- Email: [email protected]
Opportunities and Constraints to Harmonize Pharmacoeconomic Methods Across European Countries
Clinical Therapeutics Results: Our liver data suggest that the positive acute phase response is accompanied by an equally pronounced negative acute phase response, which includes primarily ADME genes. Several miRNAs were identified as significantly up- or downregulated during inflammatory conditions of diverse origin. In particular miR-130b was shown to be upregulated in inflammation and to downregulate the enzyme activity of several cytochromes P450 (CYPs 1A2, 2B6, 2C8, 2C9, 3A4) in human hepatocytes. Since modeling and experimental data suggested a central role for the orphan nuclear receptor RXRα , an obligatory heterodimerization partner for several nuclear receptors that regulate drug and lipid metabolism, we hypothesized that RXRα may be a target of inflammation-sensitive miRNAs. Indeed we could show direct binding of miR-130b to the 3’UTR of RXRα , and downregulation of RXRα protein in hepatocytes by miR-130b. Conclusions: The extensive negative acute phase response of the liver may help to save energy needed for the positive acute phase response in inflammatory conditions. Effective downregulation of ADME genes during inflammation appears to involve in part microRNAs, at least one of which (miR-130b) targets the coordinating nuclear receptor RXRα .
References 1. Rieger JK, Reutter S, Hofmann U, Schwab M, Zanger UM (2015): Inflammation-Associated microRNA-130b downregulates cytochrome P450 activities and directly targets CYP2C9. Drug Metab Dispos 43:884-8. 2. Rieger JK, Klein K, Winter S, Zanger UM (2013): Expression variability of absorption, distribution, metabolism, excretion-related microRNAs in human liver: influence of nongenetic factors and association with gene expression. Drug Metab Dispos. 41(10), 1752-62.
The Rennes Disaster: Lessons to be Drawn B. Bégaud1,2 University and University Hospital of Bordeaux, France; and 2 INSERM Research Center on Population Health, CR1219, Bordeaux, France On 10 January 2016, in Rennes (France), a first-in-human (FIH) phase 1 clinical trial turned into a drama: one healthy volunteer died and four others were hospitalized. It occurred during the multiple ascending dose (MAD) testing of a molecule (BIA 10-2474) acting on the brain « endocannabinoid system » as an inhibitor of the fatty-acid-amide-hydrolase (FAAH). Such an inhibition is expected to increase the levels of anandamide in brain tissues; the resulting effects being complex and partly unknown. Pharmacologically, the BIA 10-2474 is characterized by (i) a much lower potency than most of its predecessors, (ii) a poor selectivity for its target enzyme (FAAH), (iii) a long-lasting action and, (iv) an unusual steepness of its dose-effect curves. The animal toxicology (four species) showed toxic effects at the highest doses, particularly on the neurologic and reproductive systems; none of them made it possible to predict what would happen later in humans. Nothing special occurred in the volunteers (8 cohorts of 8) during the single ascending dose phase (0.25 mg to 100 mg/day). The MAD phase (6 cohorts of 8 volunteers) intended to test 6 doses each for 10 consecutive days. The scheduled dose escalation was 2.5, 5, 10, 20, 50, and 100 mg. The drama occurred on the 6th day of the 50mg administration. Five volunteers were hospitalized presenting various but purely central neurological symptoms: headaches, ataxia, consciousness disorders and memory impairment. One died 3 days after admission. Two presented with sequelae. In four of these volunteers, the MRI scan showed quite unusual, bilateral and symmetrical anomalies of highly variable intensity. They were located in the hippocampus and the pons, predominating in the anterior part
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and extending to the cerebral cortex in the most severely affected volunteers. This suggested a common mechanism and ruled out a primitive vascular or inflammatory process. After a 3-month assessment period, the temporary specialized scientific committee (TSSC), set up by the Directorate of the French Medicines Agency (ANSM), concluded that was observed in these volunteers (i) was clearly related to the molecule tested, (ii) resulted from a cumulative toxicity beyond a given threshold, (iii) ensued from an “off-target” mechanism, and not from stimulation of the endocannabinoid system, and (iv) was clearly favoured both by the specificities of the molecule tested (low selectivity, long-lasting effect, steep dose-effect curves, non-proportional pharmacokinetics, etc.) and by the design of the trial (geometric dose escalation, pharmacokinetic data of the preceding cohort not available, maximum dose to be tested 20-fold higher than that blocking FAAH activity in humans, etc.). As a result, the TSSC made six recommendations for conducting of FIH trials.
Reference ansm.sante.fr/var/ansm_site/storage/original/application/744c7c6da f96b141bc9509e2f85c227e.pdf
Opportunities and Constraints to Harmonize Pharmacoeconomic Methods Across European Countries Z. Kaló1,2 Eötvös Loránd University (ELTE), Budapest, Hungary; and 2 Syreon Research Institute, Budapest Objectives: Participants should be able to understand how pharmacoeconomics contribute to the value judgement of medical innovation, and how to manage the heterogeneity of methodologies and policy applications in different countries in the process pharmaceutical R&D. Purpose: The European Medicines Agency has successfully harmonized and integrated the drug regulatory approval process in the European Union. Although cost-effectiveness criterion represents the fourth hurdle of market access for new medicines, EU member states still have significant differences in the methodology of economic evaluations and how they use pharmacoeconomic evaluations for policy decisions. The presentation provides an overview on opportunities and constraints to harmonize pharmacoeconomic methods across European countries. Methods: The first step is to review major trends in the application of pharmacoeconomics for policy decisions by focusing on differences in methodologies and limitations in transferability of economic evaluation across EU member states. The second step is to review recent EU attempts for harmonization of methodologies and potential next steps in reducing heterogeneity. Results: There are significant differences across European countries in the methodologies of economic evaluation, especially in how they aggregate health benefits, how they manage time preference and how they apply decision-rules and thresholds. Major differences in the application of pharmacoeconomics are related to relative weight of economic evaluation compared to budget impact analysis, the use of these evaluations for price setting or reimbursement, and finally special criteria related to the severity or rarity of diseases. Conclusions: • Compared to the harmonisation of drug regulatory approval it is more difficult to harmonise pharmacoeconomic methods and the application of economic evaluations in the pricing and reimbursement process of new pharmaceuticals. • Although EUnetHTA has made a great step towards harmonisation of health technology assessment, pharmacoeconomic evaluations can never be fully centralized due to limitations of transferability.
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References 1. Rieger JK, Reutter S, Hofmann U, Schwab M, Zanger UM (2015): Inflammation-Associated microRNA-130b downregulates cytochrome P450 activities and directly targets CYP2C9. Drug Metab Dispos 43:884-8. 2. Rieger JK, Klein K, Winter S, Zanger UM (2013): Expression variability of absorption, distribution, metabolism, excretion-related microRNAs in human liver: influence of nongenetic factors and association with gene expression. Drug Metab Dispos. 41(10), 1752-62.
The Rennes Disaster: Lessons to be Drawn B. Bégaud1,2 University and University Hospital of Bordeaux, France; and 2 INSERM Research Center on Population Health, CR1219, Bordeaux, France On 10 January 2016, in Rennes (France), a first-in-human (FIH) phase 1 clinical trial turned into a drama: one healthy volunteer died and four others were hospitalized. It occurred during the multiple ascending dose (MAD) testing of a molecule (BIA 10-2474) acting on the brain « endocannabinoid system » as an inhibitor of the fatty-acid-amide-hydrolase (FAAH). Such an inhibition is expected to increase the levels of anandamide in brain tissues; the resulting effects being complex and partly unknown. Pharmacologically, the BIA 10-2474 is characterized by (i) a much lower potency than most of its predecessors, (ii) a poor selectivity for its target enzyme (FAAH), (iii) a long-lasting action and, (iv) an unusual steepness of its dose-effect curves. The animal toxicology (four species) showed toxic effects at the highest doses, particularly on the neurologic and reproductive systems; none of them made it possible to predict what would happen later in humans. Nothing special occurred in the volunteers (8 cohorts of 8) during the single ascending dose phase (0.25 mg to 100 mg/day). The MAD phase (6 cohorts of 8 volunteers) intended to test 6 doses each for 10 consecutive days. The scheduled dose escalation was 2.5, 5, 10, 20, 50, and 100 mg. The drama occurred on the 6th day of the 50mg administration. Five volunteers were hospitalized presenting various but purely central neurological symptoms: headaches, ataxia, consciousness disorders and memory impairment. One died 3 days after admission. Two presented with sequelae. In four of these volunteers, the MRI scan showed quite unusual, bilateral and symmetrical anomalies of highly variable intensity. They were located in the hippocampus and the pons, predominating in the anterior part
1
e110
and extending to the cerebral cortex in the most severely affected volunteers. This suggested a common mechanism and ruled out a primitive vascular or inflammatory process. After a 3-month assessment period, the temporary specialized scientific committee (TSSC), set up by the Directorate of the French Medicines Agency (ANSM), concluded that was observed in these volunteers (i) was clearly related to the molecule tested, (ii) resulted from a cumulative toxicity beyond a given threshold, (iii) ensued from an “off-target” mechanism, and not from stimulation of the endocannabinoid system, and (iv) was clearly favoured both by the specificities of the molecule tested (low selectivity, long-lasting effect, steep dose-effect curves, non-proportional pharmacokinetics, etc.) and by the design of the trial (geometric dose escalation, pharmacokinetic data of the preceding cohort not available, maximum dose to be tested 20-fold higher than that blocking FAAH activity in humans, etc.). As a result, the TSSC made six recommendations for conducting of FIH trials.
Reference ansm.sante.fr/var/ansm_site/storage/original/application/744c7c6da f96b141bc9509e2f85c227e.pdf
Opportunities and Constraints to Harmonize Pharmacoeconomic Methods Across European Countries Z. Kaló1,2 Eötvös Loránd University (ELTE), Budapest, Hungary; and 2 Syreon Research Institute, Budapest Objectives: Participants should be able to understand how pharmacoeconomics contribute to the value judgement of medical innovation, and how to manage the heterogeneity of methodologies and policy applications in different countries in the process pharmaceutical R&D. Purpose: The European Medicines Agency has successfully harmonized and integrated the drug regulatory approval process in the European Union. Although cost-effectiveness criterion represents the fourth hurdle of market access for new medicines, EU member states still have significant differences in the methodology of economic evaluations and how they use pharmacoeconomic evaluations for policy decisions. The presentation provides an overview on opportunities and constraints to harmonize pharmacoeconomic methods across European countries. Methods: The first step is to review major trends in the application of pharmacoeconomics for policy decisions by focusing on differences in methodologies and limitations in transferability of economic evaluation across EU member states. The second step is to review recent EU attempts for harmonization of methodologies and potential next steps in reducing heterogeneity. Results: There are significant differences across European countries in the methodologies of economic evaluation, especially in how they aggregate health benefits, how they manage time preference and how they apply decision-rules and thresholds. Major differences in the application of pharmacoeconomics are related to relative weight of economic evaluation compared to budget impact analysis, the use of these evaluations for price setting or reimbursement, and finally special criteria related to the severity or rarity of diseases. Conclusions: • Compared to the harmonisation of drug regulatory approval it is more difficult to harmonise pharmacoeconomic methods and the application of economic evaluations in the pricing and reimbursement process of new pharmaceuticals. • Although EUnetHTA has made a great step towards harmonisation of health technology assessment, pharmacoeconomic evaluations can never be fully centralized due to limitations of transferability.
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Volume 39 Number 8S