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Transcript of Successful Management of FDA IDE · PDF fileSuccessful Management of FDA IDE Studies...
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
3OCROffice of Clinical Research
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)
4OCROffice of Clinical Research
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
5OCROffice of Clinical Research
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
6OCROffice of Clinical Research
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))
7OCROffice of Clinical Research
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
8OCROffice of Clinical Research
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
9OCROffice of Clinical Research
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))
10OCROffice of Clinical Research
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
11OCROffice of Clinical Research
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))
12OCROffice of Clinical Research
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
13OCROffice of Clinical Research
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
14OCROffice of Clinical Research
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
15OCROffice of Clinical Research
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
16OCROffice of Clinical Research
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
17OCROffice of Clinical Research
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
18OCROffice of Clinical Research
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
21OCROffice of Clinical Research
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.
22OCROffice of Clinical Research
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
23OCROffice of Clinical Research
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
24OCROffice of Clinical Research
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)
25OCROffice of Clinical Research
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
26OCROffice of Clinical Research
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
27OCROffice of Clinical Research
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
28OCROffice of Clinical Research
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
29OCROffice of Clinical Research
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
30OCROffice of Clinical Research
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
31OCROffice of Clinical Research
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
32OCROffice of Clinical Research
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
33OCROffice of Clinical Research
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
34OCROffice of Clinical Research
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
35OCROffice of Clinical Research
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
36OCROffice of Clinical Research
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
37OCROffice of Clinical Research
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
38OCROffice of Clinical Research
Other Types of IDE Submissions Emergency Use
Compassionate Use
Treatment Use
Continued Access
40OCROffice of Clinical Research
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)
41OCROffice of Clinical Research
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
42OCROffice of Clinical Research
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
43OCROffice of Clinical Research
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
44OCROffice of Clinical Research
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
45OCROffice of Clinical Research
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
46OCROffice of Clinical Research
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
47OCROffice of Clinical Research
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
48OCROffice of Clinical Research
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
49OCROffice of Clinical Research
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
50OCROffice of Clinical Research
Unanticipated Adverse Device Effects Must be reported to the Penn IRB
• Within 3 working days
Must be reported to the FDA
• Within 10 working days
51OCROffice of Clinical Research
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
52OCROffice of Clinical Research
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
53OCROffice of Clinical Research
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
54OCROffice of Clinical Research
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
55OCROffice of Clinical Research
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
56OCROffice of Clinical Research
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
57OCROffice of Clinical Research
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)
58OCROffice of Clinical Research
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
60OCROffice of Clinical Research
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.
61OCROffice of Clinical Research
Device Documentation Both the site(s) and the Sponsor must maintain appropriate
documentation related to the investigational devices• Shipping
• Storage
• Labeling
• Use
• Disposal/Return
62OCROffice of Clinical Research
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
63OCROffice of Clinical Research
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
64OCROffice of Clinical Research
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
65OCROffice of Clinical Research
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
67OCROffice of Clinical Research
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
68OCROffice of Clinical Research
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
69OCROffice of Clinical Research
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
70OCROffice of Clinical Research
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