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

1. 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)

2. 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) Medical Device Workshop for Canadian Manufacturers

3. 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 Medical Device Workshop for Canadian Manufacturers

4. 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. Medical Device Workshop for Canadian Manufacturers

5. 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. Medical Device Workshop for Canadian Manufacturers

6. 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. Medical Device Workshop for Canadian Manufacturers

7. 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. Medical Device Workshop for Canadian Manufacturers

8. 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.” Medical Device Workshop for Canadian Manufacturers

9. 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.” Medical Device Workshop for Canadian Manufacturers

10. Recent examples of devices requiring PMA approval prior to marketing Implantable Cardiac Defibrillator (ICD) Intraocular Lens (IOLs) Glucose Monitoring System Gastric Band Deep Brain Stimulator for OCD Cervical Disc Replacement Female Condom Medical Device Workshop for Canadian Manufacturers

11. 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. Medical Device Workshop for Canadian Manufacturers

12. PMA Review Process(Very Simplified Block Diagram) Application Reviews Engineering Not File File Pre-PMA Submission Meeting w/ manufacturer Clinical & Labeling Initial Filing Meeting No Yes “Interactive” Substantive Review Major/Minor Deficiency Statistical Decide Panel Meeting or No Panel Meeting Major Deficiency Letter Inspections Bioresearch Monitoring Labeling Review with Manufacturer Manu- facturing Manufacturer & FDA Meetings can occur during the review FDA/CDRH Decision Letter Medical Device Workshop for Canadian Manufacturers

13. 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 Medical Device Workshop for Canadian Manufacturers

14. 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 Medical Device Workshop for Canadian Manufacturers

15. 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 Medical Device Workshop for Canadian Manufacturers

16. 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 Medical Device Workshop for Canadian Manufacturers

17. 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 Medical Device Workshop for Canadian Manufacturers

18. 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 Medical Device Workshop for Canadian Manufacturers

19. 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 Medical Device Workshop for Canadian Manufacturers

20. Pre-Clinical Test Data: Results • Provide data • Provide analysis of the data • Ensure the test results meet the acceptance criteria • Explain failures and resolutions Medical Device Workshop for Canadian Manufacturers

21. Valid Scientific Evidence – Clinical21 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. Medical Device Workshop for Canadian Manufacturers

22. Clinical Data • Do the study described in the approved or agreed upon protocol? • Study duration • Patient population • Sample size • Assessment Methods Medical Device Workshop for Canadian Manufacturers

23. 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 Medical Device Workshop for Canadian Manufacturers

24. 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 Medical Device Workshop for Canadian Manufacturers

25. 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 futurestudies • Using a subgroup analysis to demonstrate safety or effectiveness for a device will raise issues and questions Medical Device Workshop for Canadian Manufacturers

26. 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 Medical Device Workshop for Canadian Manufacturers

27. 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 Medical Device Workshop for Canadian Manufacturers

28. Use of Standards • CDRH Standards Program http://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 database http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm Medical Device Workshop for Canadian Manufacturers

29. 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 Medical Device Workshop for Canadian Manufacturers

30. 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 Medical Device Workshop for Canadian Manufacturers

31. 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 Medical Device Workshop for Canadian Manufacturers

32. 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 Medical Device Workshop for Canadian Manufacturers

33. 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 Medical Device Workshop for Canadian Manufacturers

34. 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 Medical Device Workshop for Canadian Manufacturers

35. 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 Medical Device Workshop for Canadian Manufacturers

36. 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 Medical Device Workshop for Canadian Manufacturers

37. 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) Medical Device Workshop for Canadian Manufacturers

38. 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 Medical Device Workshop for Canadian Manufacturers

39. 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 Medical Device Workshop for Canadian Manufacturers

40. ClinicalTrials.gov is a registry of federally and privately supported clinical trials globally Medical Device Workshop for Canadian Manufacturers

41. Major Regulatory Pathways Medical Device Workshop for Canadian Manufacturers

42. 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 Medical Device Workshop for Canadian Manufacturers

43. Thank you!