# How to differentiate between clinical added value (CAV) V drugs: What are the implications, and what is the access pathway?

Clémentine Body, Frédéric Chassagnol, Driss Berdaï, Jean-François Bergmann, Isabelle Borget, Carole Doré, Alexandra Durr, Bruno Falissard,

Joumana Hudry, Benjamin Kowalski, et al.

► To cite this version:

Clémentine Body, Frédéric Chassagnol, Driss Berdaï, Jean-François Bergmann, Isabelle Borget, et al. How to differentiate between clinical added value (CAV) V drugs: What are the implications, and what is the access pathway?. Therapies, 2025, S0040-5957 (25), pp.00160-X. 10.1016/j.therap.2025.10.010. inserm-05443634

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# How to differentiate between clinical added value (CAV) V drugs: What are the implications, and what is the access pathway? ☆

Clémentine Body<sup>a</sup>, Frédéric Chassagnol<sup>b</sup>, Driss Berdaï<sup>c, 1</sup>, Jean-François Bergmann<sup>d, 1</sup>, Isabelle Borget<sup>e, 1</sup>, Carole Doré<sup>f, 1</sup>, Alexandra Durr<sup>g, 1</sup>, Bruno Falissard<sup>h, 1</sup>, Joumana Hudry<sup>i, 1</sup>, Benjamin Kowalski<sup>j, 1</sup>, Philippe Maugendre<sup>k, 1</sup>, Nicolas Schlumberger<sup>k, 1</sup>, Elodie Wilmet<sup>l, 1</sup>, Claire Le Jeunne<sup>m, *</sup>

Received 6 October 2025; accepted 16 October 2025

DOI of original article: https://doi.org/10.1016/j.therap.2025.10.011.

☆ The articles, analyses and proposals resulting from the Giens Workshops belong to the authors and do not predict the proposals of their organization.

* Corresponding author. Department of Internal Medicine, Cochin Hospital, Paris Public Hospitals, 27, rue du faubourg Saint Jacques, 75014 Paris, France.

E-mail address: claire.le-jeunne@orange.fr (C. Le Jeunne).

¹ Participants in the 'Organisational and Regulatory Aspects' roundtable of the Giens Workshops 2025.

https://doi.org/10.1016/j.therap.2025.10.010

0040-5957/© 2025 The Authors. Published by Elsevier Masson SAS on behalf of Société française de pharmacologie et de thérapeutique. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

<footnote><sup>a</sup> Director of Cross-Functional and International Projects, Agency for Health Innovation, 75007 Paris, France</footnote>

<footnote><sup>b</sup> Executive Director Access, Public Affairs and Communication, Roche France, 92650 Boulogne Billancourt, France</footnote>

<footnote><sup>c</sup> Department of Medical Pharmacology, Public Health Unit, Bordeaux University Hospital, 33076 Bordeaux, France</footnote>

<footnote><sup>d</sup> Emeritus Professor of Therapeutics Paris Cité University, 75005 Paris, France</footnote>

<footnote><sup>e</sup> Gustave Roussy Institute, 94805 Villejuif, France</footnote>

<footnote><sup>f</sup> GlaxoSmithKline Laboratory, 92500 Rueil Malmaison, France</footnote>

<footnote><sup>g</sup> Paris Brain Institute, Pitié Salpétrière Hospital, 75013 Paris, France</footnote>

<footnote><sup>h</sup> Paris Saclay University, 91190 Gif-Sur-Yvette, France</footnote>

<footnote><sup>i</sup> Novartis, 92500 Rueil Malmaison, France</footnote>

<footnote><sup>j</sup> Bristol Myers Squibb, 92500 Rueil Malmaison, France</footnote>

<footnote><sup>k</sup> Sanofi, 75008 Paris, France</footnote>

<footnote><sup>l</sup> Biogen France, 92800 Puteaux, France</footnote>

<footnote><sup>m</sup> Paris Cité University, Paris Public Hospitals, Cochin Hospital, 75014 Paris, France</footnote>
## KEYWORDS

Clinical added value

V;

Transparency

Committee;

Economic and Public

Health Evaluation

Committee;

Health Products

Economic

Committee;

Observational
studies;

Public health impact;

Medical-economic
studies;

Drug prices

**Summary** Level V clinical added value (CAV) refers to a lack of CAV improvement of a new medicine, as assessed by the French Transparency Committee, compared to a standard of care therapeutic strategy. In 2024, 56% of medicines evaluated in primary registration or extended indication (excluding simplified procedures) were assigned an CAV V, compared with 44% in 2023. Obtaining an CAV V sometimes leads to the product not being available to patients, especially in the event of non-inclusion on the costly drug list for hospital products or after failure of negotiation between the drug manufacturers and the Health Products Economic Committee. The Giens workshops wished to devote a round table to the study of these drugs and analyse the different situations leading to CAV V to make proposals allowing access for patients to these drugs that are the subject of very specific CAV V situations.

Three situations could benefit from specific attention: (i) Medicinal products for which the submitted clinical data does not allow the French Health Authority (HAS), at the time of evaluation, to decide on the quantity of clinical effect; (ii) Drugs for which the clinical effect is low or for which clinical relevance is discussed; (iii) Drugs for which no added clinical benefit is demonstrated but for which non-clinical benefits (such as organisational impact on care, or long-term savings) are identifiable.

Following the analysis of these different situations and using examples, the members of the round table made eight concrete proposals to allow patients to access these products, in certain blocking situations.

© 2025 The Authors. Published by Elsevier Masson SAS on behalf of Société française de pharmacologie et de thérapeutique. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Abbreviations

**ANSM** French National Agency for Medicines and Health Products Safety

**ATMPs** advanced-therapy medicinal products

**CAV** clinical added value (ASMR for ‘‘amélioraton du service médical rendu’’ in French)

**CB** clinical benefit (SMR for ‘‘service médical rendu’’ in French)

**CEESP** Economic and Public Health and Evaluation Committee

**CEPS** Health Products Economic Committee

**CNEDIMTS** National Commission for the Evaluation of Medical Devices and Health Technologies

**CVA** cerebral vascular accident

**DOAC** direct oral anti-coagulants

**EA** Early access (EA1: AP1 for ‘‘accès précoce 1’’ in French) - (EA2: AP2 for ‘‘accès précoce 2’’ in French)

**EMA** European Medicines Agency

**HAS** French National Authority for Health

**INR** international normalized ratio

**LEEM** French Pharmaceuticals Association

**LOM** Ministerial Guidance Letter

**MA** marketing authorisation

**PHB** public health benefit

**PNH** paroxysmal nocturnal haemoglobinuria

**TC** Transparency Committee

**VKA** vitamin K antagonist

## Introduction

In France, medicines follow a very precise pathway of access to reimbursement and then coverage by national insurance and setting of prices, according to 3 main successive steps:

* Marketing authorisation (MA), based on risk-benefit ratio and issued, most of the time, by the European Medicines Agency (EMA) and then issued in France by the French National Agency for the Safety of Medicines and Health Products (ANSM);

* The evaluation by the French National Authority for Health (HAS), and more specifically by the Transparency Committee (TC), of the demonstrated clinical benefit (clinical benefit—CB) in order to authorize their access to reimbursement or not, and of the demonstrated added therapeutic value of the medicinal product compared with the available treatments (clinical added value—CAV). Under certain conditions, the Economic and Public Health Evaluation Committee (CEESP), within the HAS, issues a medical-economic opinion,

* The setting of prices by the Health Products Economic Committee (CEPS), an interministerial body, through an agreement signed with the manufacturer marketing the medicinal product. This takes into account, in particular, the assessment by the Transparency Committee.

It should be noted that since 2021, there has also been the possibility of derogatory access, in particular ‘‘early access’’, a system that allows patients who are at a therapeutic standstill to benefit, on an exceptional and temporary basis, from certain drugs that are not yet authorised in a specific therapeutic indication (EA1) or that have a MA in
the indication considered pending their reimbursement by Health Insurance (EA2).

The medical-technical assessment carried out by the Transparency Committee is based on two distinct criteria:

* The clinical benefit (CB) which takes into account several aspects: on the one hand, the severity of the disease for which the medicinal product is indicated; on the other hand, data specific to the medicinal product itself, in a given indication (efficacy and undesirable effects), its place in the therapeutic strategy (in particular with regard to the other available therapies) as well as its benefit for public health (PHB);

* The clinical added value (CAV), a comparative criterion, which corresponds to the therapeutic progress provided by the new drug compared to the existing one. This criterion is graded from I (corresponding to major innovation) to V (no improvement). The elements considered for the assessment of the CAV are the level of evidence of the demonstration of the therapeutic value, the medical need, the quantity of effect and possibly the transposability of the results to the French context.

CAV V refers to no improvement over a standard of care treatment strategy. In 2024, 56% of medicines evaluated in primary registration or extended indication (excluding simplified procedures) were assigned an CAV V, compared with 44% in 2023.

However, these CAV V drugs include very heterogeneous realities:

* Category 1: drugs for which the clinical data submitted do not allow the HAS, at the time of evaluation, to decide on the quantity of clinical effect;

* Category 2: drugs for which clinical effect is low or for which clinical relevance is debated;

* Category 3: Drugs for which no added clinical benefit is demonstrated, but for which non-clinical benefits (such as organisational impact on care, or long-term savings) are identifiable;

* Generic and biosimilar drugs;

* Drugs for which no clinical or organisational benefit has been demonstrated.

In situations 1, 2 and 3 described above, the granting of CAV V poses problems of access to this drug for the French patients, whether for inclusion on the additional list for expensive drugs reserved for the hospital, which allows health institutions not to have to include the cost of these products in their pricing at the activity, or at the time of the price negotiation with the Economic Committee for Health Products (CEPS). Indeed, a drug that has been granted an CAV V must, under the regulations, "provide a saving in the cost of drug treatment" (article R163-5 of the Social Security Code).

As CAV Vs cover different realities, a round table meeting was held in the context of the Giens workshops to identify the situations for which drugs with CAV V should be the subject of particular attention, in order to secure their access to patients, when necessary, and to propose recommendations.

On the basis of this observation, Round Table 6 of the Giens Workshops 2025 brought together academic, institutional and industry experts as well as representatives of the administrations, in order to categorize the different types of CAV V, based on concrete examples. The group prepared

the 2 days of discussions by 4 video meetings of the whole group and videos in 3 subgroups corresponding to the three different CAV V situations that raise questions.

The participants thanked Ms Virginie Beaumeunier, Chair of the Economic Committee for Health Products, and Prof. Pierre Cochat, Chair of the French Health Authority's Transparency Committee, who spoke as part of these studies. Their field visions and real-world experiences helped participants make pragmatic proposals.

## Different categories of CAV V

CAV V is granted to drugs for which the studies analysed do not make it possible, in a given indication, to date, to identify an improvement in therapeutic value, compared with the existing one: these are therefore products for which the HAS does not recognise therapeutic progress. The Transparency Committee assesses the amount of effect the drug has relative to a comparator or in the therapeutic strategy. To do this, it is necessary that the trial comparison methodology allows the evaluators to decide on the transposability of the trial in real life. Therefore, the evaluation doctrine favours trials of direct comparison to a clinically relevant comparator, based on a primary endpoint relevant to clinical practice and pathology, with control of the risk of error (alpha risks and statistical power) (Fig. 1) [1]. Indirect comparisons may exceptionally be considered by the Transparency Committee, in justified situations and where their methodology is robust (meta-analyses for example).

This article is intended to only address CAV Vs responding to very specific access blocking situations, which represent only a very small minority. The vast majority of CAV Vs are therefore not concerned by these proposals, namely generic and biosimilar products, as well as those for which the studies conclude that there is no clinical or organisational benefit. Except in very specific situations, no additional clinical studies are planned for these products, which does not allow the committee to change its assessment in the event of an appeal.

## Category 1: drugs for which the clinical data submitted does not allow the HAS, at the time of evaluation, to decide on the amount of clinical effect

In certain situations, the clinical data provided by the laboratory does not allow the Transparency Committee to decide on the amount of effect compared to a given comparator. Examples include:

### Medicinal products for which a conditional MA has been granted, i.e. for which clinical data is incomplete or immature, in a context of significant medical need

The data for a conditional MA is often derived from a Phase 2 non-comparative study and the manufacturer needs to complete ongoing studies or conduct new studies to provide comprehensive clinical data. In these specific situations, and
<figure><img src="image_4.png" /><figcaption>**Figure 1.** Doctrine of the Transparency Commission. February 15, 2023. French National Authority for Health. Doctrine of the Transparency Commission. Principles of evaluation of the Transparency Commission related to medicinal products for their access to reimbursement. February 15, 2023. https://www.has-sante.fr/uploads/docs/application/pdf/2021-03/doctrine CT.pdf#page=32. [Accessed 16 October 2025] [1].</figcaption></figure>

in light of its evaluation doctrine, the Transparency Committee grants an CAV V to these products, considering that the phase 2 data do not yet allow an opinion on the amount of effect compared with the clinically relevant comparator. This was the case, for example, for ABECMA®, evaluated in December 2021 and for which the Transparency Committee granted an CAV V, considering that "as the data stand, and pending in particular the results of the randomized phase III KarMMa-3 study, ABECMA (idecabtagene vicleucel) does not provide an improvement in clinical added value (CAVV) in the treatment of adult patients with multiple myeloma [...]"[2]. A re-evaluation in June 2023 raised the CAV level from V to IV, with the Transparency Committee acknowledging "the demonstration in a randomised, open-label, phase 3 study of ABECMA® superiority" [3]. In this specific situation, patients were able to benefit from the medicinal product as part of early access during the period between the first evaluation and the publication of the reimbursement decision.

Since this example, for early access products whose data set necessary for the common law assessment is not avail-

able at the end of the early access period, Article 76 of the LFSS for 2024 introduced a new ‘‘transitional access’’ scheme [4]. Its objective is to ensure the continuity of treatment of patients after early access and until the completion of their data for re-evaluation by the regulator and their reimbursement under common law.

However, an implementing decree is, at the time of drafting the article, expected for the implementation of this scheme. The working group recommends a rapid publication of this decree to secure patient access.

## Drugs for which it has not been possible in practice, to set up a comparative study

This is particularly the case for drugs targeting very small populations, for which the recruitment of patients in a clinical trial is difficult (orphan disease, paediatric trial) or the treatment alternative is very debilitating. Implementation of a control arm in the study slows the enrollment process, may discourage patients from entering a trial, and is sometimes denied by ethics committees. In these situations,
## Proposal 1

In such situations, an alternative to the issuance of the above-mentioned decree could be to delay the submission of data until the availability of the final data. It should be noted, however, that these products are very often managed via the early access system, due to the significant medical need they address. However, the Act stipulates that the manufacturer marketing the product has one month after the MA to file a reimbursement application.

The working group therefore proposes to remove the one-month deadline for submitting a reimbursement request, in the context of early access. Another proposal could be to extend the early access authorisation period to 18 months, renewable once.

manufacturers have the possibility of providing data from an indirect comparison with an external control arm or even the use of in-silico studies. However, the Transparency Commission tends not to recognise the validity of these data if the comparison to the external control arm is not stipulated in the protocol, and the issue of patient matching is highly controversial [5].

Drugs to treat diseases that progress very slowly, such as diabetes, hypercholesterolemia and Alzheimer's disease, among others.

In these situations, demonstrating the effect of a drug on a "hard" endpoint such as morbidity and mortality requires a study lasting for many years. In practice, manufacturers do not conduct such studies that are too risky and expensive; they then conduct studies with surrogate criteria, including biomarkers such as the evolution of LDL-C in familial hypercholesterolemia, the change in HbA1c in diabetes, etc. A surrogate endpoint is considered relevant by the Transparency Commission only "provided that its predictive nature of an effect on a clinical endpoint of morbidity and mortality has been demonstrated in the disease concerned" [1]. This includes whether these biomarkers are causal for disease expression (such as blood counts with microscopic examination of the shape of red blood cells in sickle cell disease) or resulting from the disease (such as troponin following myocardial infarction).

## Category 2: drugs for which clinical effect is low or for which clinical relevance is debated

In certain situations, the clinical trial methodology allows the Transparency Committee to decide on the amount of effect compared to a comparator, but this amount of effect is controversial and leads the commission to assign an CAV V.

### Drugs indicated for rare diseases

In the case of rare diseases, the selection of the primary endpoint is hampered by the lack of standardised and universally recognised criteria, in part due to the still limited knowl-

## Proposal 2

It therefore appears necessary to increase knowledge on the link between biomarkers and the evolution of pathological conditions to allow the Authorities to decide on the validity of studies using substitution criteria.

New artificial intelligence tools, combined with the consolidation of data generation, will make it possible to simulate the evolution of pathological conditions and predict the impact of a treatment on the morbidity and mortality of a pathological condition, based on the substitution criteria. Some of these algorithms are starting to be approved by regulatory agencies such as the EMA-approved iBox tool [6]. There is therefore also a need to increase knowledge on methods for simulating pathological changes, in order to allow regulatory authorities to decide on their validity and thus recognise their surrogate property.

## Proposal 3

The use of real-world data (natural history cohorts, registries, exceptional access data collection, etc.) would also make it possible to strengthen the documentation of the effectiveness of a treatment in a real-world setting, when clinical studies do not enable a definitive decision to be made. Using artificial intelligence to automate data collection is an opportunity to improve the quantity and quality of data collected, and thus make analysis more robust. Consolidation of quality data collection would also make it possible to simulate effects over the long term. The members of the working group therefore propose that the evaluators and manufacturers work together to define the acceptability conditions of these data. A rapid re-evaluation mechanism based on real-world data alone could also be considered.

The use of biobank samples and their associated data should also be facilitated, in particular by allowing the collection of patient consent before their secondary use.

Assessing clinical relevance and/or the amount of effect can be challenging, especially in populations with high interindividual variability. This is the case, for example, in the evaluation of SKYCLARYS® [7], a product indicated for the treatment of Friedreich's ataxia in patients 16 years of age and older, for which the clinical relevance of the primary endpoint of the study (mFARS, neurodegenerative score) has been qualified.

### Medicinal products for a disease in which few recent innovations have been marketed and for which the quantity of effect is considered low

In certain therapeutic areas, such as antibiotics or vaccines, but also products that have very old products as
comparators, at very low prices, the CAV V granted by the
Transparency Committee poses a problem when it comes
to negotiating prices. Indeed, the regulations stipulate that
CAV V drugs can only be reimbursed if they provide a saving
in the cost of drug treatment.

An example is AIMOVIG®, for which the Transparency Committee recognised therapeutic utility in the last line of treatment in severe patients, while assigning an CAV V due to a methodology deemed insufficient. Reimbursement was limited to severe migraine patients who failed at least two prophylactic treatments. In the second evaluation, the contribution of comparative data did not make it possible to modify the assessment and the CAV V was maintained. This product is therefore subject to a reimbursement recommendation for a product without recognised therapeutic progress, but for patients without alternatives. Of the clinical comparators mentioned in the opinion, half are from before 1980, with prices of about 20 cents per day, making it impossible to market a monoclonal antibody at an equivalent rate. AIMOVIG, like the other anti-CGRP5 that were evaluated identically taking into account a moderate therapeutic effect, therefore is still not reimbursed [8].

Proposal 4

In situations where, despite the assignment of an
CAV V, the Transparency Committee deems it necessary
to secure patient access, particularly in the case
of hospital products whose cost cannot be absorbed
via activity-based pricing, or in the case of CAV V
without comparator, the working group proposes that
the evaluation explicitly mentions this need for access,
particularly by clarifying the place in the therapeutic
strategy. This would allow the Ministers to inform
their decision to add it to the additional List or the
exemption to generate savings.

Indeed, to overcome the problem of taking into
account the prices of comparators, an exception could
be proposed to Article R163-5 of the Social Security
Code aiming to register only CAV V drugs generating
a saving in the cost of the drug treatment. The
exception would only concern situations in which the
Transparency Committee specifies the need to secure
patient access in its opinion.

Another way of thinking could be to take into
account the duration of comparators in the definition
of the price.

In the case of LUMYKRAS®, indicated for the treatment of
adult patients with KRAS G12 C mutation-positive advanced
non-small cell lung cancer, the Transparency Commission
considered this product to be a drug option in its July 2023
assessment, and assigned an CAV V, due to a statistically sig-
nificant but modest difference in progression-free survival
[9]. Again, many of the comparators mentioned in the opin-
ion are old chemotherapies, for which hospitals negotiate
very low prices in their tenders. It should be noted that none
of the comparators mentioned specifically target the KRAS-
G12 C mutation. At the time of writing, this product was not
available to patients.

Proposal 5

In order to allow manufacturers to better anticipate
the expectations of the Transparency Committee in
the valuation of the CAV, it could be considered to
strengthen the human resources capacities of the
French National Health Authority in order to increase
the number of early meetings, before the submission
of reimbursement files. It also appears necessary to
involve methodologists at these meetings, or even to
call on highly specialized methodologists, especially in
the case of trials involving new methodologies. One
avenue to explore would be to charge for these early
meetings or to call on independent external evaluators
appointed by the HAS.

Category 3: Products with potential extra-clinical benefit, with no additional clinical benefit

These are drugs that do not provide demonstrated clinical improvement versus existing therapies, but can provide benefits beyond the therapeutic benefit, for example progress in patient care or health care organisation and thus contribute to greater efficiency of the healthcare system.

The current tools for recognising this extra-clinical
value, their limitations, the proposals of the round table.

The Transparency Committee (HAS) considers that a
medicinal product may have a Public Health Benefit (PHB)
when it provides a service to the community, either because
it contributes to a significant improvement in the state of
health of the (or of a) population, or because it meets a pub-
lic health need, or because it reduces resource consumption
(Table 1) [1]. In practice, the recognition of a PHB is rare and
decreases over time: since 2023, the number of CAV Vs that
have been able to obtain a PHB is less than 5%.

On the one hand, recognition of this criterion is infre-
quent, and on the other hand, its impact on reimbursement
or price discussions is today particularly limited, thus raising
the question of its usefulness (Table 2).

The recognition of this extra-clinical benefit in the assess-
ment of HAS is also discussed in the TC doctrine via
the consideration of potential improvements in the con-
ditions of care (new methods of administration, dosage
form, follow-up, etc.). This would thus enable the CAV
to be assessed when a major change in the conditions of
care (improvement in the health care pathway, reduction
in hospitalisations, improvement in compliance, etc.) is
demonstrated [1].

In practice, very few specialties have been able to ben-
efit from an evaluation of their CAV based on this criterion.
Thus, between January 2020 and May 2025, only 10 spe-
cialties were identified as having an explicit mention of an
improvement in the conditions of care (based on identified
Key words: galenic; pathway; care; conditions; adminis-
tration; compliance; formulation) in the wording of the
CAV granted (CAV IV). An example is ULTOMIRIS®; indicated
for the treatment of paroxysmal nocturnal haemoglobinuria
(PNH) in adult patients. The Commission's initial assessment
<table><caption>**Table 1** Evolution of significant PHB attributed to medicinal products with an CAV V.</caption><thead><tr><th></th><th>2020</th><th>2021</th><th>2022</th><th>2023</th><th>2024</th></tr></thead><tbody><tr><td>Total of CAV V<sup>a</sup></td><td>66</td><td>66</td><td>60</td><td>64</td><td>65</td></tr><tr><td>Total of CAV V with a recognized public health benefit</td><td>8</td><td>7</td><td>4</td><td>2</td><td>3</td></tr><tr><td>Proportion</td><td>12,1%</td><td>10,6%</td><td>6,6%</td><td>3,1%</td><td>4,6%</td></tr></tbody></table>

CAV: clinical added value; PHB: public health benefit.

<table><caption>**Table 2** Examples of elements of assessment of the public health benefit (PHB) according to the context. Doctrine of the Transparency Commission. February 15, 2023. French National Authority for Health. Doctrine of the Transparency Commission. Principles of evaluation of the CT related to medicinal products for their access to reimbursement. February 15, 2023. https://www.has-sante.fr/uploads/docs/application/pdf/2021-03/doctrine.ct.pdf#page=32. [Accessed 16 October 2025]. [1].</caption><thead><tr><th rowspan="2">PHB criteria</th><th colspan="2">Partially met need<br>(existence of clinically relevant comparator)</th><th>Unmet need<br>(absence of clinically relevant comparator)</th></tr><tr><th>High prevalence<br>Prevalence rate > 1 / 2,000<br>Number of cases > 30,000</th><th>Low prevalence<br>Prevalence rate ≤ 1 / 2,000<br>Number of cases ≤ 30,000</th><th>Independently of prevalence</th></tr></thead><tbody><tr><td>High seriousness</td><td>Case 1 – additional impact on morbidity and mortality and absence of deterioration in the care pathway and/or life course<br>Case 2 – substantial improvement in the care pathway and/or life course without deterioration in morbidity and mortality</td><td>Additional impact on morbidity and mortality and substantial improvement in the care pathway and/or life course</td><td>Case 1 – additional impact on morbidity and mortality and absence of deterioration in the care pathway and/or life course<br>Case 2 – substantial improvement in the care pathway and/or life course without deterioration in morbidity and mortality</td></tr><tr><td>Lower seriousness</td><td>additional impact on morbidity and mortality and substantial improvement in the care pathway and/or life course</td><td></td><td>additional impact on morbidity and mortality and substantial improvement in the care pathway and/or life course</td></tr><tr><td>Specific cases</td><td colspan="3">- vaccines and preventive treatments<br>- concomitant development of two comparable medicinal products<br>- other exceptional situations, on a case-by-case basis, depending on the assessment of the TC</td></tr></tbody></table>

had decided on an CAV V; but the hearing requested by the laboratory had finally made it possible to grant an CAV IV thank to "an expected improvement in the conditions of care due to the administration methods of the infusions allowing their frequency to be reduced compared with eculizumab (every 8 weeks for ravulizumab versus every two weeks for eculizumab)" [10]. The same applies to BAQSIMI®; an intranasal glucagon formulation; indicated for the treatment of severe hypoglycemia in adults; adolescents and children 4 years of age and older with insulin-treated diabetes. An assessment of its CAV was granted thanks to "the value of making an intranasal route available to improve conditions of care" [11]. The Commission recognized the medical need "to have a route of administration that is easier to use than the injectable form in this emergency context; and therefore the potential improvement

in conditions of care associated with this new method of glucagon administration" [12].

It is interesting to note that, despite a recognized improvement in the conditions of care, the PHB has not been granted for all the products concerned. This is the case in particular for ULTOMIRIS®, cited above, for which the Transparency Committee concluded that there was no impact.

Although the Transparency Committee outlines in its doctrine the consideration of these extraclinical benefits, CEESP remains the entity of the HAS responsible for assessing these aspects and is commonly recognised as such. However, while the CEESP's stated objective is to actively contribute to ensuring that the efficiency or opportunity cost dimension is taken into account in both public and professional decision-making, the impact of its opinions in the evaluation and

<footnote><sup>a</sup> Medicines assessed with CAV V, for primary registration or extension line, during a complete evaluation process, based on PrismAccess database extraction.</footnote>
pricing of medicines remains minor. It should be remembered that, to date, only health products claiming a CAV of 1 to 3 and having an impact on the health system, i.e. generating sales of more than 20 million euros in the 2nd year of marketing or in the case of advanced therapy medicinal products (ATMPs) are eligible for the submission of an efficiency file to the CEESP. However, many stakeholders seem to see the following important exploitation potential when considering their efficiency and organizational impact:

* A recent report, commissioned by Élisabeth Borne [13] on the regulation of health products, suggests including organisational impact in the CAV endpoints;

* The National Commission for the Evaluation of Medical Devices and Health Technologies (CNEDIMTS) has already incorporated organisational impact as a criterion for improvement in expected benefit (IEB) for medical devices, demonstrating the HAS's interest in this approach [14];

* The latest ministerial guidance letter (MGL) [15], addressed to the CEPS, re-emphasizes the need for a more systematic assessment of the efficiency of products;

* Finally, the flash mission entrusted to the Chair of the CEPS, who has just issued her conclusions, recommends better use of the medical-economic evaluations and advocates a redefinition of the eligibility criteria for this evaluation. This mission also favours taking externalities into account, where relevant and demonstrated, in order to have a slightly broader view than the price of the medicinal product, for example by looking at the savings associated with a change of route of administration of a product.

## Proposal 6

* propose a PHB as a separate criterion from the CB and CAV by evolving its determinants to make them more societal through an adaptation of the TC doctrine. The PHB should also be considered as one of the determinants in the pricing and including on the Costly Drug List.

* Alternative: Like the CNEDIMTS, make organisational impact a determinant of CAV as proposed in the Borne mission report, in the same way as the existing criteria, through an evolution of the TC doctrine. Recognition of an organisational impact should be included in the CAV wording as well as in the conclusions of the TC opinion and the pricing of the drug should take this into account.

One example is ELIQUIS® (apixaban), a concrete example that innovations are not systematically associated with additional costs for health insurance. Thus, the class of direct oral anticoagulants (DOACs, to which ELIQUIS® belongs) has extra-clinical benefits and enables long-term savings. By promoting the use of this type of innovation, an environment more conducive to the attractiveness and assessment of innovation in France could be envisaged.

The NAXOS study, conducted nationwide at the request of the French Health Authority and based on real-world data from the Health Insurance Scheme (SNDS), compared direct

oral anticoagulants (DOAC: apixaban, dabigatran, rivaroxaban) with historical anticoagulants (vitamin K antagonists - VKAs) in more than 321,501 patients with atrial fibrillation in France. It showed that DOACs are more effective, safer and associated with lower total costs. The study evaluates the budget impact of DOACs over 10 years in France, focusing on the costs related to hospitalisations for stroke or major bleeding and those related to biological monitoring. Over a 10-year period, the DOAC class prevented nearly 73,000 strokes, 97,000 major bleeds and 19,000 deaths. The resulting savings in the management of stroke (-€4.24 billion), major bleeding (-€3.22 billion) and international normalized ratio (INR) laboratory tests (-€1.14 billion) were greater than the increase in the cost of treatment with DOACs (+€5.15 billion before any discounts). In total, the introduction of DOACs generated €3.45 billion savings for health insurance over 10 years [16].

This study raises several questions and problems. It highlights the interest of all stakeholders in the early identification by the CEESP of effective, or even "dominant", therapeutic strategies. In this context, it thus discusses the evolution of the eligibility criteria for the medical-economic assessment, to expand them to applications for CAV IV and V, on a voluntary basis, in particular if organisational or economic externalities for health insurance are claimed. In connection with the additional data already requested by the CEESP in its opinions, this study also shows the interest of the SNDS in evaluating the economic impact observed in real life, or re-evaluation, for certain therapeutic strategies. This thinking could be extended to other sources of real-world data (cohorts and registries). Within the framework of the work program of the HAS/CEESP and the CEPS on the place of medical-economic evaluation as a tool for negotiating prices, these results shed new light on the value of dynamic post-marketing assessment of medicinal products.

## Proposal 7

* Request re-evaluations on the basis of the submission of real-world data making it possible to concretely illustrate the organisational impact of the drug with an acceptability of these data by the HAS made possible by an evolution of the TC doctrine incorporating its expectations on the methodology associated with this type of data.

* Extending the eligibility criteria for the submission of a medical-economic model beyond the claimed CAV I, II or III: allowing volunteering manufacturers to submit a budget impact model for CAV IV or V (claimed), when an organizational impact is claimed by the manufacturer. Once the methodology is validated by the CEESP and the efficiency of the product is recognised, the conclusion of the opinion must mention this organisational and economic impact. The working group proposes setting up a trial phase of this approach that would lead to a lasting change in the eligibility criteria in the law if it is conclusive.

Although there is real interest in this more holistic approach (beyond clinical benefit) of the drug and its efficiency, these aspects still struggle to be considered in the
pricing and management of drugs. Indeed, in accordance
with Article R163-5 of the Social Security Code [17], the fol-
lowing condition is stipulated: "'Cannot be included in the
lists or one of the lists stipulated in the first and second
subparagraphs of Article L. 162-17 of this code and Arti-
cle L. 5123-2 of the Public Health Code, where applicable
for some of their indications only medicinal products that
do not provide an improvement in clinical added value
assessed by the committee mentioned in Article R. 163-15
or a saving in the cost of drug treatment'".

Thus, a drug benefiting from an CAV V is only paid for by
the community if its price is less expensive than the com-
parator, itself defined within a single and restricted scope:
that of the drug budget.

This limit is also visible in the framework agreement
between Pharmaceuticals Association and CEPS [18] in force,
in particular in Article 10, which defines that ‘‘When no
comparator satisfies the definitions mentioned above, or
if the Committee deems it appropriate with regard to the
medical need and the price level of the comparators, the
parties agree on a reference cost that they deem economi-
cally relevant (in terms of cost, duration of treatment and
population treated) based on one or more economic drug
comparator(s)’’. The comparison is limited to one (or sev-
eral) drug(s), without taking into account the overall impact
on the care pathway (organisational and economic impact).

Proposal 8

* Amend Article R 163-5 of the Social Security Code specifying that for an CAV V, savings can be considered within the scope of the treatment: "Cannot be included on the lists... Medicinal products that do not improve actual benefit, as assessed by the commission mentioned in Article R. 163-15, or provide savings in the cost of treatment or the patient pathway".

* Seize the opportunity to draft a new framework agreement in 2026 to amend 1) the articles limiting themselves to a strict consideration of drug costs as a point of comparison; 2) the articles referring to medical-economic evaluation in order to enable a better assessment of the extra-clinical impact in the determination of the price.

* For all the categories of CAV V mentioned in this article, to allow the negotiation of rebates to the CEPS for these products, i.e. to see the possibility of decorrelating public prices and net prices, respecting the absence of additional costs for health insurance, in order to obtain pricing conditions compatible with a marketing of these specialties providing technological innovation/extra-clinical benefit.

Conclusion

This collaborative study clearly demonstrates the significant
heterogeneity of CAV V products and aims to highlight three
categories of products evaluated as CAV V that seem to war-
rant particular attention.

It is important to note that these specific cases can only
represent a small proportion of all CAV Vs.

This article describes the 3 types of exceptional situation:

* Drugs for which the clinical data submitted does not allow the HAS, at the time of evaluation, to decide on the amount of clinical effect;

* Drugs for which the clinical effect is low or for which clinical relevance is discussed;

* Drugs for which no added clinical benefit is demonstrated but for which non-clinical benefits (such as organizational impact on care, or long-term savings) are identifiable.

We recommend the recognition of these particular cases
and the implementation of avenues, avenues for propos-
als described in this article and consolidated in Appendix
1, aimed at securing the possibilities of access to these
therapies for patients.

Medical-economics certainly has a promising place to
help solve some of the challenges and will likely involve
real-world collection and use of data for use in everyday
practice.

Disclosure of interest

Claire Le Jeunne: former Vice-Chair of the Transparency Commission until September 2011

Jean-François Bergmann: payments received from: Abb-vie, ALK, Astra-Zeneca, Bayer, GSK, Incyte, IQVIA, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi.

The other authors declare that they have no competing
interest.

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