1. FDA Regulation of Pharmaceuticals and Devices

2. Department of Health and Human Services Food and Drug Administration Office of the Commissioner Center for Devices and Radiological Health (CDRH) Center for Drug Evaluation And Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine Center for Food Safety And Applied Nutrition National Center for Toxicological Research FDA Organizational Chart

3. CDRH Mission: Ensure medical devices are safe and effective via premarket and postmarket evaluation CDRH Mission: Ensure medical devices are safe and effective via premarket and postmarket evaluation guide manufacturers in product development evaluate data submitted on device design, performance, and clinical use authorize marketing of devices found safe and effective ensure that claims are supported by valid scientific evidence focus special emphasis on medical breakthrough devices (expedited review)

4. Total Product Life Cycle Brachytherapy Coated Stents

5. Total Product Life Cycle

6. The Pipeline

7. FDA 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

8. FDA FDA regulations “speak” to: –Importers/exporters –Study sponsors –Nonclinical laboratory personnel –Clinical investigators –IRBs –Medical product users – hospitals, clinics, nursing homes, individual practitioners

9. 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

10. 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

11. 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

12. 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

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

14. 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

15. 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

16. 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

17. 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

18. Regulatory distinctions -1 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 notAE reports during study not to go to MedWatch (i.e., not use MDR)

19. Regulatory distinctions -2 Pharmaceuticals Manufacturing – cGMPs – Parts 210 & 211 + 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

20. 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

21. 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

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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

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

32. 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

33. 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

34. 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

35. 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

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

37. 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

38. 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

39. Resources - 1 GCP website – http://www.fda.gov/oc/gcp/ –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

40. Resources - 2 GCP queries e-mail account (about 1,200 queries answered per year) – gcp.questions@fda.hhs.gov Previous answers captured – http://www.fda.gov/oc/gcp/redactedEmails/default. htm Listserve – via GCP website – notice of updates on FDA’s GCP/HSP activities Site maintained by Good Clinical Practice Program (GCPP)

41. Acronyms -1 510(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

42. 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

43. 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

44. 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

45. 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