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OCROffice of Clinical Research

Successful Management of FDA IDE Studies

Investigational Device Exemption (IDE)

March 20, 2014

Melissa ByrnCR Monitoring ManagerInna StrakovskySr. CR Monitoring SpecialistOffice of Clinical Research

2OCROffice of Clinical Research

Learning Objectives Determine when an IDE is required

Know how to file an IDE Application

Identify strategies for IDE management

Establish a plan for device management and accountability

Interpret common IDE audit findings


What is a medical device? Instrument/machine/apparatus/related article which is:

• Intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease

• Intended to affect the structure/function of the body

– and does not achieve its primary purpose through chemical action (i.e. not a drug)


What is an investigational device? A device that is the object of an investigation

All clinical investigations of devices must have an approved IDE or be exempt from IDE regulations


What is an IDE? Investigational Device Exemption (IDE) Application

• Request for authorization from the FDA to test an investigational device for safety and effectiveness in humans in a clinical study

IDE Regulatory Sponsor is:

• Person or company who has filed the IDE with the FDA

Regulations: 21 CFR 812


DefinitionSponsor

A person/company who initiates, but does not actually conduct, the investigation. The investigational device is administered, dispensed, or used under the immediate

direction of another individual. (21 CFR 812.3(n))


IDE Sponsor Responsibilities Obtain FDA approval of IDE application prior to study start

Ensure IRB approval is obtained at all sites

Select qualified investigators

Obtain signed agreements from all investigators

Obtain financial disclosure information from all investigators

Train Penn staff/other sites on protocol requirements

Ensure investigation is conducted according to the general investigational plan and protocol at all sites


IDE Sponsor Responsibilities Ensure all significant new information is promptly

communicated to the FDA and the IRB

Maintain accurate, complete, and current records

Select qualified monitors and ensure proper monitoring of the investigation at all sites (if applicable)

Evaluate any unanticipated adverse device effects

Control the investigational device and ensure it is properly labeled

Provide reports to the FDA and IRB


DefinitionInvestigator

The individual who conducts a clinical investigation. An individual under whose immediate direction the test article is administered or dispensed to, or used involving, a subject. If a team is involved, the leader is the investigator. (21 CFR 812(i))


IDE Investigator Responsibilities Protect rights, safety, welfare of subjects

Ensure investigation is conducted according to signed agreement, investigational plan, applicable regulations

Ensure informed consent is obtained

Control devices under investigation

Communicate appropriately with the Sponsor, IRB, and research team

Follow the Sponsor’s instructions for investigational device disposal or return

Disclose accurate financial information to the Sponsor

Maintain accurate, complete, and current records


DefinitionSponsor-Investigator

An individual who both initiates and actually conducts an investigation. The obligations of a sponsor-investigator include those of an investigator and those of a sponsor. (21 CFR 812.3(o))


Significant Risk Device An investigational device that: presents a potential for serious

risk to the health, safety or welfare of a subject AND• Is intended as an implant OR• For use supporting or sustaining human life OR• Substantial importance in diagnosing, curing, mitigating, or treating

disease or otherwise preventing impairment of human health OR Requires an IDE Determination of SR must be confirmed by IRB


Non-Significant Risk Device Does not meet the criteria of a SR device

Does not require an IDE, but must meet certain regulatory requirements

• Examples: labeling requirements, IRB approval, informed consent, monitoring, etc.

Study must be approved by an IRB – must agree on NSR determination

21 CFR 812.2(b) Abbreviated requirements


Devices Exempt from IDE Regulations Distributed, marketed, and used according to their approved

indication

Substantially equivalent devices that go through a FDA review process

Some in-vitro diagnostic devices

Device undergoing consumer preference or modification testing

Custom device not intended for commercial distribution


FDA Guidance

Significant Risk and Non-Significant Risk Medical Device Studies

U.S. Department of Health and Human Services Food and Drug Administration

Center for Devices and Radiological Health (CDRH)

January 2006

http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126418.pdf


Request for FDA Feedback FDA has mechanisms for providing feedback before a

submission (“Q-Sub”)

Formal written request from a sponsor for feedback from FDA via a formal written response, teleconference, or meeting

Purpose: provide opportunity for sponsor to obtain FDA feedback prior to an IDE submission or marketing application

Timeframe: 75-90 days


Pre-Submission Meeting with FDA Pre-Submission meeting can be helpful if:

• New device involves novel technology

• “First of a kind” indication

• New indication for existing device

• New device does not clearly fall within an established regulatory pathway

• Specific protocol design questions

• Clarification of how much existing data may be leveraged in future PMA submission


Types of Pre-Submissions Pre-IDE Request for feedback from FDA

• Determination Meeting

– Identify types of scientific evidence necessary to demonstrate device effectiveness

– For applicants who plan to submit a PMA down the line or would benefit from additional input from FDA on trial design or pre-clinical testing

• Study Risk Determination

– Assistance with SR, NSR, exemption determination

• Agreement Meeting

– Any applicant investigating a Class III device or any implant

– Reach agreement on key parameters of investigational plan


Request for Feedback Using FDA Form 3514


Preparing an IDE Application


You Need an IDE…Now What?

Submit protocol to IRB

Develop IDE Application1

Once protocol is approved by IRB submit IDE to FDA2

FDA provides IDE number with date FDA received IDE

After 30 days IDE is in effect IF FDA has not requested modifications or

disapproved IDE

1This can happen at any time during the process

2You can submit the protocol to IRB and the IDE to FDA at the same time. However, if the protocol is revised based on IRB stipulations, you will need to resubmit to FDA.


IDE Application Content Cover Letter Report of prior investigations (animal, lab, clinical testing of

device) Study protocol Method, facilities and controls for the manufacturing and

processing, packing and storage of the device Investigator agreements Names and addresses of all investigators and sites Names and addresses of all IRBs that will be reviewing

investigation Amount charged for the device, if any, and rationale for why it

isn’t commercializing device at that price Product labeling Informed Consent Forms Additional information


IDE Content: Cover Letter Statement that information provided is an original IDE

submission

Device name and intended use

Sponsor name and contact information

Manufacturer information

Summary of Pre-Sub meetings or discussions with the FDA

Any requests for waivers

Referenced files (PMA, 510(k), IDE, or device master files)

Statement that eCopy contains an exact copy of the printed application (or explanation of why it does not)

Sponsor’s signature


IDE Content: Report of Prior Investigations Comprehensive report of prior lab, animal and clinical testing

of the device• Positive or negative• Published or unpublished

Should justify the proposed investigation Bibliography of publications Statement that lab data was collected in compliance with Good

Laboratory Practice (GLP) or brief statement of noncompliance (if applicable)


IDE Content: Investigational Plan Purpose

Protocol

Risk Analysis

Device description

• Address each component, ingredient, property, principle of operation

• Anticipated changes in device over course of investigation


IDE Content: Investigational Plan Monitoring Procedures

• Description of procedures

• Name and address of monitor

• Single-site Sponsor-Investigators are not required to submit a Monitoring Plan

– FDA assumes the investigator will monitor the study (unless specified otherwise)

• If sites are added to a single-site Sponsor-Investigator IDE

– Monitoring plan will need to be submitted to the FDA


IDE Content: Device Manufacturing Information Description of methods, facilities and controls used for:

• Manufacturing

• Processing

• Packing

• Storage

• Installation (as applicable)

Include • Sufficient information to allow assessment of good manufacturing

practices and quality of controls

• Copies of all device labeling

• Amount to be charged for the device, if any, with justification


IDE Content: Investigator Agreement Example of agreement investigators will sign

• No FDA-specified format

• Includes statements related to the responsibilities of investigators in conducting a protocol under an IDE

Also include list of the names and addresses of all investigators

Certification statement that all investigators who participate have signed the agreement and that no investigators will be added until an agreement has been signed


IDE Content: IRBs and ICFs Include name and address of all IRBs that have or will be

asked to review the study

• Name of IRB Chairperson, if disclosed by IRB

Certification of IRB action/decision (when available)

Sample of the consent form(s) that will be provided to sites


FDA Forms There are no FDA Forms to accompany the IDE application

• Certain information still needs to be collected and retained

• For example, may need to register on ClinicalTrials.gov

– But FDA does not require the submission of a Form 3674 with an IDE application


Preparing to Submit the IDE 1 paper copy + 2 electronic copies

• eCopy of the paper submission on a CD, DVD, or flash drive

IDE Sponsor must be located in the U.S.

IDE Sponsor must be the person submitting the IDE application • Unless authorization in writing for another to submit on their behalf

FDA Guidance for Industry: eCopy Program for Medical Device Submissions. October 10, 2013http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM313794.pdf


Common IDE Submission Problems Inadequate report of prior investigations

• Limited rationale and description of lab and animal studies

• Failure to identify relevant information in literature search summary

Inadequate protocol / design plan

• Unclear or underdeveloped study objectives

• Unacceptable risks to subjects likely based on plan

• Inadequate monitoring plan

Design and manufacturing deficiencies

• Inadequate characterization of the device and its operation

• Validation testing not sufficient


FDA Action on IDE Applications FDA will notify Sponsor in writing of the date it receives the

IDE application

IDE becomes effective 30 days after the submission has been received by FDA • Unless FDA has informed the sponsor prior to 30 days that the IDE is

approved, approved with conditions, or disapproved


FDA Approval of an IDE FDA decision letter will include:

• IDE number

• Strict subject enrollment limits

• Device Categorization (A or B)

• Possible conditions or recommendations that can be addressed or considered

– But enrollment may begin


Device Categorization by FDA FDA will categorize the device as either Category A or B

• For purposes of reimbursement under the Medicare program

FDA will copy the Health Care Financing Administration on all approval and conditional approval letters

• This will notify Medicare of the device category assigned by the FDA


FDA Approval with Conditions Issues do not preclude FDA from granting approval

• FDA letter will address conditions

Sponsor must submit additional information within 45 days from the date of the FDA’s Decision Letter

• Submit via an IDE Supplement

Sponsor may begin enrollment once IRB approval had been received unless clinical hold


Disapproval of IDE Sponsor may not initiate clinical investigation until an IDE

amendment is submitted

• Must address deficiencies identified in FDA letter

Reasons for Disapproval

• Failure to comply with regulations

• False or omitted information in application

• Risk-to-benefit ratio not appropriate

• Scientifically unsound

• Device concerns


Other Types of IDE Submissions Emergency Use

Compassionate Use

Treatment Use

Continued Access


Management of an IDE


Sponsor Responsibilities: Maintaining an IDE Financial Disclosure information (21 CFR 812.43)

Changes in Investigational Plan (21 CFR 812.35)

Unanticipated Adverse Device Effects (21 CFR 812.150)

Current List of Investigators (21 CFR 812.150)

Progress Reports (21 CFR 812.150)


Financial Disclosure Information Sponsors must collect financial disclosure information from

all Investigators conducting clinical research under the IDE

• Investigators, spouses, and dependent children

• Sub-investigators, spouses, and dependent children

Details on what must be collected: 21 CFR 54

Financial information is NOT submitted in the IDE application


How to Collect Financial Disclosures Create a questionnaire template

Include line for investigator’s signature/date

May use institutional financial disclosure information if Sponsor determines all relevant information is included

Retain collected disclosures separately from Master Regulatory File


FDA Guidance for Clinical Investigators, Industry, and FDA Staff

Financial Disclosure by Clinical InvestigatorsU.S. Department of Health and Human Services

Food and Drug Administration Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)Center for Devices and Radiological Health (CDRH)

February 2013

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM341008.pdf


Protocol Changes Protocol changes must be prospectively approved by the IRB

Protocol changes must be prospectively approved by FDA if they affect:

• Validity of data

• Risk-benefit ratio

• Scientific soundness

• Rights, safety, and welfare of subjects

Exceptions

• Emergencies

• Minor changes


Emergency Changes Protocol changes can be made without prior IRB and FDA

approval to

• Prevent apparent immediate hazards

• Protect the life or physical well-being of a subject

Must be reported to Penn IRB and FDA

• Within 5 working days


Protocol Modifications – FDA 5 Day Notice Developmental or manufacturing changes to device

• That do not constitute a significant change in design or basic principles of operation

• Made in response to information gathered during the investigation

Changes to the clinical protocol not affecting

• Validity or scientific soundness

• Rights/safety/welfare of subjects

• Study design or planned statistical analysis


Protocol Modifications – FDA 5 day notice Must be reported to FDA

• Within 5 working days after making the change

• Clearly identified as “notice of IDE change”

Clock starts when• Changed device distributed to investigators

• Sponsor notifies investigator of changes to protocol

• Sponsor-Investigator incorporates the change

Submit• Summary of the change

• Assessment/risk analysis undertaken

• Summary of supporting information for the change


Protocol Modifications – FDA annual report Minor protocol changes to:

• Risk analysis• Monitoring procedures• Labeling• Informed consent material• IRB information• Study purpose

Changes must not affect:• Validity of data• Risk-benefit ratio• Scientific soundness• Rights, safety, and welfare of subjects


Unanticipated Adverse Device Effects Any serious adverse effect on health or safety or any life-

threatening problem or death caused by, or associated with, a device

Not previously identified in nature, severity, or degree of incidence in the investigational plan or application

Any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects


Unanticipated Adverse Device Effects Must be reported to the Penn IRB


Must be reported to the FDA



Current List of Investigators Must submit to the FDA

• Current list of the names and addresses of all investigators

Submitted every 6 months

• First list submitted 6 months after FDA approval


Progress Reports Report of the investigation’s progress

Submit to the FDA annually

• OCR sends reminder emails

Send a copy of IDE Progress Report to the OCR


Other Reports Withdrawal of IRB approval

• Report to FDA and all IRBs within 5 working days

Withdrawal of FDA approval

• Report to all IRBs within 5 working days

Recall and device dispositions

• Notify the FDA and all IRBs any request for return, repair, or otherwise dispose of the device within 30 working days


Other Reports Informed consent

• Report to the FDA any investigator who used the device without obtaining informed consent within 5 working days

Final report• Notify the FDA within 30 working days of completion

• Submit final report within 6 months

Other• Provide accurate, complete, and current information about any aspect

of the investigation, upon request


Sponsor Records Correspondence with sites, monitors, FDA, and IRB

Records of device shipment• Name and address of consignee

• Type and quantity of device, date of shipment, batch #

Records of device disposition• Batch # of device(s) returned to sponsor or disposed

• Reason for and method of disposal

Signed investigator agreements including financial disclosure information

Records of complaints and adverse device effects


Strategies for Maintaining Sponsor Records Create a Master Regulatory file that will house information for

each site

• Separate sites by tab or binder

• Use same organization for each site file

• Include Sponsor review and acknowledgement of all versions of site informed consent forms

Identify person responsible for ensuring site files are up to date

Check in with sites frequently for updates


Investigator Records Correspondence with Sponsor, IRB, monitor

Records of receipt, use or disposition of device

Subject case history and exposure to device

• Documentation of informed consent

• All observations regarding UADE

Protocol and documentation of protocol deviations (including reason and date)


Monitoring A regulatory responsibility of sponsor-investigators under IDE

regulations (21 CFR 812)

Monitoring Plan

• Part of protocol

• Ensure device management and accountability is included in Monitoring activities


Device Management


Investigational Device Labeling Must be labeled according to federal regulations (21 CFR

812.5)

Label requirements

• Name of manufacturer, packer, or distributor

• Quantity of contents

• Investigational Device Statement

– CAUTION Investigational device. Limited by Federal (or United States) law to investigational use

• Description of relevant contraindications, hazards, warning, etc.


Device Documentation Both the site(s) and the Sponsor must maintain appropriate

documentation related to the investigational devices• Shipping

• Storage

• Labeling

• Use

• Disposal/Return


Device Shipping Records Sponsor Records

• Consignee name/address

• Device type and quantity shipped

• Shipment date

• Lot/Batch #

• Order fulfillment forms

Investigator Records• Date received

• Device type and quantity received

• Shipper and receiver

• Lot/Batch #

• Packing slips

• Order forms


Investigational Device Storage Secure location separate from clinical device supplies

• Accessible only to appropriate research personnel

• Operating room devices must be stored in the Stent Closet or the Radiofrequency Cabinet

IDS is able to assist in device storage and management in some circumstances


Device Accountability Records Documentation of Use

• Type

• Quantity

• Date/time Used

• Lot/Batch #

• Person documenting accountability

• Identifier of subject who received or was exposed to device

Documentation of Disposal/Return• Date/time

• Lot/Batch #

• Quantity

• Person who disposed/returned

• Reason for disposal/return

• Method of disposal

• Return shipping receipt


Device Management Best Practices Make copy of label from all device components

• Or keep original label from all device components

Ensure device information is entered into the electronic health record

Perform regular accountability checks

Coordinate closely with clinical care team so they know when a research case is occurring

• If non-routine data collection is required, work with clinical staff to determine who will collect data


Lessons Learned through Audits


Sponsor-Investigator Common Deficiencies Failure to follow the investigational plan

Inadequate subject protection

• Including informed consent issues

Protocol deviations

Inadequate recordkeeping

Inadequate accountability for the device


Resources Ad-hoc Training - www.med.upenn.edu/ocr/contact.shtml

• OCR is happy to meet with your team for protocol training or review of device management and best practices

OCR Website - www.med.upenn.edu/ocr/secure/education.shtml• Training opportunities

Penn Manual - https://somapps.med.upenn.edu/pennmanual/secure• Forms, Tools, and Templates • Overview of Regulations


OCR Core Services Research Compliance Review Program

• Routine and Non-Routine reviews for QA

• FDA & External audit assistance

• IDE Sponsor Qualification, FDA Applications and FDA Consultation

• Sponsor Training

• Research Consultative Services

• Protocol Reviews, Development of Monitoring Plans, Vendor Consultation


OCR Review: What We Check Initial IDE application and “may-proceed” letter

Informed consent forms

Confirmation of eligibility

Protocol adherence

Safety reporting

Device accountability

Regulatory documents

Confirmation of team training