France’s ATU reform: early access remains possible, but not all diseases are equal

In July 2021, the French temporary authorisation for use (Autorisation Temporaire d’Utilisation, ATU) programme was the subject of a major reform, initially published within the 2021 healthcare plan on the 14th December 2020 (Article 78 – La Loi de financement de la sécurité sociale, FSSL). Among key changes, the reform introduced the need to meet three criteria: a presumption of innovation compared with the most clinically relevant comparator, an appropriate development plan, and an absence of significant safety or tolerability unknowns¹. 

In the first seven months since this reform, July 2021 to February 2022, 17 new product applications were submitted for an autorisation d’accès précoce (AAP, which includes the previous cohort ATU). Of these, six concerned COVID-19 medications and were submitted in exceptional circumstances. To ensure applicability for the future, these applications were excluded from our analysis. Of the remaining 11, most products submitted for early access were oncology drugs and two products, Adtralza and Rinvoq, for atopic dermatitis³.

France’s temporary authorisation (ATU) programme: reform implications

Most products submitted for the ATU programme to meet all three criteria

As seen in Table 1, most manufacturers were successful in their AAP application, with the Haute Autorité de Santé (HAS) acknowledging most products met all three major criteria (ie, presumed innovation, appropriate development plan, lack of significant safety or tolerability).

An example is Trodelvy, indicated as a second or third line treatment for adult patients with unresectable or metastatic triple-negative breast cancer (TNBC) who have received two or more lines of systemic therapy, including at least one in advanced stage. At the time of AAP submission, Troveldy was already available within the compassionate use programme and under pressure from patient advocacy groups to broaden usage. The HAS viewed the unmet need to be high because of disease severity, supportive mortality data in the wider breast cancer population, and the worse prognosis and higher impact on quality of life of TNBC. The perception of high unmet need was reinforced by the limited survival outcome of the existing standard of care (SoC). The HAS considered the product as likely to be innovative, as a new treatment option for TNBC, with the potential to make a substantial difference in the management of patients demonstrated in a Phase III study versus physicians’ choice of chemotherapy.³

Another example is Abecma, indicated as a treatment for multiple myeloma (MM) adult patients refractory to at least three treatment options (ie, an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38) which was accepted in November 2021. This is an interesting example where non-comparative Phase II clinical data were seen as acceptable because of the concurrent development of comparative studies versus SoC and input of external experts who supported the expected benefit for patients when other treatment options have been exhausted.⁵

Table 1: List of non-COVID related products evaluated by the HAS for the AAP programme between July 2021 and February 2022 (inclusive)

Source: Haute Autorité de Santé. Available from: https://www.has-sante.fr/

Only two out of 11 applications were rejected by the HAS

Adtralza is an example of product that was rejected in October 2021 for the treatment of moderate-to-severe atopic dermatitis in adult patients requiring systemic treatment, in case of contraindication, intolerance, or failure to available treatments. At the time, LEO Pharma’s asset was already available through an Autorisation Temporaire d’Utilisation de cohorte (ATUc), and a re-application was submitted to renew the authorisation granted in June 2021. Although the HAS estimated that there was no significant unknown tolerability issue, they highlighted two important limitations. Firstly, the mechanism of action (MoA) was deemed not innovative and instead similar to the anti-IL4 and anti-IL13 dupilumab; secondly, the HAS criticised the absence of studies supporting clinical benefit in patients who are refractory to all currently available treatment options⁶.

In another example of HAS rejection, Bristol-Myers Squibb (BMS) aimed to renew an ATUc authorisation granted in January and May 2021 for Opdivo and Yervoy. While the first re-application regarding the use of Opdivo and Yervoy as a first-line combination treatment for adult patients with unresectable malignant pleural mesothelioma (MPM) was accepted by the HAS⁷, the second application for the treatment of a subset of adult patients with metastatic colorectal cancer was rejected⁸. The novel modality of management was valued but the lack of comparative pivotal data, limitations of indirect comparison versus SoC, and an inappropriate development plan led to the rejection of the second application. Notably, for the first indication, the manufacturer provided clinical data showing superiority of the combination treatment to SoC in improving overall survival.

What does this mean for pharma?

One may have predicted that the ATU reform would have been associated with higher requirements for ATU access. However, since July 2021, 82 percent of non-COVID-19 related applications (ie, 9 out of 11 applications) were accepted by the HAS. These observations are in line with the conclusions drawn by the HAS in May 2022 showing that 90 percent of applications submitted since the reform led to early access authorisation⁹. Though it might be too early to say, first analyses suggest that the reforms to the French early access programme, while more restrictive, have not significantly impacted patient access.

A generous programme, but with some limitations

The ATU pathway was designed to ensure patients would not suffer unnecessary health technology assessment (HTA) and pricing negotiation delays in accessing innovative treatment for severe diseases with little or no treatment options. While the AAP is an attractive programme for driving early use, the lack of exemptions for evidence development needed in rare diseases may still be a limitation.

Another hinderance is where treatment is prescribed in primary care, and where familiarity with the process and awareness of availability may be more restricted. To illustrate, when Paxlovid, Pfizer’s COVID-19 oral treatment was made available in January 2022 through an AAP and 500,000 doses were ordered by the French government. Less than one percent of these doses had been prescribed three months later¹⁰.

Re-elected earlier this year by the French people, Macron promised to put in motion reforms on healthcare¹¹. Having previously driven the July 2021 ATU reform, is this already time to adapt the AAP system?

References

1. LOI n° 2020-1576 du 14 décembre 2020 de financement de la sécurité sociale pour 2021 (1) [Internet]. gouv.fr. 2020. Available from: https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000042665307
2. Matthews, C., Stefani, S., Urruticoechea, P. (2021), France’s temporary authorisation (ATU) programme: reform implications. Available here. 
3. Haute Autorité de Santé. Available from: https://www.has-sante.fr/
4. Haute Autorité de Santé (2021), Avis sur les médicaments – Trodelvy. Available from: https://www.has-sante.fr/upload/docs/application/pdf/2021-09/trodelvy_ap_aut_avisdef_ctap5_2021-09-06_10-58-55_480.pdf
5. Haute Autorité de Santé (2021), Avis sur les médicaments – Abecma. Available from: https://www.has-sante.fr/upload/docs/application/pdf/2021-12/abecma_aap_postamm_avisdef_ctap14_.pdf
6. Haute Autorité de Santé (2021), Avis sur les médicaments – Adtralza. Available from: https://www.has-sante.fr/upload/docs/application/pdf/2021-11/adtralza_ap_aut_postamm_avis_ctap12.pdf
7. Haute Autorité de Santé (2021), Avis sur les médicaments – Opdivo & Yervoy. Available from: https://www.has-sante.fr/upload/docs/application/pdf/2021-09/opdivo-yervoy_ap_aut_postamm_avisdef_ctap6.pdf
8. Haute Autorité de Santé (2021), Avis sur les médicaments – Opdivo & Yervoy. Available from: https://www.has-sante.fr/upload/docs/application/pdf/2021-10/opdivo_aap_postamm_pic_avisdef_ctap7.pdf
9. Haute Autorité de Santé (2022), Autorisation d’accès précoce aux médicaments : un premier bilan positif et des principes d’évaluation affinés. Available from: https://www.has-sante.fr/jcms/p_3340090/fr/autorisation-d-acces-precoce-aux-medicaments-un-premier-bilan-positif-et-des-principes-d-evaluation-affines
10. Rosier, F. (2022), Le Monde. Available from: https://www.lemonde.fr/planete/article/2022/04/06/le-demarrage-rate-de-la-pilule-anti-covid-de-pfizer_6120768_3244.html
11. Politics desk (2022), Le Monde. Available from: https://www.lemonde.fr/en/2022-presidential-election/article/2022/04/24/macron-s-top-priorities-for-education-health-and-retirement-if-he-is-elected_5981492_16.html