Overview of Premarket Approval (PMA) Program Roy Baby, Investigator US Food & Drug Administration 4040 N Central Expressway, Dallas, TX

What is PMA? Premarket Approval (PMA) A regulatory pathway to market Class III (highest-risk) medical devices Application requires FDA scientific, regulatory review & quality system review. Approval requires reasonable assurance of safety and effectiveness based on intended use Typically requires clinical data Requires payment of User Fee

FY16 User Fees (in US Dollars) Application Type Standard Small Business PMA 261,388 65,347 180 Day Supplement 39,208 9,802 Real Time Supplement 18,297 4,574 PMA Annual Report 9,149 2,287

Legal Framework: Law & Regulations Section 515, Food, Drug and Cosmetic Act (FD&C Act) Part 814, Title 21Code of Federal Regulations (CFR) Section 501(f), FD&C Act Class III device that fails to meet PMA requirements considered adulterated!

Class III: Highest Tier of Scientific Review In comparison to the 510(k) / premarket notification regulatory process, PMA devices are “stand-alone” applications and not based on “substantial equivalence” to a predicate device. Typically, a multidisciplinary Review Team conducts the evaluation. Regulatory review times generally follow longer timelines. Reference: MDUFA III Performance Goals http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM295454.pdf Summary of Safety and Effectiveness Data (SSED) explains the basis of the approval decision.

Examples of devices requiring PMA approval prior to marketing Intraocular Lens Deep Brain Stimulator for OCD Cervical Disc Replacement Gastric Band Implantable Cardioverter Defibrillator (ICD) Glucose Monitoring System

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm

FDA Review: Safety and Effectiveness Valid scientific evidence Well-controlled clinical investigations or other objective information Not opinions, random reports or un-interpretable data Considerations Risks and benefits for indicated patient population Conditions of device use Device safety, performance and reliability

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.” Safety as defined in 21 CFR 860.7(d)1

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.” Effectiveness as defined in 21 CFR 860.7(e)1

Clinical Studies Clinical studies on human subjects that are conducted within the United States and U.S. territories must comply with medical devices Good Clinical Practices regulations. These regulations include: Investigation Device Exemption (IDE), 21 CFR 812, Protection of Human Subjects, 21 CFR 50, and Institutional Review Boards, 21 CFR 56 Clinical Investigators Financial Disclosure, 21 CFR 54 Design Controls (QSR), 21 CFR 820 subpart C Regulations apply to the manufacturers, sponsors, clinical investigators, institutional review boards, and the medical device

Acceptance of Foreign Clinical Studies If conducting an IDE study outside the US in support of a PMA, then it will be beneficial to have foreign sites follow the same study protocol. If the study in the foreign site is not under an IDE, the study must be in accordance with the Declaration of Helsinki and the laws/regulations of that country whichever offered greater human subjects protection. Potential challenges: Different patient demographics Differences in practice of medicine/standard of care Lack of robust clinical protocol/patient follow-up Guidance for Industry - Acceptance of Foreign Clinical Studies http://www.fda.gov/RegulatoryInformation/Guidances/ucm124932.htm

Pre-Submission Sponsors who seek approval based solely on foreign data are encouraged to meet early with FDA officials “pre-IDE” meeting prior to submission of the IDE application “pre-PMA” meeting prior to submission of the PMA application Provides the opportunity for the sponsor to obtain FDA feedback prior to intended submission of an investigational device exemption or marketing application Draft Guidance for Industry and FDA Staff Medical Devices: The Pre-Submission Program and Meetings with FDA Staff http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm310375.htm

PMA Review Process: Filing a PMA Within 45 days receipt of PMA, FDA will notify the applicant whether the application has been filed. Meets minimum threshold of acceptability, i.e., application is sufficiently complete to begin in-depth review. Information required by the FD&C Act, PMA regulations, 21 CFR 814, and Refuse to File Policy Checklist for Filing Decision for PMAs. Guidance for Industry and FDA Staff: Premarket Approval Application Filing Review http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089 430.htm

PMA Review Process: In-depth Scientific, Regulatory, Quality System Review Multidisciplinary and team-based review Communicates deficiencies to sponsor either interactively or in major deficiency letter (puts PMA on hold) Internal meetings Filing meeting Team meetings PMA Guidance Documents e.g. Filing Review Statistical Checklist Others Interactive Review with Sponsor

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm143067.htm

PMA Review Process (Very Simplified Block Diagram) Application Not File File Pre-PMA Submission Meeting FDA & Sponsor Filing Meeting No Yes “Interactive” Substantive Review Major/Minor Deficiency “Day-100 Meeting” Major Deficiency Letter Advisory Panel Review recommendations may be needed to address new safety and effectiveness questions Labeling Review with Manufacturer FDA/CDRH Decision Letter Approval Package: Approval Order, SSED, Final Draft Labeling

PMA Review Determinations Approval: Device can be marketed Letter of Approval (may include conditions of approval such as annual reports, restricted users, etc.) 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

Post Approval Study (PAS) FDA has authority to require sponsor to perform PAS at the time of PMA approval to help ensure continued safety and effectiveness (or continued probable benefit, in the case of an HDE) of the approved PMA device. The CDRH Post-Approval Studies Program encompasses design, tracking, oversight, and review responsibilities for studies mandated as a condition of approval.

Changes Requiring a PMA Supplement Changes affecting safety and effectiveness of the PMA-approved device. Examples of changes, but not limited to the following: New indication for use Labeling changes Use of different facility or establishment to manufacture, process, sterilize of package the device Changes in sterilization procedures, packaging Changes in performance or design specifications, circuits, components, principles of operation

180-day Supplements Examples Addition of a new diameter or length sizes to a vascular stent Change in software for an excimer laser system A new mechanism of action for a vascular stent delivery system Down-sized or less-featured model based on the identical platform of a family of pulse generators. Typical supplements for significant changes to: Design Materials Labeling Specifications Software May go to advisory panel

Real-Time Supplements Real-time Review (does not need to be face to face) Minor device change Change must be expected for the device type Supported by well-characterized non-clinical data Review involves a single scientific discipline Requires agreement between FDA and sponsor that real-time review is appropriate Sponsor submits request prior to submitting supplement Usually within 30 days Questions and concerns about device changes FDA provides feedback Official response letter to be sent later Guidance for Industry and FDA Staff: Real-Time Premarket Approval Application (PMA) Supplements http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089602.htm New manufacturing specification Extension of shelf-life New packaging configuration

Panel-Track Supplements Significant changes to: Indications for use Device design or performance Substantial clinical data to provide a reasonable assurance of safety and effectiveness. Examples Expansion of indications for ventricular assist device (VAD) from bridge-to-transport to destination therapy Change in indications for vascular stent from use in coronary arteries to use in renal arteries New graft material for an aortic aneurysm endovascular graft

30-Day Notice & 135 PMA Supplement Modifications to manufacturing process 135-Day Supplement required if the 30-Day Notice is inadequate Guidance for Industry and FDA Staff - 30-Day Notices, 135-Day Premarket Approval (PMA) Supplements and 75-Day Humanitarian Device Exemption (HDE) Supplements for Manufacturing Method or Process Changes http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080192.htm Automating a previously manual process New manufacturing equipment New sterilization process

Special PMA Supplement Special PMA Supplement -- Changes Being Effected Changes that enhance the safety of device Can be implemented prior to FDA approval 30-day review New quality assurance step New warnings to labeling

Expedited Reviews Device intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition, and No approved alternative treatment or means of diagnosis May offer significant advances over alternatives Breakthrough technology Availability is in best interest of patients Expedited application receives priority review Not always a faster review time Guidance for Industry and FDA Staff: Expedited Review of Premarket Submissions for Devices http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089643.htm

PMA Supplement vs. Amendment PMA supplement (e.g., P130001/S001; P130001/S002) required for a change affecting the safety or effectiveness of the device for which the applicant has an approved PMA A PMA amendment (e.g., P130001/A1, A2, etc. or P130001/S001/A1, etc.) all additional submissions to a PMA or PMA supplement before approval of the PMA or PMA supplement OR all additional correspondence after PMA or PMA supplement approval Note: Additional information provided to FDA for PMA supplement under review are amendments to a supplement.

HUD and HDE An HUD (Humanitarian Use Device) is a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in fewer than 4,000 individuals annually in the United States. An HDE (Humanitarian Device Exemption) is a marketing application submitted to FDA in order to obtain approval of an HUD. similar in both form and content to (PMA) application, but is exempt from the effectiveness requirements of a PMA. Label as Humanitarian Use Device (HUD) - Effectiveness for the specific indication has not been demonstrated http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/HumanitarianDeviceExemption/default.htm

HDE Requirements An incentive for development of devices intended for treatment or diagnosis, in small populations where otherwise a device manufacturer’s R&D costs could exceed market returns Must contain sufficient information for FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury, i.e., safety and probable benefit outweighs the risk Must demonstrate no comparable devices are available to treat or diagnose the disease or condition, via 510(k) or PMA Only used in facilities with established IRB

Summary The PMA program is a regulatory pathway to market Class III devices, the most stringent requirements for medical devices. FDA review generally begins with administrative and limited review, followed by in-depth scientific, regulatory and Quality System review, if determined suitable for “filing.” PMA data must demonstrate reasonable assurance of Safety and Effectiveness, typically with clinical data. Applicant must receive the FDA PMA approval letter prior to introduction of the device into the U.S. interstate commerce.

Selected References Premarket Approval Application Filing Review Refuse to File Policy Checklist for Filing Decision for PMAs http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089430.htm Guidance on PMA Interactive Procedures for Day 100-Meetings and Subsequent Deficiencies Discuss review status of PMA http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080190.htm Panel Review of Premarket Approval Applications #P91-2 (blue book memo) Guidance for Panel Review http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm081363.htm

Industry Education Resources Three Resources CDRH Learn – Multi-Media Industry Education over 80 modules videos, audio recordings, power point presentations, software-based “how to” modules mobile-friendly: access CDRH Learn on your portable devices http://www.fda.gov/Training/CDRHLearn Device Advice – Text-Based Education comprehensive regulatory information on premarket and postmarket topics www.fda.gov/MedicalDevices/DeviceRegulationandGuidance Division of Industry and Consumer Education (DICE) Contact DICE if you have a question Email: DICE@fda.hhs.gov Phone: 1(800) 638-2014 or (301) 796-7100 (Hours: 9 am-12:30 pm; 1 pm-4:30pm EST) Web: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ContactUs--DivisionofIndustryandConsumerEducation/default.htm 32