A Tale of Two Cities: Working Between the Different Worlds of Pharmaceuticals and Medical Devices

A Tale of Two Cities
Working Between the Different
Worlds of Pharmaceuticals and
Medical Devices

Presented by
Paul Below, CCRA,
CCRT
P. Below Consulting, Inc.

Learning Objectives
• 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

Copyright 2011 © P. Below Consulting, Inc.

Learning Objectives (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


Definitions

Drug vs. Device


Definitions
Drug

1 Articles other than
food listed in the
United States
Pharmacopeia
(USP) or the
National Formulary
(NF)


Definitions
Drug Medical Device

1 Articles other than 2 An
food listed in the instrument, apparatu
United States s, implement, machi
Pharmacopeia ne, implant, or in
(USP) or the vitro reagent listed in
National Formulary the USP or NF
(NF)


Definitions (cont.)
Drug

1 Intended to
diagnose, cure, mitig
ate, treat, or prevent
disease
Affects the structure
& function of the
human body


Definitions (cont.)
Drug Medical Device

1 Intended to 2 Same as drugs plus
diagnose, cure, mitig …
ate, treat, or prevent Does not achieve
disease primary effect
Affects the structure through chemical
& function of the action
human body Is not dependent on
being metabolized


Combination Devices

• A product comprised of two or more regulated
components, i.e., drug/device, biologic/device,
drug/biologic, or drug/device/biologic, that are
physically, chemically, or otherwise combined
or mixed and produced as a single entity
(defined in 21 CFR 3.2e).
• Regulatory pathway is defined by the primary
mechanism of action


Investigational Product Definitions
Drug

1 Being used in a
clinical investigation
Also includes
biologic products
used in vitro for
diagnostic purposes


Investigational Product Definitions
Drug Medical Device

1 Being used in a 2 Being used in a
clinical investigation clinical investigation
Also includes Not in commercial
biologic products distribution
used in vitro for Three classes of
diagnostic purposes devices based on
risk and required
controls


Device Classification (21 CFR 860)
Class I – Low Risk Class II – Moderate Risk

1 General controls only – No 2 General & special
FDA review required controls (performance.
Reasonable assurance of standards,
the safety and post-market surveillance)
effectiveness Cleared by FDA (510K
Examples: surgical process)
instruments, wound Examples: non-implanted
dressings, contact pumps, vascular
lenses, toothbrush clamps, sutures, ECGs, u
rology catheters


Device Classification (21 CFR 860)
Class III – High Risk

3 Clinical data & FDA approval
required
Life-supporting, life-
sustaining, important in
preventing impairment,
potential for unreasonable
risk
Examples: pacemakers,
defibrillators, vascular grafts,
angioplasty catheters, stents


Device Classification

• Devices classification depends on intended
use and indications for use
• For example, a scalpel’s intended use is to cut
tissue. A subset of intended use arises when
a more specialized indication is added in the
device’s labeling such as, “for making
incisions in the cornea”
• Indications for use can be found in the
device’s labeling

Device Classification

Device classification database on FDA
website:
http://www.accessdata.fda.gov/scripts/cdrh/
cfdocs/cfPCD/classification.cfm


Industry Differences

Drug vs. Device


Major Industry Differences

• Local vs. systemic effects
Mechanism
of Action • Physical effects vs.
pharmacokinetic

Business
Environment


Major Industry Differences

• Local vs. systemic effects
Mechanism
of Action • Physical effects vs.
pharmacokinetic

• Wide variety of device types
Business • Number and size of companies
Environment
• Rapid changes in device
technology


Major Industry Differences (cont.)

• Length of time & money
Product
Development • 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 Clinical Trials: Supplemental reporting
Synth. Phase I Phase IV

NDA 1.5 yrs
Pharmacology Phase II Postmarketing
Toxicology Phase III Clinical education

6 yrs 4.8 yrs 8-10 yrs


Device Development

Bench Testing & Feasibility study Human Postmarket studies
GLP Studies Studies Supplemental reporting

PMA - 14 mos
Clinical education
Medicare review

12 - 24 3-9 6 - 36
mos mos mos


FDA Governance

• 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 Governance
Drug Device

1 Federal 2 Federal requirements
requirements governing
governing safety investigations enacted
were enacted in in FD&C amendments
FD&C amendments in 1976 and 1990
in 1938 and efficacy
in 1962
Center for Drug Center for Devices
Evaluation and and Radiologic
Research (CDER) Health (CDRH)


FDA Regulations

21 CFR Part 312 21 CFR Part 812
(investigational (investigational
drugs) devices)

21 CFR Part 314 21 CFR Part 814
(market approval) (market approval)


Common Regulations for
Drugs and Devices
✓ 1 21 CFR Part 50
Protection of Human Subjects

✓ 2 21 CFR Part 56
Institutional Review Boards

✓ 3 21 CFR Part 54
Financial Disclosure

✓ 4 21 CFR Part 11
Electronic Records

✓ 5 45 CFR Part 160 & Part 164
HIPAA Privacy Rule

6

Investigational Product
Applications

Drug vs. Device


Investigational Product Applications
Drug Device

1 21 CFR Part 312 2 21 CFR 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
Drug Device

1 21 CFR Part 312.20 2 21 CFR Part 812.20
IND must be IDE required prior to
submitted to FDA conducting a clinical
prior to conducting a investigation
clinical investigation Two paths: significant
with an vs. non-significant risk
investigational drug studies
Exemptions from IDEs
Exemptions from (812.2c)
INDs (312.2b)


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 and Informed
Consent
Complies with promotion & charging rules (21 CFR
312.7)


IDE Exemptions
Used in accordance with approved 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

Device approved for Exempt
C
commercial release & used YES from
according to IDE
labeling or otherwise exempt?
NO
Abbreviated IDE required
FDA empowers the IRB
Significa NO to approve the IDE
nt Risk
Study?
Full IDE required
YES Must submit for
approval to FDA


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

IND Content (Parts Unique to Drugs)
• 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

IDE Content (Parts Unique to Devices)
• 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
Drug Device

1 21 CFR Part 314 2 21 CFR Part 814
New Drug Premarket approval
Application (NDA) application (PMA) –
Class III devices

Supplemental NDA Supplemental PMA

Abbreviated NDA 510(k) Clearance –
(generics) Class II devices


Study Design

Drug vs. Device


Study Design Differences

Number of • Single confirmatory trial for
Required
Studies
devices
• Two well controlled trials for
drugs

Study
Phases


Study Design Differences

Number of • Single confirmatory trial for
Required
Studies
devices
• Two well controlled trials for
drugs
• Feasibility and pivotal studies for
Study devices
Phases
• Phase I-III studies for drugs


Study Design Differences (cont.)

Number of
• Hundreds of subjects for
Subjects devices
• Thousands of subjects for drugs

Study
Phases



Number of
• Hundreds for devices
Subjects • Thousands for drugs

• Weeks to months for devices
Length of
Studies • Months to years for drugs



• Placebo control vs. “sham”
Type of
control
Controls • Device trials may not be
randomized
• Blinding/masking often not
possible with devices
Product
Obsolescence



• Placebo control vs. “sham”
Type of
control
Controls • Device trials may not be
randomized
• Blinding/masking often not
possible with devices
• Device technology may change
Product during the study
Obsolescence


Sponsor Responsibilities
Drug Device

1
21 CFR Part 312.50- 2 21 CFR Part 812.40
52 Same as drug but
Select qualified …
investigators No language on
Provide “transfer of
investigators info to obligations” to
conduct trial CRO
Ensure proper
monitoring
Can transfer
obligations to a
CRO Copyright 2011 © P. Below Consulting, Inc.

Investigator Selection
Drug Device

1
21 CFR Part 312.53 2 21 CFR Part 812.43
Select investigators Same as drug but
qualified by training …
and experience No 1572:
Ship invest. product Investigator
only to participating agreement instead
investigators If investigators are
Obtain investigator involved in
information terminated
(CV, Form FDA research, obtain
1572, financial) explanation of the
circumstances

Special Device Challenges -
Selecting Investigators

• Smaller pool of qualified investigators
with device expertise
• Marketing has a larger role in site
selection (investigator is viewed as
“customer”)
• Device investigators pay a larger role in
publication strategy (important for
reimbursement) and also adoption of the
device by the medical community

Monitor Selection
Drug Device

1
21 CFR Part 312.53d 2 21 CFR Part 812.43d
Select monitors Same as drug …
qualified by training
and experience to
monitor the
investigation


Monitoring Investigations
Drug Device

1
21 CFR Part 312.56 2 21 CFR Part 812.46
If non-compliance Same as drug …
is discovered, Don’t
secure compliance dispose/return
or discontinue IP device if it would
shipments, jeopardize subject
terminate
(eg., explant)
participation, and
dispose/return of IP


Monitoring Investigations (cont.)
Drug Device

1
21 CFR Part 312.70 2 21 CFR Part 812.119
Disqualification of Same as drug …
investigators by
the FDA


Monitoring Investigations (cont.)
Drug Device

1
21 CFR Part 312.56 2 21 CFR Part 812.46
Discontinue Same as drug …
investigations if Can resume
investigational terminated studies
product presents of a significant risk
an unreasonable device only after
risk FDA and IRB
approval


Sponsor Reporting to FDA
Drug Device

1 21 CFR Part 312.30- 2 21 CFR Part 812.35
31
IDE supplemental
Protocol applications
amendments and
IND amendments


Sponsor Reporting to FDA (cont.)
Drug Device

1 21 CFR Part 312.32 2 21 CFR Part 812.150b
IND Safety Unanticipated
Reports of serious adverse device
& unexpected effects - UADE
drug-related
adverse events


Drug Device

IND Annual Annual progress
Reports reports and final
report, if significant
risk device


Drug Device

New investigators Current investigator
reported as part of list every 6-months
protocol
amendments Significant risk
determination by
IRB
Any sponsor
request for device
return, repair, or
disposition
Withdrawal of IRB

Sponsor Reports to Investigators
Drug Device

1 21 CFR Part 312.55 2 21 CFR Part 812.45
Prior to the Prior to
study, provide study, provide
investigator investigational plan
brochure (IB) and report of prior
investigations


Sponsor Reports to Investigators
Drug Device

1 21 CFR Part 312.55 2 21 CFR Part 812.150
Report new Report UADEs and
observations withdrawal of IRB
through updated and/or FDA
IB, letters, and IND approval
safety reports


Sponsor Records
Drug Device

1 21 CFR Part 312.57 2 21 CFR Part 812.150
Maintain Same as drug but
investigator records …
including financial
disclosure Retention for 2
years after no
Maintain records of longer needed to
IP support a
shipment/dispositio marketing
n application
Retention for 2 Provisions for
years after market transferring records
approval or invest. custody to another

Investigator Responsibilities
Drug Device

1 21 CFR Part 312.60 2 21 CFR Part 812.110
Ensure Same as drug but
investigation …
conducted
according to Language
investigational plan permitting potential
and FDA subject recruitment
regulations (eg, interest), but
not consent, prior
Protect to IRB and FDA
rights, safety, welfar approval
e of subjects
Ensure informed Copyright 2011 © P. Below Consulting, Inc.

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

IP Administration
Drug Device

1 21 CFR Part 312.61 2 21 CFR Part 812.110c
Administer IP to Same as drug but
subjects under …
personal
supervision or Permit device to be
supervision of used with subjects
subinvestigator under the
investigator’s
Supply IP only to supervision
authorized persons (no language about
delegation to
others)

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


IP Disposition
Drug Device

1 21 CFR Part 2 21 CFR Part 812.110c
312.59, 62a
Same as drug …
If investigation is
completed or
terminated, return
supplies to sponsor
or dispose as
directed


Device Accountability

• Monitoring and controlling device
inventory may be difficult due to storage
location (ie, O.R. supply room) and
device size and portability.
• Some devices require “multi-use”
accountability
• Changes in device technology during
trial may require frequent inventory
changes

Investigator Reporting
Drug Device

1 21 CFR Part 312.64 2 21 CFR Part 812.150a
Progress reports Similar to drug but
and final report to …
sponsor
Safety reports of
Safety reports of UADEs to sponsor
causally-related and IRB
adverse events to
sponsor and IRB Report deviations
from invest. plan to
Financial disclosure protect a subject in
reports to sponsor an emergency to
sponsor and IRB

Investigator Records
Drug Device

1 21 CFR Part 312.62 2 21 CFR Part 812.140
Records of drug Same as drug but
disposition …
Subject case All correspondence
histories including with
signed & dated IRB, sponsor, other
consent forms investigators, and
FDA
Documentation that
consent obtained Dates of and
prior to participation reasons for
in the study deviations from the
protocolCopyright 2011 © P. Below Consulting, Inc.

Records Inspection by the FDA
Drug Device

1 21 CFR Part 2 21 CFR Part 812.145
312.58, 68
Same as drug …
Sponsors and
investigators will
permit FDA to
access, copy, and
verify all records
related to clinical
investigations
Investigator records
may identify
subjects if FDA
finds necessary Copyright 2011 © P. Below Consulting, Inc.

Other Similar IP Regulations

21 CFR Part 312.36 21 CFR Part
812.5
Labeling, Promotion & Charging

812.36
Treatment Use

812.47
Emergency Use


Contact Information

Paul Below
• P. Below Consulting, Inc. & GCP Training
Specialists
Burnsville, MN
• Office: (612) 643-5598
• Email: paul@pbelow-consulting.com
• Website: www.pbelow-consulting.com

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