Defibrotide in Severe Sinusoidal Obstruction Syndrome: Medicine and Economic Issues.

In Europe, Defitelio (defibrotide) has a Market Authorization in curative treatment of severe sinusoidal obstruction syndrome (SOS) but not in prophylaxis (2013). In France, defibrotide has had a compassionate-use program since 2009. Today, the high cost of defibrotide remains a major hurdle for hospital budgets. Medicine and economic issues were evaluated for the 39 hospitals of the French Public Assistance-Hospitals of Paris (AP-HP). We analyzed literature reviews, consumption, and expenditures through AP-HP data in 2014 and patient profiles with defibrotide in the corresponding diagnostic-related groups (DRGs) and consulted a board of hematologists. Finally, 18 publications were selected. Between 2011 and 2014 consumption increased to €5.2M. In 2014, 80 patients receiving defibrotide were mainly ascribed to the DRG "hematopoietic stem cell transplantation" levels 3 or 4. The tariffs attributed to drugs (€3544 to 4084) cover a small part of treatment costs (€97,524 for an adult). French experts thus recommended a harmonization of indications in prophylaxis (off-label use), improvement of pretransplant care, and optimization of the number of vials used. The economic impact led experts to change their practices. They recommended the restriction of defibrotide use to SOS curative treatment and to high-risk situations in prophylaxis.

Economic and organizational impact of the changing hospital funding practices of erythropoiesis-stimulating agents on the management of care of dialysis patients in France.

AIM: Erythropoiesis-stimulating agents (ESAs) are particularly used to treat dialysis patients suffering from anemia due to renal failure. Since March 2014, ESAs have no longer been funded on top-of-diagnosis-related groups (DRGs) in French hospitals and are funded via DRGs. There are two ways to fund dialysis in French hospitals: the 'DRG for dialysis in session' and the 'off-dialysis DRG', which is not a DRG and consists in a supplement tariff specific to dialysis for patients hospitalized for another main reason than dialysis. The aim of this study is to assess the impact of this funding change on the dialysis activity and on the budget of the 37 University Public University Hospitals in Paris (10% of the hospitalizations in France). MATERIALS & METHODS: A before-after study (March-September 2013 vs March-September 2014) was conducted. Medical activity data (and ESAs consumption data) were used to assess the number and costs of DRGs associated with ESAs use. As we do not have access to the whole dialysis activity over the period studied, two hypotheses were considered: the proportion of the dialysis activity was constant between the two periods (Hypothesis A); the dialysis activity was correlated to ESA consumptions delivered by hospital pharmacies to healthcare units (Hypothesis B). A budget impact analysis was also conducted taking into account the evolution of DRG costs and ESA prices. RESULTS: The number of dialysis 'DRG for dialysis in session' with ESA consumption have increased by 5% (Hypothesis A) and decreased by 9% (Hypothesis B) between the two periods while the volume of 'off-dialysis DRG' with ESA consumption increased by 2% (Hypothesis A) and by 9% (Hypothesis B). The budget impact was -€1.02 million (Hypothesis A) and -€0.7 million (Hypothesis B) leading to a loss for our hospitals. CONCLUSION: There is no significant impact of the change of funding of ESAs on the hospital activity. The DRG-based payment is negative for the budget of our hospitals but is positive for the French National Health Insurance. Indeed, with the price decrease, the ESAs are more costly for hospitals (not funded on top-of-DRG), but less costly for the society.

Competition Between Biosimilars and Patented Biologics: Learning from European and Japanese Experience.

BACKGROUND: The expiry of patents for costly biologics is creating new momentum on the pharmaceutical market for biosimilars (copies of off-patent biologics) and paving the way for their development. However, little is known about the competitiveness of biosimilars versus their originators and other biologics belonging to the same therapeutic class. OBJECTIVE: The main goal of this study was to analyse the type of competition generated by the first biosimilars commercialised on key global biologic markets and to grasp their economic model. The secondary goal was to distinguish the main factors likely to influence the uptake of biosimilars on national markets. METHODS: To be included in this study, countries had to meet three conditions: the regulatory framework for the development of biosimilars closely resembled that in Europe, biosimilars were marketed in 2014, and the value of the biologics market was >US$3 billion. We analysed granulocyte colony-stimulating factors (GCSFs) and erythropoietins (EPOs) over the period 2007-2014 because these are the two main therapeutic classes that have been 'biosimilarised' and thus have many years of experience available. We assessed market sizes, retail/hospital distribution mixes, incentives for using biosimilars and price discounts for originators versus biosimilars. We conducted a linear regression analysis to assess the relationship between uptakes of biosimilars and the market shares of other biologics. RESULTS: The EU-5 (France, Germany, Italy, Spain and the UK) and Japanese GCSF and EPO markets are highly-country-specific. Uptake of biosimilars seems to depend on retail/hospital distribution mixes and on medical practice. Depending on the therapeutic class and the market sector (retail or hospital), biosimilars may compete with first-generation or second-generation products or both. Some incentives implemented to encourage the use of biosimilars had mixed results. Overall, discounts for biosimilars versus originators are not factors that determine global uptake of biosimilars. CONCLUSION: Unlike generics, there appears to be no unique economic model for biosimilars. Moreover, a new phenomenon occurs with biosimilars: sometimes, they are able to take market shares from subsequent generations of biologics.

[ATC and EphMRA classifications: evolution from 1996 to 2003 and comparative analysis]. / Classifications ATC et EphMRA: evolution entre 1996 et 2003 et analyse comparative.

In their daily practice, health practitioners use one or more pharmacotherapeutic classifications. This diversity of classifications impairs the exchange of drug information, while the use of international or European classifications facilitates this diffusion. The "Hospital National Center of Drugs Information" (CNHIM) has integrated ATC (Anatomical Therapeutic Chemical) and EphMRA (European Pharmaceutical Marketing Research Association) classifications into its "Thériaque" database and has given the ATC official status in France by publishing a French translation. The objective of this article was to analyse the evolution of these two classification systems between 1996 and 2003, and to compare their allocations (of codes) with those for the drugs present in Thériaque in January 2002. The ATC comprises 14 principal groups and five levels of hierarchy, while the EphMRA comprises 16 principal groups and three to four levels. In Thériaque, the ATC is linked to active substances and drugs, and the EphMRA to drugs. Data-processing requests have made it possible to make a comparative analysis. Each year, the two classification systems evolve in terms of addition, suppression, modification and subdivision. Two principal differences are evident in the allocations in Thériaque (class EphMRA K "Hospital solutions" versus class ATC B "Blood and blood forming organ"; class EphMRA T "Diagnostic agents" versus class ATC V "Various"). Classifications evolve in parallel or independently, and although they are closely related to one another, they retain their specificities in terms of structure and uses.

Biosimilar versus patented erythropoietins: learning from 5 years of European and Japanese experience.

BACKGROUND: Patent expiries on leading biologics are creating new momentum in the market for biosimilars (copies of off-patent biologics), paving the way for their development. However, little is known about the factors influencing the competition between biosimilars and their reference products (REF). OBJECTIVES: The aim of this study was to analyse key global erythropoietin (EPO) markets and factors affecting biosimilar EPO (BIOSIM-EPO) uptakes, and to identify countries where BIOSIM-EPOs have gained significant market shares. METHODS: Inclusion criteria for countries in the study were a biosimilar regulatory framework similar to the EU framework, and biological market value higher than US$2.5 billion. Factors evaluated included EPO market size, EPO retail/hospital distribution mix, national incentives to use biosimilars and BIOSIM-EPO/REF price differences. IMS Health provided EPO consumption in volumes, values, and EPO ex-manufacturer prices from 2007 to 2012. RESULTS: Japan: large-sized market, mixed retail/hospital distribution, no incentives, low BIOSIM-EPO uptake (6.8 % in 2012). France: large-sized market, dominant retail distribution, no incentives, low BIOSIM-EPO uptake (5.8 %). Spain and Italy: medium-sized market, dominant hospital distribution, no incentives, moderate BIOSIM-EPO uptakes (11.5 and 8.6 %). Germany: small-sized market, dominant retail distribution, presence of incentives, high BIOSIM-EPO uptake (30.4 %). UK: small-sized market, mixed retail/hospital distribution, no incentives, low BIOSIM-EPO uptake (2.0 %). BIOSIM-EPO/REF price differences play no role at a global level (-10.8 % in Germany and -26.9 % in Japan). CONCLUSIONS: EPO markets have proven to be highly country-specific. EPO market sizes, EPO retail/hospital distribution mixes and BIOSIM-EPO/REF price differences may not be determining factors of BIOSIM-EPO uptakes. Prescription and substitution incentives to use BIOSIM-EPO appear to be determining factors in Germany. The heterogeneity of national EPO markets makes it impossible to outline country profile types with significant BIOSIM-EPO penetrations.

Biosimilar granulocyte colony-stimulating factor uptakes in the EU-5 markets: a descriptive analysis.

BACKGROUND: Biosimilars are copies of biological reference medicines. Unlike generics (copies of chemical molecules), biologics are complex, expensive and complicated to produce. The knowledge of the factors affecting the competition following patent expiry for biologics remains limited. OBJECTIVES: The aims of this study were to analyse the EU-5 Granulocyte-Colony Stimulating Factor (G-CSF) markets and to determine the factors affecting the G-CSF biosimilar uptakes, particularly that of biosimilar prices relative to originators. METHODS: Data on medicine volumes, values, and ex-manufacturer prices for all G-CSF categories were provided by IMS Health. Volumes were calculated in defined daily doses (DDD) and prices in Euros per DDD. In the EU-5 countries, there is 5 years of experience with biosimilar G-CSFs (2007-2011). RESULTS: Two G-CSF market profiles exist: (1) countries with a high retail market distribution, which are the largest G-CSF markets with low global G-CSF biosimilar uptakes (5.4% in France and 8.5% in Germany in 2011); and (2) countries with a dominant hospital channel, which are the smallest markets with higher G-CSF biosimilar uptakes (12.4% in Spain and 20.4% in the UK). The more the decisions are decentralized, the more their uptakes are high. The price difference between G-CSF biosimilars and their reference plays a marginal role at a global level (price differences of +13.3% in the UK and -20.4% in France). CONCLUSION: The competition with G-CSF biosimilars varies significantly between EU-5 countries, probably because of G-CSF distribution channel differences. Currently, this competition is not mainly based on prices, but on local political options to stimulate tendering between them and recently branded second- or third-generation products.

Infovigilance: reporting errors in official drug information sources.

INTRODUCTION: The French drug database Thériaque (http://www.theriaque.org) developed by the (Centre National Hospitalier d'Information sur le Médicament) (CNHIM), is responsible for the dissemination of independent information about all drugs available in France. Each month the CNHIM pharmacists report problems due to inaccuracies in these sources to the French drug agency. In daily practice we devised the term "infovigilance": "Activity of error or inaccuracy notification in information sources which could be responsible for medication errors". The aim of this study was to evaluate the impact of CNHIM infovigilance on the contents of the Summary of Product Characteristics (SPCs). METHOD: The study was a prospective study from 09/11/2001 to 31/12/2002. The problems related to the quality of information were classified into four types (inaccuracy/confusion, error/lack of information, discordance between SPC sections and discordance between generic SPCs). MAIN OUTCOME MEASURES: (1) Number of notifications and number of SPCs integrated into the database during the study period. (2) Percentage of notifications for each type: with or without potential patient impact, with or without later correction of the SPC, per section. RESULTS: 2.7% (85/3151) of SPCs integrated into the database were concerned by a notification of a problem. Notifications according to type of problem were inaccuracy/confusion (32%), error/lack of information (13%), discordance between SPC sections (27%) and discordance between generic SPCs (28%). 55% of problems were evaluated as 'likely to have an impact on the patient' and 45% as 'unlikely to have an impact on the patient'. 22 of problems which have been reported to the French drug agency were corrected and new updated SPCs were published with the corrections. CONCLUSIONS: Our efforts to improve the quality of drug information sources through a continuous "infovigilance" process need to be continued and extended to other information sources.

Medicines containing pharmaceutical excipients with known effects: a French review.

OBJECTIVE: The 13/01/01 French decree published an official list of brands and their generic drugs and identified 38 groups of excipients with known effects which are responsible for side effects and contraindication respectively. Our objective was to review all medicines marketed in France containing these excipients and to disseminate this information to French health care practitioners. METHOD: The side effects and contraindications regarding these excipients have been documented in the French drug database Thériaque (http://www.theriaque.org). They were documented for each medicine containing these excipients in addition to the data mentioned in the Summary of Product Characteristics (SPC). Results were obtained on 1 June 2001 by using computerised queries from the database. RESULTS: Within the 38 groups, 300 specific excipients and derivatives with known effects were identified. Among the 8900 medicines (100%), 5567 medicines (62.6%) contained one or more of these excipients; 2483 contained 1 excipient, 1819 contained 2 excipients and 1265 contained 3 or more excipients; 410 side effects or contra-indications--were described according to the route of administration and the threshold dose. They were linked to these 5567 medicines; 5818 excipients with a threshold dose were mentioned in the 'composition' sections of these 5567 medicines. Among these 5818 excipients, 3385 quantitative doses were documented in the SPCs or EPARs. CONCLUSION: This review shows the extent of most of the excipients contained in medicines marketed in France. The dissemination of these data offsets the lack of information in the SPCs.