Condoms -- Guidance on clinical studies

ISO 29943-2:2017 is intended to help in the design, execution, analysis, and interpretation of clinical function studies conducted in accordance with the requirements of ISO 25841 for female condoms. These clinical studies compare the performance of a new female condom to an established female condom during vaginal intercourse (not anal intercourse). In particular, these studies are designed to assess acute failure events during use. ISO 29943-2:2017 also provides direction on the analysis of data when the study is completed, as well as interpretation of these results by manufacturers and regulatory bodies. Certain clinical trial elements are not addressed in this document, including compensation, confidentiality of individuals and their records, use of local ethics committees, etc. These and many other clinical trial design issues are covered in greater detail in ISO 14155.

Préservatifs -- Lignes directrices relatives aux études cliniques

General Information

Status
Published
Publication Date
05-Jul-2017
Current Stage
6060 - International Standard published
Start Date
21-May-2017
Completion Date
06-Jul-2017
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INTERNATIONAL ISO
STANDARD 29943-2
First edition
2017-07
Condoms — Guidance on clinical
studies —
Part 2:
Female condoms, clinical function
studies based on self-reports
Préservatifs — Lignes directrices relatives aux études cliniques —
Partie 2: Préservatifs féminins, analyse fonctionnelle des défaillances
graves sur la base d’auto-déclarations
Reference number
ISO 29943-2:2017(E)
ISO 2017
---------------------- Page: 1 ----------------------
ISO 29943-2:2017(E)
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© ISO 2017, Published in Switzerland

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ii © ISO 2017 – All rights reserved
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ISO 29943-2:2017(E)
Contents Page

Foreword ..........................................................................................................................................................................................................................................v

Introduction ................................................................................................................................................................................................................................vi

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 Risk assessment .................................................................................................................................................................................................... 3

5 Pilot clinical studies .......................................................................................................................................................................................... 3

6 Clinical validation investigation ........................................................................................................................................................... 4

6.1 Objectives of clinical validation investigation .............................................................................................................. 4

6.2 Outcome measures .............................................................................................................................................................................. 4

6.3 Study subjects .......................................................................................................................................................................................... 4

6.3.1 General...................................................................................................................................................................................... 4

6.3.2 Enrolment of study subjects .................................................................................................................................. 5

6.4 Informed consent .................................................................................................................................................................................. 6

6.5 Test and control condoms ............................................................................................................................................................. 6

6.5.1 General...................................................................................................................................................................................... 6

6.5.2 Test condom ......................................................................................................................................................................... 7

6.5.3 Control condom ................................................................................................................................................................ 7

6.5.4 Trial duration exceeds one year ......................................................................................................................... 7

6.5.5 Sampling of control condoms for bench testing ................................................................................... 8

6.6 Randomization ........................................................................................................................................................................................ 8

6.7 Allocation concealment and study masking .................................................................................................................. 8

6.8 Use of additional lubricant ........................................................................................................................................................... 8

6.9 Instructions and interactions with study couples .................................................................................................... 8

6.10 Interviews and data collection .................................................................................................................................................. 9

6.10.1 Schedule for interviews and condom distribution ............................................................................. 9

6.10.2 Enrolment interview .................................................................................................................................................... 9

6.10.3 Individual condom use CRF .................................................................................................................................10

6.10.4 Mid-study CRF, crossover trial ..........................................................................................................................10

6.10.5 Compiling data from CRFs ....................................................................................................................................11

6.11 Data integrity .........................................................................................................................................................................................11

6.11.1 General...................................................................................................................................................................................11

6.11.2 Interactive voice response systems (IVRS) ............................................................................................11

6.11.3 Mail-in and web-based data reporting ......................................................................................................11

6.11.4 Web-based data collection systems, additional suggestions ..................................................12

6.12 Control of distribution chain ....................................................................................................................................................13

6.13 Analysis of returned condoms ................................................................................................................................................13

6.14 Other methodological details ..................................................................................................................................................13

6.15 Statistical analysis plan .................................................................................................................................................................14

6.15.1 General...................................................................................................................................................................................14

6.15.2 Primary study hypothesis .....................................................................................................................................14

6.15.3 Secondary study hypotheses ..............................................................................................................................15

6.15.4 Study design ......................................................................................................................................................................15

6.15.5 Statistical analysis ...................................................................... ..................................................................................15

6.15.6 Additional statistical comments and concerns ...................................................................................16

6.16 Clinical study results: Review and interpretation .................................................................................................16

6.16.1 General...................................................................................................................................................................................16

6.16.2 Total clinical failure rates for control condom ....................................................................................16

6.16.3 Non-inferiority ................................................................................................................................................................16

6.16.4 Superiority .........................................................................................................................................................................17

6.16.5 Safety (adverse events) ...........................................................................................................................................17

6.16.6 What happens if one is unable to conclude non-inferiority? ..................................................17

© ISO 2017 – All rights reserved iii
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ISO 29943-2:2017(E)

Annex A (informative) Formula for power calculation ...................................................................................................................18

Annex B (informative) Pilot clinical investigation (sample outline) ................................................................................19

Annex C (informative) Time and events schedule for individual study subject (sample) .........................21

Annex D (informative) CRF — Study entry (sample) ........................................................................................................................22

Annex E (informative) CRF — Mid-study (sample) .............................................................................................................................25

Annex F (informative) CRF — Single use of female condom (sample)............................................................................27

Annex G (informative) CRF — Adverse event (sample) ..................................................................................................................31

Annex H (informative) Protocol for evaluation of returned used condoms .............................................................33

Bibliography .............................................................................................................................................................................................................................39

iv © ISO 2017 – All rights reserved
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ISO 29943-2:2017(E)
Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards

bodies (ISO member bodies). The work of preparing International Standards is normally carried out

through ISO technical committees. Each member body interested in a subject for which a technical

committee has been established has the right to be represented on that committee. International

organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.

ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of

electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are

described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the

different types of ISO documents should be noted. This document was drafted in accordance with the

editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of

any patent rights identified during the development of the document will be in the Introduction and/or

on the ISO list of patent declarations received (see www .iso .org/ patents).

Any trade name used in this document is information given for the convenience of users and does not

constitute an endorsement.

For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and

expressions related to conformity assessment, as well as information about ISO’s adherence to the

World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following

URL: w w w . i s o .org/ iso/ foreword .html.

This document was prepared by Technical Committee ISO/TC 157, Non-systemic contraceptives and STI

barrier prophylactics.
A list of all the parts of ISO 29943 can be found on the ISO website.
© ISO 2017 – All rights reserved v
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ISO 29943-2:2017(E)
Introduction

There is limited information on the safety and effectiveness of female condoms. Therefore, clinical

validation of any new female condom is necessary to ensure that its performance during actual use is

not inferior to the performance of female condoms of existing designs.

This clinical study guidance is intended to help in the design, execution, analysis, and interpretation

of clinical function studies conducted in accordance with requirements of ISO 25841 for female

condoms. In addition to information regarding the clinical validation study, this document provides

recommendations on risk assessment, pilot studies, and statistical analysis plans. Annexes include

previously used case report forms (CRF) and protocols that can be modified or adapted.

To date, there has been considerable variation in female condom designs and materials. Many female

condoms are held in place with external rings and are often anchored within the vagina using rings,

sponges or other unique designs. From the published literature, the most common acute failure events

associated with female condom use are breakage, slippage, invagination and misdirection. However, the

definitions for these acute failure events have been inconsistent from one published study to another. A

sponsor planning to conduct a female condom study should review the definitions in this document to

determine their applicability for the product.

For further information regarding definitions of female condom failures, refer to Reference [12] and

Reference [16]. Also, note that the definitions used in this document are based on existing designs and

might need to be expanded or adapted according to the female condom under investigation. Other types

of acute failure events (unique to a particular design) can be identified as part of the risk assessment

per ISO 14971 or during the pilot study.

NOTE Based on the normative clinical requirement of relevant standards, these studies are designed to

recruit participating couples who agree to use the test and control condoms for vaginal intercourse. Such studies

can also collect incidental data on condom use during anal sex; however, that is not the primary objective. To

satisfy study power requirements, it is critical that sufficient reports are collected on condom use during vaginal

intercourse. Study sponsors typically take preventive measures, such as initial screening and consenting of study

couples, and obtain agreement that study couples will use condoms this way.

It should also be noted that these clinical function studies are not typically designed to directly evaluate

condom protection against pregnancy or sexually transmitted infections (STIs).

Finally, it is important to recognize that clinical function studies of condoms are human research

studies. Therefore, all persons designing, conducting, and analysing clinical studies of new female

condoms should be familiar with all relevant requirements for research involving human subjects,

including ethical considerations. For additional information, refer to ISO 14155.

vi © ISO 2017 – All rights reserved
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INTERNATIONAL STANDARD ISO 29943-2:2017(E)
Condoms — Guidance on clinical studies —
Part 2:
Female condoms, clinical function studies based on self-
reports
1 Scope

This document is intended to help in the design, execution, analysis, and interpretation of clinical

function studies conducted in accordance with the requirements of ISO 25841 for female condoms.

These clinical studies compare the performance of a new female condom to an established female

condom during vaginal intercourse (not anal intercourse). In particular, these studies are designed to

assess acute failure events during use.

This document also provides direction on the analysis of data when the study is completed, as well as

interpretation of these results by manufacturers and regulatory bodies.

Certain clinical trial elements are not addressed in this document, including compensation,

confidentiality of individuals and their records, use of local ethics committees, etc. These and many

other clinical trial design issues are covered in greater detail in ISO 14155.
2 Normative references
There are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

— ISO Online browsing platform: available at http:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/

NOTE All of the clinical failure events defined below represents potential vaginal exposure to semen and

other penile discharge. Non-clinical failure events do not risk exposure.
3.1
clinical breakage

breakage or tearing of the condom during intercourse or withdrawal from the vagina

Note 1 to entry: This might not be noticed until after inspection of the condom following intercourse.

Note 2 to entry: Any breakages that do not meet the definition of clinical breakage are considered “non-clinical

breakage” (e.g. tearing the condom when opening the package).
3.2
clinical breakage rate

number of female condoms broken or torn during intercourse or withdrawal divided by the number of

female condoms used during intercourse

Note 1 to entry: The clinical breakage rate is typically reported as a percentage.

© ISO 2017 – All rights reserved 1
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ISO 29943-2:2017(E)
3.3
clinical slippage
condom slipping completely out of the vagina during intercourse

Note 1 to entry: If a condom slips off primarily as a result of breakage, do not count that as a slippage event.

3.4
clinical slippage rate

number of female condoms that slipped completely out of the vagina divided by the number of female

condoms used during intercourse

Note 1 to entry: The clinical slippage rate is typically reported as a percentage.

3.5
clinical misdirection
insertion of the penis between the female condom and the vaginal wall
3.6
clinical misdirection rate

number of female condoms that misdirect divided by the number of female condoms used during

intercourse

Note 1 to entry: The clinical misdirection rate is typically reported as a percentage.

3.7
clinical invagination

external retention feature of the female condom that is partially or fully pushed into the vagina during

intercourse
3.8
clinical invagination rate

number of female condoms that invaginate divided by the number of female condoms used during

intercourse

Note 1 to entry: The clinical invagination rate is typically reported as a percentage.

3.9
clinical failure event

clinical breakage (3.1), clinical slippage (3.3), clinical misdirection (3.5) or clinical invagination (3.7)

3.10
total clinical failure

number of female condoms with at least one acute failure event that results in potential vaginal

exposure to semen and other penile discharge

Note 1 to entry: Any condom that experiences multiple clinical failure events (3.9) only counts as a single clinical

failure.

Note 2 to entry: Includes condoms with the following failures: clinical breakage (3.1), slippage (3.3), misdirection

(3.5), invagination (3.7), or any failure event(s) in the risk assessment as described in Clause 4.

3.11
total clinical failure rate

number of female condoms with clinical failure divided by the number of female condoms used during

intercourse

Note 1 to entry: The total clinical failure rate is typically reported as a percentage.

2 © ISO 2017 – All rights reserved
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ISO 29943-2:2017(E)
3.12
bias

systematic error caused by a variable not considered in the calculation of results

Note 1 to entry: Three common causes of bias in this type of clinical study are (1) selection bias, where certain

types of study subjects are not representative for the outcome being assessed, (2) recall bias, where poor

questionnaire design or lengthy time between when condom is used and when the use events are recorded, and

(3) misclassification, where the outcome of interest (e.g. breakage, slippage, invagination, or misdirection) is

recorded erroneously.

Note 2 to entry: The term bias is used in statistics to refer to how far the expected value of a statistic lies from the

parameter it is estimating.
3.13
non-inferiority margin

statistical term used to identify a clinically meaningful difference between products

Note 1 to entry: Differences between product means which are less than δ are interpreted as noise inherent in

the study while differences between product means which are greater than δ are attributed to a meaningful

difference between products.
4 Risk assessment

A risk assessment for the product shall be conducted in accordance with ISO 14971. This assessment

should identify all safety and effectiveness concerns, including potential mechanisms of condom failure

and the results of the pilot study. All possible acute failure events should be considered in the design

of the female condom, and clinical investigations should be designed to capture information on each

possible type of failure.

The risk assessment should address whether each acute failure event leads to potential vaginal

exposure to semen and other penile discharge during condom use, and therefore whether each failure

event is designated clinical or non-clinical.
Manufacturers should make this risk assessment available to regulatory bodies.
5 Pilot clinical studies

A pilot study helps to identify and evaluate the different types of acute failure events of the new female

condom prior to initiation of a larger clinical investigation (see ISO 25841:2014, Clause 8). The acute

failure rates obtained in the pilot study will influence the statistical calculations of power and sample

size for the pivotal study. The risk assessment (see Clause 4) should be conducted prior to the pilot

study and then repeated after the pilot study, with any new types of failure events reported in the pilot

study to be classified as either clinical or non-clinical failures.

In addition, the pilot study can help identify potential safety concerns, including condom features that

could cause abrasions or irritation during use. It is recommended that study subjects in the pilot study

undergo a post-coital physical examination as soon after condom use as practicable. Such exams should

be conducted by an experienced clinician.

Investigators should provide detailed verbal and written instructions on appropriate condom insertion

and use to all study participants and demonstrate correct condom placement using a pelvic model.

Collection of user acceptability information will be useful to evaluate product acceptability and to guide

further product improvements prior to the larger clinical investigation.
For additional information, see 6.15 and 6.16.
Annex B contains a sample outline for a pilot clinical study.
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ISO 29943-2:2017(E)
6 Clinical validation investigation
6.1 Objectives of clinical validation investigation

The protocol should state the purpose of the study, e.g. to evaluate the performance of a new female

condom (test condom) during vaginal intercourse compared to a control female condom. The protocol

should clearly state the hypothesis being tested (i.e. whether the non-inferiority margin between the

total clinical failure rates for test and control condoms complies with the requirements specified in of

ISO 25841:2014, 8.3).

NOTE Please refer to the WHO guidelines on clinical studies for additional information.

The primary objective of this study is to compare the total clinical failure rates of the test and control

condoms.

Secondary objectives are to evaluate each different type of failure event identified in the risk analysis

(e.g. slippage, breakage, invagination, misdirection, etc.) by comparing the new female condom to the

control female condom for each type of failure event. In addition, there should be an evaluation of total

condom failure (i.e. sum of total clinical and total non-clinical failures).

The secondary objectives of the research should also include safety and acceptability. Safety will be

determined by the proportion of women reporting adverse events reported during condom uses and

by condom type. Acceptability will be measured by the calculated frequency of key acceptability end

points including ease of insertion and removal, like or dislike of product attributes, adequacy and feel of

lubrication, etc.

These studies might also collect incidental data on female condom use during anal sex; however, that is

not the primary objective.
6.2 Outcome measures

The protocol should prospectively state and define the outcome measures to be evaluated when the

study is completed, as well as the means by which such data will be collected.

a) The primary outcome measure is total clinical failure, representing the total number of test or

control condoms for which one or more acute failure events (as defined in Clause 3) are reported by

the users.

b) Secondary outcome measures should include all types of acute failure events, reported individually.

c) Adverse events. The protocol should contain provisions for collecting data on safety outcomes, e.g.

pain, discomfort, bleeding, penile or vaginal irritation, etc.
d) Other outcome measures (optional):
1) any non-clinical failure rates;
2) total failure rate (clinical and non-clinical);
3) user acceptability.
6.3 Study subjects
6.3.1 General

The protocol should describe the exact method(s) of recruiting subjects. Recruitment should attempt

to draw from a representative target population that includes various socio-economic, ethnic, and

4 © ISO 2017 – All rights reserved
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ISO 29943-2:2017(E)

cultural, and condom user experience backgrounds. The study should include multiple investigational

sites, and the number of study subjects enrolled should be evenly distributed across sites.

NOTE Selection bias can be introduced into a study by recruiting or oversampling couples who do not

represent the target population. For example, highly experienced condom users (such as commercial sex workers)

might not challenge the condom as much as inexperienced users and so targeting these couples for recruitment

can result in artificially low failure rates.

The various stages and elements of the study are described below. Annex C provides a sample timetable

of events for the individual study subject. It may be configured to the specifics of a given study.

6.3.2 Enrolment of study subjects
6.3.2.1 General

The following inclusion and exclusion criteria are examples for a low risk study. However, other entry

criteria can be used depending on the study context.
6.3.2.2 Inclusion criteria
The following is a list of recommended criteria for selection of study couples:
a) mutually monogamous; current relationship ≥ 3 months;

b) already protected from pregnancy, e.g. oral contraceptive, intrauterine device, subdermal implant,

injectable, patch, male or female sterilization;
c) 18 years to 45 years of age;

d) sexually active, sufficient to meet protocol requirements; agree to have penile-vaginal intercour

...

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