Pamela Furman Forrest, Esq. Partner, King & Spalding LLP pforrest@kslaw 202.661.7888

1. Basic Principles of FDA Medical Device Regulation and How FDA Might Have Handled the Recent PIP CrisisBritish Institute of International and Comparative LawJune 10, 2013 Pamela Furman Forrest, Esq.Partner, King & Spalding LLPpforrest@kslaw.com202.661.7888

2. Agenda • Overview of FDA Medical Device Regulation • FDA Premarket Regulatory Scheme • How the Recent PIP Crisis Might Have Been Handled in the U.S.

3. Overview of FDA Medical Device Regulation

4. Definition of “Device” • In general, a medical “device” is an instrument, apparatus, implement, machine, contrivance, implant, invitro reagent, or other similar or related article, including any component, part, or accessory: • Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or • Intended to affect the structure or function of the body of man or other animals. See 21 U.S.C. § 321(h). • Product claims largely determine “device” status • The definition of “device” is interpreted broadly by FDA

5. General Principles • FDA imposes premarket and postmarket requirements on medical devices • The extent of regulation depends upon the device’s perceived risk • In order to be lawfully marketed, a device must comply with applicable premarket and postmarket requirements

6. Risk-Based Classification Scheme • Class I -- “Low risk” • Examples: orthopedic blade, tongue depressor • Typically exempt from premarket review requirements • Subject to postmarket “general controls.” See 21 U.S.C. § 360c(a)(1)(A) • Class II – “Moderate Risk” • Examples: powered wheelchair, endoscope • Typically subject to premarket notification (510(k)), postmarket “general controls,” and potentially “special controls.” See 21 U.S.C. § 360c(a)(1)(B) • Class III – “High Risk” • Examples: breast implants, coronary stents • Typically subject to premarket approval (PMA) and postmarket “general controls.” (See 21 U.S.C. § 360c(a)(1)(C)) • Potentially subject to additional conditions of approval

7. Premarket Controls

8. Two Main Premarket Pathways • Premarket notification (510(k)) • Premarket approval (PMA)

9. Postmarket Controls

10. Registration and Listing • Establishments “engaged in the manufacture, preparation, propagation, compounding, assembly, or processing of a device” intended for commercial distribution in the U.S. are required to register with FDA • Registration puts firms on FDA’s “radar screen” for inspection • In general, these same establishments must file with FDA a list of the devices they have placed in commercial distribution • Listing provides FDA with information about the types of devices being manufactured

11. Quality System Regulation • The Quality System Regulation (QSR) forms the basis for assuring that only products that meet company specifications are released for distribution • The FDA uses compliance with the QSR to determine if a company is in control of its manufacturing process • QSR requirements govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices

12. Medical Device Reporting • Medical Device Reports (“MDRs”) are intended to alert FDA to devices that may have caused or contributed to death or serious injury or that may eventually cause or contribute to a death or serious injury due to a malfunction • MDR requirements apply to manufacturers, importers, and device user facilities

13. Reports of Corrections and Removals • FDA has the authority to require manufacturers to recall devices, but rarely uses it. See 21 C.F.R. Part 810. Rather, most recalls (corrections and removals) are conducted voluntarily • Voluntary corrections to and removals of devices must be reported to FDA when the action is taken to reduce a risk to health or to remedy a violation of the Federal Food, Drug, and Cosmetic Act caused by the device that may present a risk to health. (See 21 C.F.R. Part 806)

14. Labeling • “Labeling”: All written, printed, or graphic matter (21 U.S.C. § 321(m)) • Upon an article or container OR • Accompanying such article • By statute, labeling cannot be “false or misleading” • All labeling claims must be: • Consistent with the product’s FDA-cleared or approved intended use (i.e., “on-label”) • Provide fair balance (i.e., provide information about risk with equal emphasis as information about benefits) • Have valid scientific support

15. Consequences of Noncompliance • Failure to comply with applicable FDA requirements typically renders a device adulterated or misbranded. (21 U.S.C. §§ 351 & 352) • Marketing an adulterated or misbranded device is a “prohibited act,” and can trigger FDA enforcement action. (21 U.S.C. § 331(a))

16. How FDA Learns of Noncompliances • Inspections • Trade Complaints • “Surfing” the web

17. Consequences of Noncompliance • FDA’s main statutory enforcement tools: • Seizure (21 U.S.C. § 334) • Injunction (21 U.S.C. § 332) • Criminal prosecution (21 U.S.C. § 333; 18 U.S.C. § 3571) • Civil Penalties (21 U.S.C. § 333(g)) • Issuance of a Warning Letter typically is the first step

18. FDA PREMARKET REGULATORY SCHEME

19. 510(k) Pathway

20. Overview • A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is “substantially equivalent” to another legally marketed device • Substantial Equivalence means the device to be marketed has: • The same intended use as all of its predicates and • Similar technological characteristics as its predicate(s) or • Its technological differences • Do not raise any new questions of safety or effectiveness; and • Performance data demonstrate that the device is as safe and effective as its predicate device(s)

21. When 510(k) Clearance is Required • Introduction of a device subject to the 510(k) requirement (i.e., a Class I or Class II reserved device) • A change/modification to an already marketed device that could significantly affect its safety or effectiveness • A major change or modification to the device’s intended use

22. Traditional 510(k) Submissions • User fee • Standard fee is $4,960 for FY 2013 • Small business (< $100 million) for FY 2013 is $2,480 • Key elements of a traditional 510(k) • Device description • Substantial equivalence discussion • Comparison table • Narrative comparison

23. Key Elements of a Traditional 510(k) (cont.’d) • Proposed labeling • Sterilization and shelf life information • Biocompatibility information • Electrical safety information • Bench testing summaries • Animal testing summaries • Clinical testing summaries

24. Alternatives to Traditional 510(k)s • Special 510(k) • No changes to the device’s intended use/indications or fundamental scientific technology • Change being made to the company’s own device • Does not include data • Abbreviated 510(k) • Where FDA has issued an applicable device-specific guidance document; recognized an applicable consensus standard; or identified another special control • Must include a declaration of conformance to an FDA-recognized consensus standard; and/or a summary report regarding how the guidance document or other special control was used to address the risk • Does not include data

25. FDA’s Decisions on a 510(k) Notice • FDA actions on a 510(k) notice • Finds the device to be substantially equivalent (“SE”), i.e., clears the device, if it is at least as safe and effective as the predicate(s); • Requests additional information • Withdraws the 510(k) if the submitter does not respond to an FDA request within the allotted time; or • Finds the device to be not substantially equivalent (“NSE”)

26. 510(k) Review Period • 90 days for traditional and abbreviated 510(k) notices • 30 days for a special 510(k) notice • FDA can extend that period by requesting additional information • When the sponsor of the 510(k) responds to FDA’s request for additional information, the 90-day (traditional / abbreviated) or 30-day (special) review period re-starts

27. PREMARKET APPROVAL

28. Overview • Not a comparative submission • The device must be safe and effective for its intended use • A PMA generally requires more information (especially clinical data) and longer review time than a 510(k)

29. Original PMA Submission • User Fee • $248,000 for FY 2013 • $62,000 for small businesses (<$100 million in gross sales or revenue) • Fee waived for first PMA for a company with gross receipts or sales less than $30 million • Key elements of an original PMA submission • Device description • Detailed description of manufacturing processes

30. Original PMA Submission (cont’d) • Key elements of an original PMA submission (cont.’d) • Nonclinical studies summaries • Clinical studies summaries • Clinical investigator financial certification or disclosure • Proposed device labeling

31. PMA Review Process • Acceptance and filing review • Review to determine whether the PMA is administratively complete • Must be conducted within 45 days of receipt of the PMA • Substantive review • Review of performance, animal, clinical, and manufacturing information • Typically conducted by a scientific team of reviewers • 180 day review time • FDA may request additional information

32. PMA Review Process • Advisory Committee (Panel) review • FDA may refer a PMA for review by a panel of experts for various reasons • Occurs during the review period, typically after FDA has completed its substantive review • Panel review is conducted via a public meeting • Panel submits a final report to FDA that includes the Committee's recommendation and the basis for such recommendation on the PMA • Panel recommendation is not binding on the Agency, but FDA typically follows the panel recommendation

33. PMA Review Process • Pre-approval Bioresearch Monitoring (BiMo) inspection • Inspection of clinical trial sites and the study sponsor to assure accuracy of clinical data • Pre-approval manufacturing inspection • Inspection of manufacturing facilities to assure compliance with FDA requirements

34. FDA’s Decision • Approval Order • Decision that the device is safe and effective and the device may be legally marketed in the U.S. subject to the conditions in the approval order • Approvable Letter • FDA believes the device can be approved if specific minor additional information, e.g., labeling changes, are provided • Not approvable letter • Generally, additional information is needed to demonstrate the safety and effectiveness of the device • Order denying approval

35. Changes to a PMA Device • Regulations (21 C.F.R. § 814.39) require that manufacturers submit and receive approval for a PMA supplement before making a change affecting the safety or effectiveness of the device: • New intended use; • Labeling changes; • Different manufacturing facility; • Changes in sterilization procedures; • Changes in packaging; • Changes in performance or design specifications, circuits, components, ingredients, principle of operation, or physical design; and/or • Extension of expiration date based on a new protocol/procedure. • In general, all changes made to a PMA approved device must, in some way, be reported to FDA

36. Why the 510(k) Route is Generally Preferred • Approximately 10% of 510(k) notices include clinical data; almost all PMAs include clinical data • Generally, the 510(k) path is a quicker route to market than the PMA path even if the 510(k) contains clinical data • Shorter submissions • Shorter FDA review periods (90 days v. 180 days) • FDA Advisory Panel review generally not required

37. How FDA Might Have Handled the Recent PIP Crisis

38. Bottom Line • The manufacturer reportedly began manufacturing breast implants with a non-medical grade silicone gel • This sort of deliberate, impermissible act is difficult for even the most stringent regulatory system to prevent

39. FDA Warning Letter and Import Detention • In June 2000, FDA issued a Warning Letter to PIP regarding its manufacturing process for saline breast implants, which cited multiple Quality System violations including: • Failure to maintain procedures for verifying and validating device design • Failure to maintain procedures for implementing corrective and preventive actions • Failure to maintain procedures for changes to a specification, method, process, or procedure • Failure to submit MDR reports • Failure to establish procedures for identifying training needs • FDA placed an import detention on PIP saline implants pending correction of the violations cited in the Warning Letter

40. FDA Advisory Panel Recommendation Against Approval of PIP PMA • PIP silicone breast implants were never sold in the U.S. • PIP saline breast implants were sold in the U.S. from 1996-2000 • In 2000, an FDA Advisory Panel voted unanimously to recommend that PIP’s PMA for saline breast implants not be approved • The Advisory Panel felt that PIP’s preclinical and clinical data were inadequate

41. Premarket Controls That Might Have Kept PIP Silicone Implants Off the Market • FDA concerns regarding PIP’s proposed clinical trials might have led to disapproval of PIP’s Investigational Device Exemption (IDE) application • Bioresearch Monitoring (BiMo) inspection might have raised concerns about PIP’s clinical study-related practices • PIP might have failed to satisfactorily respond to FDA’s deficiency letters during the PMA review process • FDA might have found violative practices during its pre-approval QSR inspection of PIP

42. Postmarket Enforcement Tools That Might Have Been Used Against PIP • FDA inspection – routine and/or for cause • Often leads to 483, Untitled Letter, Warning Letter, and/or import detention (for foreign manufacturers) • Seizure • Injunction • Civil Penalties • Initiation of criminal proceedings

43. Postmarket Tools (cont’d) • Cease Distribution and Notification (CD&N) Order • Requires a firm to immediately cease distribution of a device, notify health professionals and device user facilities of the Order, and instruct them to cease use of the device • There must be a “reasonable probability that a device . . . would cause serious, adverse health consequences or death” • Mandatory Recall • FDA can amend a CD&N order to require a recall • Repair, Replacement, or Refund Order • Among other things, device must “present an unreasonable risk of substantial harm to public health”

44. Thank you! Questions?