R&D GCP and Effective Site Management 011910

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R&D GCP and Effective Site Management 011910

  1. 1. R&D, Good Clinical Practice & Effective Site Management Myron Pyzyk, M.S. Marenon Health Group January, 2010 1/19/2010
  2. 2. Agenda • Introduction • Learning Objectives • Evolution of Good Clinical Practice Guidelines (GCP) – History of GCP and current standards – Stakeholders in GCP – Understanding GCP issues within Clinical Trial Process • Identification of current regulatory and ethical issues in clinical research – Current regulatory and ethical issues in clinical research – Applications of the regulations to practice Presentation to 1/19/2010
  3. 3. Agenda • The Clinical Trial Process – Roles involved in the Clinical Trial Process – Ensuring adequate source documentation – Informed consent process; including a role-play and interactive discussion – Succeeding with IRBs – „How-to‟ guide to adequate source documentation • Defining the major steps and phases of the drug development process Presentation to 1/19/2010
  4. 4. Learning Objectives • Review of Good Clinical Practice Guidelines • Understand the overall impact of GCP on the clinical trial process including the respective roles and responsibilities of the Investigator and the Sponsor • Understand the impact of GCP on overall study quality (e.g., source documentation, informed consent, IRB, etc.) • Review the overall drug development process Presentation to 1/19/2010
  5. 5. Drug Development Process 1/19/2010
  6. 6. Drugs Development Overview Research Development Screening Synthesis $500M - $1B USD Preclinical Testing Invested !! Acute Toxicology Chronic Toxicology Pharmacology Clinical Testing Phase I Phase II Phase IIIa Phase IIIb Phase IV Patent STOP Patent START Development Time 0… 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 …20 (years) Presentation to ABC Pharma 1/19/2010
  7. 7. Developing New Drugs • Potential “blockbuster” e.g. first effective therapy for a common and/or chronic disease and/or life-saving treatment • Market size is LARGE – Broad patient population – Multiple therapeutic indications • Several products across several companies • Similar products on the market or in development • Drug poor fit in manufacturer product portfolio – License or sell to another company sponsor Presentation to ABC Pharma 1/19/2010
  8. 8. Pre-Clinical Drug Discovery • Screening (Medicinal Chemistry) – Pharmacological and biological screening models – Computer modeling – Serendipity (Luck counts or “Do you feel lucky?”) • Synthesize – Compounds that fit the biological target (e.g., receptor) • ~ 1 out of 100,000 may reach market • Screening – Assess likelihood of safety and efficacy in humans using in vitro and in vivo testing Presentation to ABC Pharma 1/19/2010
  9. 9. Pre-clinical Objectives • Safety of drug • Effective dose range – Organ(s) or organ system affected – Drug absorbed, distributed, metabolized and excreted („ADME‟) • Cx – drug assessed as a potential carcinogen • Drug assessed for potential for producing: – birth defects – affects on fertility Presentation to ABC Pharma 1/19/2010
  10. 10. Development Benefit – Risk Assessment If… • Drug has what appears to be acceptable levels of safety and effectiveness in appropriate models And… • Potential market(s) exists for the drug Then… • Further development balances business and scientific merits Presentation to ABC Pharma 1/19/2010
  11. 11. Development Plan • Indication(s) • Preclinical testing – Genotoxicity, mutagenicity, reproduction studies, – Sub-chronic, chronic • Clinical studies • Marketing research data / Sales projection • Manufacturing issues – Scale-up, cost of goods • Regulatory issues Presentation to ABC Pharma 1/19/2010
  12. 12. IND / CTA Investigational New Drug Application (IND; USA) Clinical Trial Application (CTA; EU, Canada) • Filed with regulatory authorities by the Sponsor – Intends to conduct clinical studies using the investigational drug – Investigational drug refers to a new drug or biological used in a clinical investigation OR a marketed drug that is not licensed for usage in the proposed indication • Approval/no objection of the CTA or IND allows the investigational drug to be sent to sites for clinical investigations Presentation to ABC Pharma 1/19/2010
  13. 13. Drug Development – Regulatory • Regulatory authorities‟ goal worldwide – Safe and effective drug availability to the public • Regulatory considerations – Global: worldwide standardized procedures and practices for drug development for all sites – Local: drug tested and responsibly marketed using local and international regulations and guidelines Presentation to ABC Pharma 1/19/2010
  14. 14. Standard Operating Procedures (SOPs) Sponsors of Investigational New Drugs • Write standard operating procedures (SOPs) • Ensure study activities follow regulatory requirements • Ensure study activities follow GCP Presentation to ABC Pharma 1/19/2010
  15. 15. Clinical Development Plan (CDP) • Comprehensive plan • Map out the development of the compound • All development phases required for registration file preparation are included Presentation to ABC Pharma 1/19/2010
  16. 16. International Regulatory Major Regulatory Drivers • US Food and Drug Administration • ICH: International Conference on Harmonization • Country-specific regulations (e.g. EMEA (EU), TPD ( Canada) Presentation to ABC Pharma 1/19/2010
  17. 17. Phases of Clinical Research 1/19/2010
  18. 18. Phases of Clinical Research I II III IV PRECLINICAL CLINICAL Pre-marketing Post-marketing PHASES OF DRUG DEVELOPMENT Average A few weeks – 0.25 - 1 month A few months – A few months – 4 A few months – Time/Study 2 years 2 years years several years Number of 20 - 100 A few hundred A few hundred – About 50 - Subjects Several thousand Several thousand Subject Animals or Healthy Patients Patients Patients Laboratory Volunteers or Models Patients Primary Predict toxicity Determine safe Determine Determine safety - Condition for Purpose (humans) dose(s) dose(s) with & efficacy in approval (humans) acceptable level large - Test under real of efficacy and subpopulation(s) life situations in safety during usage clinical practice over longer periods of time Approval of a new indication Presentation to ABC Pharma 1/19/2010
  19. 19. Clinical Development – Phase I Objective • Start to determine the drug compound‟s: • Clinical Pharmacology of the Drug Compound: – Pharmacokinetics (Pk) i.e. what the body does to a drug – Pharmacodynamics (Pd) i.e. what a drug does to a body • Mechanism of action (MoA) • e.g. Drug interactions • How other drugs affect new compound • How new drug compound affect available marketed drugs • Assess tolerability, side-effects with escalating doses • Preliminary data to possibly predict efficacy Presentation to ABC Pharma 1/19/2010
  20. 20. Clinical Development – Phase I Need to Answer the Following • Safe and effective doses • Time for drug… Absorption Distribution Metabolism Elimination • Organ or systems involvement in ADME Presentation to ABC Pharma 1/19/2010
  21. 21. Clinical Development – Phase II Need to Answer the Following • Phase I dose(s) help predict efficacy and safety • Efficacy – Expected indication(s) or uses i.e. under what exact clinical circumstances or disease diagnoses, etc. is the drug compound being proposed for use in patients? – Predicted minimum/maximum dose(s) – Same dose in mild, moderate and severe cases? • Safety profile – Assess Phase II patient safety in proposed Presentation to ABC Pharma 1/19/2010 indications; use Phase I subject data to predict
  22. 22. Clinical Development – Phase III Multiple protocol, multi-center studies • Placebo control or active control • Possible uncontrolled studies, e.g.Extension studies (chronic dosing, safety) • Special populations e.g.Elderly, pediatrics • New indication(s) for approved drugs Presentation to ABC Pharma 1/19/2010
  23. 23. Clinical Development – Phase III Need to Answer the Following • Dose – as effective or more effective than „gold standard‟ currently on the market • Drug effective in broader usage, e.g., – Elderly, combination therapy, etc. • Drug effective for chronic usage without occurrence of drug tolerance • Drug interaction risk assessment for concomitant medications? Presentation to ABC Pharma 1/19/2010
  24. 24. Clinical Development – Phase IV Objective • Compare „effectiveness‟ instead of efficacy – Assess in a larger population (500 to 10,000+) – Provide additional data to receive final approval (or new formulation/condition) – Continue assessment of drug in real-life setting post- marketing – Supportive data • Cost-effectiveness, QoL, comparison to other active agents („gold standards‟) Presentation to MethylGene 1/19/2010
  25. 25. Good Clinical Practice 1/19/2010
  26. 26. International Conference of Harmonization (ICH) Purpose of Harmonization • Reduce the costs of the drug approval process • Expedite the availability of new drugs to consumers • Harmonization effort between USA, Japan & Europe Presentation to 1/19/2010
  27. 27. Declaration of Helsinki • World Medical Association statement of ethical principles in medical research with human subjects • Major driver towards development of GCP guidelines • Response to the war crimes of World War II Experiments without patient consent are unethical • All proposed studies must be evaluated by independent Ethics Committee Presentation to ABC Pharma 1/19/2010
  28. 28. Drug Development Good Laboratory Practice (GLP) Basic Good Manufacturing Pharmacology & toxicology Research Practice (GMP) Chemistry, formulation, stability, etc. Lead Compounds Manufacturing Phase I Phase II Phase III Phase IV Regulatory Submission Good Clinical Regulatory Practice (GCP) Clinical Development Authorization Marketing Presentation to ABC Pharma 1/19/2010
  29. 29. Good Clinical Practice What are GCP Guidelines? • International systematic approach • Ensuring the scientific quality and ethical standard – Designing, conducting, recording and reporting of studies involving human subjects Presentation to ABC Pharma 1/19/2010
  30. 30. GCP Principles • Compliance with the GCP Guidelines standards – Study subject rights are protected – Data/reported results are credible, accurate Presentation to ABC Pharma 1/19/2010
  31. 31. GCP Responsibilities GCP Data Protection of Quality Accuracy & Subjects’ Compliance Integrity Rights Ethics Committee   (EC) / Institutional Review Board (IRB) Investigator    Monitor    Sponsor    Presentation to ABC Pharma 1/19/2010
  32. 32. Investigator Responsibilities • Patient informed consent • Site approvals • Drug administration and accountability • Relevant data • AE reporting Presentation to ABC Pharma 1/19/2010
  33. 33. Approvals & Documentation Pre-study Approvals • Internal approvals (Sponsor) • Institutional Review Board/Ethics Committee approval • Notification to and approval by FDA Presentation to ABC Pharma 1/19/2010
  34. 34. Company Approvals • Protocol • CRF • Study medication : packaging, labeling • Budget / Contracts • Others Choice of CRO / CLO Presentation to ABC Pharma 1/19/2010
  35. 35. Ethics Committee / IRB Approval Favorable opinion/approval required from the appropriate EC / IRB • Before study medication sent to centres • Before start of patient recruitment Presentation to ABC Pharma 1/19/2010
  36. 36. Source Documents & CRFs Site Responsibility • Type of source documentation – First time an observation or data point is recorded • Storage of source documentation or study documentation – Access & confidentiality – Direct access limited to study personnel – Record retention policy & conditions – Long-term records retention crucial after study completion • Who is responsible for CRF completion? – Usually completed by the Study Coordinator Presentation to ABC Pharma 1/19/2010 – CRF data is either handwritten or in electronic form
  37. 37. Informed Consent (IC) Process Investigator should • Obtain IRB/EC written approval • Adhere to GCP • IC revised as new important information is made available • IC vs. Coercion – Neither Investigator nor staff can unduly influence a subject to participate or continue in a study Presentation to ABC Pharma 1/19/2010
  38. 38. Informed Consent (IC) Process Investigator requirements: • Submit an informed consent form – Content understood by a subject with a grade 6 (or less) education • Non-technical in nature as much as possible • Understandable by the subject‟s legal guardian where the subject cannot understand the IC • Ensure the IC uses a subject‟s native language e.g. English, French, Spanish, Mandarin, etc. • Comply with regulatory requirements Presentation to ABC Pharma 1/19/2010
  39. 39. Informed Consent (IC) Process Investigator requirements: • IC language must not try to waive any legal rights • IC wording cannot prejudice any future treatment if the subject does not agree to participate or withdraws consent Presentation to ABC Pharma 1/19/2010
  40. 40. Informed Consent (IC) Process • ALL Subjects (or Legal Guardian) must sign and date the IC form • IF Subject or legal guardian cannot read: – Impartial witness present for entire consent discussions – IC form signed and dated by subject; same for the witness • Additional signatures may be required (Sponsor, IRB or local law) E.g. specific investigator or person conducting informed consent Presentation to ABC Pharma 1/19/2010
  41. 41. Informed Consent (IC) Process In Emergency Situations (Prior consent not possible) • Consent of subject‟s legal representative requested • If no legal representative – Seek IRB/EC favorable opinion and support – Inform subject‟s legal representative as soon as possible Presentation to ABC Pharma 1/19/2010
  42. 42. Informed Consent < Exercise > • Role-play and interactive discussion at end of presentation • To follow… Presentation to ABC Pharma 1/19/2010
  43. 43. Institutional Review Boards Ethics Committees Roles and Responsibilities • Investigator – Report SAE to Ethics Committee • Company – Inform all world-wide investigators of specific SAEs within study duration reported in Company safety report – Report AEs to study report or drug brochure E.g. AEs > 2% frequency in study report E.g. All AEs reported at the end of the study report Presentation to ABC Pharma 1/19/2010
  44. 44. Institutional Review Boards / Ethics Committees How to Succeed with IRBs • Investigators – Be prepared! – CORRECTLY complete all IRB / EC Forms • Can be a major reason for study application rejection! – Contact IRB to be added to the agenda • Send IRB the correct number of copies of all documentation specified by your IRB • IRB will charge for review; IRB expenses included in your site budget? – Investigator attendance important during discussions at IRB to answer questions – Consult sponsor for questions you cannot answer Presentation to ABC Pharma 1/19/2010
  45. 45. Clinical Trial Process 1/19/2010
  46. 46. Clinical Trial Process Development plan Regulatory Regulatory Study Study approval approval initiation initiation Investigator Investigator Protocol Protocol identification / identification / Patient recruitment, treatment Site(s) Site(s) and CRF andCRF site selection site selection and follow-up closed closed Ethics Ethics Archive Archive Committee Committee Monitoring Monitoring approval approval Study Study Trial Trial documentation documentation Data Data supplies supplies retrieval retrieval Analysis and report Data processing Data processing Database and statistical Database Database closed Database closed Data clean up plan Presentation to ABC Pharma 1/19/2010
  47. 47. Traditional Data Flow Patient Hospital record visit Database Database (source data) locked complete Investigator Database Analysis CRF Validation Queries checks Report Monitoring CRF Data visit pages entry Queries Presentation to ABC Pharma 1/19/2010
  48. 48. Data Quality No errors Patient Hospital record visit Database Database 1 (source data) locked complete Investigator 4 Database Analysis CRF Validation Queries 2 checks 3 Report Monitoring CRF Data visit pages entry Queries Total number of steps = 4 Presentation to ABC Pharma 1/19/2010
  49. 49. Data Quality Impact of errors Monitoring Visits Only Patient Hospital record visit Database Database 1 (source data) locked complete Investigator 6 Database Analysis CRF 3 4 Validation Queries 2 checks 5 Report Monitoring CRF Data visit pages entry Queries Total number of steps = 6 Presentation to ABC Pharma 1/19/2010
  50. 50. Data Quality Impact of errors RDM and Monitoring Visits Patient Hospital record visit Database Database 1 (source data) locked complete Investigator 6 5 Database Analysis eCRF 3 4 Validation Queries Checks ++++ Report 2 ++ Monitoring 7 visit Remote Data Monitoring +++++ Total number of steps = 7 / Fewer Monitoring Visits Presentation to ABC Pharma 1/19/2010
  51. 51. Conclusion Conclusion • Drug development aims to provide a framework for generating empirical evidence to support claims made regarding efficacy & safety • Clinical development entails a dynamic process that is evolving to maximize ethical, scientific, regulatory and technical integrity of the resulting data quality Presentation to ABC Pharma 1/19/2010

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