1. Recalls and Field Corrections IMDMC FDA Regulatory 102 May 19, 2016

2. Field Actions - Introduction FDA Recall Classification and Authority Part 806 – Reports of Corrections and Removals Implementation, Recall Lifecycle, & Publicity 2 Agenda

3. Trickle Down Drivers – Med Devices U.S. FDA European Medicines Agency (European Community) Food, Drug, and Cosmetic Act (Law) Regulation (Title 21 CFR, Mostly 800’s) Directives (MDD, AIMDD, IVDD) ISO 13485 & 14971 Guidance Documents Recognized Standards MEDDEV Guidance Consensus Standards Forms 3

4. Trickle Down – Field Actions U.S. FDA European Medicines Agency (European Community) FDCA, 21 U.S.C. 321, 331, 332, 333, 334, 351, 352, 360h, 371, 374, 375, 519(f) Regulation – 806, 810, 7 (Title 21 CFR) MDD Various Annexes, Sec 3.1 “Guidance” – Some of Part 7MEDDEV 2-12.1 (no form)FSCA & FSN Form 4

5. US and Europe 5

6. FDA Classification System - Recalls Recall classification means the numerical designation, i.e., I, II, or III, assigned by the Food and Drug Administration to a particular product recall to indicate the relative degree of health hazard presented by the product being recalled. (1) Class I is a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death. (2) Class II is a situation in which use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote. (3) Class III is a situation in which use of, or exposure to, a violative product is not likely to cause adverse health consequences. 21 CFR Part 7.3 6

7. FDA Classification System - Recalls Class I: Dangerous or defective products that predictably could cause serious health problems or death. Examples include: food found to contain botulinum toxin, food with undeclared allergens, a label mix-up on a lifesaving drug, or a defective artificial heart valve. Class II: Products that might cause a temporary health problem, or pose only a slight threat of a serious nature. Example: a drug that is under-strength but that is not used to treat life-threatening situations. Class III: Products that are unlikely to cause any adverse health reaction, but that violate FDA labeling or manufacturing laws. Examples include: a minor container defect and lack of English labeling in a retail food. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm049070.htm 7

8. FDA Authority – MedDev Recalls Part 810 – Medical Device Recall Authority Subpart B--Mandatory Medical Device Recall Procedures Sec. 810.10 Cease distribution and notification order. (a) If, after providing the appropriate person with an opportunity to consult with the agency, FDA finds that there is a reasonable probability that a device intended for human use would cause serious, adverse health consequences or death, the agency may issue a cease distribution and notification order requiring the person named in the order to immediately: (1) Cease distribution of the device; (2) Notify health professionals and device user facilities of the order; and (3) Instruct these professionals and device user facilities to cease use of the device. 8

9. PART 806 Medical Device Reports of Corrections and Removals

10. 10 At the same time, the Neuro division is working through some HAO related product questions. Recently, they have noticed an increased frequency of bleeding in the brain. 2 lots of product manufactured 18 months ago have a reported incidence rate of 5%. Several deaths have been reported. All reports of deaths have been filed as MDRs. What should Acme do? When should they act? Acme Manufacturing

11. Part 806 – Corrections and Removals A few interesting tidbits Part 806 is specific to reports and records for medical devices. There are not similar CFR’s established for other sectors that FDA regulates (Drugs, Biologics, Food, Veterinary Medicine) Part 806 established in 1997 as the result of the Safe Medical Devices Act (SMDA) of 1990 The word “recall” is not found anywhere in this regulation Part 806 was written because the medical device industry was viewed as the “problem child” when it came to informing FDA of recalls.

12. Part 806 – FDA’s Perspective “Section 519(f) of the act was enacted because Congress was concerned that device manufacturers, distributors, and importers were carrying out product corrections or removals without notifying FDA, or without notifying the agency in a timely fashion (H. Rept. 808, 101st Cong., 2d sess. 29 (1990)). Congress explained that industry’s failure to report corrections and removals, particularly those undertaken to reduce risks associated with the use of a device, ‘‘denies the agency the opportunity to fulfill its public health responsibilities by evaluating device related problems and the adequacy of corrective actions’’ (S. Rept. 513, 101 st Cong., 2d sess. 23 (1990)), and ‘‘has seriously interfered with FDA’s ability to take prompt action against potentially dangerous devices’’ (H. Rept. 808, 101 st Cong., 2d sess. 29 (1990)).” http://www.gpo.gov/fdsys/pkg/FR-1997-05-19/pdf/97-13064.pdf 12

13. 21 CFR Part 806 – Medical Devices Reports of Corrections and Removals “This part implements the provisions of section 519(f) of the Federal Food, Drug, and Cosmetic Act (the act) requiring device manufacturers and importers to report promptly to the Food and Drug Administration (FDA) certain actions concerning device corrections and removals, and to maintain records of all corrections and removals regardless of whether such corrections and removals are required to be reported to FDA”

14. Medical Device Recall “Regulatory-speak” at FDA RemovalCorrection Reduces risk to health. Corrects FD&CA violation that is not minor. “Recall” 806 Report “Recall” 806 Report Does not reduce risk to health Violation is “minor” Removal Market Withdrawal 806 Record Correction 806 Record

15. Part 806 – “Reportable” and “Recordable”

16. “Correction” Correction means the repair, modification, adjustment, relabeling, destruction, or inspection (including patient monitoring) of a device without its physical removal from its point of use to some other location.

17. “Market Withdrawal” Market withdrawal means a correction or removal of a distributed device that involves a minor violation of the act that would not be subject to legal action by FDA or that involves no violation of the act, e.g., normal stock rotation practices.

18. “Removal” Removal means the physical removal of a device from its point of use to some other location for repair, modification, adjustment, relabeling, destruction, or inspection.

19. “Risk to Health” Risk to health means (1) A reasonable probability that use of, or exposure to, the product will cause serious adverse health consequences or death; or (2) That use of, or exposure to, the product may cause temporary or medically reversible adverse health consequences, or an outcome where the probability of serious adverse health consequences is remote.

20. “Stock Recovery” Stock recovery means the correction or removal of a device that has not been marketed or that has not left the direct control of the manufacturer, i.e., the device is located on the premises owned, or under the control of, the manufacturer, and no portion of the lot, model, code, or other relevant unit involved in the corrective or removal action has been released for sale or use.

21. Warning letter to Intuitive Surgical July 2013 “Failure to submit a written report to FDA within 10 working days of any correction or removal of a device if the correction or removal was initiated to reduce the risk to health posed by the device or to remedy a violation of the act which may present a risk to health as required by 21 CFR 806.10(b). … In October 2011, intuitive Surgical, Inc. initiated a separate field correction by sending letters to da Vinci Surgical System clients with information for inspecting the instrument cannulas, proper flushing of the instruments, and proper transportation of the da Vinci Surgical System between buildings. Though the field action was undertaken to reduce a risk to health posed by the device, you failed to report the field action to the FDA as required. Your report of this recall on April 19, 2013 has been classified by FDA as a Class II recall, Z- 1428-2013.

22. Stryker Warning Letter, March 2013 …For example, since January 2011, your firm filed seven separate MDR reports regarding broken casters on the Neptune 2 waste management system. The MDR reports were related to either complaints of back pain associated with trying to move the device with broken or stuck casters or of the device tipping over when potentially filled with bio-hazardous waste. The preliminary hazard analyses (PHA) for the device shows a severity level of “3” (any failure resulting in reversible injuries requiring medical intervention) for the hazard of the Neptune 2 tipping over, PHA-008. On May 24, 2011, your firm completed a Health Hazard Evaluation and determined that injuries associated with the Neptune 2 tipping over were temporary or reversible. Once this determination was made, your firm initiated what was termed a “nonreportable” Field Action to replace affected units. This action, which has been classified by FDA as a class II recall, was not reported to FDA within ten working days.

23. IMPLEMENTATION & LIFECYCLE Recalls

24. Code Talk at Your Company If you are in meetings and these are words being used to discuss an issue… –Swap –Upgrade –Exchange –Tradeout –Planned Obsolescence –Directed Return –Change out –Field Upgrade …you are probably talking about a removal action that is regulated under Part 806 If you are in meetings and these are words being used to discuss an issue… –Upgrade –Repair –Tips and Pearls –Field Bulletin –Alert –Surgical technique correction/addenda –Improvement –Modify …you may be talking about a correction that is regulated under Part 806

25. 25 Too many lots are failing final assembly testing because they collapsed when exposed to pressures less than what is found in the current product specifications. These specifications are based on human anatomical studies. This project team is considering a material change, new processing equipment or a change in acceptance criteria as ways to address this issue How does Part 806 apply to this situation? Of the options the project team is considering, which seems most problematic to you? Acme Manufacturing

26. CAPA and Field Actions 26 Distributed or In Use Finished Goods Considerations & Risks –“Pseudo-CAPA” –Tweaks –Dead-Ends –Scope/Bounding WIP Running – “next lot” Document your CAPA or recall rationale for anything less than the largest scope

27. The Lifecycle of a Recall(?) Recall the Product Tell FDA Done!

28. FDA Office of Reg. Affairs Detroit District Office (1 of 21) Center for Devices And Radiological Health (CDRH) Office of Device Evaluation Office of Compliance Office of Surveillance and Biometrics Office of In Vitro Diagnostics Office of Science and Eng. Labs Office of Mgmt. Ops Office of Communications CBER CFSAN CVM CDER Office Comb. Prod. Other offices FDA Structure – “Indiana & Device-centric”

30. What You Provide to FDA for a Reportable Correction or Removal (Recall) Initial Report to FDA –Main Report – Issue, Cause, Recall Strategy (806.10 Elements) –A Health Hazard Evaluation –Copies of all MDR’s (Medical Device Reports) –Name and Address of all first consignees –Labels and Labeling –Copy of Consignee Notification Letter –“Dear Dr.” Letter To Close a Recall (requested in the “classification” letter) –Report of recall results and effectiveness checks –Names and addresses of non-responsive accounts –Names and addresses of users notified –Corrective actions –CAPA record (if requested) –What you did with recalled product

31. Leading up to FDA Classification HHE FDA presumption that risk is not mitigated by the actions of the end user Use of MD’s, including an epidemiologist Sec. 7.41 Health hazard evaluation and recall classification. – (a) An evaluation of the health hazard presented by a product being recalled or considered for recall will be conducted by an ad hoc committee of Food and Drug Administration scientists and will take into account, but need not be limited to, the following factors: Root Cause Analysis 31

32. Health Hazard Evaluation 32

33. Part 7 – Implementation Guidance Regulation written as “guidance” Applicable to all FDA regulated segments Key Elements –Recall Strategy –Consignee Notification –Depth of Recall –Effectiveness Level –Effectiveness Checks By the recalling firm By FDA

34. The “Classification Letter”

35. The “Termination Letter”

36. Publicity and Publication FDA Enforcement Report CDRH Recalls Database Class I Recalls Company Press Releases Web resources Watchdog groups ECRI, Gray Sheet, etc. Investor Community 36