What is an IDE? Is Clinical Data Conducted Outside the U.S. Acceptable? Carole C. Carey, BSEE, M.Engineering [email protected] Director, International

What is an IDE? Is Clinical Data Conducted Outside the U.S. Acceptable?

Carole C. Carey, BSEE, [email protected], International StaffUS Food and Drug Administration (USFDA)Center for Devices and Radiological Health (CDRH)

2009 Sep 29 Edmonton 2009 Oct 1 Vancouver

FDA Regulatory Framework and Medical Device Workshop

Learning Objectives

To gain an understanding of the Investigational Device Exemption (IDE) regulations.

The purpose of the IDE regulation The major regulatory elements that constitute

medical device Good Clinical Practices Significant Risk and Non-Significant Risk

Studies FDA review criteria Clinical trials outside U.S. and FDA jurisdiction



What is an IDE?

Investigational Device Exemption

To encourage discovery and development of useful medical devices for human use,

to the extent consistent with the protection of the public health and safety and with ethical standards,

while maintaining optimum freedom for scientific investigators in their pursuit of that purpose.

Allows the use of unapproved devices.

statutory authority, FDCA, Section 520(g)21 CFR Part 812



Definitionsa PREMARKET deviceInvestigational

Device Is still in the

developmental stage Is not considered to

be in commercial distribution

The object of a clinical investigation is to determine safety and effectiveness

a MARKETED device

Investigational Use Clinical evaluation of

an already legally marketed device for a new intended use



Applicable Regulations (Medical Device Good Clinical Practices)

21 CFR Part 812: Investigational Device Exemptions

covers the procedures for the conduct of clinical studies with medical devices including application, responsibilities of sponsors and investigators, labeling, records, and reports.

21 CFR Part 50: Informed Consent, Human Subject Protections

Section 50.25 -- elements of IC Section 50.23 -- IC waiver (emergency) Section 50.24 -- IC waiver (emergency research)

21 CFR Part 56: Institutional Review Boards covers the procedures and responsibilities for institutional review boards (IRBs) that approve clinical investigations protocols



Applicable Regulations- cont’d (Medical Device Good Clinical Practices)

21 CFR 54, Financial Disclosure by Clinical Investigators,

covers the disclosure of financial compensation to clinical

investigators which is part of FDA’s assessment of the

reliability of the clinical data.

21 CFR 820 Subpart C,

Design Controls of the Quality System Regulation,

provides the requirement for procedures to control the

design of the device in order to ensure that the specified

design requirements are met.

IDEs are exempt from GMP/QSR (except Design Controls)



When is an IDE application required?

Research in human subjects conducted in the United States: To support device marketing application: PMA, HDE or

510(k)

To collect safety and effectiveness information (e.g., for a new intended use of a legally marketed device)

Unapproved devices or new intended use of approved device (even if no marketing application planned) by sponsor-investigator.



8

The Regulatory Path

510k PMA

IDE

!!! MARKET !!!

October 7, 2009



Valid Scientific Evidence Comes from…

Well-controlled investigationsWell-controlled investigations Partially-controlled investigationsPartially-controlled investigations Studies & objective trials without matched controlsStudies & objective trials without matched controls Well-documented case histories conducted by Well-documented case histories conducted by

qualified expertsqualified experts Reports of significant human experience with a Reports of significant human experience with a

marketed devicemarketed device Valid scientific evidence is NOT…

Isolated case reportsIsolated case reports Random experienceRandom experience Unsubstantiated opinions (e.g., testimonials)Unsubstantiated opinions (e.g., testimonials)



Required Elements of an IDE

U.S. Sponsor (manufacturer or investigator) Prior Investigations Investigational Plan Manufacturing Information Investigator and IRB Information Labeling Informed Consent Sales Information

“CAUTION - Investigational device. Limited by Federal (or United States) Law to investigational use.”



Investigational Plan

Purpose Name and intended use of device Objectives and duration of study

Written Protocol & Analysis Methodology and an analysis demonstrating scientific

soundness Number of patients and sites Inclusion and exclusion criteria Statistical methods Case Report Forms



Investigational Plan (cont’d)

Risk Analysis Description of all risks Justification for investigation

Description of the Device Each important component Principle of operation Copies of all labeling

Monitoring Procedures Monitor to oversee progress of investigtion



Endpoints: Outcome Variables

Parameters that determine study success: Primary Effectiveness: The most clinically

relevant parameters addressed by the clinical trial question

Safety Assessment: What are the expected & unexpected unfavorable outcomes & how can they be avoided?

Secondary effectiveness endpoints: Other parameters that support study success



Strategies: Clinical Considerations

For CDRH: US studies must be conducted in compliance

with the IDE regulations (21 CFR Part 812) Proper Informed Consent (21 CFR Part 50)Proper Informed Consent (21 CFR Part 50) IRB Regulations (21 CFR Part 56)IRB Regulations (21 CFR Part 56) Adequate monitoringAdequate monitoring

Dependent upon the data present & device characteristics, feasibility study often necessary prior to pivotal study Support proof of conceptSupport proof of concept Assist with refining inclusion/exclusion criteriaAssist with refining inclusion/exclusion criteria Refine surgical techniqueRefine surgical technique Recommendation of pilot study with control groupRecommendation of pilot study with control group



Significant Risk Study is…a study that presents a

potential serious risk to the health, safety, or welfare of a subject An implant for use in supporting or

sustaining human life for a use of substantial

importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health

FDA and IRB Approval is required

Cardiac catheters Surgical tissue

adhesives Vascular and arterial

graft protheses Dental endosseous

implants Cochlear implants Implantable infusion

pumps Implantable

pacemaker



Non-significant Risk Study

Do not pose significant risk to research subjects

Sponsor presents protocol to IRB and a statement why investigation does not pose significant risk

If IRB approves the investigation as NSR, it can begin.

No IDE submission requirement to the FDA

Abbreviated IDE

Daily wear contact lenses

Glucose monitor Magnetic resonance

imaging (MRI) Pulse oximeter Ob/Gyn diagnostic

ultrasound



Abbreviated IDE

No formal FDA approval is needed

IRB is required to meet all aspects of:

21 CFR Part 50 (protection of human subjects)

21 CFR Part 56 (IRB)

Labeling requirements



Studies Exempt from Part 812

Preamendments (pre-1976) devices

510(k)-cleared and HDE- or PMA-approved devices, If used in accordance with approved label

In vitro diagnostic devices (most)

Consumer preference testing of marketed devices

Combinations of legally marketed devices

Custom devices (are narrowly defined)

Studies outside the US: Declaration of Helsinki



Approved IDEs are Exempt from…

Registration Performance

Standards 510(k) regs PMA regs Misbranding regs

GMPs (except Design Controls)

Color Additive requirements Banned Devices regs Restricted Device

requirements



Approved IDEs are NOT Exempt from…

Adulteration regs Labeling regs Prohibition on: promotion/marketing,

commercialization, prolonging the investigation, representing the device as safe and effective

Import/Export Regs



Bioresearch Monitoring (BIMO) Program

To ensure the quality and integrity of data and information submitted in support of research and marketing permits that include IDE, PMA, and 510(k) submissions, and

To ensure that human subjects taking part in investigations are protected from undue hazard or risk.



Differing levels of regulatory control depending on the level of risk

Full Requirem ents

SR Investigations

A bbreviated R equirem ents

N SR Studies

Studies Subjectto IDE Regulation

Studies Exem pt fromthe IDE Regulation

All Device Investigations



FDA Review Criteria Scientifically sound Reasonably believed to be able to

provide the desired results Data from non-clinical studies support

the proposed human research Research conducted by qualified

investigators



FDA Review Criteria (cont’d) Expected benefit outweigh any expected

risks Research subjects fully informed to the

risks involved in the research, understand these risks and freely volunteer to participate

IRB approval of the research



FDA Review Times and Decision

FDA review time for IDE is 30 days.

Within 30 days, FDA will approve, approve with conditions, or disapprove an IDE application.

For disapproved IDE, the sponsor can respond to the deficiencies and/or request hearing.



Clinical Trials Outside U.S. (OUS)

“Acceptance of Foreign Clinical Studies: Guidance for Industry - Acceptance of Foreign Clinical Studies”, March 2001

FDA will accept a foreign clinical device study only if the study conforms to the ethical principles of the Declaration or with the laws and regulations of the country, whichever provides greater protection of the human subjects.

Subject to Human Subject Research Protections laws applicable in that country

Studies performed by clinical investigators of recognized competence



Same scientific and data integrity standards

FDA does not have legal authority/jurisdiction outside of the United States

But FDA has authority to set conditions for accepting non-U.S. data that is used to support marketing (PMA, 510(k), HDE, etc.) in the U.S.

Once accepted for review, the same scientific and data integrity standards are applied as for studies conducted in the U.S.



Early Consultation with FDA If intended to support eventual marketing

application in US, should: Reflect US medical practice patternsReflect US medical practice patterns Reflect US patient populationReflect US patient population Ensure adequate documentation of good Ensure adequate documentation of good

study conduct, availability of raw data study conduct, availability of raw data

Therefore: It is beneficial to consult with FDA (e.g., Pre-IDE) on clinical protocol beforehand if intended to support US marketing application



FDA Jurisdiction FDA has jurisdiction over the export of unapproved

devices exported for use in foreign studies.

FDA does not have jurisdiction over the manner in which the investigational study is conducted outside the U.S.

An IDE is not necessary for a study conducted entirely at foreign sites.

FDA has authority to accept or deny data that has been collected during a study at a foreign site that is submitted to support a research or marketing application.



Summary All clinical investigations subject to the

regulation must be approved before they can begin.

All subjects in the investigation must give informed consent – human subject protection.

The basics of good clinical studies and good

clinical practices are the same worldwide.

Documents

What is an IDE? Is Clinical Data Conducted Outside the U.S. Acceptable? Carole C. Carey, BSEE, M.Engineering [email protected] Director, International