Fireside Chat Playing By The Rules: Navigating The Regulation Pathway Plamena Entcheva-Dimitrov, PhD, RAC, Founder and Principal Consultant – PREFERRED REGULATORY CONSULTING Frank Pokrop, Director Quality and Regulatory Affairs – CAREFUSION INC 1

Fireside Chat - Playing By The Rules: Navigating The Regulation Pathway Clarifying FDA’s standards, expectations, where the rules can or can’t bend, and what to keep in mind for 2016 Reviewing 510(k), de novo, PMA submissions, and understanding what’s expected to change in the approval process How can you position your company for successful market approval? What are the important things to consider before diving into product development, and pivoting your process after the dive? 2

Regulatory Maze CE Mark FDA clearance/approval Sell in Brazil China FDA Sell in Saudi Arabia? 3

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THE BASICS 5

US – a single agency environment FDA - Federal Agency – Part of the Department of Health and Human Services – FDA’s mission is to protect and promote the public health: noble and honorable job – Established in 1938 with an act of Congress under President FD Roosevelt – What are the Rules for the FDA: The Administrative Procedure Act (APA) 6

CLARIFYING FDA’S STANDARDS, EXPECTATIONS, WHERE THE RULES CAN OR CAN’T BEND, AND WHAT TO KEEP IN MIND FOR

What do you need to know? Good Laboratory Practices Conduct of Human Research Labeling Requirements Recalls Safety Reporting Facility Registration Audits / 483s Food, Drug and Cosmetics Act of 1938 Medical Device Amendments of 1976 The Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 Laws Regulations: Code of Federal Regulations Title 21 Center specific guidance documents Draft Guidances Final Guidances A list B list 8

Final Guidance Topics Prioritized medical device guidance documents that the Agency intends to publish in FY 2015 ("A-list") Final Guidance Topics 1)Applying Human Factors & Usability Engineering to Optimize Medical Device Design – Not yet 2)510(k) Submissions for Medical Devices that Include Antimicrobial Agents – Not yet 3)Balancing Premarket and Postmarket Data Collection for Devices Subject to Premarket Approval- Complete 4)Expedited Access for Premarket Approval of Medical Devices Intended for Unmet Need for Life Threatening of Irreversibly Debilitating Diseases or Conditions - Complete 5)Framework for Regulatory Oversight of Laboratory Developed Tests - Not yet 6)FDA Notification and Medical Device Reporting for Laboratory Developed Tests - Not yet 7)Coronary Drug Eluting Stents-Nonclinical and Clinical Studies - Complete 8)Intent to Exempt Certain Class II and Class I Reserved Medical Devices From Premarket Notification Requirements - Complete 9)Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling - Complete 10)Safety Considerations for 510(k) Submissions to Mitigate the Risks of Misconnections With Small- bore Connectors Intended for Enteral Applications - Complete 11)Submission and Review of Sterility Information in 510(k) Submissions for Devices Labeled as Sterile - Not yet 12)Use of ISO , Biological Evaluation of Medical Devices Part I: Evaluation and Testing (Biocompatibility) - Not yet 9

Guidance Topics FDA - FY and Beyond (“B-list") Guidance Topics 1.General Wellness Products - Complete 2.Medical Device Accessories - Complete 3.Medical Device Decision Support Software – Not yet 4.Benefit-Risk Factors to Consider When Reviewing IDE Submissions - Complete 5.UDI Direct Marking - Complete 6.Informed Consent: Policy for Observational Data Used to Fulfill Device Requirements – Not yet 7.Adaptive Design for Medical Device Clinical Studies - Complete 8.UDI FAQs – Complete in 2014, no new FAQs in 2015, though industry needs more clarity Draft Guidance Topics 1.Medical Device Interoperability 2.Transfer of Ownership of a Premarket Notification: Questions & Answers 3.Direct Access Genetic In Vitro Diagnostics Testing (also known as Direct to Consumer Genetic Testing) 4.Patient Access to Information 5.3D Printing (Technical) 6.Manufacturing Site Change Supplements 7.Use of Symbols in Labeling 10

REVIEWING 510(K), DE NOVO, PMA SUBMISSIONS, AND UNDERSTANDING WHAT’S EXPECTED TO CHANGE IN THE APPROVAL PROCESS 11

Types of pre-market submissions 510(k) – class II devices, need predicate, low and medium risk De novos – class II devices, DOES NOT NEED predicate, low and medium risk Premarket application (PMA) – class III, DOES NOT HAVE a predicate, high risks Eclectic types of submissions: – HUD = humanitarian use device – PDP = product development protocol – BLA = biologics license applications 12

Getting Your Product into the US Market Start: ketyourdevice/default.htm The basic steps recommended by FDA are: Step One: Classify Your Device Step One: Classify Your Device Step Two: Choose the Correct Premarket Submission Step Two: Choose the Correct Premarket Submission Step Three: Prepare the Appropriate Information for your Premarket Submission to the FDA Step Three: Prepare the Appropriate Information for your Premarket Submission to the FDA Step Four: Send your Premarket Submission to the FDA and Interact with FDA Staff during Review Step Four: Send your Premarket Submission to the FDA and Interact with FDA Staff during Review Step Five: Complete the Establishment Registration and Device Listing Step Five: Complete the Establishment Registration and Device Listing 13

HOW CAN YOU POSITION YOUR COMPANY FOR SUCCESSFUL MARKET APPROVAL? IMPORTANT THINGS TO CONSIDER BEFORE DIVING INTO PRODUCT DEVELOPMENT 14

Breakdown the development and approval process Strategy Stage Strategy Stage Design Stage Design Stage Submission Stage 15

Words of Wisdom Look at your RA strategy as a value-adding asset The ultimate validation of your RA strategy is meeting with FDA - use the Pre-Sub process to your advantage - it's free of charge There is always more than one way of doing things - use risk-based approach in developing it  Balance regulatory risks with business risks Re-evaluate your strategy  New or changing legislation, regulations, guidances, standards  New approvals or clearances can impact your design decisions  Recall / warning letter of a competitor  Industry-wide trends If not done right at the get go, it can cause design confusion Damaged relationship with regulators DELAYS = $$$ 16

Considerations for the Broader Regulatory Environment for 2016 and Beyond US Continuance of FDA - UDI requirements Potential Changes in Patient Labeling LDT’s and New Generation Sequencing Ongoing review of clinical requirements… “the Common Rule” EU New version of ISO13485 Pending Issuance of the New MDD – regulations, not directives Pending Issuance of EU- Specific UDI Rules 17

Regulatory: Organizational Questions Make-Up of Today’s Audience? Question: What type of regulatory affairs department works best with:  Start-Ups  1-product, recently approved - small company  “Go’-go” phase – lot’s going on, growing fast  Mid-sized  Large  Global 18

Takeaways Talk to FDA early and often There is no other FDA, so foster good working relationship Play by the rules 19

Resources Professional Groups: – RAPS – DIA – AdvaMed – LinkedIn The Web:

Contact Information Plamena Entcheva-Dimitrov, PhD, RAC, Founder and Principal Consultant PREFERRED REGULATORY CONSULTING Frank Pokrop, Director Quality and Regulatory Affairs CAREFUSION INC 21