GUIDANCE DOCUMENT
Testing Guidance for Male Condoms Made From New Material (Non-Latex) June 1995
- Docket Number:
- FDA-2020-D-0957
- Issued by:
-
Guidance Issuing OfficeCenter for Devices and Radiological Health
This guidance was written prior to the February 27, 1997 implementation of FDA’s Good Guidance Practices, GGP’s. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be updated in the next revision to include the standard elements of GGP’s.
DRAFT: June 29, 1995
Prepared by: Center for Devices and Radiological Health
Office of Device Evaluation
Division of Reproductive, Abdominal, Ear,
Nose and Throat and Radiological Devices
Obstetrics-Gynecology Devices Branch
Table of Contents
PART A - INFORMATION FOR A NEW MATERIAL CONDOM 510(k) SUBMISSION FOR
OBSTETRICS-GYNECOLOGY DEVICES BRANCH
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PART B - CLINICAL TESTING GUIDANCE FOR NEW MATERIAL MALE
CONDOMS . . . . . . . . . . . . . . . . . . . . . . 7
Introduction. . . . . . . . . . . . . . . . . . . . 7
I. Feasibility (Safety) Testing . . . . . . . . . 9
II. Slippage and Breakage Study. . . . . . . . . . 9
III. Contraceptive Effectiveness Study. . . . . . . 12
IV. Consumer Understanding of Labeling . . . . . . 17
PART C - INTERIM LABELING FOR A NEW MATERIAL CONDOM
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
ATTACHMENT A - INFORMATION FOR DETERMINING BARRIER PROPERTIES OF
CONDOMS TO VIRUS PENETRATION. . . . . . A-1
PART A - INFORMATION FOR A NEW MATERIAL CONDOM 510(k)
SUBMISSION FOR OBSTETRICS-GYNECOLOGY
DEVICES BRANCH
This list of questions may not be all inclusive or specific for all
non-latex materials.
A. General Information
1. Identify a predicate device and compare your device to the
predicate device in terms of intended use, design, materials,
specifications, and performance.
2. Provide copies of labels, labeling, and advertisements sufficient
to describe the device, the intended uses and the directions for use.
B. Condom Sheath and Retention Mechanism Material(s)
Provide a detailed description of the condom materials for both the
sheath and any retention
mechanism, to include the following:
1. name and manufacturer of the resin;
2. chemical composition and specifications of the sheath material(s)
including molecular weight and molecular weight distribution;
3. the chemical composition and specifications for any retention ring
material(s);
4. specifications for the raw materials and a description of the
quality control testing performed;
5. molar ratio of component monomers for fabricating the material;
6. quantities of residual monomers and additives;
7. the chemical composition and specifications of any dusting
agent(s); and
8. the lubricant(s) formulation, chemical composition of each
ingredient, ingredient specifications, and quantity of lubricant
applied the condom.
C. Manufacturing Processes
Provide the following information on the processes used to manufacture
the condom:
1. flow diagram for all aspects of condom manufacturing including
points where in-line quality control testing is performed;
2. solvent based manufacturing process (blown, spun or dipped): OR
See C.3.
a) solvent(s);
b) compounding additives including any color additive that may be
added (If a color additive is used, provide its chemical
composition, and identify its CAS number or its color index
number and reference the specific color additive listing (21
CFR reference));
c) solution handling processes;
d) batch sizes of the dipping mixture;
e) filtration of the stock materials;
f) process control parameters, such as solution viscosity and
temperature, system metrology, air handling specifications,
particulate control, packaging process;
g) the handling and/or reworking procedures of the product that
fails any of the in-process quality control tests; and,
h) a detailed description of the condom mandrels and condom
manufacturing process including the rotational speed and angles
(dipping process).
3. extrusion/film based manufacturing process (with seam welds):
a) data from physical testing conducted on the extrusion/film
material using appropriate sampling procedures (See Section
E#2.);
b) data on the quantities of residual solvent(s) and additives in
the film;
c) compounding additives including any color additive that may be
added (If a color additive is used, provide its chemical
composition, and identify its CAS number or its color index
number and reference the specific color additive listing (21
CFR reference));
d) film handling processes;
e) batch sizes of the extrusion film material;
f) process control parameters, such as temperature, system
metrology, air handling specifications, particulate control,
packaging process;
g) the handling and/or reworking procedures of the product that
fails any of the in-process quality control tests; and,
h) a detailed description of the condom manufacturing process heat
sealing procedures including dwell and temperature.
4. description of the procedures used to apply the retention ring;
5. description of the molecular weight and molecular weight
distribution of the sheath material following the condom
manufacturing processes;
6. data on the quantities of residual solvent(s) and additives in the
final production condoms;
7. description of the procedure(s) to add dusting agent(s) and/or
lubricant(s); and,
8. description of the procedures used to package the condom.
D. Material Toxicity
Provide the following material toxicology information:
1. summary of known toxicity data on all the monomers, additives, and
solvents utilized in manufacturing of the material(s) of the
condom;
2. toxicity data on dusting agents and lubricants; and,
3. biocompatibility data on the finished (packaged, ready for
distribution) product demonstrating that the condom material does
not produce toxicity, including cytotoxicity, sensitization (polar
and nonpolar extracts), mucosal irritation, acute systemic
toxicity, mutagenicity, and implantation (90 day).
E. Finished Product
Please provide the following information on the finished condom:
1. a complete description of your device to include,
material(s), design (e.g., length, width, thickness, reservoir
tip, retention mechanism, etc.), and specifications (both
chemical and physical);
2. data from the following physical testing conducted on the
finished condom using appropriate sampling procedures and
established performance limits and tolerances (Cross reference
response with Section F):
a) tensile strength;
b) force at break;
c) elongation;
d) tear resistance and propagation;
e) air burst volume;
f) air burst pressure; and,
g) water leakage.
3. data to demonstrate that the product's physical integrity
is not compromised by short term exposure to body temperature,
(e.g., tensile strength and elongation at 37 C).
F. Quality Control/Quality Assurance
1. detailed description of the test procedures used to
establish the quality of each condom lot or batch (Cross
reference response with the flow diagram Section A#1),
including:
a) when testing is performed during manufacturing
processes (include sampling frequency);
b) a detailed description of any in-process testing
procedures including a description of the in process testing
machine, the machine's specifications, and operator's manual
and a description of the testing machine's calibration
procedures;
c) data to demonstrate the reliability, reproducibility
and sensitivity of the in-process testing machine;
d) a description of the relationship between the
in-process testing machines' calibration specifications to the
product release testing specifications; and,
e) for each in-process or final release test, identify
the acceptable quality level (AQL), the applicable sampling
plan and inspection level for each test. Also, provide
examples of the quality control procedures for a typical lot
size by identifying appropriate acceptance and rejection values
for each test conducted during quality control and quality
assurance testing.
2. information on the water leakage test to include a detailed
description of how the test is conducted including
specifications and operating procedures, and calibration
procedures; and,
3. information on the air burst test to include a detailed
description of how the test is conducted including
specifications and operating procedures, and calibration
procedures.
G. Packaging
Provide specifications of the package material and sealing
integrity.
H. Barrier Properties/Permeability: Viral Penetration Study
Provide data from in-vitro studies simulating actual use
conditions to demonstrate the barrier properties of the condom
with respect to the sexually transmitted disease (STD)
organisms, and compare the barrier properties of new device to
latex condom. (See attachment A, Guideline for Determining
Barrier Properties of Condoms to Virus Penetration.)
I. Shelf-Life
Real-time and/or accelerated data is necessary to substantiate
the claimed shelf-life. Testing should include but not be
limited to testing of the condom and lubricant system after
storage in the primary packaging system for materials
compatibility and spermicidal effectiveness (if applicable), to
include:
1. mechanical testing of finished condom (See Section E#2,
above);
2. an analysis of chemical degradation byproducts and physical
properties over time;
3. quantitative chemical analysis for the amount of
spermicidal lubricant available over time (e.g., High Pressure
Liquid Chromatography (HPLC));
4. bioassay of spermicidal efficacy using an accepted method
to demonstrate the contraceptive effectiveness of the condom
lubricant system (e.g., The International Planned Parenthood
Federation Agreed Test for Total Spermicidal Power (IPPF Agreed
Test). Also see the Vaginal Contraceptive Drug Products for
Over-the-Counter Human Use; Establishment of a Monograph;
Proposed Rulemaking (FR 82015-82049; 1980)).
PART B - CLINICAL TESTING GUIDANCE FOR NEW MATERIAL
MALE CONDOMS
Introduction
This section of the guidance addresses the clinical testing requirements
for any new male latex or new material condom that differs significantly
from conventional condoms in its design, materials, or technological
characteristics. As with all new contraceptive devices, clinical trials
of these condoms are considered significant risk device investigations
under the investigational device exemptions (IDE) regulation, and an IDE
application is required. An IDE application is not needed for
preliminary studies where the study subject is protected by a back-up
contraceptive, or if the contraceptive study is conducted in a post
market setting.
New material male condoms offer a potential strategy to decrease the rate
of unintended pregnancy and prevent the spread of sexually transmitted
diseases (STDs) including HIV. This guidance for clinical testing of new
condoms meets a recognized need to evaluate whether condoms of novel
design or materials differ during use. This section of the guidance
serves to provide a framework and context for clinical testing and to
define recommended studies to evaluate new products. It is intended to
be a working document, from which manufacturers initiate discussions with
the Food and Drug Administration (FDA) staff regarding testing of new
products. Alternate studies or changes in the suggested study design and
analysis require justification. As more is learned about new materials
from studies or other observations, the testing and evaluation of these
products will evolve.
Before beginning clinical studies, all preclinical studies should be
completed. All clinical studies should be conducted in accordance with
21 CFR Part 812, and FDA's investigational device exemptions (IDE) manual
(HHS Publication FDA 86-4159) should be consulted for overall guidance.
From a premarket perspective, clinical testing of a new male condom
should include an initial feasibility study to provide preliminary
information on clinical performance (slippage and breakage), as well as
to rule out any immediate adverse effects, such as irritation. (See
Section I, page 10.) A slippage and breakage study must be conducted and
provide sufficient detail and sample size for a statistically valid
comparative analysis of the study condom to a legally marketed condom.
(See Section II, page 10.) A slippage and breakage study is necessary to
assure that the properties of the new condom, such as physical attributes
and device fit, are comparable.
Please note that early clinical studies of the condom, such as slippage
and breakage studies, should generally be conducted in a low risk
population defined as one of mutually monogamous couples who are using an
effective non-barrier method of contraception (i.e., hormonal
contraception, intrauterine device (IUD), or male/female sterilization).
Alternatively, the study population could include couples at risk of
pregnancy, but not planning pregnancy at the current time. These
clinical studies of the device are generally not considered to be
significant risk device investigations (as defined at 21 CFR 812.3(m)) if
study subjects are not at significant risk of conception or of
contracting an STD. As stated above, contraceptive efficacy trials,
where study subjects are at risk for STDs and pregnancy, are generally
considered to be significant risk device investigations. Please contact
FDA if you have questions regarding the requirement for an IDE
application.
Because there are no validated models to predict the contraceptive
effectiveness of a new condom from other clinical performance such as
breakage and slippage rates, a contraceptive effectiveness study is to be
conducted. (See Section III, page 13.) The contraceptive effectiveness
study should be designed, conducted, and analyzed to compare the
pregnancy use-effectiveness, adverse events, and study discontinuation
rates of the new condom to a legally marketed latex condom. STD
screening tests may be offered, but not necessarily required.
Due to the current public health need for alternatives to latex condoms,
the contraceptive efficacy trial may be conducted in a post-market
setting. Under these circumstances, such investigations are exempt from
the IDE regulations requirement for submitting an IDE application to the
agency. To meet the exemption criteria, the product must be cleared
beforehand, through the 510(k) review process, with satisfactory
preclinical performance data and satisfactory clinical safety and
slippage and breakage performance. Interim labeling while gathering
clinical efficacy data is also required. (See Part C of this guidance.)
FDA recognizes that condoms are used during anal intercourse for STD
protection and would prefer that condoms be labeled for this use,
provided appropriate testing is conducted. In order to modify the
labeling, a clinical study of slippage and breakage during anal
intercourse is necessary to assure that the properties of the new condom,
such as physical attributes and device fit, as well as adverse effects
are comparable when used this way. This study must provide sufficient
detail and sample size to conduct a statistically valid comparative
analysis of the study condom to a legally marketed condom. In summary,
the material, design, and laboratory performance of the new male condom
should be thoroughly studied prior to beginning any clinical studies.
Results from the preclinical and clinical studies must demonstrate that
the safety and effectiveness of the new condom is substantially
equivalent to a legally marketed condom in order to proceed through the
premarket notification process.
I. Feasibility (Safety) Testing
Prior to beginning slippage and breakage studies (see Section II
below), the sponsor should conduct preliminary studies to evaluate
the clinical performance (slippage and breakage) and acceptability
of the condom. In addition, any episode of genital irritation with
product use occurring in either the male or female should be
promptly reported and the symptomatic individual should be
carefully evaluated.
II. Slippage and Breakage Study
A. Objectives
Slippage and breakage studies evaluate the breakage, slippage
and safety of the new condom for both partners in comparison to
conventional latex condoms. Data concerning adverse events and
acceptability should be collected.
B. Study Conduct
The new condom should be tested in actual use for slippage and
breakage in a randomized clinical study. Study subjects may be
randomized to either the new condom or a legally marketed condom or
may use both condoms in a randomized order. Breakage, slippage,
partial slippage, and adverse event rates should be estimated and
compared between the investigational condom and the legally
marketed condom.
FDA recommends a randomized, cross-over study design for the
slippage and breakage study. In general, at least 1000 uses of
each type condom should be documented. A sufficient number of
couples should be enrolled in the trial to ensure that each couple
uses between three (3) and five (5) condoms of each type. However,
these recommendations are general, and any clinical study must
include justification for the proposed sample sizes (see section
II. B. number 5 a-e).
The study subjects must be protected by using an effective,
non-barrier means of contraception (e.g., hormonal contraception,
intrauterine device (IUD), or male/female sterilization). An
alternative would include a patient population at risk of
pregnancy, but not planning pregnancy at the current time.
However, if a condom breakage occurs during the study, these
couples should either be willing to continue pregnancy or be
willing to use emergency contraception. Please be advised that
subjects may be considered at risk (as defined at 21 CFR 812.3(m))
under these circumstances. Please contact the FDA to discuss
alternative study populations and applicable regulations.
The ideal study population would be at low risk of STDs. In
geographic areas in which the gonorrhea and chlamydia prevalence is
high, it is recommended that study participants be screened for
these infections at study entry.
FDA recognizes that clinical trials may be conducted either as
part of or outside of clinical care settings. Investigators should
assure subject eligibility by history and, if concerns exist, by
physical examination as well. Both men and women should be offered
routine health care including a physical examination with screening
and treatment for STDs. As many study participants may receive
health care outside of the clinical trial, self-report of health
care should be obtained. As women enter the study, Pap smear
screening should be offered or self-report of a recent, normal Pap
smear should be obtained. Prior to study entry or during the
study, if symptoms of STDs or concern about STDs exist, both
partners should be screened and treated for STDs.
C. Study Design and Analysis
Provide detailed descriptions of the following elements of the
protocol:
1. study hypothesis(es) to be tested;
2. study design and duration including randomization scheme
and visit schedule;
3. participating study centers, their principal investigators;
Note: At least two centers should participate unless sufficient
justification is provided. In addition, in order to comply with
federal guidelines, minorities should be represented.
4. patient population; criteria for selection/exclusion of
subjects:
a) sexually active, of reproductive age;
b) mutually monogamous;
c) willing and able to comply with study requirements;
d) protected from pregnancy by reliable, non-barrier
method of contraception (see note
below);
e) in good health as evidenced by history and/or physical
examination (genital);
f) at low risk of sexually transmitted disease, including
HIV infection and not having a
medical history of recurrent, sexually transmitted
disease;
g) agree not to use any vaginal lubricants or treatments
except those products supplied
by the study; and,
h) not allergic or sensitive to the study products.
Note: An alternative to selection criteria II.C.4.d. would
include a patient population at risk of pregnancy, but not planning
pregnancy at the current time. However, if a condom breakage
occurs during the study, these couples should either be willing to
continue pregnancy or be willing to use emergency contraception.
Careful informed consent is essential. Please contact the FDA to
discuss alternative study populations and applicable regulations.
5. sample size, including:
a) reference for formulas used to calculate sample size;
b) Type I error (à), Type II error ( );
c) expected breakage rate of the approved condom;
d) acceptable difference to be detected between the
control and study condoms; and,
e) anticipated loss to follow-up rate.
6. data collection should include:
a) reproductive history;
b) demographic characteristics;
c) previous contraceptive experience including experience
with condoms;
d) detailed reports of study condom use (including
vaginal and anal use and all adverse
events); and,
e) acceptability.
7. data collection instruments should include:
a) interview forms;
b) physical exam forms;
c) laboratory forms
d) coital logs; and,
e) detection and management of adverse events.
8. informed consent process and consent;
9. the protocol should specify all statistical procedures
intended to compare the control and experimental condoms, provide
and reference the formulas used to analyze the data and include:
a) description of the population (e.g., age, race, study
site, reproductive history, previous contraceptive use, previous
condom use, etc.); and, b) analysis by condom type with
confidence intervals of the adverse events and the p-values for
each statistical test, including: (1) description and rate for
slippage (both partial and complete slippage); (2) description and
rate for breakage; (3) description and rate of other adverse
events, including, but not limited to genital mucosal irritation,
bleeding and discomfort. (4) subgroup analysis of
slippage/breakage/adverse events by: (a) age group; (b) race; (c)
study site; (d) socioeconomic status; (e) educational level; (f)
previous contraceptive use; and, (g) previous condom use. (5)
reasons for study discontinuation by the subject; (6) total rate
of study discontinuation and loss to follow-up; and, (7) test the
hypothesis(es) stated above relating the results to the claim for
the experimental condom.
10. Study and data monitoring procedures and quality assurance.
III. Contraceptive Effectiveness Study
A. Objectives
Contraceptive effectiveness studies evaluate the contraceptive
effectiveness, safety, and ease of use of the study condoms
compared to a legally marketed condom. Depending on the results of
the Slippage and Breakage study, it may be necessary to "nest" a
second Slippage and Breakage study within this efficacy trial.
B. Study Conduct
A randomized controlled clinical trial of at least six (6)
completed menstrual cycles of product use should be done. See
Introduction for a discussion of when an IDE application is needed.
Study participation should include additional time to assure that
the woman is not pregnant and no other adverse events have occurred
during the study period.
In general, FDA recommends that approximately 400 study couples
be enrolled in each investigational arm so that at least 300 study
couples per arm complete the study. However, these recommendations
are general, and any clinical study must include justification for
the proposed sample sizes.
As stated in the introduction to this Part, the ideal study
population would be at low risk of STDs. In geographic areas in
which the gonorrhea and chlamydia prevalence is high, it is
recommended that study participants be screened for these
infections at study entry.
FDA recognizes that clinical trials may be conducted either as
part of or outside of clinical care settings. Investigators should
assure subject eligibility by history and, if concerns exist, by
physical examination as well. Both men and women should be offered
routine health care including a physical examination with screening
and treatment for STDs. As many study participants may receive
health care outside of the clinical trial, self-report of health
care should be obtained. As women enter the study, Pap smear
screening should be offered or self-report of a recent, normal Pap
smear should be obtained. Prior to study entry or during the
study, if symptoms of STDs or concern about STDs exist, both
partners should be screened and treated for STDs.
C. Study Design and Analysis
Provide a detailed description of the following elements of the
protocol:
1. study hypothesis(es) to be tested;
2. study design, entry and duration including randomization
scheme and visit schedule;
3. participating study centers, their principal investigators;
Note: At least two centers should participate unless significant
justification is provided. Each center shall contribute an
approximately equal number of study subjects in order to allow
comparisons among investigators and sites.
In compliance with federal guidelines, minorities should be
represented.
4. study subjects who are representative of the intended
target population (e.g., age group, race, socioeconomic status,
educational level, parity vs. nulliparity, etc.) for the marketing
of the condom and include:
a) criteria for inclusion of subjects:
(1) sexually active (penile-vaginal intercourse, with
a minimum of 6-8 coital
episodes monthly);
(2) women age 18-40 and men age 18-50;
(3) mutually monogamous;
(4) willing and able to comply with study
requirements including:
(a) men - able to understand instructions for
condom use;
(b) women - willing to return to the clinic for
pregnancy testing if
indicated; and,
(c) couple - willing to use study condoms as
sole method of
contraception for study duration.
(5) in good health as evidenced by history and/or
genital physical examination
(Refer to paragraph in italics in Section III.B.,
above.);
(6) at low risk for sexually transmitted disease,
including HIV infection and not
having a medical history of recurrent sexually
transmitted diseases;
(7) agree not to use any vaginal lubricants or
treatments except those products
supplied by the study;
(8) not allergic or sensitive to the study products;
(9) no known condition that might cause infertility;
(10) study subjects must be willing to accept the
potential risk of pregnancy;
and,
(11) women with regular menses, including at least two
normal cycles:
(a) after discontinuing hormonal contraception;
(b) postpartum or postabortion; or,
(c) after breast feeding.
b) criteria for exclusion of subjects:
(1) pregnancy, suspected pregnancy, or desire to
become pregnant while
participating in the study;
(2) inability to participate in study for its
duration or study subjects who are
unable to conform to the follow-up schedule;
(3) inability to remain sexually active for the study
duration;
(4) multiple sexual partners;
(5) use of birth control methods other than the study
condom;
(6) current or chronic infection of the reproductive
tract;
(7) history of reproductive tract infection, surgery
or condition that might
impair fertility;
(8) cervical cytology equivalent to Class III or
worse;
(9) medical condition that would put the women at
risk if she were to become
pregnant; and,
(10) allergy or sensitivity to the device.
Note: Study subjects who are currently using Depo-Provera (DMPA)
or who have been prescribed and used DMPA within the last 9 months
should be excluded from the study.
Data on study subjects using the device and later found to have
one of the above conditions must be analyzed and reported
separately. Such cases may be excluded from the total number of
study subjects required for analysis.
5. sample size including:
a) reference for formulas to calculate sample size;
b) type I error ( ), type II error ( );
c) expected pregnancy rate of the approved condom;
d) acceptable difference to be detected between the
control and study condoms; and,
e) anticipated loss to follow-up rate.
6. data collection should include:
a) a complete medical history, including a detailed
reproductive history, of both
participants;
b) physical examination of both participants, when
necessary (Refer to paragraph in
italics in Section III.B., above.), to include:
(1) Female study participant;
(a) pelvic examination on entry and exit when
applicable;
(b) Pap smears when applicable; and,
(c) Chlamydia and gonorrhea cultures when
applicable:
(2) Male study participant
(a) genital examination on entry and exit when
applicable; and,
(b) Chlamydia and gonorrhea cultures when
applicable.
c) demographic characteristics;
d) previous contraceptive experience including experience
with condoms;
e) detailed reports of study condom use (including
vaginal and anal use and all adverse
events) and any other contraceptive use; and,
f) acceptability.
7. data collection instruments should include:
a) interview forms;
b) physical exam forms;
c) laboratory forms;
d) coital logs; and,
e) detection and management of adverse events.
8. informed consent process and consent.
D. Statistical Analysis
Statistical analyses of safety and effectiveness should be done
via appropriate analytic models, to permit simultaneous statistical
treatment of important outcome events. Analysis may be conducted
at regular (specify) intervals to examine the data for trends such
as specific adverse events. Appropriate actions should be taken if
the periodic analysis so warrants.
1. statistical procedures should be referenced and justified
and analyses should include:
a) description of the population (e.g., age, race, study
site, reproductive history, previous contraceptive use, previous
condom use, etc.);
b) analysis by condom type with confidence intervals for
event rates and reporting of p-values for all statistical
comparisons (analysis should include each site separately and also
combined if pooling is justified) including:
(1) pregnancy rates;
(2) description and rate for breakage;
(3) description and rate for slippage (both partial
and complete slippage);
(4) description and rate of adverse events, such as
male and female genital tract
irritation or discomfort;
Note: Present the results with the p-values for each statistical
test and place confidence bounds on each estimated adverse event
rate.
(5) subgroup analysis of rates of pregnancy/condom
breakage/condom slippage/adverse events by:
(a) age group;
(b) race;
(c) study site;
(d) socioeconomic status;
(e) educational level;
(f) previous contraceptive use;
(g) previous condom use; and,
(h) parity vs. nulliparity.
(6) description of reasons for and rate of study
discontinuation include medical reasons, personal reasons, and
dissatisfaction with the device, and loss to follow-up; and, (7)
subject compliance.
Note: Each patient who has not terminated device use or who has
not been lost to follow-up should have the required number of
months of observed use of the device prior to completion of the
analysis (unless discontinued for reason). Both net and gross life
table rates should be presented.
E. Data Reporting and Analysis
Provide demographic data on each study subject, including age,
race, and socioeconomic status. If feasible, data should be
collected on respondent satisfaction with prior contraceptive
methods, particularly barrier methods.
The following specific data should be recorded and analyzed to
evaluate safety and effectiveness of the investigational device
compared to the legally marketed device:
1. date the pregnancy is discovered (Correlate to items #8
and/or #9 below); 2. date of infection, type, and method of
diagnosis; 3. adverse events including, trauma to vagina, cervix,
or penis; discomfort; pain; or any other reported adverse effects;
4. PAP smear reports and intake history (The same laboratory
should be used for all PAP smears obtained during the
investigation, where possible.); 5. device rupture, tear, or
puncture; 6. slippage (both partial and complete) during use: how
frequently and when; 7. subject compliance with device use; 8.
subject use of emergency contraception; 9. level of acceptability
- for study subject and partner; and, 10. device discontinuations,
including: a. medical reasons (specify, e.g., allergy, infection,
trauma, odor, itching, etc.); b. dissatisfaction with device
(specify, e.g., inconvenient, uncomfortable, partner can feel it,
subject can feel it, etc.); and, c. personal reasons unrelated to
device (specify, e.g., desire to become pregnant, move from
geographical area, etc.).
IV. Consumer Understanding of Labeling
Because the effectiveness of barrier contraceptive devices is so
dependent upon proper use, contraceptive studies must also
demonstrate how well the users will understand printed instructions
for an over-the-counter (OTC) device.
During these studies, it should also be demonstrated that the
target population can follow printed instructions, especially if
the device is to be marketed as an over-the-counter (OTC) product.
That is, 1) how well does the target population properly use the
device, and 2) how well does the target population understand other
important messages, such as visually checking for defects, proper
storage, etc.
Particular effort should be made to demonstrate that consumers
with limited education and/or literacy can understand printed
instructions for an OTC device. Such studies should include
well-constructed questionnaires, as well as clinical observations
by health professionals to evaluate study subject understanding of
the instructions.
As stated, FDA recommends that applicants conduct consumer field
evaluations to determine a lay person's ability to properly use the
device unassisted, by following the printed labeling instructions.
Key features of such an evaluation are given below:
1. Lay users selected for the study should be of limited
education and literacy. (Study subject selection criteria should
be submitted to FDA with the study protocol and results.)
2. The number of subjects selected for testing should be
sufficient to support statistically valid conclusions.
3. A simple questionnaire, provided to study participants, may
be used to determine if the user understood the purpose of the
device, the conditions for its use, and any limitations or special
precautions. The study write-up should also contain the results of
observations made by investigators.
PART C - INTERIM LABELING FOR A NEW MATERIAL CONDOM
INTERIM LABELING REQUIREMENTS FOR CONDOMS
MADE FROM NEW MATERIALS
I. Principal Display Panel
The principal display panel (21 CFR §801.60) must display the following:
"For Latex Sensitive Condom Users"
This is a [Blank] condom. This is not a latex condom. See
Important Information on Back of
Package.
II. Back Panel
The following Important Consumer Information must be placed on the back
panel of the retail package, as well as within the package insert and
with any promotional material:
Important Consumer Information: [Bold]
You may use this [Blank] condom if you or your partner are
allergic to latex.
You should know:
The risks of pregnancy and sexually transmitted diseases
(STDs), including AIDS (HIV infection), are not known for this condom. A
study is being done.
There are laboratory tests on this [Blank] material. These
tests show that organisms even as small as sperm and viruses like HIV
cannot pass through it.
Latex condoms [Bold] for men, if used correctly with every act
of vaginal intercourse, are highly effective at preventing pregnancy, as
well as STDs, including AIDS (HIV infection).
CDRH/FDA: 10/25/94
ATTACHMENT A- INFORMATION FOR DETERMINING
BARRIER PROPERTIES OF CONDOMS TO
VIRUS PENETRATION
DIVISION OF LIFE SCIENCES
OFFICE OF SCIENCE AND TECHNOLOGY
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
Introduction
This guideline addresses the rationale, methodology and required
sensitivity of a test of the ability of condoms to act as barriers to
transmission of the etiological agents of sexually-transmitted diseases
(STDs), including viruses. The condom is identified in the code of
federal regulations (CFR) at Title 21 CFR Section 884.5300 as ..."a
sheath which completely covers the penis with a closely fitting membrane.
The condom is used for contraception and prophylactic purposes
(preventing transmission of venereal disease)." The device may also be
used to collect semen to aid in the diagnosis of infertility.
A medical claim for condoms as being effective against STDs requires
that appropriate laboratory tests be performed. Since viruses are the
smallest etiological STD agents and include the human immunodeficiency
virus (HIV) and hepatitis B virus (HBV), the challenge particle should be
a small virus or virus-size particle. Test conditions should account for
as many parameters as possible that are considered to be important in
real-life conditions. Appropriate choices of challenge particle,
solution properties, and test pressure and duration are considered most
important and must be included. The barrier properties of a condom may
be determined in a static test, i.e., movement of the condom during the
test is not required. Choices of parameters that make the in vitro test
more stringent than expected real-life use are encouraged, with
appropriate justification.
The choice of challenge particle has several important aspects. A
biological assay may be preferred in general because there should be no
"background" level of confounding "signal," as would be found with
radioactively-or otherwise-labeled viruses or virus-like particles.
Surrogate viruses of appropriate size and shape may substitute for human
pathogens. Such surrogates may be bacterial viruses (bacteriophages),
which are safer, faster and less expensive to use for testing and which
can be readily obtained at sufficient titer to provide an adequate
challenge concentration. However, in order for the test to be used to
demonstrate safety with regard to STDs, the test virus should be smaller
than hepatitis B virus (42 nm diameter), the smallest etiological agent
for a STD. For these reasons, the following protocol suggests use of a
small bacterial virus as challenge particle.
Preparation of Test Samples
Test condoms should be carefully handled so they are not damaged during
the test procedure. Gloves may be worn as a precautionary measure to
prevent abrasion or puncture by fingernails, rings, etc.
Most of accompanying lubricants and/or spermicides, if present, should
be removed so they don't interfere with the test. They may be removed by
rinsing with buffer and gently patting dry.
The Basic Test
The test consists of filling the condom with virus-containing buffer and
determining whether any viruses penetrate that barrier during submersion
in collection buffer. Virus penetration is quantitated and reported as
equivalent volume of challenge suspension needed to account for amount of
virus penetration. The basic methodology using simple, readily-available
equipment has been published (see Lytle et al reference). More
sophisticated apparatus (see Retta et al reference) may be used to make
the testing more convenient, although the basic test parameters should
remain similar. The elements of the test should include:
1. attaching the test condom to an apparatus which:
i. provides a leakproof seal around the top and leaves an
appropriate length of test portion available for the virus penetration
test (at least 140 mm);
ii. provides for restraining of the condom to prevent overexpansion
under pressure (Dimensions of the restrainer should allow expansion of
the test portion of the condom to a length of 140-150 mm and a
circumference of 120-130 mm. The contour of the restrainer should match
that of the condom, including the reservoir tip, if present. Restrainers
of the same size and material should be used with the test condoms and
with the comparative condoms. In the case of a condom that is larger or
smaller than a standard, an appropriate size restrainer should be used to
accommodate the dimensions of the condom (must be justified).
iii. provides for exposure of the inside of the condom to aqueous
challenge virus suspension;
iv. provides for application of pressure to that suspension;
v. allows for submersion of test portion of condom in collection
fluid; and
vi. provides for access to challenge virus suspension inside condom
for assay following the test.
2. filling the condom with a buffer that:
i. has appropriate properties (pH approximately 7.0, salinity of
any one of several variations of physiological saline, surface tension
less than 0.05 N/m [may be provided by 0.1% Triton X-100]) (Physiological
saline has a lower viscosity than semen and therefore provides a more
stringent test. The test may be performed at room temperature [68-72 F]
when saline is used); and
ii. contains the challenge virus at sufficient titer, even at the
end of the test (at least 108 plaque forming units/mL of a small,
approximately spherical virus). The bacteriophage X174 may be used as
the challenge virus. In the case of a virus other than X174, its use
must be justified.
3. providing pressure to the challenge fluid equivalent to 60 mmHg
(1.28 psi) or more (e.g., hydrostatically with a 810 mm column of water
or with air/gas pressure);
4. providing a collection container with sufficient buffer to
allow fluid contact with the test surface of the condom and to collect
any virus that penetrates through the condom;
5. submerging the filled, pressurized condom (first 140 mm from
the closed end, not including the reservoir tip, if present) in the
collection buffer for at least 30 minutes;
6. assaying the collection buffer for the challenge virus to determine
whether any virus has penetrated the condom and passed into the
collection buffer (The collection fluid must be mixed at the time of
assay so that the assay aliquots are representative.); and
7. calculating the equivalent volume of challenge virus
penetration needed to account for amount of virus found in collection
buffer.
Controls
It is known that some viruses can be removed from suspension by certain
materials through binding, or that they can be rendered biologically
undetectable by chemical inactivation. Thus controls are needed to
assure that the virus penetration test will yield meaningful data.
Positive control experiments of the same duration are needed to assure
that the overall test is functioning properly. Condoms with intentional
pinholes may be used, although it is recognized that it is difficult to
produce small pinholes.
In addition, it must be ascertained whether the challenge virus remains
at a stable concentration in the condom during the test. Data from
several condoms are needed and must be collected as part of each condom
test. The titer of the challenge virus suspension inside the condom at
the end of the test is compared to the titer originally placed in the
condom. This determines if and how much the challenge virus titer
changes during the test because of interaction with the condom and the
test apparatus, or other factors.
It must also be ascertained whether any virus that penetrates the condom
remains detectable in the collection buffer over the test period. This
can be done by "spiking" the collection buffer with a low level of virus
before a mock test (where there is no virus inside the condom and for the
same duration) and assaying the titer of the collection buffer at the
beginning and end of the mock test. This determines if and how much the
penetrated virus titer changes during the test as a result of interaction
with the outside of the condom, the restrainer or the collection
container.
If either (or both) of the above controls indicates loss of virus titer,
the starting challenge titer must be increased to compensate for the loss
in order to maintain the overall sensitivity of the test.
It may be useful to determine via controls (e.g., settle plates) whether
contamination caused by aerosolized virus or other leaks might lead to
false evidence of virus penetration of the condom.
Sampling Procedure
A complete data set should include results from at least 60 condoms (20
condoms from each of 3 lots), in order to provide assurance that overall
quality of each of three lots is satisfactory.
Comparative (predicate) samples
Latex condoms (off-the-shelf) are to be used. However, since the
history (duration and temperature of storage) of such samples is not
known and may affect the integrity of the samples, these samples must be
used before the expiration date and should give virus transmission rates
similar to those reported in the published literature. We suggest using
non-lubricated, smooth (not ribbed, non-reservoir tip) samples. They
should be treated in the identical manner as the investigational test
samples, including mock removal of lubricant/spermicide, if appropriate.
Detection Limit
A typical method to determine the virus titer in the collection buffer
would be to assay 1 mL in triplicate (3 mL total). In order to have 95%
confidence that an assay will find at least one virus when virus is
present [i.e., P(0) <0.05], the="" average="" number="" of="" infectious="" particles="" per="" total="" volume="" assayed="" must="" be="" at="" least="" three;="" e.g.,="" there="" is="" a="" 95%="" probability="" that="" a="" titer="" of="" 1="" pfu/ml="" will="" result="" in="" at="" least="" one="" plaque="" in="" a="" 3="" ml="" total="" assay.="" thus,="" the="" sensitivity="" or="" detection="" limit="" of="" this="" assay="" can="" be="" claimed="" as="" 1="" pfu/ml="" when="" 3="" ml="" is="" assayed.="" detection="" limit="" expressed="" as="" volume="" of="" challenge="" virus="" suspension="" that="" penetrated="" the="" barrier="" is="" probably="" the="" most="" useful="" measure="" of="" test="" sensitivity.="" for="" example,="" in="" a="" real-life="" risk="" assessment="" the="" volume="" of="" transmitted="" virus-containing="" fluid="" can="" be="" translated="" into="" infectious="" units="" when="" the="" titer="" of="" a="" pathogenic="" virus="" (in="" real="" life)="" is="" known.="" the="" test="" procedure="" must="" be="" able="" to="" detect="" 2="" x="" 10-6="" ml="" penetration="" of="" the="" challenge="" virus="" suspension.="" this="" can="" be="" done="" by="" using="" a="" challenge="" titer="" of="" 1="" x="" 108="" pfu/ml,="" a="" collection="" buffer="" volume="" of="" 200="" ml="" and="" assaying="" 1="" ml="" in="" triplicate="" from="" the="" collection="" buffer="" (assuming="" no="" loss="" of="" virus="" titer="" in="" the="" challenge="" buffer="" nor="" in="" the="" collection="" buffer):="" the="" assay="" detection="" limit="" of="" 1="" pfu/ml="" is="" equivalent="" to="" penetration="" by="" 200="" pfu="" (1="" pfu/ml="" x="" 200="" ml)="" or="" 2="" x="" 10-6="" ml="" (200="" pfu="" divided="" by="" 1="" x="" 108="" pfu/ml).="" presentation="" of="" results="" a="" table="" of="" the="" results="" for="" all="" the="" test="" condoms="" should="" be="" presented="" that="" includes:="" the="" challenge="" virus="" titer,="" the="" virus="" titer="" in="" the="" collection="" buffer,="" any="" correction="" factor="" for="" loss="" of="" virus="" (determined="" in="" the="" controls),="" and="" the="" calculated="" challenge="" volume="" that="" penetrated="" (for="" the="" condoms="" that="" allowed="" virus="" transmission).="" (see="" example="" below,="" table="" i.)="" the="" volume="" of="" challenge="" virus="" suspension="" needed="" to="" account="" for="" the="" virus="" penetration="" into="" the="" collection="" buffer="" can="" be="" calculated="" for="" each="" condom="" by="" the="" method="" presented="" in="" the="" previous="" section.="" if="" some="" loss="" of="" virus="" titer="" occurs="" either="" inside="" the="" condom="" or="" outside="" in="" the="" collection="" container,="" the="" calculation="" should="" include="" the="" appropriate="" correction="" for="" such="" loss.="" for="" condoms="" that="" apparently="" did="" not="" allow="" virus="" transmission,="" the="" detection="" limit="" of="" that="" particular="" test="" should="" be="" given,="" e.g.,="" as="" 2="" x="" 10-6="" ml.="" report="" forms="" test="" results="" for="" virus="" penetration="" of="" condom="" samples="" should="" be="" presented="" in="" tabular="" form,="" where="" the="" data="" for="" each="" condom="" are="" individually="" reported.="" necessary="" items="" for="" each="" test="" sample="" are:="" i.="" date="" test="" was="" performed,="" ii.="" titer="" of="" challenge="" titer="" inside="" the="" condom="" at="" the="" end="" of="" the="" test,="" iii.="" calculated="" detection="" limit="" based="" on="" the="" challenge="" virus="" titer,="" the="" collection="" fluid="" volume,="" and="" the="" volume="" assayed,="" iv.="" pfu's="" found="" in="" aerosol="" control,="" v.="" pfu's="" detected="" in="" the="" collection="" fluid,="" vi.="" calculated="" titer="" of="" penetrated="" virus="" in="" collection="" fluid,="" and="" vii.="" volume="" of="" challenge="" virus="" suspension="" needed="" to="" account="" for="" the="" amount="" of="" virus="" detected="" in="" the="" collection="" fluid.="" information="" accompanying="" the="" table="" should="" include:="" a.="" the="" challenge="" virus,="" b.="" the="" challenge="" and="" collection="" fluids="" (e.g.,="" buffer="" and="" surfactant),="" c.="" how="" the="" titer="" of="" the="" challenge="" virus="" suspension="" was="" determined="" (dilution,="" volume="" assayed,="" and="" number="" of="" replicate="" assays),="" d.="" the="" challenge="" volume="" (if="" variable="" from="" one="" test="" sample="" to="" another,="" it="" should="" be="" included="" in="" the="" table="" for="" each="" condom),="" e.="" the="" collection="" fluid="" volume="" (if="" variable="" from="" one="" test="" sample="" to="" another,="" it="" should="" be="" included="" in="" the="" table="" for="" each="" condom),="" f.="" the="" transmembrane="" condom="" pressure="" and="" how="" it="" was="" provided="" (if="" variable="" from="" one="" test="" sample="" to="" another,="" it="" should="" be="" included="" in="" the="" table="" for="" each="" condom),="" and="" g.="" any="" evidence="" of="" an="" equipment="" or="" procedural="" malfunction="" during="" any="" particular="" test.="" table="" i.="" results="" for="" virus="" penetration="" through="" condom="" samples="" of="" brand="" x,="" lot="" #34068.="" i="" ii="" iii="" iv="" v="" vi="" vii="" date="" titer="" detect="" aerosol="" collect="" titer,="" volume="" challenge="" limit="" control="" buffer="" collect="" penetra="" virus="" buffer="" virus="" (pfu/ml)="" (ml)="" (pfu)="" (pfu)="" (pfu/ml)="" (ml)="" 1="" 10/28="" 2.2x10^8="" 0.9x10-6="" 0,0,0="" 29,28,33="" 3.0x10^1="" 2.7x10-5="" (+/-0.2)="" (+/-0.2)="" 2="" 10/28="" 2.3x10^8="" 0.9x10-6="" 0,0,0="" 0,0,0=""><1><0.9x10-6 (+/-0.2)="">
Positive Control
Reporting the results of the positive control experiment should be done
using the same reporting format as with virus penetration of test
samples.
Control to Test Challenge Virus Stability
Results from the test of challenge virus stability should be presented
in tabular form, where the data for each condom are individually
reported. (See example below, Table II.) Necessary items for each test
sample are:
i. date test was performed,
ii. titer of challenge titer placed inside the condom at the
beginning of the test,
iii. titer of challenge titer inside the condom at the end of the
test, and
iv. calculated ratio of final to beginning titer.
Table II. Results of test for stability of challenge virus in condom
samples of Brand X, Lot #34068.
Sample Date Beginning Final Ratio
titer titer final/
(pfu/mL) (pfu/mL) begin
1 10/28/93 2.2x10^8 2.1x10^8 0.95
(+/-0.2) (+/-0.2)
2
3
Control to Test Detection of Virus Which Penetrates Condom ("Spiking
experiment")
Results from tests to determine the detection of penetrated virus should
be in tabular form, where the data for each condom are individually
reported. (See example below, Table II.) Necessary items for each test
sample are:
i. date test was performed,
ii. virus titer in collection buffer at the beginning of the test,
iii. virus titer in collection buffer at the end of the test, and
iv. calculated ratio of final to beginning titer.
Table III. Results of test for detection of penetrated virus in contact
with condom samples of Brand X,
Lot #34068.
Sample Date Beginning Final Ratio,
titer titer final/
(pfu/mL) (pfu/mL) begin
1 10/28/93 1.2x10^2 1.1x10^2 0.92
(+/-0.1) (+/-0.1)
2
3
References Lytle, Routson and Cyr. A simple method to test condoms for penetration by viruses. Appl. Environ. Microbiol. 58: 3180-3182, 1992. Retta, Herman, Rinaldi, Carey, Herman and Athey. Test method for evaluating the permeability of intact prophylactics to viral-size microspheres under simulated physiologic conditions. Sex. Trans. Diseases 18: 111-118, 1991.
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