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US FDA Foreign Inspection s; Clinical Investigators

US FDA Foreign Inspection s; Clinical Investigators. At: Mahidol University Date: 1 MAR 2013 By: Pravich Tanyasittisuntorn, MD, EMBA, MSc. in Pharm Med. Overview. Organizations Involved. Center headquarters :

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US FDA Foreign Inspection s; Clinical Investigators

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  1. US FDA INSPECTION US FDA Foreign Inspections;Clinical Investigators At: Mahidol University Date: 1 MAR 2013 By: Pravich Tanyasittisuntorn, MD, EMBA, MSc. in Pharm Med.

  2. US FDA INSPECTION Overview

  3. US FDA INSPECTION Organizations Involved • Center headquarters: • Office of Scientific Investigations (OSI), located in Office of Compliance, Center for Drug Evaluation and Research (CDER), US FDA • 1977 formed Bioresearch Monitoring Program (BIMO) • 2006 Human Subject Protection (HSP)/Bioresearch Monitoring (BIMO) • Field personnel (e.g., field investigator): • Office of Regulatory Affairs (ORA), Office of Global Regulatory Operations and Policy, US FDA CDER OSI ORA Clinical Investigator

  4. US FDA INSPECTION Bioresearch Monitoring Program (BIMO) • The objectives of BIMO Program are: • To protect the rights, safety, and welfare of subjects involved in FDA-regulated clinical trials • To verify the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications • To assess compliance with FDA's regulations governing the conduct of clinical trials

  5. US FDA INSPECTION Bioresearch Monitoring Program (BIMO) • Coverage • Domestic and foreign inspections • Clinical investigators (CI) and sponsor-investigators • International inspections • studies are part of a marketing application to FDA and provide data critical to decision-making on product approval • studies that are conducted under an FDA application for research e.g., • Investigational New Drug Application [IND], • Investigational Device Exemption [IDE], • Investigational New Animal Drug Application [INAD]) 21 CFR Part 312, section 312.120 (Federal Register Vol. 73, No. 82, April 28, 2008)

  6. US FDA INSPECTION Bioresearch Monitoring Program (BIMO) • Coverage • International inspections • non-U.S. sites or studies that are not conducted under an FDA application for research • Non-IND foreign studies • FDA will accept as support for an IND or application for marketing approval…if • The study was conducted in accordance with good clinical practice (GCP) • FDA is able to validate the data from the study through an onsite inspection if the agency deems it necessary 21 CFR Part 312, section 312.120 (Federal Register Vol. 73, No. 82, April 28, 2008)

  7. US FDA INSPECTION GCP Standard • FDA CDER, Title 21 CFR Parts 11/50/54/56/58/312 and 314 • ICH GCP (ICH E6)

  8. US FDA INSPECTION Inspectional Procedures • Announce the inspection • time span between initial contact and actual inspection should be kept as short as possible • any attempt to unduly delay an inspection, by more than ten working days, without sufficient justification should be reported • Conduct of inspection • FDA field personnel must present credentials along with Form FDA 482 (Notice of Inspection) • The field investigator should not attempt to scientifically evaluate the study data or protocol(s)

  9. US FDA INSPECTION Inspectional Procedures • Conduct of inspection • The field investigator issues a 483 at the conclusion of the inspection when deviations from regulations are observed • The field investigator encourages the site to submit a prompt written response regarding any inspection observations listed on the 483

  10. US FDA INSPECTION Final Inspections • Issue FDA Form 483 • Final Establishment Inspection Report (EIR) • Standard Narrative Report (OAI) • Summary of Findings Report • Classify EIR: • NAI (No Action Indicated): • no objectionable conditions or practices found; or • objectionable conditions found does not justify further FDA action (US FDA Compliance Program Guidance Manual, Program 7348.811, Chapter 48 Bioresearch Monitoring; Clinical Investigators and Sponsor-investigators, Date of Issuance Dec 8, 2008)

  11. US FDA INSPECTION Final Inspections • Classify EIR: • VAI (Voluntary Action Indicated): • objectionable conditions or practices found, • but no administrative or regulatory action taken or recommended • regulatory violations are few and do not seriously impact subject safety or data integrity (US FDA Compliance Program Guidance Manual, Program 7348.811, Chapter 48 Bioresearch Monitoring; Clinical Investigators and Sponsor-investigators, Date of Issuance Dec 8, 2008)

  12. US FDA INSPECTION Final Inspections • Classify EIR: • OAI (Official Action Indicated): • repeated or deliberate violation • repeated violation: more than one violation including same violation in one or more studies • deliberate: a willful action that need not entail knowledge that it is a violation of law as long as there is some perception of wrongdoing or of reckless disregard for obvious or known risk • and/or submission of false information to FDA or to the sponsor (US FDA Compliance Program Guidance Manual, Program 7348.811, Chapter 48 Bioresearch Monitoring; Clinical Investigators and Sponsor-investigators, Date of Issuance Dec 8, 2008)

  13. US FDA INSPECTION Final Inspections • Classify EIR: • OAI (Official Action Indicated): • violation is significant/seriousand/or numerous, • and support a finding that • subjects would be or have been exposed to an unreasonable and significant risk of illness or injury OR • subjects' rights would be or have been seriously compromised OR • data integrity or reliability is or has been compromised (US FDA Compliance Program Guidance Manual, Program 7348.811, Chapter 48 Bioresearch Monitoring; Clinical Investigators and Sponsor-investigators, Date of Issuance Dec 8, 2008)

  14. US FDA INSPECTION Final Inspections • Issue EIR & post-inspectional correspondence • NAI (No Action Indicated): • acknowledges the investigator’s basic compliance with pertinent regulations. • VAI (Voluntary Action Indicated): • identifies the issues and • states that FDA expects prompt, voluntary corrective action by the investigator (when needed). (US FDA Compliance Program Guidance Manual, Program 7348.811, Chapter 48 Bioresearch Monitoring; Clinical Investigators and Sponsor-investigators, Date of Issuance Dec 8, 2008)

  15. US FDA INSPECTION Final Inspections • Issue post-inspectional correspondence • OAI (Official Action Indicated): • Warning Letter (WL) • allow the clinical investigator to submit a detailed corrective action plan that is acceptable to FDA • violations can be corrected through specific action(s) by the CI • corrective action plan has a high probability of preventing similar or other violations • Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) (US FDA Compliance Program Guidance Manual, Program 7348.811, Chapter 48 Bioresearch Monitoring; Clinical Investigators and Sponsor-investigators, Date of Issuance Dec 8, 2008)

  16. US FDA INSPECTION Final Inspections • Issue post-inspectional correspondence • OAI (Official Action Indicated): • Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) • Findings that an CI has • Repeatedly or deliberately failed to comply with the requirements for conducting clinical trials; and/or • Repeatedly or deliberately submitted false information to FDA or to the sponsor (US FDA Compliance Program Guidance Manual, Program 7348.811, Chapter 48 Bioresearch Monitoring; Clinical Investigators and Sponsor-investigators, Date of Issuance Dec 8, 2008)

  17. US FDA INSPECTION US FDA Deficiency Codes(Inspection Observations Coding)

  18. US FDA INSPECTION US FDA Deficiency Codes 00 No deficiencies noted 01 Records availability 02 Failure to obtain and/or document subject consent 03 Inadequate informed consent form 04 Inadequate drug accountability 05 Failure to follow investigational plan 06 Inadequate and inaccurate records 07 Unapproved concomitant therapy Source: Clinical Trial Magnifier Vol. 2:4 Apr 2009; www.ClinicalTrialMagnifier.com

  19. US FDA INSPECTION US FDA Deficiency Codes 08 Inappropriate payment to volunteers 09 Unapproved use of drug before IND submission 10 Inappropriate delegation of authority 11 Inappropriate use/commercialization of IND 12 Failure to list additional investigators on 1572 13 Subjects receiving simultaneous investigational drugs 14 Failure to obtain or document IRB approval Source: Clinical Trial Magnifier Vol. 2:4 Apr 2009; www.ClinicalTrialMagnifier.com

  20. US FDA INSPECTION US FDA Deficiency Codes 15 Failure to notify IRB of changes, failure to progress reports 16 Failure to report adverse drug reactions 17 Submission of false information 18 Other 19 Failure to supervise or personally conduct the clinical investigation 20 Failure to protect the rights, safety, and welfare of subjects 21 Failure to permit FDA access to records Source: Clinical Trial Magnifier Vol. 2:4 Apr 2009; www.ClinicalTrialMagnifier.com

  21. US FDA INSPECTION US FDA Domestic & Foreign Clinical Investigator Inspections For Year 2003 – 2012

  22. US FDA INSPECTION Overall OSI CDER Inspection For Yr. 2003 – 2012 GCP Sponsor & CRO Clinical investigators & sponsor-investigators IRB Bioequivalence GLP In 2011, incorporated drug Safety programs REMS Post-marketing ADR report US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  23. US FDA INSPECTION Overall OSI CDER Inspection For Yr. 2008 – 2012: Domestic VS Foreign Foreign inspections in 2012 Sponsors & CROs 3 Clin investigators 135 GLPs 3 Bioequivalence 93 Domestic Foreign US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  24. US FDA INSPECTION OSI Clinical Investigator Inspections For Yr. 2008 – 2012:Total Number US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  25. US FDA INSPECTION OSI Clinical Investigator Inspection For Yr. 2012:Data Audit VS Referral Data Audit (routine inspection) 82% Referral (for-cause inspection) 18% US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  26. US FDA INSPECTION OSI Clinical Investigator Inspection For Yr. 2012:Locations Domestic 65% Foreign 35% Eastern Eur. 12% Western Eur. 9% Asia/Pacific 6% Latin Am. 3% Canada 2% Africa 2% Australia 1% US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  27. US FDA INSPECTION OSI Foreign Clinical Investigator Inspection For Yr. 2003 – 2012:Total Numbers 135 clinical investigators in 2012 US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  28. US FDA INSPECTION OSI Foreign Clinical Investigator Inspection For Yr. 2012:Locations Eastern Europe 35% Western Europe 27% Asia/Pacific 19% Latin American 8% Canada 5% Africa 4% Australia 2% US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  29. US FDA INSPECTION OSI Foreign Clinical Investigator Inspection For Yr. 2012:Observations NAI 60% VAI 40% US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  30. US FDA INSPECTION OSI Foreign Clinical Investigator Inspection For Yr. 2012Common Observations (compared with domestic Protocol Records Drug account Informed consent IRB communication Safety reporting US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  31. US FDA INSPECTION OSI Clinical Investigator Inspection For Yr. 2012OAI Findings Protocol Records Informed consent Drug account Clinical investigator supervision IRB communication Safety reporting Submission of false information US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  32. US FDA INSPECTION Clinical Investigator Regulatory ActionsFor Yr. 2003 – 2012 Disqualification 2003 2 2004 1 2005 2 2006 - 2007 2 2008 10 2009 3 2010 5 2011 3 2012 1 US FDA, Office of Scientific Investigations Metrics Updated: JAN 2013; http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM256376.pdf

  33. US FDA INSPECTION US FDA Clinical Investigator Inspections in Asia

  34. US FDA INSPECTION US FDA Inspection in Asia (as of FEB 2013) No. of clinical investigators inspected • Countries: PAK, IND, BGD, MMR, THA, LAO, VNM, MYS, SGP, IDN, PHL, CHN. TWN, KOR, JPN US FDA, Clinical Investigator Inspection Search; http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm. access date 25FEB2012

  35. US FDA INSPECTION No. of clinical investigators inspected in each country From 2001-2012, 11 sites in THA were inspected by UD FDA Siriraj3 Chiangmai2 Rajvithi 2 Chula 1 Tropical Med 1 Malaria Res 2 4 sites were inspected in 2012 US FDA, Clinical Investigator Inspection Search; http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm. access date 25FEB2012

  36. US FDA INSPECTION US FDA Clinical Investigator Inspections in Asia:Common Deficiencies for Year 2012

  37. US FDA INSPECTION Inspection Findings in THA US FDA, Clinical Investigator Inspection Search; http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm. access date 25FEB2012

  38. US FDA INSPECTION Inspection Findings in IND US FDA, Clinical Investigator Inspection Search; http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm. access date 25FEB2012

  39. US FDA INSPECTION Inspection Findings in CHN US FDA, Clinical Investigator Inspection Search; http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm. access date 25FEB2012

  40. US FDA INSPECTION Inspection Findings in JPN US FDA, Clinical Investigator Inspection Search; http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm. access date 25FEB2012

  41. US FDA INSPECTION Inspection Findings in MYS US FDA, Clinical Investigator Inspection Search; http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm. access date 25FEB2012

  42. US FDA INSPECTION Inspection Findings in KOR US FDA, Clinical Investigator Inspection Search; http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm. access date 25FEB2012

  43. US FDA INSPECTION Inspection Findings in PHL US FDA, Clinical Investigator Inspection Search; http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm. access date 25FEB2012

  44. US FDA INSPECTION Inspection Findings in TWN US FDA, Clinical Investigator Inspection Search; http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm. access date 25FEB2012

  45. US FDA INSPECTION US FDA Foreign Clinical Investigator InspectionCommon Deficiencies For Year 1997 – 2008 Source: Clinical Trial Magnifier Vol. 2:4 Apr 2009; www.ClinicalTrialMagnifier.com

  46. US FDA INSPECTION US FDA Deficiency Codes for site inspections findings 05 Failure to follow investigational plan (34.2%) 06 Inadequate and inaccurate records (25.1%) 04 Inadequate drug accountability (9.4%) 03 Inadequate informed consent form (9.2 %) 16 Failure to report adverse drug reactions (8.2%) Source: Clinical Trial Magnifier Vol. 2:4 Apr 2009; www.ClinicalTrialMagnifier.com

  47. US FDA INSPECTION Common Inspection Findings: Asia • Inadequate and inaccurate records (36.1%) • Inadequate drug accountability (22.2%) • Failure to follow investigational plan (16.7%) • Failure to report adverse drug reactions (11.1%) • Inadequate informed consent form (8.3%) • Failure to notify IRB of changes/progress reports (5.6%) • Failure to list additional investigators on (2.8%) • Failure to obtain or document IRB approval (2.8%) Source: Clinical Trial Magnifier Vol. 2:4 Apr 2009; www.ClinicalTrialMagnifier.com

  48. US FDA INSPECTION Common Inspection Findings:North America • Failure to follow investigational plan (34.0%) • Inadequate and inaccurate records (23.7%) • Inadequate drug accountability (9.4%) • Inadequate informed consent form (9.1%) • Failure to report adverse drug reactions (8.2%) Source: Clinical Trial Magnifier Vol. 2:4 Apr 2009; www.ClinicalTrialMagnifier.com

  49. US FDA INSPECTION Common Inspection Findings:Europe • Failure to follow investigational plan (43.6%) • Inadequate and inaccurate records (34.1%) • Inadequate drug accountability (13.6%) • Failure to report adverse drug reactions (12.9%) • Inadequate informed consent form (11.1%) Source: Clinical Trial Magnifier Vol. 2:4 Apr 2009; www.ClinicalTrialMagnifier.com

  50. US FDA INSPECTION Common Inspection Findings:Eastern Europe • Inadequate and inaccurate records (27.3%) • Failure to follow investigational plan (23.3%) • Inadequate drug accountability (4.7%) • Failure to report adverse drug reactions (4.7%) • Inadequate informed consent form (3.3%) Source: Clinical Trial Magnifier Vol. 2:4 Apr 2009; www.ClinicalTrialMagnifier.com

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