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  • GLP (animal laboratories) GMP (manufacturing facilities) Are also inspected with regards to research and new products
  • Main target is the investigator, then IRBs, then sponsor /CRO (very small numbers) US and International based Other groups listed on overhead usually are ancillary dependent on the questions and needs posed by FDA investigators
  • Other: IND Drugs, Biologics, Devices, combinations Bioequivalence (I.e., pharmacokinetics) For cause changes the whole mix, then any study is fair inspection game
  • Other: IND Drugs, Biologics, Devices, combinations Bioequivalence (I.e., pharmacokinetics) For cause changes the whole mix, then any study is fair inspection game
  • Inspectors manual cites these metrics….
  • Will cover some case studies in the last of the series However, do not want the NIH folks to get to comfortable. Just this year, a patient complained about an NIH study to FDA and they visited for 3 weeks.
  • Be in a state of readiness at all times. Eg: files organized and accessible No notice = “for cause” inspection. Example: One UM investigator (and study coordinator) arrived after FDA who already visited the IRB, then stayed 6 weeks. Be ready to validate patient existence. One study coordinator had this question posed….and had to generate lists of the screened patients, too (who did not get on study)
  • OGC Rachel Nosowsky IRBMED: Send email to general mailbox (June Insco and/or Pat Ward) Want to start tracking centrally what is happening. Have not been so good about this to date In case problems, need to address together. Do not have the sponsor present at the inspection
  • Data needs to be directly related to the study generated data
  • Target the expert, and the level headed and the knowledgeable ones
  • Clinical Investigator CPGM Headers: Authority and Administration Protocol Subjects’ Records Other Study Records Consent of Human Subjects Institutional Review Board Sponsor Investigational Product Accountability Records Retention Electronic Records and Signatures Animal Clinical Studies (if applicable) Device Studies (if applicable) Report Format Sample Collection (if applicable)
  • Be cool, calm, collected and concise! FDA inspector from Detroit nicknamed “Columbo” Self effacing, same question for numerous people, tenacious until satisfied with the answer (oh yes, also wore a rumpled lab coat that he brought along)
  • Daily summaries for next day preparation and information gathering Exit interview: Management/Investigator and key person, study coordinator Important piece of discussion especially if a written response is needed in the future
  • Does not discriminate between minor and major (misspelled words in a consent versus many missing consents)
  • Describe classifications, can view on line, that the problem situations and warning letters are subject of future date in this series
  • Included in packet Green = FDA office activities Purple = Site activities Remind about CME cards Remind about feedback Remind about next class: Oct 20, 2003 Q and A Remind about speaking into microphone
  • Cro perspectives

    1. 1. Audits & InspectionsCRO Perspective
    2. 2. What is a CRO Contract Research Organization A person or an organization (commercial,academic, or other) contracted by thesponsor to perform one or more of asponsors trial-related duties andfunctions
    3. 3. CRO types Pharmacokinetic (BABE) Clinical Research – Phase I, II, III, IV Preclinical Discovery Analytical and Microbiological Hospitals, clinics, etc. Or any other
    4. 4. Our Focus Site Where actual work will get executed Clinical Trials Any investigation in human subjects intended todiscover or verify the clinical, pharmacological, and/or otherpharmacodynamic effects of an investigationalproduct(s), and/or to identify any adverse reactions to aninvestigational product(s), and/or to study absorption, distribution, metabolism, andexcretion of an investigational product(s) with theobject of ascertaining its safety and/or efficacy.
    5. 5. Structured compliance plan CDSCO Slovac Republic WHO Brazil Zimbabwe Nigeria Thailand EU SA MCC USFDA TGACROs need to define their own Objectives and Goalsand Plans to execute according to the business needs
    6. 6. Compliance to GLP GCP GXP Applicable Rules, Regulations, Laws andguidelines of the target regulatory agencyand those of the land
    7. 7. Controlled regulated environment US: CFR and guidelines ICH Guidelines, including E6: GCP GXPs: GCP, GLP, GMP EU: Clinical trials directive and guidelines CIOMS guidelines (council for internationalorganizations of medical sciences WHO Geneva) National regulations & guidelines
    8. 8. Why Compliance? Promote quality and validity of test data Help scientists to obtain Reliable,Repeatable, Auditable, Acceptable results Necessary intrinsic scientific value Organizational requirement Management responsibility Mandatory Safety, Efficacy, Quality
    9. 9. Meeting Phenomenon We all are in a marathon meeting todiscuss why work is not being done We are conducting an Audit to check forcompliance to the remarks in the Auditconducted to check compliance……. Vicious cycle?? Or routine and sincerepractice!!!
    10. 10. To ensure compliance Build Quality systems Execute Protocols using these qualitysystems Quality Control and Assurance Monitoring Audit Review Inspection
    11. 11. Quality Control / Quality Assurance Quality Control / Operational Units Responsible for inspecting and certifyingpredefined quality expected in a product orprocess through Quality Control Systems Quality Assurance / Audit Group Assesses the Performance, Accuracy,Reliability And Integrity Of Quality Systemsthrough Independent Auditing Activities
    12. 12. Monitoring (ICH-GCP) The act of overseeing the progress of aclinical trial, and of ensuring that it is conducted, recorded, and reported inaccordance with the protocol, standard operating procedures (SOPs), GCP, and the applicable regulatory requirement(s)
    13. 13. Audit (ICH-GCP) A systematic and independent examination oftrial-related activities and documents todetermine whether the evaluated trial-related activitieswere conducted, and the data were recorded, analyzed, and accuratelyreported according to the protocol, sponsors standard operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory requirement(s).
    14. 14. Inspection (ICH-GCP) The act by a regulatory authority(ies), of conducting an official review of documents,facilities, records, and any other resources thatare deemed by the authority(ies) to be related tothe clinical trial and that may be located at the site of the trial, at thesponsors and/or contract research organization’s(CROs) facilities, or at other establishments deemed appropriate bythe regulatory authority(ies)
    15. 15. Time of Compliance Check Pre-study During Study After Study Sponsor Site Qualification CRO/ Site QA/ QC Unit Sponsor (monitoring) Sponsor (Audit of completed data) CRO/ Site QA/ QC Unit Sponsor (Audit of completed data) CRO/ Site QA/ QC Unit Inspection by RA
    16. 16. Ultimate Aim Pass Inspection by regulatoryauthority(ies) Well this means compliance!!!!
    17. 17. Compliance Certification Audit certificate: A declaration of confirmationby the auditor that an audit has taken place. Audit report: A written evaluation by thesponsors auditor of the results of the audit A written report from the monitor to the sponsorafter each site visit and/or other trial-relatedcommunication according to the sponsor’sSOPs.
    18. 18. Who and What are Inspected?
    19. 19. Who? Sites Investigators (Doctors) and Study Coordinators IRB (IRBMED) Sponsor, if applicable (Industry) Contract Research Organization, if involved Laboratories Pharmacy (e.g., Investigational Drug Services) Devices (e.g., ECG, Biomedical Engineering)
    20. 20. What studies? Usual Emphasis: Phase 3 Adequate and well controlled Blinded Safety and Efficacy Multi-site High patient enrolling sites Recent marketing application (e.g. New DrugApplication) filed to an Investigational NewDrug (IND)
    21. 21. What studies? Usual Emphasis: Bioequivalence studiesfor ANDA Clinical facilities, procedures, documentation Quality Systems Analytical facilities, procedures,documentation Clinical investigations laboratory
    22. 22. QC/ QA, Monitoring, Auditing,Inspection check for compliancePurpose is same, Objectives and methodcan be different
    23. 23. When will inspection Occur? At any time during the study After the study is complete prior toregulatory approval for the product At any time after regulatory approval (15years) if a safety concern with the product(rare)
    24. 24. FDA selects Site(s)• FDA selects site for inspection:• Usually within 6 months of marketingapplication [NDA] (Data Audit) or ANDA• Selects 3 sites (average) per study, if multi-site• May concurrently inspect the associated IRB:• If no previous inspection; or• Last inspection >5 yearsOR• May conduct a “For Cause” Audit
    25. 25. Reasons: “For Cause” Inspections Study of “singularimportance” inproduct approval Study has majorimpact on medicalpractice Sponsor reportsconcerns aboutinvestigator Patient complaint Investigator conductstoo many studies Investigator worksoutside of specialtyarea Safety or efficacyfindings areinconsistent with otherinvestigators Lab results are outsiderange of biologicalexpectations
    26. 26. FDA Inspection• May give sufficient or very short advancenotice or no notice of visit• Becomes suspicious on attempts to delayvisit (e.g., >10 days without valid reason)• Previews internally following subjectrelated data:• Number of total subjects, dropouts and evaluablesubjects• List of AEs and deaths (with description and cause)
    27. 27. Objectives of Inspecting In-vivo BE To verify the quality and integrity ofscientific data from bioequivalencestudies submitted To ensure that the rights and welfare ofhuman subjects participating in drugtesting are protected; and To ensure compliance with theregulations (21 CFR 312, 320, 50, and 56)and promptly follow-up on significantproblems, such as research misconduct orfraud.
    28. 28. Objectives of Inspecting In-vivo BE Clinical laboratories are usually certifiedunder programs based on the ClinicalLaboratories Improvement Act (42 USC263a), and are not routinely inspected bythe FDA. A clinical laboratory may be visitedduring a bioequivalence study audit toconfirm that reported screening ordiagnostic laboratory work was indeedperformed
    29. 29. Preparation Tips for Site Notify all staff involved in AND/ORknowledgeable about the study: Key staff, “information providers” are onstandby Industry sponsor
    30. 30. Preparation Tips for Site Assign a site escort/facilitator Define “SOP” for Interacting with inspectorsfrom welcome to exit and do not underplay oroverplay Assemble all study documents in One place Include list of staff responsibilities and training Request all patient charts Prepare a list of investigator’s studies Reserve adequate work space for fieldinvestigator for entire inspection Assure accessible photocopier provide a back upif necessary
    31. 31. You have 3 to 5 minutes To provide documents requested byInspector If not available be truthful Beyond five minutes inspector mayassume that it has been fabricated
    32. 32. Documentation thumb rule If not documented means not done If documented does not mean that it isdone
    33. 33. FDA Form 482 FDA written notice of inspection presentedby the investigator at the beginning of aninspection.
    34. 34. Tips on Document Requests Do not provide or copy these informationfor FDA: Financial data (salary information, budgets) (except financial disclosure of clinicalinvestigators) Personnel data (performance appraisals) (except qualifications [job descriptions] andtraining records) Remember 3-5 minute rule
    35. 35. FDA interviews Site Staff• FDA investigator interviews site staffdirectly involved in trial activities andprocesses• May question any staff member duringinspection• May use Compliance Program GuidanceManual as interview guide
    36. 36. Tips for Anticipating FDA Questions Compliance Program Guidance Manuals(CPGMs) Vivo Bioequivalence 7348.001IRBs 7348.809Sponsors, CROs and Monitors 7348.810Clinical Investigators 7348.811
    37. 37. FDA investigative techniques forGathering evidence Questioning employees at home at nightor on the weekend, permitted underFDCA Sec. 704 Can go through trash, obtain grand jurysubpoenas and search warrants fortelephone and business records Collaboration with FBI
    38. 38. Tips for Handling FDA Questions Answer Politely, cooperatively, understanding them(ask for clarification), factually, briefly, withinone’s expertise (seek expert), directly (remainwithin scope), without speculation orguesswork Avoid Unsolicited questions, hypothetical questions,long delays to requests, affidavits
    39. 39. Dos and Don’ts Effective inspection preparation requiresa multi-faceted approach. But communication issues can be just ascritical, as these dos and donts suggest.
    40. 40. What should you do for preparation? Review regulatory site files Confirm audit dates with all site staff Ensure all patient notes and other sourcedata are in good order. Ensure familiarity with the protocol andthe conduct of the study
    41. 41. Preparing for an inspection Have a written corporate policy forregulatory inspections Conduct independent audits and internalaudits Establish attitude of the company Designate an inspection coordinator haveback up
    42. 42. Training personnel for inspections Every employee must know his/her job functionand regulatory obligations Document employee credentials, training andknowledge Study related documents FDA program and inspection guidancedocuments
    43. 43. Personnel interacting with inspector (s) confirm that they are at correct name andinstitution, record inspector’s badge number Never leave investigator unattended List of inspection team members and alternatepersons: Clinical Director/Study Coordinator/PrincipalInvestigator Production V.P./Quality Control Manager Executive V.P./ President Legal Counsel
    44. 44.  Do be professional and confident Dont become argumentative or at worsthostile Attitudes are important If management is seen as "uncooperative,"the investigator may well becomesuspicious and more zealousDos and Don’ts
    45. 45.  Dont tell the investigator that aninspection isnt possible that day becausethe owner is on vacation, and suggestthey return next week.Dos and Don’ts
    46. 46.  Do balance cooperation with wariness. initial presentation about the facilitys operationsand a tour can be useful in setting a positive tone wait for the investigator to make specific requestsbefore providing records, samples, labels and thelike. Respond to requests appropriately do not offer other materials that might relate toanother matter pending with FDA but areunrelated to the request.Dos and Don’ts
    47. 47.  Do provide timely and carefully preparedwritten responses to 483s, and to anyletters issued by FDA regardingviolations identified as a result of theinspection. Often, it is appropriate toinclude a plan for corrective action. FDA wants to see that management istaking these issues seriously.Dos and Don’ts
    48. 48. FDA conducts “Exit Interview”• [Review findings with FDA investigator atend of each inspection day]• At site visit completion, FDA investigatorconducts “exit interview” with responsiblesite personnel to:• Review findings• Clarify misunderstandings• Describe any deviations from current regulations• Suggest corrective action, if appropriate
    49. 49. FDA Form 483 A summary report of inspectionalobservations. It is a list of objectionableconditions or practices observed duringthe inspection, prepared by the FDAinvestigator and presented to the auditeeat the conclusion of an inspection.
    50. 50. Most Common Observations(for Investigators) Protocol non-adherence Inadequate and inaccurate records Failure to report adverse events Failure to report concomitant therapy Inadequate drug accountability IRB/IEC problems Informed consent issues
    51. 51. FDA classifies Inspection• When evaluation is completed, FDAclassifies inspection and sends a letter tositeClassification Type of LetterNAI (No Action Indicated) Notice of no significantdeviationsVAI (Voluntary ActionIndicated)InformationalOAI (Official ActionIndicated)Warning
    52. 52. 1. Select Site2. Contact Site3. Schedule Site4. Arrive (482)5. Review Records6. Interview Staff7. Present Findings8. Depart (483)9. Write Report (EIR)10. Classify InspectionFDA Office Site LocationFDA Inspection Process
    53. 53. QC/ QA, Monitoring, Auditing,Inspection check for compliancePurpose is same, Objectives and methodcan be different
    54. 54. Audit : purpose The purpose of a sponsor’s audit is to evaluatethe trial conduct and compliance with:- Quality Systems and SOPs Protocol Good clinical practices & other applicableregulatory requirements Auditors are independent of the clinical trial/data collection system(s) Sponsor or CRO or Site
    55. 55. What to audit Organization and personnel Responsibilities and functions - Ensure clearresponsibilities exist so as to minimize ambiguitybetween:- Investigator and sub-investigator Sponsors and contractors Contractors/suppliers (CROs, Labs, IRBs) –audit suppliers! Qualification, training and adequacy of staff List of monitors List of all investigators
    56. 56. What to audit? Quality management systems Management responsibilities Procedures and their adequacy Training Documentation control Change control Deviations and non conformitiesmanagement QC, QA Internal Monitoring Program Internal Auditing Program
    57. 57. What to audit? Investigational drug Manufacturing, packaging, labeling and coding of theinvestigational product (including placebo and activecomparator where applicable) In accordance with applicable GMP standards Labelling requirments, “For Clinical Trial Use Only” to protect blinding where applicable Drug Product Accountability Control Quantity
    58. 58. What to audit IRB/EC Responsibilities Composition, functions and operations Procedures Records Investigators and sub-investigators Qualifications and agreements Essential documents
    59. 59.  Investigator’s brochure Has all current info been provided to the investigator? Signed protocol and amendments How are changes and deviations to the protocolhandled? Advertisements for subject recruitment Informed consent forms Approved by IRB/IEC? All been signed off according to requirements? Financial aspects of the trial Approved by IRB/IEC? Insurance statement (where required)What to audit (Essential documents)
    60. 60.  Subject Databank Subject screening log Subject identification code list Subject Enrollment log Case report forms Documentation of CRF corrections Serious adverse events reporting Signature sheet Signed agreements between parties IRB/IEC approval/favorable opinion IRB/IEC compositionWhat to audit (Essential documents)
    61. 61.  Regulatory authorities authorization/approval/notification of the protocol Normal value(s)/ranges for medical/laboratorytests Certifications or accreditation of labs (or othermeans that establishes competency of lab)What to audit (Essential documents)
    62. 62. What to audit (Essential documents) At the clinical site:- investigationalproduct and trial related materials Instructions for handling Shipping records Certificates of analysis of product shipped Accountability at the trial site Decoding procedures for blinded trials Master randomization list and method
    63. 63.  Records of retained body fluids/tissue samples(if any) Monitoring visit reports Pre trial During trial Post trial Final report by investigatory Clinical study report ArchivingWhat to audit (Essential documents)
    64. 64. Bio-analytical Laboratories Documentation control including archiving Qualification of instruments Qualifications and Training of staff Bio-analytical method validation Receipt and storage of samples Handling of reagents and solution Testing conducted as outlined in protocol CFR 11 compliance
    65. 65. Computerized systems (used to create, modify,maintain, archive, retrieve or transmit data) Identify software and hardware used, when and where? Check security of the system (individual Login,secure passwords) Check traceability Check audit trail capabilities where applicable:- Who made the changes? When and Why, Certification of changes by appropriate authorites Check validation status where applicable Check record retention capabilities
    66. 66.  Adequate procedures that need to be in place:- System setup/installation Data collection and handling System maintenance Data backup, recovery and contingency plans Security Change control Alternative recording methods Personnel trainingComputerized systems (used to create, modify,maintain, archive, retrieve or transmit data)
    67. 67. Statistical component Check statistical procedures and methods usedare according to protocol Check statistical package used has beenvalidated Review statistical analysis and results Check integrity of data and timely locking ofdatabase
    68. 68. QC/ QA, Monitoring, Auditing,Inspection check for compliancePurpose is same, Objectives and methodcan be different
    69. 69. Temperature Reading Display is one digit -67.8 In log book entries are -67.80, -70.50 etc Subsequently recording style changed tosingle digit -56.7, etc. Sponsors Monitor’s View Sponsors Auditors View Inspectors View
    70. 70. Participants in compliance Sponsors CROs Management of all the organizations All the employees, contractors,subcontractors
    71. 71. Key to Success for all - 01 Compliance is Organizationalresponsibility & mandatory act
    72. 72. Key to Success for all -02 Compliance is not a individual responsibility
    73. 73. Key to Success for all -03 Compliance is Organizationalresponsibility & mandatory act Compliance is not a individual responsibility Integrity as a culture Document properly what you do Do not document what you do not do Do it right at for the first time, at right time,in right manner
    74. 74. Thank you!!