a tale of two cities: working between the different worlds of pharmaceuticals and medical devices

Presented byPaul Below, CCRA, CCRTP. Below Consulting, Inc.

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

• 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

Learning Objectives

Copyright 2011 © P. Below Consulting, Inc.

• 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

Learning Objectives (cont.)



Definitions

Drug vs. Device

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

Drug

1

Definitions


An instrument, apparatus, implement, machine, implant, or in vitro reagent listed in the USP or NF

Medical Device

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

Drug

21

Definitions


Intended to diagnose, cure, mitigate, treat, or prevent disease

Affects the structure & function of the human body

Drug

1

Definitions (cont.)


Same as drugs plus …

Does not achieve primary effect through chemical action

Is not dependent on being metabolized

Medical Device

Intended to diagnose, cure, mitigate, treat, or prevent disease

Affects the structure & function of the human body

Drug

21


Definitions (cont.)

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


Being used in a clinical investigation

Also includes biologic products used in vitro for diagnostic purposes

Drug

1

Investigational Product Definitions



Not in commercial distribution

Three classes of devices based on risk and required controls

Medical Device


Also includes biologic products used in vitro for diagnostic purposes

Drug

21


Investigational Product Definitions

General & special controls (performance. standards, post-market surveillance)

Cleared by FDA (510K process)

Examples: non-implanted pumps, vascular clamps, sutures, ECGs, urology catheters

Class II – Moderate Risk

1

Class I – Low Risk

General controls only – No FDA review required

Reasonable assurance of the safety and effectiveness

Examples: surgical instruments, wound dressings, contact lenses, toothbrush

2

Device Classification (21 CFR 860)


Clinical data & FDA approval requiredLife-supporting, life-sustaining, important in preventing impairment, potential for unreasonable riskExamples: pacemakers, defibrillators, vascular grafts, angioplasty catheters, stents

Class III – High Risk

3

Device Classification (21 CFR 860)


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

• Local vs. systemic effects• Physical effects vs.

pharmacokinetic

Business Environment

Mechanism of Action

Major Industry Differences


• Local vs. systemic effects• Physical effects vs.

pharmacokinetic

Business Environment

Mechanism of Action

Major Industry Differences


• Wide variety of device types • Number and size of

companies• Rapid changes in device

technology

Product Development

Major Industry Differences (cont.)


• 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


Paten

t Appro

val

IND

FDA

Paten

t

Expira

tion

(17

yrs)

4.8 yrs 8-10 yrs

Idea

6 yrs

Chemical Synth.PharmacologyToxicology

Clinical Trials:Phase IPhase IIPhase III

Supplemental reportingPhase IVPostmarketingClinical education

Clinic

al

Pre-c

linic

al

ND

A 1

.5 y

rs

Pharmaceutical Development


Device Development

Desig

n

Pre-c

linic

al

Clinic

al

12 - 24mos

3 - 9mos

6 - 36 mos

FDA Mar

ket R

elea

se

Fea

sib

ilit

y s

tud

yPostmarket studiesSupplemental reportingClinical educationMedicare review

PM

A -

14

mo

s

IDE

Bench Testing & GLP Studies

HumanStudies

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)


Federal requirements governing investigations enacted in FD&C amendments in 1976 and 1990

Device

Federal requirements governing safety were enacted in FD&C amendments in 1938 and efficacy in 1962

Drug

21


FDA Governance

Center for Drug Evaluation and Research (CDER)

Center for Devices and Radiologic Health (CDRH)

21 CFR Part 314 (market approval)

21 CFR Part 312 (investigational

drugs)


FDA Regulations

21 CFR Part 814 (market approval)

21 CFR Part 812 (investigational

devices)

21 CFR Part 50Protection of Human Subjects

✓

✓

✓

✓

✓

1

2

3

4

5

6

Common Regulations for Drugs and Devices


21 CFR Part 54Financial Disclosure

21 CFR Part 56Institutional Review Boards

21 CFR Part 11Electronic Records

45 CFR Part 160 & Part 164 HIPAA Privacy Rule


Investigational Product Applications

Drug vs. Device

21 CFR Part 812Investigational Device Exemption (IDE)

Device

21 CFR Part 312Investigational New Drug (IND)

Drug

21



• 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

21 CFR Part 812.20

IDE required prior to conducting a clinical investigationTwo paths: significant vs. non-significant risk studiesExemptions from IDEs (812.2c)

Device

21 CFR Part 312.20

IND must be submitted to FDA prior to conducting a clinical investigation with an investigational drug

Exemptions from INDs (312.2b)

Drug

21



IND Exemptions


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

Lawfully marketed in the US and:

Complies with promotion & charging rules (21 CFR 312.7)

IDE Exemptions


Non-invasive diagnostic;

Consumer preference testing;

Solely for veterinary use;

Research on or with lab animals;

Used in accordance with approved indications or:

Custom device (not being used to determine safety and efficacy for commercial distribution)

IDE Decision Model


CDevice approved for

commercial release & used according to

labeling or otherwise exempt?

Significant Risk Study?

Exempt from IDE

YES

NO

Full IDE requiredMust submit for approval to FDA

YES

NO

Abbreviated IDE required

FDA empowers the IRB to approve the IDE

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

21 CFR Part 814Premarket approval application (PMA) – Class III devices

Supplemental PMA

510(k) Clearance – Class II devices

Device

21 CFR Part 314New Drug Application (NDA)

Supplemental NDA

Abbreviated NDA (generics)

Drug

21


Marketing Applications


Study Design

Drug vs. Device

• Single confirmatory trial for devices

• Two well controlled trials for drugs

Study Phases

Number of Required Studies

Study Design Differences


• Single confirmatory trial for devices

• Two well controlled trials for drugs

Study Phases

Number of Required Studies

Study Design Differences


• Feasibility and pivotal studies for devices

• Phase I-III studies for drugs

• Hundreds of subjects for devices

• Thousands of subjects for drugs

Study Phases

Number of Subjects

Study Design Differences (cont.)


• Hundreds for devices

• Thousands for drugs

Length of Studies

Number of Subjects



• Weeks to months for devices• Months to years for drugs

• Placebo control vs. “sham” control

• Device trials may not be randomized

• Blinding/masking often not possible with devices

Product Obsolescence

Type of Controls



• Placebo control vs. “sham” control

• Device trials may not be randomized

• Blinding/masking often not possible with devices

Product Obsolescence

Type of Controls



• Device technology may change during the study

21 CFR Part 812.40

Same as drug but …No language on “transfer of obligations” to CRO

Device

1

Drug

21 CFR Part 312.50-52

Select qualified investigators

Provide investigators info to conduct trial

Ensure proper monitoring

Can transfer obligations to a CRO

2

Sponsor Responsibilities


21 CFR Part 812.43

Same as drug but …No 1572: Investigator agreement instead

If investigators are involved in terminated research, obtain explanation of the circumstances

Device

1

Drug

21 CFR Part 312.53

Select investigators qualified by training and experience

Ship invest. product only to participating investigators

Obtain investigator information (CV, Form FDA 1572, financial)

2

Investigator Selection


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 Copyright 2011 © P. Below Consulting, Inc.

21 CFR Part 812.43d

Same as drug …

Device

1

Drug

21 CFR Part 312.53d

Select monitors qualified by training and experience to monitor the investigation

2

Monitor Selection


21 CFR Part 812.46

Same as drug …Don’t dispose/return device if it would jeopardize subject (eg., explant)

Device

1

Drug

21 CFR Part 312.56

If non-compliance is discovered, secure compliance or discontinue IP shipments, terminate participation, and dispose/return of IP

2

Monitoring Investigations


21 CFR Part 812.119

Same as drug …

Device

1

Drug

21 CFR Part 312.70

Disqualification of investigators by the FDA

2

Monitoring Investigations (cont.)


21 CFR Part 812.46

Same as drug …Can resume terminated studies of a significant risk device only after FDA and IRB approval

Device

1

Drug

21 CFR Part 312.56

Discontinue investigations if investigational product presents an unreasonable risk

2

Monitoring Investigations (cont.)


21 CFR Part 812.35

IDE supplemental applications

Device

1

Drug

21 CFR Part 312.30-31

Protocol amendments and IND amendments

2

Sponsor Reporting to FDA


21 CFR Part 812.150b

Unanticipated adverse device effects - UADE

Device

1

Drug

21 CFR Part 312.32

IND Safety Reports of serious & unexpected drug-related adverse events

2

Sponsor Reporting to FDA (cont.)



Annual progress reports and final report, if significant risk device

Device

1

Drug

21 CFR Part 312.33

IND Annual Reports

2




Current investigator list every 6-months

Significant risk determination by IRB

Any sponsor request for device return, repair, or disposition

Withdrawal of IRB approval

Device

1

Drug

21 CFR Part 312.30

New investigators reported as part of protocol amendments

2



21 CFR Part 812.45

Prior to study, provide investigational plan and report of prior investigations

Device

1

Drug

21 CFR Part 312.55

Prior to the study, provide investigator brochure (IB)

2

Sponsor Reports to Investigators


21 CFR Part 812.150

Report UADEs and withdrawal of IRB and/or FDA approval

Device

1

Drug

21 CFR Part 312.55

Report new observations through updated IB, letters, and IND safety reports

2

Sponsor Reports to Investigators


21 CFR Part 812.150

Same as drug but …

Retention for 2 years after no longer needed to support a marketing application

Provisions for transferring records custody to another person

Device

1

Drug

21 CFR Part 312.57

Maintain investigator records including financial disclosure

Maintain records of IP shipment/disposition

Retention for 2 years after market approval or invest. use is discontinued

2

Sponsor Records


21 CFR Part 812.110


Language permitting potential subject recruitment (eg, interest), but not consent, prior to IRB and FDA approval

Device

1

Drug

21 CFR Part 312.60

Ensure investigation conducted according to investigational plan and FDA regulations

Protect rights, safety, welfare of subjects

Ensure informed consent obtained per 21 CFR part 50

2

Investigator Responsibilities


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


21 CFR Part 812.110c


Permit device to be used with subjects under the investigator’s supervision (no language about delegation to others)

Device

1

Drug

21 CFR Part 312.61

Administer IP to subjects under personal supervision or supervision of subinvestigator

Supply IP only to authorized persons

2

IP Administration


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


21 CFR Part 812.110c

Same as drug …

Device

1

Drug

21 CFR Part 312.59, 62a

If investigation is completed or terminated, return supplies to sponsor or dispose as directed

2

IP Disposition


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 and portability.

• Some devices require “multi-use” accountability

• Changes in device technology during trial may require frequent inventory changes Copyright 2011 © P. Below Consulting, Inc.

21 CFR Part 812.150a

Similar to drug but …

Safety reports of UADEs to sponsor and IRB

Report deviations from invest. plan to protect a subject in an emergency to sponsor and IRB

Device

1

Drug

21 CFR Part 312.64

Progress reports and final report to sponsor

Safety reports of causally-related adverse events to sponsor and IRB

Financial disclosure reports to sponsor

2

Investigator Reporting


21 CFR Part 812.140


All correspondence with IRB, sponsor, other investigators, and FDA

Dates of and reasons for deviations from the protocol

Device

1

Drug

21 CFR Part 312.62

Records of drug disposition

Subject case histories including signed & dated consent forms

Documentation that consent obtained prior to participation in the study

2

Investigator Records


21 CFR Part 812.145

Same as drug …

Device

1

Drug

21 CFR Part 312.58, 68

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

2

Records Inspection by the FDA


21 CFR Part 312.36


Other Similar IP Regulations

21 CFR Part 812.5

Labeling, Promotion & Charging

21 CFR Part 312.34

21 CFR Part 812.36

Treatment Use

21 CFR Part 312.36

21 CFR Part 812.47

Emergency Use

Questions

Contact Information

Paul Below• P. Below Consulting, Inc. & GCP Training

SpecialistsBurnsville, MN

• Office: (612) 643-5598

• Email: [email protected]

• Website: www.pbelow-consulting.com

a tale of two cities: working between the different worlds of pharmaceuticals and medical devices

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