The Temporary Authorization for Use (ATU) program allows access before completion of P&R negotiations. This article examines the recent changes in France’s early access program and its implications for manufacturers’ European P&MA strategy.
Time to access in France, with an average duration of 209 days (2018 CEPS report) after marketing authorization in 2018, continues to exceed the European directive of 180 days. The Temporary Authorization for Use (ATU) program allows access before completion of P&R negotiations. Since its implementation in 1994, the ATU program has garnered symbolic importance, and today serves as an emblem of France’s pioneering position in this field. Although this program represents an opportunity for patients and pharmaceutical companies alike, manufacturers must carefully consider the impact on their future negotiated prices in France and in other European countries when setting prices for ATU drugs. This is even truer considering this program has been on French health authorities’ radar for the past few years and has been subject to increasingly strict pricing rules, in particular with the recent repeal of the free pricing policy for nominative ATU.
Figure 1: Comprehensive overview of cohort ATUs granted in 2018 per therapeutic area.
ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; aPTT: acquired thrombotic thrombocytopenic purpura; nmCRPC: Non-metastatic castration resistant prostate cancer: DLBCL: Diffuse Large B cell Lymphoma; NSCLC: non-small cell lung cancer; PMBCL: Primary mediastinal B-cell lymphoma; VWD: von Willebrand disease
What is the ATU program?
ATU status is granted by the French National Agency for Medicines and Health Products Safety (ANSM) to promote fast access to innovation, before marketing authorization and conventional pricing and market access process completion. In order for a drug to be granted ATU status, three key criteria must be met:
- The drug must be intended for a serious or rare indication
- There must be no other appropriate therapies available for this indication in France
- The drug must have presumed efficacy and safety in light of the available scientific data, and the treatment cannot be delayed for patients
Within this program, two types of ATU can be granted. A nominative ATU (nATU) is for one specific identified patient at the request of his or her physician. A cohort ATU (cATU) is designated for a group of patients at the request of the drug manufacturer (with requirements and eligibility criteria differing slightly between the two). ATUs allow early access for thousands of patients each year; roughly 22,000 patients benefited from the ATU program in 2018 alone including over 230 different drugs (2018 ANSM annual report – nATUs: 217 drugs and 15,987 patients; cATUs: 20 drugs and 5,642 patients) which underscores just how extensive the program is. The ATU program was initially designed to guarantee early access mainly to new HIV therapies, but now mostly covers oncology and hematology products as well (see Figure 1).
ATU status to post-ATU status: what are the implications?
Once a product has its marketing authorization (MA), it loses its ATU status. The manufacturer must then submit a request for reimbursement for the licensed indication within one month in order to benefit from post-ATU status, which enables funding during the P&R process and ensures continuous access for patients.
During the post-ATU phase, the product goes through Transparency Committee (TC) assessment and then through pricing negotiations based on the SMR and ASMR ratings granted by the TC. The ATU phase may support favorable reimbursement by providing real-world evidence (though this is not often taken into account in the TC’s evaluation due to insufficient data quality), and also by generating experience and familiarity within the clinical and patient community.
The length of the post-ATU phase heavily depends on the context of broader P&R negotiations (price level requested by the manufacturer, existence of price benchmarks, etc.).
Figure 2: Time between MA and price publication (i.e., post-ATU status) – in days. Comprehensive list of drugs with a post-ATU status start after 2014 and end before November 2019
For some ATU drugs, such as Yescarta, the P&R process can be rather quick, and may be completed within a year of their MA. However, the average post-ATU status duration is approximately 630 days1 (see Figure 2) , which is significantly longer than the average time of 209 days (2018 CEPS report) between marketing authorization and P&R completion in 2018, despite the priority review given to these drugs by the TC.
By their very nature, ATU drugs address diseases with high unmet need for which there may not be any alternative treatment available, implying a lack of price benchmarks and comparators which often results in challenging and lengthy price negotiations with the Economic Committee for Health Products (CEPS). Therefore, benefiting from the ATU/post-ATU status is a key advantage for manufacturers, as it prevents major delays in products’ commercialization. It also contributes to explaining why the post-ATU phase is longer than average. The fact that patients already have early treatment access implies limited pressure for health authorities to complete the P&R process quickly and may be another explanation for the longer P&R process of ATU drugs.
Figure 3: Time since MA for selected products that have not completed their pricing negotiations by November 2019 – in days. Selected list of drugs with a post-ATU status effective date starting in 2014
There are several products that have remained in post-ATU status for more than two years. Among these products, there are some drugs that are still in ongoing P&MA negotiations (see Figure 3), while others have paused CEPS price negotiations or may be waiting for new data and re-evaluation by the TC.
One gap from post-ATU status was the impossibility to benefit from this early access program without having previously been under ATU status (i.e., there was no possibility
of applying after the granting of marketing authorization). This gap was addressed by the December 2018 legislation Article 65 (application decree published in August 2019), which enables drugs that are not under cATU to benefit from early access through post-ATU status.
Increased scrutiny and pricing regulation for ATU drugs
The ATU scheme has progressively become a structured early access program for large volumes of patients, whose cost to health insurance has been significantly increasing over the past years and now exceeds €1 billion per year. This brought the ATU program onto payers’ radar, and resulted in the implementation of multiple recent initiatives from French authorities to control this program more closely in order to guarantee its sustainability.
Additional monitoring mechanisms/conditions
The recently-passed annual French Social Security Financing Law (LFSS) for 2020 implemented additional monitoring mechanisms/conditions for nATUs. Eligibility criteria for nATUs are now stricter and more in line with those for cATUs; for instance, drug efficacy and safety must be “strongly presumed” (instead of “presumed to be favorable”), and clinical trial programs must be “ongoing” in France (instead of “ongoing or planned”).
On top of that, there will be a cap set by the Ministry of Health (MoH) and Social Security on the number of nATUs authorized per product. Notably, once a product has reached the nATU cap, which is yet to be defined, the manufacturer is still able to apply for cATUs for that product.
ATU annual sales capping
Currently, the ATU and post-ATU programs are 100% funded through the Social Security Pharmaceutical Innovation Fund (similar to T2A-excluded and retrocession drugs). The manufacturer can supply drugs under ATU/post-ATU status for free or freely set a price. It is also possible for a manufacturer to decrease or increase the ATU/post-ATU price; for instance, Ledaga took a ~40% price increase post-ATU after transitioning from Actelion to Recordati, highlighting the degree of flexibility granted to manufacturers in regards to ATU pricing so far.
However, for ATU drugs exceeding €30 million in annual sales during the ATU or post-ATU period, a “cap” of €10k/patient/year is set for the net price, and everything above the cap is paid back. This capping rule was part of the LFSS 2017, and was created as a tool to control the ATU free pricing policy. As a result, manufacturers must carefully monitor ATU sales and manage their cash flows accordingly. So far, however, this threshold has not been reached.2
Repeal of the free pricing policy for nATU
With the recent approval of the LFSS 2020 (applicable as of March 2020), the government decided to repeal the “free pricing” law, leaving the MoH to unilaterally determine compensation rates for nATU drugs (existing drugs pricing rules should still apply, though real-life implementation remains to be seen). Manufacturers should still be able to freely set the price charged to the hospitals, but will have to pay back the difference versus the compensation amount set by the MoH. This decision was driven by the high prices set for some nATU drugs (i.e., up to ~€2,000,000 for one injection), which significantly increased the ATU budget impact and raised concerns regarding the financial sustainability for the health system. Despite this change, free pricing will still apply for cATU drugs.
This legislative change will likely have a negative impact on the pharmaceutical industry in France, since these compensation determinations may set new, lower benchmarks for future price negotiations with the CEPS.
ATU and post ATU price: a ceiling for negotiated prices?
The ATU price is referred to as a starting point (and likely as a price ceiling) during negotiations with the CEPS. An analysis of ATU drug prices before and after CEPS negotiations shows that the negotiated price is usually significantly lower than the ATU price (see Table 1), with an average price decrease of 17%.
The price decrease tends to be larger for drugs with ASMR IV/V (~20%) than those with ASMR I-III (~10%), likely resulting from the International Price Referencing (IPR) guarantee granted to ASMR I-III drugs (which assures that the price cannot be lower than the lowest price in Germany, Italy, Spain and the UK). However, no clear pattern can be outlined between ASMR rating and level of negotiated price discount, since the latter mainly depends on the manufacturer’s ATU pricing strategy. In rare cases (e.g. if IPR applies), the negotiated price could be set above the ATU price (e.g. Lutathera, where the negotiated price was a 26% premium vs. ATU price).
If the price negotiated with the CEPS is lower than the ATU price, the manufacturer can be asked to pay back all or part of the difference between the ATU price and the reference net price (calculated based on a 3-year sales forecast including all negotiated paybacks). And in the case where no agreement is reached during pricing negotiations or if the drug is not reimbursed in France, the CEPS can decide alone on a reference price and then ask the company to pay back the entire difference from the ATU price for previous sales.
Taking all of this into consideration, manufacturers should consider how the ATU price will impact the final negotiated price. Manufacturers should also be cautious and may need to expect paybacks depending on their ATU pricing strategy; the CEPS continually faces issues collecting paybacks from manufacturers who did not anticipate this possibility in their budgets. However, the LFSS 2020 has expanded on potential solutions for manufacturers struggling with paybacks by providing the option to pay in installments over two years, or to renegotiate for up to 3% payback relief.
Table 1: Differences between ATU prices and CEPS negotiated prices in France. Comprehensive list of products with both ATU prices and negotiated list prices published between 2017 and November 2019 (ATU drugs provided for free were not considered in the pricing analysis); SMR: Medical benefit rating; ASMR: Therapeutic improvement rating over existing treatments; ASMR II: important; III: moderate; IV: weak; V: no therapeutic improvement
ATU for indication expansions: a new opportunity for early access
As of August 2019 (publication of the December 2018 Article 65 application decree), ATU status can now be granted for products undergoing indication expansions, as opposed to only for initial launch indications as was previously the case. This measure, designed specifically with cancer immunotherapies in mind (due to their efficacy across multiple cancers and promising indication expansions), addresses a major gap in the ATU program and should allow for additional early access to innovative products.
ATUs for indication expansion drugs and initial launch indication drugs have similar eligibility criteria, but vary significantly in regards to pricing. The selling price for an ATU indication expansion is the existing public price for the already reimbursed indication(s). At the net price level, similarly to the future new pricing rules for nATU, the MoH sets the compensation amount (which is only applicable to units sold under the ATU indication expansion, with tracking enabled by the hospital delivery or administration of ATU products).
Once indication expansion ATU status is granted and the request for compensation is submitted, the manufacturer is notified of the total compensation amount within 45 days, with no possibility to negotiate. The same rules described previously apply in the case where the negotiated price ends up being below the compensation amount; the difference between the public price and the total compensation per unit must be paid back at the end of the year.
Although this unilaterally-set compensation may be considered by the CEPS, its impact on the drug's current price remains uncertain.
A few drugs are currently under indication expansion ATU (see Table 2) and have been provided by manufacturers for free. Some of these manufacturers submitted a request for compensation to the MoH following the publication of the decree in October 2019 specifying the documents and information to be included in the compensation request dossier.
|Dupixent||Adolescent atopic dermatitis|
Table 2: Example of drugs under indication expansion ATU as of November 2019
ATU price considerations: how is Europe affected?
For the last few years, ATU prices have been published on the MoH’s website. The published price is the maximum amount of compensation that the manufacturer charges to hospitals, with price publication occurring three times per year. These prices are referenced at the national level by the CEPS during negotiations, but they may also be used as benchmarks by other countries within the IPR. As a result, when building the French ATU P&MA strategy, manufacturers should not only consider the price potential of their drug in France, but also its price potential in other EU countries, in order to make sure that the ATU price set in France will not jeopardize price potential throughout the region.
Although there is a general trend where manufacturers adapt their French ATU pricing strategy based on their European/Germany pricing strategy, important price differences are observed for some products. For more than half of ATU drugs, the price in Germany before AMNOG (free pricing) was roughly in-line with the French ATU price (+/-10% difference)3. Accordingly, the average percentage decrease between free and negotiated prices in Germany versus France is roughly the same (22% in GE vs. 17% in FR)4.
Overall, the ATU program allows access before the completion of P&R negotiations, accelerates treatment uptake, and enhances French physicians’ familiarity with the treatment ahead of a drug’s official launch. However, the ATU program is currently undergoing significant changes, particularly in regards to eligibility criteria and pricing. Some of these aspects are still uncertain and are being discussed (e.g., the exact approach and process for compensation-setting of nATUs and indication expansion ATUs). Lastly, with the French authorities becoming stricter towards the ATU program, there is a distinct possibility that the MoH compensation structure for nATUs could be extended to cATUs, which would further alter the pricing landscape for ATU drugs and likely trigger fierce resistance from the pharmaceutical industry. In all, the ATU program merits early, thorough consideration for local and European P&MA strategy.
1 Average time between marketing authorization and post-ATU expiration date of all ATU drugs with a post-ATU effective date between 2014 and November 2019.
2 Threshold not hit in 2017 nor in 2018 – information not publicly available for 2019.
3Analysis of the price difference between Germany launch visible net ex-manu price (source: LAUER-TAXE) and French ATU price (source:MoH) for a selection of drugs with both prices published.
4Average % discount between ATU price and negotiated list ex-manu price in France vs. average % discount between launch and post-AMNOG visible net ex-manu prices in Germany for the same selection of drugs having all prices published.
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