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FDA Regulation of Pharmaceuticals and Devices

FDA Regulation of Pharmaceuticals and Devices. Jean Toth-Allen, Ph.D. Good Clinical Practice Program Office of Science and Health Coordination Office of the Commissioner. Overview. FDA regulations versus 45 CFR Part 46 Pharmaceuticals and devices What they have in common How they differ

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FDA Regulation of Pharmaceuticals and Devices

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  1. FDA Regulation of Pharmaceuticals and Devices Jean Toth-Allen, Ph.D. Good Clinical Practice Program Office of Science and Health Coordination Office of the Commissioner

  2. Overview • FDA regulations versus 45 CFR Part 46 • Pharmaceuticals and devices • What they have in common • How they differ • Bioresearch Monitoring (BIMO) • Resources • Acronyms

  3. FDA versus 45 CFR Part 46 -1 • FDA regulations found in Title 21, Code of Federal Regulations – 21 CFR • Regulate products • Coverage includes – but not limited to: • Nonclinical studies • Clinical studies • Human Subject Protection • Institutional Review Boards (IRBs) • Manufacturing • Labeling • Post-market adverse event reporting

  4. FDA versus 45 CFR Part 46 -2 • FDA regulations “speak” to: • Manufacturers • Importers/exporters • Study sponsors • Nonclinical laboratory personnel • Clinical investigators • IRBs • Medical product users – hospitals, clinics, nursing homes, individual practitioners

  5. FDA versus 45 CFR Part 46 -3 • 45 CFR Part 46 - regulates studies with human subjects that are federally funded – biomedical, sociological, behavioral, educational • Subpart A = Common Rule – general human subject protections • Remaining subparts cover research protections in studies with vulnerable populations (pregnant women, fetuses, neonates, prisoners, children) • “Speaks” to institutions and their IRBs • Crosses government agencies – enforcement led by the Office of Human Research Protections (OHRP)

  6. FDA versus 45 CFR Part 46 -4 • Human subject protections of Common Rule covered by FDA regulations in • 21 CFR Part 50 – Protection of Human Subjects • 21 CFR Part 56 – Institutional Review Boards • 45 CFR 46, Subpart D comparable to 21 CFR 50, Subpart D – research with children • Preambles to FDA regulations identify the need for special protections for other vulnerable populations but FDA regulations do not separately address

  7. FDA versus 45 CFR Part 46 -5 • Both may apply to a given research study • If there are regulatory differences, the more stringent requirements usually apply (e.g., FDA regulations allow for very few exceptions from informed consent)

  8. Pharmaceuticals versus devices • Pharmaceuticals (drugs and biologics) are covered by different FDA regulations from those covering devices, though some regulations are shared • Many differences result from differences among the products themselves

  9. SHARED REGULATIONS • Part 50 – Protection of Human Subjects • Part 56 – Institutional Review Boards • Part 54 – Financial Disclosure by Clinical Investigators • Part 58 – Good Laboratory Practices for Nonclinical Laboratory Studies • Part 11 – Electronic Records; Electronic Signatures

  10. COMPLIANCE PROGRAMS • Programs are Agency-wide (available at http://www.fda.gov/oc/gcp/compliance.html) • Contain instructions to FDA field personnel for inspecting regulated entities • Center-specific differences are included where applicable

  11. DIFFERENCES • Nature of product, firms, and studies • Statutory distinctions • Regulatory distinctions

  12. Pharmaceuticals (drugs & biologics) Molecular entities Limited shelf life Long market life Potential for interactions with other drugs Wrong drug/dose issues Devices Complex components Many = durable equipment Short product cycles – “tweaking” of design Device malfunctions User errors Nature of product

  13. Devices Entrepreneurial firms common Device “developer” often involved Many have minimal clinical trial experience Sponsor-investigators common Pharmaceuticals Large, often multi-national firms Extensive clinical trial experience Nature of firms

  14. Devices Nonclinical biocompatibility nonclinical studies may suffice Clinical subject populations usually 100s pilot study possible + pivotal blinding less common “controls” vary CI training often critical (Human Factor concerns) Pharmaceuticals Nonclinical toxicology Clinical subject populations commonly 1000s phases routinely blinded placebo = common control Studies

  15. Statutory Distinctions • Devices lack market exclusivity provisions • Waxman-Hatch – pediatric studies and extension of patent (drugs) • Orphan drug tax exemptions (drugs/biologics) • FDAMA (1997) – included a “least burdensome” provision for devices

  16. Pharmaceuticals 21 CFR Part 312 – IND Part 314 – NDA Part 600 – general biologics provisions Part 601 – BLA Devices 21 CFR Part 812 – IDE Part 809 - IVDs Part 814 – PMA Part 807, Subpart E – 510(k) Regulations

  17. Clinical Investigators -1 • Common responsibilities across products: • Personally conduct or supervise the study • Ensure site study team is properly trained • Follow FDA regulations regarding HSP, including obtaining and maintaining IRB approval and obtaining subject informed consent • Follow the approved investigational plan/protocol

  18. Clinical Investigators -2 • CI responsibilities (cont.): • Maintain adequate, complete, and accurate study records • Submit all required reports (e.g., IND safety reports, study progress reports) • Maintain control of the investigational product

  19. Sponsors -1 • Common responsibilities across products: • Obtain FDA approval, where necessary, before study initiation • Manufacture and label investigational products appropriately • Initiate, withhold, or discontinue clinical trials as required • Refrain from commercialization of investigational products • Maintain control of the investigational product

  20. Sponsors -2 • Sponsor responsibilities (cont): • Select qualified investigators and disseminate appropriate information to them • Select qualified monitors and ensure the study is adequately monitored • Evaluate and report adverse experiences • Maintain adequate records • Submit progress and final reports

  21. Pharmaceuticals Adequate, well-controlled trials CROs – 312.52 = transfer of regulatory obligations Form FDA 1572 FDA agreement not usually required before enacting studies changes AE reports during study may use Form 3500A (Med Watch) – 312.32(c)(B) Devices Valid scientific evidence CROs – regulations silent save for definition of monitor [812.3(j)] Investigator agreement [812.43(c)] Significant study changes require IDE supplement approval AE reports during studynotto go to MedWatch (i.e., not use MDR) Regulatory distinctions -1

  22. Pharmaceuticals Manufacturing – cGMPs – Parts 210 & 211 + Part 606 for blood & blood products MedWatch reports for approved pharmaceuticals are voluntary Devices Manufacturing – Part 820 (QSR) MDRs for approved devices are mandatory – Part 803 Regulatory distinctions -2

  23. Additional Device Distinctions -1 • Classes of Devices – risk-based determination • 21 CFR 860 – classification procedures • 21 CFR 862 through 892 – specific device classifications by product type

  24. Additional Device Distinctions -2 • Cleared devices – 510(k) • 21 CFR 807, subpart E – Premarket Notification Procedures • “substantially equivalent” • Approved devices • 21 CFR Part 814 • PMA, PDP, HDE • Safety and effectiveness – PMA & PDP • Safety – HDE

  25. Additional Device Distinctions -3 • Significant risk/non-significant risk studies • Exempt studies/in vitro diagnostics (IVDs) • Protocol changes and 5-day notices

  26. Significant Risk (SR) • Regulatory definition (21 CFR 812.3(m)) – device that presents potential for serious risk to health, safety, or welfare of a subject, particularly if it • Is intended as an implant • Is purported or represented for use in supporting or sustaining life • Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health

  27. Non-Significant Risk (NSR) • Decision based on use of device in study • Sponsor makes initial assessment • IRB makes determination • FDA can disagree • If NSR study, no IDE application to FDA • Informed consent required • Abbreviated requirements apply (21 CFR 812.2(b)) • Considered to have an IDE

  28. Exempt device studies • 21 CFR 812.2 (c) • Studies with cleared devices, used as specified in clearance • By policy, extended to approved devices, with same conditions • Diagnostic devices that meet requirements specified – basically IVDs, as references labeling conditions of 809.10

  29. In Vitro Diagnostics (IVDs) • SR/NSR/exempt studies • Exempt if: • labeled according to 21 CFR 809.10 • noninvasive • noninvasive sampling or no significant risk • does not introduce energy into a subject • not used as the diagnostic for determination of treatment

  30. Significant Risk IVD Studies • If study involves invasive sampling that presents a significant risk • If results from use of an investigational IVD will determine treatment, could inaccurate results: • be life-threatening • result in permanent functional impairment • result in permanent structural damage • necessitate medical or surgical intervention to prevent impairment or damage

  31. IVD Studies & HSP Issues • Studies on specimens – included in device definition of a subject (812.3(p)) • Expedited review by IRB possible • Confusion with 45 CFR Part 46 • Privacy & confidentiality • FDA data audits

  32. Additional IVD issues -1 • Drug-diagnostic co-development concept paper – April 2005 – http://www.fda.gov/cder/genomics/pharmacoconceptfn.pdf • Guidance on use of left-over specimens that are not individually identifiable – April 2006 – http://www.fda.gov/cdrh/oivd/guidance/1588.html

  33. Additional IVD issues -2 • Interim final rule regarding exception from informed consent (bioterrorism, emerging diseases) – September 2006 http://www.fda.gov/OHRMS/DOCKETS/98fr/E6-8790.pdf • Draft guidance on Analyte Specific Reagents (ASRs) – September 2006 http://www.fda.gov/cdrh/oivd/guidance/1590.pdf

  34. Additional IVD issues -3 • Draft guidance on Multivariate Index Assays (MIA) – September 2006 http://www.fda.gov/cdrh/oivd/guidance/1610.html • Public meeting held February 8, 2007

  35. WEB PAGE Office of In Vitro Diagnostic Device Evaluation and Safety(OIVD) www.fda.gov/cdrh/oivd/

  36. IDE Protocol Changes -1 • IDE Supplement required ifchanges significantly affect: • validity of data • scientific soundness of study • rights, safety, or welfare of subjects

  37. IDE Protocol Changes -2 Examples when supplement required: • indication change • different type of study control • alternative primary endpoint • reduction in study population size • change in method of evaluation • early termination of the study

  38. IDE Protocol Changes -3 5-day notice 1998 amendment to Part 812- if changes do not meet requirements for an IDE supplement Examples: • additional measurements • more targeted subject criteria • more frequent follow-ups • change in secondary endpoints

  39. IDE Protocol Changes -4 GUIDANCE DOCUMENT – issued by Office of Device Evaluation (ODE) Changes or Modifications During the Conduct of a Clinical Investigation - issued May 29, 2001 www.fda.gov/cdrh/ode/guidance/1337.html www.fda.gov/cdrh/ode/guidance/1337.pdf

  40. BIMO Program Comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA-regulated research

  41. BIMO Program Objectives • To ensure • the integrity of data supporting submissions to the Agency • the rights, safety, and welfare of study subjects

  42. Bioresearch Monitoring (BIMO) -1 • Specific group in each Center to oversee BIMO program • Bioresearch Monitoring Branch/Division of Inspections and Surveillance/Office of Compliance – CBER • Division of Scientific Investigations (DSI)/Office of Compliance - CDER • Division of Bioresearch Monitoring (DBM)/Office of Compliance – CDRH

  43. Bioresearch Monitoring (BIMO) -2 Present BIMO contacts • CBER • Pat Holobaugh • Branch Phone # - (301) 827-6220 • CDER • Gary Della’Zanna • Division Phone # - (240) 276-8817 • CDRH • Michael Marcarelli • Division Phone # - (240) 276-0125

  44. Bioresearch Monitoring (BIMO) -3 Headquarters BIMO staff: • Interact with Center reviewers • Issue inspection assignments • Interact with ORA BIMO investigators • Review and classify EIRs • Issue post-inspectional correspondence • Take part in regulatory actions (AIP, DQ) • Provide staff for ORA BIMO investigator training • Provide speakers for outreach activities

  45. Inspection assignments • Assigned by HQ BIMO staff • Majority issued on receipt of an application or submission • When for marketing, supporting study usually completed • “for cause” – usually when suspicion of integrity or human subject protection (HSP) issue – often for on-going studies

  46. BIMO Compliance Programs • Good Laboratory Practice – CP 7348.808 • Institutional Review Board – CP 7348.809 • Sponsor, Contract Research Organizations (CROs), Monitors – CP 7348.810 • Clinical Investigator – CP 7348.811 • In Vivo Bioequivalence – CP 7348.001 http://www.fda.gov/oc/gcp/compliance.html

  47. Inspectional follow-up • Final inspection classification made by HQ • Post-inspectional correspondence issued to inspected party • Administration/regulatory options vary by party inspected • Recommendations may also be sent to those reviewing a research or marketing application/submission

  48. GCP/BIMO Inspections Completed FY 2006 CenterCIIRBSpon/MonTotal CBER108 8 5 121 CDER401 66 32 499 CDRH203 48 51 302 CFSAN0 0 0 0 CVM 41 n/a 1 42 All Centers753 122 89 964

  49. GCP/BIMO Inspections by CenterFY 2006 4% 13% 31% n = 964 52%

  50. GCP/BIMO Inspections by Type FY 2006 9% 13% n = 964 78%

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