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

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).

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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

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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