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How do clinical trials relate to the MRF1?

How do clinical trials relate to the MRF1?. Lynn Katsoulis SAPPRA 23 March 2007. Points of View. Planners. Implementers. Report writers. Points of View. Development plans Details order and timing of data capture Ensure all data collected before needed

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How do clinical trials relate to the MRF1?

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  1. How do clinical trials relate to the MRF1? Lynn Katsoulis SAPPRA 23 March 2007

  2. Points of View Planners Implementers Report writers

  3. Points of View • Development plans • Details order and timing of data capture • Ensure all data collected before needed • Non-clinical tests & Clinical trials • Collect data according to overall development plan • Report written after each experiment to trial • Regulatory Submissions • Mostly report entire process • Justify next step which needs regulatory approval

  4. Drug development • High risk industry • Long and expensive process to prove drugs are safe and effective • Development process costs up to $1.5 Billion • Manufacturing • Characterize compound • Ensure same compound is produced throughout experimental phase and for each batch marketed • Nonclinical experiments • Collect sufficient data to show lack of risk to subjects • Clinical trials • Drugs given to carefully selected population • Population expands throughout development process • By end of development, should have sufficient data to extrapolate safety and efficacy of product to general population

  5. Chemistry Manufacturing and Controls mg - g Kg - tons Nonclinical Long term exposure Short term exposure Drug Development process Marketing approval Clinical First human dose Non-clinical Phase 1 Phase 2 Phase 3 Phase 4 Non-clinical

  6. Regulatory Perspective:Building a CTD Administrative Application Form Index Certifications Labeling Labeling/Summary (Annotated Package Insert) Executive Summary Integrated Analyses of Safety, Effectiveness, Benefits/Risk Human PK/ Detailed Summaries Chemistry Nonclinical Bioavailability Pharmacology/ / Toxicology Establishment Description Clinical / Statistical Tabular Clinical Tabular Chemistry Tabular Nonclinical Reports Summaries Summaries Summaries Chemistry Data/Reports Nonclinical Full Reports Clinical Full Reports Data Nonclinical Clinical Case Clinical Chemistry Data (GMP) Report Forms Data (GCP) Data (GLP) Investigators Brochure to Package Insert

  7. Clinical Development Strategy Focus on the end goal - Reversed planning Strategy Planning Marketed Product Drug Development Package insert

  8. Drug Development Process:Steps from Test Tube to New Drug Application Review http://www.fda.gov/cder/handbook/develop.htm

  9. Objective at Each Stage Non-clinical Phase 1 Phase 2 Phase 3 Phase 4 • In vitro pharmacology • In vitro safety • Respiratory, cardiac, hepatic, mutagenicity • In vivo safety • Single dose / dose ranging • Repeat dose / dose ranging • Proof of concept

  10. Toxicology Regulatory Requirements From ICH Guidance for Industry: M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals

  11. Objective – Phase 1 Non-clinical Phase 1 Phase 2 Phase 3 Phase 4 • Healthy volunteers • Tolerance • Dose range • Pharmacokinetics • Several trials • About 5 to 30 subjects/trial

  12. Objective – Phase 2 Non-clinical Phase 1 Phase 2 Phase 3 Phase 4 • Learn all there is to know about the drug • Dose comparison (2a) • May be several trials • Proof of concept • Numbers to small to show significant difference • 20 to 60 subjects/trial

  13. Objective - Phase 3 Non-clinical Phase 1 Phase 2 Phase 3 Phase 4 • Statistical confirmation of Phase 2 trial • Pivotal trials • Needs to be duplicated • Large trials • - 100s to 1000s of subjects/trial

  14. Objective - Phase 4 Non-clinical Phase 1 Phase 2 Phase 3 Phase 4 • Post-marketing observations • Confirm findings in general population • Collect safety data in large patient group • 1000s of subjects/trial

  15. Objective - Overall Non-clinical Phase 1 Phase 2 Phase 3 Phase 4 • Each phase provides information to progress to next step • Marketing approval based on pivotal trials

  16. Regulatory Perspective:Building a CTD Administrative Application Form Index Certifications Labeling Labeling/Summary (Annotated Package Insert) Executive Summary Integrated Analyses of Safety, Effectiveness, Benefits/Risk Human PK/ Detailed Summaries Chemistry Nonclinical Bioavailability Pharmacology/ / Toxicology Establishment Description Clinical / Statistical Tabular Clinical Tabular Chemistry Tabular Nonclinical Reports Summaries Summaries Summaries Chemistry Data/Reports Nonclinical Full Reports Clinical Full Reports Data Nonclinical Clinical Case Clinical Chemistry Data (GMP) Report Forms Data (GCP) Data (GLP) Investigators Brochure to Package Insert

  17. How is drug development changing?

  18. How is Drug Development Changing? Non-clinical Phase 1 Phase 2 Phase 3 Phase 4 Exploratory Confirmatory Non-clinical

  19. Change in Goals • Confirmatory • 2-3 doses • Select responders • Randomized exclusion • Goal • Increase success rate • Decrease cost of dev. • Exploratory • Exploratory IND • Several compounds • Adaptive trials • Goal • Compound selection based on clinical data • Kill compounds earlier • More compounds explored Non-clinical

  20. Change in Goals Confirmatory • Post-marketing • Carefully designed program • Confirm safety • Extend / Refine label Non-clinical Exploratory

  21. Technologies Available Electronic Data Capture Adaptive Clinical Trial Design Non-clinical Safety Database Phase 1 Biomarkers X-omics Phase 2 Image Database Phase 3 Electronic Patient Reported Outcomes Phase 4

  22. Role players in clinical trials Control use of Medical products - safety - efficacy - integrity Regulatory Authority Sponsor (/CRO) Patient protection Ensure research is ethical - justice - non-malevolence - beneficence - respect for dignity Ethics Committee Investigator (/SMO) Ethics Committee Participant / Subject

  23. Multifaceted Approach to Participant Protection Legislation Subject EC MCC Participant “debarment” of severely or persistently non-compliant industry members Audits MCC, EC, Sponsor Informed Subjects Current system

  24. Global RA & EC Review Times Quintiles data 2000 - 2006

  25. Major Markets for Drug Sales Conference on Harmonisation (ICH) Based on Declaration of Helsinki

  26. Quality and Drug Development Clinical Discovery Non-Clinical QS GCP GLP Manufacturing GMP WHO:TDR/PRD/QSBR/01.1Quality standards in basic biomedical research”

  27. Basic Principles of GXPs DOCUMENTATION RESOURCES GXP QUALITY ASSURANCE RULES CHARACTERISATION Result – high quality objective data collected in ethical manner UNDP/World Bank/WHO (TDR)/ “Quality practices for regulated non-clinical R&D”

  28. Fundamentals of GLP • GLP • Resources • Organisation, Personnel, Facilities, Equipment • Rules (SOPs and Protocols) • Consistent procedures, Optimise processes, Commitments to quality, Continuity, Training manuals, Reconstruction of study • Characterisation • Test item - receipt, storage, control of use, disposal • Documentation • Raw data, data collection & recording • What? How? When? Who? • Generated data should be identified and record directly, promptly, accurately, legibly and indelibly by the person entering them, and be signed or initialed and dated • Quality Assurance • Protocols and SOPs review, Planning (Master Schedule Sheet), Audits and inspections, Distribution and archiving of QA reports

  29. Fundamentals of GCP • GCP (ICH E6, 21 CFR) • Resources • Personnel have adequate education training and experience • Rules (Protocols) • Consistent procedures, training records • Patient protection – subject has to give individual informed consent • Control of clinical trial material • CTM only to be used under protocol • Receipt, storage, control of use, disposal • Documentation • Raw data, data collection & recording • What? How? When? Who? • Generated data should be identified and record directly, promptly, accurately, legibly and indelibly by the person entering them, and be signed or initialed and dated • Quality Assurance • Site monitoring mandatory • Sponsor or regulatory authority audits

  30. GXPs & Regulatory Submissions • In order for data to be accepted as support for a marketing application: • Data needs to be collected according to GLP and GCP • using GMP product • Needs to be shown in application • Audits and inspections • High enrollers for pivotal studies • Any reason for suspicion • Sponsor or CRO audit

  31. Documents Used in Clinical Trials • Investigator brochure (ICH template) • All information available on drug • Updated throughout development program • Used as basis of package insert • Protocol (ICH template) • Controlled document • Needs regulatory and ethics committee approval • If changed, amendment needs to be approved before being implemented • Procedures manual • Not controlled • Used for site specific, and non-essential details • Informed Consent Document (ICH template) • Sufficient information to “enable” a subject to decide whether to participate or not • Clinical study report (ICH template) • Detailed report of findings from the clinical trial

  32. Clinical Trial Design • Adequate control • Pivotal trials need to be adequately controlled • Blinding • Randomization • Placebo controlled • Comparators • If available, gold standard to be used • Dose comparison • At least two doses of the drug are compared • A dose-comparison study may include additional treatment groups, such as placebo control or active control • Dose-comparison trials usually include randomization and blinding of patients and investigators

  33. Dose 3 Ascending Dose Dose 2 Dose 1 Dose 3 Dose Titration Dose 2 Dose 1 Dose 3 Dose 2 Dose Tapering Dose 1

  34. Parallel Group 1 Treatment A Treatment B Group 2 Cross-Over Group 1 Treatment A Treatment B Treatment B Treatment A Group 2

  35. Active Responder Randomize All subjects Response Placebo Non-responder Change to clinical trial design • Currently: • In future: Active All subjects Randomize Placebo

  36. Three Common Designs 1. Retrospective • Hypothesis generating; usually needs confirmatory clinical trial(s) • 2. Prospective • a. No possible effect in marker negative group • Test must be available • b. Possible effect in marker negative group • If test not available: benefit/risk must be acceptable for whole population, even if efficacy is driven by marker positive group.

  37. 1. Retrospective

  38. 2a. Prospective, screened

  39. R R R R 2.b. Prospective, Stratified

  40. Herceptin * From Press and Seelig, Targeted Medicine 2004, New York, November 2004

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