The Current PMA Requirements Too Costly, Too Slow: The Current PMA Requirements Keith Dawkins MD FRCP FACC FSCAI Global Chief Medical Officer Executive Vice President Boston Scientific Corporation

Conflict of Interest Boston Scientific Corporation Employee Stockholder

Disclaimer ‘Too Costly, Too Slow: The Current PMA Requirements’ This title was chosen by Ron Waksman MD, and does not reflect the views of Boston Scientific Corporation…

The Perception… ‘Unpredictable, inefficient, and expensive regulatory processes are jeopardizing America’s leadership position in Medtech innovation....’ ‘U.S. patients waited an average of two years longer than those in Europe to gain access to new medical technologies from the survey companies….’

Notification of Approval (§814.44) PMA Review Process File a PMA (21 CFR. 814.42) In-depth review (21 CFR 814.44) Panel Review (21 CFR 814.44) Notification of Approval (§814.44)

Steps in the PMA Application Process ODE filing review OSB statistical review for filing OC review of manufacturing information for compliance with the Quality System regulation (21 CFR 820). PMA filing decision Day-100 Meeting Quality System Inspection(s) by the FDA field personnel. An FDA manufacturing inspection is conducted for all original PMAs and may be conducted for PMA supplements requesting approval of alternate or additional manufacturing and sterilization facilities. Bioresearch Monitoring (BIMO) Audit (audit of clinical study data) Substantive review coordination and completion in areas such as: Preparation of FDA Summary of Safety and Effectiveness Data (SSED) Nonclinical Studies Microbiological, Toxicological, Immunological, Biocompatibility, Shelf Life, Analytical (for IVDs), Animal, Engineering (Stress, Wear, Fatigue, etc.)] Clinical Studies Panel Meeting Decision and Mailing (if panel meeting is appropriate) Panel Date (if appropriate) Transcripts Received, Reviewed and Placed in Administrative Record QS/GMP Clearance Final Response from OC for GMP/BIMO Final ODE Decision Memo Approval Package Approval Order, SSED, Final Draft Labeling

Early Communication & Collaboration… …is the Key to Timely Device Approval

EFS: An alternative Pathway Andrew Farb, MD & Dorothy Abel (CDRH)

Early Feasibility Study ‘FDA recognizes the value of encouraging medical device innovation to address clinical needs and improve patient care, particularly when alternative treatments or assessments are unavailable, ineffective, or associated with substantial risks to patient safety. This guidance has been developed to facilitate the early clinical evaluation of medical devices in the United States under the IDE regulations, using risk mitigation strategies that appropriately protect human subjects in early feasibility studies…’

‘When approximately 81% of the applications filed in each fiscal year from 2007 to 2011 had a MDUFA decision, the average number of days to a decision decreased 32%’ http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM329702.pdf

Average Time to MDUFA Decision: PMAs Days http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM329702.pdf

PMAs Pending at End of Year Days http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM329702.pdf

Major Deficiency Letter (%) Percentage of PMAs with Major Deficiency Letter on 1st FDA Review Cycle Major Deficiency Letter (%) * *10 months http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM329702.pdf

Medical Device User Fees (FY 2015) Application Type Standard Small Business* Pre-Market Application $258,520 $64,630 Pre-Market Report Panel-Track PMA Supplement $193,890 $48,473 BLA Efficacy Supplement 180-Day PMA Supplement $38,778 $9,695 Real-Time PMA Supplement $18,096 $4,524 Pre-Market Notification (510k) $5,170 $2,585 30-Day Notice $4,136 $2,068 513(g) Request $3,490 $1,745 Annual Fee for Class III device reporting $9,048 $2,262 *Gross sales of $100 million or less for the most recent tax year

The European regulatory burden is increasing… Notified Bodies National Regulations IMDRF International Medical Device Regulators Forum Medical Device Directive MEDDEV Medical Devices Guidance ISO 14155 Clinical investigation of Medical Devices for Human Subjects (GCP) Device Manufacturer …which may be advantageous to the US

Conclusions The regulatory burden associated with medical device approval is increasing Worldwide The FDA is committed to a premarket review system that gives American patients timely access to safe and effective medical devices and sustains innovation in the device industry The FDA Plan of Action to modernize and improve the premarket review of medical devices has successfully increased the predictability, consistency, transparency, efficiency, and timeliness of premarket review Early communication & collaboration is the key to timely medical device approval