Transcript FDA Regulation of Pharmaceuticals and Devices

FDA Regulation of
Pharmaceuticals and
Devices
FDA Organizational Chart
Department of Health and Human Services
Center for Veterinary
Medicine
Center for Food Safety
And Applied Nutrition
Food and Drug Administration
Office of the Commissioner
National Center for
Toxicological Research
Center for Drug Evaluation
And Research
(CDER)
Center for Biologics
Evaluation and Research
(CBER)
Center for Devices and
Radiological Health
(CDRH)
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)
Total Product Life Cycle
Coated
Stents
Coated
Stents
Brachytherapy
Total Product Life Cycle
Engineering
Biocompatibility
D esign
Toxicology
Mode of
Action
End of
Life
Hazard
Analysis
Risk
Analysis
Clinical
Sciences
Study D esign
Statistics
Review Sciences
Post-M arketing
Surveillance
Environm ent
Adverse
Event
Reporting
Forensic
Engineering
Epidemiology
Quality
Systems
Reuse
Sterility
EMC
Shock
Vibration
Total Product Life Cycle
The
Pipeline
FDA
• FDA regulations found in Title 21, Code of
Federal Regulations – 21 CFR
• Regulate products
• Coverage includes – but not limited to:
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Nonclinical studies
Clinical studies
Human Subject Protection
Institutional Review Boards (IRBs)
Manufacturing
Labeling
Post-market adverse event reporting
FDA
• FDA regulations “speak” to:
– Importers/exporters
– Study sponsors
– Nonclinical laboratory personnel
– Clinical investigators
– IRBs
– Medical product users – hospitals, clinics,
nursing homes, individual practitioners
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
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
Nature of firms
Pharmaceuticals
• Large, often multinational firms
• Extensive clinical trial
experience
Devices
• Entrepreneurial firms
common
• Device “developer”
often involved
• Many have minimal
clinical trial
experience
• Sponsor-investigators
common
Studies
Pharmaceuticals
• Nonclinical
– toxicology
• Clinical
Devices
• Nonclinical
– biocompatibility
– nonclinical studies may suffice
• Clinical
– subject populations
commonly 1000s
– subject populations usually 100s
– phases
– pilot study possible + pivotal
– routinely blinded
– blinding less common
– placebo = common control
– “controls” vary
– CI training often critical (Human
Factor concerns)
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)
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
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
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
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
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)
Regulatory distinctions -2
Pharmaceuticals
Devices
• Manufacturing –
• Manufacturing – Part
cGMPs – Parts 210 &
820 (QSR)
211 + Part 606 for
• MDRs for approved
blood & blood
devices are
products
mandatory – Part 803
• MedWatch reports for
approved
pharmaceuticals are
voluntary
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
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
Additional Device Distinctions -3
• Significant risk/non-significant risk studies
• Exempt studies/in vitro diagnostics (IVDs)
• Protocol changes and 5-day notices
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
Non-Significant Risk (NSR)
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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
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
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
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
Most Common CI Deficiencies
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Failure to follow the investigational plan
Protocol deviations
Inadequate recordkeeping
Inadequate accountability for the
investigational product
• Inadequate subject protection – including
informed consent issues
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
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
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 makeup and duties
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
Most common IRB deficiencies
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Inadequate initial and/or continuing review
Inadequate SOPs
Inadequate membership rosters
Inadequate meeting minutes
Specific to devices – lack of or incorrect
SR/NSR determination
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
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
Most common S/M deficiencies
• Inadequate monitoring
• Failure to bring investigators into
compliance
• Inadequate accountability for the
investigational product
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
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
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New facilities
Previously violative sites
Suspicious data
Non-conventional studies
Studies pivotal to NDA decision-making
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
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Data monitoring committees
Use of a centralized IRB
AE reporting
CI supervisory responsibilities
Computerized systems in clinical trials
Resources - 2
• GCP queries e-mail account (about 1,200 queries
answered per year) – [email protected]
• 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)
Acronyms -1
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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
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
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
Acronyms -4
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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
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