What is the Format & Content
for a Premarket Approval
(PMA) Submission?
Carole C. Carey BSEE, MEng
carole.carey@fda.hhs.gov
Director, International Staff
US Food and Drug Administration (USFDA)
Center for Devices and Radiological Health (CDRH)
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 Edmonton
2009 Oct 1 Vancouver
Medical Device Workshop for Canadian
Manufacturers
2
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/HowtoMarket
YourDevice/PremarketSubmissions/PremarketApprovalPMA/default.htm
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2009 Oct 1 Vancouver
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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:


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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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Safety
as 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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Effectiveness
as 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
Implantable Cardiac
Defibrillator (ICD)
Gastric
Band
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Intraocular
Lens (IOLs)
Deep Brain Stimulator
for OCD
Glucose Monitoring
System
Cervical Disc
Replacement
Medical Device Workshop for Canadian
Manufacturers
Female
Condom
10
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
Not File
Pre-PMA
Submission
Meeting w/
manufacturer
No
Major Deficiency
Letter
Initial Filing
Meeting
File
Clinical &
Labeling
Yes
Decide Panel
Meeting or
No Panel Meeting
Manufacturer & FDA
Meetings can occur
during the review
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Reviews
Engineering
“Interactive”
Substantive
Review
Major/Minor
Deficiency
Labeling
Review with
Manufacturer
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Statistical
Inspections
Bioresearch
Monitoring
Manufacturing
FDA/CDRH
Decision 12
Letter
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


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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?

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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 Program
http://www.fda.gov/MedicalDevices/DeviceRegulat
ionandGuidance/Standards/default.htm
 Guidance for Industry and FDA Staff - Recognition
and Use of Consensus Standards (September 17,
2007)
http://www.fda.gov/MedicalDevices/DeviceRegulat
ionandGuidance/GuidanceDocuments/ucm077274
.htm
 Searchable database
http://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/DeviceRegulation
andGuidance/HowtoMarketYourDevice/PremarketSu
bmissions/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/DeviceRegulationandGuidan
ce/HowtoMarketYourDevice/PremarketSubmissions/PremarketA
pprovalPMA/ucm050289.htm
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Thank you!