FDA Regulation of Pharmaceuticals and Devices

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
Nature of product

• 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

13
Nature of firms

• 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

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 BLA

• Devices
• 21 CFR Part 812 IDE
• Part 809 - 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 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 study not to go to MedWatch
  (i.e., not use MDR)

22
Regulatory distinctions -2

• 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

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/pha
  rmacoconceptfn.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/OHRM
  S/DOCKETS/98fr/E6-8790.pdf
• Draft guidance on Analyte Specific Reagents
  (ASRs) September 2006 http//www.fda.gov/cdrh/oi
  vd/guidance/1590.pdf

34
Additional IVD issues -3

• Draft guidance on Multivariate Index Assays (MIA)
  September 2006 http//www.fda.gov/cdrh/oivd/guid
  ance/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 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, 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 - [phone]
• CDER
• Gary DellaZanna
• Division Phone - [phone]
• CDRH
• Michael Marcarelli
• Division Phone - [phone]

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
Center CI IRB Spon/Mon Total CBER 108 8
5 121 CDER 401
66 32 499 CDRH 203
48 51 302 CFSAN 0 0
0 0 CVM 41
n/a 1 42 All Centers 753
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
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 2006All Centers
completed classified
4
51
44
n 595
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 2006All Centers completed
classified
4
47
49
n 68
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 InspectionsFY 2006 - All Centers
completed classified
14
52
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 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

68
Resources - 2

• GCP queries e-mail account (about 1,200 queries
  answered per year) gcp.questions_at_fda.hhs.gov
• Previous answers captured http//www.fda.gov/oc/
  gcp/redactedEmails/default.htm
• Listserve via GCP website notice of updates
  on FDAs GCP/HSP activities
• Site maintained by Good Clinical Practice Program
  (GCPP)

69
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

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