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French Early Access Compassionate Use Program ATU : Still an Eternal Flame ?



When I start working on French Compassionate Use Program ( ATUs ) in my current work , I was frustrated not to find a synthesis document included all ATU lifetime stages : history ,HAS evaluation , funding , pricing data et caetera. This article is meant to be a synthesis of recent french' s ATU documents for all people working on it .
French Early Access Compassionate Use Program : Still an Eternal Flame ?
Haering , Michel - Actelion Pharmaceuticals France - EMAUD final work - 2017- 2018
July 2019
The Pharmaceutical World is dominated by the arrival of major therapeutic innovations, which
challenges the French regulatory framework, requiring to balance early market access while
maintaining financial sustainability of its health insurance system.
This article provides a synthesis of recent ATUs’ data from World War II to the current 2019 French
Act on Health Insurance Act - LFSS 2019
€1 billion is needed to develop a new drug application , from discovery to Marketing Authorization
(MA)1. Market Access time in Europe remains a significant hurdle from obtaining the MA to full
reimbursement: in France, this time is 530 days, while in Germany2 it is 106 days (Figure I), and
even while a European Directive (89/105/EEC) requires a 180-day period3: 90 days for
reimbursement fixing and 90 days for price fixing.
This 530 days French period does not include products that have previously benefited from the
Temporary Use Authorization system (ATU). When focusing only on these products, they were
available for patients 210 days before the MA, but only for 10% of the target population (LEEM
estimate). For all patients to have access to it, it is necessary to wait for the procedure between the
pharmaceutical companies and the Health Authorities to be completed. This time can even reach
630 days for anti-cancer drugs and 551 days for orphan diseases’drugs4
Thus, the average time to market access in France is then reduced to 500 days if ATU drugs are
included, which is still much longer than in other European countries.
In the case of innovative drugs, time is a major risk factor, because failure can occur at any stage of
development and even once Marketing is authorized. For a drug placed on the market, 10,000
molecules will have been screened, 100 will have been the subject of a pre-clinical trial and only 10
will have been selected as a candidate in human clinical trials.
This process takes 12 years5. This time is particularly long, for example, the development cycle is 6
to 8 years in aeronautics and 2 years in food6.
Certain urgent situations involve the vital prognosis of patients and de facto require the use of
treatments that are not yet registered, this is particularly the case of orphan diseases where the
number of drugs remains very low, early access to innovative therapies becomes a crucial issue for
patients who unfortunately do not have the time to wait for treatment or do not match the criteria
of a clinical trial.
An ATU is a Temporary Authorization for Use. This procedure, specific to France is derogatory and
strictly regulated by the ANSM. It allows certain categories of specific patients to use medicinal
products that have not yet been placed on the market when there is a therapeutic need not covered
for rare or serious diseases.
In 2018, the therapeutic areas most concerned are cancer, CNS, metabolic diseases, cardiovascular
and hematology and we note that there are currently only 2 ATUs in the field of gene therapy while
cancer research is prolific7.
The different types of ATU
ATUs are the result of the evolution of the history of the drug and its pharmaceutical and clinical
The GIPP (Groupement d'Importation des Produits Pharmaceutiques - Pharmaceutical Products
Import Group), created during the Second World War, made it possible to supply hospital
pharmacies with medicines not marketed in France but available abroad... Only few medicines were
concerned and a simple certificate was sufficient for the doctor who took full responsibility for
treatment, under the control of the Central Pharmacy Service, then in 1965, submitted to the
Ministry of Public Health for approval with technical advice from consultants. After the dissolution
of the GIPP in 1973, only the “Pharmacie Centrale des Hôpitaux de Paris” was authorized to acquire
imported medicines for the needs of any hospital in France. This derogation procedure will be
extended to all Pharmacies for domestic use until 19828.
The AIDS epidemic in the 85 90’s raised a real public health problem, seeing patients organize
themselves and become a real political issue at the international level. Organized in associations,
sensitized to medical information by the media, they set an extreme pressure on Public Authorities,
created an awareness and demanded that treatments, even while they were still under investigation,
be made available for them. In 1987, the first AZT therapy was available but it was very expensive
($10,000 for one year of treatment) this price, moreover, would mobilize patients, some of whom
could not afford it: Act Up was born and would express its anger 2 years later on Wall Street in 1989.
In France, de facto , mentalities are changing, thus, the 8th December 1992 Act marks the creation
of ATUs, an ATU committee was created in 1994 within the Agence du Médicament (which will
become AFSSAPS in 1999 and then ANSM in 2012) composed of MD’s and pharmacists in charge of
evaluating and granting ATUs, putting an end to "compassionate use" or "humanitarian use",
practice with good intent but not aligned to a regulatory or legal framework.
A new act, that of 28th May 1996 will define the conditions of the ATUs as we know them today,
namely that the exceptional use of certain medicines is permitted when:
- The drug does not have a MA in France
- It is proposed for a rare or serious disease
- There is no appropriate treatment
- There is a presumption of effectiveness and safety9
Cohort ATUs (ATUc)
These ATUc only concern medicinal products whose efficacy and safety are strongly anticipated
(or correlated) and intended for a group of patients treated and monitored according to criteria
defined in a therapeutic use with information gathering protocol10 (PTU as Protocol for Therapeutic
Use). They shall be issued at the request of the holder of the exploitation rights, under their
responsibility, who has simultaneously filed or has undertaken to file a Marketing Authorization
application within a defined period , are granted for a period of one year11 and may be renewed12
The list is available on the ANSM website13, the evolution seems fairly stable since 2014 (Figure III)
Nominative or named-patients ATUn
They are requested by the prescribing physician for the benefit of a named patient who is unable
to participate in biomedical research. ATUs are granted by the ANSM ATU Group for a limited
period of time from 1 day to 1 year if efficacy and safety are presumed based on current scientific
knowledge and can be renewed for 1 year.
The ATUn can only be issued by the ANSM if there has been a request for an ATUc or AMM for the
drug concerned (or if the laboratory undertakes to submit such a request within a specified period
of time), or if a clinical trial is ongoing in France (or in the process of being submitted), for example
outside an ATUc indication.
However, by way of derogation, the ATUn may also be issued in one of the following 3 cases, even
though the above requirements would not be met:
- in the current state of available therapies, serious adverse consequences for the patient are very
- when the medicinal product has been stopped from being marketed, the therapeutic indication
requested is different from that authorized and there are strong presumptions of the efficacy and
safety of the medicinal product in the therapeutic indication requested.
- a request for ATUc or a request for clinical trial authorization has been refused in the requested
therapeutic indication but there is an individual benefit for the patient for whom the ATU is
requested and the prescriber and the patient are informed of the reasons for this refusal.
The ANSM has published the new system for processing applications for Temporary Use
Authorization (ATUn) for a medicinal product, which will apply from 17th September 2018, as part
of the ANSM's modernization and transparency program. It is based on a single point of contact for
health professionals in order to simplify the procedures for requesting ATUs and exchanges
between prescribers and the Agency.
The response times of the ANSM depend on the therapeutic and can be very rapid from 24 to 48
hours on average) and will obviously depend on the quality of the file provided. 186 molecules were
the subject of nominative ATUs between 1st January and 30th June 2018, full list available on ANSM
public website and their number is generally stable (Figure IV).The fields are varied, the most
represented being parasitology, oncology, metabolic diseases and neurology.
HAS Assessment and Market Access deadlines
The Transparency Commitee ( TC ) is faced with a growing number of drugs that are coming to
evaluation with increasingly limited and early data. It must therefore decide on the value of the
product in a context of significant uncertainties about clinical outcomes. This trend is growing and
similar developments can be observed at European level in the context of conditional MA and
adaptive pathways.
As there are no drug comparators other than "best supportive care", an ASMR IV is most often
granted to signal the new therapeutic modality, accompanied by a weak or moderate SMR that
characterizes the weakness of the effect or demonstration, which may seem inconsistent at first
glance. This will obviously have an impact on the price proposed by CEPS, which may be different
from other European countries. An European price is only guaranteed if an ASMR from I to III is
granted by the TC , for only innovative molecules.
In November 2017, LEEM conducted a particularly interesting survey on the evaluation of 34 cohort
and 5 protocolized nominal ATUs whose opinions were published by the HAS between 2012 and
The TC justifies its choice most often by indicating that the quantity of effect and/or robustness of
the demonstration is insufficient, and thus returns to the assessment of the benefit/risk ratio of
European MA obtained in the context of a centralized or decentralized procedure at the EMA.
Thus, a drug that has been the subject of an ATU only obtains an ASMR between I and III in 43.5%
of cases. It should be noted that some SMRs may be low - but related to an ALD (Long Term
Affection) - will still be 100% supported by the French National Health System.
On average, the time to obtain an ATU is 87 days, 148 days between the granting of the ATU and
the opinion of the CHMP, 209 days between ATU and AMM. 145 days to obtain the publication of
the TC notice without a hearing, if necessary, this period is extended to 189 days (Figure VI)
However, the average time between HAS filing and FROG publication price remains 361 days.
In addition of this information, a very interesting and relevant poster from M Corthier was
presented at ISPOR in Barcelona in November 2018 focusing on cohort ATUs15 including DGOS and
CEPS data ( figure VII-VIII & IX ) from 2012 to 2017 .
From the ATU via the AMM to the publication of the price in the JORF: the Post ATU period
Article R.5121-76 of the French Public Health Code provides that when a medicinal product that
benefits from a ATU obtains a MA, the Director of the ANSM shall set the date on which the cohort
ATU ceases to produce its effects or the date on which the issuance of nominative ATU ceases,
depending on the date of notification of the MA and essentially the time required to make the
medicinal product available in accordance with its MA. This period shall not be less than one month
from the notification of the MA decision and shall be limited to three months, except in exceptional
The end of ATU is therefore automatically pronounced but the life of the drug continues, there is
then the problem of community coverage between the end of the ATU and the publication of the
price in the FROG.
The negotiations undertaken with the HAS (High Authority of Health) and then with the CEPS by
the pharmaceutical companies can be very long, it is the framework of the post-ATU, often
commonly called "Article 48" or "sustainable mechanism" born with the of Financing of Social
Security Act for 201416.
"A medicinal product which, prior to obtaining its marketing authorization, has benefited from a
ATU may, from the date on which the ATU ceases to produce its effects, be purchased, supplied,
managed and used for the benefit of patients by public authorities for an indication responding to
certain specific situations (Figure X)
The payment, guaranteed by the State as a whole, lasts until the price is published in the FROG by
the CEPS or a decision is taken following its MA.
During this period, the price is still not regulated and remains freely fixed by the same comment as
above. All these specialties are available on the website of the Ministry of Health in a specific table17
Financing of ATUs: simplified modalities but a capped CA
Talking about the reimbursement of ATUs consists in briefly discussing their price and obviously
their cost.
The 2013 report by Prof. Woronoff - Lemsi already opened up avenues for improvement to limit the
increasing cost of ATUs because prices are not regulated. One of the suggestions was to set up a
price justification file for CEPS to provide more transparency18. However, the first measure aimed
at limiting this effect only came into force in 2006 in the Social Security Financing Act (LFSS) of
2007 with the creation of Article L. 162-16-5-1 in the Social Security Code, which requires
reimbursement between ATU and CEPS prices if the set price is lower.
Thus, in a context of controlling health expenditure and in order to prevent manufacturers from
taking advantage of the status of ATU to bypass price administration, the Senate's information
report at the end of the Mediator® mission's work proposed that CEPS be entrusted with setting the
price of ATU19. Nevertheless, this proposal will not be accepted because the risk of creating a
precedent in the administrative path of the drug by bypassing the evaluation carried out by the
HAS was major. AFSSAPS had gone even further by proposing to make the free provision of ATUs
mandatory, as in Germany20. These measures have not been included in the bill. The scheme may
appear less attractive to laboratories that remain at the origin of the demand for ATUc. Public
decision-makers have therefore focused mainly on promoting the removal of medicines from this
system in order to limit the period of price freedom21, and later with the creation of the FFIP, as
discussed below, to cap the impact of expensive molecules' expenditure.
As we have seen, drugs benefiting from an ATU are 100% covered by the French State. Unlike
medicines with a MA, no opinion from the Transparency Commission and therefore no negotiation
with the CEPS are involved in setting the price of medicines subject to a ATU. The latter, in the
form of free or onerous compensation, is therefore freely determined by the laboratories holding
the exploitation rights that it must declare to the CEPS.
Article 9 of the current LEEM-CEPS framework agreement specifies that "in the case of specialties
that have benefited from a paid cohort ATU, the European price guarantee period includes the
period between the MA and the publication of the price in the official journal within a limit of 7
months, unless otherwise provided by agreement, taking into account a very small population
reached during the post-ATU period and confirmed by consumption data"22
The specialties concerned by this device, and not classified as hospital reserves, may be sold to the
public by the in-patient pharmacies authorized for this activity. In this case, they are covered
directly by the Health Insurance, at 100%, based on their purchase price by the institution, plus the
amount of the flat-rate margin and, where applicable, the amount of value added tax. This is the
case with the retrocession process.
For hospitalized patients, until 31 December 2016, the cost of treatment with an ATU was financed
by the appropriations relating to missions of general interest and assistance with contractualization
(MIGAC), supported by a specific allocation for teaching, research, reference and innovation
missions (MERRI). This envelope, which was not expandable and granted annually, resulted in
deferred reimbursements ranging from 6 to 12 months, thus creating many problems and forcing
pharmacists to anticipate expenses in collaboration with their own Financial Affairs Department
in the event of the release of new drugs in ATU. Expenses were therefore borne by the hospital,
which could lead to funding difficulties or even possible inequalities between institutions allowing
or not access to medicines for patients.
The 2017 Social Security Financing Act (LFSS) repeals this method of payment by introducing the
Pharmaceutical Innovation Financing Fund (FFIP) to cover the cost of medicines benefiting from
an ATU or post-ATU device, but also in extenso, those included on the “liste en sus” to and on the
retrocession list as well as the RTU22. Thus, since January 1st, 2017, funding has been provided in
addition to the GHS, on a run-of-river basis. The amount reimbursed is the purchase price indicated
by the institution, including all taxes, which simplifies the mechanism and no longer depends at all
on the publication of the budget circulars to which the MERRI credits responded.
This Fund is made up of:
- An annual allocation to ONDAM (greater than or equal to the amount set the previous
year plus the average rate of change in the fund's expenditure (now net of discounts) for the
period 2018 2021). This amount may be reviewed in the event of a significant surplus or
deficit. The initial allocation was €876 M for 2017, resulting from surpluses from the Old Age
Solidarity Fund
- A difference between the "indemnity" set by the manufacturer for the ATU/post ATU and
invoiced to the establishments, and the CEPS price, which will therefore be paid by the
- Discounts received under macro-ecological regulatory measures: Rate W (Hepatitis
C contribution, set at €600 million in 2017) and Rate Lh (level of change in pharmaceutical
industry turnover from which a safeguard clause is triggered for the hospital)
- Discounts granted on the turnover of drugs on the “liste en sus” to and retroceded
This Fund aims to smooth the spending on innovative and expensive medicines.
For 2017, the fund's projected account shows a revenue of €7 billion and a deficit of €220 M. For
2018, revenues are estimated at €7.3 billion, with a deficit estimated at €164 M.
In its September 2017 report, the French “Cour des Comptes” noted that this fund was "likely to
remain in a long-term deficit situation". It also considers that the abolition of this fund and the
reinstatement of all drug expenditure within the scope of ONDAM appear essential to ensure
consistency in the management of health insurance expenditure23
As mentioned above, the amount of the ATU allowances is freely determined by Pharma
Companies. Nevertheless, Article L. 162-16-5-1 of the Social Security Code provides that the holder
of the rights to use the medicinal product must declare to the Economic Committee for Health
Products (CEPS), within one month of the granting of the ATU by the ANSM, the maximum amount
of compensation he claims from health establishments, even if this amount is zero. These amounts
are public and published on the Ministry of Health and to date 67 molecules have post-ATU status24.
The laboratory holding the exploitation rights to the drug benefiting from an ATU may be subject
to mandatory payments in 3 cases:
If, on 31 March of each year, and in view of the data provided to the CEPS by the CNAMTS
for the previous calendar year, the average amount paid per patient for an ATU exceeds
10 K: the holder of the rights to use the medicinal product shall pay back to the health
insurance schemes, in the form of a discount, the difference between the turnover invoiced
to the health establishments and the amount of € 10 K multiplied by the number of patients
treated. A ceiling on compensation per patient is therefore set. This reversal only concerns
medicinal products whose turnover excluding tax in the previous calendar year exceeds
€30 M25. According to CEPS, by 2015, only 10% of ATUs would be affected.
If the price or reimbursement rate subsequently set by CEPS under the MA is lower than
the amount of the indemnity requested by the manufacturer, CEPS shall require the
laboratory to pay, in the form of a discount, all or part of the difference between the turnover
invoiced to health establishments for the ATU and post-ATU periods and the net reference
price calculated by CEPS on the basis of the application of three-year sales forecasts and all
the price conditions negotiated with the laboratory. The proceeds of this remittance, which
were collected by the unions for the collection of social security contributions and family
allowances (URSSAF) and then allocated directly to health insurance schemes, will now be
paid to the FFIP.
In practice, the FFIP has not provided an additional financing solution for expensive or innovative
drugs, but has made the drug management system more complex. The LFSS 2019 will rescind it.
LFSS 2019
Innovative medicines are playing an increasingly important role in health expenditure, while early
access to them has already exceeded 1 billion since 2014, whereas it represented only a few
hundred thousand euros in 2013 (Figure XI).
Regulation was indeed necessary and indispensable to the legislator’s eyes26
The challenge of the system is to maintain this essential early access without unbalancing the
negotiations within a regulated financial framework with unavoidable principles (net discount price
negotiated with retroactive effect, controlled budgetary framework that encourages rapid
conclusion of negotiations with CEPS while maintaining the principle of an indemnity freely set by
the industrialists upstream)
As seen above, Article 42 will delete the FFIP. The French “Cour des Comptes” had already severely
criticized it27 and the Government had neutralized it in the construction of the ONDAM in LFSS
2018 and Article L221 - 1 - 1 - 1 of LFSS 2017 will be repealed.
The Senate's remarkable work on ATUs28 and recent CSIS proposals29 had already highlighted this
Among the measures proposed in the LFSS 201930:
- Extend access to post-ATU access for drugs that have not had an ATU: submission
deadlines will be better regulated for urgent access drugs .
- Simplify the negotiation of the ATU price: net price and provisional volume reduced
to 1 year instead of 3 currently to facilitate industrialists’ forecast.
- Create an early mechanism for extensions of indications with a confidential net
indemnity for the indication concerned. The net price will be set by the Public
Authorities and no longer by the Industrialists.
- Provide for continuity of treatment at the end of the ATU period: when the laboratory
decides to withdraw the MA request, it will be necessary to maintain a period of access
to the drug to allow the prescriber to adapt his management strategy.
- Strengthen the collection and analysis of health product data: this already exists for
ATU and to a lesser extent for post-ATU.
- Grant access for specialties in the ATUs form in an indication different for those who
already have a marketing authorization .
- The codage by indication ( like the “liste en sus process” ) will become mandatory for
intra hospital use from 1st septembre 2019 and from the 1st January 2020 for retrocession
patient access .
All these regulations have been voted in December 2018 and applied on 1st march 2019. The
ministerial note indicates that practical implementation arrangements will be facilitated by the
adaptation of prescription, dispensing and billing software. The Observatories for Medicines,
Medical Devices and Therapeutic Innovations (OMEDIT) will be able to support health
establishments in the implementation of this system.
France, through the creation of the ATUs, has made it possible to quickly grant status to innovative
medicines without MA and early access based on available data and to become a model within the
EU and worldwide. Many patients could benefit from it more quickly than if they had to wait for a
conventional Market Authorization.
Until 2013, the total turnover of drugs retroceded under ATU /Post ATU capped at 110 M per year,
drugs against hepatitis C (anti-HCV) considerably increase the spending in 2014 but made a
significant impact on patient care ... with hepatitis C almost eradicated. In 2016, this figure
increased by 48% to 997 M, with the arrival of anti-PD1 drugs in oncology. Purchases of non-
refundable drugs with ATU / or Post ATU status amounted to €471 M in 2016. In total, the turnover
of orphan drugs covered by ATU funding almost tripled in 2016 from €82 M to €207 M31
The arrival of innovative drugs in immunotherapy will see this budget explode in the coming years
and therefore obviously threaten this financial balance as for example CAR - T Cells were rated
Therapeutic Advance of the Year 2018 by ASCO.
Over the past 10 years, many regulatory tools have been introduced in Europe to facilitate patients'
earlier access to effective and safe medicines. These tools may be based on early, iterative and
continuous dialogue or risk-based marketing authorization channels. These risk-based approaches
are programs that accept a higher degree of uncertainty if a drug has very promising efficacy results
and acceptable safety, resulting in risk sharing between the regulator, the public and the applicant.
Since Europe plays a real role in this early access by developing certain programs, PRIME is an
illustration of this, but also the ADAPT - SMART project of September 2015 within the Innovative
Medical Initiative, which includes upstream reflection with all stakeholders: patient organizations,
health technology assessment (HTA) bodies, regulatory bodies, payers, academics and industry.
The very encouraging conclusions were reached in March in Budapest32
The benefits for patients are numerous and provide real incentives for the pharmaceutical
companies to develop innovation. In addition, the experience and familiarization of patients and
physicians with therapy can also have a very positive effect, especially in the context of
compassionate use. Indeed, these real-life data are major assets for the future evaluation of the MA,
but also for the evaluation of pricing and the optimization of reimbursement conditions, which are
sometimes very long and laborious. Real-world data collected during early access can also reduce
the payor's uncertainty about the effectiveness and demonstrated benefit over a traditional MA
It should be noted that these faster access routes do not necessarily lead to access to medicines for
patients, since after authorization by the competent authority, reimbursement and price must then
be assessed by HTA agencies, constituting an increasingly difficult barrier to cross. De facto, the
problem, particularly in European markets, is whether HTA and other entities responsible for
assessing pricing and reimbursement also accept incomplete but promising evidence submitted.
HTA organizations may be reluctant to accept these incomplete data and may request additional
data collection, which therefore increases the time to market and cancels out all the benefit and
reason why these programs exist... This is all the truer as the bodies responsible for assessing pricing
and reimbursement are specific to each EU country and therefore have their own requirements and
regulations, in France, only molecules with an ASMR between I and III will benefit from a European
price guarantee and, as we have seen with the example of ATUs, not all of them obtain one of the
major ASMRs in the face of an increasingly demanding HAS. Especially since access to the market
does not stop at the national level, but extends to the Comédims of each hospital (Commission on
Medicines and Sterile Medical Devices), which may also decide to restrict access to drugs according
to their financial impact, even though the State guarantees their coverage.
Early access to new medicines is a particular, sensitive, risky area, both for health professionals
seeking new therapeutic opportunities to offer their patients and for companies seeking to develop
new medicines where there is a real need without being forced to offer them. Considering early
approval of promising products based on data from the early stages of development is now possible
if you consider and have a true global strategic vision. These programs have become a fundamental
element of a global market access strategy, generating development strategies but also negotiations
with increasingly innovative and global health authorities, trying as possible to reduce uncertainty.
The French government has undertaken to accelerate the reduction of market access deadlines for
innovative products with the aim of meeting the deadline set by the Transparency Directive of 180
days by 2022 by strengthening the CEPS’ staff.
French ANSM is implementing the new mechanism for rapid and early access to innovative
treatments. It has just granted the first cohort ATU (ATUc) for a drug that already has a marketing
authorization in a different indication. Thanks to this first special ATUc, some patients with
advanced ovarian cancer will be able to benefit from maintenance treatment with Lynparza
(olaparib) after a first line of platinum-based chemotherapy.
France is once again distinguished by its ability to challenge itself so that the French model can
continue and remain one of the best in the world, while remaining attractive to industry.
Obviously, and this will be my conclusion, my last word will be for patients, who suffer from rare,
life-threatening diseases, because it is above all for them that we, pharmaceutical companies, health
professionals and health authorities, are working together. The pioneering, and effective French
system of ATUs perfectly illustrates this collaboration by giving patients access to new perspectives
for recovery at an earlier stage, thanks to the many therapeutic innovations that the State is
committed to financing: this remains quite simply exceptional.
French ATU Eternal Flame is still burning.
List of Abbreviations used:
AFSSAPS: Former French ANSM
ANSM : French National Agency for Healthcare Products and Safety
ARS : Agence Régionale de Santé : French Regional Health Agency
ATU: Temporary Authorization for Use
ATUc: Cohort ATU
ATUn : Nominative ATU
ASCO: American Society of Clinical Oncology
CAR T Cells: Chimeric Antigen Receptors T Cells
CEESP: Economic and Public Health Evaluation Committee
CEPS: Comité Economique des Produits de Santé : Economic Committee for Health Products
CHMP: Committee for Medicinal Products for Human Use
CSIS: Strategic Council of Health Industries
DGOS : General Directorate for Healthcare Provision
EAS: Early Access Scheme
EFPIA: European Federation of Pharmaceutical Industries and Associations
EMA: European Medicines Agency
GHS: Homogeneous Group of Stay
HAS: French National Agency for Health
HTA: Health Technology Assessment
FROG: French Republic Official Gazette
FFIP: Pharmaceutical Innovation Financing Fund
LEEM: LEs Entreprises du Médicament France based Pharma Companies
LFSS: Social Security Financing Act
MERRI: Teaching, Research, Reference and Innovation Missions
MIGAC: General Interest and Contractualization Assistance Missions
ONDAM: French National Target for Healthcare Expenditure
PLFSS: Financing of Social Security Act Project
PRIME: Priority Access to Medicines Program (PRIority Medicines)
PTU: Protocol for Therapeutic Use
UNCAM: French National Health Insurance Fund
URSSAF : Union de Recouvrement des cotisations de Sécurité Sociale et d'Allocations Familiales
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santé French MoH website
25. Article 97 Préservation du dispositif d’autorisation temporaire d’utilisation (ATU) et de post-
ATU et création d’un outil de maîtrise financière garantissant la soutenabilité de ce dispositif - Loi de
Financement Sécurité Sociale 2017 Journal Officiel de la République Française
26. LFSS 2019 : December 22th Social Security 2019 Act Journal Officiel République Française
27. Suivi des Recommandations de la Cour des Comptes Tome 1 - 2017
28. Rapport d’information sur l’accès précoce à l’innovation en matière de produits de santé N° 569
Daudigny Deroche Guillotin 13 June 2018
29. 8ème Conseil Stratégique des Industries de Santé Notre ambition pour les Industries de Santé
Matignon - 10 july 2018
30. Rapport d’activité 2016 CEPS section médicaments december 2017
31. Adapt Smart Closing Meeting Medecine Development in the Adaptive ERA 22 march 2018
... In France, the ATU system encompasses aspects of both compassionate use and named-patient use, but with a different system of reimbursement prior to market approval [20]. During the ATU validity period, products are entirely reimbursed by the French National Health Insurance, potentially having a large budget impact on the French healthcare system [21]. Manufacturers are required to pay back the total revenue difference between ATU pricing and the final negotiated price after market access in the case of a lower post-launch price. ...
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Somatic gene editing (SGE) holds great promise for making genetic therapy possible for many monogenic conditions very soon. Is our current system of European market authorization and reimbursement ready for the expected tsunami of gene therapies? At a recent workshop of the Netherlands ZonMw consortium on ethical, legal, and social implications of personalized medicine, we discussed the current possibilities for bringing new gene therapies to the clinic. In Europe, it is not yet clear whether the route via the European medicines agency as an advanced therapy medicinal product is the most appropriate for evaluation of highly personalized SGE applications, although this may optimally guarantee safety and effectiveness. Compassionate use may ensure faster access than the centralized procedure but does not stimulate the commercial development of products. Prescription to named patients may only provide adequate access for single patients. Temporary authorization of use may allow access to medication half a year before formal market authorization has been granted, but may also have large budget impacts. Magistral compounding under a hospital exemption may be an attractive solution for rare, tailor-made applications at an acceptable price. To approve local experimental use of a therapy on a case-by-case basis may be fast, but does not guarantee optimal safety, effectiveness, and broad implementation. We argue that alternative routes should be considered for products developed for a market of large groups of patients versus unique personalized treatments. A balance between scientific evidence for safety and effectiveness, affordability, and fast access may demand a range of alternative solutions.
Concorde is a double-blind randomised comparison of two policies of zidovudine treatment in symptom-free individuals infected with human immunodeficiency virus (HIV): (a) immediate zidovudine from the time of randomisation (Imm); and (b) deferred zidovudine (Def) until the onset of AIDS-related complex (ARC) or AIDS (CDC group IV disease) or the development of persistently low CD4 cell counts if the clinician judged that treatment was indicated. Between October, 1988, and October, 1991, 1749 HIV-infected individuals from centres in the UK, Ireland, and France were randomly allocated to zidovudine 250 mg four times daily (877 Imm) or matching placebo (872 Def). Follow-up was to death or Dec 31, 1992 (total 5419 person-years; median 3.3 years) and only 7% of the 1749 had not had a full clinical assessment after July 1, 1992. Of those allocated to the Def group, 418 started zidovudine at some time during the trial, 174 (42%) of them at or after they were judged by the clinician to have developed ARC or AIDS (nearly all confirmed subsequently) and most of the remainder on the basis of low CD4 cell counts. Those in the Imm group spent 81% of the time before ARC or AIDS on zidovudine compared with only 16% for those in the Def group. Despite the large difference in the amount of zidovudine between the two groups and the fact that the number of clinical endpoints (AIDS and death) in Concorde (347) outnumbers the total of those in all other published trials in symptom-free and early symptomatic infection, there was no statistically significant difference in clinical outcome between the two therapeutic policies. The 3-year estimated survival probabilities were 92% (95% CI 90-94%) in Imm and 94% (92-95%) in Def (log-rank p = 0.13), with no significant differences overall or in subgroup analyses by CD4 cell count at baseline. Similarly, there was no significant difference in progression of HIV disease: 3-year progression rates to AIDS or death were 18% in both groups, and to ARC, AIDS, or death were 29% (Imm) and 32% (Def) (p = 0.18), although there was an indication of an early but transient clinical benefit in favour of Imm in progression to ARC, AIDS, or death. However, there was a clear difference in changes in CD4 cell count over time in the two groups. Median changes from baseline at 3 months were +20 cells/mu L (Imm) and -9 cells/mu L (Def), a difference of 29 cells/mu L (95% CI 16-42; p < 0.0001) which persisted for up to 3 years. Thus such persistent differences in CD4 cell count do not necessarily imply long-term differences in clinical outcome. 6 participants had life-threatening adverse events that were judged to be possibly drug related: 4 occurred on trial capsules before unblinding (3 on zidovudine, 1 on placebo) and 2 occurred on open zidovudine. Despite a daily dose of 1 g of zidovudine, the frequency of severe haematological and other adverse events on trial therapy was low but significantly higher in the Imm group: 16 Imm and 2 Def participants stopped trial drug for haematological events and the estimated proportions with haemoglobin dropping below 10 g/dL were 5% and 1%, respectively, at 1 year and 8% and 2%, respectively, at 3 years. Another 83 (9%) Imm and 36 (4%) Def participants stopped for other adverse events, predominantly gastrointestinal or neurological symptoms (headaches) or malaise.
The research and development costs of 106 randomly selected new drugs were obtained from a survey of 10 pharmaceutical firms. These data were used to estimate the average pre-tax cost of new drug and biologics development. The costs of compounds abandoned during testing were linked to the costs of compounds that obtained marketing approval. The estimated average out-of-pocket cost per approved new compound is $1,395 million (2013 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a real discount rate of 10.5% yields a total pre-approval cost estimate of $2,588 million (2013 dollars). When compared to the results of the previous study in this series, total capitalized costs were shown to have increased at an annual rate of 8.5% above general price inflation. Adding an estimate of post-approval R&D costs increases the cost estimate to $2,870 million (2013 dollars).
Usage compassionnel en Europe et en France
  • Thèse Pharmacie Marie Rolland
Thèse Pharmacie Marie Rolland. Usage compassionnel en Europe et en France. Université Lille 2 31 january 2014
French Compassionate Use Program : Health Technologies Assessment and Pricing Implications , ISPOR Barcelona Poster 14-18
  • M Corthier
  • B Mézerethe
  • L Maillant
  • J P Sales
  • M P Planel
  • E Sam
M Corthier, Mézerethe B, Maillant L, Sales JP, Planel MP, Sam E : French Compassionate Use Program : Health Technologies Assessment and Pricing Implications, ISPOR Barcelona Poster 14-18 nov 2018
Le médicament à l'hôpital. Rapport
  • M C Woronoff-Lemsi
  • J Y Grall
  • B Monier 18. Woronoff-Lemsi MC, Grall JY, Monier B, et al. Le médicament à l'hôpital. Rapport 2003. 19. Rapport du Sénat N°675 -session 2010 -2011 : Médiator : évaluation et contrôle des médicaments
Article 97 -Préservation du dispositif d'autorisation temporaire d'utilisation (ATU) et de post-ATU et création d'un outil de maîtrise financière garantissant la soutenabilité de ce dispositif -Loi de Financement Sécurité Sociale
Article 97 -Préservation du dispositif d'autorisation temporaire d'utilisation (ATU) et de post-ATU et création d'un outil de maîtrise financière garantissant la soutenabilité de ce dispositif -Loi de Financement Sécurité Sociale 2017 -Journal Officiel de la République Française 26. LFSS 2019 : December 22th Social Security 2019 Act -Journal Officiel République Française 27. Suivi des Recommandations de la Cour des Comptes -Tome 1 -2017
Guideline on Compassionate Use of medicinal products
  • Marion Thèse Pharmacie
  • Bourdoncle
Thèse Pharmacie Marion Bourdoncle : Accessibility of drugs for rare diseases : feedback from a french reference centre 2016 32. Guideline on Compassionate Use of medicinal products, pursuant to Article 83 of Regulation (EC) no 726/2004