Clinical trials flow process


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Life Cycle of Clinical Trials

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Clinical trials flow process

  1. 1. Clinical Trials Flow Process: The life Cycle of Clinical Trials Tamer Hifnawy MD. Dr. PH Associate Professor Public Health & Community Medicine Faculty of Medicine – BSU- Egypt College of Dentistry Taibah University- KSA Vice Dean For Quality, Development & International Affairs Certified Trainer for International Research Ethics
  2. 2. Objectives  Developing/Writing a protocol.  Developing an Investigator Site File (ISF) – Regulatory Binder.  Screening, Recruitment, Enrollment and Retention.  Safety reporting (SAE &AE) SUSARS.  Interim and Annual Reports.  End of Study Visit.
  3. 3. The great tragedy of science.. the slaying of a beautiful hypothesis by an ugly fact. Thomas Henry Huxley
  4. 4. Clinical Trials
  5. 5. Preparation of trial Clinical Trials
  6. 6. Preparation of trial Clinical Trials
  7. 7. Preparation of trial Pre-Study Activities IP Clinical Trials
  8. 8. Preparation of trial Serology + CRF Monitoring visits Pre-Study Activities Clinical Trials IP
  9. 9. Monitoring visits Serology CRF Data analysis + Development Plan Preparation of trial Study report Registration file Scientific publications IP Pre-Study Activities End of study activity Clinical Trials
  10. 10. Designing a protocol
  11. 11. General Information  Protocol title, and date.  Name and address of the Investigator & sponsor  Name, title, address, and telephone number(s) of the sponsor's medical expert for the trial.
  12. 12. Background Information  Name and description of the investigational product(s).  A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.  Summary of the known and potential risks and benefits, if any, to human subjects.  Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s).
  13. 13. Background Information  A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s).  Description of the population to be studied.  References to literature and data that are relevant to the trial, and that provide background for the trial.
  14. 14. Trial Objectives and Purpose  A detailed description of the objectives and the purpose of the trial.
  15. 15. Trial Design  Primary secondary endpoints, if any, to be measured during the trial.  A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages.  A description of the measures taken to minimize/avoid bias, including:  (a) Randomization.  (b) Blinding.  A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s
  16. 16. Selection and Withdrawal of Subjects  Subject inclusion criteria.  Subject exclusion criteria.  Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures.
  17. 17. Assessment of Efficacy  Specification of the efficacy parameters.  Methods and timing for assessing, recording, and analysing of efficacy parameters.
  18. 18. Assessment of Safety  Specification , methods & timing of safety parameters.  Procedures for eliciting reports for recording and reporting adverse event.  The type and duration of the follow-up of subjects after adverse events.
  19. 19. Statistics  Statistical methods to be employed, and planned interim analysis(ses).  Sample size & its justification (Power).  The level of significance to be used.  Criteria for the termination of the trial.
  20. 20. Quality Control and Quality Assurance Ethics Data Handling and Record Keeping Financing and Insurance
  21. 21. Objectives  Developing/Writing a protocol.  Developing an Investigator Site File (ISF) – Regulatory Binder.  Screening, Recruitment, Enrollment and Retention.  Safety reporting (SAE &AE) SUSARS.  Interim and Annual Reports.  End of Study Visit.  Key Players in Clinical Trials
  22. 22. Investigator Study File & Essential Documents
  23. 23. Definition Essential Documents: Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced
  24. 24. Sections  Grouped in 3 sections: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the trial
  25. 25. • Investigator Brochure • Signed protocol, amendments, sample CRF • Informed consent and any other written information given to subject • Advertisement to recruit subjects • Financial aspects of trial • Insurance statement, where required • Signed agreement between involved parties Before clinical phase of trial commences INV SPO              
  26. 26. • Dated, documented EC favorable opinion • EC membership list / composition • Clinical Trial Authorization • CVs of investigator/sub-investigators • Laboratory normal values/ranges • Laboratory accreditation/certification • Sample of label(s) attached to IMP container Before clinical phase of trial commences INV SPO            Where required  
  27. 27. • Instructions for handling IMPs & materials • Shipping records for IMPs & materials • Certificate(s) of analysis for shipped IMPs • Decoding procedures, if trial blinded • Master randomisation list • Pre-trial monitoring report (site suitable) • Initiation monitoring report Before clinical phase of trial commences INV SPO     (or third party)    (or third party)   
  28. 28. • Effective commencement date to CA, EC • IB updates • Revisions to protocol/amendment(s), CRF, informed consent form, other written info for subjects, advertisements, etc. • Dated, documented EC favorable opinion of substantial amendments • CA authorization of substantial amendments During trial INV SPO        where required 
  29. 29. • Updates of CVs, CVs for new investigators • Updates to laboratory normal values/ranges • Updates to lab accreditation/certification • Documentation of IMP & materials shipments • Certificate(s) of analysis for new batches of IMPs • Monitoring visit reports INV SPO      where required      During trial
  30. 30. • Relevant communications other than site visits • Signed informed consent forms • Source documents • Signed, dated, completed CRFs • Documentation of CRF corrections • SAE reports (Investigator to Sponsor) INV SPO      copy  original  copy  original   During trial
  31. 31. • Notification by sponsor to investigators of safety information • Interim or annual reports to EC & CA • Subject screening log • Subject identification code list INV SPO       Where required  During trial
  32. 32. • IMP accountability at site • Signature sheet • Record of retained body fluids/tissue samples (if any) INV SPO       During trial
  33. 33. • IMP accountability at site • Documentation of IMP destruction • Subject identification code list • Audit certificate, if available • Close-out monitoring report After completion/termination of trial INV SPO   if destroyed at site    
  34. 34. • Treatment allocation & decoding info • Notification(s) of end of trial to CA, EC • Clinical study report • Final Study Report submission to CA, EC INV SPO  returned to sponsor  if applicable   After completion/termination of trial
  35. 35. Objectives  Developing/Writing a protocol.  Developing an Investigator Site File (ISF) – Regulatory Binder.  Screening, Recruitment, Enrollment and Retention.  Safety reporting (SAE &AE) SUSARS.  Interim and Annual Reports.  End of Study Visit.  Key Players in Clinical Trials.
  36. 36. Patient Recruitment Determining the best way to recruit for a particular study requires experience plus an understanding of the recruitment process.
  37. 37. Planning  Determine who will be involved?  Discuss multiple strategies  Establish goals and timelines  Develop recruitment materials  Ads, brochures, educational materials  Plan to be flexible
  38. 38. Enrolment  Enroll only individuals who meet ALL of the Eligibility Criteria.  Using individuals that do not meet each of the inclusion and exclusion criteria constitutes a protocol violation.
  39. 39. Barriers to Recruitment and Retention  Subject-related barriers  Investigator-related barriers  Protocol-related barriers  Other barriers
  40. 40. Subject Barriers  Long clinic waiting times  Inconvenient appointment scheduling  Dislike of uncertainty associated with the trial; prefer the doctor to make the decision about their treatment  Perceived risks outweigh benefits  Unrealistic expectations of the clinical trial  Site accessibility barriers
  41. 41. Investigator Barriers  Lack of enthusiasm for the design or aims of the study protocol  Lack of time to recruit due to the investigator’s clinical workload and other duties  Conflict of roles between caregiver and clinical investigator  Investigator involved in too many clinical trials
  42. 42. Protocol Barriers  Eligibility criteria that are so tight that potential study subjects do not qualify for entry  Protocol too difficult to follow due to complex study designs  Lengthy study periods or excessive visit schedules
  43. 43. Other Barriers  Negative influence of the media  Social stigma associated with the research  Lengthy ethical approval process may delay recruitment and trial commencement  Multiple studies competing for same patients  Lack of referrals from colleagues to the clinical trial  Poor choice of study site by the sponsor  Inaccurate estimate of patient population  Not enough staff resources for the site
  44. 44. Methods for Patient Retention  Don’t recruit “doubtful” patients  Determine availability to attend visits  Get as many contact details as possible: friends, family, caregiver, employer, usual medical practitioner
  45. 45. Methods for Patient Retention (cont.)  Transportation money  Be flexible  Dignity and respect
  46. 46. Methods for Patient Retention (cont.)  Clean and comfortable waiting area  Tea, coffee, sandwiches  Make patient feel special
  47. 47. Methods for Patient Retention (cont.)  Serious adverse events – explain and make sure patient understand what is going on  Always encourage communication by phone, email, letters  Home-visits  End of year party
  48. 48. Objectives  Developing/Writing a protocol.  Developing an Investigator Site File (ISF) – Regulatory Binder.  Screening, Recruitment, Enrollment and Retention.  Safety reporting (SAE &AE) SUSARS.  Interim and Annual Reports.  End of Study Visit.  Key Players in clinical trials
  49. 49. Adverse Events DEFINITION : An adverse event is any undesirable/ untoward medical occurrence/ experience associated with the use of a medical product in a patient and which does not necessarily have a causal realtionship with this treatment. KINDS OF AEs: • Adverse event (AE) • Serious adverse event (SAE) • (Unexpected) adverse drug reaction (ADR) • Serious adverse drug reaction (SADR) Safety Reporting
  50. 50. Adverse event (AE)  Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment
  51. 51. Adverse drug reaction (ADR)  A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function
  52. 52. Unexpected adverse reaction (UAR)  An adverse reaction, the nature or severity of which is not consistent with the applicable product information
  53. 53. Serious adverse event (SAE)  Results in death  Is life-threatening  Requires hospitalisation or prolongation of existing hospitalisation  Results in persistent or significant disability or incapacity  Involves a congenital anomaly or birth defect  Is medically significant !!!!!
  54. 54. Medically significant  An event may be considered a SAE when, based upon appropriate medical judgment, it may jeopardize the patient or may require medical or surgical intervention to prevent one of the outcomes listed in the definitions for SAEs
  55. 55. SUSAR  Suspected , Unexpected Serious, Adverse drug Reactions associated with the use of the study medication,
  56. 56. AE/SAE evaluation  INTENSITY  CAUSALITY
  57. 57. INTENSITY Grade 1 - MILD Transient events, requiring no special treatment and not interfering with patient's daily activities Grade 2 - MODERATE Events introducing some level of inconvenience and may interfere with daily activities, but are usually ameliorated by simple therapeutic measures (may include drug therapy)
  58. 58. INTENSITY Grade 3 – SEVERE Unacceptable or intolerable events, significantly interrupting patient's normal life and requiring systemic drug therapy or other treatment
  59. 59. CAUSALITY (relationship to study drug)  CERTAIN A clinical event occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals.
  60. 60. PROBABLE  A clinical event, including laboratory test abnormality, with a reasonable time sequence to drug administration, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinical plausible response on withdrawal (dechallenge)
  61. 61. POSSIBLE  A clinical event with a reasonable time sequence to drug administration, but which could also be explained by concurrent disease or other drugs or chemicals.  Information on drug withdrawal may be lacking or unclear
  62. 62. UNLIKELY  A clinical event with temporal relationship to drug administration which makes a causal relationship improbable, and in which other drugs, chemicals or underlying disease provide more plausible explanations
  63. 63. UNASSESSABLE  A report suggesting an adverse drug reaction, which cannot be judged because information is insufficient or contradictory and which cannot be supplemented or verified
  64. 64. NOT RELATED  An adverse event, which is definitely not related causally to drug administration
  65. 65. SAE/SUSAR reporting  SAEs must be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g. Investigator’s Brochure) identifies as not needing immediate reporting  The investigator should also comply with applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions
  66. 66. Reporting of SAEs - Timelines All Serious Adverse Events (Immediate Reportable Events) should be reported to the Sponsor within 24 hours after Detection of the Event. Initial and Follow-up reports as soon as possible after receipt of all the information needed As per Sponsor’s SOPs As per regulatory requirements Include reporting unexpected ADRs (SUSARs) OR
  67. 67. What to report?  Subject number and initials  Description of the event  Severity  Causal relationship  Frequency  Outcome  Diagnostic tests  Treatment procedures  Medication administered
  68. 68. Objectives  Developing/Writing a protocol.  Developing an Investigator Site File (ISF) – Regulatory Binder.  Screening, Recruitment, Enrollment and Retention.  Safety reporting (SAE &AE) SUSARS.  Interim and Annual Reports.  End of Study Visit.  Key Players in Clinical Trials.
  69. 69. Reporting in Clinical Trials  Describe the Plan  Report the Results  Confess to Problems  Interpret Objectively
  70. 70. End of Study Visit To close down the study officially at the centre • Visit performed once all patients have completed the trial • Last opportunity to resolve all outstanding matters • To collect all unused material • A very last check
  71. 71. Close Out Visit is used to Remind the investigator of his continuing responsibilities The investigator should: - Inform the IRB/IEC on the end of the trial - Archive all study documentation for approx. 15 years
  72. 72. Did we “BRIDGE THE GAP”?
  73. 73. THANK YOU Tamer Hifnawy MD. Dr PH. Associate Professor of Public Health & Community Medicine Faculty of Medicine, Beni Suef University, Egypt College of Dentistry Taibah University, KSA Certified Trainer on Ethics of Human Research Research Consultant Email: Mobile: +201114130107 Egypt +966564356123 KSA