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Preparing for Regulatory InspectionsRobert A. Noland, Senior Director of QA
MTN Regional MeetingNorth Bethesda, MD23 February 2014
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Presentation Outline
• Definitions• QA Audits of MTN‐020• All About Inspections• Preparing for an Inspection• Conduct during an Inspection
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Definitions
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• “Audit” ‐‐ a systematic examination of records by personnel independent of the operation of the system being examined
• “Inspection”‐‐ an audit conducted by a representative of a regulatory authority
• “Observation” ‐‐ a detailed description of a set of circumstances that appears to represent a departure from established standards
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Ratings of Observations
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• Critical – where evidence exists that a significant or unjustified departure from (standards) has occurred with evidence that:o The safety, well‐being or confidentiality of clinical trial participants has been jeopardized
o Serious doubt exists relating to accuracy or credibility of datao There are a large number of major observationso Previous major observations were not corrected appropriately
• Major – a non‐critical observation where evidence exists that a significant or unjustified departure from standards has occurred and/or a number of departures indicating a systematic failure
• Other – departure from standards that is not major or critical
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IPM QA Audits of MTN‐020
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• 12 clinical research site (CRS) audits were conducted from December 2012 to January 2014o 0 critical observations (congratulations are in order!)o 7 major observationso 39 other observations
• Remember that we’re only sampling during QA audits
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Responses to MTN‐020 Audits
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• Comprehensive and thorough• All clinical research sites were considered in response to individual site observations
• All audits are closed except where responses are not yet due
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All About Inspections
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Inspection Experience
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• Primary sponsor host for: o four FDA GLP inspectionso five FDA GCP/PV inspections (PV=pharmacovigilance)o one FDA QSR inspection (medical devices)o one EMA GCP inspection
• Sponsor representative at: o two foreign FDA GCP inspections (Bulgaria, Romania)o five foreign EMA GCP inspections (Russia, Bulgaria, Romania)o one foreign EMA CRO inspection (Poland)o two MHRA PV inspections (United Kingdom) o one foreign HPB GCP inspection (Canada)
• Facilitated many inspections while not on site
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Inspection Experiences
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• Low points: o six FDA inspectors arrive unannounced for a “for cause” inspection, which lasts for six weeks
o poor inspection outcome triggered further inspections and delayed approval for two years
• High points:o managed QA program for 5 approved NDAs
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What triggers inspections?
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• Submission for approvalo Pre‐approval inspection of manufacturingo Several clinical investigatorso Sometimes a sponsor inspection
• Complaints or allegations made to regulatory authority byo Clinical trial participants or consumerso Disgruntled ex‐employeeso Activists
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Why are inspections a good thing?
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• It means we have positive results from clinical trials
• It means we have submitted a complete application
• It means the regulatory agencies are taking our application seriously
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FDA Inspections in the USA
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• Usually unannounced*• Begin with issuance of Form FDA‐482 “Notice of Inspection” to highest level employee presento Anything you say can and will be used against you in court (if it comes to that)
o You do not have the right to remain silento Making a knowingly false statement is a crimeo You are not guaranteed the right to a lawyer
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Foreign Inspections (FDA, EMA)
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• There will be plenty of advance notice• Sponsor usually makes travel arrangements and accompanies inspector
• FDA notifies local regulatory agency and invites them to join inspection
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Foreign FDA Inspections
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• FDA cannot prosecute foreign clinical investigators (they don’t issue Form FDA‐482)
• But they can issue Warning Letters, which become publicly available on FDA website and newsletters
• And, of course, they can reject the data and application
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GCP Inspections by MCC
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• Arranged in advance, unless there is suspicion of serious issues
• Clinical investigator is contacted by phone to make arrangements and written confirmation
• Medical Director of sponsor is also notifiedo Monitor of site is expected to be present
• Delays in conduct of inspection need to be investigated
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Preparing for Inspections
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Pre‐inspection Visits
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• You can’t “fix” poor study conduct at this point• These are not monitoring visits or audits
o do not verify CRFs vs. source o do not sign monitoring log
• Conducted by combined Clinical & QA personnel• Timing is an important consideration
o Begin during NDA filing period in US
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Pre‐inspection Visits
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• Inventory of the study documents and datao Work with Clinical Operations to create a list of documents and data that should be at the CRS
• Training session with staffo Regulatory timelineo Preparing for an inspectiono Conduct during an inspection
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Follow‐up to Pre‐inspection Visits
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• Replace documents that were misplaced or lost during or after the trial
• Do not file documents at the clinical site that were never provided during the trial
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Before the Inspection
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• Develop an SOP and a policy for inspections• Educate your staff on the process• Assign responsibilities in advance, e.g. host, scribes, document reviewers, photocopier, answering questions
• Determine where to put inspector during inspection
• Have a mock inspection or conduct mock interviews
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Before the Inspection (2)
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• Read the SOPs and Guidance Manualo FDA Compliance Program Guidance Manual for Clinical Investigators (7348.811)
o SOP for EMA GCP inspections http://www.ema.europa.eu/ema/index
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Conduct during an Inspection
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• DO the following:o Be polite, courteous and professionalo Establish the scope of the inspectiono Fully understand questions before answering (ask questions to clarify)
o Answer questions truthfully and directlyo Pursue clarification of any possible misunderstandings
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Conduct during an Inspection (2)
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• DO the following:o Make duplicate copies of any documents copied for the inspector
o Remember that everything you say is “on the record”o Follow your SOP and policyo Ask for a summary of observations at the end of every day
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Conduct during an Inspection (3)
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• DO NOT do the following:o Guess, lie or deny the obviouso Volunteer additional information, unless clearly in your best interests
o Answer hypothetical questionso Answer questions outside of your knowledge or expertise (find the right person)
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Conduct during an Inspection (4)
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• DO NOT do the following:o Engage in arguments o Make all‐encompassing statements, like those using “always” or “never” or “impossible”
o Allow inspectors to wander unescorted or have unrestricted access to files
o Sign anything (e.g., affidavits, written statements)o Make promises without due consideration
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Conduct during an Inspection (5)
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• DO NOT do the following:o Attempt to mislead the inspectoro Try to be funnyo Become openly defensive or fearful (genuine concern may sometimes be appropriate)
o Comment on the quality of the inspection
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The Exit Meeting
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• FDA issues Form FDA‐483 to summarize any significant observations—review it carefully and propose corrections when applicableo Respond in writing in agreed‐upon timeframe
• EMA and MCC provide oral summary of observations and send written report to sponsor and investigator for a collaborative response
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Questions?