific classes of innovative products dominate the oncology treatment landscape, testifying to the accelerated pace of innovation in this field[23]. With decisions delivered within 70 days on average, ANSM and HAS comply with the regulatory deadline in 87% of cases. This is outstanding as it granted immediate access for AEA drugs to patients. The AEA process is notably quicker than the current drug reimbursement process and the previous ATU evaluation, which required 503 days[5] and 257 days[24], respectively. In addition, approved indications were supported by high-quality methodological studies, with mostly phase III trials including direct comparison, randomisation and OS as primary endpoint in nearly one-third of cases, underlining the continued significance of OS results as pivotal requirement in the French context. This differs from FDA approach for cancer accelerated approvals, whom often rely on ORR data from early trial or single-arm trial[25]. It is however in accordance with the French evaluation performed by the HAS for common drug reimbursement, which enhance drugs with substantial clinical benefits supported by methodologically rigorous studies[13]. Previous studies also demonstrated that ATU programs were based on robust approvals characterized by substantial enhancements in clinical benefit and mature OS data, as supported by high ESMO-MCBS and ASCO-VF scores[15].

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238 The large proportion of trials containing mature OS data may be explained by the fact that 62% of demands concern post-MA drugs, where final results are more legitimate to be found. Unlike the FDA's accelerated approval pathway, the French AEA does not require confirmatory trials to verify the drug's clinical benefit and obtain definitive approval. Manufacturers are therefore inclined to submit demands containing more mature OS data to comply with HAS requirements. However, as the reform is still recent, it is possible that the trend will change and that drugs with early clinical endpoints such as ORR or PFS will be candidates to obtain an AEA [26-28].
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244 Using national medico-administrative databases, our study also unveiled, the patient benefiting from EA oncology drugs and associated reimbursement costs. We observed a significant rise in the number of patients receiving AEA treatments, with a six-fold increase between 2019 and 2022, accompanied by an increase in costs by ten-fold over the period. This growing number of patients and treatment costs appears to be connected to the simultaneous availability of new drugs under EA, as well as new indications for existing drugs now encompassing multiple therapeutic areas, as also noticed in other countries [15,16,23]. However, the momentum of increase in number of indications (figure 2) and patients treated (figure 5) was already discernible during the ATU period and appear to be continuing since the reform. The EA reform has thus facilitated but cannot explain the expansion of innovations into the market in oncology.
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253 Questions however remain regarding the financial aspects and the organisational modalities of the reform. The very significant increase in costs may appear worrying, although the reform aimed to control expenditure to ensure the health care sustainability. Despite the great increase in the number of indications and patients treated, the trend may be explained by the fact that drug price are freely fixed by the manufacturer during the AEA period. However, the cost presented in figure 4 does not reflect the final expense for the French health system, as the laboratory will pay discounts based on AEA sales and the final drug price negotiated. Consequently, the reform is too recent to estimate the economic burden of AEA on drug expenditures, and it impact regarding the sustainability and the financing of therapeutic innovations. However, it is essential to closely monitor the impact of the reform and assess whether adjustments are needed to the current system of financing early access, as well as to the mechanism of post-regulatory control through rebates. Questions also linger about the successful and long-time efficacy of the system. As part of the EA agreement, laboratories must provide real-life data on the use, the effectiveness, the side-effects and sometimes the quality of life to HAS and ANSM, offering complementary insights to trials. If the usefulness of this data collection is not questioned, challenges regarding the methods, quality, and funding of real-word data collection, which currently rely on hospital teams, are now being raised by French experts [29].
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267 Despite these points of caution, the EA reform in France has allowed fast arrival for patients to a significant number of therapeutic innovations. It concerns innovative medicines for unmet medical needs for serious and sometimes rare cancers, and are supported by high quality methodology studies with a demonstrated added clinical benefit.
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**Declarations:**

**Funding:** No external funding was used in the preparation of this manuscript.

**Conflicts of interests:** Tess Martin, Catherine Rioufol, Bertrand Favier, Nicolas Martelli, Isabelle Madelaine, Christos Chouaid and Isabelle Borget declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. **Ethics approval:** Not applicable

**Consent to participate:** Not applicable

**Consent for publication:** Not applicable

**Availability of data and material:** The data that support the findings of this study are available from the Systeme National des Données de Santé (SNDS) but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Indeed, under French law and regulations, databases extracted from the Systeme National des Données de Santé (SNDS) cannot be publicly available.

**Code availability:** Not applicable

**Authors' contributions:** **CREDIT Statement:** Tess Martin: Conceptualization, Data curation, Methodology, Writing original draft, Writing-Reviewing. **Catherine Rioufol:** Conceptualization, Methodology, Writing-Reviewing, **Bertrand Favier:** Conceptualization, Writing-Reviewing, **Nicolas Martelli:** Conceptualization, Writing-Reviewing, **Isabelle Madelaine:** Conceptualization, Writing-Reviewing, **Christos Chouaid:** Methodology, Writing-Reviewing, **Isabelle Borget:** Conceptualization, Data curation, Methodology, Writing-Reviewing.
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339 15. Pham FY-V, Jacquet E, Taleb A, Monard A, Kerouani-Lafaye G, Turcry F, et al. Survival, cost and added therapeutic benefit of drugs granted early access through the French temporary authorization for use program in solid tumors from 2009 to 2019. Int J Cancer. 2022;151:1345–54.

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367 25. Agrawal S, Arora S, Amiri-Kordestani L, de Claro RA, Fashoyin-Aje L, Gormley N, et al. Use of Single-Arm Trials for US Food and Drug Administration Drug Approval in Oncology, 2002-2021. JAMA Oncology [Internet]. 2022 [cited 2023 Jan 11]; Available from: https://doi.org/10.1001/jamaoncol.2022.5985

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373 27. Beaver JA, Pazdur R. "Dangling" Accelerated Approvals in Oncology. N Engl J Med. 2021;384:e68.

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378 29. Renne M, Maquin G, Rosant D, Villiet M, Seron A. Feedback from a university hospital one year after the "simplified" reform of early and expanded access programm: a growing complexity for health professionals. Journal de Pharmacie Clinique. 2022;41:149-57.

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## Figure Legends

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383 Figure 1: Flow-Chart for Early Access approvals analysis

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384 Figure 2: Number of distinct ATU/EA indications of oncology drugs used in real-world practice (quarterly-month representation) from 2019 to 2022

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386 Figure 3: Number of patients treated by an ATU/AEA oncology drug, per tumor localization and per month

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## Figures captions

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393 Fig. 1 Flow-Chart for Early Access approvals analysis

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394 This flow chart illustrates the process of selecting early access authorization applications issued by the HAS for the first part of the study.

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397 Fig. 2 Number of distinct ATU/EA indications of oncology drugs used in real-world practice (quarterly-month representation) from 2019 to 2022

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399 This figure represents, by trimester, the number of oncology indications in early access, associated with hospital prescriptions, between 2019 and 2022 found in the real-world database of the SNDS.

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402 **Fig.3** Number of patients treated by an ATU/AEA oncology drug, per tumor localization and per month
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2 403 This figure represents the number of patients treated with a molecule for an oncology indication in early
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4 404 access, by tumor location and per month between 2019 and 2022. The data is derived from the real-
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6 405 world database of the SNDS.
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9 406

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11 407 **Fig. 4** Reimbursement costs for ATU/AEA oncology drugs, per tumor localization and per month
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13 408 This figure represents the reimbursement costs associated treated for early access treatments in
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15 409 oncology, by tumor location and per month between 2019 and 2022. The data is derived from the real-
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17 410 world database of the SNDS.
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22 412 **Fig. 5** Number of patients treated with an early access oncology drug according to their regulatory status
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24 413 (ATU/EA/Mixed status) and per month
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27 414 This figure represents the number of patients treated with an early access oncolodry drug according to
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29 415 their refulatory status : ATU, Early access or mixed status. Of note, the mixed status corresponds to the
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38 419 Supplementary captions (submitted in a editable format separately)

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40 420 **Supplementary Table 1:** List of drugs and related-indications granted with AE in oncology (solid
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42 oncology and onco-hematology) between 07/01/2021 and 31/12/2022
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<table><caption>428 Table 1: Characteristics of oncology drugs with an early access decision</caption><thead><tr><th></th><th>Early access<br>decision granted<br>(n=39)</th><th>Early access<br>decision denied<br>(n=7)</th></tr></thead><tbody><tr><td colspan="3"><strong>Characteristics of the drugs - Therapeutic class</strong></td></tr><tr><td colspan="3"><strong>Radiopharmaceuticals</strong></td></tr><tr><td>Diagnostic radiopharmaceuticals</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td>Therapeutic radiopharmaceuticals</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td colspan="3"><strong>Antineoplastic agents</strong></td></tr><tr><td>Alkylating agents</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td>Antimetabolites</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td>Antineoplastic cell and gene therapy</td><td>6 (15%)</td><td>0 (0%)</td></tr><tr><td>Monoclonal antibodies and antibody<br>drug conjugates</td><td>18 (46%)</td><td>2 (29%)</td></tr><tr><td>Other antineoplastic agents</td><td>5 (13%)</td><td>0 (0%)</td></tr><tr><td>Protein kinase inhibitors</td><td>6 (15%)</td><td>5 (71%)</td></tr><tr><td colspan="3"><strong>Cancer situation</strong></td></tr><tr><td colspan="3"><strong>Solid tumors</strong></td></tr><tr><td>Localized situation, adjuvant</td><td>3 (8%)</td><td>2 (29%)</td></tr><tr><td>Localized situation, neo adjuvant</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td>Metastatic situation, 1st line</td><td>9 (23%)</td><td>1 (14%)</td></tr><tr><td>Metastatic situation, 2nd line</td><td>9 (23%)</td><td>3 (43%)</td></tr><tr><td>Metastatic situation, > 3 lines</td><td>4 (10%)</td><td>0 (0%)</td></tr><tr><td colspan="3"><strong>Hematological malignancies</strong></td></tr><tr><td>1st line</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td>2nd line</td><td>7 (18%)</td><td>1 (14%)</td></tr><tr><td>> 3 lines</td><td>5 (13%)</td><td>0 (0%)</td></tr><tr><td colspan="3"><strong>Characteristics of clinical trials</strong></td></tr><tr><td colspan="3"><strong>Development phase</strong></td></tr><tr><td>I, I/II</td><td>7 (18%)</td><td>2 (29%)</td></tr><tr><td>II</td><td>7 (18%)</td><td>2 (29%)</td></tr><tr><td>III</td><td>26 (67%)</td><td>3 (43%)</td></tr><tr><td colspan="3"><strong>Study type</strong></td></tr><tr><td>Comparative study</td><td></td><td></td></tr><tr><td>Direct comparison</td><td>27 (69%)</td><td>3 (43%)</td></tr><tr><td>Indirect comparison</td><td>0 (0%)</td><td>1 (14%)</td></tr><tr><td>Basket trial</td><td>1 (2%)</td><td>0 (0%)</td></tr><tr><td>Non comparative study</td><td>12 (31%)</td><td>3 (43%)</td></tr><tr><td>Randomization</td><td></td><td></td></tr><tr><td>Randomized study</td><td>27 (69%)</td><td>3 (43%)</td></tr><tr><td>Non randomized study</td><td>12 (31%)</td><td>4 (57%)</td></tr><tr><td>Double blind study</td><td></td><td></td></tr><tr><td>Yes</td><td>10 (26%)</td><td>0 (0%)</td></tr><tr><td>No</td><td>29 (74%)</td><td>7 (100%)</td></tr><tr><td>Comparator</td><td></td><td></td></tr><tr><td>Clinically relevant comparator</td><td>20 (51%)</td><td>3 (43%)</td></tr></tbody></table>
<table><tbody><tr><td>Placebo or supportive care</td><td>7 (18%)</td><td>1 (14%)</td></tr><tr><td>NA<sup>a</sup></td><td>12 (31%)</td><td>3 (43%)</td></tr><tr><td colspan="3">Primary Endpoint</td></tr><tr><td>Overall survival (OS)</td><td>11* (28%)</td><td>0 (0%)</td></tr><tr><td>Overall response rate (ORR)</td><td>11*(28%)</td><td>5 (71%)</td></tr><tr><td>Progression free survival (PFS)</td><td>11* (28%)</td><td>0 (0%)</td></tr><tr><td>Other</td><td>9*(23%)</td><td>2 (29%)</td></tr><tr><td colspan="3">Exploration of OS</td></tr><tr><td>OS as primary endpoint or co-primary endpoint</td><td>11 (28%)</td><td>0 (0%)</td></tr><tr><td>OS as secondary endpoint</td><td>25 (64%)</td><td>6 (86%)</td></tr><tr><td>Indirect comparison</td><td>0 (0%)</td><td>1 (14%)</td></tr><tr><td>Non included in the statistical analysis plan</td><td>3 (8%)</td><td>0 (0%)</td></tr><tr><td colspan="3">Maturity of OS data</td></tr><tr><td>Mature OS data</td><td>16 (41%)</td><td>0 (0%)</td></tr><tr><td>Non mature OS data</td><td>19 (49%)</td><td>7 (100%)</td></tr><tr><td>NA</td><td>4 (10%)</td><td>0 (0%)</td></tr></tbody></table>

<sup>a</sup>Non comparative studies

**The total sum exceeds 39 final early access decisions related to the presence of co-primary endpoints

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Impact of Early Access Reform on Oncology Innovation in France: Approvals, Patients, and
Costs

Tess Martin¹,², Catherine Rioufol³,⁴, Bertrand Favier⁵, Nicolas Martelli¹,², Isabelle Madelaine⁶,

Christos Chouaid⁷,⁸, Isabelle Borget⁹,¹⁰

Affiliations:

¹Pharmacy Department, Georges Pompidou European Hospital, AP-HP, 20 Rue Leblanc, 75015, Paris,

France.

²Paris-Saclay University, GRADES, Faculty of Pharmacy, 17 Av. des Sciences, 91400 Orsay, France.

³Pharmacy Department, Lyon Sud Hospital, Hospices Civils de Lyon, Lyon, France.

⁴EA3738, CICLY, UCBL1, Lyon, France

⁵Centre Léon Bérard, Pharmacy Department, 28 rue Laennec, 69008 Lyon, France

⁶Pharmacy Department, Saint-Louis Hospital, AP-HP, 1 avenue Vellefaux 75010 Paris, France, Vice

president of Société Française de Pharmacie Oncologique (SFPO)

⁷Service de Pneumologie, CHI Créteil,

⁸Inserm U955, UPEC, IMRB, Créteil France

⁹Gustave Roussy, Biostatistics and Epidemiology Office, Université Paris-Saclay, Villejuif, France

¹⁰Inserm, Université Paris-Saclay, CESP U1018, Oncostat, labeled Ligue Contre le Cancer, Villejuif,

France

Corresponding author: Tess Martin

Paris-Saclay University, GRADES, Faculty of Pharmacy, 17 Av. des Sciences, 91400 Orsay, France.

Tel: +33156092575

E-mail: tess.martin@universite-paris-saclay.fr

Short Title: Impact of Early Access Reform on Oncology Innovation in France

Acknowledgments: The authors would like to thank the following individuals for their expertise and
assistance in building the study database: Emilie Nohet and Ilan Moralli.

**Conflicts of interests:** All authors certify that they have no affiliations with or involvement in any
organization or entity with any financial interest or non-financial interest in the subject matter or
materials discussed in this manuscript.
Abstract

Background

An ambitious reform of the Early Access (EA) process was set up in July 2021 in France, aiming to simplify procedures and accelerate access of innovative drugs. An ambitious reform of the Early Access (EA) process was implemented in France in July 2021.

Objective

This study analyzes the characteristics of oncology drug approvals through the EA process, and its impact in real-life data for oncology patients.

Methods

The number and characteristics of EA demands concerning oncology drugs submitted to the National Health Authority (HAS) were reviewed until December 31, 2022. A longitudinal retrospective study on patients treated with an EA oncology drug between January 1, 2019, and December 31, 2022 was also performed using the French Nationwide claims database (SNDS) to assess the impact of the reform in number of indications, patients and costs.

Results

Among 110 published decisions, HAS granted 88 (80%) EA indications within 70 days of assessment on average, including 46 (52%) in oncology (67% in solid tumors and 33% in hematological malignancies). Approved indications were mostly supported by randomized phase III trials (67%), whereas refused EA relied more on non-randomised (57%) trials. Overall survival was the primary endpoint of 28% of EA approvals versus none of denied EA. In the SNDS data, the annual number of patients with cancer treated with an AEA drug increased from 3,137 patients in 2019 to 18,341 in 2022 (+484%), whereas the number of indications rose from 12 to 62, mainly in oncohematology (n=17), lung (n=12), digestive (n=9) and breast cancer (n=9). Reimbursement costs for EA treatments surged from €42 to €526 million (+1159%).

Conclusion

The French EA reform contributed to enabling rapid access to innovations in a wide range of indications for oncology patients. However, the findings highlight ongoing challenges in financial sustainability, warranting continued evaluation and adjustments.

Key points:

* The early access reform in France has enabled rapid access to innovation, particularly for oncology drugs.
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Approved oncology drugs are mostly supported by high-level evidence studies (phase III trials) with mature overall survival data provided.

The reform also led to a significant increase in the annual number of patients treated and reimbursement costs.
## 1. INTRODUCTION

Cancer is a major public health concern. In 2020, there were 2.7 million new cases in the European Union (EU) countries, leading to 1.3 million deaths [1]. Cancer-related deaths are expected to rise by over 24% by 2035, making it the leading cause of death [2], even with therapeutic innovations.

Drugs innovations, as targeted therapies, immunotherapies or CAR-T cells, have represented a significant breakthrough in the treatment of advanced cancer, significantly improving overall survival and patient's quality of life [3,4]. However, the process of reimbursement and drug pricing has become much more complex and long-prolonged, attaining taking 530-503 days on average after the EMA approval in France [5]. Since then, access to medicines in the EU has been accelerated, largely encouraged by the 'Europe's beating cancer' plan [6], and various schemes have emerged [7], such as the PRIME (priority medicines) programme for medicines to address unmet needs [8].

Early access programs (EAPs) are designed to provide patients access to medicines before their marketing authorization (MA) or during the national reimbursement & pricing process. In 1994, France was pioneer by implementing an EAP framework called authorization for temporary use (ATU) [9]. Due to successive modifications over time, the ATU system became however increasingly complex with six different pathways [10]. Concomitantly, expenditures related to innovative drugs (including those in ATU program) continued to rise significantly in France, exhibiting an annual growth rate of 54% between 2019 and 2022. Among these, oncology drugs have seen their costs more than triple over the past three years [11].

In July 2021, an ambitious reform of the French early access (EA) system was thus implemented with three main objectives: to simplify and harmonize procedures for EA to innovative drugs, allow patients faster access to drugs, and guarantee financial sustainability for the healthcare system [12]. Two pathways now exist: authorization for early access (AEA) and authorization for compassionate use (ACU). AEA concerns drugs in specific indications, aiming at treating serious, rare or desabilitating disease, when all the following criteria are met: (i) in exceptional circumstances, (ii) no appropriate treatment exists, (iii) treatment cannot be postponed, (iv) efficacy and safety of the drug are highly presumed according to clinical trials and (v) the drug is presumed innovative in regards to a possible clinically meaningful comparator. AEA is applicable both to drugs in "Pre-MA" EA (before MA by EMA) or in "Post-MA" EA (MA is approved by EMA that not yet reimbursed/priced) [13]. Conversely, ACU eovers allows, the use of drugs without MA indications in France to treat severe or rare diseases when there is no appropriate treatment available, the patient cannot be enrolled in a clinical trial, and the implementation of
treatment cannot be delayed. This applies to drugs not intended for registration or marketing. For example, EA has been granted for therapeutic innovations such as CAR T cell therapy and antibody drug conjugates for severe solid tumors and hematologic malignancies. Additionally, compassionate use has been granted for certain drugs already on the market but lacking marketing authorization for specific indications, such as dapsone for the treatment of autoimmune bullous dermatosis, drugs not intended to be registered or marketed.

The reform also changes the procedure pathway: whereas ATU was only regulated by the French Medicines Agency (ANSM, Agence nationale de sécurité du médicament et des produits de santé), the National Health Authority (HAS, Haute Autorité de Santé) is now also involved in AEA decisions. ANSM and HAS are expected to deliver a common decision within 90 days to allow patients prompt access to drugs. Regarding financing for EA pathway, the drug is provided to healthcare institutions hospitals at a price freely fixed by the manufacturer and communicated to the Economic Committee for Healthcare Products (CEPS). However, two types of rebates are applied afterwards: annual rebates based on the net invoiced turnover to healthcare institutions hospitals, following a progressive scale set by decree. These rebates can be increased if the manufacturer fails to adhere to the terms of the early access agreement. Additionally, there are "unwinding" rebates based on the final negotiated price with the CEPS.

At the European level, various models of early access to medicines have also emerged. Spain regulates EAPs under Royal Decree 1015/2009, mainly nominal-based but with some cohort-based options like compassionate use. The UK's Early Access to Medicines Scheme (EAMS) covers pre-MA drugs for all trial-eligible patients, offered as either nominal or cohort-based. In Italy, multiple lists oversee early access and off-label use, including Law 648/96, Well-Established Use, and the 5% Fund. While Italy has shown generosity in implementing EAPs, it faces challenges due to mixed approaches combining early access with off-label use. The comparative study of these different early access systems has led researchers to consider the French EA reform as a potential model for harmonizing different European EAP. Some experts now consider the French EA reform as a potential model for harmonizing different European EAPs[7,13,14]. However, there is currently insufficient data assessing it—the impact in terms of drug approvals and number of treated patients in France, and no economic data is available since the EA reform[7,15,16]. This study aims to review the first 18 months of the reform, focusing on oncology (including hematological malignancies) drugs attending following an EAE demand AEA decision. The objectives were to analyse the characteristics of oncology drug approvals through the new AEA process and to evaluate the
impact of the reform in real-life, in terms of number of indications, number of treated patients and costs, using the
nationwide claims database.

## 2. MATERIAL AND METHODS

The present study follows a two-step approach. First, it used the National Health Authority data to identify and analyse the characteristics (number, acceptance rate, delay for decision, tumor type, methodological issues of the trial) of the AEA demands related to oncology drugs since the reform (July 1, 2021). Secondly, a longitudinal study using data from the French Nationwide claims reimbursement database (SNDS) from 2019 to 2022 was performed to evaluate the impact of the AEA reform in real-life conditions, in terms of number of drugs/indications used, number of patients treated and reimbursement costs.

### 2.1 Number and characteristics of drug demands to the AEA pathway

All the AEA demands submitted to the HAS since the reform (July 1, 2021) until December 31, 2022 were identified and reviewed. Given that HAS is now *responsive responsible for of the* AEA decisions, all the information's regarding the corresponding demands are now available on the HAS website[17]. It included information's regarding the drug, the claimed indication, the eligibility criteria to AEA program, the pivotal data supporting the demand, the decision (approval/failure) and its reasons, and the submission and decision dates. Note that these dossiers are presented by indication (rather than by drug), as authorization and reimbursement occur on a per-indication basis.

For oncology (solid tumors and hematological malignancies) indications, we collected the drug's name, therapeutic class (using WHO Anatomical Therapeutic Chemical classification[18]), the decision, and the time between submission and decision. Data related on the methodology of the main trial supporting the EA demand (phase, design, comparator, primary endpoint, presence of overall survival (OS) data and OS maturity if provided) were also collected and compared between approval and failure decisions. Combination therapies that submitted two similar demands were counted as a single one (n=4). Three demands for indication renewals with no significant modification were excluded, as well as one demand concerning an antidote (glucarpidase), considering it has no anti-tumor effect. Figure 1 presents the flowchart of the selected demands.

### 2.2 Real-word data on patients receiving an EA drug

The second part of our analysis aimed to quantify the impact of the AEA reform in real life conditions, regarding the number of drugs (or indications) administered, the number of patients treated by an EAE drug and their costs
in France. To do that, we performed an observational retrospective longitudinal study using the nationwide claims database (SNDS) between January 1, 2019, and December 31, 2022. The SNDS database contains claims data for more than 99% of the French population, covering both hospital and community care and both the public and private sectors[19]. The SNDS uses a unique and anonymous patient identifier, so that individual patients can be followed over their lifetime. Regarding medicines, ATU/AE treatments administered or delivered at hospital are documented into the MEDATU/MEDAPAC database, including information's on the drug code (UCD, unite commune de dispensation), the indication code<fnref n="1" />, the anonymous patient identifier, the month and year of delivery and the reimbursement cost from the French National Health Insurance's perspective (in €), before discounts are applied. For each indication code identified, the molecule's name, reimbursement dates under ATU/EA pathway, therapeutic area and anatomical location can be retrieved using a Ministry of Health's file[10].

All ATU/EA drug deliveries between 1 January 2019 and 31 December 2022 corresponding to solid tumours and haematological malignancies indications were extracted from the MEDATU/MEDAPAC databases. Analysis was restricted to indications included in the AEA pathway (from 07/01/2021 to 12/31/2022) and certain ATU indications (cohort ATU, "post-ATU," indication extension ATU, and direct access post-MAA, which later merged to become AEA status, during the period from 01/01/2019 to 06/30/2021), excluding ACU indications. For the selected indications, the number of indications used, the number of (prevalent) patients treated and the costs were calculated monthly and annually, and presented both globally and by tumor localisation.

Of note, the sum of the number of patients treated monthly is not equal to the number of patients treated annually, since patients are generally treated over several months.

Statistics were descriptive. Data from the HAS website were collected in Excel® (Microsoft Office 2016), whereas analyses from the SNDS data were conducted using SAS® software version 9.4.

# 3. RESULTS

## 3.1 Characteristics of drugs and demands approved under the AEA reform

By December 31, 2022, 130 demands for AEA have been submitted by manufacturers to the HAS. Among the 110 decisions published, 54 (49%) concerned oncology indications (67% in solid tumors and 33% in hematological malignancies). Across all therapeutic areas, the HAS has granted 88 (80%) positive access decisions, while the acceptance rate for oncology/hematological malignancies indications is 85%. Oncology drugs that were approved

<footnote n="1">¹ A code provided by the French ministry used to label the drug under ATU/EA pathway in an authorized indication.</footnote>
and their indication are listed in Supplementary Table 1. Another point is the speed in decisions, as HAS and ANSM have rendered them within 70 days on average [range: 47-113], and in less than 90 days in 87% of cases. Regarding therapeutic classes, 21 (46%) approvals concerned monoclonal antibodies and antibody-drug conjugates drugs, 7 (15%) concerned protein kinase inhibitors (16%) and 6 (13%) concerned CAR-T cells agents. The methodological characteristics of the trials supporting the EA decisions are presented on Table 1, according if AEA was granted (n=39) or denied (n=7). Granted AEA were mostly supported by phase III trials (67%) that included a randomisation (69%), whereas refused AEA were mainly phase I or II trials (58%), mostly non-comparative (43%). The notion of comparator is important, as 51% of granted AEA had a clinically relevant comparator<fnref n="2" />. But trials *versus* placebo or supportive care were also accepted in 18% of cases, in accordance with the HAS methodological guide[21] that accepts them when justified, particularly for rare diseases or when no treatment exists. Regarding primary (or co-primary) endpoint, they were distributed among overall survival (OS, 28%), progression free survival (PFS, 28%), overall response rate (ORR, 28%) or another endpoint (23%) for granted demands. OS was also explored as secondary endpoint in 25 (64%) of granted cases. Conversely, primary endpoints were mostly ORR (71%) or other endpoints (29%) but never OS or PFS for denied demands. To date, all demands having mature OS data (41% of cases) in a comparative trial were accepted, meaning that OS data remain a major endpoint, including for the EA process. For the 7 denied demands, the HAS considered that an appropriate treatment already existed in the indication (6/7), or/and that the drug was not presumed innovative (5/7).

## 3.2 Evolution of the number of indications, patients and cost for AEA oncology drugs

The figure 2 presents the evolution of the number of distinct ATU/EA indications of oncology drugs used in real-world practice from 2019 to 2022, by trimester. It showed that the number of indications strongly increased over the period, ranging from 12 ATU indications (7 for solid cancers and 5 for hematological malignancies) in 2019 to 62 EA indications in 2022, predominantly in hematological malignancies (n=17), lung cancer (n=12), digestive cancer (n=9) and breast cancer (n=9). This may be explained by multiple extension of indications (like CAR-T cells in multiple myeloma or pembrolizumab in 4 indications (2 in breast, 1 in pancreatic and 1 in cervical cancers), the arrival of new therapeutic classes (2 indications for the trastuzumab deruxtecan in breast cancer and in digestive cancer or teclistamab), or the pursuit of treatment under EA reform.

<footnote n="2">² According to the definition of HAS transparency committee's doctrine, a clinically relevant comparator may be a medicinal product (active substance or pla-cebo, with or without MA), a medical device, a procedure or any other non-medicinal therapy (or diagnostic method). It plays the same role in the therapeutic strategy as the new medicinal product and is aimed at the same patients.[20]</footnote>
As a possible consequence, the annual number of patients with cancer who were treated with an AEA drug strongly increased from 3,137 patients in 2019 to 18,341 in 2022 (+484%). The figure 3 shows the evolution of the number of patients treated by an AEA drug in France, by month and by tumor localization. It reveals that the number of patients treated monthly with an oncology AEA treatment has risen steadily, being multiplied by 20 over the period, from 326 in Jan 2019 to 6,800 in Dec 2022. It mainly concerned patients treated for breast (from 68 to 2,877 patients, +4131%) or lung cancers (from 84 to 650 patients, +674%). New localizations have also emerged like digestive and urological cancers, with 866 and 619 patients in December 2022, respectively. Hematologic oncology, which represented approximately half of the treated patients in January 2019 (168 patients), saw a sevenfold increase in its number of patients (1251 patients in December 2022) and represents only 18% of patients treated with an EA oncologic drug at the end of the study period.

Reimbursement costs also increase significantly, from 42 to 526 million (M) between 2019 and 2022 (+1159%).

In 2022, the higher reimbursement costs concerned treatments for hematological malignancies (180 M€), breast cancer (159 M€), urology (68 M€), and lung cancer (64 M€). Figure 4 shows the evolution of monthly reimbursement costs for AEA drugs in France by tumor localization.

## 4. DISCUSSION

With 88 indications approved within 18 months, the French early access reform has allowed rapid access to innovations with a high level of evidence and a regulatory simplification of the previous EA systems. More than half of approvals concerned oncology indications, predominantly for solid tumors, notably targeted kinase-inhibitors and immunotherapy. The same trend is found in the US where roughly one-quarter of accelerated-approved drugs are precision medicines for treating solid tumors since 1992 [22]. This trend highlights the fact that specific classes of innovative products dominate the oncology treatment landscape, testifying to the accelerated pace of innovation in this field [23]. With decisions delivered within 70 days on average, ANSM and HAS comply with the regulatory deadline in 87% of cases. This is outstanding as it granted immediate access for AEA drugs to patients. The AEA process is notably quicker than the current drug reimbursement process and the previous ATU evaluation, which required 497-503 days [5] [22] and 257 days [24], respectively. In addition, approved indications were supported by high-quality methodological studies, with mostly phase III trials including direct comparison, randomisation and OS as primary endpoint in nearly one-third of cases, underlining the continued significance of OS results as pivotal requirement in the French context. This differs from FDA approach for cancer accelerated approvals, whom often rely on ORR data from early trial or single-arm trial [25]. It is however in accordance with
the French evaluation performed by the HAS for common drug reimbursement, which enhance drugs with substantial clinical benefits supported by methodologically rigorous studies[13]. Previous studies also demonstrated that ATU programs were based on robust approvals characterized by substantial enhancements in clinical benefit and mature OS data, as supported by high ESMO-MCBS and ASCO-VF scores[15].

The large proportion of trials containing mature OS data may be explained by the fact that 62% of demands concern post-MA drugs, where final results are more legitimate to be found. Unlike the FDA's accelerated approval pathway, the French AEA does not require confirmatory trials to verify the drug's clinical benefit and obtain definitive approval. Manufacturers are therefore inclined to submit demands containing more mature OS data to comply with HAS requirements. However, as the reform is still recent, it is possible that the trend will change and that drugs with early clinical endpoints such as ORR or PFS will be candidates to obtain an AEA [26-28].

Using national medico-administrative databases, our study also unveiled, the patient benefiting from EA oncology drugs and associated reimbursement costs. We observed a significant rise in the number of patients receiving AEA treatments, with a six-fold increase between 2019 and 2022, accompanied by an increase in costs by ten-fold over the period. This growing number of patients and treatment costs appears to be connected to the simultaneous availability of new drugs under EA, as well as new indications for existing drugs now encompassing multiple therapeutic areas, as also noticed in other countries[15,16,23]. However, the momentum of increase in number of indications (figure 2) and patients treated (figure 5) was already discernible during the ATU period and appear to be continuing since the reform. The EA reform has thus facilitated but cannot explain the expansion of innovations into the market in oncology.

Questions however remain regarding the financial aspects and the organisational modalities of the reform. The very significant increase in costs may appear worrying, although the reform aimed to control expenditure to ensure the health care sustainability. Despite the great increase in the number of indications and patients treated, the trend may be explained by the fact that drug price are freely fixed by the manufacturer during the AEA period. However, the cost presented in figure 4 does not reflect the final expense for the French health system, as the laboratory will pay discounts based on AEA sales and the final drug price negotiated. Consequently, the reform is too recent to estimate the economic burden of AEA on drug expenditures, and it impact regarding the sustainability and the financing of therapeutic innovations. However, it is essential to closely monitor the impact of the reform and assess whether adjustments are needed to the current system of financing early access, as well as to the mechanism of post-regulatory control through rebates. Questions also linger about the successful and long-time efficacy of the system. As part of the EA agreement, laboratories must provide real-life data on the use, the effectiveness, the
side-effects and sometimes the quality of life to HAS and ANSM, offering complementary insights to trials. If the usefulness of this data collection is not questioned, challenges regarding the methods, quality, and funding of real-word data collection, which currently rely on hospital teams, are now being raised by French experts [29].

Despite these points of caution, the EA reform in France has allowed fast arrival for patients to a significant number of therapeutic innovations. It concerns innovative medicines for unmet medical needs for serious and sometimes rare cancers, and are supported by high quality methodology studies with a demonstrated added clinical benefit.

The French EA system therefore appears to offer insights for other countries seeking to support and accelerate access to innovations in oncology[7].

**Declarations:**

**Funding:** No external funding was used in the preparation of this manuscript.

**Conflicts of interests:** Tess Martin, Catherine Rioufol, Bertrand Favier, Nicolas Martelli, Isabelle Madelaine, Christos Chouaid and Isabelle Borget declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

**Ethics approval:** Not applicable

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**Consent to participate:** Not applicable

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**Consent for publication:** Not applicable

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**Availability of data and material:** **Data availability:** The data that support the findings of this study are available from the Systeme National des Données de Santé (SNDS) but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Indeed, under French law and regulations, databases extracted from the Systeme National des Données de Santé (SNDS) cannot be publicly available.

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Under French law and regulations, databases extracted from the Systeme National des Données de Santé (SNDS) cannot be made available.

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**Funding:** This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
**Conflicts of interests:** All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

**Code availability:** Not applicable

**Authors' contributions** : **CREDIT Statement:** Tess Martin: Conceptualization, Data curation, Methodology, Writing original draft, **Writing-Reviewing. Catherine Rioufol:** Conceptualization, Methodology, Writing-Reviewing, **Bertrand Favier:** Conceptualization, Writing-Reviewing, **Nicolas Martelli:** Conceptualization, Writing-Reviewing, **Isabelle Madelaine:** Conceptualization, Writing-Reviewing, **Christos Chouaid:** Methodology, Writing-Reviewing, **Isabelle Borget:** Conceptualization, Data curation, Methodology, Writing-Reviewing.

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Figure Legends

40399 Figure 1: Flow-Chart for Early Access approvals analysis

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4000 Figure 2: Number of distinct ATU/EA indications of oncology drugs used in real-world practice (quarterly-month representation) from 2019 to 2022

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4002 Figure 3: Number of patients treated by an ATU/AEA oncology drug, per tumor localization and per month

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Figure 5: Number of patients treated with an early access oncology drug according to their regulatory status (ATU/EA/Mixed status) and per month

Figures captions

Fig. 1 Flow-Chart for Early Access approvals analysis

This flow chart illustrates the process of selecting early access authorization applications issued by the HAS for the first part of the study.

Fig. 2 Number of distinct ATU/EA indications of oncology drugs used in real-world practice (quarterly-month representation) from 2019 to 2022

This figure represents, by trimester, the number of oncology indications in early access, associated with hospital prescriptions, between 2019 and 2022 found in the real-world database of the SNDS.

Fig. 3 Number of patients treated by an ATU/AEA oncology drug, per tumor localization and per month

This figure represents the number of patients treated with a molecule for an oncology indication in early access, by tumor location and per month between 2019 and 2022. The data is derived from the real-world database of the SNDS.

Fig. 4 Reimbursement costs for ATU/AEA oncology drugs, per tumor localization and per month

This figure represents the reimbursement costs associated treated for early access treatments in oncology, by tumor location and per month between 2019 and 2022. The data is derived from the real-world database of the SNDS.

Fig. 5 Number of patients treated with an early access oncology drug according to their regulatory status

(ATU/EA/Mixed status) and per month

This figure represents the number of patients treated with an early access oncolodry drug according to their regulatory status: ATU, Early access or mixed status. Of note, the mixed status corresponds to the
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Supplementary captions (submitted in a editable format separately)

**Supplementary Table 1:** List of drugs and related-indications granted with AE in oncology (solid oncology and onco-hematology) between 07/01/2021 and 31/12/2022

This table provides a list of early access authorizations granted by the National Health Authority since the implementation of the early access reform (07/01/2021) and up to 12/21/2022, by molecule and by indication.
List of Tables

<table><caption>Table 1: Characteristics of oncology drugs with an early access decision</caption><thead><tr><th></th><th>Early access<br>decision granted<br>(n=39)</th><th>Early access<br>decision denied<br>(n=7)</th></tr></thead><tbody><tr><td colspan="3"><strong>Characteristics of the drugs - Therapeutic class</strong></td></tr><tr><td colspan="3"><strong>Radiopharmaceuticals</strong></td></tr><tr><td>Diagnostic radiopharmaceuticals</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td>Therapeutic radiopharmaceuticals</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td colspan="3"><strong>Antineoplastic agents</strong></td></tr><tr><td>Alkylating agents</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td>Antimetabolites</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td>Antineoplastic cell and gene therapy</td><td>6 (15%)</td><td>0 (0%)</td></tr><tr><td>Monoclonal antibodies and antibody<br>drug conjugates</td><td>18 (46%)</td><td>2 (29%)</td></tr><tr><td>Other antineoplastic agents</td><td>5 (13%)</td><td>0 (0%)</td></tr><tr><td>Protein kinase inhibitors</td><td>6 (15%)</td><td>5 (71%)</td></tr><tr><td colspan="3"><strong>Cancer situation</strong></td></tr><tr><td colspan="3"><strong>Solid tumors</strong></td></tr><tr><td>Localized situation, adjuvant</td><td>3 (8%)</td><td>2 (29%)</td></tr><tr><td>Localized situation, neo adjuvant</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td>Metastatic situation, 1st line</td><td>9 (23%)</td><td>1 (14%)</td></tr><tr><td>Metastatic situation, 2nd line</td><td>9 (23%)</td><td>3 (43%)</td></tr><tr><td>Metastatic situation, &gt; 3 lines</td><td>4 (10%)</td><td>0 (0%)</td></tr><tr><td colspan="3"><strong>Hematological malignancies</strong></td></tr><tr><td>1st line</td><td>1 (3%)</td><td>0 (0%)</td></tr><tr><td>2nd line</td><td>7 (18%)</td><td>1 (14%)</td></tr><tr><td>&gt; 3 lines</td><td>5 (13%)</td><td>0 (0%)</td></tr><tr><td colspan="3"><strong>Characteristics of clinical trials</strong></td></tr><tr><td colspan="3"><strong>Development phase</strong></td></tr><tr><td>I, I/II</td><td>7 (18%)</td><td>2 (29%)</td></tr><tr><td>II</td><td>7 (18%)</td><td>2 (29%)</td></tr><tr><td>III</td><td>26 (67%)</td><td>3 (43%)</td></tr><tr><td colspan="3"><strong>Study type</strong></td></tr><tr><td colspan="3"><strong>Comparative study</strong></td></tr><tr><td>Direct comparison</td><td>27 (69%)</td><td>3 (43%)</td></tr><tr><td>Indirect comparison</td><td>0 (0%)</td><td>1 (14%)</td></tr><tr><td>Basket trial</td><td>1 (2%)</td><td>0 (0%)</td></tr><tr><td>Non comparative study</td><td>12 (31%)</td><td>3 (43%)</td></tr><tr><td colspan="3"><strong>Randomization</strong></td></tr><tr><td>Randomized study</td><td>27 (69%)</td><td>3 (43%)</td></tr><tr><td>Non randomized study</td><td>12 (31%)</td><td>4 (57%)</td></tr><tr><td colspan="3"><strong>Double blind study</strong></td></tr><tr><td>Yes</td><td>10 (26%)</td><td>0 (0%)</td></tr><tr><td>No</td><td>29 (74%)</td><td>7 (100%)</td></tr><tr><td colspan="3"><strong>Comparator</strong></td></tr><tr><td>Clinically relevant comparator</td><td>20 (51%)</td><td>3 (43%)</td></tr></tbody></table>
<table><tbody><tr><td>Placebo or supportive care</td><td>7 (18%)</td><td>1 (14%)</td></tr><tr><td>NA<sup>a</sup></td><td>12 (31%)</td><td>3 (43%)</td></tr><tr><td><strong>Primary Endpoint</strong></td><td></td><td></td></tr><tr><td>Overall survival (OS)</td><td>11* (28%)</td><td>0 (0%)</td></tr><tr><td>Overall response rate (ORR)</td><td>11*(28%)</td><td>5 (71%)</td></tr><tr><td>Progression free survival (PFS)</td><td>11* (28%)</td><td>0 (0%)</td></tr><tr><td>Other</td><td>9*(23%)</td><td>2 (29%)</td></tr><tr><td><strong>Exploration of OS</strong></td><td></td><td></td></tr><tr><td>OS as primary endpoint or co-primary endpoint</td><td>11 (28%)</td><td>0 (0%)</td></tr><tr><td>OS as secondary endpoint</td><td>25 (64%)</td><td>6 (86%)</td></tr><tr><td>Indirect comparison</td><td>0 (0%)</td><td>1 (14%)</td></tr><tr><td>Non included in the statistical analysis plan</td><td>3 (8%)</td><td>0 (0%)</td></tr><tr><td><strong>Maturity of OS data</strong></td><td></td><td></td></tr><tr><td>Mature OS data</td><td>16 (41%)</td><td>0 (0%)</td></tr><tr><td>Non mature OS data</td><td>19 (49%)</td><td>7 (100%)</td></tr><tr><td>NA</td><td>4 (10%)</td><td>0 (0%)</td></tr></tbody></table>

<sup>a</sup>Non comparative studies

**The total sum exceeds 39 final early access decisions related to the presence of co-primary endpoints

<table><caption>Table 1: Characteristics of clinical trials of oncology drugs with an early access decision</caption><thead><tr><th></th><th>Early access decision granted (n=39)</th><th>Early access decision denied (n=7)</th></tr></thead><tbody><tr><td><strong>Development phase</strong></td><td></td><td></td></tr><tr><td>I, I/II</td><td>7 (18%)</td><td>2 (29%)</td></tr><tr><td>II</td><td>7 (18%)</td><td>2 (29%)</td></tr><tr><td>III</td><td>26 (67%)</td><td>3 (43%)</td></tr><tr><td><strong>Study type</strong></td><td></td><td></td></tr><tr><td>Comparative study</td><td></td><td></td></tr><tr><td>Direct comparison</td><td>27 (69%)</td><td>3 (43%)</td></tr><tr><td>Indirect comparison</td><td>0 (0%)</td><td>1 (14%)</td></tr><tr><td>Basket trial</td><td>1 (2%)</td><td>0 (0%)</td></tr><tr><td>Non comparative study</td><td>12 (31%)</td><td>3 (43%)</td></tr><tr><td>Randomization</td><td></td><td></td></tr><tr><td>Randomized study</td><td>27 (69%)</td><td>3 (43%)</td></tr><tr><td>Non randomized study</td><td>12 (31%)</td><td>4 (57%)</td></tr><tr><td>Double blind study</td><td></td><td></td></tr><tr><td>Yes</td><td>10 (26%)</td><td>0 (0%)</td></tr><tr><td>No</td><td>29 (74%)</td><td>7 (100%)</td></tr><tr><td><strong>Comparator</strong></td><td></td><td></td></tr><tr><td>Clinically relevant comparator</td><td>20 (51%)</td><td>3 (43%)</td></tr><tr><td>Placebo or supportive care</td><td>7 (18%)</td><td>1 (14%)</td></tr><tr><td>NA<sup>a</sup></td><td>12 (31%)</td><td>3 (43%)</td></tr></tbody></table>
<table><thead><tr><th colspan="3">Primary Endpoint</th></tr></thead><tbody><tr><td>Overall survival (OS)</td><td>11* (28%)</td><td>0 (0%)</td></tr><tr><td>Overall response rate (ORR)</td><td>11* (28%)</td><td>5 (71%)</td></tr><tr><td>Progression free survival (PFS)</td><td>11* (28%)</td><td>0 (0%)</td></tr><tr><td>Other</td><td>9* (23%)</td><td>2 (29%)</td></tr></tbody><thead><tr><th colspan="3">Exploration of OS</th></tr></thead><tbody><tr><td>OS as primary endpoint or co-primary endpoint</td><td>11 (28%)</td><td>0 (0%)</td></tr><tr><td>OS as secondary endpoint</td><td>25 (64%)</td><td>6 (86%)</td></tr><tr><td>Indirect comparison</td><td>0 (0%)</td><td>1 (14%)</td></tr><tr><td>Non included in the statistical analysis plan</td><td>3 (8%)</td><td>0 (0%)</td></tr></tbody><thead><tr><th colspan="3">Maturity of OS data</th></tr></thead><tbody><tr><td>Mature OS data</td><td>16 (41%)</td><td>0 (0%)</td></tr><tr><td>Non mature OS data</td><td>19 (49%)</td><td>7 (100%)</td></tr><tr><td>NA</td><td>4 (10%)</td><td>0 (0%)</td></tr></tbody></table>

*Non comparative studies

**The total sum exceeds 39 final early access decisions related to the presence of co-primary endpoints
<figure><img src="image_2.png" /></figure>

EA = Early Access

HAS = Haute Autorité de Santé (National Health Authority)
<figure><img src="image_3.png" /></figure>

EA reform = Early access reform
<figure><img src="image_4.png" /></figure>

Others = Uveal Melanoma, Central Nervous System, Thyroid, Skin.
<figure><img src="image_5.png" /></figure>

Others = Uveal Melanoma, Central Nervous System, Thyroid, Skin.
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

EA = Early Access

ATU = Authorization for use
<table><caption>Table 1: List of drugs and related-indications granted with AE in oncology (solid oncology and onco-hematology) between 07/01/2021 and 31/12/2022</caption><thead><tr><td>Drugs</td><td>Indication granted with EA approval</td></tr></thead><tbody><tr><td>[18F]PSMA-1007</td><td>[18F]PSMA-1007 is intended for use in positron emission tomography (PET). PET imaging following administration of Radelumin is indicated in patients experiencing biochemical recurrence of prostate cancer, initially treated radically, with a rise in serum prostate-specific antigen (PSA) levels. This medication is for diagnostic use only.</td></tr><tr><td>Amivantamab</td><td>In monotherapy, treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring activating mutations of the epidermal growth factor receptor (EGFR) with exon 20 insertion, following failure of platinum-based therapy.</td></tr><tr><td>Asciminib</td><td>Monotherapy treatment for chronic myeloid leukemia with or without T315I mutation in patients previously treated with all available tyrosine kinase inhibitors on the market and who have relapsed, or in patients refractory or intolerant to tyrosine kinase inhibitors, or for whom treatment with one or more available tyrosine kinase inhibitors is contraindicated.</td></tr><tr><td>Avapritinib</td><td>Aggressive systemic mastocytosis (ASM), Systemic mastocytosis associated with haematological neoplasm (SM-AHN) or Mast cell leukaemia (MCL), after at least one systemic treatment.</td></tr><tr><td>Axicabtagene ciloleucel</td><td>Treatment for adult patients with relapsed or refractory follicular lymphoma, after at least three lines of systemic therapy.<br/>Treatment for adult patients with refractory or relapsed diffuse large B-cell lymphoma within 12 months after completion of first-line therapy, and eligible for salvage chemotherapy followed by intensified chemotherapy for hematopoietic stem cell transplantation.</td></tr><tr><td>Azacitidine</td><td>Maintenance therapy for adult patients with acute myeloid leukemia (AML) who have achieved complete remission (CR) or complete remission with incomplete count recovery (CRi) after induction therapy with or without consolidation treatment and who are not candidates (including patients who choose not to undergo) for hematopoietic stem cell transplantation (HSCT).</td></tr><tr><td>Ciltacabtagene autoleucel (cilta-cel)</td><td>Treatment for adult patients with relapsed and refractory multiple myeloma, who have received at least 3 prior treatments including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody, and whose disease has progressed during the most recent treatment.</td></tr><tr><td>Crizotinib</td><td>Treatment for relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL), from the second line of therapy, in pediatric patients aged 6 years and older and young adults.</td></tr><tr><td>Durvalumab</td><td>Locally advanced or metastatic Bile Duct Cancer (in combination with cisplatin/gemcitabin).</td></tr><tr><td>Enfortumab vedotin</td><td>In combination with gemcitabine/cisplatin chemotherapy, first-line treatment for adult patients with advanced or metastatic biliary tract cancer.</td></tr><tr><td>Glucarpidase</td><td>Reduce toxic plasma concentrations of methotrexate in adults and children (from 28 days old) exhibiting delayed methotrexate elimination or at risk of methotrexate toxicity.</td></tr><tr><td>Idecabtagene vicleucel</td><td>Treatment of adult patients with relapsed and refractory multiple myeloma who have received at least three prior treatments, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody, and whose disease has progressed during the last treatment.</td></tr></tbody></table>
<table>
   <tr>
    <td>Ipilimumab</td>
    <td>Indicated in combination with nivolumab, as first-line treatment, for adult patients with unresectable malignant pleural mesothelioma.</td>
   </tr>
   <tr>
    <td>Ivosidenib</td>
    <td>Monotherapy treatment for adult patients with unresectable or metastatic advanced cholangiocarcinoma harboring an isocitrate dehydrogenase 1 (IDH1) mutation and progressing after two lines of treatment for advanced unresectable and/or metastatic disease.</td>
   </tr>
   <tr>
    <td>Lenvatinib</td>
    <td>In combination with pembrolizumab, treatment for adult patients with advanced or recurrent endometrial cancer, whose disease progresses during or following prior platinum-based chemotherapy received at any stage and who are not eligible for curative surgery or radiotherapy.</td>
   </tr>
   <tr>
    <td>Lisocabtagene Maraleucel</td>
    <td>Treatment for adult patients with diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), or primary mediastinal large B-cell lymphoma (PMBCL), refractory or relapsed within 12 months following first-line treatment and eligible for hematopoietic stem cell transplantation (HSCT).</td>
   </tr>
   <tr>
    <td>Lutetium (177Lu) vipivotide tetraxetan (PSMA-617)</td>
    <td>Treatment for adults with progressive, metastatic, castration-resistant prostate cancer that overexpresses prostate-specific membrane antigen (PSMA) who have been treated with taxane chemotherapy and at least one anti-androgenic hormone therapy.</td>
   </tr>
   <tr>
    <td>Nivolumab</td>
    <td>As monotherapy in the adjuvant treatment of adult patients with residual disease after prior neoadjuvant radiochemotherapy for esophageal or esophagogastric junction cancer.<br/>In combination with a fluoropyrimidine-platinum-based chemotherapy regimen as first-line treatment for adult patients with advanced or metastatic HER2-negative gastric adenocarcinoma, esophagogastric junction adenocarcinoma, or esophageal cancer whose tumors express PD-L1 with a combined positive score (CPS) ≥ 5.<br/>As monotherapy for the adjuvant treatment of adult patients with muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence after complete resection, whose tumor cells express PD-L1 at a threshold of ≥ 1%.</td>
   </tr>
   <tr>
    <td>Olaparib</td>
    <td>As monotherapy for the adjuvant treatment of adult patients with early-stage HER2-negative breast cancer at high risk who harbor a BRCA mutation and have received prior neoadjuvant or adjuvant chemotherapy.</td>
   </tr>
   <tr>
    <td rowspan="3">Pembrolizumab</td>
    <td>In combination with chemotherapy for the treatment of adult patients with locally recurrent or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 with a CPS ≥ 10 and have not received prior systemic therapy for metastatic disease.</td>
   </tr>
   <tr>
    <td>In combination with chemotherapy as neoadjuvant treatment, followed by monotherapy after surgery as adjuvant treatment, in the treatment of adult patients with locally advanced, inflammatory, or early-stage triple-negative breast cancer at high risk of recurrence</td>
   </tr>
   <tr>
    <td>In combination with platinum-based and fluoropyrimidine chemotherapy, first-line treatment for adult patients with esophageal cancer or HER-2 negative adenocarcinoma of the gastroesophageal junction type I (Siewert classification), locally advanced unresectable, or metastatic, whose tumors express PD-L1 with a CPS ≥ 10.<br/>In combination with chemotherapy with or without bevacizumab, treatment for adult female patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 with a CPS ≥ 1.</td>
   </tr>
   <tr>
    <td>Ripretinib</td>
    <td>Treatment for adult patients with advanced gastrointestinal stromal tumor (GIST) who have previously been treated with at least three kinase inhibitors, including imatinib</td>
   </tr>
  </table>
<table><tr><td>Sacituzumab govitecan</td><td>Monotherapy treatment for adult patients with unresectable or metastatic triple-negative breast cancer who have received two or more prior lines of systemic therapy, including at least one in the advanced stage.*</td></tr><tr><td>Selpercatinib</td><td>Monotherapy treatment for adult and adolescent patients aged 12 years and older with advanced medullary thyroid cancer (MTC) harboring a RET gene mutation, requiring systemic treatment after prior treatment with cabozantinib and/or vandetanib.</td></tr><tr><td>Sotorasib</td><td>Monotherapy treatment for adult patients with advanced non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation, whose disease has progressed after at least one prior systemic therapy.</td></tr><tr><td>Tafasitamab</td><td>In combination with lenalidomide, followed by MINJUVI monotherapy, treatment for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for hematopoietic stem cell transplantation (HSCT)</td></tr><tr><td>Tebentafusp</td><td>Monotherapy for the treatment of adult patients with unresectable or metastatic uveal melanoma. HLA-A*02:01-positive.*</td></tr><tr><td>Teclistamab</td><td>Monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least three previous treatments, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody, and whose disease has progressed during the last treatment, when all therapeutic options have been exhausted (excluding cellular therapies), based on the advice of a multidisciplinary consultation meeting.</td></tr><tr><td>Témozolomide</td><td>Treatment for pediatric patients aged 12 months and older with refractory high-risk neuroblastoma or inadequate response to induction chemotherapy; and for pediatric patients aged 12 months and older with relapsed high-risk neuroblastoma after at least a partial response to induction chemotherapy followed by myeloablative therapy and stem cell transplantation</td></tr><tr><td>Tisagenlecleucel</td><td>Treatment for adult patients with follicular lymphoma after at least two lines of treatment: those with refractory disease, those who relapse during or within 6 months following the end of their maintenance treatment, or those who relapse after hematopoietic stem cell transplantation.</td></tr><tr><td>Trastuzumab deruxtecan</td><td>Treatment for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received anti-HER2 therapy. Specifically, monotherapy for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received anti-HER2 therapy and must have received prior treatment for locally advanced or metastatic disease or have experienced disease progression during adjuvant treatment or within six months after its completion.<br>Monotherapy for adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have previously received at least two lines of treatment including trastuzumab.<br>Monotherapy for adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior systemic therapy in the metastatic stage or have developed a recurrence of the disease during or within 6 months following the completion of adjuvant chemotherapy. Patients with hormone receptor-positive (HR+) breast cancer must also have received or be ineligible for hormone therapy.</td></tr><tr><td>Venetoclax</td><td>In combination with obinutuzumab, indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL) who are ineligible for BTK inhibitors and either ineligible for fludarabine-based treatment or have del(17p) and/or TP53 mutation.</td></tr></table>

<footnote>*Indications with early access renewals</footnote>