1. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 1 How do clinical trials relate to the MRF1? Lynn Katsoulis SAPPRA 23 March 2007

2. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 2 Points of View Planners Implementers Report writers

3. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 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. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 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. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 5 Drug Development process Non-clinical Phase 1Phase 2Phase 3Phase 4 Non-clinical Nonclinical Short term exposure Long term exposure Chemistry Manufacturing and Controls mg - g Kg - tons Clinical Marketing approval First human dose

6. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 6 Regulatory Perspective: Building a CTD Index Application Labeling/Summary (Annotated Package Insert) Integrated Analyses of Safety, Effectiveness, Benefits/Risk Nonclinical Pharmacology/ Toxicology Human PK/ Bioavailability / Clinical/Statistical Establishment Description Chemistry Clinical Full Reports Chemistry Tabular Summaries Nonclinical Tabular Summaries Clinical Tabular Summaries Chemistry Data/ReportsNonclinical Full Reports Chemistry Data (GMP) Nonclinical Data (GLP) Clinical Case Report Forms Clinical Data (GCP) Investigators Brochure to Package Insert Detailed Summaries Reports Data Form Administrative Labeling Executive Summary Certifications

7. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 7 Clinical Development Strategy Focus on the end goal - Reversed planning Planning Strategy Package insert Drug Development MarketedProduct

8. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 8 Drug Development Process: Steps from Test Tube to New Drug Application Review http://www.fda.gov/cder/handbook/develop.htm

9. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 9 Objective at Each Stage Non-clinical Phase 1Phase 2Phase 3Phase 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. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 10 Toxicology Regulatory Requirements From ICH Guidance for Industry: M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals

11. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 11 Objective – Phase 1 Non-clinical Phase 1Phase 2Phase 3Phase 4 -Healthy volunteers -Tolerance -Dose range -Pharmacokinetics -Several trials -About 5 to 30 subjects/trial

12. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 12 Objective – Phase 2 Non-clinical Phase 1Phase 2Phase 3Phase 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. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 13 Objective - Phase 3 Non-clinical Phase 1Phase 2Phase 3Phase 4 -Statistical confirmation of Phase 2 trial -Pivotal trials -Needs to be duplicated -Large trials - 100s to 1000s of subjects/trial

14. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 14 Objective - Phase 4 Non-clinical Phase 1Phase 2Phase 3Phase 4 Post-marketing observations Confirm findings in general population Collect safety data in large patient group 1000s of subjects/trial

15. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 15 Objective - Overall Non-clinical Phase 1Phase 2Phase 3Phase 4 -Each phase provides information to progress to next step -Marketing approval based on pivotal trials

16. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 16 Regulatory Perspective: Building a CTD Index Application Labeling/Summary (Annotated Package Insert) Integrated Analyses of Safety, Effectiveness, Benefits/Risk Nonclinical Pharmacology/ Toxicology Human PK/ Bioavailability / Clinical/Statistical Establishment Description Chemistry Clinical Full Reports Chemistry Tabular Summaries Nonclinical Tabular Summaries Clinical Tabular Summaries Chemistry Data/ReportsNonclinical Full Reports Chemistry Data (GMP) Nonclinical Data (GLP) Clinical Case Report Forms Clinical Data (GCP) Investigators Brochure to Package Insert Detailed Summaries Reports Data Form Administrative Labeling Executive Summary Certifications

17. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 17 How is drug development changing?

18. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 18 How is Drug Development Changing? Non-clinical Phase 1Phase 2Phase 3Phase 4 Non-clinical Exploratory Confirmatory

19. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 19 Change in Goals Non-clinical Exploratory Exploratory IND Several compounds Adaptive trials Goal Compound selection based on clinical data Kill compounds earlier More compounds explored Confirmatory 2-3 doses Select responders Randomized exclusion Goal Increase success rate Decrease cost of dev.

20. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 20 Change in Goals Non-clinical Exploratory ConfirmatoryPost-marketing Carefully designed program Confirm safety Extend / Refine label

21. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 21 Technologies Available Non-clinical Phase 1 Phase 2 Phase 3 Phase 4 Adaptive Clinical Trial Design Biomarkers X-omics Electronic Data Capture Safety Database Image Database Electronic Patient Reported Outcomes

22. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 22 Role players in clinical trials Sponsor (/CRO) Regulatory Authority Investigator (/SMO) Ethics Committee Participant / Subject Ethics Committee Control use of Medical products - safety - efficacy - integrity Patient protection Ensure research is ethical - justice - non-malevolence - beneficence - respect for dignity

23. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 23 Multifaceted Approach to Participant Protection Subject Legislation MCC EC Audits MCC, EC, Sponsor Informed Subjects “debarment” of severely or persistently non-compliant industry members Participant Current system

24. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 24 Global RA & EC Review Times Quintiles data 2000 - 2006

25. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 25 Major Markets for Drug Sales Conference on Harmonisation (ICH) Based on Declaration of Helsinki

26. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 26 Quality and Drug Development Non-Clinical Manufacturing Discovery QS GMP GLP WHO:TDR/PRD/QSBR/01.1Quality standards in basic biomedical research” Clinica l GCP

27. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 27 UNDP/World Bank/WHO (TDR)/ “Quality practices for regulated non-clinical R&D” RESOURCES RULES CHARACTERISATION DOCUMENTATION QUALITYASSURANCE GXP Basic Principles of GXPs Result – high quality objective data collected in ethical manner

28. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 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. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 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. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 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. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 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. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 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. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 33 Ascending Dose Dose Titration Dose Tapering Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3

34. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 34 Cross-Over Group 1 Group 2 Treatment A Treatment BTreatment A Treatment B Parallel Group 1 Group 2 Treatment A Treatment B

35. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 35 Change to clinical trial design  Currently:  In future: All subjectsRandomize Placebo Active All subjectsResponse Non-responder Responder Placebo Active Randomize

36. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 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. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 37 1. Retrospective

38. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 38 2a. Prospective, screened

39. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 39 2.b. Prospective, Stratified R R R R

40. CONFIDENTIAL Copyright  2007. Cato Research Ltd. 40 Herceptin * From Press and Seelig, Targeted Medicine 2004, New York, November 2004