The requirements for a Transparency Dossier are not defined by its formal structure alone. The key question is whether the submitted evidence robustly addresses the assessment questions of the Transparency Committee. This includes the comparateur cliniquement pertinent (CCP), comparative evidence, clinically relevant endpoints, quality of life and the derivation of the French target population.
The Transparency Dossier as the evidence base for HAS assessment
The Transparency Dossier provides the Transparency Committee with the information and evidence required to assess a medicine for standard reimbursement in France.
On this basis, the CT assesses medical benefit, therapeutic improvement over existing alternatives and the reimbursement-relevant target population. Key outputs include SMR, ASMR and the population cible.
The Transparency Dossier is the manufacturer's submission; the HAS submission is the assessment process in which the CT evaluates that information and evidence.
Structure of the Transparency Dossier
The Transparency Dossier combines regulatory information, the medical and treatment context, clinical evidence and the manufacturer's proposed assessment of the medicine.
Its central areas include administrative and regulatory information, medical context and therapeutic strategy, clinical evidence, and manufacturer claims for SMR, ASMR and the target population.
Administrative and regulatory information in the Transparency Dossier
Core information includes details of the medicine, regulatory status, authorised indication and dosing.
Medical context and therapeutic strategy in the Transparency Dossier
The medical context describes the disease, current standard of care, medical need and the intended place of the new medicine in the therapeutic strategy.
Clinical evidence in the Transparency Dossier
Clinical evidence includes data on efficacy, tolerability, relevant endpoints, quality of life and comparative performance against treatment alternatives relevant in France.
SMR, ASMR and target population as manufacturer claims
The dossier includes the claimed SMR, claimed ASMR and derivation of the target population. The CT reviews these claims against the submitted evidence.
Medical need in the Transparency Dossier
Medical need is assessed in the context of the disease, available treatment options and the quality of existing care.
HAS distinguishes between partially met and unmet medical need. Medical need may inform SMR and ASMR, but it does not establish therapeutic improvement on its own.
The comparateur cliniquement pertinent in the Transparency Dossier
The comparateur cliniquement pertinent (CCP) is an intervention positioned at the same level of the therapeutic strategy and intended for the same patients as the medicine under assessment.
A CCP 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. Early-access, compassionate-access and certain off-label therapies may also be relevant.
The key question is whether the evidence enables comparison with treatment alternatives that are clinically relevant in France at the time of assessment.
Comparative evidence in the Transparency Dossier
The Transparency Committee generally expects direct comparative evidence against a comparateur cliniquement pertinent whenever such a comparison is feasible.
Randomised, double-blind controlled trials are the methodological reference standard. The quality of comparative evidence is particularly relevant to ASMR.
Direct comparative evidence against the CCP
A direct comparative study against the relevant CCP provides the methodologically preferred basis for the relative assessment of a medicine.
It is therefore important to determine whether the comparator used in clinical development remains a relevant CCP for France at the time of HAS assessment.
Indirect comparisons in the Transparency Dossier
Indirect comparisons may contribute to the HAS assessment when no direct comparison is available, the absence of direct evidence is adequately justified and the methodology supports a robust comparative conclusion.
Key methodological expectations include a prespecified protocol and statistical analysis plan, justified populations and comparators, clinically relevant endpoints, appropriate prognostic factors and effect modifiers, suitable data sources, sensitivity analyses and transparent reporting.
External control arms for single-arm studies
Single-arm studies with external control arms may be considered under certain conditions but require stronger methodological justification.
Real patient-level data from registries or databases and appropriate adjustment methods may support external comparisons. Simulated data are not considered suitable confirmatory comparative evidence.
Clinically relevant endpoints in the Transparency Dossier
The Transparency Dossier should present endpoints that capture a clinically relevant treatment effect for patients and support a robust assessment.
Clinical endpoints
Clinical endpoints directly reflect the effect of treatment on patients' health status.
Surrogate endpoints
A surrogate endpoint may be relevant when its ability to predict an effect on a clinical endpoint has been sufficiently established.
Intermediate endpoints
Intermediate endpoints without fully validated surrogacy may contribute to the assessment depending on the medical context.
Effect size and clinical relevance in the Transparency Dossier
A statistically significant difference is not sufficient for the HAS assessment if the observed effect is not clinically relevant to patients.
The CT assesses additional effect size relative to the CCP, particularly in terms of morbidity, mortality, quality of life and tolerability. HAS does not define a universal threshold for clinical relevance.
Quality-of-life data in the Transparency Dossier
Quality-of-life data can contribute to the assessment of clinical effect and ASMR when their collection has been planned and conducted using a methodologically robust approach.
Relevant considerations include validated instruments, prespecified objectives and thresholds for clinical relevance, appropriate study methodology, management of multiplicity, suitable assessment timing and as few missing data as possible.
The absence of expected quality-of-life data may negatively affect ASMR.
Derivation of the target population in the Transparency Dossier
The target population should transparently derive the number of patients eligible for treatment within the requested reimbursement scope.
Potential sources include epidemiological data, registries, prescription data, hospital activity data, reimbursement data and scientific literature.
Target population and marketing authorisation population may differ
The French target population may be narrower than the authorised population because the CT estimates the target population for the population in which SMR is considered sufficient.
Real-world data in the Transparency Dossier
Real-world data can complement the evidence, particularly regarding actual use, effectiveness, therapeutic positioning and the target population.
Potential sources include observational studies, registries, French healthcare databases, early- and compassionate-access data and post-registration studies. Observational evidence generally does not replace randomised evidence when such evidence can reasonably be expected.
Data from French early access
Data generated under an Autorisation d'accès précoce may subsequently contribute to the standard Transparency Dossier.
Data collected through the Protocole d'utilisation thérapeutique et de recueil de données (PUT-RD) may complement the subsequent standard reimbursement assessment.
Organisational impacts in the Transparency Dossier
Organisational impacts may be relevant when a medicine changes the organisation of care, required resources or the patient pathway.
HAS distinguishes impacts on the care process, on the capacities and competencies required to deliver care, and on society or the wider community. Relevant positive and negative impacts should be identified and, where possible, substantiated.
Transparency Dossier, SMR and ASMR are directly connected
The evidence presented in the Transparency Dossier provides an important basis for the CT assessment of SMR, ASMR and the target population.
Medical context and medical need
→ Characterisation of the disease, current care and treatment need
Comparateur cliniquement pertinent
→ Definition of the relevant comparative context
Clinical evidence and endpoints
→ Assessment of efficacy, tolerability and quality of the evidence
Effect size, clinical relevance and quality of life
→ Assessment of additional clinical value
Epidemiology and healthcare data
→ Derivation of the population cible
Eight evidence questions before submitting the Transparency Dossier
- Has the comparateur cliniquement pertinent relevant for France been fully identified?
- Is direct comparative evidence against the relevant CCP available?
- Is the absence of a direct comparison adequately justified?
- Are indirect comparisons or external control arms methodologically robust and appropriately documented?
- Do the endpoints capture a clinical benefit relevant to the CT?
- Are effect size, clinical relevance and quality of life adequately presented?
- Is the target population transparently derived?
- Are relevant real-world or early-access data included?
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.