# Presentation: 278306

## Points To Consider in Ethically Conducting Medical Device Clinical Trials  

***Office of Research Oversight***
***Veterans Administration***
***Bimonthly Teleconference:  May 11, 2005***
*Elisa D. Harvey, D.V.M., Ph.D.*
*Director, Investigational Device Exemption (IDE) and*
* **Humanitarian Device Exemption (HDE) Programs*
*Food and Drug Administration*

## Objectives Today

- IDEs
- Early/Expanded Access Provisions
- Investigator and IRB Responsibilities
- HDEs

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## Section 520(g) of FD&C Act

_**Purpose of IDE:**_
-   *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*

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## Applicable Regulations

- 21 CFR Part 50:                     	**Informed Consent,                 ****	****Human Subject Protections**
- 21 CFR Part 56:                     	**Institutional Review Boards **
- 21 CFR Part 812:           	**Investigational Device Exemptions**

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## 21 CFR Part 50:  Informed Consent

- Required for ALL participants in ALL clinical studies in U.S.
- Exception:  Emergency Research        (see §50.24)
- Legally authorized representative
**Written **(with few exceptions)
- Sponsor and IRB must monitor

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## Informed Consent Elements (§50.25)

- Study involves research; purpose, procedures,  	duration of the study
- Risks or discomforts
- Expected benefits
- Alternative procedures
- Extent of confidentiality
- Any compensation if available
- Whom to contact for questions
- Participation is voluntary
- Others when appropriate (e.g., risk to fetus)
**No “exculpatory” language**
**Laymen’s terms**

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## 21 CFR Part 56:  IRBs  

_**Extremely important**_** role in the protection of rights, safety and welfare of human research subjects**
- Study risk determinations
- Specific constitution of diverse members (scientists, physicians, clergy, laypeople, attorneys)
- Review protocols, adverse events
- Lots of guidance from FDA and HHS

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## “IDEs 101”

##  Approved IDEs are Exempt from:

- Misbranding regs
- Registration
- Performance Standards
- 510(k) regs
- PMA regs

- GMPs
- Color Additive requirements
- Banned Devices regs
- Restricted Device requirements

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## 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

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## Definitions

- Investigational _Device_
- Is still in the developmental stage
- Object of a clinical investigation is to determine safety and efficacy
- Is not considered to be in commercial distribution
- Investigational _Use_
- Clinical evaluation of an already legally marketed device for a _new_ intended use

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## Provisions of the IDE Regulation

- All clinical investigations subject to Part 812 must be _approved_ before they can begin
- _Assigns responsibilities_ to all participants in clinical investigation
- All subjects in the investigation must give _informed consent_

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## Studies Subject to Part 812

- ALL studies conducted in human subjects in the United States done to:
- Support device marketing application: PMA, HDE or 510(k), OR
- Collect safety and effectiveness information   (e.g., for a new intended use of a legally marketed device), OR
- Evaluate unapproved devices or new intended use of approved device (_even if no marketing application planned_) by sponsor-investigator

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## Studies Exempt from Part 812    (no IDE needed)

- 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 devices
- Combinations of legally marketed devices
- Custom devices (NARROWLY defined)
- OUS Studies:  **Declaration of Helsinki**

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## Significant Risk (SR) Study

-    Presents a potential serious risk to the health, safety, and welfare of a subject and is:
- an implant; OR
- used in supporting or sustaining human life; OR
- of substantial importance in diagnosing, curing, mitigating, or treating disease or preventing impairment of human health

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## Significant Risk IDEs 

- Sponsor submits IDE application to FDA
- FDA approves, conditionally approves or disapproves IDE within 30 calender days
- Sponsor obtains IRB approval
- After both FDA and IRB approve the investigation, study can begin

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## Required Elements of an IDE

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

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## Prior Investigations

- Reports of _**ALL**_ testing
- Bibliography of all relevant publications
- Copies of _**published/unpublished adverse information**_
- Summary of all unpublished information
- Compliance with GLPs

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## Investigational Plan

- Purpose
- Name and Intended Use of device
- Objectives and Duration of study
- Protocol
- Methodology and an analysis demonstrating scientific soundness
- Number of subjects and sites
- Inclusion/exclusion criteria
- Statistical method(s)
- Case Report Forms

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## Investigational Plan

- 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

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## Manufacturing*

- Manufacturing Information
- Processing, Sterilization
- Packaging
- Storage
- Installation
- * IDEs are exempt from Good Manufacturing Practices                          (except Design Controls)

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## Investigator Information

- Copy of the investigator agreement
- Investigator CV(s)
- Relevant experience
- Statement of the investigator’s commitment
- Certification that all will sign the agreement

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## Sales Information

- State whether the device is to be sold
- Explain why sale does not constitute commercialization

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## Labeling Requirements

- Name of Device
- Name/Address of Manufacturer
- Quantity (if appropriate)
- Warnings, Hazards, Known Adverse Events, Interfering Devices, Contraindications, Precautions
- “CAUTION - Investigational device.  Limited by Federal (or United States) Law to investigational use.”

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## Informed Consent Elements (§50.25)

- Study involves research; the purpose, procedures, & duration of the study
- Risks or discomforts
- Expected benefits
- Alternative procedures
- Extent of confidentiality
- Any compensation if available
- Whom to contact for questions
- Participation is voluntary
- Others when appropriate (e.g., risk to fetus)
**No “exculpatory” language**
**Laymen’s terms**

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## IDE Supplement Needed? 

- Change to the investigational plan affecting:
- scientific soundness of study
- rights, safety, or welfare of the subjects
- Significant change(s) to the device
- Expansion of study (add sites and/or subjects)
- Unanticipated adverse events _or unanticipated frequency of anticipated adverse events_
- Suspension of the study
- Progress, Annual, Final Reports

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## Non-significant Risk IDEs 

- 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
- Abbreviated IDE requirements
- No IDE submission to FDA

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## Early/Expanded Access Provisions

- Emergency Use
- Single Patient/Small Group
- Treatment Use
- Continued Access

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## Emergency Use: 21 CFR 812.35(a)(2)

- Life-threatening or serious condition; no alternative
- Before or during an IDE
- Prior FDA approval not required – no time!
- Limited access

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## Single Patient/Small Group*

- Serious condition
- Usually during an IDE; no alternative
- FDA approval required
- Limited access

*** ****Also referred to as “Compassionate Use”**

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## Treatment IDE: 21 CFR 812.36

- Life-threatening or serious condition
- During an IDE; no alternative
- Prior FDA approval required
- Wide access

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## Continued Access

- Any condition
- After IDE _complete _(intended to bridge the gap to marketing)
- FDA approval required
- Controlled access:  same investigational sites and investigators at ~ enrollment rate as pivotal study

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## EARLY/

**EXPANDED **
**ACCESS**

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## Investigator and IRB Responsibilities in Clinical Trials

- “Alphabet Soup” of Clinical Trials
- Investigator Responsibilities
- IRB Responsibilities
- Adverse Event & Other Reporting

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## “Alphabet Soup”

- Acronyms
- CI:  Clinical investigator
- IRB:  Institutional Review Board
- DMC:  Data Monitoring Committee
- CRO:  Contract research organization
- SR/NSR:  Significant vs. non-significant risk
- IDE:  Investigational Device Exemption (Device research application to FDA)
- 510(k), PMA, HDE:  Marketing applications

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## “Alphabet Soup” continued

- Regulations
- Part 812 -- IDE
- Part 50 -- Informed Consent
- Section 50.25 -- elements of IC
- Section 50.23 -- IC waiver (emergency)
- Section 50.24 -- IC waiver (emergency research)
- Part 56 -- IRB
- Part 54 -- Financial Disclosure

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## Investigator Responsibilities

- Sign Investigator Agreement-- Commit to:
- Follow protocol, FDA regs, and IRB/FDA conditions of approval
- Provide financial disclosure or certification to sponsor initially and updates
- Obtain IRB Approval
- Initially, for study changes, & at least annually

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## Investigator Responsibilities

- Conduct Study:
- Obtain informed consent from subjects
- Enroll subjects, follow protocol, collect data (fill out CRFs)
- Submit required reports to IRB and sponsor

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## IRB Responsibilities

- Determine jurisdiction
- FDA, NIH,“basic physiologic research”
- Determine the risk
- Minimal risk (expedited IRB procedures)
- NSR or SR (unless FDA has already decided)
- Review study
- Approve, approve w/modifications, disapprove

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## IRB Responsibilities

- Review informed consent
- For SR device trials, FDA has reviewed for compliance w/section 50.25
- Review study changes & adverse events;  do continuing review
- Submit reports to sponsor & FDA

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## Reports

- Anticipated Adverse Events
- Unanticipated Adverse Events
- Other Reportable Events

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## Anticipated Adverse Events

- No definition in IDE regulation:    Those prospectively identified in the investigational plan in IDE
- Reported by sponsor to FDA, CIs, and IRBs in progress reports

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## Anticipated AEs

- Reports used by FDA to monitor study -- assess risk/benefit relationship as study progresses
- If risk/benefit profile changes or new AEs are detected, may need to modify informed consent document, protocol, etc.

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## Unanticipated Adverse Event (UAE)

-    Any serious adverse event or any life-threatening problem or death _caused by, or associated with_, a device, _if_ that effect, problem, or death was not previously identified as anticipated in nature, severity, or frequency of incidence in the investigational plan...

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## Unanticipated Adverse Event continued

**  **_Or_ any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of the subjects. (Section 812.3(s))

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## Reporting Requirementsfor Unanticipated Adverse Events

- CI reports to sponsor & IRB w/in 10 days of learning of the effect
- Sponsor must “immediately” conduct evaluation of the effect to determine if the UAE presents an “unreasonable risk to subjects”

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## Reporting Requirements for UAEs

- Sponsor determines if study (and any other
- studies) should:
- _Continue_; report evaluation to FDA, all IRBs, and all CIs w/in 10 days of being notified of the effect
- _Terminate_: report to FDA w/in 5 days of making the determination and not later than 15 days of learning of the effect

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## Other Reportable Events

- Failure to obtain informed consent; Emergency use; Protocol deviations
- CI  Sponsor and IRB
- Sponsor  FDA
- Withdrawal of IRB approval
- IRB  CI, Institution, & FDA
- CI  Sponsor  FDA & _all_ IRBs

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## Summary

-   ALL participants in a clinical trial (CI, IRB, Sponsor, Monitor and FDA) need to do their part so that the risks to subjects are minimized and so that the trial results in meaningful data.

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## Humanitarian Use Devices (HUDs) and Humanitarian Device Exemptions (HDEs):“Orphan Devices”

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## HDE Requirement (21 CFR 814 Subpart H)

-    _**Probable benefit**_** to health **_**outweighs the risk**_** of injury or illness from its use, **_**taking into account the probable risks and benefits of currently available devices or alternative therapies**_

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## Section 520(m) of the       Food, Drug and Cosmetic Act

-   “... to encourage the discovery and use of   devices intended to benefit patients in            the treatment and diagnosis of diseases            or conditions that affect fewer than           4,000 individuals in the United States.” [yearly]

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## Statute to Regulation

- Post-Safe Medical Devices Act (SMDA) of 1990, proposed rule based on modified IDE regulation
- Final rule June 1996 - new subpart H added to existing PMA regulation          (21 CFR 814)
- Effective October 1996
- Modified by Food and Drug Modernization Act (FDAMA) November 1997

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## HUDs

- FDA’s Office of Orphan Products makes HUD designation based on:
- Population < 4000/year in U.S.
- No comparable device or alternative treatment

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## Intent of HDE Provisions

- Provide incentive for development of devices
- intended for treatment or diagnosis, _**in small **_
_**patient populations where otherwise a **_
_**device manufacturer’s R&D costs could **_
_**exceed market returns**_

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## HDE

_**NO**_** effectiveness required**
_**NO**_** clinical data required**

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## Statutory Conditions

- Approval authorizes marketing of HUD
- IRB approval required before device used
_**Latitude**_ in how IRB elects to oversee use of HUD at their institution; individual cases, per protocol w/i  FDA- approved indication, or no restrictions
- Emergency and/or Compassionate Use outside approved indication:  recommend same patient protection measures as for IDE device
- Local IRB may approve or defer

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## Statutory Conditions

- Labeling must clearly identify device as HUD, and that effectiveness for that indication has not been demonstrated
- Amount charged cannot exceed cost of research, development, manufacturing and distribution

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## Approval of an HDE

- Based on:
- Data
- Preclinical testing
- OUS marketing information
- Published literature on disease and/or device
- Clinical _information_, if any
- What is known about the disease
- Disease effects
-  Prognosis
- What is known about the alternatives        (if any)
- Benefits vs. risks

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## Key Points

-   HDE is marketing approval
-   Approval threshold like an IDE (safety and probable 	benefit)
-   IRB approval required
-   Informed Consent not required (not research)
-   No requirement to submit PMA to FDA
-   Can have multiple HDEs for same indication from 	different sponsors

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## Questions/Comments?

- _[elisa.harvey@fda.hhs.gov](mailto:elisa.harvey@fda.hhs.gov)_
- 301-594-1190 x 106

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