Premarket Approval - PMA The route to market for Class III devices - - PowerPoint PPT Presentation

FDA Medical Device Industry Coalition

Premarket Approval - PMA

The “route to market” for Class III devices –Fees required

PM A

□ “515(c)” of the Medical Device Amendments

• f 1976 (but no one calls it a “515(c)”)

□ 21 CFR 814 (Humanitarian) □ Required primarily for Class III devices □ All “new” devices, that are not substantially

equivalent to a Class I or Class II device are automatically class III –until otherwise acted on

21 CFR 814

Subpart A--General § 814.1 - Scope § 814.2 - Purpose § 814.3 - Definitions § 814.9 - Confidentiality of data and information in a premarket approval application (PMA) file § 814.15 - Research conducted outside the United States § 814.17 - Service of orders § 814.19 - Product development protocol (PDP) Subpart B--Premarket Approval Application (PMA) § 814.20 - Application § 814.37 - PMA amendments and resubmitted PMA's § 814.39 - PMA supplements

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=814

21 CFR 814

Subpart C--FDA Action on a PMA § 814.40 - Time frames for reviewing a PMA § 814.42 - Filing a PMA § 814.44 - Procedures for review of a PMA § 814.45 - Denial of approval of a PMA § 814.46 - Withdrawal of approval of a PMA § 814.47 - Temporary suspension of approval of a PMA Subpart D--Administrative Review [Reserved] Subpart E--Postapproval Requirements § 814.80 - General § 814.82 - Postapproval requirements § 814.84 - Reports

Premarket Approval (PMA)

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

PMA Device Advice Topics

□ Definitions □ Review Process □ Fees □ Application Methods □ Application Contents □ Quality System □ Labeling □ Clinical Studies □ Postapproval

requirements

□ Supplements and

Amendments

□ Special Considerations □ Import/Export □ FAQ’s □ Regulations

PM A

□ The PMA is required to prove safety

and efficacy

□ It requires substantial information, study,

data, time and money.

□ It receives the “most stringent” review □ Often requires bench and animal testing,

and human clinical trials

PM A

□ There are (primarily):

> Original PMAs for new submissions > Modular PMAs > PMA Supplements for changes Real-Time Supplements for “minor” changes > Streamlined PMAs (clinical lab)

□ Presubmission meetings are encouraged

Original PMA - Content

□

Name and address of the applicant

□

Table of contents specifying volume and page number

□

Summary section (10-15 pages) including

 Indications for use  Device description  Alternative practices and procedures  Marketing history(foreign and US)  Summary of studies  Conclusions drawn from the studies

Original PMA - Content

□ Acomplete description of the device □ Reference to any performance standard or

voluntary standard.

□ Technical sections containing data and information

in sufficient detail to permit FDA to determine whether to approve or deny the application.

□ Results of nonclinical laboratory studies □ Results of clinical investigations involving

human

□ Justification of a single investigator if applicable

Original PMA - Content

□ Bibliography □ One or more samples of the device and its

components, if requested by FDA

□ Draft copies of labeling □ Environmental assessment if applicable □ Financial certification or disclosure

statement or both

□ Such other information as FDA may

request

And –

□ A

draft of the FDA releasable Summary of Safety and Effectiveness See PMA database for examples: https://www.accessdata.fda.gov/scripts/cdrh /cfdocs/cfPMA/pma.cfm Pre-approval inspection generally required

PMA database

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm

Original PMA

□ Six copies each bound in one or more

numbered volumes of reasonable size

□ Trade secret or confidential

commercial or financial information must be included and identified

PMA –Primary Review Steps

□ Administrative review by FDA

to determine completeness (filing review)

□ In-depth scientific, regulatory, and Quality

System review by appropriate FDA personnel

□ Review and recommendation by the

appropriate advisory committee (panel review)

□ Final deliberations, documentation, and

notification of the FDAdecision.

The Approval Letter!

□ Approved for marketing □ Post approval requirements may include

> Restricted sale > Continuing evaluation –Post market Surveillance > Device tracking > Annual reports > QSR requirements (e.g. CAPA)

Device Approvals, Denials and Clearances

https://www.fda.gov/medical-devices/products-and-medical- procedures/device-approvals-denials-and-clearances

Approval order (letter) example

you have agreed report clinical outcomes collect information required training conditions of approval

Approval letter example

http://www.accessdata.fda.gov/cdrh_docs/pdf7/P070014a.pdf

expiration dating final labeling

Post-Approval Studies

□ When ordered, or “agreed to” □ Tracked on line

□

The CDRH Post-Approval Studies Program encompasses design, tracking, oversight, and review responsibilities for studies mandated as a condition of approval of a premarket approval (PMA) application…

□

The program helps ensure that well-designed post- approval studies (PAS) are conducted effectively and efficiently and in the least burdensome manner

Guidance Document: Procedures for Handling Post-Approval Studies Imposed by PMA Order https://www.fda.gov/regulatory-information/search-fda-guidance- documents/procedures-handling-post-approval-studies-imposed-pma-order

Generic Conditions of Approval

□ Requirements for PMAsupplements □ Post approval reports □ Adverse reaction and device defect

reporting

□ M D R reporting

Also on line

□ Summary of Safety and Effectiveness □ Labeling

□

Professional

□

Patient (when applicable)

□ Consumer Information

PMA FEESFOR FY 2020

□ Premarket Application - $341K

□ Small Business - $85K

□ 180-Day PMA

Supplement - $51K

□ Small Business - $13K

□ Real-time PMA

Supplement - $24K

□ Small Business - $6K

□ 30-Day Notice - $5K

□ Small Business - $3K

PMA Web Listing

Questions?

FDA Medical Device Industry Coalition

IDE HDE

Investigational Device Exemption Humanitarian Device Exemption

IDE –Investigational Device Exemption

□ Required for all clinical trials or testing of

devices on humans, whether or not for marketing submission data

□ “Exemption” is a bit of a misnomer—you are

exempt from certain provisions having to do with legally marketed devices…but you have another set of regulations to deal with instead

IDE –21 CFR 812

Subpart A--General Provisions § 812.1 - Scope. § 812.2 - Applicability. § 812.3 - Definitions. § 812.5 - Labeling of investigational devices. § 812.7 - Prohibition of promotion and other practices. § 812.10 - Waivers. § 812.18 - Import and export requirements. § 812.19 - Address for IDE correspondence. Subpart B--Application and Administrative Action § 812.20 - Application. § 812.25 - Investigational plan. § 812.27 - Report of prior investigations. § 812.30 - FDA action on applications. § 812.35 - Supplemental applications. § 812.36 - Treatment use of an investigational device. § 812.38 - Confidentiality of data and information.

IDE –21 CFR 812

Subpart C--Responsibilities of Sponsors § 812.40 - General responsibilities of sponsors. § 812.42 - FDA and IRB approval. § 812.43 - Selecting investigators and monitors. § 812.45 - Informing investigators. § 812.46 - Monitoring investigations. § 812.47 - Emergency research under 50.24 of this chapter. Subpart D--IRB Review and Approval § 812.60 - IRB composition, duties, and functions. § 812.62 - IRB approval. § 812.64 - IRB's continuing review. § 812.65 - [Reserved] § 812.66 - Significant risk device determinations.

IDE –21 CFR 812

Subpart E--Responsibilities of Investigators § 812.100 - General responsibilities of investigators. § 812.110 - Specific responsibilities of investigators. § 812.119 - Disqualification of a clinical investigator. Subpart F [Reserved] Subpart G--Records and Reports § 812.140 - Records. § 812.145 - Inspections. § 812.150 - Reports.

IDE

Also

□ 21 CFR 50, Protection of Human Subjects □ 21 CFR 56, Institutional Review Boards, □ 21 CFR 54, Financial Disclosure by Clinical

Investigators

IDE

https://www.fda.gov/medical-devices/premarket-submissions/premarket-notification-510k

IDE

□ Pre-IDE discussions are encouraged □ Process depends on degree of risk

Significant or Nonsignificant risk

> Significant: IRB

FDA > Nonsignificant: IRB only

Note: In some Guidance Documents the degree of risk is defined, e.g. all spinal implants are significant risk

IDE –Contents –Significant

□ Name and address of sponsor □ Complete report of prior investigations □ Investigational plan □ Design and manufacturing information □ Sample agreement and investigator

certification

□ Registered clinical trial

and…

IDE –Contents –Significant

□ All IRBapprovals □ Device charges if any □ Labeling □ Informed consent □ Other

IDE –Contents -Nonsignificant

□ IRB approval □ Informed consent □ Appropriate monitoring and records □ There are some investigations that are

exempt from the IDE requirements - >e.g. non-invasive diagnostics consumer preference testing

IDE

□

Proper conduct of an IDE is subject to monitoring by the FDA, and has been the subject of Warning Letters

WARNING LETTERS

• to a company

Failure to maintain accurate, complete, and current records relating to an investigation [21 CFR 812.140(b)(6)].

• to an investigator

Our review of the inspection report…revealed serious violations of Title 21, Code of Federal Regulations (21 CFR), Part 812 -- Investigational Device Exemptions, Part 50 -- Protection of Human Subjects, and Section 520(g) (21 U.S.C. 360j(g)) of the Act.

Questions?

HDE –Humanitarian Device Exemption

□ Applicable to Humanitarian Use Devices

(HUDs)

□ Small markets (<4000/yr) □ Usually for a device for which a PMA

would

• therwise be required (Class III)

□ If approved by FDA

requires IRB approval to be used

HDE –21 CFR 814

Subpart H--Humanitarian Use Devices § 814.100 - Purpose and scope. § 814.102 - Designation of HUD status. § 814.104 - Original applications. § 814.106 - HDE amendments and resubmitted HDE's. § 814.108 - Supplemental applications. § 814.110 - New indications for use. § 814.112 - Filing an HDE. § 814.114 - Timeframes for reviewing an HDE. § 814.116 - Procedures for review of an HDE. § 814.118 - Denial of approval or withdrawal of approval of an HDE. § 814.120 - Temporary suspension of approval of an HDE. § 814.122 - Confidentiality of data and information. § 814.124 - Institutional Review Board requirements. § 814.126 - Postapproval requirements and reports.

HDE

https://www.fda.gov/medical-devices/premarket-submissions/humanitarian-device-exemption

HDE Application for a HUD

□ Must establish that

> does not pose an unreasonable risk > probable benefit to health

• utweighs risk

> no comparable devices/treatment available > could not market if PMA required > price does not exceed cost of research, development, fabrication and distribution

HDE Application for a HUD

□ Similar to PMA, but without proof of

effectiveness from a clinical trial

□ Successful application requires:

> ongoing IRB approval for use > registration as an ongoing clinical trial > appropriate labeling as to HUD status

HUDs with HDEs

□ 2015 –6 □ 2014 –4

https://www.fda.gov/medical-devices/device-approvals-denials-and- clearances/hde-approvals

□ 2018 –1 (through June) □ 2017 –3 □ 2016 –0

Novel devices approved in 2018 included automated insulin dosing systems for children as young as 7, the world’s smallest heart valve for newborns, the first mobile medical app to help manage opioid and substance abuse disorders, and artificial intelligence technologies that diagnose diabetic retinopathy.

By comparison approximately 50 PMAs are approved each year; and approximately 3700 510(k)s are cleared each year

Questions?

FDA Medical Device Industry Coalition

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Device Labeling Requirements

Contributes to the safety and effectiveness of the device

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□ Labeling regulations

□ 21 CFR 801- General Device Labeling □ 21 CFR 809 - In Vitro Diagnostic Products □ 21 CFR 812 - Investigational Device Exemptions □ 21 CFR 820 –Good Manufacturing Practices □ 21 CFR 1010 - General Electronic Products

Background -Introduction

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□ Label

□ What is on the ‘immediate container’

□ Labeling

□ All written material including:

□ IFU □ Advertising □ Sales materials □ Pamphlets –Professional and Patient □ Etc

Definitions

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□ Label content □ Label design □ Label management

General Device Labeling

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□ Proper identification

□ Manufacturer □ Intended use □ Adequate directions for use*

□ Nothing false or misleading

* Varies for lay user vs. professional user

Label contents

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□ Statements of all purposes for which, and conditions

under which, the device can be used

□ Quantity of dose for each use and usual quantities for

persons of different ages and physical conditions

□ Frequency of administration □ Duration of application □ Time of administration in relation to other factors □ Route or method of application □ Any preparation necessary for use

Label contents –Lay user

21CFR801.5

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Information for use including

□ Indications □ Effects □ Routes □ Methods and frequency and duration of

administration

□ Relevant hazards, contraindications, side

effects, and precautions

Label contents –Professional

21CFR801.109

Note: Professional devices may also need a patientIFU

Other considerations (non reg)

□ Can the instructions actually be effectively

followed?

“Do not use excessive force”

□ Address residual risks arising from the design

process under Design Controls

• those that could not reasonably be

designed out

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□ Dentures □ Impact resistant glasses □ Chloroflourocarbon containing □ Hearing aids □ Tampons □ Condoms □ Latex containing □ And as suggested in Guidance Documents

Some devices have specified label contents

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□ Sterile Device Labeling

□

What is sterile if only part of package is sterilized

□

Handling

□

Expiration

□ Contract Sterilization

□

Control issues

□ Unique Device Identification*

□

Device label includes a unique device identifier (UDI) in human- and machine-readable form, to improve patient safety, modernize device post- market surveillance, and facilitate medical device innovation.

□ Investigational Device Labeling

https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory- assistance/unique-device-identification-system-udi-system

Additional Labeling Requirements

Considerations on Label design – (non reg)

□ Who are the users?

□ Are there multiple users?

□ MDs, nurses, technicians, patients?

□ Avoiding product confusion/user error □ Physical design

□ Font types and sizes □ Layout □ Colors

Label & Labeling Design

http://academy.gmp-compliance.org/guidemgr/files/227-A.PDF

Other Resources:

https://www.fda.gov/regulatory- information/search-fda-guidance- documents/human-factors-studies-and-related- clinical-study-considerations-combination- product-design-and https://www.fda.gov/medical-devices/device-advice- comprehensive-regulatory-assistance/human-factors- and-medical-devices https://www.fda.gov/regulatory-information/search- fda-guidance-documents/applying-human-factors-and- usability-engineering-medical-devices IEC 62366-1:2015 Medical devices -- Part 1: Application of usability engineering to medical devices

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□ Maintain procedures to control labeling activities □ General Device Labeling Requirements

□

Design documents

□

Label Integrity

□

Receipt Inspection

□

Storage

□

Check and Record

□

Changes

□

Re-labeling

Good Manufacturing Practice Labeling Requirements

21CFR 820.129

The right label on the right device

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□ And a variety of other deviations

Labeling Problems

□ Misbranding

□ Including asserting “approval” for a “cleared”

device

Any representation that creates an impression of

• fficial approval of a device because of complying

with the premarket notification regulations is misleading and constitutes misbranding.

21CFR807.97

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□

Label Content

• Additional warning in Instructions for Use for guide wire

management

• The firm is updating their instructions for use to require

inspection of the IUI connectors for blue or green discoloration (corrosion) before every use of the device.

□

Mix-up

• A label for an indicated use was applied to product sizes

that are not approved for that use

• Mislabeled as to size. An 18 mm x 65 mmtibula implant

is enclosed in a package labeled as 12 mm x 80 mm

Labeling Problems - Recalls

Off-label Use

□ Medical professionals may use a device “off

label” at their discretion

□ But manufacturers may not promote off-

label uses –including on websites or by links to websites

□ FDA Guidance for more information

 Good Reprint Practices for the Distribution of Medical

Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/good- reprint-practices-distribution-medical-journal-articles-and-medical-or-scientific- reference

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Questions ?

Labeling