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management of clinical trials: sponser perspective from falgun vyas


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management of clinical trials: sponser perspective from falgun vyas

  1. 1. Conduct of clinical trials: an overview: Sponsor perspective 9:53 PM
  2. 2. Outlines of the presentation Standard Operating Procedures (SOPs) for clinical trial Protocol – a brief overview Selection of Clinical investigator Investigator training (during SIV and meeting) Periodic monitoring Audits/ inspections 9:53 PM
  3. 3. 9:53 PM
  4. 4. SOPs for clinical trial “Detailed, written instructions to achieve uniformity of the performance of a specific function". Majority of penalties from regulatory authority imposed due to the carelessness which is a byproduct of not following SOPs in performing clinical trials. 9:53 PM
  5. 5. SOPs answers- 4 Ws and H concept of clinical trial management who SOP should be prepared with utmost care how what and then it should be followed religiously where when 9:53 PM
  6. 6. Objectives of SOPs Standardize the working practices Improve and maintain the quality of operations Ensures quality, consistent and reproducible results Defines the methodology to be followed Defines the roles and responsibilities of the individuals Ensures compliance to regulatory guidelines Saves times 9:53 PM
  7. 7. Effective SOP should Simple, easy to understand Comprehensive Differentiate between instructions and general information Describe procedure in a familiar way Descriptive title 9:53 PM
  8. 8. Protocol: definition “A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial.” Background and rationale for study allows researchers at multiple locations to perform the study in same way, so that their data can be combined 9:53 PM
  9. 9. Protocol:the plan; at the heart of every trial Organizations have their own format Generated from a standard template, which complies with regulatory requirements and company policy „copied and pasted‟ from a previous protocol avoid repetition in multiple sections Better to have protocol review boards with representatives from QA, data management, physician and statistician. 9:53 PM
  10. 10. Protocol After approval of the protocol by the ethics committee and the regulatory authority, any changes must be documented. Signed off by a senior representative of the medical department, the statistician & a medical advisor Professional responsibility for the content Each individual investigator will sign the protocol, thereby agreeing to comply with it 9:53 PM
  11. 11. Protocol amendmentsMinor: known as protocol revisions or administrative amendments no impact on risks, clinical decision-makingMajor: more significant inclusion/exclusion criteria, a lab test & changes to definition of what constitutes an AE Any change must be submitted to an IRB. Some IRBs merely acknowledge their receipt, while others actively review & approve changes 9:53 PM
  12. 12. Protocol Deviation any change, divergence, or departure from the study design or procedures Failure of subject to return unused study drug Participant is seen outside of the visit “window” Participant forgets to take 1 dose of study medication 9:53 PM
  13. 13. Protocol Violation Deviation that affect the subjects rights, safety, or well being and/or accuracy and reliability of the study data. Failure to obtain prior informed consent/inadequate or improper consent procedure Enrolled not meet eligibility criteria Withdrawal criteria met but not withdrawn Wrong treatment/dose Excluded concomitant medication Failure to follow protocol related to primary efficacy outcomes Loss of samples/data Repeated minor deviations A breach of confidentiality 9:53 PM
  14. 14. Minor protocol deviations-NO RISK any change from study protocol-not been approved by the IRB and which DOES NOT have a major impact only logistical or administrative aspects of the trial (e.g. change in monitor(s), change of telephone number(s)). 9:53 PM
  15. 15. Reporting of protocoldeviations Protocol violation should be reported within __ days of the investigator‟s knowledge of the deviation. Reports should be made using the Deviation Report Form Protocol deviation documented in the study file; not need to be submitted to the EC as they occur-annual study status report to EC and at final study closure. Subject-specific waiver from sponsor 9:53 PM
  16. 16. Selection of an investigator andsite pre-assessmentObjectives of Site Selection Assessment of potential problems Budget estimate Concerns about site / investigator Decision about conduct / site Investigator = Protective Physician + Responsible Researcher 9:53 PM
  17. 17. Selection Process Potential Criteria for Feasibility Report investigators evaluation studyIdentifying Potential Investigators Marketing department Literature Review Medical society directories Reference from investigator Professional colleagues Clinical trial registries 9:53 PM
  18. 18. Site evaluation Investigator Facility Protocol feasibilityQualifications Appropriateness Availability of potential subjectsLicense Storage facilities Interest levelSpecialty Special equipment Study coordinator availabilityClinical trial experience Active practice Attendance of investigator meetingFDA audits EC availability Competing studies 9:53 PM
  19. 19. SELECT criteria 9:53 PM
  20. 20. Knowledge & Skills for Feasibility Study Knowledge Skills Disease  Business etiquette Drug  Communication Design  Decision making Protocol  Interpersonal GCP  Planning SOPs  Time management Investigator  Negotiation Literature search  Computer 9:53 PM
  21. 21. Feasibility Study Questionnaire Initial contact – phone / email Visit Report Discussion DecisionSelection of Site is Art Of Investigating Investigator 9:53 PM
  22. 22. Investigator meetingand training regulatory volunteer sponsor Ethics committee 9:53 PM
  23. 23. Difference between practice and research Practice ≠ Research- exercise of an – systematic investigationoccupation or a designed to contribute toprofession generalizable knowledge – No protocol – Protocol – Administer to all – Administer to some patients patients – Some documentation– Much documentation – Not intended to – Intend to publish publish 9:53 PM
  24. 24. Investigator training Ethically, legally & clinically responsible for the conduct of study PIs primary clinicians routinely claim to be busy to attend training, not be allowed to conduct GCP training responsibility of sponsor- GCP noncompliance linked to inadequate training. Sponsors and EC each having authority to mandate GCP training as a prerequisite In US, holds IRBs accountable for dismal state of investigator GCP training!! 9:53 PM
  25. 25. Challenges with investigatortrainingBusy investigator Coordinators can be trained in the GCP training several times but investigators not finding time Coordinator training is not surrogate Not understanding the importance ”what‟s in it for me”? Poor past historyExperienced investigator “oh, I know all about that.” 9:53 PM
  26. 26. Investigator meeting Complex protocols, new technologies and increased regulatory scrutiny have all made study execution more challenging Amount of information a site must understand about a protocol is enough to make ones head spin. Moreover, sites participating in several studies; a lot of room for error Primary goal of meeting-- improve the performance of study site staff and ensure quality of data Ultimate purpose of the investigator meeting: to enable the safe and effective execution of a study protocol. 9:53 PM
  27. 27. Make meetings better and moreeffective Improved and simplified agendas, Increased interactivity, Shorter meetings, Less travel time, Enhanced speaker performance and An elimination of training redundancies. Start with training outcomes in mind and plan their meetings around those stated goals. Incorporating adult learning techniques such as interactive case studies or break out sessions 9:53 PM
  28. 28. eLearning alternatives Saves time and at the same time provide a self-paced and effective training Can be used to track who has completed and, comprehended the training and allow the sponsor to retain training records thus addressing potential compliance issues 9:53 PM
  29. 29. Optimal solution: in-personmeetings and eLearning Both. i.e. experienced investigators-eLearning, while inexperienced investigators & coordinators-in person Another option everyone‟s GCP training via eLearning, & then a shorter, more focused protocol specific meeting After training no resources to draw any output- only field monitors-this run the risk of allowing to forget much Turnover among site (or sponsor) staff, namely ensuring that everyone receives the same training Benefits of continuous education: higher quality data, better performing sites, enhanced site relationships, and significant cost and time savings. 9:53 PM
  30. 30. Informed consent 9:53 PM
  31. 31. Informed consent process Investigator‟s Responsibility Continuous process – starts with initial presentation of research activity – continues until the subject participation ends present the information accurately In a manner minimizing the possibility of coercion or undue influence 9:53 PM
  32. 32. Methods to improve consentprocess To record the consent process using recorders Consent for recording consent QuIC- Questionnaire to measure subjects actual vs. perceived understanding of CT what it includes: basic elements, therapeutic misconception, language and structure Group discussion Giving documents well in advance 9:53 PM
  33. 33. Documentation of the Informed Consent Process:Check all that apply The subject meets all eligibility requirements. Discussed, explained and reviewed the consent form with subject.- add time schedule Verbal consent/ Surrogate consent was obtained (per IRB approved consent process) All of the subject‟s questions were answered/concerns addressed. (document multiple subject question) Subject did not have any questions/concerns 9:53 PM
  34. 34. Documentation of theInformed Consent Process: Subject was given time to review the consent form and to discuss participation in this study with family members/others. The subject has agreed to participate in study & signed/dated a valid consent form prior to the start of any study procedures. The consent process was witnessed by a third party (if applicable). Witnessed by: A copy of the signed and dated consent form was given to the subject. A copy of the signed and dated consent form was placed in the medical record/ research record. Documentation of other conversation 9:53 PM
  35. 35. Monitoring of trial:Difference between QC and QA QC QA the operational  Verifies that the QC has techniques and activities satisfied these undertaken by all; to requirements. verify that the quality requirements fulfilled Includes checks that the  Includes the data recorded are establishment of SOPs consistent with source that oblige staff to follow documents; correct dose uniform practice, and administered & SOPs and checks that QC is in protocol are followed place and is effective. 9:53 PM
  36. 36. Periodic monitoring: Objectives1) Documentation of Informed Consent Process.2) Protocol enrollment eligibility criteria3) Data entry is complete & consistent between CRFs and source Documents.4) IP Accountability- accurately documented5) Ensure Laboratory procedures documented6) Ensure compliance of all Essential Regulatory Documents per regulations 9:53 PM
  37. 37. The intensity of monitoring Vary across studies and among sites Who will monitor- – sponsor‟s SOPs, – the complexity of the protocol, – condition being studied, – the experience of the investigator and – the training and experience of the CRA Overall plan remain fairly consistent, but strategy for individual sites may change depending on study conditions and site performance 9:53 PM
  38. 38. Frequency of monitoring visits Complexity of protocol Disease being evaluated Experience of the investigator/staff Number of study subjects enrolled at the site Rate of enrollment Site performance Sponsor monitoring SOPs CRA experience and effectiveness 9:53 PM
  39. 39. Monitoring activity General plan for what will be monitored at each site visit Most sponsors have a site visit or monitoring report-which is a standard document that a CRA will use for all field monitoring visits Serves as both a checklist for the CRA and as documentation of the visit. However, the CRA must not view this as the only list of activities that must be done. 9:53 PM
  40. 40. Top 5 deficiency categories for siteinspections1. Failure to follow the protocol2. Failure to keep adequate and accurate records3. Problems with the informed consent form4. Failure to report adverse events5. Failure to account for the disposition of study drugs 9:53 PM
  41. 41. Audits A Systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted and the data were recorded, analysed and accurately reported according to the - Protocol, - Sponsor‟s SOP - Good Clinical Practice and - Applicable Regulatory requirement 9:53 PM
  42. 42. What is difference between Audit and Inspection Audit Inspection Inspectors of the  Inspector by government, company who work for a through the agency of the active clinical quality regulatory or competent assurance (CQA) function Authority (i.e. FDA/DCGI) (i.e. Sponsor/CRO) To ensure that a site is  To ensure that trial complying with Protocol, related obligations and SOP, GCP and acceptability of resultant Applicable regulatory clinical data is in support requirements. of a new drug approval. 9:53 PM
  43. 43. Monitoring Auditing continuous process i.e. it  not a continuous process, is a part of the study, it may or may not happen done for each and every  few sites and selected site and for every subject, subjects; samples 100% for each activity Responsibility of the  done by Regulatory body Sponsor only, as well as sponsor Monitoring is Quality  Auditing is Quality Control Assurance 9:53 PM
  44. 44. What can be Audited: Site Investigators and Study Team IRB/IEC Sponsor CRO, if involved Laboratories Pharmacy (e.g. Investigational Drug Services) Devices (e.g. ECG, Biomedical, Engineering) 9:53 PM
  45. 45. How they select site: Study oriented audits:  Investigator oriented– Patient Enrollment: audits Highest enrolling sites  generally occur when the– Patient Retention: Large drug regulatory authority no. of screen failures, has cause to suspect drop-out rates particular research‟s– AE: Large no. of SAE at conduct i.e. “For-cause only 1/2 sites Audit”– Trial Importance: Pivotal studies. 9:53 PM
  46. 46. Audit Procedure Audit plan/Agenda Notify conduct of audit to CRA and Site present their credentials (photo ID) & a Notice of Inspections Form Introductory Meeting start auditing by reviewing specific data interview site staff directly involved in trial activities and process Closing meeting (exit interview) 9:53 PM
  47. 47. How to select sample no. of CRFs forSDV  square root of number of CRFs plus one (screened/randomized)  a minimum range-3-5 CRFs.  100 % SDV for ICFs and then 100 % of SDV for 10 % of total CRFs.  all primary efficacy data and AE would be audited 100% for all patients randomized and/ or enrolled.  If particular problems found then 9:53 PM
  48. 48. Auditor’ s commonobservations for study1. Protocol Non-adherence2. Inadequate & inaccurate records3. Failure to report adverse events4. Failure to report concomitant Rx5. Inadequate drug accountability6. IRB/IEC problems7. Informed Consent issues 9:53 PM
  49. 49. After Audit Procedure:After the Audit is complete, the Auditor prepare an Audit certificate Audit report / Establishment Inspection Report (EIR):Classification Type of LetterNAI (No Action Indicated) Notice of no significant deviationsVAI (Voluntary Action Indicated) InformationalOAI (Official Action Indicated) Warning 9:53 PM
  50. 50. Thank you any?? 9:53 PM