Enhanced recovery protocols in colonic surgery: retrospective cohort analysis of economic impact from an institutional point of view.

BACKGROUND: Despite increasing evidence supporting the beneficial effects of enhanced recovery protocols (ERPs), their accurate economic impact on institutions remains lacking. The aim of this study was to analyze ERP economic impact in a French center in order to further encourage implementation. METHODS: All patients who underwent elective laparoscopic right or left colectomy for benign or malignant pathology from 2014 to 2017 in a single center were retrospectively reviewed. ERP according to national recommendations was effective starting November 2015. Perioperative data and all direct costs borne by the institution were collected for each patient. Patients who underwent colectomy before and after ERP implementation were compared. RESULTS: Overall, 288 patients were included of which 144 received conventional perioperative care (CC) and 144 received ERP. There were 161 (56%) men, median age was 71 (28-92) years, and 242 (84%) patients underwent surgery for malignant disease. Operative time, intraoperative blood loss, and severe postoperative complications were similar between both groups. ERP was associated with reduced Clavien-Dindo I-II postoperative complications (15% vs. 28%, p = 0.010) and overall in-hospital stay (6 vs. 7 days, p = 0.003). Overall institutional costs were lower in the ERP group although difference was not statistically significant (7022 vs. 7501 euros, p = 0.098). Estimated savings per patient reached a mean of 480 euros. CONCLUSIONS: In a tertiary French center, ERP was associated with reduced postoperative morbidity and in-hospital stay resulting in considerable cost savings. Although not significant, ERP resulted in positive economic impact even in an early implementation phase.

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.

Comparison of Two Financial Incentives to Encourage the Use of Adalimumab Biosimilars: Results of a French Experiment Close to Clinicians.

BACKGROUND: In 2018, the French government introduced two mutually exclusive financial incentives to increase etanercept and insulin glargine biosimilar use. The general case redirects 20% of the price difference between the reference product and its biosimilars to hospitals for every biosimilar dispensed in community pharmacies from hospital prescriptions. The experimental case redirects 30% to prescribing clinical units after hospital selection. Adalimumab was added to these incentives in 2019, after its first biosimilar was launched. OBJECTIVE: This retrospective observational study aimed to compare both general and experimental incentives after 19 months to assess the impact of directly incentivizing clinical units for adalimumab biosimilars. METHOD: The monthly number of adalimumab boxes dispensed in community pharmacies was linked to the corresponding hospital's prescription using IQVIA Xponent data from November 2017 to October 2020. The monthly mean rate of adalimumab biosimilars was compared between incentive groups and subgroups depending on hospitals' prior experience with the etanercept experimental case. RESULTS: General case hospitals had a significantly lower mean biosimilar uptake (16.7% vs 23.2%, p = 0.029) than those included in the experimental case. Twenty-three of the 40 hospitals in the experimental case and ten out of the 91 hospitals studied in the general case had already taken part in the etanercept experiment. Biosimilar uptake was higher, but not statistically significant, for hospitals with prior experience in the adalimumab general case group (p = 0.086). CONCLUSIONS: This study confirmed that incentivizing close to physicians was more effective in increasing the biosimilar rate. It also suggested that previous incentive experience positively influenced biosimilar penetration.

What About Offering a Financial Incentive Directly to Clinical Units to Encourage the Use of Biosimilars? Results of a Two-Year National Experiment in France.

BACKGROUND: Regarding the low penetration of biosimilars in the French market, in 2018, the government introduced two mutually exclusive financial incentives to increase biosimilar use. They redirect 20% (general case) or 30% (experimental case) of the price difference between the reference product and its biosimilar to hospitals for every biosimilar delivered in retail pharmacies from these hospital prescriptions. The experimental case specifically targets prescribing clinical units. OBJECTIVES: Our study aimed to assess whether the new payment scheme closer to physicians (experimental case) improved etanercept biosimilar penetration after 25 months. METHOD: We evaluated hospital prescriptions using IQVIA Xponent data. The monthly number of etanercept boxes delivered in retail pharmacies was linked to the corresponding hospital prescription. The impact of the experimental case on the etanercept biosimilar rate was assessed by a difference-in-difference method. RESULTS: Among the 39 hospitals studied in the experimental case compared with the 169 belonging to the general case, a similar growing trend of etanercept biosimilar use was observed before October 2018. At the start of the experiment, there was an acceleration of biosimilar penetration in the experimental group, until both groups reached a plateau. A significant double difference estimator of 9.72 percentage points in favor of the experiment confirmed this (p < 2.2.10-16). CONCLUSION: The French experimental incentive appeared to be more effective at increasing biosimilar use. As it is expected to be implemented in all hospitals, the knowledge gained during this testing phase should allow adjustment of some of its terms and increase physician engagement.

Effect of cyamemazine on the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone: a preliminary retrospective study.

Administration of cyamemazine, an antipsychotic drug with anxiolytic properties, together with other antipsychotic agents is common in patients with schizophrenia. This retrospective study investigated the effects of cyamemazine on the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone in 47 patients treated with 1 to 12 mg/day of risperidone. Of these 47 patients, 24 were receiving cyamemazine comedication ("cyamemazine" group) and 23 patients were treated with risperidone alone ("control" group). Plasma concentrations were measured using a high-performance liquid chromatographic method with photodiode-array ultraviolet detection. The median plasma concentration of risperidone was significantly higher in the cyamemazine group (31.5 ng/mL) than in the control group (5.0 ng/mL), whereas the 9-hydroxyrisperidone median concentration was significantly lower in the cyamemazine group (16.5 ng/mL versus 39.0 ng/mL in the control group). However, the sum of risperidone plus 9-hydroxyrisperidone (active moiety) plasma concentration was not significantly affected by cyamemazine comedication. A combination with cyamemazine resulted in an inverted metabolic ratio (risperidone/9-hydroxyrisperidone). These findings suggest that cyamemazine inhibits the 9-hydroxylation of risperidone and is probably an inhibitor of cytochrome P450 2D6 as are many other phenothiazine drugs.

Preconceived notions about biosimilars-a French experience.

Since the arrival of the first biosimilar monoclonal antibodies into the market, many information has been circulating, leading to preconceived notions for patients and healthcare professionals. In a pressing economic context and faced with a growing number of available biosimilars, we (clinician, patient association, biologist, pharmacists, health economists) propose to take stock by trying to distinguish facts from misconceptions.

Development and validation of a high-performance liquid chromatography method using diode array detection for the simultaneous quantification of aripiprazole and dehydro-aripiprazole in human plasma.

A high-performance liquid chromatography method with diode array detection (HPLC-DAD) was developed for quantification of aripiprazole and dehydro-aripiprazole, in human plasma. After a simple liquid-liquid extraction, chromatographic separation was carried out on a C18 reversed-phase column, using an ammonium buffer-acetonitrile mobile phase (40:60, v/v). The total run time was only 7 min at a flow-rate of 1.0 ml/min. The precision values were less than 12% and the accuracy values were ranging from 98 to 113% and the lower limit of quantification was 2 ng/ml for both compounds. Calibration curves were linear over a range of 2-1000 ng/ml. The mean trough plasma concentrations in patients treated with aripiprazole were 157 and 29 ng/ml for aripiprazole and dehydro-aripiprazole, respectively.

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.

The new regulatory tools of the 2016 Health Law to fight drug shortages in France.

Drug shortages are becoming worrying for public health in the European Union. The French public authorities first took action against the causes of drug shortages in 2011 with a law, followed by a decree in 2012 to overcome the dysfunctions of the pharmaceutical distribution channel. These texts would establish emergency call centres implemented by pharmaceutical companies for pharmacists and for wholesalers to inform of shortages, and would oblige pharmaceutical companies to inform health authorities of any risk of potential shortage situation; they would also reinforce the declaration regime of the territory served by wholesalers. Through the Health Law of January 2016, France acquired new regulatory tools in order to fight against these shortages and wanted to target the drugs for which they are the most detrimental: the major therapeutic interest (MTI) drugs. Furthermore, this new text reinforces the legal obligations of pharmaceutical companies and of wholesalers for drug shortages and sets out the enforcement of sanctions in case of breach of these obligations. France's goal is ambitious: to implement coercive measures aiming at making the actors of the drug distribution channel aware of their responsibilities in order to take up the public health challenge triggered by drug shortages.

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.

[Care pathways of cancer patients: Modeling and risks analysis induced by oral anticancer drugs]. / Parcours de soins : modélisation et analyse des risques induits par les anticancéreux oraux.

The care pathway of cancer patients is complex and therefore difficult to define. The oral anticancers (AKPO) have shown their benefits to patients and health professionals, however, the risks induced on the care pathway remain unknown. The objective of the study is to define, quantify the risks from AKPO and their effects on the care pathway (breakdown [Ds], rupture [Rt]). From the proposed care pathway model, FMEA method is used to analyze risks. For the 3 identified processes (1 monotherapy, 2 bitherapies: 2 AKPO or 1 AKPO/1 AKIV), analysis revealed an average of 91 risks, 173 Ds, 147 Rt, increased for 1 AKPO/1 AKIV therapy. The administration and delivery are the most risky steps. The lack of training and information of patients and healthcare professionals generates 80% of Ds and Rt. This model confirms the complexity, variability of the care pathway. The development of actions to improve town-hospital coordination and exchange of information is required to optimize and secure the route, confirming the objectives of "Plan Cancer 3".

Trabectedin for sarcomas in daily clinical practice: analysis of 45 patients treated in a French institution.

INTRODUCTION: The active clinical research programme of trabectedin continues to improve knowledge on the therapeutic activity and toxicity of the drug in the treatment of soft tissue sarcomas (STS). In contrast, limited number of data is available on its use outside of clinical trials. PATIENTS AND METHODS: We retrospectively analysed efficacy and safety of trabectedin when given in daily practice to patients with advanced/recurrent STS. Outcomes were compared with previously published works including clinical and retrospective studies. RESULTS: Forty-five patients received trabectedin between January 2005 and May 2014. Sarcomas were histologically heterogeneous in our cohort (37.9% of other types of sarcomas than L-sarcomas). Our patients had poor baseline health status (ECOG ≥ 2 [17.8%]) and had received multiple previous lines of chemotherapy. Patients received a median of five cycles of treatment (1-22). The objective response rate was statistically superior in our study (37.8%) compared to the other works. However, median PFS was similar. Trabectedin-related serious adverse events (AEs) induced hospitalizations and treatment discontinuation in 22 and 15% of patients. CONCLUSION: This analysis confirms the efficacy of trabectedin in clinical practice (with a third of patients experiencing prolonged disease control) and highlighted the importance of its administration as early line therapy to allow the best management of serious AEs.

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.