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Device Labeling Guidance #G91-1 (blue book memo) (Text Only)

This guidance was written prior to the February 27, 1997 implementation of FDA's Good Guidance Practices, GGP's. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be updated in the next revision to include the standard elements of GGP's.


General Program Memorandum #G91-1

Date:  March 8, 1991                    

From:  Director, Office of Device Evaluation (HFZ-400) 
 
Subject:  Device Labeling Guidance 

To:  ODE Review Staff 
 

Purpose 
 
The primary purpose of this memorandum is to formalize guidance to ODE 
reviewers concerning their review of labeling in device marketing 
submissionsr especially premarket approval applications (PhAs). This 
guidance is intended to ensure the adequacy of, and consistency in, 
device labeling information.  The guidance is also intended for industry 
use in preparing device labeling. 
 
Background 
 
General labeling requirements for medical devices have been established 
in 21 CFR Part 801.  Detailed and specific labeling requirements for in 
vitro diagnostic products were promulgated under 21 CFR 809.10.  Neither 
of these, however, provide specific definitions or explanations of some 
significant terms such as warnings, precautions, contraindications and 
adverse reactions.  The lack of definitions for such terms leads to 
misunderstandings and disagreements between PMA applicants and the ODE 
review staff.  Because labeling content is a key factor in the CDRH 
determination of whether there is reasonable assurance that a device is 
safe and effective for its intended user such disputes have unnecessarily 
prolonged PMA review times. 
 
 
Scope and Application of the Guidance 

Portions of the attached "Device Labeling Guidance" that are based upon 
definitions and requirements in the act and applicable regulations 
include appropriate references thereto.  Guidance on "Indications for 
Use," "Contraindications," "Warnings," "Precautions" and "Adverse 
Reactions" paraphrase applicable provisions in the labeling requirements 
for prescription drugs (21 CFR Part 201).  Consistency between drug and 
device labeling content and the terminology therein will help minimize 
misunderstandings by medical practitioners and patients. 
While this guidance is primarily intended to ensure the adequacy of, and 
the consistency in, the labeling information for devices subject to 
premarket approval, it may also contribute to premarket notification 
reviews.  As indicated in the "Blue Book" 510(k) Memorandum #86-3 dated 
June 30, 1986, a premarket notification must normally only contain 
proposed labeling sufficient to describe the device's intended use. 
Accordingly, the Sl0(k) decision letter finding a device to be 
substantially equivalent advises that this finding does not connote 
approval of the proposed labeling.  Nevertheless, in the case of in vitro 
diagnostic devices, devices with special labeling requirements under 
Subpart H of 21 CFR Part 801, and devices for which the inclusion of 
specific directions for use, contraindications, warnings, etc. in the 
labeling may be critical to a finding of equivalence, the ODE premarket 
notification labeling review includes an evaluation of the compliance of 
the proposed labeling, or portions thereof, with applicable requirements 
under 21 CFR Parts 801 and 809, as appropriate. 
 
This guidance was prepared by Charles H. Kyper, Assistant to the 
Director, Office of Device Evaluation, with input from the CDRH Office of 
Compliance and Surveillance, Office of Health Affairs, and Office of 
Training and Assistance. 
 
It should be understood that the attached guidance is not a regulation 
and that, as such, variations can occur and should be given appropriate 
consideration.  Based upon the preceding discussion, the need for and 
usefulness of this guidance should be apparent.  ODE reviewers are 
encouraged to refer to this guidance during labeling reviews and to 
provide it in correspondence and meetings with representatives of the 
device industry when appropriate.  Reviewers should also keep in mind 
that this guidance is not intended to limit the consideration of factors 
that may be specific to the device when reviewing its labeling. 
 
Effective Date:   This memorandum is effective immediately. 
 
 
                                                 \s\ 
 
 
Attachment

Attachment - Page 1

                        DEVICE LABELING GUIDANCE
                            Table of Contents

     I. Definitions                        V.  Warnings
           Label                          VI.  Precautions
           Labeling                      VII.  Special Patient Populations
           Intended Uses                VIII.  Adverse Reactions  
           Directions for Use             IX.  Prescription Devices  
    II.  Safety and Effectiveness          X.  Restricted Devices
         Considerations                   XI.  Patient Information Labeling
   III.  Indications for Use             XII.  Disclaimer of Liability
    IV.  Contraindications              XIII.  Misbranding                    
                                         XIV.  Prohibited Acts
     I.  Definitions

         Label:              A "label" is a display of written, printed or 
                             graphic matter upon the immediate container of 
                             any article.[section 201(k).] 

         Labeling:           "Labeling" includes 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. 
                             [section 201(m).]

        Intended Uses:       The term "intended uses" refers to the 
                             objective intent of the persons legally 
                             responsible for the labeling of the device.  
                             The intent is determined by their expressions 
                             or may be shown by the circumstances 
                             surrounding the distribution of the device.  
                             This objective intent may, for example, be 
                             shown by labeling claims, advertising matter, 
                             or oral or written statements by such
                             representatives.  It 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.  (21 CFR 
                             801.4)                                             
                             
        Directions for Use:  The term "Directions for use" provides 
                             directions under which the practitioner or 
                             layman (e.g., patient or unlicensed health 
                             care provider), as appropriate, can use 
                             the device safely and for the purposes for 
                             which it is intended.  Directions for use 
                             also include indications for use and 
                             appropriate contraindications, warnings,              
                             precautions and adverse reaction
                             information.  Directions for use 
                             requirements applicable to prescription 
                             and over-the-counter devices appear 
                             throughout 21 CFR Part 801 and, in the 
                             case of in vitro diagnostic products, 
                             under 21 CFR 809.10.

   II.  Safety and Effectiveness Considerations (21 CFR 860.7)

        In determining the safety and effectiveness of a device for    
        its intended use, the following factors are to be considered 
        and addressed in the device's labeling by the inclusion of 
        appropriate information:

            The persons for whose use the device is represented or intended 
        -   The conditions of use for the device, including conditions of 
            use prescribed, recommended or suggested in the labeling or 
            advertising of the device, and other intended conditions of use;
            The probable benefit to health from the use of the device 
            weighed against any probable injury or illness from such use;
            The reliability of the device; and,
            Other relevant factors.
          
  III.  Indications for Use

        General Statement of Indications for Use

        The general statement of the "Indications for Use" identifies the 
        target population in a significant portion of which sufficient 
        valid scientific evidence has demonstrated that the device as 
        labeled will provide clinically significant results and at the same 
        time does not present an unreasonable risk of illness or injury 
        associated with the use of the device.  As appropriate, the 
        labeling should state that the device (trade name) is "indicated"  
        or "intended for use"

            (1)  in the treatment, mitigation, prevention or diagnosis of a 
                 recognized disease or condition or an important 
                 manifestation of a disease or condition; and/or,
            
            (2)  in the relief or mitigation of symptoms associated with a 
                 disease or condition; and/or,
            
            (3)  as an aid or adjunct to a mode of therapy or diagnosis.

        Additional Information

        When indicated or intended for use in selected subgroups of a 
        population with a disease, symptom, or syndrome, the labeling 
        should

            (1)  describe the available evidence and state the                  
                 limitations of usefulness of the device;

            (2)  identify specific tests needed for the selection or 
                 monitoring of the patients;

            (3)  if available, provide information on the 
                 approximate kind, degree and duration of improvement 
                 to be anticipated; and 

            (4)  if relevant, include information regarding the 
                 recommended intervals between device use, the usual 
                 duration of treatment, or any modifications of such.

       When safety considerations are such that the device should be 
       reserved or restricted for use in certain situations 
       (e.g., cases not responsive to other devices, surgical        
       procedures or drugs), this information shall be stated.
       
       When there are specific conditions that should be met before the 
       device is used on a long-term basis (e.g., demonstration of 
       responsiveness to the device in a short term trial), the 
       labeling should identify the conditions or, if the indications 
       for long-term use are different from those for short-term use, 
       the labeling shall identify the specific indications for each 
       use.
       
       When there is a common belief that the device may be effective 
       for a certain use or there is a common use of the device for a 
       condition but the preponderance of evidence related to the use 
       or condition demonstrates that the device is ineffective, FDA 
       may require that the labeling state that there is a lack of 
       evidence that the device is effective for that use or condition.

  IV.  Contraindications

       This section describes situations in which the device should not 
       be used because the risk of use clearly outweights any possible 
       benefit.  Examples that may, but not always, contraindicate the 
       use of a device include:

            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; or,
            Continued use in the face of an unacceptably hazardous 
            adverse reaction. 

       Known hazards and not theoretical possibilities are to be
       listed, e.g., if hypersensitivity to an ingredient in the device 
       has not been demonstrated, it should not be listed as a     
       contraindication.  The "Contraindications" section shall 
       immediately follow the "Indications for Use" section of the 
       labeling.  If no contraindications are known, this section of 
       the labeling should state "None known."

   V.  Warnings

       Describe serious adverse reactions and potential safety hazards, 
       limitations in use imposed by them, and steps that should be 
       taken if they occur.
       
       Include an appropriate warning if there is reasonable evidence 
       of an association of a serious hazard with the use of the 
       device.  A causal relationship need not have been proved.

       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.

  VI.  Precautions

       Include information regarding 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.

            - Identify any laboratory tests or other evaluations that
              may be helpful in following the patient's response or in
              identifying adverse reactions and, if appropriate,             
              specify  the frequency of such tests or evaluations 
              before, during and after use of the device.

       The "Precautions" section of the labeling includes precautionary 
       statements not appropriate for inclusion under other sections of 
       the labeling.  Additional guidance regarding precautions will be      
       found in the "Special Patient Populations" section below.

 VII.  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.  

       If the safety and effectiveness of the device for use in 
       specific patient populations have not been established on the        
       basis of valid scientific evidence, the "Indications for Use" 
       section shall specifically identify the persons for whose use 
       the device is indicated and the "Precautions" section shall 
       include the following statement:
       
            "Safety and effectiveness in (e.g., pregnant women, 
            children under the age of ..., etc.) have not been 
            established." 

       If use of the device in a certain patient population is 
       associated with a specific hazard, the hazard shall be described 
       in the "Precautions" section or, if appropriate, the hazard 
       shall be stated in the "Warnings" or "Contraindications" section 
       and the "Precautions" section of the labeling shall refer to it, 
       e.g., "See 'Warnings' section for information on....."

VIII.  Adverse Reactions

       An adverse reaction is 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.

       This section includes all adverse reactions reasonably 
       associated with the use of the device, including those mentioned 
       in the "Contraindications", "Warnings" and "Precautions" 
       sections of the labeling.  The listing of the adverse reactions 
       should be followed, if appropriate, by statements directing the 
       reader to other sections of the labeling for additional 
       information regarding these adverse reactions and any steps that 
       should be taken.

       Adverse reactions should be listed in descending order according 
       to their clinical significance as determined by their severity 
       and frequency.  Provide frequency data from adequately reported 
       clinical studies when the data is not well known to the device 
       user (practitioner and/or patient) and/or when needed in 
       deciding between the use of the device and an alternative 
       procedure or approach.

  IX.  Prescription Devices

       A prescription device is, by definition under 21 CFR 801.109, 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" (21 CFR 801.5) 
      cannot be prepared.

       A prescription device, other than surgical instruments, is 
       misbranded if its label does not bear:
       
            (1)  the statement, "Caution: Federal law restricts this 
                 device to sale by or on the order of a              ",  
                 the blank to be filled with the word "physician", 
                 "dentist", or with the descriptive designation of any 
                 other practitioners licensed by the law of the 
                 State  in which that person practices to use or order 
                 the use of the device; and 

            (2)  the method of application or use of the device.

 
       A prescription device is misbranded if its labeling does not 
       bear:
  
             (1) information for use including indications, effects, 
                 routes, methods, frequency and duration of 
                 administration, and any relevant hazards, 
                 contraindications, side effects, and precautions under
                 which practitioners licensed by law to administer the 
                 device can use the device safely and for the purpose 
                 for which it is intended, including all purposes for 
                 which it is advertised or represented, with the 
                 exceptions that

                       (a) such information may be omitted from the    
                           dispensing package if, but only if, the 
                           directions, hazards, warnings, and other 
                           information are commonly known to 
                           practitioners licensed by law to use the    
                           device and the FDA Commissioner is requested 
                           to offer an opinion on a written proposal 
                           stating reasonable grounds to omit such 
                           information from the dispensing package;

                       (b) such information will not be required on so 
                           called reminder-piece labeling which calls 
                           attention to the name of the device but does 
                           not include indications or other use 
                           information; and

            (2)  the date of the issuance or the latest revision of the 
                 labeling, except for labels and cartons, that bears 
                 directions for the use of the device.
  
   X.  Restricted Device

       Under the authority of section 515(d)(1)(B)(ii) of the Federal  
       Food, Drug, and Cosmetic Act (the act), the approval order for a 
       premarket approval application (PMA) may require, as a condition        
       of approval, that the sale, distribution and use of the device 
       be restricted but only to the extent permitted under section 
       520(e) of the act.  Under section 520(e) of the act, FDA may 
       require that a device be restricted to sale, distribution and 
       use only upon the written or oral authorization of a 
       practitioner licensed by law to administer or use such devices 
       (i.e., prescription device) or upon such other conditions that 
       FDA may prescribe.  Such a requirement must be based upon a 
       determination by FDA that, because of the device's potentiality 
       for harmful effect or the collateral measures necessary to its
       use, there cannot otherwise be reasonable assurance of its 
       safety and effectiveness.  If the device is restricted to use by
       persons with specific training or experience in its use or by 
       persons for use in certain facilities, FDA must determine that 
       such a restriction is required for the safe and effective use of 
       the device.  A person cannot be excluded from using a device, 
       however, solely because that person does not have the training
       and experience to make him/her eligible for certification by a
       certifying board recognized by the American Board of Medical 
       Specialties or has not been certified by such a Board.

       When the sale, distribution and use of a device are restricted 
       in a PMA approval order or by regulation under section 520(e) of 
       the act, the label must include appropriate statements of the 
       restrictions imposed by FDA (e.g., restrictions on the sale, 
       distribution and use of the device or restrictions on the use of 
       the device to persons with specific training or experience in 
       its use or to persons for use   in certain facilities).  The 
       label shall bear the statement, "Caution: Federal law restricts 
       this device to sale, distribution and use by or on the order of 
       a               ", the blank to be filled with the word 
       "physician", "dentist", or with the descriptive designation of 
       any other practitioners licensed by the law of the State in 
       which that person practices to use or order the use of the 
       device and, if applicable, followed by a descriptive phrase of 
       the training or experience required (e.g.,"trained and/or 
       experienced in             ",the blank to be filled with, as 
       appropriate, "the use of this device" or specified therapeutic 
       or diagnostic procedures) and/or the facilities to which use is 
       restricted.

       In accordance with the provisions of section 502(r) of the  act, 
       advertisements and other descriptive printed material issued  by 
       the manufacturer, packer or distributor with respect to a 
       restricted device must include the following among other 
       things:

            (1)  a true statement of the device's established name 
                 (common or usual name unless there is an official name 
                 designated by FDA or recognized in an official 
                 compendium), printed prominently and in type at least                         
                 half as large as that for any trade or brand name for 
                 the device; and

            (2)  a brief statement of the intended uses of the device 
                 and relevant warnings, precautions, side effects, and 
                 contraindications.  

       Except in extraordinary circumstances, FDA cannot require prior 
       approval of the content of any advertisement except in the case 
       of any printed matter which FDA determines to be labeling as 
       defined in section 201(m) of the act.
       
  XI.   Patient Information Labeling

       Patient information labeling includes labeling directed to the 
       patient as well as family members and others who administer home 
       use devices to patients, e.g., care providers who oversee the 
       use of infant apnea monitors and nebulizers.  In determining
       whether patient information labeling is appropriate for a 
       prescription device, the following factors, among others, should 
       be considered:

            -    Should the patient be aware of alternative(s) to      
                 the use of the device if a choice is available?

                 Are substantial risks or discomforts associated with 
                 the use of the device?

                 Is the need for strict patient adherence to a specific 
                 treatment regimen required?

                 Does substantial public or professional controversy 
                 exist about the device and its related procedures?

       Patient information labeling shall include the indications for 
       use and relevant contraindications, warnings, precautions and 
       adverse reactions using terminology well known and understood by 
       the average layman.  Technical terms should be kept to a minimum 
       and should be defined when necessary.  If applicable, directions 
       to ensure safe and effective use of the device by the patient 
       shall be included.  Patient information labeling, if possible, 
       should not exceed the seventh grade reading comprehension level.

       The following sources may provide useful information regarding 
       the information to be included as well as the terminology to be 
       used in patient information labeling:

       1.  U.S.P. Dispensing Information, Volume II, Advice for the 
           PatientR, Drug information in Lay Language
       2.  American Medical Association Drug Evaluations

 XII.  Disclaimer of Liability

       Inclusion in the labeling of a disclaimer regarding the safety 
       and effectiveness of the device for its indicated or intended 
       use is to be avoided.  Instead, labeling and promotional 
       material may include an objective and accurate representation 
       of the clinical experience with the device whereby the 
       practitioner and patient are made aware not to expect a 
       completely safe and effective outcome with the use of the 
       device in all cases.
                                                                     
       Inclusion of disclaimers of liability for any medical expenses 
       or any direct or consequential damages resulting from or 
       caused by any defect, failure or malfunction of the device 
       will not inhibit FDA in imposing the notification and 
       otherremedies (repair, replacement or refund) provisions of 
       section 518 of the act.  The provisions of section 518 may be 
       imposed whenever FDA determines that:
                                                                     
            (1)  The device presents an unreasonable risk of 
                 substantial harm to the public health;

            (2)  There are reasonable grounds to believe that the 
                 device was not properly designed and manufactured 
                 within the state of the art; or

            (3)  There are reasonable grounds to believe that the 
                 unreasonable risk was not caused by failure of a 
                 person other than the manufacturer, importer, 
                 distributor or retailer of the device to exercise  
                 due care in the ... use of the device.

XIII.  Misbranding

       Pertinent provisions in the law and implementing regulations 
       related to medical device labeling and enforced by FDA appear 
       below.  It is important that these provisions be kept in mind 
       both in the development of labeling by the device industry and 
       in the labeling review by CDRH.

       Section 502 of the Federal Food,Drug, and Cosmetic Act (the 
       act) provides that a device shall be deemed misbranded if:
       
            (1) Its labeling is false or misleading in any particular.

            (2) The label does not bear the name and place of business 
                of the manufacturer, packer or distributor and an 
                accurate statement of the quantity of contents in 
                terms of weight, measure or numerical count.
           
            (3) Any required word, statement or other information to 
                appear on the label or labeling is not prominently 
                placed thereon with such conspicuousness and in such
                terms as to render it likely to be read and understood 
                by the ordinary individual under customary conditions 
                of purchase and use.

            (4) Labeling does not bear adequate directions for use and 
                such adequate warnings against use in those 
                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 in such manner and form as are necessary 
                for the protection of users.

            (5) In the case of a restricted device, its advertising is 
                false or misleading in any particular.
                                                                      
            (6) In the case of a restricted device, advertisements and 
                other descriptive printed matter (other than labeling) 
                issued by the manufacturer, packer or distributor do 
                not include a brief statement of the intended uses of 
                the device and relevant warnings, precautions, side 
                effects and contraindications.

       In determining whether a device is misbranded because the 
       labeling or advertising is misleading, section 201(n) of the 
       act permits the following to be taken into account among other 
       things:
  
            (1)  representations made or suggested by statement, 
                 word, design, device, or any combination thereof; or

            (2)  the extent to which the labeling or advertising 
                 fails to reveal facts material in the light of such 
                 representations or material with respect to the 
                 consequences which may result from the use of the 
                 device to which the labeling or advertising 
                 relates under the conditions of use prescribed in 
                 the labeling or advertising or under such conditions 
                 of use as are customary or usual.

       Regulations applicable to medical devices provide that the 
       inclusion of any of the following representations in device 
       labeling constitutes misbranding of the device:

       21 CFR 801.6 - False or misleading representation with respect
                      to another device or a drug

       21 CFR 807.39 -Any representation that creates an impression
                      of official approval because of registration or
                     (e.g.,i clusion of FDA establishment 
                      registration number)

       21 CFR 807.97 - Any representation that creates an impression 
                      of official approval because of complying with 
                      the premarket notification regulations 
                      (e.g., inclusion of premarket notification
                      reference number)

 XIV.  Prohibited Acts
       
       Section 301(1) of the act prohibits the use in any labeling or 
       advertising for the device of any representation or suggestion 
       that approval of an application with respect to the device is 
       in effect under section 515 of the act (premarket approval) or 
       that the device complies with the provisions of section 515.