[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
