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What is the Format & Content for a Premarket Approval (PMA) Submission?

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What is the Format & Content for a Premarket Approval (PMA) Submission?. Carole C. Carey BSEE, MEng [email protected] Director, International Staff US Food and Drug Administration (USFDA) Center for Devices and Radiological Health (CDRH). Learning Objectives. - PowerPoint PPT Presentation
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What is the Format & Content for a Premarket Approval (PMA) Submission? Carole C. Carey BSEE, MEng [email protected] Director, International Staff US Food and Drug Administration (USFDA) Center for Devices and Radiological Health (CDRH)
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Page 1: What is the Format & Content for a Premarket Approval (PMA) Submission?

What is the Format & Content for a Premarket Approval (PMA) Submission?

Carole C. Carey BSEE, [email protected], International Staff

US Food and Drug Administration (USFDA)Center for Devices and Radiological Health (CDRH)

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Learning Objectives

To provide an overview and understanding of the premarket approval (PMA) regulations and review process.

You will learn: What is a PMA? How does CDRH review PMAs? Criteria for PMA Approval (determination of safety and

effectivness) Practical tips for quality submission (form and content)

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What is a PMA (premarket approval application)? Required for most (highest risk) devices and scientific

review by FDA. High risk, first of a kind No predicate, new technology, Class III

Approval requires reasonable assurance of safety and effectiveness based on intended use. Typically requires clinical data

~7% of the devices that enter the U.S. market each year require PMA approval

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/default.htm

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Who is the PMA applicant?

The PMA applicant is usually the person who owns the rights, or otherwise has authorized access, to the data and other information to be submitted in support of FDA approval.

This person may be an individual, partnership, corporation, association, scientific or academic establishment, government agency or organizational unit, or other legal entity.

The applicant is often the inventor/developer and ultimately the manufacturer.

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What does it mean for the device industry? an approved PMA in effect, a private license granted

to the applicant for marketing a particular medical device.

A Class III device that fails to meet PMA requirements is considered to be adulterated under Section 501(f) of the act and cannot be marketed.

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FDA review and criteria for PMA approval

It is based on a determination that the PMA contains sufficient valid scientific evidence to assure that the device is safe and effective for its intended use or uses.

Target FDA review: 180 days

Panel Meeting: an FDA advisory committee may review an original PMA at a public meeting.

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Safety and Effectivess

Consider: Risks and benefits for indicated patient population Conditions of device use Device reliability

Valid scientific evidence Controlled studies or other objective information Not opinions, random reports, or uninterpretable data

Summary of Safety and Effectiveness Data (SSED) explains approval decision - This is public information.

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Safetyas defined in 21 CFR 860.7(d)1

“There is reasonable assurance that a device is safe when it can be determined, based upon valid scientific evidence, that the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by adequate directions and warnings against unsafe use, outweigh any probable risks.”

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Effectivenessas defined in 21 CFR 860.7(e)1

“There is reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results.”

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Recent examples of devices requiring PMA approval prior to marketing

Female Condom

Intraocular Lens (IOLs)

Deep Brain Stimulator for OCD

Glucose Monitoring System

Cervical Disc Replacement

Gastric Band

Implantable Cardiac Defibrillator (ICD)

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Team-based Review Process

A team leader and multidiscipline-team members Communicates deficiencies to sponsor either

interactively or in major deficiency letter (puts PMA on hold)

Review can not be conducted unless PMA is administratively complete

Internal meetings External meetings

Advisory panel recommendations may be needed to address new safety/effectiveness questions, especially clinical issues.

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PMA Review Process (Very Simplified Block Diagram)

Application

Initial Filing Meeting

Statistical

Inspections BioresearchMonitoring

Manu-facturing

Clinical & Labeling

LabelingReview with

Manufacturer

Pre-PMA Submission Meeting w/manufacturer

No

Major DeficiencyLetter

Yes

“Interactive”SubstantiveReviewMajor/MinorDeficiency

ReviewsEngineering

FDA/CDRH DecisionLetter

Decide Panel Meeting or

No Panel Meeting

Manufacturer & FDAMeetings can occur during the review

FileNot File

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PMA Review Determinations

Approval: Device can be marketed

Approvable: Specific deficiencies

Manufacturing deficiencies

Labeling changes

Agreement on conditions of approval

Not Approvable: Identify steps needed to make PMA approvable, such as new data

Resets review clock

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Pre-PMA submission meetings

Purpose – allow for input from FDA before application is submitted, not an in-depth review

Schedule at an appropriate time Provide a pre-meeting package

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Descriptive Information

Description of Device What the device is, principle of operation,

intended patient population, pictures/drawings Device Specifications With Rationales Analyses of the Design

Failure Modes and Effect Analyses (FMEA) Hazard Analyses

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Pre-Clinical Test Data: Test Protocol Provide Test Protocol

Objective -What the test is intended to accomplish

Rationale - Why the test is appropriate Description of test set up

diagram of test set up test equipment used

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Test Protocol (cont’d)

Description of test set up (cont.) location of measurement instruments description of test conditions with

rationale (i.e., relate test conditions to anticipated clinical use)

Sample size and rationale Data to be collected

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Test Protocol (cont’d)

Test Protocol (cont.) Duration of the test and rationale Acceptance criteria

Justification as to why acceptance criteria are suitable (relates to device specification)

If protocol refers to other company documents, provide the documents if necessary

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Test Protocol (cont’d)

Identify the hardware/software version used Provide the differences between the device

tested (e.g., prototype, different models of the same device) and the device to be marketed

Explain why the differences do not affect the outcome

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Pre-Clinical Test Data: Results

Provide data Provide analysis of the data Ensure the test results meet the acceptance

criteria Explain failures and resolutions

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Valid Scientific Evidence – Clinical 21 CFR Sec. 860.7

Well-controlled investigations Partially controlled studies Studies and objective trials without matched controls Well-documented case histories conducted by qualified

experts Reports of significant human experience with a marketed

device

Isolated case reports, random experience, reports lacking sufficient details to permit scientific evaluation, and unsubstantiated opinions are not regarded as valid scientific evidence.

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Clinical Data

Do the study described in the approved or agreed upon protocol? Study duration Patient population Sample size Assessment Methods

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Clinical Data (cont’d)

Don’t change your statistical analysis plan without prior consultation with FDA Interim analyses should be agreed upon in advance;

consider ramifications Changes in control group

Concurrent control to historical control Cross-over of control patients

Changes in sample size Changing anticipated effect size to decrease sample

size Increasing the sample size

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Clinical Data (cont’d)

Pay close attention to adverse event reporting Be consistent in how adverse events are

categorized Avoid extremes in “lumping” and “splitting” Avoid “cascading” events

Work with FDA during IDE stage or before trial begins on how adverse events are to be categorized

Get FDA input on Case Report Forms

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Clinical Data (cont’d)

Subgroup Analyses: Proceed with Caution Subgroup analyses are useful for:

Defining a particular group that benefited more or less than the overall patient population, provided that an overall effect was shown.

Defining a population worthy of future studies

Using a subgroup analysis to demonstrate safety or effectiveness for a device will raise issues and questions

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Clinical Data (cont’d)

Address the “Future Concerns” items in IDE letters

The “Future Concerns” section of IDE letters contains information that we expect you to address in your PMA submission. It may include:

Long term biocompatibility or laboratory tests Labeling or indication limitations/issues Statistical issues Clinical trial design issues

Failure to address these concerns will raise questions and may lead to a delay in the review process

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Clinical Data (cont’d)

Carefully monitor your study Patient enrollment issues

Inclusion/exclusion criteria Informed consent

Data collection Adverse events Use agreed upon assessment tools/methods Blinding

Lost to follow up

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Use of Standards

CDRH Standards Programhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Standards/default.htm

Guidance for Industry and FDA Staff - Recognition and Use of Consensus Standards (September 17, 2007)

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm077274.htm

Searchable databasehttp://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm

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Use of Standards (cont’d)

Provide all necessary documentation if claim performance to FDA- recognized standard or device specific guidance document

Be aware of the extent of the recognition (i.e., Supplemental Data Sheet)

If declare conformance to FDA-recognized standards

Ensure that it is the correct standard (e.g., IEC and not EN), or

Explain why the differences are acceptable

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Use of Standards (cont’d)

If standard is not recognize by FDA Explain why the selected standard is

appropriate Use the most current version of the standard

If standard allows for selection of acceptance criteria, explain why the selected criteria is suitable

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CDRH eCopy Initiative

Manufacturers submit an exact duplicate of a premarket submission in electronic form

Electronic copy replaces one of the required paper copies

Document is immediately loaded into our electronic system and available for reviewer to use.

Some paper copies are still required

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/ucm134508.htm

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Basic Information: Tips

Provide executive summary Provide detailed table of contents Ensure that submission is well organized

(table of contents, sections, pagination) Provide copies of all test reports (unless it

has already been agreed that reports are not needed)

Ensure that text/table/graphs are clearly labeled and are legible

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Tips (cont’d)

Provide text in English only Provide draft labeling (operator’s manual,

instruction for use, patient manual, promotional literature, etc)

Ensure consistency throughout submission No data dumps

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Tips (cont’d)

Keep your commitments on sending in additional information BUT don’t sacrifice quality for speed

Be prepared for quick turnaround times Ask for clarification on deficiencies if needed If you believe deficiencies are not appropriate,

contact lead reviewer and branch chief Save the phone calls and meeting requests for when

you really need them – avoid excessive status checks

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Tips (cont’d)

Ensure that the manufacturing sites are ready to be inspected

Call FDA if you have questions Request for pre-PMA meetings

to allow for input from FDA before application is submitted, not an in-depth review

Schedule at an appropriate time Provide a pre-meeting package

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Tips (cont’d)

Submit clinical data to prove device is safe and effective

Foreign data is acceptable if:

Scientifically sound

Human subjects are protected

FDA Advisory Panel reviews some PMAs

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Tips (cont’d)

Important considerations Persons for whose use the device is intended Conditions of use of the device Possible benefit to health vs probable injury or

illness from use Reliability of the Device

Reliance on Valid Scientific Evidence Only

(defined in 21 CFR 860.7)

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PMA – Summary of Contents of Application Applicant’s Name and Address Signature of U.S. Representative Summary of S & E Data Device Description and Manufacturing

Section Voluntary Performance Standards Non-clinical and Clinical Data Financial Disclosure of Investigators

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Summary Contents of Application, cont’d Justification for Sole Investigator Bibliography and Other Relevant

Information Samples of Device (If requested by FDA) Proposed Draft Labeling Registration on ClinicalTrials.gov

http://clinicaltrials.gov/ Environmental Assessment Other Information Requested by FDA

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ClinicalTrials.gov is a registry of federally and privately supported clinical trials globally

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Major Regulatory Pathways

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In Summary

PMA only applies to Class III devices – most stringent requirements for medical devices. Proof of Safety and Effectiveness required

An FDA-approved PMA is a private license granted to the applicant to market the device in the U.S.

Quality submissions and engaging with FDA early will lead to better outcome.

More detailed format requirements and application contents are available at:http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm050289.htm

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Thank you!


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