Development of a PMA Submission Strategy

Laura J. Byrd Premarket Approval Section FDA/CDRH/ODE

Topics
Know your product
Desired patient population Desired claims

Early interactions with FDA

Development of testing requirements and strategy

Managing change During the PMA review The Long View

Know your product

PMAs are submitted for a device plus its indication Device
What is it? How is it made? What is the primary mechanism of action?

Indication
What is the patient population? What is the clinical benefit to the patient? What claims do you intend to make?

The answers to these questions will drive your submission content and strategy

Early interactions with FDA

Before the IDE
Based on the proposed device design, development of appropriate nonclinical testing (bench, software, animal) Based on the proposed indication, development of an appropriate clinical protocol, statistical analysis plan FDA is generally willing to informally review protocols for long-term or difficult tests (e.g., animal studies, fatigue testing, shelf-life) or an outline of the proposed clinical protocol

Early interactions with FDA

During the IDE
Changes to the device design or protocol Preplanning for the PMA, especially if modular

Pre-PMA meeting
Content and format of PMA submission Presentation of data (especially clinical and statistical) Additional analyses or testing needed to address changes made to device or protocol during the IDE study

Early interactions with FDA

Pre-PMA meeting (cont.)
Analyses specific to inclusion of foreign data Plans to address future PMA concerns concerns Special data requests for statisticians, BIMO
See Electronic clinical data at data http://www.fda.gov/MedicalDevices/DeviceRegulationandGui dance/HowtoMarketYourDevice/PremarketSubmissions/ucm1 34508.htm

Potential for postapproval study, or if already planned, outline of postapproval study protocol

Managing change
Device industry and clinical practice are constantly changing If modification needed, possible to incorporate the change without significant disruption
Talk to us about the change Work with our statisticians to plan for appropriate analyses Earlier in the clinical study is better (dont request a (don change with 5 patients left to enroll!) If need for change arises late, consider whether data could be collected in a postapproval setting, if study is planned or anticipated (note that data would need to be collected under IDE)

Managing change
Unanticipated changes
Manufacturing scale-up (clinical to commercial) Changes by vendor (or to a different vendor) for significant components Changes in clinical practice patterns, availability of alternative therapies

Bottom line: plan for changes to occur

During the PMA review

Managing expectations with respect to timelines
Management Understand FDAs Interactive Review policies and FDA procedures be prepared for rapid turn-around turnhttp://www.fda.gov/downloads/MedicalDevices/De viceRegulationandGuidance/GuidanceDocuments/u cm089425.pdf With MDUFA II timelines, only one round of major deficiencies next step either will be approval or not approvable

Example Timeline (MDUFA II)

Total days 0 60 FDA initial review Initial submission 120 180 Sponsor prepares responses; often consults with FDA 240 300 FDA 2nd review; may include Panel Meeting Amendment Approval Order 360

Major Deficiency Letter

During the PMA review

Managing expectations with respect to timelines
Marketing Please dont print your labeling the week after the PMA is filed Manufacturing Be realistic when advising on timelines for ramp up of manufacturing facilities and distribution chains

During the PMA review (Contd)

Be upfront
Even if you slip it in the back of volume 65, well find it! we

Be in touch
With the lead reviewer; please dont call the consulting don reviewers directly unless arranged by the lead reviewer

Be prepared
Have your team ready to answer questions; have copies of the submission and any previously submitted info (i.e., IDE) available Be ready for GMP and BIMO inspections

Be responsive
Answer our questions when you say you will If you dont understand a question, call/email and ask don

During the PMA review (Contd)

Plan to request a Day 100 meeting
You can always cancel if its not needed it

Plan for the possibility of a Panel meeting

FDA will tell you as soon as we know many times decision is driven by data in the PMA

Be ready to interact on labeling

Have your decision makers available for quick turnaround

Work with the epidemiologist on postapproval study plans early our goal is to approve protocol at time of PMA approval

The Long View

Ultimate goal is approval of your PMA FDA is always willing to consider an alternative or a rationale to omit information; however,
Consider whether the time to develop rationale will take longer than the time to do the test Can a compromise on an interim measure be reached? Sometimes saving 2 weeks now will cost you 2 months later think about both the current product and future changes

The Long View (Contd)

Post-approval product iterations Posthttp://www.fda.gov/MedicalDevices/DeviceRegulationand Guidance/GuidanceDocuments/ucm089274.htm
Panel-track PMA supplement Panel180 Day PMA supplement Real-Time Review supplement Realhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance /GuidanceDocuments/ucm089602.htm Special PMA Supplement Changes Being Effected 30 Day Notice supplement http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance /GuidanceDocuments/ucm080192.htm Manufacturing Site Change

Contact Information
ODE
PMA Staff: Nicole Wolanski (Director), Laura Byrd, Lisa Fisher, Laura Byrd, Ed Webman, Wanda Webman, Sawyer-Major, Donna Headlee Sawyer301-796-5640 301- 796-

OIVD
Kelly Wilkicki 301-796-4608 301- 796-

Back-Up Slides

Modular PMA
Contents of a PMA are broken down into well-delineated wellmodules Modular Shell: plan for submission of the modules Typical Modules
FDA and Sponsor agree to contents and timeframe of each No two can overlap timeframes, except for manufacturing Bench testing Animal studies Biocompatibility Manufacturing Clinical data

Guidance Document: http://www.fda.gov/MedicalDevices/DeviceRegulationan dGuidance/GuidanceDocuments/ucm089764.htm

Modular PMA (Contd)

MDUFA II goals for each individual module
75% in 90 days 90% in 120 days

Actions:
Deficiency Letter Acceptance Letter

Unsolicited major amendment resets clock to day 0 Amendments with responses to deficiency letters start new clock Last module (clinical data) reviewed subject to Original PMA goals and actions Full fee due with first module

Expedited PMA
Eligibility based on the following:
Device intended to treat or diagnose a lifelifethreatening or irreversibly debilitating disease or condition, and Device addresses an unmet medical need, as demonstrated by one of the following:
The device represents a breakthrough technology that provides a clinically meaningful advantage over existing technology; or No approved alternative treatment or means of diagnosis exists; or The device offers significant, clinically meaningful advantages over existing approved alternative treatments; or The availability of the device is in the best interest of patients.

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Expedited PMA (Contd)

Actions: same as Original PMAs MDUFA II goals
50% in 180 days (vs 60% for non-Expedited) 90% in 280 days (vs 295 days for nonExpedited)

Guidance Document:

http://www.fda.gov/MedicalDevices/DeviceRegulat ionandGuidance/GuidanceDocuments/ucm089643. htm

180 Day PMA Supplement

for significant changes that affect the safety and effectiveness of the device, such as those involving:
the principle of operation; the control mechanism; the device design or performance; the labeling (e.g., removal of a contraindication); or new testing requirements or acceptance criteria.

clinical data for the original device must still be applicable to the modified device MDUFA II goals
85% in 180 days 95% in 210 days

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Panel Track PMA Supplement

A significant change in design or performance of the device, or a new indication for use of the device, and for which clinical data are generally necessary to provide a reasonable assurance of safety and effectiveness Review similar to the level of an Original PMA
Same MDUFA II goals
60% in 180 days 90% in 295 days

FDA publishes a new Summary of Safety & Effectiveness of the Device (SSED)

Real Time Review PMA Supplement

for a minor change that can be expected within a product line, such as:
device design software instructions for use, warnings, or precautions or other labeling that does not affect the indications or contraindications sterilization and packaging methods. expected for that device type validated according to scientific principles we have relied on in in previous reviews and accepted test methods or procedures for devices of that type adequately supported by pre-clinical or animal testing, with no prenew clinical data typically involving review within a single scientific discipline

In addition, a minor change should be one that is:

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Real Time Review PMA Supplement (Contd)

Sponsor faxes real time review request to Branch Chief time Branch Chief responds within 14 days Meeting/telecon scheduled ~ day 30 - 45 Meeting/telecon FDA issues letter within ~ 1 week of meeting MDUFA II goals:
80% in 60 days 90% in 90 days

Guidance Document http://www.fda.gov/MedicalDevices/DeviceRegulationan dGuidance/GuidanceDocuments/ucm089602.htm

30 Day Notice
Used for modifications to manufacturing procedures or methods of manufacture that affect the safety and effectiveness of the device.
Changes in a manufacturing/sterilization site or to design or performance specifications do not qualify

Compliance has lead review No performance goal; Statutory timeframe: 30 Days

If deficiencies noted, placed on hold and converted to a 135 Day Supplement

Guidance Document http://www.fda.gov/MedicalDevices/DeviceRegulationan dGuidance/GuidanceDocuments/ucm080192.htm

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PMA Annual Report

Required per 814.84 No performance goal; Internal 90 day review goal Contents:
Identification of changes described in 814.39(a) (PMA supplements) and changes required to be reported to FDA under 814.39(b). Bibliography and summary of the following information not previously submitted as part of the PMA and that is known to or reasonably should be known to the applicant:
unpublished reports of data from any clinical investigations or nonclinical laboratory studies involving the device or related devices devices ("related" devices include devices which are the same or substantially similar to the applicant`s device); and reports in the scientific literature concerning the device.

Special PMA Supplement Changes Being Effected (CBE)

for any change that enhances the safety of the device or the safety in the use of the device, such as:
labeling changes that add or strengthen a contraindication, warning, precaution, or information about an adverse reaction; labeling changes that add or strengthen an instruction that is intended to enhance the safe use of the device; labeling changes that delete misleading, false, or unsupported indications; and changes in quality controls or the manufacturing process that add a new specification or test method, or otherwise provide additional assurance of purity, identity, strength, or reliability of reliability the device.

No user fee; no performance goal; internal 30 day review goal

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FY11 MDUFA Fees

Original PMA Panel Track Supplement 180 Day Supplement Real Time Review Supplement 30 Day Notice Special CBE Annual Report Guidance Documents $236,298 $177,224 $35,445 $16,541 $3,781 no fee $8,270

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidan ce/GuidanceDocuments/ucm089726.htm http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidan ce/GuidanceDocuments/ucm089744.htm

Medical Device User Fee and Modernization Act (MDUFMA) http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ Overview/MedicalDeviceUserFeeandModernizationActMDUFMA/defau lt.htm Important Information on the Medical Device User Fee Rates for FY2011* http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ Overview/MedicalDeviceUserFeeandModernizationActMDUFMA/ucm1 09179.htm (*see next slide for table of user fees for FY11) FY

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FY 2011 Fees for Review of Premarket Applications

Submission
Premarket Application (PMA, PDP, BLA, PMR)

Standard Fee Small Business Fee

$236,298

$59,075
Fee is Waived

First premarket application from firms Not Applicable with gross receipts or sales < $30 million

Panel-track Supplement PanelEfficacy Supplement (for BLA) 180-day Supplement 180Real-time Supplement RealAnnual Report 30-day Notice 30-

$177,224 $236,298 $35,445 $16,541 $8,270 $3,781

$44,306 $59,075 $8,861 $4,135 $2,068 $1,890

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