US FDA Investigational Device Exemption (IDE) 21 CFR 812

 IDE allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data.

IDE definition and GCP regulations are given in below figure.

Device Study Classification:

Common IDE Application (812.20) contents are listed below,

• Name and address of sponsor
• Report of prior investigations and investigational plan
• Manufacturing, processing, packing, and storage of device
• Investigator agreement
• List of the name, address, and chairperson of each IRB
• Participating institutions
• Charge for device
• Environmental assessment
• Labeling
• Subject materials including informed consent
• Additional information requested by FDA

Study Risk Determination:

Option 1:Study risk can be determined by sponsor and IRB reviews the sponsor’s determination

Option 2: Sponsor submits “Study Risk Determination” Q-Submission.

FDA issues letter indicating if study is

• Basic physiological research
• Exempt
• Not exempt: SR or NSR

Application process

1.Sponsor submits the IDE application too FDA CDRH's or CBER’s Document Control Center (DCC). FDA will send the acknowledgement letter IDE number: GYYxxxxx (e.g. G140001)

2.IDE sent to appropriate review division based on intended use

3.Lead reviewer assembles team of experts to review the application and make decision with management concurrence within 30 days

4.FDA issues a decision letter to the sponsor

Decision:

• Approval
• Approval with conditions
• Disapproval

IDE supplements: Any significant  changes in approved IDE may require IDE Supplements(812.35)

• Change in protocol
• Change in device

 Sponsor can submit Reports(812.150) of the following

• Annual progress
• Unanticipated adverse device effects
• Follow-up completion
• Current list of investigators
• Final report

References:

Investigational Device Exemption (IDE)) : https://www.fda.gov/medical-devices/how-study-and-market-your-device/investigational-device-exemption-ide

Guidance:“FDA Decisions for IDE Clinical Investigations”

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279107.pdf

US FDA Premarket Approval(PMA) 21 CFR 814

 Premarket Approval (PMA) is a scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices.

515 of the FD&C Act

• It is a marketing approval application. Manufacturer shall receive FDA approval of its PMA application prior to marketing the device.
• Devices fails to meet PMA requirements is adulterated under section 501(f) of the FD&C Act and may not be marketed.

Types of PMA

Traditional PMA

• Common method for achieving FDA approval.
• Ideal method for devices with already completed clinical studies.
• complete PMA application is submitted to FDA at once.

Modular PMA 

• Ideal method for devices with not completed clinical studies.
• PMA contents are divided into modules (example modules are preclinical, clinical, manufacturing etc.). Each module is submitted to FDA as soon as the applicant has completed the module

 Product Development Protocol

• Ideal method for devices in which the technology is well established in industry
• Manufacturer can have an early agreement with FDA as to what would be done to demonstrate the safety and effectiveness of a new device

Humanitarian Device Exemption

A Humanitarian Use Device (HUD) is a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in not more than 8,000 individuals in the United States per year (Section 3052 of the 21st Century Cures Act (Pub. L. No. 114-255)

 PMA can be amended before approval.

Click here to know more about HUD/HDE

PMA supplements: Any significant changes in approved PMA may require PMA supplements

Types of PMA supplements:

1. Panel-Track supplement: Significant change requiring new substantial clinical data
2. 180-Day supplement: Significant change requiring new preclinical test data, no clinical data required.
3. Real-Time supplement: Minor changes supported by pre-clinical or animal testing, with no new clinical data. Involves review within a single scientific discipline.
4. Special PMA supplement: Changes Being Effected: This change Must enhance safety. Change may be implemented prior to FDA approval order
5. Manufacturing site change supplement: Use of a different site or moving the manufacturing site require a 180-day PMA supplement (referred to as a “site change supplement”). Supplement must demonstrate compliance with QS regulation.
6. 30-Day Notice: Written notification of change in manufacturing procedure or method, affecting safety and effectiveness

Annual (periodic) Report or 30-day Supplements: FDA will notify the manufacture for certain changes to be reported in an annual report instead of a PMA supplement submission

 Common documents included in PMA

There is no pre-printed form for a PMA Application. Required elements are listed in 814.20

PMA content consists of below listed administrative and technical data.

1.       The name and address of the applicant.

2.       A table of contents

3.       The summary shall contain the following information:

a.       Indications for use.

b.       Device description.

c.       Alternative practices and procedures.

d.       Marketing history.

e.       Summary of non-clinical and clinical studies.

f.        Conclusions drawn from the studies.

4.       Device Description of device and functional components or ingredients

5.       Manufacturing

6.       Reference to any performance standard

7.       Q-Submission(s)

8.       Results of Nonclinical Laboratory Studies: results of the nonclinical laboratory studies with the device including microbiological, toxicological, immunological, biocompatibility, stress, wear, shelf life, and other laboratory or animal tests as appropriate.

9.       Results of clinical investigations involving human subjects Conducted inside US and Outside US

10.   Statements of Compliance for Clinical Investigations

11.   FORM FDA 3674, Certification with Requirements of ClinicalTrials.gov Data Bank?

12.   A bibliography of all published reports not submitted

13.   Sample of device, if practical

14.   Copies of all proposed Labeling for the device. Such Labeling may include, e.g., instructions for installation and any information, literature, or advertising that constitutes Labeling

15.   Environmental assessment

16.   A financial certification or disclosure statement or both

a.       A signed and dated Certification Form (3454)

b.       A signed and dated Disclosure Form (3455)

17.   Information concerning uses in pediatric patients.

Documents issued by FDA for Product PMA Approval

Once FDA approve the PMA, Manufacturer will receive an Approval Order and Summary of Safety and Effectiveness Data (SSED)

The following are posted on the FDA’s public PMA database:

·       Approval Order

·       Summary of Safety and Effectiveness Data (SSED)

·       Labeling

FDA Review

1.Sponsor submits the ecopy to FDA CDRH's or CBER’s Document Control Center (DCC). FDA will send the acceptance status. (15 days) Assess administrative completeness of application and required elements per 21 CFR 814.20.

Decision: Accepted or Not accepted

2.FDA Filing Review: Threshold determination that application is sufficiently complete to review.

Manufacturer can use Acceptance and Filing Reviews for PMAs

Within 45 calendar days FDA will notify below to manufacturer: Decision: Accepted or Not accepted

3. Substantive Review: Lead reviewer will assess the application and share the below information to manufacturer (Day 90)

·       Interactive review

·       Issue Major Deficiency Letter.PMA request will be placed on hold.

·       Advisory Panel Meeting.Public meeting to review the PMA in accordance with 21 CFR 14.

·       Manufacturing facility inspection

·        Day 100 Meeting (Requested by Applicant)

Decision:

Approval Order:Device may be marketed.Identifies conditions of approval
Approvable Pending Deficiencies Letter: Device can not be marketed.deficiencies to be addressed
Approvable Pending GMP Letter: Device can not be marketed.GMP not confirmed  Not Approvable Letter:Device can not be marketed

References:

PMA : https://www.fda.gov/medical-devices/premarket-submissions/premarket-approval-pma

 PMA database: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm

PMA Guidance: https://www.fda.gov/medical-devices/premarket-approval-pma/pma-guidance-documents

 

 

 

US FDA 510(k) 21 CFR 807

A 510(k) is a Premarket Notification which demonstrates that device to be marketed is at least as safe and effective, that is, substantially equivalent, to a legally marketed device (21 CFR 807.92(a)(3)) that is not subject to PMA.

Section 510(k) of Federal FD&C Act

Predicate: The legally marketed device(s) to which equivalence is drawn.

It is a marketing clearance application. 21 CFR 807 Subpart E describes requirements for a 510(k) submission. There is no 510(k) form.

This submission is mostly for class II and some class I devices. Few class III devices which is not subject to PMA may require 510(k)

Substantial Equivalence (SE)

Manufacturer needs to compare their device characteristics (intended use and technological characteristics) with predicate to determine the substantial equivalence.

Both Type I & Type II scenarios are considered as substantially equivalent.

Characteristics	Device to be marketed	Legally marketed device (Predicate)
Type I
Intended use	Same	Same
Technological characteristics	Same	Same
Type II
Intended use	Same	Same
Technological characteristics*	Different	Different
*submit an information to FDA to demonstrate that the device is at least as safe and effective as the legally marketed device

 Types of 510(k)

Traditional 510(k)

• Most common type and used under any circumstances.
• It may be used for any original 510(k) or for a modification to a previously cleared device under 510(k).
•  The traditional method is the original complete submission as provided in 21 CFR 807.

Click here to get the Format for Traditional and Abbreviated 510(k)s: 

Special 510(k)

• Submitted for a modification to a device cleared under the 510(k) process (usually modification of own legally marked device).
• Modification does not affect the device’s intended use or alter its fundamental scientific technology
• Design controls and risk analysis of device modification used to clear the 510(k)

 Abbreviated 510(k)

• If the device has any FDA guidance documents, special control(s) for the device type, or voluntary consensus standard(s) then abbreviated 510(k) is preferred.

 Common 510(k) submission documents are listed below,

1. Medical Device User Fee Cover Sheet (Form FDA 3601)
2. Center for Devices and Radiological Health (CDRH) Premarket Review Submission Cover Sheet (Form FDA 3514)
3. 510(k) Cover Letter
4. Indications for Use Statement (Form FDA 3881)
5. 510(k) Summary or 510(k) Statement
6. Truthful and Accuracy Statement
7. Class III Summary and Certification
8. Financial Certification or Disclosure Statement
9. Declarations of Conformity and Summary Reports
10. Proposed Labeling
11. Sterilization and Shelf Life
12. Biocompatibility
13. Software
14. Electromagnetic Compatibility and Electrical Safety
15. Performance Testing – Bench
16. Performance Testing – Animal
17. Performance Testing – Clinical 

 510(K) application also includes below information,

1. Device Description
2. Executive Summary/Predicate Comparison
3. Substantial Equivalence Discussion 

Documents issued by FDA for product 510(k) clearance

After FDA 510(k) clearance, manufacturer will receive Substantial Equivalence (SE) Letter and 510(k) Summary (if provided instead of 510(k) Statement)

The following are posted on the FDA’s public 510(k) database:

1. Substantial Equivalence (SE) Letter
2. Indications for Use Form
3. 510(k) Summary (if provided instead of 510(k) Statement)

FDA Review – 90 days for traditional /abbreviated 510(k),30 days for special 510(k)

1.Sponsor submits the ecopy to FDA CDRH's or CBER’s Document Control Center (DCC). FDA will send the acknowledgement letter or hold letter if there is any issues with ecopy or user fees (7days)

2.FDA Acceptance Review: Administrative review to assess the completeness of the application.

Manufacturer can use Refuse to AcceptPolicy for 510(k)s: 

Within 15 calendar days FDA will notify below to manufacturer:

• Request accepted for substantive review;
• Not been accepted for review (i.e., considered refused to accept RTA  -Manufacturer shall address within 180 days
• Request is under substantive review and the FDA did not complete the acceptance review within 15 calendar day

3. Substantive Review (60 days): Lead reviewer will assess the application and share the below information to manufacturer

• Interactive review
• Additional Information letter .510(k) request will be placed on hold. Manufacturer shall address within 180 days

3.510(k) decision(90 days): MDUFA(medical device user fee amendments) Decision

• Substantial Equivalence (SE) Decision: Device 510(k) Cleared. Market the device
• Non-Substantial Equivalence (NSE) Decision: Device not 510(k) Cleared. Resubmit another 510(k) with new data, PMA, de novo or reclassification petition

4.Missed MDUFA Decision communication to the manufacturer

 References :

Premarket Notification 510(k) : https://www.fda.gov/medical-devices/premarket-submissions/premarket-notification-510k

RTA Checklist : http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm315014.pdf

510(k) database: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm

 

US FDA Denovo Classification

 FD&C Act Medical Device Amendments (1976) Section 513(f)(1): “new devices”

·       Automatically classified as Class III regardless of risk

FD&C Act –modified in 1997 Food and Drug Administration Modernization Act (FDAMA)

·       Established de novo classification process and also known as “Evaluation of Automatic Class III Designation”.

·       Pathway for classification of low-risk devices when there is no predicate.

Application process

1.510(k) Submission:

·       Sponsor submits 501(k) and FDA issues a decision of “not substantially equivalent” due to no predicate

2. De novo request:

·       Sponsor submits de novo request and FDA classify device from Class III to Class I or II with new classification/regulation

FD&C Act –further modified in 2012 Food and Drug Administration Safety and Innovation Act (FDASIA)

·       Established direct de novo classification process .There is no 510(k) submission is required.Sponser can submit directly if there is no predicate

Common denovo submission documents are listed below

1.      Coversheet clearly identifying the request as a "Request for Evaluation of Automatic Class III Designation" under 513(f)(2) De Novo request

2.      Administrative Information including applicant name and address

3.      Regulatory History

4.      Device Description, including technology, proposed conditions of use, accessory, components, etc

5.      Classification Summary

6.      Recommended Classification and Proposed Special Controls for  Class II devices ONLY

7.      Supportive Evidence pre-clinical, animal, clinical

8.      Summary of Benefits

9.      Summary of Known/Potential Risks to Health

10.   Risk and Mitigation Information

11.   Benefit-Risk Considerations

12.   Device Labelling

FDA Review - 150 review days

1.Sponsor submits the application.use the acceptance review checklist guidance  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-review-de-novo-classification-requests

2.FDA Acceptance Review :Administrative review to assess the completeness of the application.

Within 15 calendar days FDA will notify below to manufacturer:

• Request accepted for substantive review;
• Not been accepted for review (i.e., considered refused to accept RTA  -Manufacturer shall address within 180 days
• Request is under substantive review and the FDA did not complete the acceptance review within 15 calendar day

3. Substantive Review:Lead reviewer will assess the application and share the below information to manufacturer

·       Interactive review

·       Additional Information letter .De Novo request will be placed on hold. Manufacturer shall address within 180 days

3.Denovo decision:

·      Grant

·       Decline

Reference:

De Novo Classification Request: https://www.fda.gov/medical-devices/premarket-submissions/de-novo-classification-request

RTA Checklist : https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-review-de-novo-classification-requests

Denovo database: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/denovo.cfm

Evaluation of Automatic Class III Designation (De Novo) Summaries: https://www.fda.gov/about-fda/cdrh-transparency/evaluation-automatic-class-iii-designation-de-novo-summaries