Heart failure with mildly reduced and preserved ejection fraction: A review of disease burden and remaining unmet medical needs within a new treatment landscape.

This review provides a comprehensive overview of heart failure with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF), including its definition, diagnosis, and epidemiology; clinical, humanistic, and economic burdens; current pharmacologic landscape in key pharmaceutical markets; and unmet needs to identify key knowledge gaps. We conducted a targeted literature review in electronic databases and prioritized articles with valuable insights into HFmrEF/HFpEF. Overall, 27 randomized controlled trials (RCTs), 66 real-world evidence studies, 18 clinical practice guidelines, and 25 additional publications were included. Although recent heart failure (HF) guidelines set left ventricular ejection fraction thresholds to differentiate categories, characterization and diagnosis criteria vary because of the incomplete disease understanding. Recent epidemiological data are limited and diverse. Approximately 50% of symptomatic HF patients have HFpEF, more common than HFmrEF. Prevalence varies with country because of differing definitions and study characteristics, making prevalence interpretation challenging. HFmrEF/HFpEF has considerable mortality risk, and the mortality rate varies with study and patient characteristics and treatments. HFmrEF/HFpEF is associated with considerable morbidity, poor patient outcomes, and common comorbidities. Patients require frequent hospitalizations; therefore, early intervention is crucial to prevent disease burden. Recent RCTs show promising results like risk reduction of composite cardiovascular death or HF hospitalization. Costs data are scarce, but the economic burden is increasing. Despite new drugs, unmet medical needs requiring new treatments remain. Thus, HFmrEF/HFpEF is a growing global healthcare concern. With improving yet incomplete understanding of this disease and its promising treatments, further research is required for better patient outcomes.

Analysis of health economics assessment reports for pharmaceuticals in France - understanding the underlying philosophy of CEESP assessment.

Background: Despite the guidelines for Economic and Public Health Assessment Committee (CEESP) submission having been available for nearly six years, the dossiers submitted continue to deviate from them, potentially impacting product prices. Objective: to review the reports published by CEESP, analyse deviations from the guidelines, and discuss their implications for the pricing and reimbursement process. Study design: CEESP reports published until January 2017 were reviewed, and deviations from the guidelines were extracted. The frequency of deviations was described by type of methodological concern (minor, important or major). Results: In 19 reports, we identified 243 methodological concerns, most often concerning modelling, measurement and valuation of health states and results presentation and sensitivity analyses; nearly 63% were minor, 33% were important and 4.5% were major. All reports included minor methodological concerns, and 17 (89%) included at least one important and/or major methodological concern. Global major methodological concerns completely invalidated the analysis in seven dossiers (37%). Conclusion: The CEESP submission dossiers fail to adhere to the guidelines, potentially invalidating the health economics analysis and resulting in pricing negotiations. As these negotiations tend to be unfavourable for the manufacturer, the industry should strive to improve the quality of the analyses submitted to CEESP.

Towards a more transparent HTA process in Poland: new Polish HTA methodological guidelines.

Introduction: Health technology assessment (HTA) in Poland supports reimbursement decisions via the Polish HTA Agency (AOTMiT), whose guidelines were updated in 2016. Methods: We identified key changes introduced by the update and, before guideline publication, analysed discrepancies between AOTMiT assessments and the submitting marketing authorisation holders (MAHs) to elucidate the context of the update. We compared the clarity and detail of the new guidelines versus those of the UK's National Institute for Health and Care Excellence (NICE). Results: The update specified more precise requirements for items such as indirect comparison or input data for economic modelling. Agency-MAH discrepancies relating to the subjects of the HTA update were found in 14.6% of published documents. The new Polish HTA guidelines were as clear and detailed as NICE's on topics such as assessing quality of evidence and economic modelling, but were less informative when describing (for example) pairwise meta-analysis. Conclusions: The Polish HTA guidelines update demonstrates lessons learned from internal and external experiences. The new guidelines adhere more closely to UK HTA standards, being clearer and more informative. While the update is expected to reduce Agency-MAH discrepancies, there remain areas for development, such as providing templates to aid HTA submissions.

Supply-side and demand-side policies for biosimilars: an overview in 10 European member states.

OBJECTIVE: This study aimed to provide an overview of biosimilar policies in 10 EU MSs. Methods: Ten EU MS pharmaceutical markets (Belgium, France, Germany, Greece, Hungary, Italy, Poland, Spain, Sweden, and the UK) were selected. A comprehensive literature review was performed to identify supply-side and demand-side policies in place in the selected countries. Results: Supply-side policies for biosimilars commonly include price linkage, price re-evaluation, and tendering; the use of internal or external reference pricing varies between countries; health technology assessment is conducted in six countries. Regarding demand-side policies, pharmaceutical prescription budgets or quotas and monitoring of prescriptions (with potential financial incentives or penalties) are in place in eight and in seven countries respectively. Switching is generally allowed, but is solely the physician's responsibility. Automatic substitution is not recommended, or even forbidden, in most EU MSs. Prescription conditions or guidelines that apply to biosimilars are established in nearly all surveyed EU MSs. Conclusions: Important heterogeneity in policies on biosimilars was seen between (and even within) selected countries, which may partly explain variations in biosimilar uptake. Supply-side policies targeting price have been reported to limit biosimilar penetration in the long term, despite short-term savings, while demand-side policies are considered to positively impact uptake.

Value added medicines: what value repurposed medicines might bring to society?

Background & objectives: Despite the wide interest surrounding drug repurposing, no common terminology has been yet agreed for these products and their full potential value is not always recognised and rewarded, creating a disincentive for further development. The objectives of the present study were to assess from a wide perspective which value drug repurposing might bring to society, but also to identify key obstacles for adoption of these medicines and to discuss policy recommendations. Methods: A preliminary comprehensive search was conducted to assess how the concept of drug repurposing was described in the literature. Following completion of the literature review, a primary research was conducted to get perspective of various stakeholders across EU member states on drug repurposing (healthcare professionals, regulatory authorities and Health Technology Assessment (HTA) bodies/payers, patients, and representatives of the pharmaceutical industry developing medicines in this field). Ad hoc literature review was performed to illustrate, when appropriate, statements of the various stakeholders. Results: Various nomenclatures have been used to describe the concept of drug repurposing in the literature, with more or less broad definitions either based on outcomes, processes, or being a mix of both. In this context, Medicines for Europe (http://www.medicinesforeurope.com/value-added-medicines/) established one single terminology for these medicines, known as value added medicines, defined as 'medicines based on known molecules that address healthcare needs and deliver relevant improvements for patients, healthcare professionals and/or payers'. Stakeholder interviews highlighted three main potential benefits for value added medicines: (1) to address a number of medicine-related healthcare inefficiencies related to irrational use of medicines, non-availability of appropriate treatment options, shortage of mature products, geographical inequity in medicine access; (2) to improve healthcare system efficiency; and (3) to contribute to sustainability of healthcare systems through economic advantages. Current HTA framework, generic stigma, and pricing rules, such as internal reference pricing or tendering processes in place in some countries, were reported as the current key hurdles preventing the full recognition of value added medicines' benefits, discouraging manufacturers from bringing such products to the market. Discussion & conclusions: There is currently a gap between increasing regulatory authority interest in capturing value added medicines' benefits and the resistance of HTA bodies/payers, who tend to ignore this important segment of the pharmaceutical field. This situation calls for policy changes to foster appropriate incentives to enhance value recognition of value added medicines and deliver the expected benefit to society. Policy changes from HTA perspective should include: absence of any legislative barriers preventing companies from pursuing HTA; HTA requirements proportionate to potential reward; HTA decision-making framework taking into account the specific characteristics of value added medicines; eligibility for early HTA dialogues; Policy changes from pricing perspective should encompass: tenders/procurement policies allowing differentiation from generic medicines; eligibility for early entry agreement; non-systematic implementation of external and internal reference pricing policies; recognition of indication-specific pricing. At the same time, the pharmaceutical industry should engage all the stakeholders (patients, healthcare providers, HTA bodies/payers) in early dialogues to identify their expectations and to ensure the developed value added medicines address their needs.

French Health Technology Assessment of Antineoplastic Drugs Indicated in the Treatment of Solid Tumours: Perspective for Future Trends.

BACKGROUND: France is one of the European countries that spend the most on oncology drugs. To keep pharmaceutical expenditure under control, Health Authorities highly scrutinize market access of costly medicines. OBJECTIVE: To assess current and future trends in French health technology assessment (HTA) of antineoplastic drugs indicated in the treatment of solid tumours. METHODS: A review of the SMR and ASMR drivers of the Transparency Committee (CT) opinions issued for antineoplastic drugs indicated in the treatment of solid tumours and approved between 2009 and 2014 was performed to assess current trends in French health technology assessment (HTA), complemented by an expert board consultation to capture the critical issues on the future of antineoplastic drugs HTA. RESULTS: Thirty-one drugs indicated for the treatment of solid tumours were identified (77 % targeted therapies). Initial CT assessments were available for 26 drugs. Four key items in the CT assessment were identified: 1) Clinical trial methodology; 2) Acceptance of progression-free survival (PFS) as a valuable endpoint; 3) Transferability of clinical trials in clinical practice; 4) Unpredictability of CT decisions. Experts raised the important development of personalised medicines in oncology and key challenges for oncology products to generate information expected from HTA perspective. CONCLUSION: The French system remains committed to its values and philosophy (access of all innovations for everybody) which are threatened by the increasing launch of innovative therapies and budget constraint. Both HTA decision framework evolution and revision of the current pricing process should be considered in France to cope with these new challenges.

Current process and future path for health economic assessment of pharmaceuticals in France.

The Social Security Funding Law for 2012 introduced the Economic and Public Health Assessment Committee (Commission Evaluation Economique et de Santé Publique, or CEESP) in the Social Security Code as a specialised committee affiliated with the Haute Autorité de Santé in charge of providing recommendations and health economic opinions. This article provides an in-depth description of the CEESP's structure and working methods, and analyses the impact of health economic assessment on market access of drugs in France. It also points out the areas of uncertainty and the conflicting rules following the introduction of the health economic assessment in France. The authors also provide their personal opinion on the likely future of health economic assessment of drugs in France, including the possible merge of the CEESP and the Transparency Committee, the implementation of a French threshold, and the extension of health economic assessment to a larger number of products.

Market access pathways for cell therapies in France.

INTRODUCTION AND OBJECTIVE: Cell therapies can be classified into three main categories of products: advanced therapy medicinal products (ATMPs), ATMPs prepared on a non-routine basis (hospital exemptions), and minimally manipulated cells. Despite the benefits that cell therapies can bring to patients, they are subject to complex pathways to reach the market in France. The objective of this study was to identify and describe routes to market access for cell therapies in France and how these vary by regulatory status. METHODOLOGY: The research was structured following five main steps: (1) identification of the French regulatory framework for cell therapies; (2) identification of the health products categorised as cell therapies in France; (3) mapping of the market access pathways per category of cell therapy; (4) validation of findings by interviewing experts; and (5) development of a roadmap summarising market access pathways for cell therapies in France. The secondary research methodology included a comprehensive literature review conducted on websites of French public health institutions, complemented by a research for peer-reviewed articles, abstracts, and grey literature. RESULTS: Different market access pathways are possible depending on the cell therapy category. For ATMPs, market access pathways depend on the licensing status of the therapy. Licensed ATMPs followed the same market access pathways as 'conventional' pharmaceuticals, whereas not-yet-licensed ATMPs can be funded via a specific financial allowance under the framework of a Temporary Authorisation for Use procedure or various research programmes. For new ATMPs that are associated with a separate medical device (not considered as 'combined ATMPs') or associated with a new medical procedure, additional pathways will apply for the medical device and/or medical procedure to be reimbursed in the ambulatory settings or at hospital. The most likely funding option for ATMPs prepared on a non-routine basis is outside the diagnosis-related group (DRG) system through Missions of General Interest and Support to Contracting (MIGAC). For minimally manipulated cells, four different funding processes are applicable, depending on the type of activity: (1) inclusion in a DRG; (2) inclusion in the list of products and services qualifying for reimbursement (LPPR) (as a medical device); (3) an annual lump sum provided by regional health agencies; and (4) a financial allowance under Missions of General Interest (MIG). CONCLUSION: Cell therapy is a diverse and promising category of medical interventions. Its heterogeneity and complexity mean that several funding options and market access pathways apply. The main challenges facing cell therapies relate to (1) the identification of the most appropriate path to reimbursement, and (2) price setting, whereas high manufacturing costs of these therapies will dictate a high price that could only be achieved by a product that leads to important additional patient benefits compared to available treatment options. More specific funding options could emerge as the number of cell therapies increases and the authorities face the need to structure and stabilise funding. It will be vital for manufacturers to have a clear understanding of the various temporary funding opportunities early in a product's lifecycle for the adoption of a stepwise approach to secure permanent funding. Furthermore, due to the very limited Health Technology Assessment (HTA) bodies experience for cell therapies, manufacturers should enter into dialogues with HTA agencies at an early stage to optimise market access conditions.

Overview of external reference pricing systems in Europe.

BACKGROUND AND OBJECTIVES: External reference pricing (ERP) is a price regulation tool widely used by policy makers in the European Union (EU) Member States (MS) to contain drug cost, although in theory, it may contribute to modulate prices up and down. The objective of this article was to summarise and discuss the main findings of part of a large project conducted for the European Commission ('External reference pricing of medicinal products: simulation-based considerations for cross-country coordination'; see www.ec.europa.eu/health/healthcare/docs/erp_reimbursement_medicinal_products_en.pdf) that aimed to provide an overview of ERP systems, both on processes and potential issues in 31 European countries (28 EU MS, Iceland, Norway, and Switzerland). METHODS: A systematic structured literature review was conducted to identify and characterise the use of ERP in the selected countries, to describe its impact on the prices of pharmaceuticals, and to discuss the possible cross-country coordination issues in EU MS. This research was complemented with a consultation of competent authorities' and international organisations' representatives to address the main issues or uncertainties identified through the literature review. RESULTS: All selected countries applied ERP, except the United Kingdom and Sweden. Twenty-three countries used ERP as the main systematic criterion for pricing. In the majority of European countries, ERP was based on legislated pricing rules with different levels of accuracy. ERP was applied either for all marketed drugs or for specific categories of medicines; it was mainly used for publicly reimbursed medicines. The number of reference countries included in the basket varied from 1 to 31. There was a great variation in the calculation methods used to compute the price; 15 countries used the average price, 7 countries used the lowest price, and 7 countries used other calculation methods. Reported limitations of ERP application included the lack of reliable sources of price information, price heterogeneity, exchange rate volatility, and hidden discounts. Spill-over effect and downward price convergence have often been mentioned as ERP's consequences leading to pricing strategies from pharmaceutical companies. CONCLUSION: While ERP is widely used in Europe, processes and availability of price information vary from one country to another, thus limiting ERP implementation. Furthermore, ERP spill-over effect is a major concern of pharmaceutical firms leading to implementation of the so-called 'launch sequence strategies'.

A comparison of HAS & NICE guidelines for the economic evaluation of health technologies in the context of their respective national health care systems and cultural environments.

BACKGROUND: Health technology assessment (HTA) has been reinforced in France, notably with the introduction of economic evaluation in the pricing process for the most innovative and expensive treatments. Similarly to the National Institute for Clinical Excellence (NICE) in England, the National Authority for Health (HAS), which is responsible for economic evaluation of new health technologies in France, has published recommendations on the methods of economic evaluation. Since economic assessment represents a major element of HTA in England, exploring the differences between these methodological guidelines might help to comprehend both the shape and the role economic assessment is intended to have in the French health care system. METHODS: Methodological guidelines for economic evaluation in France and England have been compared topic-by-topic in order to bring out key differences in the recommended methods for economic evaluation. RESULTS: The analysis of both guidelines has revealed multiple similarities between France and England, although a number of differences were also noted regarding the elected methodology of analysis, the comparison of studies' outcomes with cost-effectiveness thresholds, the study population to consider, the quality of life valuation methods, the perspective on costs, the types of resources considered and their valuation, the discount rates to apply in order to reflect the present value of interventions, etc. To account for these differences, modifications will be required in order to adapt economic models from one country to the other. CONCLUSIONS: Changes in HTA assessment methods occur in response to different challenges determined by the different philosophical and cultural considerations surrounding health and welfare as well as the political considerations regarding the role of public policies and the importance of their evaluation.

Conflict of interest in Health Technology Assessment decisions: case law in France and impact on reimbursement decisions.

The slow reaction of French authorities to the so-called Mediator® saga in 2009 in France led to investigations that questioned the way conflicts of interest are reported. France implemented the Loi Bertrand ('Bertrand Law') in May 2013, known as the 'French Sunshine Act', with the aim of specifying the scope of disclosure obligations. This policy research reviewed the Loi Bertrand and reported case law from the French Council of State (COS) related to conflicts of interest in French Health technology assessment (HTA) opinion. The Loi Bertrand requires the publication of most of the agreements concluded between health-care professionals and companies and covers a vast range of health products. Commercial sales agreements of goods and services concluded between manufacturers and health-care professionals are a strong exception to this disclosure obligation. Six cases examined by the COS were analyzed, most of them related to the publication of guidelines or the removal of products from the list of reimbursed drugs and devices. These cases have been reviewed, as well as the impact of the ruling on reimbursement decisions. Four cases led to suspension or invalidation of decisions based on the Haute Autorité de Santé (HAS) recommendations due to conflicts of interest. In the two other cases, the HAS provided post hoc declarations of interest when required by the COS, and the COS considered the conflicts of interest as irrelevant for the decision. It appears that the COS based its decisions on two main criteria: the acknowledgement of negative conflicts of interest (a link with competitors) and the absence of declarations of conflicts of interest, which have to be presented when required by legal authorities irrespective of when they were completed (even posterior to the HAS opinion). However, the number of cases that have been decided against the HAS remains very limited with respect to the volume of assessments performed yearly. The strengthening of the regulation on declarations of interest might lead to more transparency but also to more cases decided by the COS. A new press investigation (in March 2015) related to alleged cases of conflict of interests led policy makers to amend the Bertrand Law in April 2015 and require the disclosure of amounts paid to health-care professionals by the industry.

Routine clinical assessment of cognitive functioning in schizophrenia, major depressive disorder, and bipolar disorder.

As more evidence points to the association of cognitive dysfunction with mental health disorders, the assessment of cognitive function in routine clinical care of these disorders is increasingly important. Despite this, it remains unknown how cognitive function is measured in routine clinical practice. The objective of this study was to assess psychiatrists' awareness of cognitive dysfunction in mental health disorders and their methods of cognitive assessment. An online survey was disseminated to psychiatrists in Europe, Asia, Australia and the United States. The survey asked about their perceptions of cognitive dysfunction in several mental health disorders, knowledge of cognitive assessment, method of cognitive assessment, and instruments used to measure cognitive function. Among the 61 respondents, most perceived that schizophrenia was associated with the greatest cognitive dysfunction. Many were unaware whether guidelines were available on cognitive assessment. In schizophrenia, 59% of psychiatrists reportedly used cognitive instruments, while the remainder relied solely on patient history interviews. The use of instruments to assess cognition in major depressive disorder (MDD) and bipolar disorder (BPD) was lower, 38% and 37% respectively. Of the reported instruments used, only a few were actually appropriate for use in the diseases of interest (12% in schizophrenia, 3% in MDD and 0% in BPD). Other instruments reported were clinical measures that did not assess cognition. These findings reveal some inconsistencies in psychiatrists' routine clinical evaluation of cognitive function. There appeared to be low use of true cognitive assessment instruments in clinical practice and confusion regarding what constituted a cognitive assessment instrument.

Pharmaceutical expenditure forecast model to support health policy decision making.

BACKGROUND AND OBJECTIVE: With constant incentives for healthcare payers to contain their pharmaceutical budgets, modelling policy decision impact became critical. The objective of this project was to test the impact of various policy decisions on pharmaceutical budget (developed for the European Commission for the project 'European Union (EU) Pharmaceutical expenditure forecast' - http://ec.europa.eu/health/healthcare/key_documents/index_en.htm). METHODS: A model was built to assess policy scenarios' impact on the pharmaceutical budgets of seven member states of the EU, namely France, Germany, Greece, Hungary, Poland, Portugal, and the United Kingdom. The following scenarios were tested: expanding the UK policies to EU, changing time to market access, modifying generic price and penetration, shifting the distribution chain of biosimilars (retail/hospital). RESULTS: Applying the UK policy resulted in dramatic savings for Germany (10 times the base case forecast) and substantial additional savings for France and Portugal (2 and 4 times the base case forecast, respectively). Delaying time to market was found be to a very powerful tool to reduce pharmaceutical expenditure. Applying the EU transparency directive (6-month process for pricing and reimbursement) increased pharmaceutical expenditure for all countries (from 1.1 to 4 times the base case forecast), except in Germany (additional savings). Decreasing the price of generics and boosting the penetration rate, as well as shifting distribution of biosimilars through hospital chain were also key methods to reduce pharmaceutical expenditure. Change in the level of reimbursement rate to 100% in all countries led to an important increase in the pharmaceutical budget. CONCLUSIONS: Forecasting pharmaceutical expenditure is a critical exercise to inform policy decision makers. The most important leverages identified by the model on pharmaceutical budget were driven by generic and biosimilar prices, penetration rate, and distribution. Reducing, even slightly, the prices of generics had a major impact on savings. However, very aggressive pricing of generic and biosimilar products might make this market unattractive and can be counterproductive. Worth noting, delaying time to access innovative products was also identified as an effective leverage to increase savings but might not be a desirable policy for breakthrough products. Increasing patient financial contributions, either directly or indirectly via their private insurances, is a more likely scenario rather than expanding the national pharmaceutical expenditure coverage.

EU pharmaceutical expenditure forecast.

BACKGROUND AND OBJECTIVES: With constant incentives for healthcare payers to contain their pharmaceutical budgets, forecasting has become critically important. Some countries have, for instance, developed pharmaceutical horizon scanning units. The objective of this project was to build a model to assess the net effect of the entrance of new patented medicinal products versus medicinal products going off-patent, with a defined forecast horizon, on selected European Union (EU) Member States' pharmaceutical budgets. This model took into account population ageing, as well as current and future country-specific pricing, reimbursement, and market access policies (the project was performed for the European Commission; see http://ec.europa.eu/health/healthcare/key_documents/index_en.htm). METHOD: In order to have a representative heterogeneity of EU Member States, the following countries were selected for the analysis: France, Germany, Greece, Hungary, Poland, Portugal, and the United Kingdom. A forecasting period of 5 years (2012-2016) was chosen to assess the net pharmaceutical budget impact. A model for generics and biosimilars was developed for each country. The model estimated a separate and combined effect of the direct and indirect impacts of the patent cliff. A second model, estimating the sales development and the risk of development failure, was developed for new drugs. New drugs were reviewed individually to assess their clinical potential and translate it into commercial potential. The forecast was carried out according to three perspectives (healthcare public payer, society, and manufacturer), and several types of distribution chains (retail, hospital, and combined retail and hospital). Probabilistic and deterministic sensitivity analyses were carried out. RESULTS: According to the model, all countries experienced drug budget reductions except Poland (+€41 million). Savings were expected to be the highest in the United Kingdom (-€9,367 million), France (-€5,589 million), and, far behind them, Germany (-€831 million), Greece (-€808 million), Portugal (-€243 million), and Hungary (-€84 million). The main source of savings came from the cardiovascular, central nervous system, and respiratory areas and from biosimilar entries. Oncology, immunology, and inflammation, in contrast, lead to additional expenditure. The model was particularly sensitive to the time to market of branded products, generic prices, generic penetration, and the distribution of biosimilars. CONCLUSIONS: The results of this forecast suggested a decrease in pharmaceutical expenditure in the studied period. The model was sensitive to pharmaceutical policy decisions.

Novel methodology for pharmaceutical expenditure forecast.

BACKGROUND AND OBJECTIVE: The value appreciation of new drugs across countries today features a disruption that is making the historical data that are used for forecasting pharmaceutical expenditure poorly reliable. Forecasting methods rarely addressed uncertainty. The objective of this project was to propose a methodology to perform pharmaceutical expenditure forecasting that integrates expected policy changes and uncertainty (developed for the European Commission as the 'EU Pharmaceutical expenditure forecast'; see http://ec.europa.eu/health/healthcare/key_documents/index_en.htm). METHODS: 1) Identification of all pharmaceuticals going off-patent and new branded medicinal products over a 5-year forecasting period in seven European Union (EU) Member States. 2) Development of a model to estimate direct and indirect impacts (based on health policies and clinical experts) on savings of generics and biosimilars. Inputs were originator sales value, patent expiry date, time to launch after marketing authorization, price discount, penetration rate, time to peak sales, and impact on brand price. 3) Development of a model for new drugs, which estimated sales progression in a competitive environment. Clinical expected benefits as well as commercial potential were assessed for each product by clinical experts. Inputs were development phase, marketing authorization dates, orphan condition, market size, and competitors. 4) Separate analysis of the budget impact of products going off-patent and new drugs according to several perspectives, distribution chains, and outcomes. 5) Addressing uncertainty surrounding estimations via deterministic and probabilistic sensitivity analysis. RESULTS: This methodology has proven to be effective by 1) identifying the main parameters impacting the variations in pharmaceutical expenditure forecasting across countries: generics discounts and penetration, brand price after patent loss, reimbursement rate, the penetration of biosimilars and discount price, distribution chains, and the time to reach peak sales for new drugs; 2) estimating the statistical distribution of the budget impact; and 3) testing different pricing and reimbursement policy decisions on health expenditures. CONCLUSIONS: This methodology was independent of historical data and appeared to be highly flexible and adapted to test robustness and provide probabilistic analysis to support policy decision making.

New drug regulations in France: what are the impacts on market access? Part 1 - Overview of new drug regulations in France.

Access to the French drug market is being impacted by an ongoing dramatic shift in practice as well as by two laws that came into force in December 2011. This new environment has been described and analyzed in two separate articles. The first article aims to describe the recent changes in access to the French drug market. The severity of the condition being treated, which used to be the main determinant of the drug's reimbursement level in France, has now been replaced with the drugs' efficacy criterion. Moreover, the effect size required for acknowledging drug innovation has substantially increased. Perceived evidence might also be more important than actual evidence. Comparative evidence and real-world data are considered critical conditions for marketing authorization. Cost-effectiveness studies will now be part of the market access requirements for all drugs in order to satisfy the selection criteria for medico-economic assessment.