The "Temporary Recommendations for Use": A dual-purpose regulatory framework for off-label drug use in France.

In 2012, following the Mediator(®) (benfluorex) scandal, France displayed the ambitious goal to implement a regulatory framework for controlling off-label drug use: the "Temporary Recommendations for Use" (RTUs). It aims to regulate the use of pharmaceuticals outside the scope of a marketing authorization (MA) by establishing a framework for patient monitoring and data collection. This is intended to ensure that the benefit/risk ratio is favorable for the indication approved by the RTU. The granting of an RTU enables the reimbursement of off-label drug use and encourages pharmaceutical companies to expand their MA. Between 2012 and 2014, the regulator framework for RTUs was amended twice in order to allow the bypassing of an MA for economic reasons, when a licensed alternative drug exists (so far, this is only illustrated by the bevacizumab (Avastin(®))/ranibizumab (Lucentis(®)) case). The primary purpose of the RTU framework is interesting by implementing an original national control for off-label uses that respond to a public health need. The secondary purpose is more controversial as it promotes off-label use. This has raised legal issues and has created a ground for litigation between pharmaceutical firms and health authorities. RTUs provide an interesting example for other countries that are exploring the possibility of regulating off-label drug use. At the same time, the processes surrounding the implementation of RTUs illustrate the difficulties of public policies to balance public health needs, safety and economic goals.

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.

Temporary authorization for use: does the French patient access programme for unlicensed medicines impact market access after formal licensing?

BACKGROUND: To reach the French market, a new drug requires a marketing authorization (MA) and price and reimbursement agreements. These hurdles could delay access to new and promising drugs. Since 1992, French law authorizes the use of unlicensed drugs on an exceptional and temporary basis through a compassionate-use programme, known as Temporary Authorization for Use (ATU). This programme was implemented to improve early access to drugs under development or authorized abroad. However, it is suspected to be inflationary, bypassing public bodies in charge of health technology assessment (HTA) and of pricing. OBJECTIVE: The aim of this study is to observe the market access after the formal licensing of drugs that went through this compassionate-use programme. METHODS: We included all ATUs that received an MA between 1 January 2005 and 30 June 2010. We first examined market access delays from these drugs using the standard administrative path. We positioned this result in relation to launch delays observed in France (for all outpatient drugs) and in other major European markets. Second, we assessed the bargaining power of a hospital purchaser after those drugs had obtained an MA by calculating the price growth rate after the approval. RESULTS: During the study period, 77 ATUs were formally licensed. The study concluded that, from the patient's perspective, licensing and public bodies' review time was shortened by a combined total of 36 months. The projected 11-month review time of public bodies may be longer than delays usually observed for outpatient drugs. Nonetheless, the study revealed significant benefits for French patient access based on comparable processing to launch time with those of other European countries with tight price control policies. In return, a 12 % premium, on average, is paid to pharmaceutical companies while drugs are under this status (sub-analysis on 56 drugs). CONCLUSIONS: In many instances, the ATU programme responds to a public health need by accelerating the availability of new drugs even though this study suggests an impact of the programme on the market access of these drugs for which the standard administrative path is longer than usual. In addition, pharmaceutical companies seem to market compassionate-use drugs with a presumed benefit/risk ratio at a price that guarantees a margin for future negotiation.

Pharmacokinetic/pharmacodynamic and time-to-event models of ribavirin-induced anaemia in chronic hepatitis C.

BACKGROUND: Interferon (IFN)-alpha and ribavirin combination therapy is the standard treatment for patients with chronic hepatitis C. However, ribavirin induces anaemia, especially by haemolysis, an adverse effect that is dose-limiting. OBJECTIVES: The aim of this study was to determine the relationships between ribavirin exposure and haemoglobin time-course, the time-to-anaemia and the covariates influencing these relationships in a population of patients treated for chronic hepatitis C. In addition, we also intended to establish a simple rule defining the need for dosage adjustment, using data obtained during the first month of treatment. METHODS: A retrospective analysis of 99 patients treated with IFNalpha plus ribavirin, with known dosage administration history, liver biopsy, demographic data, red blood cell counts, haemoglobin level (1037 measurements, median 10 per patient, range 2-31) and serum creatinine during the entire treatment period (178 days, range 53-382 days) was conducted. The data were analysed by a pharmacokinetic/pharmacodynamic population model and Weibull time-to-anaemia model. The rule defining the need for dosage adjustment was as follows: adjustment was needed if haemoglobin at steady state (H(ss)), estimated by the Bayesian method based on data obtained during the first month of treatment, was <12 g/dL for men or <11 g/dL for women. RESULTS: In both models, anaemia was related to the exposure of erythrocytes to ribavirin at time t (RT in mg/kg/day) by a maximum effect model, with RT(50) (dosage administration rate at which half the maximal effect is reached) approximately 12 mg/kg/day, and the significant covariates were initial haemoglobin level and bodyweight. Performances of a Bayesian prediction of H(ss) based on two early haemoglobin level measurements were encouraging (mean prediction error 0.12 g/dL, precision 0.85 g/dL). The proposed rule for the need of dosage adjustment was able to predict the actual evolution of the dosage regimen in 76% of non-adapted patients and 69% of adapted patients. CONCLUSION: The current guidelines for ribavirin dosage administration, based on bodyweight, are adequate, at least in the 45-105 kg range. Results indicate that Bayesian therapeutic monitoring could be helpful in controlling ribavirin-induced anaemia.