For manufacturers, the HAS submission connects marketing authorisation with the French assessment that informs subsequent reimbursement and pricing decisions. Particularly relevant are the medicine's place in the therapeutic strategy, the comparateur cliniquement pertinent, the quality of comparative evidence, clinically relevant endpoints, and the derivation of the target population.
The HAS submission process in France
The HAS submission leads from filing with HAS through assessment by the Transparency Committee to an opinion that informs subsequent reimbursement and pricing decisions.
Following marketing authorisation, the manufacturer submits the documentation required for the French assessment. The Transparency Committee then conducts the scientific and medical assessment.
The basic process comprises:
- Marketing authorisation of the medicine
- Submission to HAS
- Assessment by the Transparency Committee
- Assessment of SMR, ASMR and the target population
- Opinion of the Transparency Committee (Avis de la Commission de la Transparence)
- Subsequent reimbursement and pricing decisions
The clinical assessment by HAS is therefore part of a broader French market access process. The French process separates the HAS assessment from the subsequent responsibilities for reimbursement and pricing.
The Transparency Committee as the central assessment committee
The Transparency Committee is the specialised HAS committee responsible for the scientific and medical assessment of medicines for reimbursement.
The CT is composed of multidisciplinary experts, including physicians, pharmacists and representatives of patient and healthcare-user organisations. Its opinions are addressed to public decision-makers and are intended to inform decisions on the reimbursement of medicines.
The CT assessment is distinct from the marketing authorisation assessment. EMA and ANSM assess the benefit-risk balance in the regulatory context. The Transparency Committee, by contrast, assesses the medical benefit of the medicine in the French healthcare context and its therapeutic improvement over available alternatives.
The CT does not itself make the final decision on standard reimbursement. Its opinion provides a scientific basis for subsequent decisions.
SMR, ASMR and target population as outcomes of the CT assessment
SMR, ASMR and the target population are central outcomes of the assessment by the Transparency Committee. They address different questions concerning reimbursement, therapeutic improvement and the size of the relevant patient population.
|
Assessment |
Central question |
Relevance |
|---|---|---|
|
SMR |
Does the medicine provide sufficient medical benefit? |
Assessment relevant to reimbursement |
|
ASMR |
What therapeutic improvement does the medicine provide over existing alternatives? |
Assessment of medical added value and framework for subsequent price negotiation |
|
Population cible |
Which patient population is relevant for reimbursement? |
Quantification of the reimbursement-relevant target population |
Service médical rendu (SMR)
The SMR assesses the medical benefit of a medicine in a specific indication. It is particularly relevant to determining whether the medical benefit justifies reimbursement.
Amélioration du service médical rendu (ASMR)
The ASMR assesses therapeutic or diagnostic improvement over existing alternatives. It therefore quantifies the additional medical value of the medicine and influences the framework for subsequent price negotiation.
Population cible
The target population quantifies the patient population for whom reimbursement is relevant on the basis of the CT assessment. It may be narrower than the population covered by the marketing authorisation.
Service médical rendu determines relevance for reimbursement
Service médical rendu assesses whether a medicine provides sufficient medical benefit in a specific indication to justify reimbursement by the French solidarity-based healthcare system.
According to the HAS doctrine, the SMR assessment is based on five determinants:
- Efficacy and adverse effects of the medicine
- Its place in the therapeutic strategy, particularly in relation to other available therapies
- Severity of the disease
- Preventive, curative or symptomatic nature of the medicine
- Public health interest (Intérêt de santé publique, ISP)
The medicine's place in the therapeutic strategy is assessed in the relevant medical context. The CT may position the medicine relative to other available therapies and reassess this position during subsequent reassessments.
SMR is therefore not an isolated assessment of efficacy. Quality of evidence, effect size, tolerability, available therapeutic alternatives and medical need all contribute to the assessment of the medicine.
Sufficient and insufficient SMR
A sufficient SMR generally requires clinically relevant efficacy, an acceptable safety profile and a level of evidence considered sufficient for the medical context. HAS highlights, in particular, an appropriate study design with respect to population, comparator, endpoint and study duration.
Factors that may result in an insufficient SMR include:
- efficacy that is too small, not clinically relevant or insufficiently established
- a negative comparative study
- a comparator that is not clinically relevant without adequate justification
- a non-comparative study when a comparative study would have been feasible
- insufficient transferability of the study population to patients to be treated in France
- an endpoint considered insufficiently relevant to patients
- multiple methodological biases resulting in substantial uncertainty about the true treatment effect
- an effect size that is not clinically relevant
- unacceptable toxicity relative to available alternatives
According to the HAS doctrine, a single such factor may result in an insufficient SMR. The CT nevertheless assesses these factors in the relevant medical context and in light of the available therapeutic alternatives.
ASMR assesses therapeutic improvement
Amélioration du service médical rendu assesses the therapeutic or diagnostic improvement provided by a medicine over existing alternatives. ASMR is therefore a relative assessment of the medicine's additional medical value.
The CT distinguishes five ASMR levels:
|
ASMR |
Classification |
|---|---|
|
ASMR I |
major (majeure) |
|
ASMR II |
important (importante) |
|
ASMR III |
moderate (modérée) |
|
ASMR IV |
minor (mineure) |
|
ASMR V |
no improvement (inexistante) |
The ASMR assessment considers, in particular, the quality of the evidence, additional effect size and its clinical relevance, quality of life, tolerability and medical need.
An ASMR V may result, for example, when no therapeutic improvement has been demonstrated or when the medicine's additional value remains uncertain on the basis of the available data. HAS identifies non-inferiority studies and clinically non-relevant differences, among others, as possible situations in which therapeutic progress has not been demonstrated.
The difference between SMR and ASMR
The difference between SMR and ASMR lies in the assessment question: SMR assesses the medical benefit of a medicine in relation to reimbursement, whereas ASMR assesses therapeutic improvement over existing alternatives.
A medicine may therefore receive a sufficient SMR without demonstrating additional therapeutic improvement. SMR and ASMR are separate but interconnected components of the French pharmaceutical assessment.
The comparateur cliniquement pertinent in the HAS assessment
The comparateur cliniquement pertinent (CCP) is a relevant comparator intervention intended for the same patients and positioned at the same level of the therapeutic strategy as the medicine under assessment. The choice of CCP is particularly important for the relative ASMR assessment.
A comparateur cliniquement pertinent may be an active medicine with or without marketing authorisation for the relevant use, placebo, a medical device, a medical procedure, a non-pharmacological therapy or a diagnostic method.
A medicine available through early access or compassionate access, or used off-label in routine practice, may also be considered a CCP under certain circumstances.
Direct comparative evidence against the CCP
The Transparency Committee expects a direct comparative study against the comparateur cliniquement pertinent whenever such a comparison is feasible.
HAS describes randomised, double-blind controlled trials as the reference standard for pharmaceutical assessment. Randomisation and blinding are intended to ensure comparability between groups and support causal attribution of observed differences to the medicine under study.
Comparator selection and the availability of appropriate comparative evidence are therefore central components of the ASMR assessment.
Indirect comparisons and external controls
Indirect comparisons and external control arms may be considered in justified circumstances when an appropriate direct comparison is unavailable and the alternative comparative method is methodologically robust.
HAS identifies particular populations, rare diseases and situations with limited therapeutic options as examples of contexts in which deviation from the preferred randomised comparison may be justifiable. Single-arm studies with external control arms or other forms of indirect comparison may then contribute to the assessment.
By contrast, if a direct comparison is absent even though the CT considers that it would have been feasible, this may contribute to an ASMR V.
Clinically relevant endpoints in the HAS assessment
The Transparency Committee generally expects a clinically relevant primary endpoint whenever such an endpoint can be collected in a study.
A surrogate endpoint may be considered if its ability to predict an effect on a clinical morbidity or mortality endpoint has been demonstrated in the relevant disease. Intermediate endpoints may also contribute to the assessment depending on the medical context.
HAS cites progression-free survival in oncology, for example, in situations where overall survival cannot reasonably be documented in the short or medium term or where an appropriate predictive relationship has been demonstrated. In certain rare diseases, biomarkers may also be considered when a robust relationship with a clinical endpoint exists.
Statistical significance and clinical relevance
A statistically significant difference is not automatically considered clinically relevant by the Transparency Committee.
The CT assesses effect size relative to the comparateur cliniquement pertinent, particularly in terms of morbidity, mortality, quality of life and tolerability. Clinical relevance refers to whether the observed effect is substantial for patients.
HAS does not define a universal threshold for clinical relevance. Effect size and clinical relevance are assessed in the relevant medical context and in light of medical need.
Quality of life as part of the HAS assessment
Quality-of-life data can contribute to the assessment of a medicine's clinical effect and to the ASMR when they have been collected using a methodologically robust approach.
HAS highlights, in particular:
- validated instruments appropriate to the research question
- objectives and thresholds for clinical relevance prespecified in the study protocol
- appropriate study methodology
- appropriate management of multiplicity
- suitable timing and duration of assessment
- as few missing data as possible
The absence of quality-of-life data may negatively affect the ASMR when such data are expected by the CT. HAS particularly highlights chronic or disabling diseases and end-of-life situations in this context.
Determination of the target population by the Transparency Committee
The Transparency Committee estimates the target population for the patient population for which a sufficient SMR has been established.
The derivation may use epidemiological data, registries, prescription data, hospital activity data, reimbursement data and scientific literature. The CT expects a stepwise derivation of the population eligible for treatment and reimbursement.
Whether incidence or prevalence provides the appropriate starting point depends on how the medicine is used. Incidence may be relevant for a one-off or short-term treatment, whereas prevalence may be required for chronic treatment.
Target population and marketing authorisation population may differ
The target population determined by the Transparency Committee may be narrower than the population covered by the marketing authorisation.
The CT estimates the target population for patients with a sufficient SMR. If sufficient medical benefit is established only for part of the authorised population, the reimbursement-relevant target population may accordingly be restricted to that subgroup.
Real-world data as complementary evidence for HAS
Real-world data can complement the HAS assessment and provide information on the actual use of a medicine and on remaining uncertainties.
Potential data sources include observational studies, registries, French healthcare databases, data from early or compassionate access programmes and post-registration studies. The CT may use such data, among other purposes, to assess real-world use, effectiveness, therapeutic positioning and the target population.
Where uncertainties remain, the CT may request additional data for a subsequent reassessment. Post-registration studies may, for example, document use under routine-care conditions, effectiveness or other outstanding questions.
HAS also makes clear that observational studies do not replace randomised clinical trials when randomised evidence can reasonably be expected. Real-world evidence is assessed in the context of the totality of available evidence.
Early access and the standard HAS submission are separate pathways
The standard HAS assessment for reimbursement must be distinguished from the French early access pathway, the Autorisation d'accès précoce (AAP). Early access enables earlier availability and funding than the standard reimbursement pathway when defined conditions are met.
AAP may be used before or after marketing authorisation. The November 2025 HAS doctrine identifies four central conditions: a serious, rare or disabling disease; the absence of an appropriate treatment; treatment that cannot be deferred; and presumed innovation. For pre-authorisation early access, a strong presumption of efficacy and safety, assessed by ANSM, is also required.
Presumed innovation in the early access pathway does not prejudge the subsequent assessment for standard reimbursement. HAS explicitly distinguishes the early access decision from the later CT assessment for standard reimbursement.
Data generated through the early access programme may nevertheless remain relevant later. For the standard reimbursement assessment, HAS expects the available data from the Protocole d'utilisation thérapeutique et de recueil de données (PUT-RD) to be submitted.
From the Transparency Committee opinion to reimbursement and price
The opinion of the Transparency Committee provides a scientific basis for subsequent reimbursement and pricing decisions for a medicine in France.
The clinical assessment by the CT is separate from the subsequent responsibilities for reimbursement and pricing. In the French process, UNCAM is associated with setting the reimbursement rate and CEPS with price negotiation; final inclusion for reimbursement takes place through the competent public decision-making processes.
SMR and ASMR have different functions in this process. SMR addresses medical benefit in relation to reimbursement. ASMR quantifies therapeutic improvement and therefore contributes to the framework for subsequent price negotiation.
Seven evidence questions for preparing a HAS submission
Preparing a HAS submission requires an early assessment of whether the clinical evidence addresses the central requirements of the Transparency Committee in France.
Manufacturers should consider seven questions in particular:
- Which comparateur cliniquement pertinent is relevant for France?
- Is direct comparative evidence against this CCP available?
- If direct evidence is absent, is this adequately justified and is the alternative evidence methodologically robust?
- Do the endpoints capture a clinical benefit that is relevant to the CT?
- Are relevant quality-of-life data available and methodologically interpretable?
- Is the study population transferable to the population to be treated in France?
- Can the reimbursement-relevant target population be derived transparently from epidemiological and healthcare data?
Comparator selection, endpoints, population and study design are determined during clinical evidence generation. French assessment requirements are therefore relevant well before the eventual HAS submission. Comparing procedures helps with evidence planning: at EU level, the JCA process and the JCA dossier define the requirements of the joint clinical assessment, and Joint Scientific Consultation offers early advice. In Germany, the early benefit assessment follows the AMNOG process and is based on the AMNOG dossier.