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Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
Preparing For Sponsor Audits Rpci 4 10
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Preparing For Sponsor Audits Rpci 4 10

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  • 1. Preparing for Sponsor Audits Lorrie D. Divers, CCRP, RQAP-GCP Director, Clinical Trials Quality Assurance ACM Global Central Laboratory RPCI Education Day for Clinical Research Staff April 16, 2010 – Buffalo NY
  • 2. Disclaimers The contents of this presentation are my own and do not represent the opinions or advice of my employer, ACM Global Central Laboratory. Information regarding FDA inspections contained in this presentation was obtained from publicly available sources. My interpretation of this information is also my own. 16-Apr-2010 16-Apr- Divers, RPCI Education Day 2
  • 3. Preparing for Sponsor Audits Follow the Protocol! Comply with the Regulations! Document Everything! 16-Apr-2010 16-Apr- Divers, RPCI Education Day 3
  • 4. Objectives Why Do Sponsors Audit Investigators / Study Sites? What Should You Expect? How to Prepare for a Sponsor Audit How to Respond to Observations and Recommendations How to Be Prepared 16-Apr-2010 16-Apr- Divers, RPCI Education Day 4
  • 5. Why Sponsors Audit Sites 16-Apr-2010 16-Apr- Divers, RPCI Education Day 5
  • 6. Why Sponsors Audit Sites Sponsors have a regulatory obligation to monitor investigators / study sites Auditing is a GCP best practice Auditing is different than monitoring Audits evaluate all study activities to ensure Protection of subjects’ rights Integrity and reliability of the data generated A well-controlled clinical trial was conducted 16-Apr-2010 16-Apr- Divers, RPCI Education Day 6
  • 7. Why Sponsors Audit Sites Routine per Sponsor Procedures Specific pre-defined criteria: New investigators, data trends, study sites with past issues, new monitor, etc. Evaluate the monitoring, adequacy of Sponsor procedures Just good business / GCP practice In preparation for FDA submission It’s better to know sooner rather than later 16-Apr-2010 16-Apr- Divers, RPCI Education Day 7
  • 8. Why Sponsors Audit Sites In anticipation of an FDA inspection Prepare investigator and study site staff Who? High enrollers, sites with significant differences in comparison with others (AEs, deviations, high response rate), new investigator / study conducted was not the investigator’s specialty For cause Persistent non-compliance, suspected fraud, other concerns expressed by monitor or sponsor staff Observations from audit of in-house study files / records and/or data 16-Apr-2010 16-Apr- Divers, RPCI Education Day 8
  • 9. What to Expect Audits should provide education, not be perceived as punishment Generally two to three days in length Agenda provided prior to audit, including list of records and documents to be reviewed Monitor may or may not attend Auditor(s) may be Sponsor staff or may be consultants Suggestion: Ask for identification if not accompanied by a monitor you know 16-Apr-2010 16-Apr- Divers, RPCI Education Day 9
  • 10. What to Expect Auditors are not monitors Primary concern is overall compliance Regulations, GCP guidance / standards Protocol and associated documents Procedures – Yours and the Sponsors What is revealed about the conduct of the study? Documents and records Investigator, all study staff Monitors, monitoring reports 16-Apr-2010 16-Apr- Divers, RPCI Education Day 10
  • 11. What to Expect Auditors will talk to people and ask questions, not just look at documents Auditors will be looking at both the big picture and the details Questions about parts are used to evaluate systems (parts = whole) Questions about systems may reveal concerns about parts (hole = missing parts) 16-Apr-2010 16-Apr- Divers, RPCI Education Day 11
  • 12. A few ‘secrets’ about Auditors 16-Apr-2010 16-Apr- Divers, RPCI Education Day 12
  • 13. A few ‘secrets’ about Auditors Our Obsessive-Compulsive Disorder is encouraged and may be pronounced We will pull at threads and push against boundaries “What if…” We will repeat ourselves Frequently, on purpose, and often 16-Apr-2010 16-Apr- Divers, RPCI Education Day 13
  • 14. A few ‘secrets’ about Auditors We are generally natural investigators Skilled at formulating pictures from very few puzzle pieces Have had significant training and/or experience with investigative techniques Can read people May be intentionally obtuse May use the ‘Mr. Rogers’ approach or the ‘Dirty Harry’ approach (or both) 16-Apr-2010 16-Apr- Divers, RPCI Education Day 14
  • 15. How to Prepare 16-Apr-2010 16-Apr- Divers, RPCI Education Day 15
  • 16. How to Prepare Review the agenda and ensure all records and all personnel will be available Have a quiet location for the auditor(s) to work Preferably empty of other records Conference room is ideal Most auditors will not want someone in attendance at all times Assign one person to interact regularly with auditor(s) Agree upon frequency of checking in 16-Apr-2010 16-Apr- Divers, RPCI Education Day 16
  • 17. How to Prepare Have all documentation related to the study readily available Regulatory binder Exclude: Audit-related; financial/contractual documents Original signed informed consent forms Case report forms Source documentation All charts, records, worksheets Original or certified copies 16-Apr-2010 16-Apr- Divers, RPCI Education Day 17
  • 18. How to Prepare If the study was conducted in the past, PI and study staff should re-familiarize themselves with the protocol and records Additional documents to have available: All clinical research related procedures and operational documentation (standard forms, checklists, etc.) Training records for all study personnel 16-Apr-2010 16-Apr- Divers, RPCI Education Day 18
  • 19. During the Audit Keep brief notes Questions asked / answers given Documents requested and provided Discussions of complex issues Keep copies of documents collected Stamp or mark ‘copy’ and ‘confidential’ documents collected by the auditor Suggest a brief wrap-up at the end of each day to confirm outstanding items, questions and any requests for next day 16-Apr-2010 16-Apr- Divers, RPCI Education Day 19
  • 20. During the Audit Respond to the question asked with simple, honest, and complete answers Listen actively and ask for clarification if you are unsure of what is being asked Don’t rely on memory alone – review the documents yourself if necessary ‘I don’t know; we will review and get back to you by the end of the day’ is an acceptable answer, if appropriate Deferring to and locating the correct person to answer the question within a specified time frame is also acceptable 16-Apr-2010 16-Apr- Divers, RPCI Education Day 20
  • 21. During the Audit Don’t hide Don’t just say ‘Yes’ when additional information is helpful and relevant You may create the wrong picture Don’t reveal Don’t answer an unasked question It may lead to unnecessary thread-pulling Don’t debate Clarify misunderstandings with positive rather than negative statements Be professional at all times Auditors are always listening and observing 16-Apr-2010 16-Apr- Divers, RPCI Education Day 21
  • 22. At the End of the Audit The auditor(s) should conduct an ‘exit interview’ Review observations and findings May provide recommendations Caution may be warranted May review specific regulatory obligations PI and key study staff should participate There is no expectation of perfection Clinical trials are conducted, monitored and audited by human beings Remember, it should be educational 16-Apr-2010 16-Apr- Divers, RPCI Education Day 22
  • 23. What Happens After the Audit 16-Apr-2010 16-Apr- Divers, RPCI Education Day 23
  • 24. What Happens After the Audit Auditor and/or Sponsor should provide a written report 3 – 6 weeks after the audit Review and compare with your notes Clarify any questions or concerns Observations are most often rated as Critical: An error that calls into question the reliability and integrity of the data, presents significant risk(s) to study subjects, indicates a lack of compliance with GCP regulations. An accumulation of major errors indicates a high level of suspicion for a systems failure. 16-Apr-2010 16-Apr- Divers, RPCI Education Day 24
  • 25. An Auditor’s Perspective Major: An error that suggests deficiencies in compliance with GCP and/or the site’s procedures but does not result in a critical error. An accumulation of minor errors suggests a systematic failure may have occurred. Minor: An error that does not meet the definition of critical or major but may suggest some deficiencies in compliance. May also include Recommendations 16-Apr-2010 16-Apr- Divers, RPCI Education Day 25
  • 26. Responding to Audit Findings Will generally request a written response and/or a corrective and preventive action plan (CAPA) Your written responses should be SMART Specific, Measurable, Attainable, Relevant, Time- bound / Trackable Be clear, be precise Back up statements with facts (documents, data) Try to avoid being defensive 16-Apr-2010 16-Apr- Divers, RPCI Education Day 26
  • 27. Responding to Audit Findings Don’t promise actions you cannot, or do not intend to, follow through on If a corrective action cannot be carried out right away, respond with a proposed completion date 16-Apr-2010 16-Apr- Divers, RPCI Education Day 27
  • 28. Corrective & Preventive Action Plans Corrective Actions = Reactive Correct the source of non-compliance and prevent future, similar problems Start with root cause analysis (the ‘5 why’s’ of a problem) Then develop effective resolutions based on true cause, such as: SOPs – May need to be study specific Checklists Remedial training Quality control checks 16-Apr-2010 16-Apr- Divers, RPCI Education Day 28
  • 29. Root Cause Investigation When a mistake or an error or an incident of non-compliance occurs, evaluate why What was the actual mistake? Hint: It may not be what it appears to be Under what circumstances did it occur? Who was involved? When was the error detected and how? What were the consequences? Were subjects’ safety, rights or welfare impacted? 16-Apr-2010 16-Apr- Divers, RPCI Education Day 29
  • 30. CAPA Preventive Actions = Proactive Ensure quality and compliance the first time, every time SOPs Checklists Record keeping/actions as events occur Training prior to duties Good documentation practices Frequent meetings and internal reviews 16-Apr-2010 16-Apr- Divers, RPCI Education Day 30
  • 31. How to Be Prepared 16-Apr-2010 16-Apr- Divers, RPCI Education Day 31
  • 32. How to Be Prepared Know and understand regulations and GCP guidance documents http://www.fda.gov/ScienceResearch/Special Topics/RunningClinicalTrials/default.htm Investigator Responsibility – Protecting the Rights, Safety, and Welfare of Study Subjects (FDA Guidance, Oct. 2009) Seek training Reliable sessions can now be found on-line Participate in national organizations’ meetings 16-Apr-2010 16-Apr- Divers, RPCI Education Day 32
  • 33. How to Be Prepared Review the protocol and associated documents Consider how to conduct the study at your site and in accordance with your procedures Participate in investigator meetings, SIVs Learn from monitoring visits and audits Ask questions Apply the concept of Quality Systems 16-Apr-2010 16-Apr- Divers, RPCI Education Day 33
  • 34. Being Prepared Avoids… In both 2000 and 2004, the most common observations cited by FDA inspectors Failure to follow the protocol / investigational plan Failure to maintain adequate and accurate records Failure to account for disposition of study drugs / test articles Failure to report Adverse Events Problems related to informed consent 16-Apr-2010 16-Apr- Divers, RPCI Education Day 34
  • 35. Being Prepared & Quality Systems “Janet Woodcock, the Deputy Commissioner of Operations at the FDA, stated that she is strongly encouraging all parties conducting clinical research to recognize that quality is a ‘system’ characteristic and that quality cannot be inspected into a trial but instead must be designed into the process.” Kit Howard, A Risk-Based Approach for Assessing Data Quality, Journal of Clinical Research Vol. 3, No. 6, June 2007 16-Apr-2010 16-Apr- Divers, RPCI Education Day 35
  • 36. Quality Systems A comprehensive approach that Complies with regulations and GCP Assures control and integrity of data, protection of subjects’ rights and welfare Standardizes processes to minimize unintended variability and diminish risk Measures quality at each critical step “Quality system means the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management.” 21 CFR 820.3(v) 16-Apr-2010 16-Apr- Divers, RPCI Education Day 36
  • 37. An FDA Inspection Perspective “This letter also discusses your written response dated February 23, 2005, to the inspectional observations noted on the Form FDA 483. While the submission provides an explanation of events that occurred at your site, it does not discuss how you personally intend to address the deficiencies, nor does it provide a detailed explanation of system- wide corrective actions that will be take to prevent these deficiencies from occurring in the future. It is recommended, at a minimum, that staff training be provided that includes retraining on Good Clinical Practices (GCP) guideline with emphasis on safety. 16-Apr-2010 16-Apr- Divers, RPCI Education Day 37
  • 38. An FDA Inspection Perspective This will assist you and your staff in the protection of human subjects as it relates to the informed consent process and the federal regulations for investigational device exemption studies. In addition, we recommend that you establish specific Standard Operating Procedures (SOPs) for your research activities.” Source: FDA Warning letter, Jun 23, 2005; Khoury 16-Apr-2010 16-Apr- Divers, RPCI Education Day 38
  • 39. Unfortunately, “no magic formula” “Currently, some individuals suggest using a quality system approach to avoid compliance actions, improve research data quality and facilitate the advance of new technologies into the marketplace. Unfortunately, there is no magic formula for how to devise or implement a quality system in the clinical trial setting…..” ME Marcarelli, ‘5 Habits of Highly Effective Sponsors’ Regulatory Affairs Focus, April 2007 16-Apr-2010 16-Apr- Divers, RPCI Education Day 39
  • 40. 7 Elements of a Quality System Equipment and Facility controls Records, Documents, Change Controls Material Controls i.e., Investigational product(s) and ancillary supplies Design Controls i.e., Key study design elements such as subject screening/selection, AE reporting, laboratory or other special testing 16-Apr-2010 16-Apr- Divers, RPCI Education Day 40
  • 41. 7 Elements of a Quality System Production & Process Controls i.e., Study personnel, PI role and responsibilities, monitoring Management Controls i.e., Procedures, policies, structure Corrective and Preventive Actions 16-Apr-2010 16-Apr- Divers, RPCI Education Day 41
  • 42. A Quality Systems Approach 16-Apr-2010 16-Apr- Divers, RPCI Education Day 42
  • 43. A Quality Systems Approach Failure to follow the protocol / investigational plan 16-Apr-2010 16-Apr- Divers, RPCI Education Day 43
  • 44. A Quality Systems Approach Principal Investigator should personally conduct / supervise the conduct of the clinical trial A PI can delegate authority but cannot delegate responsibility for clinical trials Read the protocol, IB, other documents related to the conduct of the study provided by the sponsor PI should keep himself/herself informed throughout the conduct of the study Meet with sub-investigators, study staff Read IRB and sponsor correspondence Make time to meet with the monitor Provide training opportunities for self and study staff 16-Apr-2010 16-Apr- Divers, RPCI Education Day 44
  • 45. A Quality Systems Approach PI should ensure staff (and self) are adequately trained on / understand delegated tasks (and responsibilities) Protocol procedures Regulatory commitments Investigational product accountability Informed consent process Good documentation practices Document training If needed, request protocol-specific training from sponsor 16-Apr-2010 16-Apr- Divers, RPCI Education Day 45
  • 46. A Quality Systems Approach Sites should develop and use standard operating procedures (SOPs) to ensure accuracy and consistency Checklists, forms, process flowcharts Create and use accurate eligibility, study procedure, reminder checklists Inclusion and exclusion criteria exist to protect subjects and ensure scientific validity of the results, thus protecting future recipients of the product Adhere to all the other protocol, sponsor, IRB and institutional requirements 16-Apr-2010 16-Apr- Divers, RPCI Education Day 46
  • 47. An Auditor’s Perspective Auditors will be sensitive to warning signs of lack of PI involvement, over-delegation or delegation to non-qualified personnel No source notes with PI signature Never available to meet with monitor Not initialing/dating IRB and/or sponsor correspondence No evidence of assessment of AEs or SAEs, inclusion/exclusion, study procedure results, informed consent process Study staff express frustration with investigator 16-Apr-2010 16-Apr- Divers, RPCI Education Day 47
  • 48. A Quality Systems Approach Failure to maintain adequate and accurate records 16-Apr-2010 16-Apr- Divers, RPCI Education Day 48
  • 49. A Quality Systems Approach Document, document, document Less is not “better” Standard of care PLUS protocol required information If it’s a document related to the study, keep it! Don’t throw it out, shred it, misplace it, put it in a pile, stuff it in a drawer, leave it at home, let the kids use it for scrap paper, keep it in the trunk of the car…. Maintain a date-ordered, topic-ordered file, preferably in a study-specific binder 16-Apr-2010 16-Apr- Divers, RPCI Education Day 49
  • 50. A Quality Systems Approach Keep CRFs up to date to ensure accurate information is recorded and maintained Use a quality control process to ensure IRB approval is in place prior to enrolling subjects Examples: Checklist; internal study start-up meeting with all sub-investigators and study staff 16-Apr-2010 16-Apr- Divers, RPCI Education Day 50
  • 51. A Quality Systems Approach Make sure you are aware of, and understand, your IRB’s policies and practices How do they issue approvals; is the ICF stamped or watermarked? Complete the continuing review report accurately and in a timely manner 16-Apr-2010 16-Apr- Divers, RPCI Education Day 51
  • 52. A Quality Systems Approach A simple information log / spreadsheet for IRB submissions and documents can be used to track: Date of initial IRB approval Documents approved Expected date(s) of continuing review report(s) Date of re-approval(s) Version/approval date(s) of updated ICFs 16-Apr-2010 16-Apr- Divers, RPCI Education Day 52
  • 53. Documentation > Documents How the paper tells the story is important Inaccurate or incomplete records Late entries Improper corrections Inappropriate personnel completing Electronic records 21 CFR Part 11 FDA Guidance: Computerized Systems Used In Clinical Investigations, May 2007 16-Apr-2010 16-Apr- Divers, RPCI Education Day 53
  • 54. ALCOA Principles for GDP Attributable: Appropriately signed, initialed, dated, (who wrote it when) Legible: No hieroglyphics; properly corrected One line through, add new information, initial and date Contemporaneous: Documented in proximity to occurrence, not 6 months later Original: If not, why not? Certified copies Accurate: Correct subject; sensible dates; modifications clearly explained if not self-evident 16-Apr-2010 16-Apr- Divers, RPCI Education Day 54
  • 55. And now a few words about… 16-Apr-2010 16-Apr- Divers, RPCI Education Day 55
  • 56. Notes to File From ‘Note to Self: No More Notes to File’ by Carl Anderson, Applied Clinical Trials, March 2008 “A common document at many clinical sites is the memo or note to file (NTF). When used properly, an NTF can be a positive practice. Some in the clinical trials community, however, seem to think an NTF is a panacea for all things that have gone wrong. Make a mistake? Then write an NTF…” 16-Apr-2010 16-Apr- Divers, RPCI Education Day 56
  • 57. Notes to File Retrospective “documentation” is a very risky practice for both sponsors and sites From a Warning Letter issued to Sanofi- Aventis in October, 2007 “Our investigation found that Aventis failed to take any action to secure compliance while the study was ongoing except to generate numerous memos to file after all subjects had completed the study.” 16-Apr-2010 16-Apr- Divers, RPCI Education Day 57
  • 58. Notes to File From a Warning Letter issued to a clinical investigator “We note that there were no medical histories in these subjects’ research files. For subjects [-] you created Memos to File stating that medical records were not obtained due to subjects’ primary care physicians being located in Mexico. These memos do not sufficiently address the issue of the missing medical histories. Without the medical histories…it is not possible to verify if the subjects met inclusion criteria for the study.” [Source: June 30, 2008; Hsueh] 16-Apr-2010 16-Apr- Divers, RPCI Education Day 58
  • 59. An Auditor’s Perspective Notes to file are “flags” for auditors and regulatory authority inspectors Prompt us to look at processes and procedures related to the issue documented Prompt us to ask more specific questions Tell us a “story” about the conduct of the study, including about the monitoring So, how do you want your NTFs to look? 16-Apr-2010 16-Apr- Divers, RPCI Education Day 59
  • 60. Do you want… NTFs that just document errors without Examining the cause of the problem Explaining the remediation Being necessary Notes to file that are Poorly and/or inaccurately written Frequent and repetitive 16-Apr-2010 16-Apr- Divers, RPCI Education Day 60
  • 61. Do you want… Effective notes to file that correct, clarify, or add to the existing source documentation and are Well-written – clear and accurate Relevant – appropriate level of detail Infrequent – and not repetitive Timely – not written the day before an audit or inspection NTFs that demonstrate GCP compliance by documenting corrective and preventive actions (CAPA) 16-Apr-2010 16-Apr- Divers, RPCI Education Day 61
  • 62. An Auditor’s Perspective Good Documentation Practices prevent the need for retrospective Notes to File Examples of how poor practices lead to this “Late entries are sometimes made without adequate documentation by the person making the entry including the time and date the entry was made. In addition, the actual source of the late entry is not always evident. This is particularly evident with regards to AEs.” “Progress notes occasionally had multiple date stamps, or were undated, making it difficult to determine the date the exam was actually performed. In addition, some of the date changes are not dated or initialed and it cannot be determined when or by whom these changes were made.” 16-Apr-2010 16-Apr- Divers, RPCI Education Day 62
  • 63. A Quality Systems Approach Failure to account for disposition of study drugs / test articles 16-Apr-2010 16-Apr- Divers, RPCI Education Day 63
  • 64. A Quality Systems Approach Maintain prospective accountability records Use the sponsor-provided form, if possible Keep all shipping receipts and return records Check the protocol and/or request written information from the sponsor on accountability Periodically reconcile against stock and against patient administration/use records Resolve and document any discrepancies at the time they occur or as soon as discovered 16-Apr-2010 16-Apr- Divers, RPCI Education Day 64
  • 65. A Quality Systems Approach Review the protocol’s randomization (or treatment assignment) requirements Ensure all staff understand and are aware If it is an oral medication the study subject will be taking at home, determine how treatment compliance will be documented Diary card, PDA, IVRS, daily phone log 16-Apr-2010 16-Apr- Divers, RPCI Education Day 65
  • 66. A Quality Systems Approach Failure to report Adverse Events 16-Apr-2010 16-Apr- Divers, RPCI Education Day 66
  • 67. A Quality Systems Approach Understand the protocol, sponsor, and IRB requirements for reporting adverse events, serious adverse events, and safety updates Medically qualified study staff (investigator or sub-investigator) should document assessment of all adverse events 16-Apr-2010 16-Apr- Divers, RPCI Education Day 67
  • 68. A Quality Systems Approach Use a dated cover letter when submitting information to the IRB and maintain a copy with the submitted information A simple tracking spreadsheet can also be helpful Date SAE or safety report was submitted Description / identification of what was submitted, when, to whom (IRB, Sponsor, others) 16-Apr-2010 16-Apr- Divers, RPCI Education Day 68
  • 69. A more few words about… 16-Apr-2010 16-Apr- Divers, RPCI Education Day 69
  • 70. Source / Study Worksheets Source documentation is a regulatory responsibility of clinical investigators Can delegate authority but not responsibility Delegation of authority log with printed name, signature, initials, roles, date(s) involved Appropriately trained, qualified and supervised personnel No appearance of falsification or fraud 16-Apr-2010 16-Apr- Divers, RPCI Education Day 70
  • 71. Sponsor’s Expectations FDA Guideline for the Monitoring of Clinical Investigations, January 1988 “A sponsor is responsible for assuring that data submitted to FDA in support of safety and effectiveness of a test article are accurate and complete. The most effective way to assure the accuracy of data submitted to FDA is to review individual subject records and other supporting documents and compare those records with the reports prepared by the investigator for submission to the sponsor.” 16-Apr-2010 16-Apr- Divers, RPCI Education Day 71
  • 72. Source Data Verification “All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.” [ICH E6, 1.51] FDA has consistently advised that source record quality is enhanced by using the site’s normal record keeping system to the maximum extent possible See for example, “The Facts About Source Documents,” www.fda.gov/Cder/present/dia-699/wollen-dia99/wollen-dia99.ppt) 16-Apr-2010 16-Apr- Divers, RPCI Education Day 72
  • 73. Normal Records vs. Source Worksheets What are your routine records? Are they adequate and accurate? Source worksheets should supplement, not substitute for or duplicate records Normal clinical documentation ≠ clinical research record-keeping but if normal documentation is adequate for the protocol, using different documentation is risky And what if there are only source worksheets? 16-Apr-2010 16-Apr- Divers, RPCI Education Day 73
  • 74. An Auditor’s Perspective An Example “Recommendation: The site should reconsider their use of sponsor-provided source worksheets in situations where their routine clinic documentation is adequate. They should not duplicate information but should use the source worksheets only to document information not captured as part of their normal record-keeping. One recommendation is to cross-out unnecessary portions of source worksheets, indicating “see clinic chart,” and fill out only study-specific questions / information not otherwise adequately documented in the clinic and/or surgery records. In addition, if source worksheets are used, they must be signed like a clinic chart note would be.” 16-Apr-2010 16-Apr- Divers, RPCI Education Day 74
  • 75. A Quality Systems Approach Problems related to informed consent 16-Apr-2010 16-Apr- Divers, RPCI Education Day 75
  • 76. A Quality Systems Approach Learn the history of the ethics of clinical research On-line courses are available from the NCI and NIH A number of good reference books are available Check with your IRB, ask the sponsor Read the regulations Ethical obligations became regulatory obligations and regulatory obligations are the LAW Numerous guidance documents aid in understanding 16-Apr-2010 16-Apr- Divers, RPCI Education Day 76
  • 77. A Quality Systems Approach Adequacy of informed consent is an investigator responsibility Carefully review any sponsor-provided ICF template Compare it to the protocol, the product information, and your IRB requirements Persons obtaining consent should be appropriately qualified / trained to do so If not done by PI or medically qualified sub- investigator, subject should have opportunity to discuss any questions or concerns 16-Apr-2010 16-Apr- Divers, RPCI Education Day 77
  • 78. A Quality Systems Approach Establish and follow good document control practices for ICFs If your IRB does not stamp or watermark the IRB-approved consent form, ask them to consider this or do it yourself (SOP) Password-protect / limit access to any non- approved versions that may be stored on the computer Use a tracking and/or filing method to ensure only the current IRB-approved version is used 16-Apr-2010 16-Apr- Divers, RPCI Education Day 78
  • 79. A Quality Systems Approach The form is just a document - Informed consent is a process Auditors look for evidence of the process ICF version used consistent with IRB approved version? How is this ensured? Who obtained consent? Were all questions addressed? Was consent obtained prior to any protocol- specific procedures? How was re-consent carried out and documented? 16-Apr-2010 16-Apr- Divers, RPCI Education Day 79
  • 80. An Auditor’s Perspective Informed Consent process issues are often illustrated by a pattern of errors “A significant number of signed Consent Forms have date and signature anomalies made both by subjects and study personnel.” Date(s) changed – In several instances, changed by several days, weeks, or in one case, by more than a month Two instances of subject signing on ‘Person obtaining consent line’ – One instance remained uncorrected Often not dated by subject and/or PI themselves “For multiple subjects, the incorrect version of the ICF was used initially, and re-consent with the correct version not obtained, until observed by the monitor.” 16-Apr-2010 16-Apr- Divers, RPCI Education Day 80
  • 81. What Can You Do? 16-Apr-2010 16-Apr- Divers, RPCI Education Day 81
  • 82. The Paper Tells the Story Documentation is how auditors determine how the study was conducted Help them just turn the pages…. Accurate, complete documentation of all aspects of the study illustrates regulatory and protocol compliance Subject records IRB records Drug or device accountability Informed consent AE / SAE reporting Correspondence 16-Apr-2010 16-Apr- Divers, RPCI Education Day 82
  • 83. The Paper Tells the Story Correction is a documented action Appropriate to the cause of the problem Procedures, checklists, templates, etc. Training Quality control checks Compliance is a behavior exhibited by Documentation Knowledge of regulations Execution of procedures Audits 16-Apr-2010 16-Apr- Divers, RPCI Education Day 83
  • 84. What Can You Do Practice good documentation practices from the start of the study (ALCOA) Document errors and their correction in a timely manner Recognize patterns and consider the story they tell Make CAPA a habit, including assessing effectiveness Understand the protocol, GCP requirements and investigator responsibilities Ask questions of the monitor, sponsor, PI, IRB, auditors Checkout the FDA, NIH and NCI websites 16-Apr-2010 16-Apr- Divers, RPCI Education Day 84
  • 85. What Can You Do Remember the key areas of GCP compliance Subject welfare Data validity and integrity Test article (study drug, investigational device) control Ignorance of the regulations (law) is not an excuse Remember the keys to quality Effective and adequate the first time = the best way every time If it isn’t documented…. 16-Apr-2010 16-Apr- Divers, RPCI Education Day 85
  • 86. Questions 16-Apr-2010 16-Apr- Divers, RPCI Education Day 86
  • 87. Contact Information Lorrie D. Divers, CCRP, RQAP-GCP 585-429-2386 LDivers@acmgloballab.com “Quality is never an accident; it is always the result of high intention, sincere effort, intelligent direction and skillful execution; it represents the wise choice of many alternatives.” Willa A. Foster 16-Apr-2010 16-Apr- Divers, RPCI Education Day 87

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