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Development of a Development of a PMA Submission PMA Submission

StrategyStrategy

Laura J. ByrdPremarket Approval SectionFDA/CDRH/ODE

TopicsTopics

Know your product Know your product Desired patient populationDesired patient populationDesired claimsDesired claims

Early interactions with FDAEarly interactions with FDADevelopment of testing requirements and Development of testing requirements and strategystrategy

Managing changeManaging changeDuring the PMA reviewDuring the PMA reviewThe Long ViewThe Long View

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Know your productKnow your productPMAs are submitted for a device plus its PMAs are submitted for a device plus its indicationindication

DeviceDeviceWhat is it? How is it made? What is the primary What is it? How is it made? What is the primary mechanism of action?mechanism of action?

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

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

Early interactions with FDAEarly interactions with FDA

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

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Early interactions with FDAEarly interactions with FDADuring the IDEDuring the IDE……

Changes to the device design or protocolChanges to the device design or protocolPreplanning for the PMA, especially if modularPreplanning for the PMA, especially if modular

PrePre--PMA meetingPMA meeting……Content and format of PMA submissionContent and format of PMA submissionPresentation of data (especially clinical and statistical)Presentation of data (especially clinical and statistical)Additional analyses or testing needed to address Additional analyses or testing needed to address changes made to device or protocol during the IDE changes made to device or protocol during the IDE studystudy

Early interactions with FDAEarly interactions with FDA

PrePre--PMA meeting (cont.)PMA meeting (cont.)……Analyses specific to inclusion of foreign dataAnalyses specific to inclusion of foreign data

Plans to address Plans to address ““future PMA concernsfuture PMA concerns””

Special data requests for statisticians, BIMOSpecial data requests for statisticians, BIMOSee See ““Electronic clinical dataElectronic clinical data”” at at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuihttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/ucm1dance/HowtoMarketYourDevice/PremarketSubmissions/ucm134508.htm34508.htm

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

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Managing changeManaging change

Device industry and clinical practice are constantly Device industry and clinical practice are constantly changingchangingIf modification needed, possible to incorporate the If modification needed, possible to incorporate the change without significant disruptionchange without significant disruption

Talk to us about the changeTalk to us about the changeWork with our statisticians to plan for appropriate Work with our statisticians to plan for appropriate analysesanalysesEarlier in the clinical study is better (donEarlier in the clinical study is better (don’’t request a t request a change with 5 patients left to enroll!)change with 5 patients left to enroll!)If need for change arises late, consider whether data If need for change arises late, consider whether data could be collected in a postapproval setting, if study is could be collected in a postapproval setting, if study is planned or anticipated (note that data would need to be planned or anticipated (note that data would need to be collected under IDE)collected under IDE)

Managing changeManaging change

Unanticipated changesUnanticipated changesManufacturing scaleManufacturing scale--up (clinical to up (clinical to commercial) commercial) Changes by vendor (or to a different vendor) Changes by vendor (or to a different vendor) for significant components for significant components Changes in clinical practice patterns, Changes in clinical practice patterns, availability of alternative therapiesavailability of alternative therapies

Bottom line: plan for changes to occurBottom line: plan for changes to occur

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During the PMA reviewDuring the PMA review

Managing expectations with respect to timelinesManaging expectations with respect to timelinesManagementManagement

Understand FDAUnderstand FDA’’s Interactive Review policies and s Interactive Review policies and procedures procedures –– be prepared for rapid turnbe prepared for rapid turn--aroundaround

http://www.fda.gov/downloads/MedicalDevices/Dehttp://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uviceRegulationandGuidance/GuidanceDocuments/ucm089425.pdfcm089425.pdf

With MDUFA II timelines, only one round of major With MDUFA II timelines, only one round of major deficiencies deficiencies –– next step either will be approval or next step either will be approval or not approvablenot approvable

Example Timeline (MDUFA II)Example Timeline (MDUFA II)

0 60 120 180 240 360300

FDA initial

review Major Deficiency

Letter

Sponsor prepares responses; often

consults with FDA

Amendment

FDA 2nd review; may include

Panel Meeting

Approval Order

Total days

Initial submission

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During the PMA reviewDuring the PMA review

Managing expectations with respect to Managing expectations with respect to timelinestimelines

Marketing Marketing Please donPlease don’’t print your labeling the week t print your labeling the week after the PMA is filedafter the PMA is filed

ManufacturingManufacturingBe realistic when advising on timelines for Be realistic when advising on timelines for ramp up of manufacturing facilities and ramp up of manufacturing facilities and distribution chainsdistribution chains

During the PMA review (ContDuring the PMA review (Cont’’d)d)

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

Be in touch Be in touch With the lead reviewer; please donWith the lead reviewer; please don’’t call the consulting t call the consulting reviewers directly unless arranged by the lead reviewerreviewers directly unless arranged by the lead reviewer

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

Be responsiveBe responsiveAnswer our questions when you say you willAnswer our questions when you say you willIf you donIf you don’’t understand a question, call/email and askt understand a question, call/email and ask

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During the PMA review (ContDuring the PMA review (Cont’’d)d)

Plan to request a Day 100 meetingPlan to request a Day 100 meetingYou can always cancel if itYou can always cancel if it’’s not neededs not needed

Plan for the possibility of a Panel meetingPlan for the possibility of a Panel meetingFDA will tell you as soon as we know FDA will tell you as soon as we know –– many times many times decision is driven by data in the PMAdecision is driven by data in the PMA

Be ready to interact on labelingBe ready to interact on labelingHave your decision makers available for quick Have your decision makers available for quick turnaroundturnaround

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

The Long ViewThe Long View

Ultimate goal is approval of your PMAUltimate goal is approval of your PMA

FDA is always willing to consider an alternative FDA is always willing to consider an alternative or a rationale to omit information; however,or a rationale to omit information; however,

Consider whether the time to develop rationale will Consider whether the time to develop rationale will take longer than the time to do the testtake longer than the time to do the test

Can a compromise on an interim measure be Can a compromise on an interim measure be reached?reached?

Sometimes saving 2 weeks now will cost you 2 Sometimes saving 2 weeks now will cost you 2 months later months later –– think about both the current product think about both the current product andand future changesfuture changes

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The Long View (ContThe Long View (Cont’’d)d)

PostPost--approval product iterationsapproval product iterationshttp://www.fda.gov/MedicalDevices/DeviceRegulationandhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089274.htmGuidance/GuidanceDocuments/ucm089274.htm

PanelPanel--track PMA supplementtrack PMA supplement180 Day PMA supplement180 Day PMA supplementRealReal--Time Review supplementTime Review supplementhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidancehttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089602.htm/GuidanceDocuments/ucm089602.htmSpecial PMA Supplement Special PMA Supplement –– Changes Being Effected Changes Being Effected 30 Day Notice supplement30 Day Notice supplementhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidancehttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080192.htm/GuidanceDocuments/ucm080192.htmManufacturing Site ChangeManufacturing Site Change

Contact InformationContact Information

ODE ODE PMA Staff: Nicole PMA Staff: Nicole WolanskiWolanski (Director), Laura Byrd, (Director), Laura Byrd, Lisa Fisher, Laura Byrd, Ed Lisa Fisher, Laura Byrd, Ed WebmanWebman, Wanda , Wanda SawyerSawyer--Major, Donna Major, Donna HeadleeHeadlee301301--796796--56405640

OIVD OIVD Kelly Kelly WilkickiWilkicki301301--796796--46084608

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BackBack--Up SlidesUp Slides

Modular PMAModular PMAContents of a PMA are broken down into wellContents of a PMA are broken down into well--delineated delineated modulesmodulesModular Shell: plan for submission of the modulesModular Shell: plan for submission of the modules

FDA and Sponsor agree to contents and timeframe of eachFDA and Sponsor agree to contents and timeframe of eachNo two can overlap timeframes, except for manufacturingNo two can overlap timeframes, except for manufacturing

Typical ModulesTypical ModulesBench testingBench testingAnimal studiesAnimal studiesBiocompatibilityBiocompatibilityManufacturingManufacturingClinical data Clinical data

Guidance Document: Guidance Document: http://www.fda.gov/MedicalDevices/DeviceRegulationanhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089764.htmdGuidance/GuidanceDocuments/ucm089764.htm

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Modular PMA (ContModular PMA (Cont’’d)d)MDUFA II goals for each individual moduleMDUFA II goals for each individual module

75% in 90 days 75% in 90 days 90% in 120 days90% in 120 days

Actions:Actions:Deficiency LetterDeficiency LetterAcceptance Letter Acceptance Letter

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

Expedited PMAExpedited PMA

Eligibility based on the following:Eligibility based on the following:Device intended to treat or diagnose a lifeDevice intended to treat or diagnose a life--threatening or irreversibly debilitating disease or threatening or irreversibly debilitating disease or condition, and condition, and Device addresses an unmet medical need, as Device addresses an unmet medical need, as demonstrated by one of the following: demonstrated by one of the following:

The device represents a breakthrough technology that The device represents a breakthrough technology that provides a clinically meaningful advantage over existing provides a clinically meaningful advantage over existing technology; or technology; or No approved alternative treatment or means of diagnosis No approved alternative treatment or means of diagnosis exists; or exists; or The device offers significant, clinically meaningful advantages The device offers significant, clinically meaningful advantages over existing approved alternative treatments; or over existing approved alternative treatments; or The availability of the device is in the best interest of The availability of the device is in the best interest of patients.patients.

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Expedited PMA (ContExpedited PMA (Cont’’d)d)

Actions: same as Original Actions: same as Original PMAsPMAsMDUFA II goalsMDUFA II goals

50% in 180 days (50% in 180 days (vsvs 60% for non60% for non--ExpeditedExpedited))90% in 280 days (90% in 280 days (vsvs 295 days for non295 days for non--ExpeditedExpedited))

Guidance Document:Guidance Document:http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089643.htm

180 Day PMA Supplement180 Day PMA Supplementfor significant changes that affect the safety and for significant changes that affect the safety and effectiveness of the device, such as those involving:effectiveness of the device, such as those involving:

the principle of operation; the principle of operation; the control mechanism; the control mechanism; the device design or performance; the device design or performance; the labeling (e.g., removal of a contraindication); or the labeling (e.g., removal of a contraindication); or new testing requirements or acceptance criteria.new testing requirements or acceptance criteria.

clinical data for the original device must still be clinical data for the original device must still be applicable to the modified deviceapplicable to the modified deviceMDUFA II goalsMDUFA II goals

85% in 180 days 85% in 180 days 95% in 210 days 95% in 210 days

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Panel Track PMA SupplementPanel Track PMA Supplement

A significant change in design or performance of A significant change in design or performance of the device, or a new indication for use of the the device, or a new indication for use of the device, and for which clinical data are generally device, and for which clinical data are generally necessary to provide a reasonable assurance of necessary to provide a reasonable assurance of safety and effectiveness safety and effectiveness Review similar to the level of an Original PMAReview similar to the level of an Original PMA

Same MDUFA II goalsSame MDUFA II goals60% in 180 days 60% in 180 days 90% in 295 days 90% in 295 days

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

Real Time Review Real Time Review PMA SupplementPMA Supplement

for a minor change that can be expected within a for a minor change that can be expected within a product line, such as:product line, such as:

device design device design software software instructions for use, warnings, or precautions or other labelinginstructions for use, warnings, or precautions or other labelingthat does not affect the indications or contraindications that does not affect the indications or contraindications sterilization and packaging methods.sterilization and packaging methods.

In addition, a minor change should be one that is:In addition, a minor change should be one that is:expected for that device type expected for that device type validated according to scientific principles we have relied on ivalidated according to scientific principles we have relied on in n previous reviews and accepted test methods or procedures for previous reviews and accepted test methods or procedures for devices of that typedevices of that typeadequately supported by preadequately supported by pre--clinical or animal testing, with no clinical or animal testing, with no new clinical data new clinical data typically involving review within a single scientific disciplinetypically involving review within a single scientific discipline

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Real Time Review Real Time Review PMA Supplement (ContPMA Supplement (Cont’’d)d)

Sponsor faxes Sponsor faxes ““real timereal time”” review request to Branch Chief review request to Branch Chief Branch Chief responds within 14 daysBranch Chief responds within 14 daysMeeting/Meeting/telecontelecon scheduled ~ day 30 scheduled ~ day 30 -- 4545FDA issues letter within ~ 1 week of meetingFDA issues letter within ~ 1 week of meetingMDUFA II goals:MDUFA II goals:

80% in 60 days 80% in 60 days 90% in 90 days 90% in 90 days

Guidance Document Guidance Document http://www.fda.gov/MedicalDevices/DeviceRegulationanhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089602.htmdGuidance/GuidanceDocuments/ucm089602.htm

30 Day Notice30 Day NoticeUsed for modifications to manufacturing procedures or Used for modifications to manufacturing procedures or methods of manufacture that affect the safety and methods of manufacture that affect the safety and effectiveness of the device. effectiveness of the device.

Changes in a manufacturing/sterilization site or to design or Changes in a manufacturing/sterilization site or to design or performance specifications do not qualify performance specifications do not qualify

Compliance has lead reviewCompliance has lead reviewNo performance goal; Statutory timeframe: 30 DaysNo performance goal; Statutory timeframe: 30 Days

If deficiencies noted, placed on hold and converted to a 135 DayIf deficiencies noted, placed on hold and converted to a 135 DaySupplementSupplement

Guidance Document Guidance Document http://www.fda.gov/MedicalDevices/DeviceRegulationanhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080192.htmdGuidance/GuidanceDocuments/ucm080192.htm

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PMA Annual ReportPMA Annual ReportRequired per Required per §§814.84814.84No performance goal; Internal 90 day review goalNo performance goal; Internal 90 day review goalContents:Contents:

Identification of changes described in Identification of changes described in §§814.39(a) (PMA 814.39(a) (PMA supplements) and changes required to be reported to FDA under supplements) and changes required to be reported to FDA under §§814.39(b).814.39(b).Bibliography and summary of the following information not Bibliography and summary of the following information not previously submitted as part of the PMA and that is known to or previously submitted as part of the PMA and that is known to or reasonably should be known to the applicant:reasonably should be known to the applicant:

unpublished reports of data from any clinical investigations or unpublished reports of data from any clinical investigations or nonclinical laboratory studies involving the device or related dnonclinical laboratory studies involving the device or related devices evices ("related" devices include devices which are the same or ("related" devices include devices which are the same or substantially similar to the substantially similar to the applicant`sapplicant`s device); and device); and reports in the scientific literature concerning the device.reports in the scientific literature concerning the device.

Special PMA SupplementSpecial PMA SupplementChanges Being Effected (CBE)Changes Being Effected (CBE)for any change that enhances the safety of the device or for any change that enhances the safety of the device or the safety in the use of the device, such as:the safety in the use of the device, such as:

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

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

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FYFY’’11 MDUFA Fees11 MDUFA FeesOriginal PMAOriginal PMA $236,298$236,298Panel Track SupplementPanel Track Supplement $177,224 $177,224 180 Day Supplement180 Day Supplement $35,445 $35,445 Real Time Review SupplementReal Time Review Supplement $16,541 $16,541 30 Day Notice30 Day Notice $3,781 $3,781 Special CBESpecial CBE no feeno feeAnnual ReportAnnual Report $8,270 $8,270

Guidance DocumentsGuidance Documentshttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidanhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089726.htmce/GuidanceDocuments/ucm089726.htmhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidanhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089744.htmce/GuidanceDocuments/ucm089744.htm

Medical Device User Fee and Modernization Act (MDUFMA)Medical Device User Fee and Modernization Act (MDUFMA)

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/MedicalDeviceUserFeeandModernizationActMDUFMA/defauOverview/MedicalDeviceUserFeeandModernizationActMDUFMA/default.htmlt.htm

Important Information on the Medical Device User Fee Rates for Important Information on the Medical Device User Fee Rates for FY2011*FY2011*

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/MedicalDeviceUserFeeandModernizationActMDUFMA/ucm1Overview/MedicalDeviceUserFeeandModernizationActMDUFMA/ucm109179.htm09179.htm

(*see next slide for table of user fees for FY(*see next slide for table of user fees for FY’’11)11)

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FY 2011 Fees for Review of Premarket ApplicationsFY 2011 Fees for Review of Premarket Applications

$1,890$1,890$3,781$3,7813030--day Noticeday Notice

$2,068$2,068$8,270$8,270Annual ReportAnnual Report

$4,135$4,135$16,541$16,541RealReal--time Supplementtime Supplement

$8,861$8,861$35,445$35,445180180--day Supplementday Supplement

$59,075$59,075$236,298$236,298Efficacy Supplement (for BLA)Efficacy Supplement (for BLA)

$44,306$44,306$177,224$177,224PanelPanel--track Supplementtrack Supplement

Fee is WaivedFee is WaivedNot ApplicableNot ApplicableFirst premarket application from firms First premarket application from firms with gross receipts or sales < $30 millionwith gross receipts or sales < $30 million

$59,075$59,075$236,298$236,298Premarket Application (PMA, PDP, Premarket Application (PMA, PDP, BLA, PMR)BLA, PMR)

Small Business FeeStandard FeeSubmission