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

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Presentation on theme: "FDA Regulation of Pharmaceuticals and Devices Jean Toth-Allen, Ph.D. Good Clinical Practice Program Office of Science and Health Coordination Office of."— Presentation transcript:

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

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

14 Studies 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

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

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 Regulatory distinctions -1 Pharmaceuticals Adequate, well-controlled trials CROs – = 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) – (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 notAE reports during study not to go to MedWatch (i.e., not use MDR)

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

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 (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

29 In Vitro Diagnostics (IVDs) SR/NSR/exempt studies Exempt if: labeled according to 21 CFR 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 – pharmacoconceptfn.pdf Guidance on use of left-over specimens that are not individually identifiable – April 2006 – html

33 Additional IVD issues -2 Interim final rule regarding exception from informed consent (bioterrorism, emerging diseases) – September /98fr/E pdf Draft guidance on Analyte Specific Reagents (ASRs) – September pdf

34 Additional IVD issues -3 Draft guidance on Multivariate Index Assays (MIA) – September html –Public meeting held February 8, 2007

35 WEB PAGE Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)

36 IDE Protocol Changes -1 IDE Supplement required if changes 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,

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) CDER –Gary DellaZanna –Division Phone # - (240) CDRH –Michael Marcarelli –Division Phone # - (240)

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 Institutional Review Board – CP Sponsor, Contract Research Organizations (CROs), Monitors – CP Clinical Investigator – CP In Vivo Bioequivalence – CP

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 CBER CBER CDER CDER CDRH CDRH CFSAN CFSAN CVM CVM 41 n/a 1 42 All Centers

49 GCP/BIMO Inspections by Center FY 2006 n = % 52% 13% 4%

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

51 Clinical Investigators Compliance inspection program covers study specific inspections and audits of CIs (physicians, veterinarians, others) conducting clinical trials on human and veterinary products Usually preannounced Inspection includes an interview with the clinical investigator and pertinent study staff + an in-depth study/data audit – to validate study findings and verify compliance with regulations

52 BIMO CI Inspections – FY 2006 All Centers – completed & classified n = 595 4% 51% 44%

53 Most Common CI Deficiencies Failure to follow the investigational plan Protocol deviations Inadequate recordkeeping Inadequate accountability for the investigational product Inadequate subject protection – including informed consent issues

54 Administrative/regulatory options Untitled or Warning letter Initiation of disqualification procedures Sharing information with Office of Criminal Investigations (OCI) for pursuit of prosecution Recommendation for rejection of site/study data

55 Institutional Review Boards (IRBs) Board, committee, or other group formally designated by an institution to –review –approve the initiation of –conduct periodic review of research involving human subjects Primary purpose of review = ensure protection of rights, safety, and welfare of the human subjects

56 Applicable regulations 21 CFR Part 50 – Protection of Human Subjects – contains informed consent requirements 21 CFR Part 56 – Institutional Review Boards – includes specifics of IRBs make- up and duties

57 IRB Inspections Compliance program provides for regularly scheduled inspections to verify compliance with regulations Objective is protection of human subjects rather than data validation Inspections –usually preannounced –consist of interviews with responsible IRB staff in-depth review of SOPs, files, and records review of active studies to assess IRB operations

58 IRB Inspections – FY 2006 All Centers – completed & classified 47% n = 68 4% 49%

59 Most common IRB deficiencies Inadequate initial and/or continuing review Inadequate SOPs Inadequate membership rosters Inadequate meeting minutes Specific to devices – lack of or incorrect SR/NSR determination

60 Administrative/regulatory options Untitled or Warning letter Restriction of functions –prohibiting increase of subject population in on-going FDA-regulated studies –prohibiting review of new FDA-regulated studies Initiation of disqualification procedures

61 Sponsors/CROs/Monitors Compliance program –covers parties responsible for initiating and overseeing research and for submitting research results to FDA –lists sponsor responsibilities Inspections –usually preannounced –consist of interviews and audits of study records –objective is to both evaluate compliance with regulations and validate data –commonly assigned for NDAs for new molecular entities (NMEs) and for PMAs

62 Sponsor-Monitor Inspections FY All Centers – completed & classified 52% 14% 34% n = 64

63 Most common S/M deficiencies Inadequate monitoring Failure to bring investigators into compliance Inadequate accountability for the investigational product

64 Administrative/regulatory options Untitled or Warning letter Invocation of the Application Integrity Policy (AIP) Refusal to accept site or study data Denial of NDA/BLA/PMA Sharing information with Office of Criminal Investigations (OCI) for pursuit of prosecution

65 Bioequivalence (BEQ) studies Primarily support –Abbreviated drug applications (ANDA) for generic drugs –Applications for new form or formulation of marketed drugs Compliance program –Provides for inspection of both clinical facilities and analytical laboratories involved with BEQ studies –Focuses on inspecting New facilities Previously violative sites Suspicious data Non-conventional studies Studies pivotal to NDA decision-making

66 BEQ inspections Conducted by an inspection team, including a laboratory chemist and an ORA field investigator May involve multiple facilities Include –physical inspection and technical evaluation of laboratory facilities and methods –audits of analytical and clinical data

67 Resources - 1 GCP website – –Links include pertinent regulations and guidance FDA contacts related sites with HSP/GCP information Recent documents of interest relate to –Data monitoring committees –Use of a centralized IRB –AE reporting –CI supervisory responsibilities –Computerized systems in clinical trials

68 Resources - 2 GCP queries account (about 1,200 queries answered per year) – Previous answers captured – htm Listserve – via GCP website – notice of updates on FDAs GCP/HSP activities Site maintained by Good Clinical Practice Program (GCPP)

69 Acronyms (k) – premarket notification AE – adverse event (or effect) AIP – Application Integrity Policy BEQ – bioequivalence BIMO – Bioresearch Monitoring BLA – biologics license application CBER – Center for Biologics Evaluation and Research CDER – Center for Drug Evaluation and Research

70 Acronyms -2 CDRH – Center for Devices and Radiological Health CFR – Code of Federal Regulations CI – clinical investigator cGMPs – current good manufacturing practices CRO – contract research organization DBM – Division of Bioresearch Monitoring DSI – Division of Scientific Investigations DQ – disqualification

71 Acronyms -3 EIR – establishment inspection report FDAMA – Food and Drug Administration Modernization Act (1997) GCP – Good Clinical Practice GCPP – Good Clinical Practice Program HDE – humanitarian device exemption HSP – human subject protection HQ – headquarters IDE – investigational device exemption IND – investigational new drug

72 Acronyms -4 IRB – institutional review board IVD – in vitro diagnostic MDR – medical device report NAI – no action indicated NDA – new drug application NME – new molecular entity NSR – non-significant risk OAI – official action indicated OHRP – Office of Human Research Protections

73 Acronyms -5 OIVD – Office of In Vitro Diagnostic Device Evaluation and Safety ORA – Office of Regulatory Affairs PDP – product development protocol PMA – premarket approval QSR – quality system regulation SOPs – standard operating procedures SR – significant risk VAI – voluntary action indicated


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