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Date 01.12.2008 Drug regulatory process, the supporting information systems, and the Escherproject Tommi Tervonen Faculty of Economics and Business University of Groningen [email protected] Date 01.12.2008 What is drug discovery and drug development? Ambit biosciences, commercial compound DBs (ambitbio.com) Example drug development costs of Trimeris Inc. (thebody.com) Date 01.12.2008 >What are Drug Information Systems (DISs)? >What are they being used for? >Who uses them? >What could they be used for? Discovery Preclinical trials Clinical trials Phase I Phase II Phase III Drug lifecycle Launch Development Marketing Phase IV clinical trials Date 01.12.2008 > DIS classes Compound DBs Pre/clinical trial DBs Summary of Product Characteristics (SmPC) DBs Adverse Drug Reaction (ADR) DBs CPOEs Discovery Preclinical trials Clinical trials Phase I Phase II Phase III Launch Development Marketing Phase IV clinical trials Compound DBs Pre/clinical trial DBs Time SmPC DBs ADR DBs CPOEs Date 01.12.2008 DIS Class Compound Compound CT CT CT CT CT CT / SmPC Name Cambridge structural database NCI 3D database clinicaltrials.gov Janus EudraCT Cochrane clinicalstudyresults.org NCI Drug Dictionary/thesaurus Data Type (Structural/Trial/Reg ulative/Patient) Details S S T T, R T T T T, R SmPC Drug Information Online R SmPC R SmPC RxList Lung Association of Saskatchewan lung disease drug repository SmPC SmPC SmPC ADR ADR ADR CPOE Drug Digest DailyMed EMEA EPAR MedEffect FDA ADR EMEA ADR Various R R R R R R R, P R Molecule crystal structures Molecular 3d structures Only CT settings and objectives Not functional yet No public functionality* CT Meta-analyses Detailed clinical study results SmPC and clinical trials for cancer drugs SmPC, drug interactions, condition medication, pill labeling SmPC, drug interactions, condition medication, pill labeling SmPCs for drugs with indication in lung diseases SmPC, drug interactions, pill labeling Detailed SmPC EPAR, incl. detailed SmPC Superficial ADR ADR quarterly reports No public functionality* SmPC through internal SmPC DB Organization Quanti tative (Yes/N Aggregat o) ed/Raw Name Non-profit (Yes/No) Y Y N Y N Y N R R A A, R A A A CCDC NCI NIH / FDA FDA EMEA Cochrane PhRMA N Y Y Y Y Y N N A Y N A NCI Micromedex, Cerner Multum, Wolter Kluwer, and others N N A RxList, Inc. N A Lung Association of Saskatchewan Y NLM EMEA Health Canada FDA EMEA Various N Y Y Y Y Y N N N N Y N N N N A A A A A A Date 01.12.2008 > The drug regulatory process Aims to make sure, that the drugs entering market are both safe and efficient Is laborious and slow Has relatively poor dissemination of results Doesn’t have transparent decision making Has recently all participating parties (drug industry, academia, and regulatory authorities) concerned about reforming the process > The main reason for reforming the regulatory process is to limit the linear growth of costs, but… Benefit-risk assessment Regulatory Logic Data and evidence Date 01.12.2008 >The current DISs don’t store regulatory information of sufficient precision; only aggregated information is available >Systematic, quantitative analysis is not possible without suitable quantitative information. Current Benefit-Risk analysis is qualitative! Discovery Preclinical trials Clinical trials Phase I Phase II Phase III Launch Development Marketing Phase IV clinical trials Compound DBs Pre/clinical trial DBs Time SmPC DBs ADR DBs CPOEs Date 01.12.2008 >Dose-response curve-fitting with various A-II antagonists Dose (mg/d) 100 200 0 300 0 0 -2 -2 -4 -6 -8 -10 Trough DBP (mm Hg) 8 16 24 32 -4 -6 -8 Dose (mg/d) 0 -10 50 100 Dose (mg/d) 150 200 0 0 0 -12 -2 Similar compounds, partially different indications, totally different clinical data! -4 -6 -8 -2 Trough DBP (mm Hg) -12 Trough DBP (mm Hg) Trough DBP (mm Hg) 0 Dose (mg/d) -4 -6 -8 -10 -10 -12 -12 80 160 240 320 Date 01.12.2008 Escher-project Workpackages 3.1 and 3.2 Date 01.12.2008 >ESCHER Is a TI-Pharma project with an objective to “demonstrate, that another way is possible” Incorporates 3 universities (+medical centers), 4 PostDocs, 17 PhD students, 4 drug development companies, and x external personnel WP 3.1: develop a new framework for drug benefit-risk assessment WP 3.2: build a drug information system that allows quantitative comparisons >Benefit-risk analysis of WP 3.1 requires data from the DIS of WP 3.2 Date 01.12.2008 >Escher 3.1 How can we measure benefits and risks? - Rank drugs and placebo for the same indication - Multiple criteria Inherent value judgements - But what about clashing / missing preference information? Quantitative data available - But data is uncertain! - Should it be used “as is”? Multi-Criteria Decision Analysis (MCDA) Date 01.12.2008 > Stochastic Multicriteria Acceptability Analysis (SMAA) Allows MCDA with imprecise criteria measurements and missing/incomplete preference information Criteria measurements can be defined through joint probability distributions -> RCT data can be used +directly Date 01.12.2008 > SMAA central weights Central weights are “typical” preferences that favour different alternatives Although drug A might not have “better” benefitrisk ratio than drug B with all preferences, some preferences usually support A as well Elevator planning with SMAA Date 01.12.2008 >Rank acceptability indices describe stability of ranking, and can be used in risk management Rank acceptability indices 80 CAS 50 DAK 30 b9 CAS DAK TAN RAB b1 OUJ b3 MAR Rank AGA b5 BEN b7 Alternative BEN 60 40 Acceptability FEZ Choosing a location for a new cargo airport in Morocco with SMAA 70 TAN AGA RAB 20 OUJ 10 MAR 0 FEZ Date 01.12.2008 >Escher 3.2 Supports various other workpackages by building an information system that allows quantitative analyses Web-based drug repository (Java, Spring) Agile development Enables various new research topics Why Agile? Date 01.12.2008 Date 01.12.2008 >How to model relevant data (SmPC)? 5.1 Pharmacodynamic properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: {group [lowest available level]}, ATC code: {code} [For products approved under “conditional approval”, include the following statement:] <This medicinal product has been authorised under a so-called “conditional approval” scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency (EMEA) will review new information on the product every year and this SPC will be updated as necessary.> [For products approved under “exceptional circumstances”, include the following statement:] <This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to <the rarity of the disease> <for scientific reasons> <for ethical reasons> it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.> Pharmacotherapeutic group: Drugs used in erectile dysfunction. ATC Code: G04B E03 … Studies in vitro have shown that sildenafil is selective for PDE5, which is involved in the erection process. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved in the phototransduction pathway in the retina. At maximum recommended doses, there is an 80-fold selectivity over PDE1, and over 700-fold over PDE2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. … Template Viagra SmPC Date 01.12.2008 >US Food and Drug Administration (FDA) is working to build a DIS (Janus) incorporating “raw” data >The European Medicines Agency (EMEA) doesn’t see aggregated data as a problem >Cause? FDA is multidisciplinary, EMEA consists of medical doctors Date 01.12.2008 >Conclusions Drug regulatory process is in need of reform Current drug information systems cannot support the future needs, because they don’t store the data in an appropriate format Escher-project tries to show, that a different “way of doing things” is possible Department of B&IS participates in the project through Bert, Tommi, Vahid, Douwe (starting 1d/w@Jan), and 1 more PhDstudent (starting@Apr) Date 01.12.2008 >Thank you! >Q? >Future publications: T. Tervonen, V. Oskuee, E.O. de Brock, P.A. de Graef, H.L. Hillege (2008). Current status and future perspectives in Drug Information Systems (manuscript) T. Tervonen, D. Postmus, H.L. Hillege (2009) Multi-criteria decision analysis in drug benefit-risk analysis. Invited presentation, 23rd European Conference on Operational Research, Bonn, Germany. July 5-8, 2009 >/dev/null