The public health benefit of medicines

Health Policy 112 (2013) 273–284

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The public health benefit of medicines: How it has been assessed in France? The principles and results of five years’ experience Patrick Maison a , Laura Zanetti b,∗ , Anne Solesse b , Gilles Bouvenot c , Jacques Massol d , The ISPEP group of the French National Authority for Health1 a b c d

Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Créteil, INSERM U955, Créteil, France Haute Autorité de Santé, Unité Méthodologie et Études Post-inscription, Saint-Denis, France Haute Autorité de Santé, Commission de la Transparence (President), Saint-Denis, France Hôpital Saint Jacques, Besanc¸on, France

a r t i c l e

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Article history: Received 3 July 2012 Received in revised form 1 March 2013 Accepted 9 April 2013 Keywords: Public health Drugs policy Health technology assessment Pharmaco-epidemiology

a b s t r a c t Health technology assessment seeks to inform health policy- and decision-makers by promoting use of current best evidence and by addressing country specific factors, such as local context and values. In France, public health benefit (PHB) is one of the criteria used to inform decisions on the reimbursement of medicines. This article describes the methodological framework and the results after five years of assessment of PHB, by the French National Authority for Health. The semi-quantitative method used includes three dimensions that are: (1) the ability of a drug to improve the population’s health status, (2) the drug’s adequacy to cover public health needs, and; (3) the impact of the drug on the healthcare system. From 2005 to 2010, the PHB of 530 drugs was estimated, and 72% were assessed as having no PHB. The PHB was “low” for 88% of drugs expected to have a PHB, “medium” for 10%, and was considered to be “high” in only one case. The results of this experience show that it is feasible to assess the public health impact of drugs. But the high level of uncertainties at the time of a drug’s first appraisal limits the assessment, which obviously has to be completed by reappraisal with post-marketing studies. © 2013 Elsevier Ireland Ltd. All rights reserved.

∗ Corresponding author at: Haute Autorité de Santé, 2 avenue du stade de France, 93218 St Denis La Plaine Cedex. Tel.: +33 1 55 93 37 65; fax: +33 1 49 81 37 79.

E-mail address: l.zanetti@has-sante.fr (L. Zanetti).

1 Groupe Intérêt de Santé Publique et Etudes Post-inscription [Public health benefit and post-registration study group] of the Haute Autorité de Santé since 2005: Pascal Auquier, Elisabeth Baumelou, Frédéric de Bels (2005–2007), Marie-Christine Béné, Alain Bernard, Jean-Pierre Boissel, Marie-Odile Carrère (2009–2011), Pierre Czernichow, Benoît Dervaux, Eveline Eschwege, Pascale Fabbro-Peray, Bruno Falissard (2005–2010), Annie Fourrier,Didier Guillemot (2005–2007), Franc¸ois Lacoin, Maryse Lapeyre-Mestre, Patrick Maison (President), Jacques Massol (2005–2009, President), Emmanuel Oger, Franc¸oise Roudot-Thoraval, Patrice Trouiller (2009–2011), Muriel Vray, Mahmoud Zureik.

0168-8510/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.healthpol.2013.04.007

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Key points • The benefit of a drug should be assessed at both the individual and population levels.

• The public health benefit (PHB) takes into account: (i) the ability of a drug to improve the population’s health status; (ii) the drug’s adequacy to cover public health needs according to health policies, and; (iii) the impact of the drug on the healthcare system.

• The French experience of the expected PHB evaluation demonstrates a high level of uncertainty, at the time of first appraisal.

• A re-assessment of PHB should be performed at the time of reappraisal, in order to confirm the expected PHB. 1. Introduction The evaluation of health technologies, especially drugs, is becoming an international matter. The decision process for market approval of new medicines requires evidence of efficacy given by well-controlled, randomised clinical trials, as well as the safety and the quality of manufacturing. The assessment of clinical benefit in regulatory setting is based on the assessment of the benefit/risk ratio [1].

Health technology assessment (HTA) is defined as “a multidisciplinary field of policy analysis, studying the medical, economic, social and ethical implications of development, diffusion and use of heath technology” [2]. A major use of HTAs is to provide information for reimbursement or coverage decisions. In principle, HTA explores all the elements contributing to the value of a technology, not just those that can be demonstrated in randomised clinical trials [3].

Collective earnings in terms of economics and public health are worth considering as regards national public investments. Some European countries have well established procedures for considering a drug’s cost effectiveness in reimbursement decisions (e.g., the United Kingdom, the Netherlands and Sweden). In contrast, until recently the French HTA model did not consider health economic information as a formal reimbursement criterion, even if manufacturers are recommended to provide cost-effectiveness analysis when submitting applications for reimbursement [4,5]. A population-level approach with the likelihood of society-wide benefits was however considered in terms of public health benefit (PHB): it was one of the criteria used to inform decisions on the reimbursement of medicines.

This article describes the methodological framework and the results of five years’ experience in the assessment of drugs’ PHB in France, carried out by the French National Authority for Health (Haute Autorité de Santé).

1.1. The regulatory background In France, once marketing authorisation has been granted by the Regulatory Authorities, the reimbursement of medicines depends on their registration in a positive list enforced by ministerial orders [6]. The Transparency Committee (part of the French National Authority for Health) assists Minister’s decision-making by providing guidance on the positive listing. This takes into account the comparative value of alternative drugs and their intended role within the overall therapeutic strategy for the target

disease (Fig. 1). The Committee uses standardised scientific methodology to assign two levels of benefit to each drug prescribed (except for generics): (i) the level of benefit rendered by the medicine to the patient, expressed as “actual benefit” (actual clinical benefit, or ACB, which is classified as “important”, “moderate”, “minor” or “insufficient”), and; (ii) the level of benefit that the new drug is expected to provide compared to alternatives, namely the “improvement in actual clinical benefit” (IACB) (expressed in five levels, from Level I “major improvement”, to Level V “no improvement”) [7,8]. The ACB classification determines the inclusion in the positive lists and the reimbursement rate fixed by the Association of Health Insurance Funds (UNCAM). Drugs with insufficient ACB are not recommended for reimbursement: others are granted 15%, 30% and 65% reimbursement according to their level of ACB [5]. The level of IACB contributes to setting a price for the drug, the final outcome of the negotiations between the manufacturer and the Committee for the Pricing of Healthcare Products. Inclusion in the positive list lasts for five years. The final decision – admittance to the lists with details about the reimbursement rate and price – is taken by the Ministry of Health and the Ministry of Budget and formalised by means of a Ministerial Decree which is published in the France’s Official Journal (Fig. 1) [9].

In 1999, public health benefit (PHB) was introduced as one of the components of ACB. In addition, the reassessment of drugs every five years became compulsory [10].

Concurrently, the Ministry of Health adopted a policy of requesting post-marketing studies from the holders of marketing authorisation, in order to assess the benefits under “real-world” conditions. In 2002, the Ministry defined criteria intended to estimate the expected PHB of drugs at the time of marketing [11].

Since 2005, a specific working group made up of 17 independent experts has defined the principles of PHB assessment, taking into account three dimensions: (i) the ability of the drug to improve the population’s health status; (ii) the drug’s adequacy to cover public health needs according to health policies, and; iii) the impact of the drug on the healthcare system.

2. The method of assessing PHB The method used by the French National Authority for Health is based on all data available on first appraisal.

This first appraisal corresponds to the first application for inscription in the positive lists and a reimbursement rate, for a new product, a new indication, or an extension of indications. It is based on all data provided by the manufacturers and all other available data on the drug.

At this stage, only an expected PHB can be estimated.

The following process and criteria (Table 1) are applied: (I) The ability of the drug to improve the population’s health status.

To assess the potential impact of a drug on the general population’s health status, account must be taken of: (i) the burden of the disease treated or prevented by the drug examined; (ii) its theoretical relative impact on mortality/morbidity and quality of life, and; (iii) applicability of evidence.

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Fig. 1. Organisation of drug registration in France.

(1) Estimation of the burden of a disease is based on World Health Organization (WHO) analyses, which provide a comprehensive and comparable assessment of mortality and loss of health due to diseases, injuries and risk factors for all regions of the world [12,13]. The burden of a disease is thus estimated using a timebased measure of “disability adjusted life years” (DALYs). This combines the years of life lost due to premature mortality and the years of life lost due to time lived in states of less than

full health [14,15]. DALYs are designed to guide health policies on investments, and to provide information internationally for setting priorities in health research. The WHO provides estimates for European zone A, and for WHO Member States [16]. In practice, the burden of each disease roughly estimated from available data is ranked in four classes: “low” (<20,000 DALYs), “medium” (20,000–200,000 DALYs), “high” (200,000–1,000,000 DALYs) and “major” (>1,000,000 DALYs).

Table 1 The three dimensions of public health benefit.

(I) Ability of the drug to improve the population’s health status

Burden of targeted disease Theoretical impact

Extent of impact

Study’s evidence level Applicability (II) Drug’s adequacy in covering public health needs, according to health policies

Existence of public health needs Responsiveness to public health needs

(III) Impact of a drug on the healthcare system

Criteria Type Quantification

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The second step is to assess whether the use of the drug under real-world conditions could contribute to decreasing the burden of a disease. This depends on the theoretical impact based on randomised controlled trials and its applicability.

(2) From clinical trial data, the theoretical impact of drugs on a population in a real life setting can be predicted, taking into account: (i) the benefit/risk balance, (ii) the size of the effect, (iii) the type of outcome (direct or intermediate/surrogate), (iv) the availability of other therapeutic agents and possibly, (v) the indirect impact on populations not treated. In order to estimate the importance of the improved state of health expected from a drug in a population, demonstrative clinical data on direct impact criteria (mortality, morbidity or quality of life) should be obtained. In the absence of any proven drug effect on one of these direct criteria, surrogate outcomes are taken into account, but only when shown to be predictive of final outcomes.

In some cases, the drug may modify the state of health not only of the treated population but also of the untreated population: this is an indirect impact. Such examples are the herd immunity conferred by vaccines, or the impact for parents and helpers of treating a child’s behaviour disorder.

In some areas, the impact on public health might be very different from the individual benefit, if a drug is just one part of the therapeutic or preventive treatment. For example, even if the efficacy of a contraceptive drug is well established, details of its accessibility, its use and the information provided to women (especially young women) are essential in order to assess its impact on the population [17].

Finally, the level of evidence based on the quality of both trials and outcomes weights the theoretical impact.

(3) Question relating to the applicability of evidence is then raised. Applicability is defined as the extent to which the efficacy observed in trials is likely to reflect the expected impact in the population of interest in real-life setting [18]. Rating applicability is performed on a case-by-case basis and consists in considering factors that may influence applicability, including: (i) the ability to identify the patients to be treated and the reliability of the diagnosis in practice; (ii) the similarity of characteristics (age, severity, comorbidities, other prescribed medications, etc.) of the subjects included in the trials, as well as those subjects treated with the drug in real life; (iii) the proper use of the drug in real life compared with clinical studies in terms of labelled indication (off-label use), compliance, as well as duration of treatment, and; (iv) country specificities in terms of healthcare organisation (making it impossible to guarantee the same benefit for the whole population) or disease frequencies (leading to differences between populations in the numbers of patients treated or events avoided). For

example, in oncology, patients are often treated under conditions quite similar to those of clinical trials and applicability is therefore often considered to be satisfactory a priori. In contrast, with chronic diseases such as diabetes mellitus, asthma or asymptomatic diseases, the level of compliance and the rates of repeat prescriptions are low, so that applicability is often not assured [19,20].

Overall, the expected impact on the population is evaluated semi-quantitatively as “none”, “low”, “medium” or “high”.

(II) The drug’s adequacy in covering public health needs, according to health policies.

The second aspect of PHB is the drug’s adequacy given public health needs in France. The definition of public health needs is related not only to the frequency and severity of diseases, or to the lack of available standard therapeutic care for serious diseases, but it is also linked to public health priorities. In October 2002, a national technical group of about 80 experts was set up and submitted a report to the Ministry of Health [21]. A set of 100 health-related issues were identified as being Public Health priorities and were embedded in the first public health law in France, in 2004 [22]. Moreover, other national health plans (e.g., the national plan against Alzheimer’s disease or Cancer), and priorities for drug development (e.g., orphan drugs or paediatric formulations) have been set up since then and are regularly updated (such as the third national plan on antibiotics). Each year, the Ministry of Health publishes a health status report with the updated indicators, in order to evaluate periodically whether goals have been achieved [23]. When assessing PHB, it is considered whether or not the drug helps to address public health concerns and contributes to achieving established public health objectives. This drug’s adequacy to cover public health needs is estimated with a dichotomous score: “yes” or “no”.

(III) The impact of the drug on the healthcare system.

The last aspect of PHB is the impact of a drug on the organisation of the healthcare system. The type and the extent of resources consumed or saved (healthcare personnel’s time, diagnostic explorations, hospitalisations, etc.) should play a role in evaluating the impact of a drug on public health. Certain drugs require the mobilisation of substantial material and human resources. Others allow those same resources to be saved, while others still have no effect on the healthcare system. Thus, drugs may necessitate adjustments to the healthcare system to allow for an optimal impact on the population. For example, some drugs such as new targeted therapies for cancer have to be combined with a laboratory test or with specific equipment that is supposed to be easily accessible and routinely used. Assessing the impact on the healthcare system requires good knowledge of the diagnostic procedure, and/or the therapeutic strategy, as well knowledge of how both of these are organised throughout a country.

Detailed examples of the PHB assessment method and the conclusions assigned for three drug examined

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Table 2 Three examples of public health benefit (PHB) assessment.

Drug examined

Trastuzumab

Toxin botulinum A

Panitumumab

No DALY nor French epidemiological data available

“Major” for colorectal cancer (more than 1 million DALYs); moderate in the restricted indication of the product (approximately 150,000 DALYs)

Direct = survival, progression free survival, but no health related quality of life (HRQoL) Direct Important: clinically significant decrease of mortality: 3.5% in the herceptin group versus 5.3% in the untreated group Good: well conducted randomised, controlled clinical trial

Surrogate = muscle tone measured using Ashworth scale; range of motion measured using a goniometer Direct Unquantifiable as no relevant morbidity data nor on quality of life data available

Direct = progression free survival; overall survival

Acceptable: patients are similar to those in real life

Unacceptable: lack of data on associated functional rehabilitation, only short term studies

Unacceptable: uncertainty regarding the wide used of the genetic tests, to identify patient with wild-type KRAS-gene

Yes: improving handicap is part of public health priorities

Yes: National Cancer Plan and objective 49 of the Public Health Law No

(1) Ability of the drug to improve the population’s health status “Major” for the breast Burden of targeted disease cancer (near from 1 million DALYs); moderate in the restricted indication of the product (approximately 110,000 DALYs) Theoretical impact

Extent of impact

Criteria

Type Quantification

Study’s evidence level Applicability

(2) Drug’s adequacy to cover public health needs according to health policies Yes: National Cancer Plan Existence of public health needs and objective 49 of the Public Health Law Yes Responsiveness to public health needs (3) Impact of the drug on the healthcare system

No

Public health benefit conclusion

Important

by the Transparency Committee are described hereafter: (i) trastuzumab as adjuvant therapy of beast cancer over-expressing HER 2 after surgery, chemotherapy and radiotherapy; (ii) botulinum toxin A as symptomatic treatment of upper and/or lower limb spasticity in children over 2 years of age, and; (iii) panitumumab as a treatment for metastatic colorectal carcinoma with EGFR expression and non mutated KRAS (Table 2).

Finally, the total PHB score can be given: “high”, “medium”, “low” or “none”.

3. The results of five years’ experience in France From May 2005 to April 2010, the PHB of 530 drugs for which manufacturers had submitted a request for inclusion in the positive list was estimated using this method, relating to the development of a new drug or a

Insufficient: small number of patients, large number of surrogate endpoints, no active comparator drug

No Yes: need to establish a multidisciplinary medical and paramedical organisation, need for clinicians to be trained and gain experience and for personalised patient follow-up Not assessable

Direct No: No clinically relevant absolute gain: 5 days in terms of progression free survival; no difference in overall survival Insufficient: exploratory post hoc analysis according to KRAS gene mutation status

Yes: need to implement a new genetic test on French territory

None

new indication or an extension of an existing indication.

Generics, new dosages, new formulations and resubmissions were not included.

On first appraisal, 72% (n = 381) of these drugs were assessed as having no public health benefit mainly due to the absence of any impact on the population’s health. In this case, the three dimensions of PHB were not systematically, fully documented and each dimension was analysed as best as possible (Table 3). Applicability of the clinical trials’ results was documented only when a population impact existed; and the response to public health needs was documented only when there were public health needs and a population impact. The impact on the organisation of healthcare was the most difficult aspect to assess, at the time of first appraisal, and was documented in only 38% of cases: usually when a population impact was expected.

In 3% of cases (n = 17), PHB could not be evaluated on first appraisal, due to high level of uncertainty.

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Table 3 Public health benefit (PHB) and its components: the assessment of 530 first appraisals in France, since 2005.

Burden of targeted disease

Population impact

Applicability

Public health needs

Response to needs

Impact on the organisation of healthcare

PHB conclusion

2% (11) Major

1% (5) High

63% (334) Yes

16% (85) Yes

6% (32) Yes

0.2% (1) High

18% (95) High

5%(27) Medium

28% (148) Acceptable 7% (37) Questionable

6% (32) Partial

28% (148) No

32% (170) No

3% (16) Medium

25% (132) Medium

18% (96) Low

32% (170) Unacceptable

21% (111) None

42% (223) Low

42% (224) None 33% (175) Missing

10% (53) Missing

13% (69) Missing or 33% (177) Missing unknown

22% (116) Low 72% (381) None

Table 4 Public health benefit (PHB), actual clinical benefit (ACB) and improvement in actual clinical benefit (IACB), in the first 530 first appraisals since 2005.

PHB

ACB

IACB

0.2% (1) High 3% (16) Medium 22% (117) Low

89% (471) High 6% (32) Medium 2% (11) Low

3% (16) Major 8.5% (45) High 13% (69) Medium

72% (390) None

3% (16) Insufficient

18% (95) Low 51.5% (273) None

3% (16) Not evaluated

0 Missing

6% (32) Not evaluated

Among the 132 drugs with an expected public health benefit (i.e., a “low”, “medium” or “high” PHB) excluding drugs with no expected public health benefit (i.e., PHB “none”), the PHB was “low” in 88% of cases (n = 116/132), “medium” in 10% (n = 15, namely CERVARIX®, GARDASIL®, HEXVIX®, LUCENTIS®, MYOZYME®, ORFADIN®, PREVENAR 13®, RISPERDAL®, SPRYCEL®, TAHOR®, TASIGNA®, TAXOL®, TAXOTERE®, THALIDOMIDE CELGENE®, VELCADE®), and was considered “high” in only one case (HERCEPTIN 150 mg®).

In parallel, the actual benefit (actual clinical benefit, ACB) and the relative improvement in actual clinical benefit (IACB) were assigned for most of these drugs (n = 501), based on the clinical and individual benefit of each medicine. Since this takes into account the relative clinical efficacy of the drug, the IACB is more closely linked to the PHB. The PHB rating did not always however match the IACB, but an overall percentage of agreement was observed: 72%, by combining the last two categories of IACB, (see Table 4).

4. Discussion The growing importance of heath technology assessment has generated recent controversy regardless of definition and country-specific application. While some European countries have well-established procedures for considering cost effectiveness in reimbursement decisions, French decision-makers have remained reticent about using health economic evaluations in the reimbursement process. A population-level approach with a likelihood of society-wide benefits has, however, been considered in terms of public health benefit (PHB). Assessment of the PHB of a drug is based: (i) the predictable improvement in the

56% (297) Missing

62% (328) Missing

3% (16) Missing or not done

population’s state of health under real-life conditions; (ii) its ability to meet public health needs, and; (iii) its impact on the organisation of healthcare.

The method reported here for assessing the PHB of each individual product takes account of these three dimensions and was prepared in accordance with the mission assigned to the Transparency Committee of the French National Authority for Health.

The PHB and IACB appear to be complementary. If an assessment of therapeutic benefit is necessary for clinical decision-making, a PHB indicator taking account of the population and non-clinical aspects should also influence the decisions of policy-makers. The outcome of the PHB criterion is difficult to assess independently, as it is part of the ACB criterion. In 2008, a report commissioned by the French Parliament described clinical efficacy as the primary key assessment factor of reimbursement, while it pointed to the lower impact of the public health impact criterion in the assessment of the ACB. According to the authors, this resulted in a lack of selectivity, as 95% of drugs for which reimbursement is requested were deemed suitable to be included in the positive list [24]. This large rate of inclusion in the list is partly explained by the current rigorous evaluation for entry on the drug market.

In contrast, Level I of the IACB, which reflects the therapeutic progress, is rarely achieved and mainly restricted to orphan drugs or products that significantly reduce mortality. The importance of the IACB assessment for pharmaceutical companies is noteworthy, along with its impact on drug-pricing [8].

One of the recommendations to emerge from the parliamentary Commission’s report was to revise the current legislation, in order to form the basis of the eligibility of reimbursement relating to collective consequences, such as PHB and economic evaluation [24].

The results of five years’ experience of PHB drug assessments highlight the fact that such assessment is possible on first appraisal, despite its difficulties and limitations, which are due to a lack of sufficient, relevant data [25]. However, it often leads to the absence or a low level of expected PHB. The scarcity of drugs with a relevant PHB might be due to the rarity of new drugs of medical interest, as suggested by the high incidence of drugs with no improvement in actual clinical benefit during these five years. Another possible explanation is the difficulty in using clinical trial data alone, to assess an impact under real conditions of use by

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comparison with all other therapeutic strategies used in the whole population. Indeed, these clinical trial data are rarely based on such relevant endpoints as mortality, morbidity, handicap, quality of life, organisation of healthcare, or long-term usage. Furthermore, when the prescription or patients’ profiles differ greatly from the experimental conditions in randomised, controlled trials, their applicability is highly variable. Finally, the size of the treated (exposed) population may differ from the target population or remain unknown. At this early stage, its assessment is a prediction which should be adjusted over time as further studies are conducted after marketing authorisation.

A complete post-marketing evaluation with at least appropriate comparative effectiveness studies (pragmatic trials) and observational studies would make it possible to formulate an actual PHB on reappraisal, in comparison to the expected PHB prior to a drug’s launch.

In general, the results of health technology assessments are highly country-dependent and influenced by national contexts (organisation of the healthcare system, burdensharing of the disease, etc.), the processes of HTA agencies, price negotiations, social values and national health policies [26]. Lexchin and Mintzes have shown there is a relatively low level of agreement on recommendations about individual drugs between different agencies [27]. All these specificities need to be considered, and PHBs provide a means of assessing this necessarily-national aspect of the HTA process.

For a long time, clinical evaluation was central in France’s reimbursement process. Growing criticism of the failure of the advisory body to perform health economic evaluation led to a significant reform of this matter. In a context of limited healthcare resources and the need for better control of healthcare spending by the National Insurance System, the French National Authority for Health was assigned the new mission of conducting health economics assessments. The specialised Economic and Public Health Committee was established in July 2008 for this purpose.

More recently, since the 2nd October 2012, a new decree has rendered health economic studies compulsory for the marketing authorisation holder, at the time of the first appraisal for certain categories of drugs [28].

Analysis of the relationship between the disease burden and the economic evaluations performed has revealed that some important health issues have not been covered by previous economical studies [29,30].

Therefore, combining the assessment of public health benefit (which takes into account the reduction of the burden of a disease allowed by the drug), with others evaluations (such as cost-effectiveness or cost-utility evidence, and social equity within a full, health technology assessment) would undoubtedly improve the reimbursement decision-process. Greater experience of the process is required to allow for more pragmatic assessment.

5. Conclusion Results of the French experience in public health benefit assessment show the level of uncertainties at the time of first appraisal, which needs to be completed by data

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from medical practice in real life, and consequently the necessary dynamic process of HTA assessment. These results also highlight the relevance of taking a global public health and epidemiological approach together with others evaluations (such as economical evidence and social equity), in order for policy makers to allocate health care resources and prioritise public health investments better.

Contributors All authors devised and designed the study. PM and LZ analysed the data. LZ, PM and JM drafted the manuscript and are guarantors. All authors helped to interpret the results.

Funding No specific funding source has been received to support this study.

Competing interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi disclosure.pdf (available on request from the corresponding author). The authors have no non-financial interests that may be relevant to the work submitted.

Funding sources None.

Financial disclosure None.

Acknowledgements We thank Christelle Gastaldi-Menager, Gaelle Gernigon, Philippe Maugendre, Sophie Stamenkovic, Pascale Zagury for their involvement in public health benefit assessment, for 5 years at the French National Authority for Health.

Appendix A. Listing of drugs assessed ABILIFY 5 mg–10 mg–15 mg ABILIFY 5 mg–10 mg–15 mg–1 mg/ml ABRAXANE 5 mg/ml ACLASTA ACLASTA 5 mg ACLASTA 5 mg ACLASTA 5 mg ACOMPLIA 20 mg ACTILYSE ACTONEL 35 mg ACTOS 15 mg–30 mg ACTOSOLV 100,000 U.I.–600,000 U.I. ADCIRCA 20 mg ADENURIC 80 mg–120 mg ADIXONE 50 ␮g ADVAGRAF 0.5 mg–1 mg–5 mg ADVATE

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Appendix A. (continued) AFINITOR 5 mg–10 mg ALDARA 5% ALDARA 5% ALFALASTIN 33.33 mg/ml ALIMTA 100 mg–500 mg ALIMTA 100 mg–500 mg ALIMTA 500 mg ALOXI 250 ␮g ALTEISDUO 40 mg/12.5 mg–40 mg/25 mg ANDROCUR 100 mg ANGIOX 250 mg ANGIOX 250 mg ANGIOX 250 mg ANTARENE CODEINE 200 mg/30 mg–400 mg/60 mg APIDRA 100 U/ml APSOR 4 ␮g/g APTIVUS 100 mg/ml APTIVUS 250 mg APTIVUS 250 mg ARANESP 10–15–20–25–30–40–50–60–80–100–150–300–500 ␮g ARCOXIA 30 mg–60 mg–90 mg–120 mg ARIDOL ARIXTRA 1.5 mg/0.3 ml ARIXTRA 2.5 mg/0.5 ml ARIXTRA 2.5 mg/0.5 ml ARIXTRA 2.5 mg/0.5 ml ARIXTRA 2.5 mg/0.5 ml AROMASINE 25 mg ARZERRA 100 mg ATACAND 32 mg ATARAX ATIMOS 12 ␮g/dose ATRIANCE 5 mg/ml ATRIPLA 600 mg/200 mg/245 mg AVANDIA 2–4–8 mg AVASTIN 25 mg/ml AVASTIN 25 mg/ml AVASTIN 25 mg/ml AVASTIN 25 mg/ml AVASTIN 25 mg/ml AVAXIM 160 U AVAXIM 80 U PEDIATRIQUE AXELER 20 mg/5 mg–40 mg/5 mg–40 mg/10 mg AZARGA 10 mg/ml + 5 mg/ml AZILECT AZYTER 15 mg/g BACTROBAN 2% BARACLUDE 0.05 mg/ml–0.5 mg–1 mg BERINERT 500 U BETAFERON 250 ␮g/ml BONVIVA 150 mg BONVIVA 2.5 mg BONVIVA 3 mg/3 ml BOTOX 100 U BOTOX 50 U–100 U–200 U BRICANYL 5 mg/2 ml BRIDION 100 mg/ml BUCCOBET 0.1 mg BUSILVEX 6 mg/ml BYETTA 5 ␮g–10 ␮g CADUET 5 mg/10 mg–10 mg/10 mg CAELYX 2 mg/ml CANCIDAS 50 mg–70 mg CANCIDAS 50 mg–70 mg CARDIOCOR 1.25 mg–2.5 mg–5 mg CASODEX 150 mg (suite) et 50 mg CELEBREX 100 mg–200 mg CELLCEPT 1 g/5 ml CELSENTRI 150 mg–300 mg CEPLENE 0.5 mg/0.5 ml CERVARIX CHOLESTAGEL 625 mg CHONDROCELECT 10,000 cellules/microlitre

Appendix A. (continued) CIMZIA 200 mg CIRCADIN 2 mg CISNAF 100 MBq/ml CITRAFLEET CLOBEX 500 ␮g/g CLOTTAFACT 1.5 g/100 ml COLOKIT COMBIVIR 150 mg/300 mg COOLMETEC 40 mg/12.5 mg–40 mg/25 mg CORDARONE COSOPT 20 mg/5 mg/ml COTRIATEC COVERAM 5 mg/5 mg–5 mg/10 mg–10 mg/5 mg–10 mg/10 mg COVERSYL 2 mg–4 mg–8 mg CRESTOR 5 mg CRESTOR 5 mg–10 mg–20 mg CRESTOR 5 mg–10 mg–20 mg CUBICIN CUROSURF 120 mg/1.5 ml–240 mg/3 ml CYMBALTA 30 mg–60 mg CYSTADANE 1 g DATSCAN 74 MBq/ml DECAPEPTYL LP 3 mg–LP 11.25 mg DEROXAT 20 mg–20 mg/10 ml DIACOMIT 250 mg–500 mg DIVARIUS 20 mg DORIBAX 500 mg DROLEPTAN 2.5 mg/ml DUKORAL DUODOPA DUOPLAVIN 75 mg/75 mg–75 mg/100 mg DYNEPO 2000–3000–4000–5000–6000–8000–10000 DYSPORT 500 UNITES SPEYWOOD EBIXA 10 mg ECALTA 100 mg EFFENTORA 100 ␮g–200 ␮g–400 ␮g–600 ␮g–800 ␮g EFFEXOR LP 37.5 mg–LP 75 mg EFIENT 10 mg ELAPRASE 2 mg/ml ELLAONE 30 mg ELONVA ELOXATINE 5 mg/ml EMEND EMEND 40 mg ENBREL 25 mg–50 mg ENBREL 25 mg ENCEPUR 1.5 ␮g/0.5 ml ENDOBULINE 50 mg/ml ENTOCORT 3 mg EPIPEN 0.15 mg/0.3 ml–0.30 mg/0.3 ml ERBITUX 2 mg/ml ERBITUX 5 mg/ml ERBITUX 5 mg/ml EUCREAS 50 mg/850 mg–50 mg/1000 mg EVICEL 1 ml–2 ml–5 ml EVOLTRA 1 mg/ml EXELON 1.5 mg–3 mg–4.5 mg–6 mg–2 mg/ml EXELON 4.6 mg/24 h–9.5 mg/24 h EXFORGE HCT 5 mg/160 mg/12.5 mg–10 mg/160 mg/12.5 mg–5 mg/160 mg/25 mg– 10 mg/160 mg/25 mg EXJADE 125 mg–250 mg–500 mg EXUBERA 1 mg–3 mg FACTANE 100 U.I./ml FEIBA 500 U/20 ml–100 U/20 ml FEIBA 500 U/20 ml–1000 U/20 ml FEMARA FEMARA 2.5 mg FEMARA 2.5 mg FEMSEPTEVO 50 ␮g/7 ␮g/24 heures FENDRIX FER AP-HP 0.5 mg FER FERREUX SCHWARZ PHARMA 100 mg

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Appendix A. (continued) FERRISAT 50 mg/ml FIBROGAMMIN 62.5 U/ml FINACEA 15% FIRAZYR 30 mg FIRDAPSE 10 mg FIRMAGON 80 mg–120 mg FLEXEA 625 mg FLISINT 20 mg FLOLAN FLUDARA 10 mg FORMOAIR 12 ␮g/dose FORSTEO 20 ␮g/80 ␮l FORSTEO 20 ␮g/80 ␮L FOSAVANCE FOSRENOL 250 mg–500 mg–750 mg–1000 mg FRAGMINE 5000 U.I. anti-Xa/0.2 ml FRAGMINE 7500 U.I. anti-Xa/0.3 ml–12,500 U.I. anti-Xa/0.5 ml– 15,000 U.I. anti-Xa/0.6 ml–18,000 U.I. anti-Xa/0.72 ml GADOVIST 1 mmol/l GADOVIST 1 mmol/ml GALVUS 50 mg GAMMANORM 165 mg/ml GARDASIL GLIADEL 7.7 mg GLIOLAN 30 mg/ml GLIVEC GLIVEC GLIVEC GLIVEC 100 mg–400 mg GLIVEC 100 mg–400 mg GLUCOPHAGE GLUCOPHAGE 500 mg–850 mg–1000 mg GLUSCAN GRANOCYTE 13 MUI–14 MUI GRANUDOXY Gé 100 mg GRAZAX 75,000 SQ-T GRAZAX 75,000 SQ-T GUTRON 2.5 mg GYMISO 200 ␮g HAVRIX 720 U/0.5 ml NOURRISSONS ET ENFANTS HAVRIX 1440 U/1 ml ADULTES HELICOBACTER TEST INFAI 45 mg HELI-KIT 75 mg HERCEPTIN 150 mg HERCEPTIN 150 mg HERCEPTIN 150 mg HEXVIX 85 mg HUMALOG NPL 100 U.I./ml HUMIRA 40 mg HUMIRA 40 mg HUMIRA 40 mg HUMIRA 40 mg HUMIRA 40 mg HYCAMTIN 0.25 mg–1 mg HYCAMTIN 4 mg HYCAMTIN 4 mg IASODOPA ILARIS 150 mg/ml IMUKIN INCRELEX 10 mg/ml INDUCTOS 12 mg INEGY 10 mg/20 mg–10 mg/40 mg INEXIUM 10 mg INEXIUM 40 mg INFRACYANINE 25 mg/10 ml INFRACYANINE 25 mg/10 ml INOFER INOVELON 100 mg–200 mg–400 mg INSPRA INSTANYL 50 ␮g/dose–100 ␮g/dose–200 ␮g/dose INSUPLANT 400 U.I./1 ml INTELENCE 100 mg

281

Appendix A. (continued) INTRALIPIDE 20% INTRINSA 300 ␮g/24 h INVEGA 3 mg–6 mg–9 mg IODENCE 100 et 200 ␮g IONITAN IONSYS 40 ␮g IRESSA 250 mg ISENTRESS 400 mg ISENTRESS 400 mg ISOFUNDINE IXIARO IZILOX 400 mg/250 ml JANUMET 50 mg/850 mg–50 mg/1000 mg JANUVIA 100 mg JANUVIA 100 mg JAVLOR 25 mg/ml KALETRA 100/25 mg KANOKAD 25 U.I./ml KEPIVANCE KEPPRA 100 mg/ml KEPPRA 100 mg/ml–100 mg–250 mg–500 mg–1000 mg KEPPRA 100 mg/ml–250 mg–500 mg–1000 mg KEPPRA 100 mg/ml solution buvable KEPPRA 100 mg/ml solution pour perfusion KEPPRA 250 mg–500 mg–1000 mg KINOX KIOVIG 100 mg/ml KIVEXA KUVAN 100 mg LAMICTAL 2 mg–5 mg–25 mg–50 mg–100 mg–200 mg–LAMICSTART 25–50 mg LAMICTAL 2 mg–5 mg–25 mg–50 mg–100 mg–200 mg–LAMICSTART 25–50 mg LAMICTAL 5 mg–25 mg–50 mg–100 mg–200 mg LEDERMYCINE 150 mg LEELOO 0.1 mg/0.02 mg LENOXE 100% (v/v) LERCAPRESS 10 mg/10 mg–20 mg/10 mg LEVACT 2.5 mg/ml LEVEMIR PENFILL et FLEXPEN LEVOCARNIL LEVOFREE 0.05% LIPIDEM 20% LORAMYC 50 mg LOVENOX 6000 U.I.–8000 U.I.–10,000 U.I.–30,000 U.I. LUCENTIS 10 mg/ml LUMINITY 150 ␮l/ml* LUTENYL 3.75 mg LYRICA 25–50–75–100–150–200–300 mg LYRICA 25/50/75/100/150/200/300 mg MABCAMPATH 30 mg/ml MABTHERA 100 mg–500 mg MABTHERA 100 mg–500 mg MABTHERA 100 mg–500 mg MABTHERA 100 mg–500 mg MACUGEN 0.3 mg MATRIFEN 12 ␮g–25 ␮g–50 ␮g–75 ␮g–100 ␮g/heure MEDROL 100 mg MENCEVAX MENINGITEC MENJUGATEKIT MENVEO MEPACT 4 mg MERONEM 1 g METHADONE AP-HP 1 mg–5 mg–10 mg–20 mg–40 mg METHOTREXATE BELLON 2.5 mg–5 mg–25 mg METVIXIA 168 mg/g MEZAVANT LP 1200 mg MIGARD 2.5 mg MIMPARA 30 mg–60 mg–90 mg MIMPARA 30 mg–60 mg–90 mg MINIRIN 0.1 mg–0.2 mg

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Appendix A. (continued) MINIRINMELT 60 ␮g–120 ␮g–240 ␮g MIOSTAT 100 ␮g/ml MIRCERA MIRENA 52 mg MODIGRAF 0.2 mg–1 mg MODIODAL 100 mg MONOTRAMAL LP 100 mg–LP 200 mg–LP 300 mg MOVICOL ENFANTS MOVIPREP MOZOBIL 20 mg/ml MULTAQ 400 mg MULTIHANCE 0.5 mmol/ml MYCAMINE 50 mg–100 mg MYOZYME 50 mg NAGLAZYME 1 mg/ml NANOGAM 50 mg/ml NAROPEINE 2 mg/ml NAROPEINE 5 mg/ml NAVELBINE 20 mg–30 mg NAVELBINE 20 mg–30 mg NAVELBINE 20 mg–30 mg NEBILOX 5 mg NEISVAC NEUPOGEN 30 MU–48 MU NEUPRO NEUPRO 2 mg/24 h–4 mg/24 h–6 mg/24 h–8 mg/24 h NEVANAC 1 mg/ml NEXAVAR 200 mg NEXAVAR 200 mg NEXEN 100 mg NIASPAN LP 375 mg–500 mg–750 mg–1000 mg NIMOTOP 30 mg NISIS 40 mg–80 mg–160 mg NISIS 40 mg–80 mg–160 mg NOVOMIX 50–70 Penfill 100 U/ml–50–70 FlexPen 100 U/ml NOXAFIL 40 mg/ml NOXAFIL 40 mg/ml NP100 PREMATURES AP-HP NPLATE 250 ␮g–500 ␮g OCTAPLEX OMNITROPE 5 mg/ml ONBREZ BREEZHALER–OSLIF BREEZHALER–HIROBRIZ BREEZHALER ONGLYZA 5 mg ONYTEC 80 mg/g ORAQIX ORENCIA 250 mg ORFADIN 2 mg–5 mg–10 mg OZURDEX PABAL 100 microgrammes/ml PAMIDRONATE DE SODIUM FAULDING PEDEA 5 mg/ml PEGASYS PEGASYS 135 ␮g–180 ␮g PERGOVERIS 150 U.I./75 U.I. PHOCYTAN PHOSPHOSORB 660 mg PLASMAVOLUME 6% PLAVIX 75 mg PLETAL 50 mg–100 mg PRADAXA 75 mg–110 mg PRAVADUAL 40 mg PREOTACT 100 ␮g PREVENAR 13 PREZISTA 300 mg PREZISTA 600 mg PREZISTA 75 mg–150 mg–300 mg–600 mg PRIALT 100 ␮g/ml PRIDAX 200 mg–300 mg–400 mg PRINCI B PROCORALAN 5 mg–7.5 mg PROGRAF 0.5 mg–1 mg–5 mg–5 mg/ml PROTELOS 2 g

Appendix A. (continued) QUASYM LP 10 mg–20 mg–30 mg QUTENZA 179 mg RAFTON 3 mg RANEXA 375 mg–500 mg–750 mg RAPYDAN 70 mg/70 mg RASILEZ 150 mg–300 mg RASILEZ HCT REBETOL 200 mg RECTOGESIC 4 mg/g RELENZA 5 mg/dose RELISTOR 12 mg/0.6 ml REMICADE 100 mg REMICADE 100 mg REMICADE 100 mg REMODULIN 1 mg/ml–2.5 mg/ml–5 mg/ml–10 mg/ml REMOVAB 10 ␮g–50 ␮g RENAGEL 400 mg–800 mg REVASC 15 mg/0.5 ml REVATIO 20 mg REVLIMID 5 mg–10 mg–15 mg–25 mg REVOLADE 25 mg–50 mg REYATAZ 50 mg/1.5 g–150 mg–200 mg–300 mg RHESONATIV 625 U.I./ml RIAMET 20 mg/120 mg RISPERDAL ROACTEMRA 20 mg/ml SALVACYL LP 11.25 mg SAMSCA 15 mg–30 mg SANDOGLOBULINE 120 mg/ml SAVENE 20 mg/ml SEBIVO 600 mg SECTRAL 40 mg/ml SERETIDE 50/25 ␮g/dose SEROPLEX 5 mg–10 mg–20 mg SEVIKAR 20 mg/5 mg–40 mg/5 mg–40 mg/10 mg SIFROL 0.125 mg–0.25 mg–0.5 mg–1 mg SIKLOS 1000 mg SINGULAIR 4 mg SINGULAIR 5 mg SOLARAZE 3% SOLIRIS 300 mg SOMATULINE L.P. 60 mg–90 mg–120 mg SPIRIVA 18 ␮g SPORANOX 10 mg/ml–100 mg SPRYCEL 20 mg–50 mg–70 mg STIMU-TSH 125 ␮g/ml SUBCUVIA 160 g/l SUBCUVIA 160 mg/ml SUBOXONE 2 mg/0.5 mg–8 mg/2 mg SUTENT 12.5 mg–25 mg–50 mg SUTENT 12.5 mg–25 mg–50 mg TACHOSIL TAHOR 10 mg–20 mg–40 mg–80 mg TAMIFLU 75 mg–12 mg/ml TANDEMACT 30 mg/2 mg–30 mg/4 mg TARCEVA 25 mg–100 mg–150 mg TARCEVA 25 mg–100 mg–150 mg TAREG 40 mg–80 mg–160 mg TAREG 40 mg–80 mg–160 mg TAREG 40 mg–80 mg–160 mg TASIGNA 200 mg TAXOL 6 mg/ml TAXOTERE 20 mg–80 mg TAXOTERE 20 mg–80 mg TAXOTERE 20 mg–80 mg TAXOTERE 20 mg–80 mg TECHNESCAN DMSA TECHNESCAN PYP TEGELINE 50 mg/ml TEGELINE 50 mg/ml TEGRETOL 20 mg/ml–200 mg–LP 200 mg–LP 400 mg TELZIR 50 mg/ml–700 mg

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Appendix A. (continued) TEMERIT 5 mg TEMODAL 5 mg–20 mg–100 mg–250 mg THALIDOMIDE CELGENE 50 mg THELIN 100 mg THERACAP THYROGEN 0.9 mg TICOVAC 0.25 ml ENFANTS TICOVAC 0.50 ml ADULTES TIGREAT 2.5 mg TIORFANOR 175 mg TOBI 300 mg/5 ml TOCTINO 10 mg–30 mg TOFRANIL 10 mg–25 mg TORISEL 25 mg/ml TORISEL 25 mg/ml TRACLEER 32 mg TRACLEER 62.5 mg–125 mg TRACLEER 62.5 mg–125 mg TRACLEER 62.5 mg–125 mg TRANXENE 20 mg B/50 TRIATECKIT TRIFLUCAN TRONOTHANE 1% TRUVADA TYGACIL 50 mg TYVERB 250 mg TYVERB 250 mg UBIT 100 mg ULTRAVIST 300–370 ULTRAVIST 300 (300 mg d’Iode/ml)–370 (370 mg d’Iode/ml) UMATROPE 6 mg–12 mg–24 mg UMATROPE 6 mg/3 ml–12 mg/3 ml–24 mg/3 ml UVADEX 20 ␮g/ml VALDOXAN 25 mg VAQTA 25 U/0.5 ml–ENFANT VAQTA 50 U/1 ml–ADULTES VARNOLINE CONTINU VASOVIST 0.25 mmol/ml VECTIBIX 20 mg/ml VEDROP 50 mg/ml VELCADE 1 mg–3.5 mg VELCADE 3.5 mg VELMETIA 50 mg/850 mg–50 mg/1000 mg VENOFER VENTOLINE 1.25 mg/2.5 ml–2.5 mg/2.5 ml–5 mg/2.5 ml–5 mg/1 ml VERSATIS 5% VERSATIS 5% VESICARE 5 mg–10 mg VESICARE 5 mg–10 mg VFEND VICTOZA 6 mg/ml VIDAZA 25 mg/ml VIMPAT 10 mg/ml–15 mg/ml–50 mg–100 mg–150 mg–200 mg VIRAFERONPEG 50 ␮g–80 ␮g–100 ␮g–120 ␮g–150 ␮g VIREAD 245 mg VISANNE 2 mg VITAMINE C 10% Aguettant VIVAGLOBIN 160 mg/ml VOLIBRIS 5 mg–10 mg VOLTARENE EMULGEL 1% VPRIV 400 Unités WILZIN 25 mg–50 mg XAGRID 0.5 mg XAMIOL 50 ␮g/0.5 mg/g XARELTO 10 mg XELEVIA 100 mg XELODA 150 mg–300 mg XELODA 150 mg–500 mg XENAZINE 25 mg XENICAL 120 mg XILANIK 100 mg/20 mg–200 mg/20 mg XOLAIR 150 mg

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Appendix A. (continued) XOLAIR 75 mg–150 mg XYREM 500 mg/ml YONDELIS 0.25 mg YONDELIS 0.25 mg–1 mg ZANEXTRA 10 mg/10 mg–20 mg/10 mg ZAVEDOS 5 mg–10 mg–25 mg ZAVESCA 100 mg ZEBINIX 800 mg ZELITREX 500 mg ZONEGRAN 25 mg–50 mg–100 mg ZOPHREN 2 mg/ml ZYPADHERA 210 mg–300 mg–405 mg

References [1] ICH Harmonised tripartite guideline. In: Efficacy guidelines, 1997. http://www.ich.org/products/guidelines/efficacy/article/efficacyguidelines.html [last accessed 14 November 2012].

[2] International Network of Agencies for Health Technology Assessment. HTA Resources. www.inahta.net/HTA/ [last accessed 14 November 2012].

[3] Drummond MF, Schwartz JS, Jönsson B, Luce BR, Neumann PJ, Siebert U, et al. Key principles for the improved conduct of health technology assessments for resource allocation decisions. International Journal of Technology Assessment in Health Care 2008;24(3):244–58 [discussion 362-8].

[4] Sorenson C, Kanavos P, Drummond M. Ensuring value for money in health care: the role of HTA in the European Union. Copenhaguen: European Observatory on Health Systems and Policies. World Health Organization; 2008.

[5] Le Polain M, Franken M, Koopmanschap M, Cleemput I. Les systèmes de remboursement des médicaments: Comparaison internationale et recommandations aux décideurs. KCE reports 147B. Centre fédéral d’expertise des soins de santé, Federaal Kenniscentrum voor de Gezondheidszorg; 2010. https://kce.fgov.be/sites/default/ files/page documents/KCE 147B systemes de remboursement des médicaments.pdf [last accessed 14 Novermber 2012].

[6] Bellanger M, Cherilova V, Paris V. The “Health Benefit Basket” in France. European Journal of Health Economics 2005;6(Suppl.

1):24–9.

[7] Bouvenot G. Service medical rendu des medicaments. Revue du rhumatisme 2006;73:409–12.

[8] Le Jeunne C. Assessment of actual benefits of new drugs by the Transparency Committee. Journal Francais D Ophtalmologie 2008;31(January (1)):90–3.

[9] Journal Officiel de la République Franc¸aise. http://www. legifrance.gouv.fr/ [last accessed 14 November 2012].

[10] Décret no99-915 du 27 octobre 1999 relatif aux médicaments remboursables et modifiant le code de la sécurité sociale. Journal Officiel; 1999. http://www.legifrance.gouv.fr/affichTexte. do;jsessionid=5B9D8B581081DFA1E73C1586628C32F9.tpdjo13v 3?cidTexte=JORFTEXT000000384938&categorieLien=id [last accessed 14 November 2012].

[11] Direction Générale de la Santé. “L’évaluation de l’impact du médicament sur la santé des populations et la santé publique. January 2002. http://www.rees-france.com/IMG/pdf/DOC evaluation dgs.pdf [last accessed 14 November 2012].

[12] World Bank. World development Report 1993, Investing in health.

Washington DC: World Bank; 1993.

[13] World Health Organization. Ad hoc Committee on Health Research relating to future intervention options: investing in health research ABD development. Geneva: World Health Organization; 1996.

[14] Murray CJL, Lopez A. The global burden of disease. Cambridge: Harvard University Press; 1996.

[15] World Health Organisation: the global burden of disease. 2004 update. Geneva: World Health Organization; 2008. http://www.who. int/healthinfo/global burden disease/GBD report 2004update.pdf [last accessed 14 November 2012].

[16] World Health Organisation: disease and injury regional estimates.

Regional burden of disease estimates for 2004. http://www. who.int/healthinfo/global burden disease/estimates regional/en/ index.html [last accessed 14 November 2012].

[17] Bajos N, Leridon H, Goulard H, Oustry P, Job-Spira N, COCON Group.

Contraception: from accessibility to efficiency. Human Reproduction 2003;18(May (5)):994–9.

284

P. Maison et al. / Health Policy 112 (2013) 273–284

[18] Atkins DCS, Gartlehner G, Buckley DI, Whitlock EP, Berliner E, Matchar D. Assessing the applicability of studies when comparing medical interventions. AHRQ and the effective health care program. Journal of Clinical Epidemiology 2011;64(November (11)):1198–207.

[19] Brunton SA. Improving medication adherence in chronic disease management. Journal of Family Practice 2011;60(April (4 Suppl.

Improving)):S1–8.

[20] World Health Organization. Adherence to long term therapies: evidence for action. Switzerland; 2003.

[21] Abenhaim L, Le Gales C. Elaboration de la loi d’orientation de santé publique: rapport du Groupe Technique National de Définition des Objectifs (Report of the national technical group on the objectives of the Public Health Orientation law); Ministry of Health; ref no. 034000115, March 2003. http://www.ladocumentationfrancaise. fr/var/storage/rapports-publics/034000115/0000.pdf [last accessed 14 November 2012].

[22] Loi no. 2004-806 du 9 août 2004 relative à la politique de santé publique. Journal officiel de la République Franc¸aise n◦ 185 du 11 août 2004. http://www.legifrance.gouv.fr/affichTexte.do; jsessionid=0EC510DEF4366A3BCB491EB73C87CE74.tpdjo13v 3? cidTexte=JORFTEXT000000787078&categorieLien=id [last accessed 14 November 2012].

[23] L’état de santé de la population en France. Suivi des objectifs annexés à la loi de santé publique Rapport 2011. http://www.sante. gouv.fr/IMG/pdf/Etat sante-population 2011.pdf [last accessed 14 November 2012].

[24] Lemorton C. Commission des affaires culturelles familiales et sociales. Prescription, consommation et fiscalité des médicaments.

[25]

[26]

[27]

[28]

[29]

[30]

Paris: Assemblée nationale; 30 avril 2008. http://www.assembleenationale.fr/13/pdf/rap-info/i0848.pdf [last accessed 14 November 2012].

Massol M, Puech A, Boissel J-P. Participants in Round Table No 7, Giens XXII. How to anticipate the assessment of the public health benefit of new medicines? Therapie 2007;62(September–October (5)):427–35 [Epub 2008 Jan 19].

Clement FM, Harris A, Li JJ, Yong K, Lee KM, Manns BJ. Using effectiveness and cost-effectiveness to make drug coverage decisions: a comparison of Britain, Australia, and Canada. JAMA 2009;302(October (13)):1437–43.

Lexchin J, Mintzes B. Medicine reimbursement recommendations in Canada, Australia, and Scotland. American Journal of Managed Care 2008;14(September (9)):581–8.

Décret no. 2012-1116 du 2 octobre 2012 relatif aux missions médico-économiques de la Haute Autorité de santé. Journal officiel de la République Franc¸aise n◦ 0231 du 4 octobre 2012. http://www. legifrance.gouv.fr/affichTexte.do;jsessionid=75D5214C1AA1F18E04 5CA50FA0E96E4D.tpdjo13v 3?cidTexte=JORFTEXT000026453514& categorieLien=id [last accessed 14 November 2012].

Neumann PJ, Rosen AB, Greenberg D, Olchanski NV, Pande R, Chapman RH, et al. Can we better prioritize resources for costutility research? Medical Decision Making 2005;25(July–August (4)):429–36.

Catalá-López F, García-Altés A, Alvarez-Martín E, Gènova-Maleras R, Morant-Ginestar C, Parada A. Burden of disease and economic evaluation of healthcare interventions: are we investigating what really matters? BMC Health Services Research 2011;11(April): 75.