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IDE Preparation and Maintenance:
Best Practices Workshop
Erika Segear Johnson, PhD, RAC
Regulatory Affairs Scientist
PART ...
Regulatory Affairs Office
2
Bruce Burnett, PhD, RAC (US, EU)
Director of Regulatory Affairs and Quality
Audrey Perry
Regul...
Our Website:
Templates and Instructions
 Best Practices Templates/Instructions
https://www.dtmi.duke.edu/dtmi-teams/regul...
PART 1: Medical Device Studies
and the IDE
• Definitions and Clinical Investigations
• IDE Exemption
• SR/NSR Determinatio...
What is a Medical Device?
513(a)(1) for the FD&C Act
Its an instrument, apparatus, implement, machine,
contrivance, implan...
What is a Medical Device?
6
What is a Clinical Investigation?
 A clinical Investigation is any experiment in which a
drug or device is administered, ...
When is a Clinical Investigation a
“Device Study”?
 If the objective of the clinical investigation is to
assess the safet...
What is an Investigational Device
Exemption (IDE)?
 An IDE is a regulatory submission to the FDA
that permits the clinica...
Are all clinical investigations that
use devices subject to regulatory
oversight by FDA?
 No. If the objective of the stu...
Clinical Investigation of a
Medical Device
Objective of the study is to assess the safety or
effectiveness of the device
B...
PART 1: Medical Device Studies
and the IDE
• Definitions and Clinical Investigations
• IDE Exemption
• SR/NSR Determinatio...
Investigations Exempt from
the IDE Regulations
• A legally marketed device when used in accordance
with its labeling.
• A ...
In Vitro Diagnostics –
Why are They Devices?
It is an instrument, apparatus, implement, machine,
contrivance, implant, in ...
In Vitro Diagnostics (IVD)
 IVD products are different from other medical devices
such that they don’t function ON or IN ...
In Vitro Diagnostics (IVD)
 The FDA considers the IVD to be the entire process
from specimen collection to results report...
Diagnostic Exemption Criteria
 Per 21 CFR 812.2(c), a diagnostic device study
is exempt of the IDE regulations when it:
-...
When is a Diagnostic Device
Noninvasive?
“A noninvasive device is one that does not, by
design or intention:
• penetrate o...
How Do I Determine if an Invasive
Sampling Procedure Presents a
Significant Risk?
“…we recommend that you base your risk d...
What Does Confirmation by
another Medically Established
Product Mean?
“…test results …should not influence patient treatme...
Diagnostic Exemption Criteria
 Per 21 CFR 812.2(c), a diagnostic device study
is exempt of the IDE regulations when it:
-...
PART 1: Medical Device Studies
and the IDE
• Definitions and Clinical Investigations
• IDE Exemption
• SR/NSR Determinatio...
Clinical Investigation of a
Medical Device
Objective of the study is to assess the safety or
effectiveness of the device
B...
Significant Risk Device Studies
 A significant risk device is one that:
• Is intended as an implant and presents a potent...
http://tinyurl.com/48ywrw8
25
Significant Risk Device Studies
Study Risk Determination
26
Sponsor Risk Assessment
(based on clinical protocol, description of device, reports of prior
i...
Non-Significant Risk (NSR)
Device Studies
• NSR device studies do not need an IDE application
approved by FDA.
• The IRB s...
Abbreviated IDE Requirements
(21 CFR 812.2 (b)(1))
• Label the device properly (21 CFR 812.5)
• Obtain and maintain IRB ap...
Study Risk Determination
29
Sponsor Risk Assessment
(based on clinical protocol, description of device, reports of prior
i...
• Q-Submission: Study Risk Determination
• Device Description and Clinical Protocol
• Recommend Cover Letter- Highlight Na...
Study Risk Determination
31
Sponsor Risk Assessment
(based on clinical protocol, description of device, reports of prior
i...
PART 1: Medical Device Studies
and the IDE
• Definitions and Clinical Investigations
• IDE Exemption
• SR/NSR Determinatio...
IDE Content (21 CFR 812.20 (b))
1. Cover Sheet – form 3514
2. Name and Address of the Sponsor
3. Report of Prior Investiga...
1. Cover Sheet – Form 3514
 Used voluntarily
 Same form is used for IDE, 510(k), PMA, meetings,
513(g), etc.
 Captures ...
IDE Content
21 CFR 812.20 (b)
1. Cover Sheet – form 3514
2. Name and Address of the Sponsor
3. Report of Prior Investigati...
3. Report of Prior Investigations
(21 CFR 812.27)
 General
 Prior clinical, animal, and laboratory testing
 Specific
 ...
IDE Content
21 CFR 812.20 (b)
1. Cover Sheet – form 3514
2. Name and Address of the Sponsor
3. Report of Prior Investigati...
4. Investigational Plan
(21 CFR 812.25)
 Purpose
 Name and intended use of the device
 Objectives and duration of the i...
IDE Content
21 CFR 812.20 (b)
1. Cover Sheet – form 3514
2. Name and Address of the Sponsor
3. Report of Prior Investigati...
5. Manufacturing Information
21 CFR 812.20(b)(3)
 FDA-Approved Device – off label and/or modified
 Non-FDA Approved Devi...
5. Manufacturing Information
21 CFR 812.20(b)(3)
41
 Refer to the approved product label
 Refer to the approved product ...
What is an LoA?
 This is a letter from a sponsor (company) to their IDE
(or IND or MF) stating that confidential informat...
5. Manufacturing Information
21 CFR 812.20(b)(3)
43
 Methods, facilities, and controls for:
 Manufacturing
 Packaging
...
IDE Content
21 CFR 812.20 (b)
1. Cover Sheet – form 3514
2. Name and Address of the Sponsor
3. Report of Prior Investigati...
6. Investigators Agreement
(21 CFR 812.43)
 Who is the investigator?
 The investigator is the individual who actually co...
6. Investigators Agreement
(21 CFR 812.43)
 CV of the investigator
 Statement of investigator’s relevant experience
 If...
IDE Content (21 CFR 812.20 (b))
1. Cover Sheet – form 3514
2. Name and Address of the Sponsor
3. Report of Prior Investiga...
Original IDE Submission
 3 copies of your application are required.
 Since Dec 2012 eCopy necessary!!
 An exact duplica...
49
Creating an eCopy
 Non-Volume Based eCopy
 001_G010101_Annual report 2014.pdf
 Volume Based eCopy
 VOL_001_Cover lette...
IDE Submission
IDE should be sent to:
Food and Drug Administration
Center for Devices and Radiological Health
Document Mai...
FDA Review Process
 Sponsors are notified of the date that
FDA receives the original application.
 IDE number is assigne...
FDA Review Process
 Within 30 calendar days of the receipt date, FDA may
grant:
- IDE Approval
- IDE Approval with Condit...
Let’s Take a Break!
54
IDE Preparation and Maintenance:
Best Practices Workshop
Erika Segear Johnson, PhD, RAC
Regulatory Affairs Scientist
PART ...
PART 2: IDE Maintenance and
Additional Device Studies
• IDE Maintenance
• Expanded Access Programs
• Algorithms and Mobile...
Once you have an active IDE…
 Make sure that you also have IRB
approval(s) in place
 Register trial at the ClinicalTrial...
Requirements for IDE
Modifications
 Modifications to the Investigational Plan (device or
clinical protocol) need to be su...
IDE Modifications
 Changes that require prior approval (30-day
reply from FDA):
 Changes that could impact validity of d...
 Changes that require 5-day notice to FDA:
• Emergency change
• Changes that do not affect scientific soundness or
the ri...
 Changes that can be sent to FDA as part of the
annual report:
• Minor changes to study materials that do not affect
the ...
Supplements/Reports to FDA
FDA
Unanticipated Adverse Device Effects 10 working days
Withdrawal from FDA/IRB approval 5 wor...
IDE Maintenance - UADEs
 Unanticipated Adverse Device Effect - Any serious
adverse effect on health or safety or any life...
Progress/Final Report
1. Basic information
2. Study Progress
- Brief summary of the study progress
- Number of investigato...
3. Risk Analysis
- Summary of any new adverse information (since the last
progress report) that may affect the risk analys...
IDE Submission Types
 Supplements
 Reports
 Amendments
http://tinyurl.com/lxrmd9u
Supplements
 Approval for change (prior-approval, 5-day notice)
 Request approval for a new study under the same IDE
 R...
Reports
 Provide biannual investigator/IRB information
 Annual reports
 Failure to obtain ICF
 Notify the FDA of the E...
Amendments
 Any repose to deficiency letter is an amendment.
Amendment may be submitted to each of the 3
parent document ...
Terminating/Closing an IDE
 If IDE is not yet approved: request a withdrawal
 If you have an active IDE, but no subjects...
PART 2: IDE Maintenance and
Additional Device Studies
• IDE Maintenance
• Expanded Access Programs
• Algorithms and Mobile...
Additional Types of
Device Studies
 Early and expanded access (http://tinyurl.com/yhkv7o2)
 Emergency Use of Unapproved ...
 Single Patient or Compassionate Use IDE:
 Serious condition for which device is the only option
 Patient does not meet...
 Continued Access:
 Trial is completed and marketing application is being prepared
 There is a public health need for t...
 Humanitarian Device Exemption (21 CFR 814.100)
 An Humanitarian Use Device (HUD) is a device that is
intended to benefi...
Before
IDE
IDE
Approval
IDE
Completion
Marketing
Approval
Emergency Use
Traditional IDE
Compassionate Use
Treatment Use
Co...
PART 2: IDE Maintenance and
Additional Device Studies
• IDE Maintenance
• Expanded Access Programs
• Algorithms and Mobile...
Algorithm as a Medical Device
 An algorithm can be defined as combination of
multiple variables using an interpretation
f...
In Vitro Diagnostic
Multivariate Index Assays
(IVDMIA)
 IVDMIA is a device that:
1) “Combines the values of multiple vari...
IVDMIA Examples
Examples of what the FDA considers IVDMIA:
 A device that integrates quantitative results from
multiple i...
Examples of what the FDA DOES NOT consider
IVDMIA:
 Common clinical calculations (e.g., creatinine clearance,
cholesterol...
Regulation of IVDMIAs
 Device classification is based on the intended
use and level of controls necessary to assure
safet...
 Any calculation that would have a multiple inputs and would
result in an output that will be used to assign the patient ...
Mobile Medical Applications
Mobile Application (Mobile App)
 “. . .defined as a software application that can be executed...
Risk Based Approach for
Mobile Apps
MAs that do not
meet the
definition of a
medical device
MAs that may
meet the
definiti...
Mobile Apps that are Not
Medical Devices
Mobile Apps that could be used in a healthcare
environment, in clinical care or p...
Mobile Medical Apps: Focus of
FDA Regulatory Oversight
Mobile Apps that meet the definition of a medical device
and can po...
Enforcement Discretion
Mobile Apps that may meet the definition of a medical
devices for which the FDA intends to exercise...
Let’s Practice…
89
Scenario 1
 An investigator is assessing the efficacy of an algorithm
(software) which would predict if a patient should ...
 Is the algorithm/software used in this scenario a
device?
 Yes. The algorithm is “intended” for use:
In the diagnosis o...
 Can this study be IDE exempt or does it require an abbreviated or full
IDE?
Per 21 CFR 812.2 (c), a diagnostic device st...
Scenario 2
 The objective of the study is to assess which of 2
FDA-approved imaging devices provides better
images for di...
 Is this a device study?
Yes. The objective of the study is to assess the safety
and/or efficacy of the device. Therefor...
 An investigator is evaluating the utility of a software
program for motion correction in MRI imaging.
 The MRI pulse se...
 Is there a medical device in this study?
 Yes. The software system is “intended” for use in the
diagnosis of disease or...
 Can this study be IDE exempt or does it require an abbreviated or full
IDE?
Per 21 CFR 812.2 (c), a diagnostic device st...
 Mobile apps that use video and video games to
motivate patients to do their physical therapy
exercises at home.
 Not a ...
99
Scenario 5
 A mobile app which uses a electrodes and
sensors attached to the mobile platform to
measure physiological ...
Useful Websites:
CDRH Learn Course List
http://www.fda.gov/Training/CDRHLearn/
default.htm
Device Advice:
http://www.fda.g...
Thank you!
erika.segearjohnson@duke.edu
or
(919) 668-4639
101
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IDE Application Process and Best Practices

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CFTCC
2015 Learning about the IND/IDE Process and Reimbursements for New Drugs and Devices

Erika Segear Johnson, PhD, RAC
Regulatory Affairs Scientist
Duke Translational Medicine Institute

Introduces the basics of filing an Investigational Device Exeption (IDE) Application with the FDA

Published in: Engineering
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IDE Application Process and Best Practices

  1. 1. IDE Preparation and Maintenance: Best Practices Workshop Erika Segear Johnson, PhD, RAC Regulatory Affairs Scientist PART 1: Medical Device Studies and the IDE PART 2: IDE Maintenance and Additional Studies 1
  2. 2. Regulatory Affairs Office 2 Bruce Burnett, PhD, RAC (US, EU) Director of Regulatory Affairs and Quality Audrey Perry Regulatory Document Specialist Erin O’Reilly, PhD, RAC Director of Regulatory Affairs And Operations Jelena P. Berglund, PhD, RAC Director of Regulatory Affairs Head of Regulatory Training Amanda Parrish, PhD, RAC Director of Regulatory Affairs and Quality Erika Segear Johnson, PhD, RAC Regulatory Affairs Scientist Preeti Chugha, PhD, PMP, RAC Regulatory Affairs Scientist Carey Hobbs, PhD, RAC Regulatory Affairs Scientist Susan Nagorski Staff Assistant Training Program Coordinator Kristen Foss, PhD Regulatory Affairs Scientist
  3. 3. Our Website: Templates and Instructions  Best Practices Templates/Instructions https://www.dtmi.duke.edu/dtmi-teams/regulatory- affairs/indide-template-documents  Recorded Webcasts https://www.dtmi.duke.edu/dtmi-teams/regulatory- affairs/regulatory-affairs-webinars 3
  4. 4. PART 1: Medical Device Studies and the IDE • Definitions and Clinical Investigations • IDE Exemption • SR/NSR Determination and the IDE • IDE Preparation and Submission 4
  5. 5. What is a Medical Device? 513(a)(1) for the FD&C Act Its an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or other similar or related article or component part or accessory which: • is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease • is intended to affect the structure or any function of the body  achieve its primary intended purposes through physical action and NOT chemical or metabolic action 5
  6. 6. What is a Medical Device? 6
  7. 7. What is a Clinical Investigation?  A clinical Investigation is any experiment in which a drug or device is administered, dispensed to, or used involving, one or more human subjects, except for the use of a marketed product in the course of medical practice.  This would include clinical studies in which a subject is assigned to specific intervention according to a study protocol.
  8. 8. When is a Clinical Investigation a “Device Study”?  If the objective of the clinical investigation is to assess the safety and/or effectiveness of a medical device, then the study is a device study and is subject to regulatory oversight by the US Food and Drug Administration (FDA).  21 CFR 812 (Investigational Device Exemption)
  9. 9. What is an Investigational Device Exemption (IDE)?  An IDE is a regulatory submission to the FDA that permits the clinical investigation of devices.  An approved IDE allows: • an investigational device to be used in a clinical study in order to collect safety and effectiveness data. • a device to be shipped lawfully for the purpose of conducting clinical investigations. 9
  10. 10. Are all clinical investigations that use devices subject to regulatory oversight by FDA?  No. If the objective of the study is not to test the safety or effectiveness of the device, then the study would not fall within the scope of 21 CFR 812.  Devices used as “tools” 10
  11. 11. Clinical Investigation of a Medical Device Objective of the study is to assess the safety or effectiveness of the device Be exempt of the IDE regulations (21 CFR 812.2 (c)) Have an approved IDE a) abbreviated IDE (21 CFR 812.2 (b)) b) IDE (21 CFR 812.20)
  12. 12. PART 1: Medical Device Studies and the IDE • Definitions and Clinical Investigations • IDE Exemption • SR/NSR Determination and the IDE • IDE Preparation and Submission 12
  13. 13. Investigations Exempt from the IDE Regulations • A legally marketed device when used in accordance with its labeling. • A diagnostic device meeting 4 specified criteria. • A device undergoing a consumer preference testing, testing of modification or testing of a combination of two or more devices in commercial distribution if the testing is not for the purpose of determining safety or effectiveness. • A device intended solely for veterinary use. • A device for research on or with laboratory animals. • A custom device. (21 CFR 812.3(b)) (http://tinyurl.com/lbxl9k8)
  14. 14. In Vitro Diagnostics – Why are They Devices? It is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article or component part or accessory that:  Is intended for use in the diagnosis of disease or other condition, or in the cure, mitigation, treatment, or prevention of disease, or  Is intended to affect the structure or any function of the body  And achieve it's primary intended purposes through physical action and NOT chemical or metabolic action
  15. 15. In Vitro Diagnostics (IVD)  IVD products are different from other medical devices such that they don’t function ON or IN a patient.  IVDs are those reagents, instruments, and systems intended for use in diagnosis of disease or other conditions.  Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.  Blood, spinal fluid, tissue samples, serum, urine
  16. 16. In Vitro Diagnostics (IVD)  The FDA considers the IVD to be the entire process from specimen collection to results reporting:  Specimen collection and transport  Specimen preparation  Specimen examination/analysis  Method of calculating/reporting result
  17. 17. Diagnostic Exemption Criteria  Per 21 CFR 812.2(c), a diagnostic device study is exempt of the IDE regulations when it: - Is noninvasive - Does not require an invasive sampling procedure that presents a significant risk - Does not by design or intention introduce energy into a subject - Is not used as a diagnostic procedure without confirmation of the diagnosis by another medically established diagnostic product or procedure
  18. 18. When is a Diagnostic Device Noninvasive? “A noninvasive device is one that does not, by design or intention: • penetrate or pierce the skin or mucous membranes of the body, the ocular cavity, or the urethra; or • enter the ear beyond the external auditory canal, the nose beyond the nares, the mouth beyond the pharynx, the anal canal beyond the rectum, or the vagina beyond the cervical os (21 CFR 812.3(k)).”
  19. 19. How Do I Determine if an Invasive Sampling Procedure Presents a Significant Risk? “…we recommend that you base your risk determination on the nature of the harm that may result from sampling. For example, FDA considers sampling techniques that require biopsy of a major organ, use of general anesthesia, or placement of a blood access line into an artery or large vein (subclavian, femoral, or iliac) to present a significant risk.” “…Blood sampling that involves simple venipuncture is considered noninvasive, and the use of surplus samples of body fluids or tissues that are left over from samples taken for noninvestigational purposes is also considered noninvasive (21 CFR 812.3(k)).”
  20. 20. What Does Confirmation by another Medically Established Product Mean? “…test results …should not influence patient treatment or clinical management decisions before the diagnosis is established by a medically established product or procedure” “…If an investigational test uses a new technology or represents a significant technological advance, established diagnostic products or procedures may not be adequate to confirm the diagnosis provided by the investigational IVD.”
  21. 21. Diagnostic Exemption Criteria  Per 21 CFR 812.2(c), a diagnostic device study is exempt of the IDE regulations when it: - Is noninvasive - Does not require an invasive sampling procedure that presents a significant risk - Does not by design or intention introduce energy into a subject - Is not used as a diagnostic procedure without confirmation of the diagnosis by another medically established diagnostic product or procedure
  22. 22. PART 1: Medical Device Studies and the IDE • Definitions and Clinical Investigations • IDE Exemption • SR/NSR Determination and the IDE • IDE Preparation and Submission 22
  23. 23. Clinical Investigation of a Medical Device Objective of the study is to assess the safety or effectiveness of the device Be exempt of the IDE regulations (21 CFR 812.2 (c)) Have an approved IDE a) abbreviated IDE (21 CFR 812.2 (b)) b) IDE (21 CFR 812.20)
  24. 24. Significant Risk Device Studies  A significant risk device is one that: • Is intended as an implant and presents a potential for serious risk to the health, safety, and welfare of a subject. • Is used to support or sustain human life. • Is of substantial importance in diagnosing, curing, mitigating, or treating disease and/or otherwise preventing impairment of human health. • Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. 24
  25. 25. http://tinyurl.com/48ywrw8 25 Significant Risk Device Studies
  26. 26. Study Risk Determination 26 Sponsor Risk Assessment (based on clinical protocol, description of device, reports of prior investigations, subject selection criteria, etc.) Submit to IRB NSR Agreement Requires an abbreviated IDE
  27. 27. Non-Significant Risk (NSR) Device Studies • NSR device studies do not need an IDE application approved by FDA. • The IRB serves as the FDA’s surrogate for review, approval, and continuing review of NSR device studies. • NSR device studies must follow the abbreviated requirements at 21 CFR 812.2 (b). 27
  28. 28. Abbreviated IDE Requirements (21 CFR 812.2 (b)(1)) • Label the device properly (21 CFR 812.5) • Obtain and maintain IRB approval after presenting why the device study is NSR • Obtain informed consent (21 CFR 50) • Monitor the study (21 CFR 812.46) • Maintain required records and reports • Comply with prohibitions against promotion (21 CFR 812.7) 28
  29. 29. Study Risk Determination 29 Sponsor Risk Assessment (based on clinical protocol, description of device, reports of prior investigations, subject selection criteria, etc.) Submit to IRB NSR Agreement Requires an abbreviated IDE Unsure of NSR/SR; Request FDA Input
  30. 30. • Q-Submission: Study Risk Determination • Device Description and Clinical Protocol • Recommend Cover Letter- Highlight Nature of Request • No Require Timeframe for Response • Response usually within 60 days • Binding Determination • Full IDE Submission • Response within 30 days 30 Study Risk Determination
  31. 31. Study Risk Determination 31 Sponsor Risk Assessment (based on clinical protocol, description of device, reports of prior investigations, subject selection criteria, etc.) Submit to IRB NSR Agreement Requires an abbreviated IDE Requires submission of IDE to the FDA SR Determination
  32. 32. PART 1: Medical Device Studies and the IDE • Definitions and Clinical Investigations • IDE Exemption • SR/NSR Determination and the IDE • IDE Preparation and Submission 32
  33. 33. IDE Content (21 CFR 812.20 (b)) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 4. Investigational Plan 5. Manufacturing Information 6. Investigators Agreement 7. Investigators Certification 8. IRB Information 9. Name and Address of Investigators Institution 10. Financial Claims 11. Environmental Assessment 12. Labeling 13. Informed Consent 14. Additional Information 33
  34. 34. 1. Cover Sheet – Form 3514  Used voluntarily  Same form is used for IDE, 510(k), PMA, meetings, 513(g), etc.  Captures the following information: - original submission, amendment, report or supplement - device information (name, intended use, classification) - sponsor and manufacturer contact information - any previous discussion with the FDA 34
  35. 35. IDE Content 21 CFR 812.20 (b) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 35
  36. 36. 3. Report of Prior Investigations (21 CFR 812.27)  General  Prior clinical, animal, and laboratory testing  Specific  Bibliography of all publications  Summary of all unpublished information  If laboratory studies are referenced, state whether studies were conducted in accordance with good laboratory practice (GLP) regulations (21 CFR 58) 36
  37. 37. IDE Content 21 CFR 812.20 (b) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 4. Investigational Plan 37
  38. 38. 4. Investigational Plan (21 CFR 812.25)  Purpose  Name and intended use of the device  Objectives and duration of the investigation  Protocol  Methodology  Risk Analysis  Description of the Device  Monitoring Procedures  Additional Records and Reports 38
  39. 39. IDE Content 21 CFR 812.20 (b) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 4. Investigational Plan 5. Manufacturing Information 39
  40. 40. 5. Manufacturing Information 21 CFR 812.20(b)(3)  FDA-Approved Device – off label and/or modified  Non-FDA Approved Device – from a company  Non-FDA Approved Device – you control manufacturing 40
  41. 41. 5. Manufacturing Information 21 CFR 812.20(b)(3) 41  Refer to the approved product label  Refer to the approved product label & describe the changes that you have made  Refer to a Letter of Authorization (LoA)
  42. 42. What is an LoA?  This is a letter from a sponsor (company) to their IDE (or IND or MF) stating that confidential information from their submission can be used in support of your submission.  It gives the FDA “permission” to reference the named materials in support of your IDE application.  Get copies of the letters to include in your submission! 42
  43. 43. 5. Manufacturing Information 21 CFR 812.20(b)(3) 43  Methods, facilities, and controls for:  Manufacturing  Packaging  Storage  Installation
  44. 44. IDE Content 21 CFR 812.20 (b) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 4. Investigational Plan 5. Manufacturing Information 6. Investigators Agreement 44
  45. 45. 6. Investigators Agreement (21 CFR 812.43)  Who is the investigator?  The investigator is the individual who actually conducts a clinical investigation (i.e., under whose immediate direction the investigational device is administered, dispensed to, or used involving human subjects).  In the event of an investigation being conducted by a team of individuals, "investigator" refers to the responsible leader of that team. 45
  46. 46. 6. Investigators Agreement (21 CFR 812.43)  CV of the investigator  Statement of investigator’s relevant experience  If the investigator was involved in an investigation that was terminated, explain the circumstances  Financial disclosure information  Statement of investigators commitment to:  Conduct the investigation according to the agreement  Supervise all testing  Ensure that requirements for obtaining IC are met 46
  47. 47. IDE Content (21 CFR 812.20 (b)) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 4. Investigational Plan 5. Manufacturing Information 6. Investigators Agreement 7. Investigators Certification 8. IRB Information 9. Name and Address of Investigators Institution 10. Financial Claims 11. Environmental Assessment 12. Labeling 13. Informed Consent 14. Additional Information 47
  48. 48. Original IDE Submission  3 copies of your application are required.  Since Dec 2012 eCopy necessary!!  An exact duplicate of the paper submission  It can be CD, DVD, or flash drive  If identical copy is not feasible, hard copy needs to have a placeholder cross-referencing the location of certain info on eCopy  Cover letter must contain eCopy statement  Use Adobe Acrobat 11 and below  No security settings  50MB or smaller in size 48
  49. 49. 49
  50. 50. Creating an eCopy  Non-Volume Based eCopy  001_G010101_Annual report 2014.pdf  Volume Based eCopy  VOL_001_Cover letter  VOL_002_Report of Prior Investigations http://tinyurl.com/99jtgle 50
  51. 51. IDE Submission IDE should be sent to: Food and Drug Administration Center for Devices and Radiological Health Document Mail Center - WO66-G609 10903 New Hampshire Avenue Silver Spring, Maryland 20993-0002 51
  52. 52. FDA Review Process  Sponsors are notified of the date that FDA receives the original application.  IDE number is assigned (e.g., G096000)  If eCopy is missing, you will be placed on “eCopy Hold”  Send revised eCopy only, with a paper cover letter and an appropriate eCopy statement 52
  53. 53. FDA Review Process  Within 30 calendar days of the receipt date, FDA may grant: - IDE Approval - IDE Approval with Conditions - Staged Approval (with Conditions) - IDE Disapproval  An IDE application is considered approved 30 days after it has been received by FDA. http://tinyurl.com/lxrmd9u 53
  54. 54. Let’s Take a Break! 54
  55. 55. IDE Preparation and Maintenance: Best Practices Workshop Erika Segear Johnson, PhD, RAC Regulatory Affairs Scientist PART 1: Medical Device Studies and the IDE PART 2: IDE Maintenance and Additional Studies 55
  56. 56. PART 2: IDE Maintenance and Additional Device Studies • IDE Maintenance • Expanded Access Programs • Algorithms and Mobile Medical Applications • Case Scenarios 56
  57. 57. Once you have an active IDE…  Make sure that you also have IRB approval(s) in place  Register trial at the ClinicalTrials.gov  Check local policies
  58. 58. Requirements for IDE Modifications  Modifications to the Investigational Plan (device or clinical protocol) need to be submitted to FDA:  Changes that REQUIRE prior approval (30-day reply from FDA)  Changes that DO NOT require prior approval (5-day notice)  Changes submitted as a part of annual report http://tinyurl.com/42wvtny
  59. 59. IDE Modifications  Changes that require prior approval (30-day reply from FDA):  Changes that could impact validity of data, scientific soundness, or the rights/safety/welfare of study subjects Indication Type or nature of study control Primary end point Statistical methods evaluation Expanding the study Significant design changes Early termination
  60. 60.  Changes that require 5-day notice to FDA: • Emergency change • Changes that do not affect scientific soundness or the rights/safety/welfare of study subjects - Modification of incl/excl criteria to better define target population - Increasing frequency at which information is gathered - Modifying the secondary study endpoints - Design or manufacturing changes that are not significant IDE Modifications
  61. 61.  Changes that can be sent to FDA as part of the annual report: • Minor changes to study materials that do not affect the validity of data, scientific soundness, or the rights/safety/welfare of study subjects Monitoring procedures Labeling Informed Consent Materials IRB Information Purpose of the study Risk Analysis IDE Modifications
  62. 62. Supplements/Reports to FDA FDA Unanticipated Adverse Device Effects 10 working days Withdrawal from FDA/IRB approval 5 working days Investigator List Every 6 months Progress Report (Annual Report) At least yearly Deviation from Investigational Plan 5 working days or pre-approval Failure to Obtain Informed Consent 5 working days Recall and Device Disposition 30 working days Significant Risk Determination 5 working days Final Report 30 working days- notification 6 months- report 21 CFR 812.150
  63. 63. IDE Maintenance - UADEs  Unanticipated Adverse Device Effect - Any serious adverse effect on health or safety or any life- threatening problem or death caused by, or associated with, a device if that effect, problem or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (21 CFR 812.3 (s)).  Conduct an evaluation of the UADE and report to the FDA within 10 working days.
  64. 64. Progress/Final Report 1. Basic information 2. Study Progress - Brief summary of the study progress - Number of investigators/investigational sites - Number of subjects enrolled - Number of devices shipped - Disposition of all device shipped - Brief summary of results - Summary of anticipated and unanticipated adverse effects - Description of any deviations from the investigational plan (since last progress report)
  65. 65. 3. Risk Analysis - Summary of any new adverse information (since the last progress report) that may affect the risk analysis - Reprints of any articles published from data collected from this study - New risk analysis, if necessary, based on new information and on study progress 4. Other Changes - Summary of any changes in manufacturing practices and quality control - Summary of all changes in the investigational plan not required to be submitted in a supplemental application 5. Marketing Application or Future Plans Progress/Final Report
  66. 66. IDE Submission Types  Supplements  Reports  Amendments http://tinyurl.com/lxrmd9u
  67. 67. Supplements  Approval for change (prior-approval, 5-day notice)  Request approval for a new study under the same IDE  Request study expansion (new sites, more patients)  Request approval to terminate enrollment/study  Notify FDA if the study been suspended  Request approval for the compassionate use  Request the extension of time to respond to the FDA The FDA will usually reply to supplements. Reply is similar to the Original IDE submission.
  68. 68. Reports  Provide biannual investigator/IRB information  Annual reports  Failure to obtain ICF  Notify the FDA of the Emergency Use  Report the unanticipated adverse device effect  Report completion of enrolment/study  Provide final IDE report The FDA will reply within 30 days only if they have any comments or questions.
  69. 69. Amendments  Any repose to deficiency letter is an amendment. Amendment may be submitted to each of the 3 parent document types:  Original IDE submission  IDE Supplement  IDE Report
  70. 70. Terminating/Closing an IDE  If IDE is not yet approved: request a withdrawal  If you have an active IDE, but no subjects enrolled: request a withdrawal, but state why and account for all the device  If subjects have been enrolled: you might need to complete follow-up of already enrolled subjects  If you completed the study: notify FDA within 30-days and send Final Report within 6 months
  71. 71. PART 2: IDE Maintenance and Additional Device Studies • IDE Maintenance • Expanded Access Programs • Algorithms and Mobile Medical Applications • Case Scenarios 71
  72. 72. Additional Types of Device Studies  Early and expanded access (http://tinyurl.com/yhkv7o2)  Emergency Use of Unapproved Medical Device:  An IDE may or may not exist for the device  Life-threatening situation that needs immediate treatment  There is no generally acceptable alternative for treating the patient  There is no time to use existing procedures to get FDA approval  Must be reported to FDA, IRB within 5 days
  73. 73.  Single Patient or Compassionate Use IDE:  Serious condition for which device is the only option  Patient does not meet inc/exc criteria  Prior approval of FDA and IRB is required  Time-frame: during clinical trial  Treatment IDE:  For serious or life-threatening condition with no alternative therapy  An appropriate level of safety and efficacy has been demonstrated in clinical studies  Prior approval of FDA and IRB is required  Time-frame: late stage clinical trials Additional Types of Device Studies
  74. 74.  Continued Access:  Trial is completed and marketing application is being prepared  There is a public health need for the device  Preliminary evidence shows that device is likely to be effective and no significant safety concerns have been identified  Time-frame: Marketing application preparation and review  Difference between Treatment IDE and Continued Access:  Treatment IDE you can apply earlier  Treatment has more narrow patient population Additional Types of Device Studies
  75. 75.  Humanitarian Device Exemption (21 CFR 814.100)  An Humanitarian Use Device (HUD) is a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in fewer than 4,000 individuals in the US per year  HDE application is similar to PMA but is exempt from the effectiveness requirements.  With exception of emergency use, even if used per its approved label, the use of HUD requires IRB approval Additional Types of Device Studies
  76. 76. Before IDE IDE Approval IDE Completion Marketing Approval Emergency Use Traditional IDE Compassionate Use Treatment Use Continued Access Additional Types of Device Studies
  77. 77. PART 2: IDE Maintenance and Additional Device Studies • IDE Maintenance • Expanded Access Programs • Algorithms and Mobile Medical Applications • Case Scenarios 77
  78. 78. Algorithm as a Medical Device  An algorithm can be defined as combination of multiple variables using an interpretation function to yield a single, patient-specific result that is intended for use in the diagnosis of disease or other condition, or in the cure, mitigation, treatment, or prevention of disease. 78
  79. 79. In Vitro Diagnostic Multivariate Index Assays (IVDMIA)  IVDMIA is a device that: 1) “Combines the values of multiple variables using an interpretation function to yield a single, patient-specific result (e.g. a “classification”, “score”, “index” etc.), that is intended for use in the diagnosis of disease or other condition, or in the cure, mitigation, treatment or prevention” 2) “Provides a result whose derivation is non- transparent and cannot be independently derived or verified by the end user” http://tinyurl.com/mgmnrt7 79
  80. 80. IVDMIA Examples Examples of what the FDA considers IVDMIA:  A device that integrates quantitative results from multiple immunoassays to obtain a qualitative “score” that predicts a person’s risk of developing a disease or condition.  A device that integrates a patient’s age, sex, and genotype of multiple genes to predict risk of or diagnose a disease or condition. 80
  81. 81. Examples of what the FDA DOES NOT consider IVDMIA:  Common clinical calculations (e.g., creatinine clearance, cholesterol ratios, glucose level)  Device does not incorporate a unique interpretation function, but rather provides standard interpretation of individual variables that clinicians could do themselves.  Common, public demographic risk calculations (e.g., Gail Index, Framingham Risk Score)  These calculations are generally freely available to the clinical community, through wide dissemination in peer-reviewed publications, practice guidelines, etc. Clinicians are able to use and interpret this type of calculation in the context of their own clinical knowledge. 81
  82. 82. Regulation of IVDMIAs  Device classification is based on the intended use and level of controls necessary to assure safety and effectiveness. Example: A device intended as an indicator of a patient's risk of cancer recurrence may be a Class II device, while the same device intended to predict which patients should receive chemotherapy might be a Class III device. 82
  83. 83.  Any calculation that would have a multiple inputs and would result in an output that will be used to assign the patient to different arms of a treatment would be considered an algorithm.  All algorithms are subject to 21 CFR 812, regardless of format.  Even if the study is designed in a way that the “calculation” randomizes the patients to the drug/device whose label is so broad that the treatment itself is “within the label”, the calculation/formula based on which the treatment is assigned would still be considered an algorithm. 83 Questions to FDA: Algorithm as a Medical Device
  84. 84. Mobile Medical Applications Mobile Application (Mobile App)  “. . .defined as a software application that can be executed (run) on a mobile platform. . ., or a web-based software application that is tailored to a mobile platform but is executed on a server.” Mobile Medical Application (MMA)  “. . .is a mobile app that meets the definition of device in section 201(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act); and either is intended: • to be used as an accessory to a regulated medical device; or • to transform a mobile platform into a regulated medical device.”
  85. 85. Risk Based Approach for Mobile Apps MAs that do not meet the definition of a medical device MAs that may meet the definition of a medical device but are lower risk MAs that meet the definition of a medical device and are higher risk Not medical devices “Enforcement Discretion” MMA Focus of Regulatory Oversight
  86. 86. Mobile Apps that are Not Medical Devices Mobile Apps that could be used in a healthcare environment, in clinical care or patient management, but are not considered medical devices. 1) Mobile apps that are intended to provide access to electronic “copies” (e.g., e-books, audio books) of medical textbooks or other reference materials. 2) Mobile apps that are intended for health care providers to use as educational tools for medical training. 3) Mobile apps that are intended for general patient education and facilitate patient access to commonly used reference information. 4) Mobile apps that automate general office operations in a health care setting. 5) Mobile apps that are generic aids or general purpose products.
  87. 87. Mobile Medical Apps: Focus of FDA Regulatory Oversight Mobile Apps that meet the definition of a medical device and can pose potential risk to public health. 1) Mobile apps that are an extension of one or more medical devices by connecting to such device(s) for purposes of controlling the device(s) or for use in active patient monitoring or analyzing medical device data. 2) Mobile apps that transform the mobile platform into a regulated medical device by using attachments, display screens, or sensors or by including functionalities similar to those of currently regulated medical devices. 3) Mobile apps that become a regulated medical device (software) by performing patient-specific analysis and providing patient-specific diagnosis, or treatment recommendations.
  88. 88. Enforcement Discretion Mobile Apps that may meet the definition of a medical devices for which the FDA intends to exercise ‘enforcement discretion’ • Help patients (i.e., users) self-manage their disease or conditions without providing specific treatment or treatment suggestions. • Provide patients with simple tools to organize and track their health information. • Help patients document, show, or communicate potential medical conditions to health care providers. • Enable patients or providers to interact with Personal Health Record (PHR) or Electronic Health Record (EHR) systems.
  89. 89. Let’s Practice… 89
  90. 90. Scenario 1  An investigator is assessing the efficacy of an algorithm (software) which would predict if a patient should be treated with the drug A or drug B  Both drugs are FDA approved for the treatment of that particular indication, but drug A is defined as a first line of therapy  In order to complete the algorithm, the following parameters are needed: BP, IgE levels (blood draw), cytokine level (blood draw) and BMI. The result is guiding the therapy w/o being confirmed with another device or method
  91. 91.  Is the algorithm/software used in this scenario a device?  Yes. The algorithm is “intended” for use: In the diagnosis of disease or other conditions In the cure, mitigation, treatment and prevention of disease  Is this a device/diagnostic device study? Yes. The objective of the study is to assess the safety and/or efficacy of the device. Therefore the study is subject to 21 CFR 812.  Scenario 1
  92. 92.  Can this study be IDE exempt or does it require an abbreviated or full IDE? Per 21 CFR 812.2 (c), a diagnostic device study is IDE exempt when it: - Is noninvasive - Does not require an invasive sampling procedure that presents a significant risk - Does not by design or intention introduce energy into a subject - Is not used as a diagnostic procedure without confirmation of the diagnosis by another medically established diagnostic product or procedure  No, the study cannot be IDE exempt. SR/NSR determination needs to be made. Scenario 1
  93. 93. Scenario 2  The objective of the study is to assess which of 2 FDA-approved imaging devices provides better images for diagnosis and evaluation of stroke.  The devices used in the study are: 3D Volumetrics scanner and Siemens Antares scanner and appear to be used per their approved label.
  94. 94.  Is this a device study? Yes. The objective of the study is to assess the safety and/or efficacy of the device. Therefore the study is subject to 21 CFR 812. Can this study be IDE exempt or does it require an abbreviated or full IDE? It appears that the devices will be used according to their label and thus, this study could be IDE exempt.  Scenario 2
  95. 95.  An investigator is evaluating the utility of a software program for motion correction in MRI imaging.  The MRI pulse sequences used to perform these scans are FDA approved.  Images collected as part of routine clinical care will be analyzed using this software and compared to those processed conventionally. Scenario 3
  96. 96.  Is there a medical device in this study?  Yes. The software system is “intended” for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease. Thus, this study appears to contain a diagnostic medical device.  Is this a device study? Yes. The objective of the study is to assess the effectiveness of the software device in correcting motion artifacts. Therefore, this study is subject to 21 CFR 812.  Scenario 3
  97. 97.  Can this study be IDE exempt or does it require an abbreviated or full IDE? Per 21 CFR 812.2 (c), a diagnostic device study is IDE exempt when it: - Is noninvasive - Does not require an invasive sampling procedure that presents a significant risk - Does not by design or intention introduce energy into a subject - Is not used as a diagnostic procedure without confirmation of the diagnosis by another medically established diagnostic product or procedure  Yes, the study can be IDE exempt since the MRI scans are being performed for clinical care.  What if additional scans were being performed for research purposes? Scenario 3
  98. 98.  Mobile apps that use video and video games to motivate patients to do their physical therapy exercises at home.  Not a medical device  Regulated MMA  Enforcement Discretion 98 Scenario 4 
  99. 99. 99 Scenario 5  A mobile app which uses a electrodes and sensors attached to the mobile platform to measure physiological parameters during CPR and provides feedback about the quality of CPR being delivered.  Not a medical device  Regulated MMA  Enforcement Discretion 
  100. 100. Useful Websites: CDRH Learn Course List http://www.fda.gov/Training/CDRHLearn/ default.htm Device Advice: http://www.fda.gov/MedicalDevices/Devi ceRegulationandGuidance/default.htm 100
  101. 101. Thank you! erika.segearjohnson@duke.edu or (919) 668-4639 101

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