[Federal Register: May 10, 1999 (Volume 64, Number 89)]
[Proposed Rules]
[Page 24967-24972]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr10my99-20]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 884

[Docket No. 99N-0922]


Obstetrics and Gynecology Devices; Proposed Requirement for
Premarket Approval and Change in Classification of Glans Sheath Devices

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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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 glans sheath
medical device. 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 device to meet the statute's
approval requirements as well as the benefits to the public from the
use of the device. In addition, FDA is announcing the opportunity for
interested persons to request the agency to change the classification
of the device based on new information. This action is being taken to
establish that there is sufficient information to provide reasonable
assurance of the safety and effectiveness of this type of device.

DATES: Written comments by August 9, 1999; requests for a change in
classification by May 26, 1999.

ADDRESSES: Submit written comments or requests for a change in
classification to the Dockets Management Branch (HFA-305), Food and
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Colin M. Pollard, Center for Devices
and Radiological Health (HFZ-470), Food and Drug Administration, 9200
Corporate Blvd., Rockville, MD 20850, 301-594-1180.

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). Generally,
devices that were on the market before May 28, 1976, the date of
enactment of the Medical Device Amendments of 1976 (the amendments)
(Pub. L. 94-295), and devices marketed on or after that date that are
substantially equivalent to such devices have been, or are being,
classified by FDA. For convenience, this preamble refers to both 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 a
notice of completion of a PDP until 90 days after the effective date of
the final rule FDA issues requiring premarket approval for the device,
or 30 months after final classification of the device, 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 PDP for the device. At that time, an IDE must be submitted only if a
PMA has not been submitted or a PDP has not been declared 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 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 to
submit 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 513(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 after the effective
date of the final rule or 30 months after FDA's 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 the glans sheath device.
    The act does not permit an extension of the 90-day period after the
effective date of the final rule, within which an

[[Page 24968]]

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)).
    The Safe Medical Devices Act of 1990 (the SMDA) added section
515(i) to the act requiring FDA to review the classification of
preamendments class III devices for which no final rule has been issued
requiring the submission of PMA's and to determine whether or not each
device should be reclassified into class I or class II or remain in
class III. For devices remaining in class III, the SMDA directed FDA to
develop a schedule for issuing regulations to require premarket
approval. The SMDA does not, however, prevent FDA from proceeding
immediately to rulemaking under section 515(b) of the act on specific
devices, in the interest of public health, independent of the
procedures of section 515(i) of the act. Indeed, proceeding directly to
rulemaking under section 515(b) of the act is consistent with Congress'
objective in enacting section 515(i) of the act, i.e., that
preamendments class III devices for which PMA's or notices of completed
PDP's have not been required either be reclassified to class I or class
II or be subject to the requirements of premarket approval. Moreover,
in this proposal, interested persons are being offered the opportunity
to request reclassification of glans sheath devices.

A. Classification of the Glans Sheath Device(s)

    In the Federal Register of December 29, 1994 (59 FR 67185), FDA
issued a final rule classifying glans sheath devices into class III.
The preamble to the proposal to classify these devices (57 FR 42908,
September 17, 1992) included the recommendation of the Obstetrics-
Gynecology Devices Panel (the Panel), an FDA advisory committee, which
met on March 7, 1989, regarding the classification of these devices
(Ref. 1). During that meeting, the Panel concluded that ``glans cap''
devices, whose generic description FDA later changed to glans sheath
devices (59 FR 67185), were a different type of generic device than
were condom devices classified at 21 CFR 884.5300. The Panel
recommended that glans sheath devices 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 special
controls would provide such assurance.
    FDA agreed with the Panel's recommendations and proposed that glans
sheath devices be classified into class III (57 FR 42908). The proposal
stated that FDA believed that general controls, or special controls,
such as postmarket surveillance, the development of guidelines, the
establishment of a performance standard, or other actions, are
insufficient to provide reasonable assurance of the safety and
effectiveness of the devices. The proposal stated that FDA believes
that such devices present a potential unreasonable risk of illness or
injury and that, in the absence of valid scientific evidence in the
literature from published studies or test and clinical data that
demonstrate the biocompatibility of materials, or that measure
performance characteristics, such as slippage, bursting, and tearing,
the devices should be subject to premarket approval to ensure the
safety and effectiveness of 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. In the Federal
Register of May 6, 1994 (59 FR 23731), FDA issued a notice of
availability of a preamendments class III devices strategy document
which updated its priorities and set forth the agency's plans for
implementing the provisions of section 515(i) of the act for
preamendments class III devices for which FDA had not yet required PMA
approval. Although glans sheath devices were not included in the lists
of devices identified in these notices and the strategy paper, using
the factors set forth in these documents, FDA has recently determined
that glans sheath devices identified in Sec. 884.5320 (21 CFR 884.5320)
have a high priority for initiating a proceeding for requiring
premarket approval because the safety and effectiveness of these
devices have 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 assess the safety and effectiveness
of glans cap devices in preventing pregnancy and to derive reported
failure or pregnancy rates based upon usage of the devices. FDA also
believes that failure of the devices, which do not protect the shaft
and foreskin of the penis against infection, may result in the release
of infected semen into the vagina or otherwise result in the
transmission of disease. Accordingly, FDA is commencing a proceeding
under section 515(b) of the act to require that the glans sheath 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 glans sheath device within 90 days after the effective
date of any final rule issued on the basis of this proposal. An
applicant whose device was 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 glans sheath 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(d), 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
exemptions 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 glans sheath device 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
a glans sheath device is not submitted to FDA within 90 days after the
effective date of any final rule FDA may issue requiring premarket
approval for the devices, commercial distribution of the devices must
cease. FDA , therefore, cautions that for manufacturers not planning to

[[Page 24969]]

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 effective date of the final rule
that is published to minimize the possibility of interrupting all
availability of the device. FDA considers investigations of glans
sheath devices to pose a significant risk as defined in the IDE
regulation.

C. Description of the Device

    The glans sheath device is a sheath which covers only the glans
penis or part thereof, and may also cover the area in the immediate
proximity thereof, the corona and frenulum, but not the entire shaft of
the penis. It is indicated only for the prevention of pregnancy and not
for the prevention of sexually transmitted diseases (STD's).
    FDA considers the use of glans sheath devices for preventing the
transmission of STD's, such as, acquired immunodeficiency syndrome
(AIDS) caused by the human immunodeficiency virus (HIV) from HIV-
infected semen or vaginal secretions, to constitute investigational use
of the device. Any glans sheath device in interstate commerce that is
used, or that is labeled or promoted to be used, for preventing the
transmission of STD's must already have in effect an approved IDE, or
an approved PMA or declared completed PDP.

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 glans
sheath 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

    Glans sheath devices are associated with the following risks:
    1. Pregnancy
    Undesired pregnancy could occur if the device leaks, breaks, or
dislodges during intercourse. For women for whom pregnancy is
contraindicated due to medical conditions such as heart disease or
diabetes mellitus, the risk of an unwanted pregnancy can be severe,
even life threatening (Ref. 2). A search of the literature found no
published studies or controlled clinical data which demonstrated the
safety and effectiveness of the glans sheath device, or the expected
failure or pregnancy rates for use of the glans sheath. Additionally,
no testing or clinical study data were available regarding leakage,
breakage, or dislodgement of glans sheaths during intercourse.
References to this type of device in the literature described it as an
unsafe method of contraception (Refs. 3 and 4).
    2. Transmission of Diseases
    If the device fails due to leakage, breakage, or dislodgement
during intercourse, contact with infected semen or vaginal secretions
containing infectious agents could result in the transmission of STD's,
including AIDS, hepatitis B, cytomegalovirus infection, syphilis, and
disseminated gonorrhea (Refs. 5 through 8). Organisms causing these
systemic infections remain viable in the blood stream rendering almost
all body fluids and semen infectious. The HIV virus causing AIDS has
been isolated from infected blood, saliva, vaginal secretions, and
semen. Semen from infected persons has been shown to be an important
vehicle in spreading the disease (Refs. 5 through 8).
    3. Adverse Tissue Reaction
    Materials and substances that comprise the glans sheath could cause
local tissue irritation and sensitization or systemic toxicity when the
device contacts the glans penis or vaginal and cervical mucosa. Because
of such intended contact, testing the biocompatibility of materials and
substances that comprise the glans sheath is essential to provide
reasonable assurance of the device's safety.

F. Benefits of the Device

    The glans sheath covers only the glans penis or part thereof, and
may also cover the area in the immediate proximity thereof, the corona
and frenulum, so it may be acceptable to those individuals who would
not otherwise use a full-sheath condom. The glans sheath may be an
alternate preferred method of contraception which, arguably, may serve
to increase penile stimulation by reducing the degree of interference
and loss of sensitivity attributed to the use of contraceptives, in
particular, in comparison to the use of full-sheath condoms. FDA has
concluded from a review of the scientific literature that the safety
and effectiveness of the glans sheath device for contraceptive use for
the prevention of pregnancy have not been established by valid
scientific evidence as defined in Sec. 860.7.

II. PMA Requirements

    A PMA for the glans sheath device 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 42908); (2) the
effectiveness of the specific glans sheath 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 glans sheath 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 criteria described in the following
paragraphs.
    Applicants should submit any PMA in accordance with FDA's
``Premarket Approval Manual.'' This manual is available on the world
wide web at ``http://www.fda.gov/cdrh/dsma/manuals.html''.

A. General Protocol Requirements

    Glans sheath devices 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 (ODE) blue book memorandum #G95-1 entitled ``Use of
International Standard ISO-10993, `Biological Evaluation of Medical
Devices Part 1: Evaluation and Testing''' (Ref. 9). This memorandum
includes the FDA-modified matrix that designates the type of testing
needed for various medical devices. The memorandum is available upon
request from CDRH's Division of Small Manufacturers Assistance (address
above) and is also available on the world wide web at ``http://
www.fda.gov/cdrh/g951.html''. The following tests should be considered:
Cytotoxicity, sensitization, mucosal irritation, acute systemic

[[Page 24970]]

toxicity, mutagenicity, and implantation (90 day).
    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.
    Guidance concerning the type of information that should be provided
regarding materials, finished product, processing, testing, and
labeling may be found in the Office of Device Evaluation's draft
guidance entitled ``Testing Guidance For Male Condoms Made From New
Material,'' June 29, 1995 (Ref. 10). This guidance is available upon
request from CDRH's Division of Small Manufacturers Assistance and is
also available on the world wide web at ``http://www.fda.gov/cdrh/ode/
oderp455.html''. The following types of information should be provided:
    1. The identity of resin manufacturers.
    2. The chemical composition and specifications for raw materials,
including molecular weight and molecular weight distribution, and a
description of the quality control testing performed.
    3. A complete description of the chemical composition and
specifications for the finished device, including the molar ratio of
component monomers for fabricating the finished material(s), physical
characteristics (length, width, thickness, etc.).
    4. The chemical composition and specifications for any retention
ring materials, lubricants, or dusting agent.
    5. Details on the processes used to manufacture the finished device
to include: A flow diagram for all aspects of manufacturing and points
where in-process quality assurance testing is performed, and
descriptions of process control parameters, handling and/or reworking
procedures for product that fails in-process quality assurance tests,
procedures for adding lubricants and/or dusting agents, and packaging
procedures.
    6. Data from physical testing conducted on the finished device
using appropriate sampling procedures and established performance
limits and tolerances, to include tensile strength, force at break
(vulnerability to puncture), elongation (elasticity), tear resistance,
and other measures of flexural characteristics.
    7. If a shelf-life period or expiration date is stated in device
labeling, data from accelerated and/or real time testing of the
packaged product, including lubricants and other agents, demonstrating
the physical and mechanical integrity of the device for the shelf-life
or expiration date period claimed in labeling.
    8. Labeling providing: A complete description of the device,
indications, adequate directions for use, and full disclosure of the
safety and effectiveness findings from preclinical and clinical
studies, including the recommended use of a pregnancy rate table and
the disclosure that the product does not protect against HIV infection
and other STD's. (See FDA guidance entitled ``Uniform Contraceptive
Labeling,'' July 23, 1998, which is available from CDRH's Division of
Small Manufacturers Assistance (address above) and is also available on
the world wide web at ``http://www.fda.gov/cdrh/ode/contrlab.html''.)
    Examples of questions to be addressed by the clinical studies
include, but are not limited to, the following:
    1. What are the findings of preliminary studies conducted to
evaluate the clinical performance (slippage and breakage) and the
acceptability for use of the glans sheath device, including incidents
of genital irritation or other adverse occurrences?
    2. What breakage, slippage, partial slippage, dislodgement and
adverse reaction data and rates are derived from the clinical trial(s)
studying slippage and breakage, and what are the design and statistical
analysis particulars of the trial(s), including whether the study
followed a randomized, cross-over design and what patient population,
inclusion/exclusion criteria, sample size, and statistical analysis
models were chosen?
    3. What pregnancy, breakage, slippage, and adverse event data and
rates are derived from the clinical trial(s) evaluating the safety,
effectiveness, and ease of use of the glans sheath device, and what are
the design and statistical analysis particulars of the clinical
study(ies), including whether the study(ies) followed a randomized
controlled design, and what number of menstrual cycles of product use,
population size, inclusion/exclusion criteria, sample size, and
statistical analysis models were chosen?
    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 glans sheath device 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. Justification
must be provided for the sample size used to show that a sufficient
number of 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 multi-center 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

[[Page 24971]]

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 practitioners. Subject exclusion due to
dropout or loss to followup 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. However,
under certain restricted circumstances, a clinically significant result
may be documented without statistical significance.
    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 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. PDP Requirements

    A PDP for any of these devices may be submitted in lieu of a PMA
and must follow the procedures outlined in section 515(f) of the act. A
PDP should provide: (1) A description of the device; (2) preclinical
trial information (if any); (3) clinical trial information (if any);
(4) a description of the manufacturing and processing of the device;
(5) the labeling of the device; and (6) all other relevant information
about the device. In addition, the PDP must include progress reports
and records of the trials conducted under the protocol on the safety
and effectiveness of the device for which the completed PDP is sought.
FDA's current thinking on the PDP process and the relative duties and
responsibilities of the agency and applicant is provided in the draft
guidance entitled ``Guidance for Industry--Contents of a Product
Development Protocol; Draft.'' This draft guidance is available on the
world wide web at ``http://www.fda.gov/cdrh/pdp/pdp.html''.

IV. 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
(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 authority of section
513(e) of the act.
    A request for a change in the classification of the glans sheath
device 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 May 26, 1999.
    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 glans sheath is submitted, FDA will, by July 9,
1999 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.

V. References

    The following references have been placed on 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 Obstetrics-Gynecology Devices Panel
meeting, March 7, 1989.
    2. Willson, J., and E. Carrington, Obstetrics and Gynecology, C.
V. Mosby Co., chs. 22 and 27, 1987.
    3. ``Other Methods, Past, Present and Future * * * American, or
Grecian Tips,'' in ``Sex With Health The Which? Guide to
Contraceptives, Abortion and Sex-related Diseases,'' published by
Consumers' Association (British), November 1974.
    4. Peel, J., and M. Potts, ``The Condom,'' in ``Textbook of
Contraceptive Practice,'' Cambridge University Press, p. 58, 1969.
    5. ``Leads from the MMWR Morbidity and Mortality Weekly Report *
* * `Heterosexual

[[Page 24972]]

Transmission of Human T-Lymphotropic Virus Type III/Lymphadenopathy-
Associated Virus,''' Journal of the American Medical Association,
254(15): pp. 2051 to 2054, 1985.
    6. Winklestein, Jr., W. et al., ``Sexual Practices and Risk of
Infection by the Human Immunodeficiency Virus,'' Journal of the
American Medical Association, 253(3): pp. 321 to 325, 1987.
    7. Stone, K. M. et al., ``Primary Prevention of Sexually
Transmitted Diseases,'' Journal of the American Medical Association,
255(13): pp. 1763 to 1766, 1986.
    8. Peterman, T. A., and J. W. Curran, ``Sexual Transmission of
Human Immunodeficiency Virus,'' Journal of the American Medical
Association, 256(16): pp. 2222 to 2226, 1986.
    9. ``Use of International Standard ISO-10993, `Biological
Evaluation of Medical Devices Part 1: Evaluation and Testing,''' ODE
``Blue Book,'' General Program Memorandum #G95-1, FDA, Center for
Devices and Radiological Health, Office of Device Evaluation,
Rockville, MD 20857, May 1, 1995.
    10. ``Testing Guidance for Male Condoms Made From New
Materials,'' FDA, Center for Devices and Radiological Health, Office
of Device Evaluation, Obstetrics-Gynecology Devices Branch,
Rockville, MD 20857, June 29, 1995.

VI. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) 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.

VII. 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) (as
amended by subtitle D of the Small Business Regulatory Fairness Act of
1996 (Pub. L. 104-121) and the Unfunded Mandates Reform Act of 1995
(Pub. L. 104-4)). 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 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. FDA believes that only one firm, which previously
distributed a glans sheath type of device in 1989, may be affected and
required to submit a PMA at a cost of approximately $1.2 million.
However, because this type device has been classified into class III
since December 29, 1994, and any manufacturer of this device that was
legally in commercial distribution before May 28, 1976, or found by FDA
to be substantially equivalent to such a device, will be permitted to
continue marketing during FDA's review of the PMA or notice of
completion of the PDP, the agency 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.

VIII. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The
burden hours required for Sec. 884.5320(c) are included in the
collection entitled ``Premarket Approval of Medical Devices--21 CFR
Part 814,'' submitted on January 27, 1999 (64 FR 4112), for OMB
approval.

IX. Submission of Comments with Data

    Interested persons may, on or before August 9, 1999, 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 May 26, 1999 submit to the Dockets Management Branch a written
request to change the classification of the glans sheath. 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 884

    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 884 be amended as follows:

PART 884--OBSTETRICAL AND GYNECOLOGICAL DEVICES

    1. The authority citation for 21 CFR part 884 continues to read as
follows:

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.
    2. Section 884.5320 is amended by revising paragraph (c) to read as
follows:

Sec. 884.5320  Glans sheath.

* * * * *
    (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 with the
Food and Drug Administration on or before (date 90 days after date of
publication of the final rule in the Federal Register), for any glans
sheath that was in commercial distribution before May 28, 1976, or that
has, on or before (date 90 days after date of publication of the final
rule in the Federal Register) been found to be substantially equivalent
to a glans sheath that was in commercial distribution before May 28,
1976. Any other glans sheath shall have an approved PMA or a declared
completed PDP in effect before being placed in commercial distribution.

    Dated: April 30, 1999.
Linda S. Kahan,
Deputy Director for Regulations Policy, Center for Devices and
Radiological Health.
[FR Doc. 99-11733 Filed 5-7-99; 8:45 am]
BILLING CODE 4160-01-F