[Federal Register Volume 64, Number 89 (Monday, May 10, 1999)]
[Proposed Rules]
[Pages 24967-24972]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-11733]



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