Medical Device Labeling

1. Medical Device Labeling May 15, 2014 Allison Scott, RAC

2. About Navigant • Global expert services firm headquartered in Chicago • Approximately 1,700 professionals • Healthcare Life Science practice includes an Indianapolis-based Regulatory Services practice • We are regulatory experts for the Medical Device, IVD, Combination Product, Companion Diagnostics, Pharma & Biotech, and Health Information Technology industries • Full service offering: Strategy and Commercialization to Compliance and Remediation • 70+ consultants averaging 20+ years of experience ranging from working at FDA to holding senior positions in the life science industry and academia

3. Presentation Overview • Definitions • General Label Requirements (CFR 801) • UDI and GUDID • OTC Label Requirements • Prescription Label Requirements • Exemptions from Label Requirements • IDE Label Requirements • IVD Label Requirements • Misbranding • Special Requirements • Symbols Used in Labeling • Instructions for Use • Quality System Label Requirements

4. Definitions

5. Definitions • Label – display of written, printed, or graphic matter upon the immediate container of any article • Labeling – all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article' at any time while a device is held for sale after shipment or delivery for shipment in interstate commerce. This includes advertising • Accompanying – interpreted liberally to mean more than physical association with the product. It extends to posters, tags, pamphlets, circulars, booklets, brochures, instruction books, direction sheets, fillers, etc. 'Accompanying' also includes labeling that is brought together with the device after shipment or delivery for shipment in interstate commerce • Immediate Container – does not include package liners. Any word, statement, or other information appearing on the immediate container must also appear on the outside container or wrapper, if any there be, of the retain package of such article, or is easily legible through the outside container of wrapper

6. Definitions cont’d • Intended Uses – the objective intent of the persons legally responsible for the labeling of the device • Intent is determined by expressions or the circumstances surrounding the distribution of the device • May be shown by labeling claims, advertising matter, or oral or written statements by such representatives • May be shown by the offering or the using of the device, with the knowledge of such persons or their representatives, for a purpose for which it is neither labeled nor advertised • Directions/Instructions for Use – provides directions under which the User (practitioner, layman, patient), as appropriate, can use the device safely and for the purposes for which it is intended • Include indications for use and appropriate contraindications, warnings, precautions and adverse reaction information

7. Definitions cont’d • Contraindications – situations in which the device should not be used because the risk of use clearly outweighs any possible benefit. Examples: • Hypersensitivity to an ingredient of a permanently implanted device • Substantial risk of being harmed because of age, sex, concomitant therapy, disease state or other condition • Continued use in the face of an unacceptably hazardous adverse reaction • Warning – describes serious adverse reactions and potential safety hazards, limitations in use imposed by them, and steps that should be taken if they occur • A warning is appropriate when the device is commonly used for a disease or condition for which there is a lack of valid scientific evidence of effectiveness for that disease or condition and such usage is associated with a serious risk or hazard

8. Definitions cont’d • Precaution – any special care to be exercised by the practitioner and/or patient for the safe and effective use of the device. For example, indicate or emphasize any need for protective wear during use • Special Patient Populations – limitations on the usage of a device may be necessary for various reasons including lack of long-term safety and effectiveness data, lack of safety and effectiveness data for specific patient populations (e.g., pregnant women), growth processes still occurring in the body, and anatomical or physiological limitations on the effectiveness of the device • Could be a contraindication, warning, or precaution depending situation and severity • Adverse Reaction – an undesirable effect, reasonably associated with the use of the device, that may occur as part of the effect of the device or may be unpredictable in its occurrence

9. Definitions cont’d • Prescription Device – a device which, because of any potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe except under the supervision of a practitioner licensed by law to direct the use of the device, and hence for which "adequate directions for use" cannot be prepared • Principal Display Panel – the portion of the label which is intended to be displayed, presented, shown, or examined under customary conditions for retail sales. The area of the principal display panel is considered to be: • In the case of a rectangular package, the height x width of one side • In the case of a cylindrical or nearly cylindrical package, 40% of height x circumference • In the case of any other shapes, 40% of the total surface area of the container, unless a more prominent site exists

10. General Label Requirements

11. General Label Requirements • Device Label to include: • Device name • Description of the device (if not indicated by device name) • Quantity of devices in package • Manufacturing date (YYYY-MM) • Manufacturer Name and Address • Indication of prescription, sterile status • Part/Item Number • Lot Number • Expiration/use by date (if sterile) • Unique Device Identifier (UDI) • Required elements must be displayed prominently

12. General Label Example

13. UDI and GUDID

14. UDI and GUDID • FDA requires most devices distributed in the U.S. to carry a unique device identifier ("UDI"), which is intended to act as a universal identification number for FDA • Includes combination products containing devices and devices licensed under the Public Health Service ("PHS") Act • The UDI is a unique numeric or alphanumeric code that consists of two parts: • a device identifier ("DI"), a mandatory, fixed portion of a UDI that identifies the labeler and the specific version or model of a device, and • a production identifier ("PI"), a conditional, variable portion of a UDI that identifies one or more of the following when included on the label of a device: • the lot or batch number within which a device was manufactured; • the serial number of a specific device; • the expiration date of a specific device; • the date a specific device was manufactured; and/or • the distinct identification code required by §1271.290(c) for a human cell, tissue, or cellular and tissue-based product ("HCT/P") regulated as a device.

15. UDI and GUDID • FDA is also creating the Global Unique Device Identification Database ("GUDID") • Includes standard set of basic identifying elements for each device with a UDI • Most of the information will be available to the public • No personal privacy information or device user tracking • Anticipated benefits of UDI include: • Prompt recalls of any devices that could jeopardize safety • Increase in supply chain security • Reduction in device counterfeiting • Better inventory management • Reduction in errors such as implantation of the incorrect device

16. UDI and GUDID • Exemptions • Class I devices are not exempt from UDI, but they do not need to include production identifier • Class I GMP-exempt devices are exempt from UDI • Existing inventory out to three years is exempt (i.e. finished device packaged and labeled prior to the compliance date) • Shipping containers are exempt • If a UDI is on a kit/combination product, then components or combination product constituent parts are exempt • Individual single-use devices do not need to have a separate UDI, provided: • hey are distributed together in a single device package (in which case the package would bear the UDI); • they are intended to be stored in that package until removed for use; and • they are not intended for individual distribution.

17. UDI and GUDID

18. UDI and GUDID

19. UDI and GUDID

20. OTC Label Requirements

21. OTC Label Requirements Statement of identity of the device must be listed on the principal display panel Must list the common name of the device, followed by a statement of its principal intended action(s) Indications for use must be listed in the directions for use Statement must be in bold type, reasonably related in size to the most prominent printed matter on the display panel, and must be in lines generally parallel to the base of the package on which it rests Must contain a statement of net quantity of contents in terms of weight, measure, numerical count, or a combination of numerical count and weight, measure, or size

22. Prescription Label Requirements

23. Prescription Label Requirements • Prescription devices are exempt from "adequate directions for use,“ provided: • the device is in the possession of either a licensed practitioner or persons lawfully engaged in the manufacture or distribution of the product; • its labeling bears an Rx statement, e.g. "Caution: Federal law restricts this device to sale by or on the order of a (insert name of physician, dentist, or other licensed practitioner)”; • its labeling bears information for use, including indications, effects, routes, methods, and frequency and duration of administration, and relevant hazards, contraindications, side effects, and precautions under which the device can safely be used; and • all labeling other than labels and cartons bears the date of issuance or date of the latest revision.

24. Exemptions from Label Requirements

25. Exemptions from Label Requirements • Exemptions may be granted in those instances where device labeling lacks sufficient space for required labeling provided that: • existing label space is not taken up by including non-required information or by giving prominence to a portion of the required labeling; and • existing label space is not used for any representations in a foreign language. • All labeling shall be in English, except those products distributed solely within Puerto Rico or a U.S. territory where the predominant language is other than English. In these instances the predominant language may be substituted for English • If any representation on the device label or labeling appears in a foreign language, then all required labeling shall also appear in that foreign language

26. Exemptions from Label Requirements Retail Exemption – A device which is delivered to the ultimate user by a licensed practitioner in the course of his practice or upon prescription are required only to bear the name and address of the practitioner, directions for use, and any required cautionary statements A device is exempt from adequate directions for use if adequate directions for common uses are known to the ordinary individual IVDs are exempt from adequate directions for use provided that they meet those requirements found in 809.10 Devices used for processing, repacking, or manufacturing of another drug or device are exempt from adequate directions for use if they bear the statement: "Caution: For manufacturing, processing, or repacking“ Devices for use in teaching, law enforcement, research, and analysis are exempt if the device is shipped or sold to, or in the possession of, persons lawfully engaged in instruction in pharmacy, chemistry, or medicine (not involving clinical use), law enforcement, or chemical analysis or physical testing Certain exemptions for In-process devices that are being transported (in transit) from one manufacturing site to another

27. IDE Label Requirements

28. IDE Label Requirements • In addition to any labeling requirements specified in the IDE study protocol, the following general labeling is required: • Name and place of business of the firm, quantity, and following statement: "CAUTION: Investigational Device. Limited by Federal (or United States) law to investigational use" • A description of all relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings and precautions • Absence of any statements that are false or misleading, or that represent the device as safe and effective for its investigational purpose • Any device shipped solely for use on laboratory animals must be labeled "CAUTION – Device for investigational use in laboratory animals or other tests that do not involve human subjects"

29. IVD Label Requirements

30. IVD Label Requirements • Exceptions to label requirements: • Where information is not applicable • If the presence of any label information will interfere with the test, information can appear on outside wrapper or container vs. label • All information must appear on the outside container or wrapper, or be easily legible through the outside container or wrapper

31. IVD Label Requirements • IVD Label Requirements: • The established and proprietary names of the product • The intended use or uses* • A statement of warnings or precautions for users and a statement "For In Vitro Diagnostic Use"* • Name and place of business of the manufacturer, packer, or distributor • Lot or control number traceable to the production history • Multiple unit products must have traceability of the individual units • Instrument lot numbers must allow for traceability of subassemblies • A multiple unit product that requires use of its components as a system should units * may appear on the outer container labeling only

32. IVD Label Requirements • For Reagents*: • Established (common or usual) name • Quantity, proportion, or concentration of all active ingredients • Storage instructions, i.e., temperature, humidity, etc. • Instructions for manipulation of products requiring mixing or reconstitution • Means to assure that the product meets appropriate standards of purity, quality, etc., at the time of use, including one or more of the following: • expiration date (date beyond which the product is not to be used) • statement of any visual indication of alteration* • instructions for a simple check to assure product usefulness* • The net quantity of contents* * may appear on the outer container labeling only

33. Misbranding

34. Misbranding • Misbranding – device labeling that is false and misleading. Misbranding can occur in several instances, including: • Its packaging does not bear a label containing the required components • Any word, statement, or other required information is not prominently placed on the labeling or not clearly stated so as to be read and understood by the ordinary individual under customary conditions of purchase and use • Contains any quantity of narcotic or habit forming substance but does not warn against its effects (e.g. "Warning – may be habit forming") • Its label does not bear adequate directions for use • The label does not warn against use in certain pathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application

35. Misbranding • Misbranding • It is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling • The device commercially distributed without FDA concurrence on a 510(k) submission • The device is subject to a performance standard and it does not bear the labeling prescribed in that standard • Making reference to a medical device registration, or a 510(k) number, as these assigned numbers do not constitute official FDA approval of the device • Any representation that connotes FDA approval as a result of complying with the device regulations is misleading and constitutes misbranding

36. Misbranding • Misbranding • Examples of false representations: • Incorrect, inadequate or incomplete identification • Unsubstantiated claims of therapeutic value • Inaccuracies concerning condition, state, treatment, size, shape or style • Substitution of parts or material • Use of the prefix "U.S." or other similar indication suggesting Government or Agency approval or endorsement of the product • Examples of misleading labeling: • Ambiguity, half-truths, and trade puffery • Expressions of opinion or subjective statements • Failure to reveal material facts, consequences that may result from use, or the existence of difference of opinion

37. Special Requirements

38. Special Requirements There are occasionally device-specific labeling requirements (for example, X-Ray machines, lasers, ultrasonic therapies, and sunglasses/eyeglasses). Refer to CFR to find those that pertain to your device Sterile devices must be marked as sterile and provide the sterilization method (for example, ETO, radiation)

39. Special Requirements • For certain devices to be used in a Magnetic Resonance (“MR”) MR environment, manufacturers must determine the MR compatibility of the device and identify this in the labeling • Manufacturers of implanted devices should include statements of MRI safety, even if only "This device not tested for MRI Safety" • MR Safe: This term indicates that the device, when used in the MR environment, has been demonstrated to present no additional risk to the patient, but may affect the quality of the diagnostic information  • MR Compatible: This term indicates that the device, when used in the MR environment, is MR Safe and has been demonstrated to neither significantly affect the quality of the diagnostic information nor have its operations affected by the MR device  • MR Unsafe: This term indicates that the device is not safe for use in the MR environment and should be labeled as such. • Labeling for an MR Unsafe implant should recommend that patients register their implant information with the MedicAlert Foundation or equivalent organization

40. Special Requirements • Medical Products labelled as “latex-free,” “does not contain natural rubber latex,” or “does not contain latex” are not scientifically accurate because it is not possible to reliably assure that there is an absence of the allergens associated with hypersensitivity reactions to natural rubber latex in the medical product • FDA strongly recommends that these statements not be used in medical product labeling • Currently, there are no regulations requiring a manufacturer to state that natural rubber latex was not used as a material in their medical product or medical product container   • If a manufacturer elects to add a claim in the labeling indicating that natural rubber latex or synthetic derivatives of natural rubber latex were not used as materials in the manufacture of their medical product and container, FDA recommends the use of the statement “Not made with natural rubber latex” 

41. Symbols Used in Labeling

42. Symbols Used in Labeling • Rx = Prescription Use Only • Currently, symbols on label must be accompanied by English text • Example: • FDA will begin recognizing additional symbols found in recognized consensus standards (ex. ISO 15223-1) • Labeling must contain index of symbols with English text

43. Symbols Used in Labeling FDA recognizes 25 symbols for IVD devices for professional use from ISO 15223, which do not require accompaniment by English text FDA does not recognize these or any symbols for use in the labels and labeling of over-the-counter or prescription home-use devices unless accompanied by equivalent text in English

44. Instructions for Use

45. Instructions for Use • Writing instructions for use • Consider the reader when choosing terminology • Keep language clear and concise, and use proper punctuation • Use charts, screen shots, or pictures to refer to your device • Provide step-by-step instructions and refer to labeled figures • Adequate Directions For Use – means directions under which the layman can use a device safely and for the purposes intended. This includes: • Statements of all purposes for which and conditions under which the device can be used • Quantity of dose for each use and usual quantities for persons of different ages and physical conditions • Frequency of administration • Duration of application • Time of administration in relation to other factors • Route or method of application • Any preparation necessary for use

46. Instructions for Use • Pretesting of medical device patient labeling • Systematic and formal gathering of target audience reactions to medical device patient labeling content and format, before the medical device patient labeling is issued in final form • Checks the potential users’ comprehension of the device patient labeling and their ability to follow instructions and operate the device effectively • Typically one of the evaluations conducted in the early stages of message development. Pretesting may assist you in: • Determining which of a number of labeling presentations is most effective for the intended audience and in identifying strengths and weaknesses in the presentation • Identifying sensitive and controversial elements • Revising and improving materials before distribution to users • Identifying the best method to distribute the labeling to the target audience • Methods include: individual in-depth interviews, focus group interviews, self-administered questionnaires, usability testing, and readability testing • User-oriented testing helps to find places where the patient labeling may be inaccurate, incomprehensible, or poorly organized. • Pretesting is very important for new device types, devices directed towards special patient populations, OTC devices, and home-use devices

47. Instructions for Use • Instructions for Use should include: • Company Name • Device Name • Part/Item/Reference Number of Device(s) • Indications for Use • Device Description • Warnings, Contraindications, Precautions • Company Name, Address, and contact information • Instructions for using the device • Instructions for maintenance and/or cleaning/sterilization of the device • Troubleshooting guidance (not required) • Disposal/environmental instructions (not FDA required)

48. Quality System LabelingRequirements

49. Quality System Labeling Requirements • Labels and labeling are subject to GMP requirements and should be controlled accordingly: • Label integrity • Labeling inspection • Labeling storage • Labeling operations • Control number

50. Quality System Labeling Requirements • Changes • Labeling is part of the device master record; therefore, changes to labeling must be made under a formal change control system, and be formally reviewed and authorized before implementation • Relabeling and Over-Labeling • Over-labeling by placing a new label over an old label is discouraged by FDA but is acceptable as long as the new label and its use meet GMP requirements (820.120, 820.1 15) for attachment, legibility, reprocessing, and change control • Over-labeling is also discouraged in some foreign countries