what is the format & content for a premarket approval (pma) submission? carole c. carey bsee,...
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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)
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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)
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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.
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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.
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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.
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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.
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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.”
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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.”
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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)
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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.
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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.
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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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Medical Device Workshop for Canadian Manufacturers
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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
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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
2009 Sep 29 Edmonton2009 Oct 1 Vancouver
Medical Device Workshop for Canadian Manufacturers
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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
Thank you!