[Federal Register Volume 62, Number 137 (Thursday, July 17, 1997)]
[Proposed Rules]
[Pages 38231-38237]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-18831]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 872

[Docket No. 97N-0239]


Dental Devices; Effective Date of Requirement for Premarket 
Approval; Temporomandibular Joint Prostheses

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; opportunity to request a change in 
classification.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to require 
the filing of a premarket approval application (PMA) or a notice of 
completion of a product development protocol (PDP) for the total 
temporomandibular joint (TMJ) prosthesis, the glenoid fossa prosthesis, 
the mandibular condyle prosthesis, and the interarticular disc 
prosthesis (interpositional implant). The agency is also summarizing 
its proposed findings regarding the degree of risk of illness or injury 
intended to be eliminated or reduced by requiring the devices to meet 
the statute's approval requirements as well as the benefits to the 
public from the use of the devices. In addition, FDA is announcing the 
opportunity for interested persons to request the agency to change the 
classification of the devices based on new information.

DATES: Submit written comments by October 15, 1997; requests for a 
change in classification by August 1, 1997. FDA intends that if a final 
rule based on this proposed rule is issued, PMA's or notices of 
completion of PDP's will be required to be submitted within 90 days of 
the effective date of the final rule.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:  Mary S. Runner, Center for Devices 
and Radiological Health (HFZ-480), Food and Drug Administration, 9200 
Corporate Blvd., Rockville, MD 20850, 301-827-5283.

SUPPLEMENTARY INFORMATION:

I. Background

    Section 513 of the Federal Food, Drug, and Cosmetic Act (the act) 
(21 U.S.C. 360c) requires the classification of medical devices into 
one of three regulatory classes: Class I (general controls), class II 
(special controls), and class III (premarket approval).

[[Page 38232]]

 Generally, devices that were on the market before May 28, 1976, the 
date of enactment of the Medical Device Amendments of 1976 (the 1976 
amendments) (Pub. L. 94-295), and devices marketed on or after that 
date that are substantially equivalent to such devices, have been 
classified by FDA. For the sake of convenience, this preamble refers to 
the devices that were on the market before May 28, 1976, and the 
substantially equivalent devices that were marketed on or after that 
date as ``preamendments devices.''
    Section 515(b)(1) of the act (21 U.S.C. 360e(b)(1)) establishes the 
requirement that a preamendments device that FDA has classified into 
class III is subject to premarket approval. A preamendments class III 
device may be commercially distributed without an approved PMA or 
notice of completion of a PDP until 90 days after FDA issues a final 
rule requiring premarket approval for the device, or 30 months after 
final classification of the device under section 513 of the act, 
whichever is later. Also, a preamendments device subject to the 
rulemaking procedure under section 515(b) of the act, is not required 
to have an approved investigational device exemption (IDE) (part 812 
(21 CFR part 812)) contemporaneous with its interstate distribution 
until the date identified by FDA in the final rule requiring the 
submission of a PMA or a PDP for the device. At that time, an IDE must 
be submitted only if a PMA has not been submitted or a PDP completed.
    Section 515(b)(2)(A) of the act provides that a proceeding to issue 
a final rule to require premarket approval shall be initiated by 
publication of a notice of proposed findings rulemaking containing: (1) 
The proposed rule, (2) proposed findings with respect to the degree of 
risk of illness or injury designed to be eliminated or reduced by 
requiring the device to have an approved PMA or a declared completed 
PDP and the benefit to the public from the use of the device, (3) an 
opportunity for the submission of comments on the proposed rule and the 
proposed findings, and (4) an opportunity to request a change in the 
classification of the device based on new information relevant to the 
classification of the device.
    Section 515(b)(2)(B) of the act provides that if FDA receives a 
request for a change in the classification of the device within 15 days 
of the publication of the notice, FDA shall, within 60 days of the 
publication of the notice, consult with the appropriate FDA advisory 
committee and publish a notice denying the request for change of 
classification or announcing its intent to initiate a proceeding to 
reclassify the device under section 513(e) of the act. If FDA does not 
initiate such a proceeding, section 515(b)(3) of the act provides that 
FDA shall, after the close of the comment period on the proposed rule 
and consideration of any comments received, issue a final rule to 
require premarket approval, or publish a notice terminating the 
proceeding. If FDA terminates the proceeding, FDA is required to 
initiate reclassification of the device under section 513(e) of the 
act, unless the reason for termination is that the device is a banned 
device under section 516 of the act (21 U.S.C. 360f).
    If a proposed rule to require premarket approval for a 
preamendments device is made final, section 501(f)(2)(B) of the act (21 
U.S.C. 351(f)(2)(B)) requires that a PMA or a notice of completion of a 
PDP for any such device be filed within 90 days of the date of issuance 
of the final rule or 30 months after final classification of the device 
under section 513 of the act, whichever is later. If a PMA or a notice 
of completion of a PDP is not filed by the later of the two dates, 
commercial distribution of the device is required to cease. The device 
may, however, be distributed for investigational use if the 
manufacturer, importer, or other sponsor of the device complies with 
the IDE regulations. If a PMA or a notice of completion of a PDP is not 
filed by the later of the two dates, and no IDE is in effect, the 
device is deemed to be adulterated within the meaning of section 
501(f)(1)(A) of the act, and subject to seizure and condemnation under 
section 304 of the act (21 U.S.C. 334) if its distribution continues. 
Shipment of the device in interstate commerce will be subject to 
injunction under section 302 of the act (21 U.S.C. 332), and the 
individuals responsible for such shipment will be subject to 
prosecution under section 303 of the act (21 U.S.C. 333). In the past, 
FDA has requested that manufacturers take action to prevent the further 
use of devices for which no PMA has been filed and may determine that 
such a request is appropriate for total TMJ prostheses, glenoid fossa 
prostheses, mandibular condyle prostheses, and interarticular disc 
prostheses (interpositional implants).
    The act does not permit an extension of the 90-day period after 
issuance of a final rule within which an application or a notice is 
required to be filed. The House Report on the amendments states that 
``the thirty month `grace period' afforded after classification of a 
device into class III * * * is sufficient time for manufacturers and 
importers to develop the data and conduct the investigations necessary 
to support an application for premarket approval'' (H. Rept. 94-853; 
94th Cong., 2d sess. 42 (1976)).

A. Classification of Total TMJ Prostheses, Glenoid Fossa Prostheses, 
Mandibular Condyle Prostheses and Interarticular Disc Prostheses 
(Interpositional Implants)

    In the Federal Register of December 20, 1994 (59 FR 65475), FDA 
issued a final rule classifying the total TMJ prosthesis, the glenoid 
fossa prosthesis, the mandibular condyle prosthesis, and the 
interarticular disc prosthesis (interpositional implant) into class 
III. The preamble to the proposal to classify these devices (57 FR 
43165, September 18, 1992) included the recommendation of the Dental 
Products Panel (the Panel), an FDA advisory committee, which met on 
April 21, 1989, regarding the classification of the devices (Ref. 1), 
in particular, the total TMJ prosthesis and the interarticular disc 
prosthesis (interpositional implant). The preamble to the reproposed 
rule to classify the glenoid fossa prosthesis and the mandibular 
condyle prosthesis (59 FR 6935, February 14, 1994) included the 
recommendation of the panel that reconvened on February 11, 1993, (Ref. 
2) regarding the classification of these two TMJ prostheses. The Panel 
recommended at the April 1989 meeting that the total TMJ prosthesis and 
the interarticular disc prosthesis (interpositional implant), and at 
the February 1993 meeting that the glenoid fossa prosthesis and the 
mandibular condyle prosthesis, be classified into class III, and 
identified certain risks to health presented by the devices. The Panel 
believed that the devices presented a potential unreasonable risk to 
health and that insufficient information existed to determine that 
general controls are sufficient to provide reasonable assurance of the 
safety and effectiveness of the devices or that application of 
performance standards would provide such assurance.
    FDA agreed with the Panel's recommendations and, in the proposal 
(57 FR 43165) and in the reproposed rule (59 FR 6935), proposed that 
the total TMJ prosthesis, the glenoid fossa prosthesis, the mandibular 
condyle prosthesis and the interarticular disc prosthesis 
(interpositional implant) be classified into class III. The proposal 
and reproposal stated that FDA believed that general controls, either 
alone or in combination with the special controls applicable to class 
II devices, are insufficient to provide reasonable assurance of the 
safety and effectiveness of the devices. The proposal and

[[Page 38233]]

reproposal stated that premarket approval is necessary for the devices 
because the devices present potential unreasonable risks of illness or 
injury if there are not adequate data to ensure the safe and effective 
use of the devices.
    The preamble to the final rule (59 FR 65475) classifying the total 
TMJ prosthesis, the glenoid fossa prosthesis, the mandibular condyle 
prosthesis and the interarticular disc prosthesis (interpositional 
implant) into class III advised that the earliest date by which PMA's 
or notices of completion of PDP's for the devices could be required was 
June 30, 1997, or 90 days after issuance of a rule requiring premarket 
approval for the devices. In the Federal Register of January 6, 1989 
(54 FR 550), FDA published a notice of intent to initiate proceedings 
to require premarket approval for 31 class III preamendments devices. 
Among other items, the notice described the factors FDA takes into 
account in establishing priorities for proceedings under section 515(b) 
of the act for issuing final rules requiring that preamendments class 
III devices have approved PMA's or declared completed PDP's. FDA 
updated its priorities in a preamendments class III strategy notice of 
availability document published in the Federal Register of May 6, 1994 
(59 FR 23731). Although the previous TMJ prostheses were not included 
in the lists of devices identified in the notice and the strategy 
paper, using the factors set forth in these documents, FDA has recently 
determined that the total TMJ prosthesis identified in Sec. 872.3940 
(21 CFR 872.3940), the glenoid fossa prosthesis identified in 
Sec. 872.3950 (21 CFR 872.3950), the mandibular condyle prosthesis 
identified in Sec. 872.3960 (21 CFR 872.3960), and the interarticular 
disc prosthesis identified in Sec. 872.3970 (21 CFR 872.3970) have a 
high priority for initiating a proceeding to require premarket approval 
because the safety and effectiveness of these devices has not been 
established by valid scientific evidence as defined in Sec. 860.7 (21 
CFR 860.7). Moreover, FDA believes that insufficient information exists 
to identify the proper materials or design for the total TMJ, the 
glenoid fossa, and the mandibular condyle prostheses. Accordingly, FDA 
is commencing a proceeding under section 515(b) of the act to require 
that the previous four TMJ prostheses have an approved PMA or declared 
completed PDP.

B. Dates New Requirements Apply

    In accordance with section 515(b) of the act, FDA is proposing to 
require that a PMA or a notice of completion of a PDP be filed with the 
agency for the total TMJ prosthesis, the glenoid fossa prosthesis, the 
mandibular condyle prosthesis, and the interarticular disc prosthesis 
(interpositional implant) within 90 days after issuance of any final 
rule based on this proposal. An applicant whose device was legally in 
commercial distribution before May 28, 1976, or whose device has been 
found by FDA to be substantially equivalent to such a device, will be 
permitted to continue marketing the total TMJ prosthesis, the glenoid 
fossa prosthesis, the mandibular condyle prosthesis, and the 
interarticular disc prosthesis (interpositional implant) during FDA's 
review of the PMA or notice of completion of the PDP. FDA intends to 
review any PMA for the device within 180 days, and any notice of 
completion of a PDP for the device within 90 days of the date of 
filing. FDA cautions that, under section 515(d)(1)(B)(I) of the act, 
FDA may not enter into an agreement to extend the review period of a 
PMA beyond 180 days unless the agency finds that `` * * * the continued 
availability of the device is necessary for the public health.''
    FDA intends that, under Sec. 812.2(c)(2), the preamble to any final 
rule based on this proposal will state that, as of the date on which a 
PMA or a notice of completion of a PDP is required to be filed, the 
exemption in Sec. 812.2(c)(1) and (c)(2) from the requirements of the 
IDE regulations for preamendments class III devices will cease to apply 
to any total TMJ prosthesis, glenoid fossa prosthesis, mandibular 
condyle prosthesis, and interarticular disc prosthesis (interpositional 
implant) which is: (1) Not legally on the market on or before that 
date; or (2) legally on the market on or before that date but for which 
a PMA or notice of completion of PDP is not filed by that date, or for 
which PMA approval has been denied or withdrawn.
    If a PMA, notice of completion of a PDP, or an IDE application for 
the total TMJ prosthesis, glenoid fossa prosthesis, mandibular condyle 
prosthesis, and interarticular disc prosthesis (interpositional 
implant) is not submitted to FDA within 90 days after the date of 
issuance of any final rule requiring premarket approval for the 
devices, commercial distribution for the devices must cease. FDA, 
therefore, cautions that for manufacturers not planning to submit a PMA 
or notice of completion of a PDP immediately, IDE applications should 
be submitted to FDA, at least 30 days before the end of the 90-day 
period after the final rule is published to minimize the possibility of 
interrupting all availability of the device. FDA considers 
investigations of the total TMJ prosthesis, the glenoid fossa 
prosthesis, the mandibular condyle prosthesis, and the interarticular 
disc prosthesis (interpositional implant) to pose a significant risk as 
defined in the IDE regulation.

C. Description of Devices

    A total TMJ prosthesis is a device that is intended to be implanted 
in the human jaw to replace the mandibular condyle and augment the 
glenoid fossa to functionally reconstruct the TMJ.
    A glenoid fossa prosthesis is a device that is intended to be 
implanted in the TMJ to augment a glenoid fossa or to provide an 
articulation surface for the head of a mandibular condyle.
    A mandibular condyle prosthesis is a device that is intended to be 
implanted in the human jaw to replace the mandibular condyle and to 
articulate within a glenoid fossa.
    An interarticular disc prosthesis (interpositional implant) is a 
device that is intended to be an interface between the natural 
articulating surface of the mandibular condyle and glenoid fossa.

D. Proposed Findings With Respect to Risks and Benefits

    As required by section 515(b) of the act, FDA is publishing its 
proposed findings regarding: (1) The degree of risk of illness or 
injury designed to be eliminated or reduced by requiring the total TMJ 
prosthesis, the glenoid fossa prosthesis, the mandibular condyle 
prosthesis, and the interarticular disc prosthesis (interpositional 
implant) to have an approved PMA or a declared completed PDP; and (2) 
the benefits to the public from the use of the device.

E. Risk Factors

1. Total TMJ Prosthesis (Sec. 872.3940), Glenoid Fossa Prosthesis 
(Sec. 872.3950), and Mandibular Condyle Prosthesis (Sec. 872.3960)
     The total TMJ prostheses, the glenoid fossa prostheses, and the 
mandibular condyle prostheses are associated with the following risks:
    1. Implant loosening or displacement. The screws used to anchor the 
implant may loosen, resulting in implant loosening or displacement, 
causing changes in bite, difficulty in chewing, limited joint function 
and unpredictable wear on implant components (Refs. 3 through 6);
    2. Degenerative changes to the natural articulating surfaces. 
Implant breakdown may result in erosion or resorption of the glenoid 
fossa, or the head of the mandibular condyle . The erosion or 
resorption may result in intense pain, changes in bite, difficulty in 
chewing, limited joint function and,

[[Page 38234]]

in the case of glenoid fossa prostheses, perforation into the middle 
cranial fossa (Refs. 3 through 6);
    3. Foreign body reaction. Implant deterioration and migration may 
result in a foreign body reaction characterized by multinucleated giant 
cells (Refs. 3 through 6);
    4. Infection. If the implant cannot be properly sterilized, 
infection may result;
    5. Loss of implant integrity. If the implant materials are unable 
to withstand mechanical loading, the implant can be torn, worn, 
perforated, delaminated, fragmented, fatigued, or fractured, resulting 
in failure of the devices to function properly (Refs. 3 through 6);
    6. Chronic pain. Degenerative changes within the articular surfaces 
and components of the TMJ due to implant breakdown may result in 
chronic pain (Refs. 3 through 6);
    7. Corrosion. If the implant materials are subject to corrosion, 
toxic elements may migrate to various parts of the body;
    8. Changes to the contralateral joint. Unilateral placement of the 
implant may result in deleterious effects to the contralateral joint; 
and
    9. Malocclusion. Placement of the device may produce an improper 
occlusal relationship.
2. Interarticular Disc Prosthesis (Interpositional Implant) 
(Sec. 872.3970)
    Interarticular disc prostheses (interpositional implants) are 
associated with the following risks:
    1. Loss of implant integrity. If the implant materials are unable 
to withstand mechanical loading, the implant materials can be torn, 
perforated, delaminated, or fragmented, resulting in failure of the 
device to function properly (Refs. 5, 7 through 11, and 13 through 16);
    2. Implant migration. Torn, worn, perforated, delaminated, and 
fragmented implant materials are capable of migrating to surrounding 
tissues, including the lymph nodes (Refs. 5 and 14);
    3. Foreign body reaction. Implant deterioration and migration may 
result in a foreign body reaction characterized by multinucleated giant 
cells (Refs. 5 and 7 through 16);
    4. Degenerative changes within the articular surfaces and 
components of the joint. Implant breakdown may result in severe 
resorption of the head of the mandibular condyle and glenoid fossa. The 
degenerative changes may result in joint noise, changes in bite, 
difficulty in breathing, severely limited joint function, erosion or 
perforation into the middle cranial fossa, crepitus, avascular necrosis 
and fibrous ankylosis (Refs. 5 and 7 through 15);
    5. Implant displacement. Displacement of the implant may result in 
changes in bite, difficulty in chewing and limited joint function 
(Refs. 7 through 10, 12, and 13);
    6. Infection. If the implant cannot be properly sterilized, 
infection may result;
    7. Chronic pain. Degenerative changes within the articular surfaces 
and components of the joint due to implant breakdown may result in 
chronic pain (Refs. 7 through 9 and 12);
    8. Calcification. Implant breakdown may result in the formation of 
scar tissue, leading to calcification (Refs. 11 and 16);
    9. Granulomatous reaction. Implant particulate may produce a mass 
or nodule of chronically inflamed tissue with granulation (Refs. 13 
through 16); and
    10. Leaching of elements. Toxic elements may be leached from the 
implant materials and migrate to various parts of the body.

F. Benefits of the Devices

     The total TMJ prosthesis, glenoid fossa prosthesis, mandibular 
condyle prosthesis, and interarticular joint prosthesis 
(interpositional implant) are implanted devices which are placed in the 
jaw either to functionally reconstruct the TMJ by replacing the 
mandibular condyle and augmenting the glenoid fossa; to augment a 
glenoid fossa, to substitute for the naturally occurring mandibular 
condyle or to provide an interface between the natural articulating 
surfaces of the mandibular condyle and glenoid fossa. The potential 
benefits intended from the use of these four TMJ prostheses are 
reconstruction of the articulation surface(s) for the restoration of 
jaw function and stability, and improvement in mastication, speech, 
esthetics, comfort, and pain relief.

II. PMA Requirements

     A PMA for these TMJ prosthetic devices must include the 
information required by section 515(c)(1) of the act and Sec. 814.20 
(21 CFR 814.20) of the procedural regulations for PMA's. Such a PMA 
should include a detailed discussion of the risks as well as a 
discussion of the effectiveness of the device for which premarket 
approval is sought. In addition, a PMA must include all data and 
information on: (1) Any risks known, or that should be reasonably known 
to the applicant that have not been identified in the proposal (57 FR 
43165) and in the reproposed rule (59 FR 6935); (2) the effectiveness 
of the specific TMJ prosthesis that is the subject of the application; 
and (3) full reports of all preclinical and clinical information from 
investigations on the safety and effectiveness of the device for which 
premarket approval is sought.
     A PMA should include valid scientific evidence as defined in 
Sec. 860.7 and should be obtained from well-controlled clinical 
studies, with detailed data, in order to provide reasonable assurance 
of the safety and effectiveness of the particular TMJ implant for its 
intended use. In addition to the basic requirements described in 
Sec. 814.20(b)(6)(ii) for a PMA, it is recommended that such studies 
employ a protocol that meets the following criteria.
     Applicants should submit PMA's in accordance with FDA's guideline 
entitled ``Guideline for the Arrangement and Content of a PMA 
Application.'' The guideline is available upon request from FDA, Center 
for Devices and Radiological Health, Division of Small Manufacturers 
Assistance (HFZ-220), 1350 Piccard Dr., Rockville, MD 20850.

A. General Protocol Requirements

    The total TMJ prosthesis, the glenoid fossa prosthesis, the 
mandibular condyle prosthesis, and the interarticular disc prosthesis 
(interpositional implant) should be evaluated in a prospective, 
randomized, clinical trial that uses adequate controls. The study must 
attempt to answer all of the questions concerning safety and 
effectiveness of the devices, including the risk to benefit ratio. The 
questions should relate to the pathophysiologic effects which the 
devices produce, as well as the primary and secondary variables 
analyzed to evaluate safety and effectiveness. Study endpoints and 
study success must be defined.
    Biocompatibility testing for new material and/or the finished 
devices should be performed according to the Office of Device 
Evaluation blue book memorandum G95-1 entitled ``Use of International 
Standard ISO-10993, ``Biological Evaluation of Medical Devices Part-1: 
Evaluation and Testing.'' This memorandum includes the FDA-modified 
matrix that designates the type of testing needed for various medical 
devices. The following tests should be considered:
    1. Cytotoxicity
    2. Sensitization
    3. Irritation or intracutaneous reactivity
    4. Acute systemic toxicity
    5. Sub-acute toxicity
    6. Genotoxicity
    7. Implantation
    8. Hemocompatibility
    9. Chronic toxicity

[[Page 38235]]

    10. Carcinogenicity
    Specific considerations include the following:
    1. The selection of materials to be used in device manufacture and 
their toxicological evaluation should initially take into account a 
full characterization of the materials, such as chemical composition of 
components, known and suspected impurities, and processing. Any surface 
coatings to be applied are to be fully characterized, including 
materials, physical specifications, and application processes.
    2. The materials of manufacture, the final product and possible 
leachable chemicals or degradation products should be considered for 
their relevance to the overall toxicological evaluation of the devices.
    3. Any in vitro or in vivo experiments or tests must be conducted 
according to recognized good laboratory practices followed by an 
evaluation by competent informed persons.
    4. Any change in chemical composition, manufacturing process, 
physical configuration or intended use of the devices must be evaluated 
with respect to possible changes in toxicological effects and the need 
for additional testing.
    5. The biocompatibility evaluation performed in accordance with the 
guidance should be considered in conjunction with other information 
from other nonclinical studies and postmarket experiences for an 
overall safety assessment.
    Examples of questions to be addressed by the clinical studies may 
include the following:
    1. What morbidity (jaw dysfunction or limited range of motion, 
degenerative changes to the natural articulating surfaces, erosion or 
resorption of the glenoid fossa or mandibular condyle, intense pain, 
joint arthritis, perforation into the middle cranial fossa, foreign 
body or allergic reactions, multinucleated giant cells, infection, 
chronic pain, changes in the contralateral joint, malocclusion, joint 
noise, crepitus, avascular necrosis, fibrous ankylosis difficulty in 
chewing, calcification, granulomatous reaction, facial nerve and muscle 
weakness, paralysis, hearing problems, or hematoma formation) is 
associated with the subject device in the patient population and how 
does this compare to the control?
    2. What impact do the devices have on the jaw function?
    3. What are the long term effects of the devices on the oral 
tissue?
    4. What changes in physical characteristics of the prostheses can 
take place over time?
    5. What potential problems (such as prosthesis loosening or 
displacement, wear evidence and debris, cracking, or fracture) may be 
associated with the use of the devices over time?
    6. Do the devices allow sufficient comfort for the user?
    7. What criteria are used to select the correct size of TMJ 
prostheses for individual patients?
    8. How is the individual occlusal plane determined to avoid 
traumatic occlusion?
    9. Do the devices allow the patients to be able to masticate food, 
insofar as oral and psychologic conditions will permit?
    10. Does use of the devices result in the individual patient 
presenting a normal individual appearance that satisfies esthetic 
requirements?
    Statistically valid investigations should include a clear statement 
of the objectives, method of selection of subjects, nature of the 
control group, effectiveness and/or safety parameters, method of 
analysis, and presentation of statistical results of the study. 
Appropriate rationale, supported by background literature on previous 
uses of the particular TMJ prosthesis and proposed mechanisms for its 
effect, should be presented as justification for the questions to be 
answered, and the definitions of study endpoints and success. Clear 
study hypotheses should be formulated based on this information.

B. Study Sample Requirements

    The subject population should be well defined. Ideally, the study 
population should be as homogeneous as possible in order to minimize 
selection bias and reduce variability. Otherwise a large population may 
be necessary to achieve statistical significance. Independent studies 
producing comparable results at multiple study sites using identical 
protocols are necessary to demonstrate repeatability. Justification 
must be provided for the sample size used to show that a sufficient 
number of TMJ disorder patients were enrolled to attain statistically 
and clinically meaningful results. Eligibility criteria for the subject 
population should include the subject's potential for benefit, the 
ability to detect a benefit in the subject, the absence of both 
contraindications and any competing risk and assurance of subject 
compliance. In a heterogeneous sample, stratification of the patient 
groups participating in the clinical study may be necessary to analyze 
homogeneous subgroups and thereby minimize potential bias. All endpoint 
variables should be identified, and a sufficient number of patients 
from each subgroup analysis should be included to allow for 
stratification by pertinent demographic characteristics.
    The investigations should include an evaluation of comparability 
between treatment groups and control groups (including historical 
controls). Baseline (e.g., age, gender, etc.) and other variables 
should be measured and compared between the treatment and control 
groups. The baseline variables should be measured at the time of 
treatment assignment, not during the course of the study. Other 
variables should be measured during the study as needed to completely 
characterize the particular device's safety and effectiveness.

C. Study Design

    All potential sources of error, including selection bias, 
information bias, misclassification bias, comparison bias, or other 
potential biases should be evaluated and minimized. The study should 
clearly measure any possible placebo effect. Treatment effects should 
be based on objective measurements. The validity of these measurement 
scales should be shown to ensure that the treatment effect being 
measured reflects the intended uses of the particular device.
    Adherence to the protocol by subjects, investigators, and all other 
individuals involved is essential and requires monitoring to assure 
compliance by both patients and dental practitioners. Subject exclusion 
due to dropout or loss to follow up greater than 20 percent may 
invalidate the study due to bias potential; therefore, initial patient 
screening and compliance of the final subject population will be needed 
to minimize the dropout rate. All dropouts must be accounted for and 
the circumstances and procedures used to ensure patient compliance must 
be well documented.
    Endpoint assessment cannot be based solely on statistical value. 
Instead, the clinical outcome must be carefully defined to distinguish 
between the evaluation of the proper function of the device versus its 
benefit to the subject. Statistical significance and effectiveness of 
the device must be demonstrated by the statistical results.
    Observation of all potential adverse effects must be recorded and 
monitored throughout the study and the followup period. All adverse 
effects must be documented and evaluated.

D. Statistical Analysis Plan

    The involvement of a biostatistician is recommended to provide 
proper guidance in the planning, design, conduct, and analysis of a 
clinical study. There must be sufficient

[[Page 38236]]

documentation of the statistical analysis and results including 
comparison group selection, sample size justification, stated 
hypothesis test(s), population demographics, study site pooling 
justification, description of statistical tests applied, clear 
presentation of data and a clear discussion of the statistical results, 
and conclusions.
    In addition to this generalized guidance, the investigator or 
sponsor is expected to incorporate additional requirements necessary 
for a well-controlled scientific study. These additional requirements 
are dependent on what the investigator or sponsor intends to measure or 
what the expected treatment effect is based on each device's intended 
use.

E. Clinical Analysis

     The analysis which results from the study should include a 
complete description of all the statistical procedures employed, 
including assumption verification, pooling justification, population 
selection, statistical model selection, etc. If any procedures are 
uncommon or derived by the investigator or sponsor for the specific 
analysis, an adequate description must be provided of the procedure for 
FDA to assess its utility and adequacy. Data analysis and 
interpretations from the clinical investigation should relate to the 
medical claims.

F. Monitoring

    Rigorous monitoring is required to assure that the study procedures 
are collected in accordance with the study protocol. Attentive 
monitors, who have appropriate credentials and who are not aligned with 
patient management or otherwise biased, contribute prominently to a 
successful study.

III. Opportunity to Request a Change in Classification

    Before requiring the filing of a PMA or a notice of completion of a 
PDP for a device, FDA is required by section 515(b)(2)(A)(i) through 
(b)(2)(A)(iv) of the act and 21 CFR 860.132 to provide an opportunity 
for interested persons to request a change in the classification of the 
device based on new information relevant to its classification. Any 
proceeding to reclassify the device will be under the authority of 
section 513(e) of the act.
    A request for a change in the classification of the total TMJ 
prosthesis, the glenoid fossa prosthesis, the mandibular condyle 
prosthesis, and the interarticular disc prosthesis (interpositional 
implant) is to be in the form of a reclassification petition containing 
the information required by Sec. 860.123 (21 CFR 860.123), including 
information relevant to the classification of the device, and shall, 
under section 515(b)(2)(B) of the act, be submitted by August 1, 1997.
    The agency advises that, to ensure timely filing of any such 
petition, any request should be submitted to the Dockets Management 
Branch (address above) and not to the address provided in 
Sec. 860.123(b)(1). If a timely request for a change in the 
classification of the total TMJ prosthesis, the glenoid fossa 
prosthesis, the mandibular condyle prosthesis or the interarticular 
disc prosthesis (interpositional implant) is submitted, the agency 
will, by September 15, 1997, after consultation with the appropriate 
FDA advisory committee and by an order published in the Federal 
Register, either deny the request or give notice of its intent to 
initiate a change in the classification of the device in accordance 
with section 513(e) of the act and 21 CFR 860.130 of the regulations.

IV. References

    The following references have been placed on public display in the 
Dockets Management Branch (address above) and may be seen by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Transcripts of the Dental Products Panel meeting, April 
21,1989.
    2. Transcripts of the Dental Products Panel meeting, February 
11,1993.
    3. Fontenot, M. G., and J. N. Kent, ``In-Vitro and In-Vivo Wear 
Performance of TMJ Implants,'' abstract, International Association 
of Dental Research, 1991.
    4. Kent, J. N., and M. S. Block, ``Comparison of FEP and UPE 
Glenoid Fossa Prosthesis,'' abstract, International Association of 
Dental Research, 1991.
    5. ``Clinical Information on the Vitek TMJ Interpositional (IPI) 
Implant and the Vitek-Kent (VK) Vitek-Kent 1 (VK-1) TMJ Implants,'' 
and ``Vitek Patient Notification Program,'' an FDA publication, 
1991.
    6. Kent, J. N., ``VK Partial and Total Joint Reconstruction,'' 
Current Concepts of TMJ Total Joint Replacement, University of 
Medicine and Dentistry of New Jersey, pp. 1-8, March 1992.
    7. Primely, D., ``Histological and Radiological Evaluation of 
the ProplastTM-Teflon Interpositional Implant in 
Temporomandibular Joint Reconstruction Following Meniscectomy,'' 
thesis, Masters degree in Oral Maxillofacial Surgery, University of 
Iowa, May 1987.
    8. Westlund, K. J.,``An Evaluation Using Computerized Tomography 
of Clinically Asymptomatic Patients Following Meniscectomy and 
Temporomandibular Joint Reconstruction Using the 
ProplastTM-Teflon Interpositional Implant,'' thesis, 
Masters Degree in Oral and Maxillofacial Surgery, University of 
Iowa, May 1989.
    9. Wagner, J. D., and E. L. Mosby, ``Assessment of 
ProplastTM-Teflon Disc Replacements,'' Journal of Oral 
and Maxillofacial Surgery, 48:1140-1144, 1990.
    10. Florine, B. K. et al., ``Tomographic Evaluation of 
Temporomandibular Joints Following Discoplasty or Replacement of 
Polytetrafluoroethylene Implants,'' Journal of Oral and 
Maxillofacial Surgery, 48:183-188, 1988.
    11. Heffez, L. et al., ``CT Evaluation of TMJ Disc Replacement 
with a ProplastTM Teflon Laminate,'' Journal of Oral and 
Maxillofacial Surgery, 45:657-665, 1987.
    12. Ryan, D. E., ``Alloplastic Implants in the Temporomandibular 
Joint,'' Oral and Maxillofacial Surgery Clinics of North America, 
1:427, 1989.
    13. Valentine, J. D., ``Light and Electron Microscopic 
Evaluation of ProplastTM II TMJ Disc Implants,'' Journal 
of Oral and Maxillofacial Surgery, 47:689-696, 1989.
    14. Logrotteria, L. et al., ``Patient with Lymphadenopathy 
Following Temporomandibular Joint Arthroplasty with 
ProplastTM,'' The Hour of Craniomandibular Practice, vol. 
4, No. 2:172-178, 1986.
    15. Berarduci, J. P. et al., ``Perforation into Middle Cranial 
Fossa as a Sequel to Use of a ProplastTM Teflon Implant 
for Temporomandibular Joint Reconstruction,'' Journal of Oral and 
Maxillofacial Surgery, 46:496-498, 1990.
    16. Berman, D. N., and S. L. Pronstein, ``Osteo Phytic Reaction 
to a Polytetrafluoroethylene Temporomandibular Joint Implant,'' Oral 
Surgery, Oral Medicine, Oral Pathology (continues the Oral Surgery 
Section of the American Journal of Orthodontics and Oral Surgery), 
69:20-23, 1990.

V. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(8) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VI. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is not a significant regulatory action as defined by the

[[Page 38237]]

Executive Order and so is not subject to review under the Executive 
Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the total TMJ prosthesis, the glenoid fossa 
prosthesis, the mandibular condyle prosthesis and the interarticular 
disc prosthesis (interpositional implant) have been classified into 
class III since December 12, 1994, and manufacturers of such TMJ 
prostheses legally in commercial distribution before May 28, 1976, or 
found by FDA to be substantially equivalent to such devices, will be 
permitted to continue marketing during FDA's review of the PMA or 
notice of completion of the PDP, the Commissioner of Food and Drugs 
certifies that the proposed rule will not have a significant economic 
impact on a substantial number of small entities. Therefore, under the 
Regulatory Flexibility Act, no further analysis is required.

VII. Comments

    Interested persons may, on or before October 15, 1997, submit to 
the Dockets Management Branch (address above) written comments 
regarding this proposal. Two copies of any comments are to be 
submitted, except that individuals may submit one copy. Interested 
persons may, on or before August 1, 1997, submit to the Dockets 
Management Branch a written request to change the classification of the 
total TMJ prosthesis, glenoid fossa prosthesis, mandibular condyle 
prosthesis, or the interarticular disc prosthesis (interpositional 
implant). Two copies of any request are to be submitted, except that 
individuals may submit one copy. Comments or requests are to be 
identified with the docket number found in brackets in the heading of 
this document. Received comments and requests may be seen in the office 
above between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 872

     Medical devices.
     Therefore, under the Federal Food, Drug, and Cosmetic Act and 
under authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 872 be amended as follows:

PART 872--DENTAL DEVICES

     1. The authority citation for 21 CFR part 872 continues to read as 
follows:

    Authority: Secs. 501, 510, 513, 515, 520, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 351, 360, 360c, 360e, 360j, 
371).
    2. Section 872.3940 is amended by revising paragraph (c) to read as 
follows:


Sec. 872.3940  Total temporomandibular joint prosthesis.

 * * * * *
    (c) Date premarket approval application (PMA) or notice of 
completion of a product development protocol (PDP) is required. A PMA 
or a notice of completion of a PDP is required to be filed on or before 
(date 90 days after the effective date of a final rule based on this 
proposed rule), for any total temporomandibular joint (TMJ) prosthesis 
that was in commercial distribution before May 28, 1976, or that has on 
or before (date 90 days after the effective date of a final rule), been 
found to be substantially equivalent to a total TMJ prosthesis that was 
in commercial distribution before May 28, 1976. Any other total TMJ 
prosthesis shall have an approved PMA or a declared completed PDP in 
effect before being placed in commercial distribution.
    3. Section 872.3950 is amended by revising paragraph (c) to read as 
follows:


Sec. 872.3950  Glenoid fossa prosthesis.

* * * * *
    (c) Date premarket approval application (PMA) or notice of 
completion of a product development protocol (PDP) is required. A PMA 
or a notice of completion of a PDP is required to be filed on or before 
(date 90 days after the effective date of a final rule based on this 
proposed rule), for any glenoid fossa prosthesis that was in commercial 
distribution before May 28, 1976, or that has on or before (date 90 
days after the effective date of a final rule), been found to be 
substantially equivalent to a glenoid fossa prosthesis that was in 
commercial distribution before May 28, 1976. Any other glenoid fossa 
prosthesis shall have an approved PMA or a declared completed PDP in 
effect before being placed in commercial distribution.
    4. Section 872.3960 is amended by revising paragraph (c) to read as 
follows:


Sec. 872.3960  Mandibular condyle prosthesis.

 * * * * *
    (c) Date premarket approval application (PMA) or notice of 
completion of a product development protocol (PDP) is required. A PMA 
or a notice of completion of a PDP is required to be filed on or before 
(date 90 days after the effective date of a final rule based on this 
proposed rule), for any mandibular condyle prosthesis that was in 
commercial distribution before May 28, 1976, or that has on or before 
(date 90 days after the effective date of a final rule), been found to 
be substantially equivalent to a mandibular condyle prosthesis that was 
in commercial distribution before May 28, 1976. Any other mandibular 
condyle prosthesis shall have an approved PMA or a declared completed 
PDP in effect before being placed in commercial distribution.
    5. Section 872.3970 is amended by revising paragraph (c) to read as 
follows:


Sec. 872.3970  Interarticular disc prosthesis (interpositional 
implant).

 * * * * *
    (c) Date premarket approval application (PMA) or notice of 
completion of a product development protocol (PDP) is required. A PMA 
or a notice of completion of a PDP is required to be filed on or before 
(date 90 days after the effective date of a final rule based on this 
proposed rule), for any interarticular disc prosthesis (interpositional 
implant) that was in commercial distribution before May 28, 1976, or 
that has on or before (date 90 days after the effective date of a final 
rule), been found to be substantially equivalent to an interarticular 
disc prosthesis (interpositional implant) that was in commercial 
distribution before May 28, 1976. Any other interarticular disc 
prosthesis (interpositional implant) shall have a PMA or a declared PDP 
in effect before being placed in commercial distribution.

    Dated: July 3, 1997.
Joseph A. Levitt,
Deputy Director for Regulations Policy, Center for Devices and 
Radiological Health.
[FR Doc. 97-18831 Filed 7-16-97; 8:45 am]
BILLING CODE 4160-01-F