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Document Sample
Similarities and Differences
in Conducting Medical
Device and Pharmaceutical
Clinical Trials
Paul Below, 3M Pharmaceuticals
Barbara Westrum, Medtronic, Inc.
North Central Regional Chapter of SoCRA
February 26, 2003
Purpose
• Define drugs and medical devices
• Review major differences between
pharmaceutical and device industries
• Review FDA structure and regulatory
authority over drugs and devices
• Review requirements for investigational
drug and device applications
Purpose (cont)
• Review different pathways for marketing
approval for drugs and devices
• Review differences in study design in drug
and device clinical trials
• Review sponsor and investigator
responsibilities for conducting clinical trials
with drugs and devices
Disclaimer
• The views and opinions expressed by the
presenters are not necessarily those of
the 3M Company, 3M Pharmaceuticals or
its subsidiaries
Audience Poll
• How many work in pharmaceuticals?
• How many work in medical devices?
• How many work in both?
• How many work for manufacturers?
• How many work at investigator sites?
• Others: IRB? FDA?
Definitions
Drugs Devices
• Articles other than • An instrument,
food listed in the apparatus,
USP, USHP, or NF implement, machine,
implant, or in vitro
reagent listed in the
USP or NF
Definitions (cont)
Drugs Devices
• Intended to diagnose, • Same as drugs plus…
cure, mitigate, treat, • Does not achieve
or prevent disease primary effect through
• Affect the structure & chemical action
function of the human • Is not dependent on
body being metabolized
• Includes device/drug
and device/biologic
combinations
Investigational Product
Definitions
Drugs Devices
• Being used in a • Being used in a
clinical investigation clinical investigation
• Also includes biologic • Not in commercial
products used in vitro distribution
for diagnostic • Three classes of
purposes devices based on risk
and required controls
Device Classification (21 CFR 860)
• Class I (46% of all devices):
- Low risk devices - general controls only (reasonable
assurance of the safety and effectiveness
- Examples: surgical instruments, wound dressings,
contact lenses, toothbrush
• Class II (47% of all devices):
- Moderate risk – general & special controls (eg,
performance standards, surveillance)
- Examples: infusion pumps (non-implanted), vascular
clamps, sutures, ECGs, urology catheters
Device Classification (cont)
• Class III (<10% of all devices):
- Moderate and high risk – general & special
controls alone are insufficient
- Clinical data & pre-market approval required
- Life-supporting, life-sustaining, important in
preventing impairment, potential for
unreasonable risk
- Examples: pacemakers, defibrillators,
vascular grafts, angioplasty catheters
Device Classification (cont)
• Devices classification depends on
intended use and indications for use
• Product classification database on FDA
website: www.accessdata.fda.gov/scripts/
cdrh/cfdocs/cfPCD/classification.cfm
Major Industry Differences
• Devices and drugs have different
mechanisms of action:
- Local vs systemic effects
- Physical effects vs pharmacokinetic
• Different business environments:
- Wide variety of device types
- Number and size of companies
- Changes in device technology are rapid
Industry Differences (cont)
• Differences in product development:
- Length of time & money*
- Pre-clinical differences
- Different regulatory pathways for marketing
approval*
- Clinical trial differences*
- Post-approval surveillance, device tracking,
conditional approval requiring long-term study
Pharmaceutical Development
Chemical Synth. Clinical Trials: Supplemental reporting
NDA 1.5 yrs
Pharmacology Phase I Phase IV
Toxicology Phase II Postmarketing
Phase III Clinical education
6 yrs 4.8 yrs 8-10 yrs
Source: Parexel’s Pharmaceutical R&D Statistical Sourcebook 2001
Slide courtesy of Mayo Clinical Trial Services
Device Development
Feasibility study
PMA - 14 mos
Bench Testing & Human Postmarket studies
GLP Studies Studies Supplemental reporting
Clinical education
Medicare review
12 - 24 3-9 6 - 36
mos mos mos
Source: AdvaMed, The Lewin Group
Slide courtesy of Mayo Clinical Trial Services
Drug & Device Regulation
• Drugs and devices are both regulated by
the US Food and Drug Administration
(Department of Health & Human Services)
• FDA’s legal authority comes from the
Federal Food, Drug, and Cosmetic Act
(FD&C)
FDA Regulation
Drugs Devices
• Federal requirements • Federal requirements
governing safety were governing
enacted in FD&C investigations with
amendments in 1938 devices enacted in
and efficacy in 1962 FD&C amendments in
1976 and further
amended in 1990
• Center for Drug • Center for Devices
Evaluation and and Radiological
Research (CDER) Health (CDRH)
FDA Regulation (cont)
Drugs Devices
• 21 CFR part 312 • 21 CFR part 812
(investigational drugs) (investigational devices)
• 21 CFR part 314 • 21 CFR part 814
(market approval) (market approval)
FDA Regulation (cont)
Common requirements for drugs & devices:
• 21 CFR part 50 (Protection of Human Subjects)*
• 21 CFR part 56 (Institutional Review Boards)*
• 21 CFR part 54 (Financial Disclosure)
• 21 CFR part 11 (Electronic Records)
• HIPAA Privacy Rule
* Different from “Common Rule” regulations (45 CFR 46) governing
federally-funded research.
Investigational Product
Applications
Drugs (part 312) Devices (part 812)
• Investigational New • Investigational Device
Drug (IND) Exemption (IDE)
• Both are requests for exemption from Federal
law prohibiting shipment of an unapproved drug
or device in interstate commerce
• Both also permit use of product in a clinical
study to collect safety and efficacy data
Investigational Product
Applications (cont)
Drugs Devices
• IND must be • IDE required prior to
submitted prior to conducting a clinical
conducting a clinical investigation (812.20)
investigation with an • Two paths: significant
investigational drug vs non-significant risk
(312.20) studies
• Exemptions (312.2b) • Exemptions (812.2c)
IND Exemptions
• Lawfully marketed in the US and:
• Not intended to support a new indication;
• Not intended to support a change in advertising;
• Doesn't involve a factor that increases risk of use;
• Conducted in compliance with IRB (part 56) and
Informed Consent (part 50) requirements;
• Complies with the requirements for promotion
and charging of investigational drugs (312.7)
IDE Exemptions
• Use in accordance with indications or:
• Non-invasive diagnostic;
• Consumer preference testing;
• Solely for veterinary use;
• Research on or with lab animals;
• Custom device (not being used to determine
safety and efficacy for commercial distribution)
IDE Decision Model
Approved for commercial Yes Exempt
release & used according to
from IDE
labeling or otherwise exempt
No
Significant Non-significant
Risk Device Risk Device
• Full IDE • Abbreviated IDE
• Must submit requirements
to FDA • FDA empowers IRB
IND Content
• Form FDA 1571
• Introductory statement
• General investigational plan
• Investigator brochure
• Protocols (study, investigator, facilities, IRB)
• Chemistry, manufacturing, control data
• Environmental impact statement
• Pharmacology and toxicology data
• Previous human experience
IDE Content
• Report of prior investigations
• Protocol including case report forms
• Risk analysis
• Description of the device
• Monitoring procedures
• Manufacturing info & environmental impact
• Investigator information
• Sales information
• Labeling
• Informed consent materials and IRB info
Marketing Applications
Drugs (part 314) Devices (part 814)
• New Drug Application • Premarket approval
(NDA) application (PMA) -
Class III devices
• Supplemental NDA
• Supplemental PMA
• Abbreviated NDA -
generics • 510(k) - Class II
devices
Study Design Differences
• Single confirmatory trial for devices
• Feasibility & pivotal studies vs. Phase I-III
• Fewer subjects for device trials due to
large effect size
• Shorter participation in device trials (but
may be subject to post-market study)
Design Differences (cont)
• Placebo control vs “sham” control
• Device trials may not be randomized or
may employ device features
• Blinding/masking often not possible with
devices
• Device technology may change during the
study
Sponsor Responsibilities
Drugs (312.50-52) Devices (812.40)
• Select qualified • Same as drug but …
investigators • No language on
• Provide investigators “transfer of
info to conduct trial obligations” to CRO
• Ensure proper
monitoring
• Can transfer
obligations to a CRO
Selecting Investigators
Drugs (312.53) Devices (812.43)
• Select investigators • Same as drug but …
qualified by training • No 1572: Investigator
and experience agreement instead (PI
• Ship inv. product (IP) and Co-investigators)
only to participating • If investigators
investigators involved in terminated
• Obtain investigator research, obtain
information (CV, Form explanation of the
FDA 1572, financial) circumstances
Special Device Challenges -
Selecting Investigators
• Smaller pool of investigators with device
expertise
• Marketing tends to have a larger role in
site selection (investigator is viewed as
“customer”)
Selecting Monitors
Drugs (312.53d) Devices (812.43d)
• Select monitors • Same as drug
qualified by training
and experience to
monitor the
investigation
Monitoring Investigations
Drugs (312.56) Devices (812.46)
• If non-compliance • Same as drug but …
discovered, secure • Don’t dispose/return
compliance or device if it would
discontinue IP jeopardize subject
shipments, terminate (eg., explant)
participation, and
dispose/return of IP
• Disqualification by • Disqualification by
FDA (312.70) FDA (812.119)
Monitoring (cont)
Drugs (312.56) Devices (812.46)
• Discontinue • Same as drug plus…
investigations if IP • Can resume
presents an terminated studies of
unreasonable risk significant risk device
only after FDA and
IRB approval
Sponsor Reporting to FDA
Drugs Devices
• Protocol amendments • IDE supplemental
(312.30) and IND applications (812.35)
amendments (312.31) • Unanticipated adverse
• IND Safety Reports of device effects - UADE
serious & unexpected (812.150b)
drug-related adverse • Annual progress
events (312.32) reports and final
• IND Annual Reports report, if significant
(312.33) risk device (812.150b)
Unanticipated Adverse
Device Effect (21 CFR 812.3r)
Serious adverse effect on health or safety or
any life-threatening problem or death caused
by, or associated with a device, if that effect,
problem, or death was not previously identified
in nature, severity, or degree of incidence in
the investigational plan or application, or any
other unanticipated serious problem associated
with a device that relates to the rights, safety or
welfare of patients.
Reporting to FDA (cont)
Drugs (312.30) Devices (812.150b)
• New investigators • Current investigator list
reported as part of every 6-months
protocol • Significant risk
amendments determination by IRB
• Any sponsor request for
device return, repair, or
disposition (eg, recall)
• Withdrawal IRB approval
Informing Investigators
Drugs (312.55) Devices (812.45)
• Prior to the study, • Prior to study, provide
provide investigator investigational plan
brochure (IB) and report of prior
investigations
• Report new
observations through • Report UADEs and
updated IB, letters, withdrawal of IRB
and IND safety and/or FDA approval
reports (812.150)
Sponsor Records
Drugs (312.57) Devices (812.140)
• Maintain investigator • Same as drug but…
records including • Retention for 2 years
financial disclosure after no longer needed
• Maintain records of IP to support a market
shipment/disposition approval application
• Retention for 2 years • Provisions for
after market approval transferring records
or investigational use custody to another
is discontinued person
Investigator Responsibilities
Drugs (312.60) Devices (812.100)
• Ensure investigation • Same as drug plus …
conducted according • Language permitting
to investigational plan potential subject
and FDA regulations recruitment (eg,
• Protect rights, safety, interest), but not
welfare of subjects consent, prior to IRB
and FDA approval
• Ensure informed
(812.110)
consent obtained per
part 50
Special Device Challenges -
Obtaining Informed Consent
• Timing of informed consent can be difficult
as subjects often enroll on same day of
treatment;
• Indications for use of specific device may
not be confirmed until some time during a
surgical procedure; and
• Subjects may require pre-medication for
treatment
Drug/Device Administration
Drugs (312.61) Devices (812.110c)
• Administer IP to • Same as drug but …
subjects under • Permit device to be
personal supervision used with subjects
or supervision of under investigator’s
subinvestigator supervision – no
• Supply IP only to language about
authorized persons delegation to others
Special Device Challenges -
Device Administration
• Investigator skill with equipment varies
• Investigator training on device use may be
difficult due to influx of new residents and
fellows and rapid changes in technology
Drug/Device Disposition
Drugs (312.59, 62a) Devices (812.110e)
• If investigation is • Same as drug
completed or
terminated, return
supplies to sponsor or
dispose as directed
Special Device Challenges -
Device Accountability
• Monitoring and controlling device
inventory may be difficult due to storage
location (ie, O.R. supply room) and device
size/portability.
• Some devices require “multi-use”
accountability
• Changes in device technology during trial
may require frequent inventory changes
Investigator Reporting
Drugs (312.64) Devices (812.150a)
• Progress reports and • Similar to drugs but …
final report to sponsor • Safety reports of
• Safety reports of UADEs to sponsor
causally-related and IRB
adverse events to • Report deviations from
sponsor and IRB investigational plan to
• Financial disclosure protect a subject in an
reports to sponsor emergency to sponsor
and IRB
Investigator Records
Drugs (312.62) Devices (812.140)
• Records of drug • Same as drug plus…
disposition • All correspondence
• Subject case histories with IRB, sponsor,
including signed & other investigators,
dated consent forms and FDA
• Documentation that • Dates of and reasons
consent obtained for deviations from the
prior to participation in protocol
the study
Records Inspection by FDA
Drugs (312.58, 68) Devices (812.145)
• Sponsors and • Same as drug
investigators will
permit FDA to access,
copy, and verify all
records related to
clinical investigations
• Investigator records
may identify subjects if
FDA finds necessary
Other Similar Investigational
Product Regulations
• Labeling (312.36 vs 812.5)
• Promotion & charging (312.36 vs 812.5)
• Treatment use (312.34 vs 812.36)
• Emergency use (312.36 vs 812.47)
• Use of foreign data (312.120 vs 814.15)
Good Web Sites
“Device Advice” (CDRH)
www.fda.gov/cdrh/devadvice/ide/index.shtml
Investigational Device Exemptions Manual
www.fda.gov/cdrh/manual/idemanul.html
Good Clinical Practice (FDA)
www.fda.gov/oc/gcp/default.htm
BIMO Inspection Manuals (See IRB, Sponsors,
or Investigators)
www.fda.gov/ora/compliance_ref/bimo/default.htm
Contact Information
• Paul Below
- Senior CRA, 3M Pharmaceuticals
- Phone: (952) 882-4083
- E-Mail: vicepresident@mnacrp.org
• Barb Westrum
- Director, Corporate Clinical Affairs, Medtronic
- Phone: (763) 505-2600
- E-Mail: barbara.westrum@medtronic.com
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