New Early Access and Off-Label Use Rules in France

On 1 July 2021, the new French rules on early access to unauthorized medicinal products and off-label use of authorized medicinal products entered into force.  The rules were introduced by the Social Security Financing Law for 2021 (LOI n° 2020-1576 du 14 décembre 2020 de financement de la sécurité sociale pour 2021 or “LFSS 2021”, available here).  The reform seeks to simplify existing rules, make early access and off-label use more predictable for all users, and ensure the sustainability of these programs for the public health insurance system.  In this blog, we present an overview of the new rules.

From ATU, post-ATU, and RTU to AAP, AAC, and CPC

Prior to 1 July, early access and off-label use were regulated through 6 interlinked programs:

• The main early access program was the temporary use authorization (Autorisation Temporaire d’Utilisation or “ATU”), for access by a named patient (ATU nominative or “ATUn”) or a group of patients (ATU de cohorte or “ATUc”). The ATU was introduced in 1992, in response to the HIV outbreak.  The ATU rules were amended over time.
• In 2014, the interim “post-ATU” program was introduced to ensure continued access to the product in ATU conditions after a marketing authorization was granted, but before the decision on the reimbursement of the authorized product by the public health insurance system.
• Early access was further expanded in 2019. The “direct access to post-ATU” (accès direct au post-ATU) opened post-ATU to authorized products that had not obtained an ATU, prior to the decision on their reimbursement.  The “ATU for a new therapeutic indication” (ATU pour extension d’indication) opened ATU to therapeutic indications not covered by the product’s marketing authorization.
• A system for regulating off-label use of authorized medicinal products under a temporary use recommendation (Recommandation Temporaire d’Utilisation or “RTU”) was put in place in 2011. It was broadened in 2012 and 2014 to allow endorsement of off-label use also for economic reasons.  It was, for instance, used to formalize off-label use of bevacizumab to treat macular degeneration.

Subject to transitional provisions (detailed below), Article 78 of the LFSS 2021 replaces the ATU, post-ATU and RTU programs by two distinct regimes:

• Early access: the early access authorization (autorisation d’accès précoce or “AAP”) allows the use of an innovative medicinal product for which the manufacturer agrees to apply for a marketing authorization or, if already authorized, to submit a request for reimbursement (Article L. 5121-12 I. of the Public Health Code or “PHC”, as amended). The pre-marketing authorization AAP replaces the cohort ATU, and the post-marketing authorization AAP replaces the post-ATU.
• Compassionate access: there are two types of compassionate access schemes. The compassionate access authorization (autorisation d’accès compassionnel or “AAC”) and the compassionate access framework (cadre de prescription compassionnel or “CPC”).  These allow the use of a medicinal product that is not necessarily innovative or initially intended to obtain a marketing authorization, but which meets a therapeutic need (Article L. 5121-12-1 I. PHC).  The AAC replaces the nominative ATU, and the CPC replaces the RTU.

A new role for the Haute Autorité de la Santé

The French Medicines Agency (Agence nationale de sécurité du médicament et des produits de santé or “ANSM”) was responsible for the ATU and RTU, with subsequent reimbursement decisions.  Now, the AAP will be granted and administered by the main HTA authority (Haute Autorité de Santé or “HAS”), at the request of the interested pharmaceutical company (Article L. 5121-12 III. PHC).  For the pre-marketing authorization AAP, the ANSM is however responsible for the assessment of the safety and effectiveness of the product.  The ANSM remains responsible for both compassionate access programs.  The AAC is requested by the prescribing healthcare professional (“HCP”), and the CPC is requested by the Ministry of Health or set up on the ANSM’s own initiative (Article L. 5121-12-1 II. and III. PHC).

The AAP: a new “presumption of innovation” condition

The conditions for the grant of an AAP mirror the conditions of the cohort ATU.  These conditions are (Article L. 5121-12 I. 1° to 3° PHC):

• the patient is affected by a serious, rare, or disabling disease; and
• no appropriate treatment exists; and
• the treatment cannot be delayed, and
• there is a strong presumption that the product is effective and safe based on the results of therapeutic trials.

However, the reform introduces an additional condition for the AAP, that will likely restrict the types of products eligible for early access, as compared to the cohort ATU.  The product must be “presumed to be innovative, including with regard to a potential clinically-relevant comparator” (Article L. 5121-12 4° PHC).  In guidance (available here), the HAS specifies that a product is presumed innovative if it meets three conditions:

• it represents a new treatment modality for the disease, that brings a “substantial change” to patients (g., in terms of quality of life or convenience of use); and
• it has an appropriate development plan and presents clinical results that support the presumption of a benefit to the patient; and
• there are no significant “unknowns” relating to safety or other important data.

The AAP: more predictable timelines

Before the reform, the ANSM was not bound to take a decision on ATU applications within a set period.  The HAS now has three months from the notification that the AAP application is complete to communicate its decision (Article R. 5121-69 I. PHC).  The company must also agree to make the product available within two months following the grant of the AAP (Article R. 5121-68 II. 12° PHC).

The AAC and CPC: limited to products in indications not under commercial clinical research

The AAC and CPC share the following conditions (Article L. 5121-12-1 I. PHC):

• the medicinal product is not the object of a clinical research (recherche impliquant la personne humaine) for commercial purposes; and
• no appropriate treatment exists; and
• clinical data (which can be “work and data collected by HCPs”) in case of rare diseases) support at least a presumption of effectiveness and safety of the product.

The condition on the absence of commercial clinical research is new.  The ANSM very recently specified that the condition applies only to research in the relevant indication, and that clinical research conducted outside of the EU should also be considered.  It remains unclear, however, whether the condition applies only to the group marketing the product or more widely, also covering repurposing research by independent companies.

In certain cases, exemptions from the conditions can apply:

• Especially relevant is the possibility to adopt a CPC also when there is already an appropriate treatment, provided the product that will be used off-label “at least as well” meets the patient’s needs (Article L. 5121-12-1 III. §2 PHC). This allows again for an economic off-label regime, with the repurposing of active substances.
• An AAC may be granted if research is at a very early stage, in order to meet a patient’s urgent, unmet medical needs and provided the company undertakes to submit an AAP application as part of the AAC application. This is “very early compassionate access”, or accès compassionnel très précoce (Article L. 5121-12-1 II. §2 PHC).

Clearer patient monitoring and data collection obligations

The obligation for the company to adopt and comply with a protocol for therapeutic use and the monitoring of patients (“PUT”) is maintained for the AAP, AAC, and CPC.  The PUT provides a framework for the collection of data on efficacy, adverse effects, real conditions of use and the characteristics of the population treated with the product (Articles L. 5121-12 IV. and L. 5121-12-1 V. PHC).

The PUT obligation is waived for the CPC if there is sufficient hindsight on the conditions of use of the medicinal product in the relevant indication, or when a comparable medicinal product authorized in that indication exists.  This was also the case for the RTU.

The HAS is developing guidance on the PUT for products under AAP.  It specified (see guidance linked above) that patients will be better integrated in the implementation of the PUT through the use of patient-reported outcome measures (“PROMs”), defined by the company together with patient organizations.

Pricing and reimbursement: revised rules on rebates

The AAP

As a general principle, a product under AAP can be provided either free of charge or for a freely-set maximum fee (indemnité).  The fee must be declared to the inter-ministerial Economic Committee for Health Products (Comité économique des produits de santé or “CEPS”) after the grant of the AAP, and is subject to a double system of rebates (Article L. 162-16-5-1 I. of the Social Security Code or “SSC”).  These principles also applied in the context of the ATU.

However, the rebates are now calculated differently (Article L. 162-16-5-1-1 II. A. and III. SSC), to improve predictability:

• A first rebate, applied on a yearly basis, depends on the sales amount (chiffre d’affaires) billed to healthcare establishments for the product in the indication covered by the AAP. The rebate follows a progressive scale, set in the Ministerial Order of 1 July implementing Article L. 162-16-5-1-1 SSC (available here).  It replaces the rebate equal to the amount above a fee of 10 000 euros per patient and per year, for products for which the turnover per year was greater than 30 million euros.
• A second rebate, applied retroactively, is equal to the difference between the sales amount billed during the AAP (less the above rebate), and the sales amount that would have been billed for that period had the final negotiated price of the product (the net reference price or prix net de référence) been applied. For the ATU, this rebate was instead based on projected sales over a three-year period.

As part of the new measures, the first rebate may be increased in certain circumstances, e.g., if the company fails to submit a MAA for the product under pre-marketing authorization AAP (Article L. 162-16-5-1-1 II. B. SSC).

The AAC and CPC

The pricing and reimbursement of the product under AAC or CPC will depend on whether it is reimbursed in another indication.  In this case, the price and reimbursement rate applied to the product in this indication will be applied to the product in the indication covered by the AAC or CPC (Article L. 162-16-5-2 II. A. SSC).  If not, and no annual flat rate has been defined by Ministerial Order, the company if free, as a general principle, to set a fee declared to the CEPS.

However, the fee now is subject to the first rebate detailed above, using the progressive scales set out in the Ministerial Order of 1 July implementing Articles L. 162-16-5-2 SSC (available here) depending on whether the product is under AAC, CPC, or very early compassionate access.  This rebate may be increased in certain circumstances (Article L. 162-16-5-2 II. B. and III. A. and B. SSC).

There are revised rules to ensure continued access for ongoing treatments, which now also cover the use of a product off-label under CPC.

Transitional provisions

Detailed transitional provisions organize the entry into force of the new rules (Article 78 IV. LFSS 2021, Article 4 of Decree n° 2021-869 of 30 June 2021 on early and compassionate access authorizations (available here).  As to ongoing authorizations,

• Ongoing ATUs are subject to the rules in force before 1 July 2021. However, renewal is not possible.
• Ongoing post-ATU are subject to the new rules.
• Ongoing RTUs automatically fall under the CPC since 1 July 2021 and until their end date, but will be submitted to the pricing and reimbursement rules in force before 1 July 2021.

Early access and off-label use terminology under the new rules and the old rules