C) Curriculum for training in pharmaceutical medicine (relevant topics for specialist examinations):

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1 C) Curriculum for training in pharmaceutical medicine (relevant topics for specialist examinations): Entdeckung neuer Substanzen / Découverte de nouvelles substances / Drug discovery Wirkstoffe, Wirkstoffselektion Phytotpharmaka / NCEs / Biologika: Welches sind Charakteristika und die Unterschiede zwischen den 3 Gruppen in Bezug auf Entdeckung, Selektion erfolgversprechender Wirksubstanzen und Anwendungen. NCEs: Effiziente Herstellunsgverfahren wie Kombinatorische Chemie Selektion pharmakologisch aktiver Moleküle: High Through-put Screening (NCE), Leitsubstanzen (Phytopharmaka), wichtigste gentechnologische Techniken (Biologika). In vitro und in vivo Selektionserfahren. Biomarker, Rezeptoren, Zellsysteme, Tiermodell. Proof of concept am Tiermodell und am Menschen Labor- und Tierversuche Wozu dient die medizinische Toxikologie? Erfassung und Untersuchung unerwünschter Effekte Abschätzung des Nutzen/Risiko-Verhältnisses Feststellen der Sicherheit eines Medikamentes während Klinischen Studien Typen von präklinischen, toxikologischen Test:s Allgemeine Toxizität (akut, sub-chronisch, chronisch, Reproduktive Toxizität, Genotoxizität, Carcinogenizität, Lokale Verträglichkeit, Immunotoxizität. Tierpezies. Wichtigste in vitro Systeme Welches sind die häufigsten Untersuchungen (e.g. Verhalten, Histologie etc.) Dosis / Dosisfindung für weitere Untersuchungen Klassifikation / Einteilung go/no go Entscheidung ADME (Absorption, Distribution, Metabolism, Excretion) Topic S7A, Step 5 Note for Guidance on Safety Pharmacology Studies for Human Pharmaceuticals (CPMP/ICH/539/00 adopted November 2000) Topic S4A, Step 4 Note for guidance on Duration of Chronic Toxicity Testing in Animals (Rodent and non Rodent Toxicity Testing) (CPMP/ICH/300/95 adopted Nov. 98) Topic S1B, Step 4 Note for Guidance on Carcinogenicity: Testing for Carcinogenicity of Pharmaceuticals (CPMP/ICH/299/95 adopted Sept. 97) Topic S2B, Step 4 Note for Guidance on Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals (CPMP/ICH/174/95 adopted Sept. 97) Topic S2A, Step 5 Note for Guidance on Genotoxicity: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals (CPMP/ICH/141/95 adopted September 95) Topic S3A, Step 5 Note for Guidance on Toxicokinetics: A Guidance for Assessing Systemic Exposure in Toxicology Studies (CPMP/ICH/384/95 adopted November 94) Topic S5A, Step 5 Note for Guidance on Reproductive Toxicology: Detection of Toxicity to Reproduction for Medicinal Products(CPMP adopted September 93) Methods: Definitions and

2 Terminology (CPMP/ICH/386/95 adopted Nov. 94) Topic S3B, Step 5 Note for Guidance on PharmacoKinetics: Guidance for Repeated Dose Tissue Distribution Studies (CPMP/ICH/385/95 adopted Nov.94) Topic S1A, Step 4 Note for Guidance on the need for Carcinogenicity Studies of Pharmaceuticals (CPMP/ICH/140/95 adopted Dec. 95) Topic S5B, Step 4 Note for Guidance on Reproductive Toxicology: Toxicity on Male Fertility (CPMP/ICH/136/95 adopted Dec. 95) CPMP/SWP/2145/00 Note for Guidance on Non-Clinical Local Tolerance Testing of Medicinal Productsl, (CPMP adopted Feb. 01). CPMP/SWP/1042/99 Note for Guidance on Repeated Dose Toxicity (CPMP adopted July 2000) CPMP/SWP/728/95 Replacement of Animal Studies by In Vitro Models(CPMP adopted February 97). Pharmazeutische Entwicklung / Développement pharmaceutique / Development of pharmaceutics Galenik Vom medizinischen Rationale zur Entwicklung entsprechender Darreichungsformen. Grundsätzliche Zielsetzungen in der galenischen Entwicklung. Applikationswege von Wirkstoffen, Vor- und Nachteile. Anforderungen an orale Darreichungsformen (Anwendung und Zielsetzung von magenresistenten Formen, Extended Release Formulierungen, Tabletten, Filmtabletten, Kapseln, Kapletten) Transdermale Systeme, photodynamische Therapie, Bolus- und Infusionstherapien. Stabilitätsunterrsuchungen: wozu, wie lange, unter welchen Bedingungen. Primär- und Sekundärverpackungen. (CPMP/QWP/155/96) Note for guidance on the development of pharmaeutics Topic Q1A, Step 5 Note for Guidance on Stability Testing of New Drug Substances and Products (CPMP/ICH/2736/99 ( Revision of CPMP/ICH/380/95), adopted - November 2000 CPMP/QWP/848/96 Note for guidance on process validation CPMP/QWP/072/96 CPMP/CVMP Note for Guidance on Start of Shelf -Life of the Finished Dosage Form (Annex to the NFG on the Manufacture of the Finished Dosage Form) (Adopted by CPMP/CVMP May 2001)

3 Methoden der Analytik und ihre Aussagekraft Grundkenntnisse der wichtigsten analytischen Methoden (Photometrie, Fluroeszenzphotometrie, Scinitillationszählung, HPLC, Gelchromatographie, ELISA, MS-GC) Validierung der Methoden: die kritischen Aspekte (Sensitiivutät, Linearität, Spezifität, Reprodzierbarkeit, Shifts) Unterschied zwischen Bioanalytik und chemischen Labor. Topic Q2B, Step 4 Note for Guidance on Validation of Analytical Procedures: Methodology (CPMP/ICH/281/95 - adopted December 96 Draft Guidance for Industry: Analytical Procedures and Methods Validation - Chemistry, Manufacturing, and Controls Documentation - 8/30/ (PDF), Klinische Prüfmuster Randomisierung, Verblindung, verschiedene Typen Studiendesigns und Implikationen auf Prüfmusterherstellung (Plazebo, doppel-blind, double-dummy) Beispiele von nicht verblindbaren Darreichungsformen und Lösungsmöglichkeiten Anforderungen an Label und Labeltexten Prüfmusterversand und aufbewahrung kritische Punkte Aussagen von ICH-GCP Guidelines über Prüfmuster Spilker B., Randomization Procedures, Guide to Clinical Trials Raven Press 1991, New York Spilker B., Method of Assessing and Improving Patient Compliance in Clinical Trials, Guide to Clinical Trials Raven Press 1991, New York Präklinische Entwicklung / Développement pré clinique / Preclinical Development Methodik Siehe Kapitel 3.1. Eudralex, Volume 2B, Notice to applicants Tierpharmakologie ICH Guidelines Safety Eudralex, Volume 2B, Notice to applicants Tier-Pharmakokinetik Toxikologie The Textbook of Pharmaceutical Medicine, 3rd edition, J.P. Griffin et al. 1998; ISBN ICH Guidelines Safety Eudralex, Volume 2B, Notice to applicants Reference 89 ICH Guidelines Safety The Textbook of Pharmaceutical Medicine, 3rd edition, J.P. Griffin et al. 1998; ISBN

4 Klinische Entwicklung / Développement clinique / Clinical Development Ethik und Gesetz: Heilmittelgesetz: Loi sur les produits thérapeutiques (LPT): Law on Therapeutic Products: Federal Law on Medicinal Products and Med. Devices GPKV: Gute Praxis der Klinischen Versuche GCP: Guideline for Good Clinical Practice THE PRINCIPLES OF ICH GCP; INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE (IRB/IEC): Responsibilities; Composition, Functions and Operations; Procedures; Records INVESTIGATOR: Investigator's Qualifications and Agreements; Adequate Resources; Medical Care of Trial Subjects; Communication with IRB/IEC; Compliance with Protocol; Investigational Product(s); Randomization Procedures and Unblinding; Informed Consent of Trial Subjects; Records and Reports Progress Reports; Safety Reporting; Premature Termination or Suspension of a Trial; Final Report(s) by Investigator SPONSOR : Quality Assurance and Quality Control; Contract Research Organization (CRO); Medical Expertise; Trial Design Trial Management, Data Handling, and Record Keeping; Investigator Selection; Allocation of Responsibilities; Compensation to Subjects and Investigators; Financing; Notification/ Submission to Regulatory Authority(ies); Confirmation of Review by IRB/IEC; Information on Investigational Product(s); Manufacturing, Packaging, Labelling, and Coding Investigational Product(s); Supplying and Handling Investigational Product(s); Record Access; Safety Information; Adverse Drug Reaction Reporting; Monitoring; Audit Noncompliance; Premature Termination of a Trial; Clinical Trial/Study Reports; Multicentre Trials CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) : General Information; Back- Vklin:Verordnung über klinische Versuche mit Heilmitteln OClin: Ordonnance sur les essais cliniques de produits thérapeutiques ICH Topics and Guidelines: ICH- E6 Guideline for Good Clinical Practice

5 ground Information; Trial Objectives and Purpose; Trial Design; Selection and Withdrawal of Subjects; Treatment of Subjects; Assessment of Efficacy; Assessment of Safety; Statistics; Direct Access to Source Data/Documents; Quality Control and Quality Assurance Procedures; Ethics; Data Handling and Record Keeping; Financing and Insurance; Publication Policy; Supplements INVESTIGATOR S BROCHURE: General Considerations; Contents of the Investigator s Brochure ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL: Before the Clinical Phase of the Trial Commences; During the Clinical Conduct of the Trial; After Completion or Termination of the Trial; General Considerations for Clinical Trials Protection of Clinical Trial Subjects; Scientific Approach in Design and Analysis; Considerations for the Development Plan; Considerations for Individual Clinical Trials; Reporting Statistical Principles for Clinical Trials Overall Clinical Development Trial Context: Development Plan; Confirmatory Plan; Exploratory Plan; Scope of Trials: Population; Primary and Secondary Variables; Composite Variables; Global Assessment Variables; Multiple Primary Variables; Surrogate Variables; Categorised Variables; Design Techniques to Avoid Bias: Blinding; Randomisation; Trial Design Considerations; Design Configuration: Parallel Group Design; Crossover Design; Factorial Design; Multicentre Trials: Type of Comparison Trials to Show Superiority; Trials to Show Equivalence or Non-inferiority; Trials to Show Doseresponse Relationship; Group Sequential Designs; Sample Size; Data Capture and Processing ICH-E8 Guidelines: General Considerations for Clinical Trials ICH-E9 Guidelines: Statistical Principles for Clinical Trials TRIAL CONDUCT CONSIDERATIONS: Trial Monitoring and Interim Analysis; Changes in Inclusion and Exclusion Criteria; Accrual Rates; Sample Size Adjustment ; Interim Analysis and Early Stopping; Role of Independent Data; Monitoring Committee DATA ANALYSIS CONSIDERATIONS: Prespecification of the Analysis; Analysis Sets Missing Values and Outliers; Data Transformation; Estimation, Confidence Intervals and Hypothesis Testing; Adjustment of Significance and Confidence Levels; Subgroups, Interactions and Covariates; Integrity of Data and Computer Software Validity EVALUATION OF SAFETY AND TOLERABILITY: Scope of Evaluation; Choice of Variables and Data Collection; Set of Subjects to be Evaluated and Presentation of Data; Statistical Evaluation; Integrated Summary REPORTING: Evaluation and Reporting; Summarising the Clinical Database Choice of Control Group and Related Issues in Clinical Trials Purpose of Control Group: Randomization; Blinding Types of Controls: Placebo Concurrent Control; No-treatment Concurrent Control; Dose-response ICH-E10 Guidelines: Choice of Control Group and Related Issues in Clinical Trials

6 Concurrent Control; Active (Positive) Concurrent Control; External Control (Including Historical Control); Multiple Control Groups Purposes of Clinical Trials and Related Issues: Evidence of Efficacy; Comparative Efficacy and Safety ; Fairness of Comparisons Assay Sensitivity: Assay Sensitivity in Non-inferiority or Equivalence Trials; Assay Sensitivity in Trials Intended to Demonstrate Superiority Detailed Considerations of Types of Control Placebo Control: Description; Ability to Minimize Bias Ethical Issues; Usefulness of Placebocontrolled Trials and Validity of Inference in Particular Situations Modifications of Design and Combinations with Other Controls That Can Resolve Ethical, Practical, or Inferential Issues; Advantages of Placebo-controlled Trials; Disadvantages of Placebo-controlled Trials; No-treatment Concurrent Control; Dose-response Concurrent Control; Active Control; External Control Choosing the concurrent control group Structure and Content of Clinical Study Reports: Dose Response Studies: ICH-E3 Guidelines: Structure and Content of Clinical Study Reports ICH-E4 Guidelines: Dose Response Studies Declaration of Helsinki: Swissmedic: Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects Erklärungen zur DoH: Allgemeine Rechtsgrundlagen 002&theme_id=518 Activité législative et normalisation eme_id=428 Klinische Versuche; Rechte und Normen

7 005&theme_id=882 Essais cliniques : Activité législative et normalisation: 005&theme_id=862 Neuregelung bei den Sonderbewilligungen für den Einsatz nicht zugelassener Arzneimittel: Sonderbewilligung für nicht zugelassene Arzneimittel: 003&theme_id=734 Autorisations spéciales pour les médicaments non autorisés et &theme_id=734 Books in Clinical Pharmacology Books in Medical Statistics Human-Pharmakokogie und Pharmakokinetik Definition und Bedeutung von pharmakokinetischen Parametern (Absorption, Bioverfügbarkeit, Proteinbindung, Verteilung, Clearance, T-max, C-max, Eliminationshalbwertszeit, AUC) First-pass Effect: wo findet er statt? Welche Implikationen? Lehrbuch in Klinischer Pharmakologie: Melmon and Morelli's Clinical Pharmacology (Mc Graw Hill) Godman and Gilman's The pharmacological basis of therapeutics" (Mc Graw Hill) Lehrbücher in Statistics: Statistical Issues in Drug Development Stephen Senn, John Wiley & Sons Ltd. ISBN Using and Understanding Medical Statistics 3rd, revised edition, hard cover, 1996 CHF 40. (prices subject to change) ISBN Galeazzi R. L., Vozeh S. Pharmakokinetische Grundlangen, Grundlagen der Arzneimitteltherapie. 1996; Basel: Documed: 1-9

8 Nahrungsmittelinteraktionen Medikamanteninteraktionen The Merck Manual of Diagnosis and Therapy Section 22. Clinical Pharmacology m CPMP/EWP/QWP/1401/98 Note For Guidance on the Investigation of Bioavailability and Bioequivalence (Adopted July 2001) Pharmakokinetik und Metabolismus in speziellen Patientengruppen (z.b. Leber-, Niereninsuffizienz und Schwangerschaft, Kindern) Guidance for Industry: Population Pharmacokinetics - 2/10/ (PDF), (Text) Williams RL, Benet LZ. Drug pharmacokinetics in cardiac and hepatic disease. Annu Rev Pharmacol Toxicol. 1980;20: Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function - Study Design, Data Analysis and Impact on Dosing and Labeling - 5/15/ (PDF) Draft Guidance for Industry: Pharmacokinetics in Patients With Impaired Hepatic Function: Study Design, Data Analysis and Impact on Dosing and Labeling - 12/7/ (PDF), (Text) Secor JW, Schenker S. Drug metabolism in patients with liver disease. Adv Intern Med. 1987;32: Topic E7 Step 5 Note for Guidance on Studies in support of Special Populations: Geriatrics( CPMP/ICH/379/95 - adopted Sept. 93) Draft Guidance for Industry: General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products - (12 pages) - 11/30/ (PDF), (Text)

9 Spezielle humanpharmakokinetische Studien: Bioverfügbarkeits-Studien, Bioäquivalenz-Studien (single, multiple dose), Interaktionsstudien CPMP/EWP/QWP/1401/98 Note For Guidance on the Investigation of Bioavailability and Bioequivalence (Adopted July 2001) CPMP/EWP/560/95 Note for Guidance on the Investigation of Drug Interactions (CPMP adopted Dec. 97) CPMP/EWP/280/96 Note For Guidance on Modified Release Oral and Transdermal Dosage Forms: Section II (PharmacoKinetic and Clinical Evaluation) Qualitätssicherung, Dokumentation, Audit, Inspektion Begriffliche Abgrenzung zwischen Qualitätssicherung und Qualitätskontrolle: welche Ziele werden verfolgt? System versus Studienaudit. Johannes, K.J., Pohl,I., Rämsch, K.-D., Checklisten für das Prüfplan-Audit- Pharm.Ind.55: (1993) Reichert, G., Fichtner, E., Lange, J., et al., Checklisten für das On-site-Audit Audit beim Prüfzentrum/Prüfarzt.Pharm.Ind.57:26-31 (1995) Revised compilation of community procedures on administrative collaboration and harmonisation of inspections Spezielle klinische Studien / Etudes cliniques spéciales / Special clinical studies Phase I in clinical development: Role, questions to be answered, and study designs. Proof of concept Dose response assessment. Dose finding in early clinical development. Appropriate study designs concentration response studies. ICH E8: Note for Guidance on General Considerations for Clinical Trials ICH E4: Dose Response Assessment in Clinical Drug Development ICH E10: Note for Guidance on Choice of Control Group for Clinical Trials

10 Bioavailability and bioequivalence studies: basic regulatory requirements. Role and use of different study designs (parallel group studies, factorial design studies, cross over studies, titration study designs, Placebo active controlled studies, open-label studies. Population studies. PK/PD modelling. Sequential study designs. ICH E11: Guideline on Clinical Investigation of Medicinal Products in the pediatric population CPMP Note for Guidance on the Investigation of bioavailability and bioequivalence (CPMP / EWP / QWP / 1401/98) Studies in special populations: Children, elderly, women, different ethnic groups, patients with renal or hepatic impairment. Socioeconomic studies (see chapter 3.8) Gentherapiestudien Verordnung über klinische Versuche mit Heilmitteln; 5. Abschnitt, Art Human Genome Project Information (Gene Therapy); Arzneimittelsicherheit / Pharmacovigilance / Drug Safety Definition and classification of adverse events (AE) and adverse drug reactions (ADR) Seriousness criteria. Difference of serious and severe. Relationship to a medicinal product. Causality criteria. Unexpected (unlabelled) AE and ADR. Reporting frequencies of AE/ADR (e.g. according to CIOMS). Analyses of AE/ADR incidences. The Swiss pharmacovigilance system. Reporting obligations (reporting criteria, reporting timelines) of spontaneous ADR and of AE/ADR in the context of clinical studies. Heilmittelgesetz (Art. 59) Arzneimittelverordnung (Art. 32, 34-39) ICH Guidelines on Safety E1A Population exposure E2A Clinical Safety data management E2B Clinical Safety data management E2C PSUR M7 Safety pharmacology CPMP points to consider: assessment of potential QT prologation Safety issues due to quality deficiencies. How to address safety questions/issues in a drug development plan and in a clinical study.

11 Investigating safety in pharmacoepidemiology studies (PMS; cohort studies). Relevance of the investigators brochure for safety in clinical studies. Investigator notifications. Safety information from preclinical studies (safety pharmacology, toxicology, pharmaco- /toxicokinetics). Significance and contents of periodic safety update reports (PSUR). Difference betweeen individual reports and summary reports. Different sources of safety signals. Overall safety evaluation. Risk/benefit assessment. Text revisions. Crisis management. Dear Health Provider Letter (Dear Doctor Letter). Recalls. Types of adverse drug reactions (e.g. type I, II, intolerance, idiosynkratic reactions, allergy, immune complex reactions). QT prolongation syndrome. Labelling types for pregnancy and lactation. Mechanisms of drug/drug interactions. 3.6 Medizinisch-wissenschaftliche Information / Information medicale / Medical Information Investigators brochure - significance, contents, updates. Definition and significance of - Summary of Product Characteristics (SPC) - Core data sheet - National Prescribing Information (Patienteninformation, Fachinformation) - Succinct Statement (Kurzfassung der Fachinformation für Werbematerialien) - ICH E6 GCP Guideline - Arzneimittelwerbeverordnung (AWV) - SGCI Pharma-Fachwerbungskodex - Begg C, et al. the CONSORT statement. JAMA 1996; 276: Moher D, et al. the revised CONSORT statement. JAMA 2001; 285: Basis brochures.

12 How to approve advertisement material and promotional claims (Medical Clearing Process). Product briefing documents for the media. Press releases. To be familiar with the basic publication guidelines (guidelines/instructions for authors; CONSORT statement). How to manage the publication process. To have a working knowledge of - training of product managers / sales representatives - preparation of meetings, symposia, press conferences - answering scientific / medical quieires - opinion leader management - public relations 3.7 Zulassung von Heilmitteln / Autorisation de mise sur le marché / Drug Regulatory Affairs General tasks and responsibilities of health (regulatory) agencies. Overview skills of Swissmedic, EMEA, FDA. Responsibilities of the different authorities in Switzerland dealing with health issues (Swissmedic, Bundesamt für Gesundheit, Bundesamt für Sozialversicherungen). Heilmittelgesetz Arzneimittelverordnung (VAM) Anleitung zum Einreichen von Gesuchen von Arzneimitteln der Humanmedizin mit neuen aktiven Substanzen. The 2-step decision procedure of Swissmedic. Fast track procedure (= beschleunigtes Zulassungsverfahren; BZV). Basic knowledge of European approval procedures (centralised procedure; decentralised = mutual recognition procedure) and US approval procedures. General contents of a registration dossier. The Common Technical Document (CTD).

13 Definition and Significance of - New Chemical Entity (NCE) - New Active Substance (NAS) - New Drug Application (NDA) - Supplementary new drug application (snda) - Approval (Zulassung) - Approvable letter (Voranzeige) - Postapproval commitments (Auflagen) - Rejection (Abweis) - Variations (Änderung der Zulassung) - Vigilance (Marktüberwachung) Significance of the summary of product characteristics (SPC), Prescribing information (Fachinformation), patient information (Patienteninformation), periodic safety update reports (PSUR). Basic knowledge of Orphan drugs, orphan indications, orphan designations. Basic knowledge of approval requirements of drugs for pediatric use in the international environment. Incentive systems for studies in children. Basic knowledge of patent regulations. Basic knowledge of generic drugs and medical devices. 3.8 Sozioökonomie des Gesundheitssystems / Aspects socio-économiques du système de santé / Socioeconomics of the health care system Knowledge of the Health System in Switzerland. Knowing the role of BSV, Eidgenössische Arzneimittelkommission, Eidgenössische Leistungskommission, Sante Suisse, Health Insurances. - Overview of the Swiss health system at and - BSV-Weisungen How to apply for reimbursement of a medical product in Switzerland. The different application

14 forms (Neuaufnahmegesuch, Preiserhöhungsgesuch, andere Packungen und Dosierungen, Erweiterung der Limitatio, Neuüberprüfungsgesuch). Basic knowledge of pricing strategy. Definition of "Wirksamkeit, Zweckmässigkeit, Wirtschaftlichkeit" eines Arzneimittels. Definition of "Limitatio". Different types of (pharmaco) economic analysis (Assessment of cost effectiveness, cost benefit, cost utility). Definition, concept, and significance of Evidence based Medicine. Value of different study designs. Definition of: Absolute and relative risk. Absolute and relative risk reduction. Odds and odds ratio. Number needed to treat (NNTT), number needed to harm (NNTH) The significance of meta-analyses. Definition of sensitvity, specifity, and prediction value. Pre-test and post-test probability. Cochrane collaboration and Cochrane Reviews. Different forms of bias in research and publication (e.g. selection bias, language bias, publication bias, citation bias). Confounders.