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U.S. Department of Health and Human Services

Medical Devices

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Testing guidance for Male Condoms Made from New Material (Non-Latex) (Text Only)

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.