1、Condoms Guidance on clinical studiesPart 2: Female condoms, clinical function studies based on self-reportsBS ISO 29943-2:2017BSI Standards PublicationWB11885_BSI_StandardCovs_2013_AW.indd 1 15/05/2013 15:06National forewordThis British Standard is the UK implementation of ISO 29943-2:2017.The UK pa
2、rticipation in its preparation was entrusted to Technical Committee CH/157, Mechanical contraceptives.A list of organizations represented on this committee can be obtained on request to its secretary.This publication does not purport to include all the necessary provisions of a contract. Users are r
3、esponsible for its correct application. The British Standards Institution 2017 Published by BSI Standards Limited 2017ISBN 978 0 580 85594 8ICS 11.200Compliance with a British Standard cannot confer immunity from legal obligations. This British Standard was published under the authority of the Stand
4、ards Policy and Strategy Committee on 31 July 2017.Amendments/corrigenda issued since publicationDate Text affectedBRITISH STANDARDBS ISO 299432:2017 ISO 2017Condoms Guidance on clinical studies Part 2: Female condoms, clinical function studies based on self-reportsPrservatifs Lignes directrices rel
5、atives aux tudes cliniques Partie 2: Prservatifs fminins, analyse fonctionnelle des dfaillances graves sur la base dauto-dclarationsINTERNATIONAL STANDARDISO29943-2First edition2017-07-15Reference numberISO 29943-2:2017(E)BS ISO 299432:2017ISO 29943-2:2017(E)ii ISO 2017 All rights reservedCOPYRIGHT
6、PROTECTED DOCUMENT ISO 2017, Published in SwitzerlandAll rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without
7、prior written permission. Permission can be requested from either ISO at the address below or ISOs member body in the country of the requester.ISO copyright officeCh. de Blandonnet 8 CP 401CH-1214 Vernier, Geneva, SwitzerlandTel. +41 22 749 01 11Fax +41 22 749 09 47copyrightiso.orgwww.iso.orgBS ISO
8、299432:2017ISO 29943-2:2017(E)Foreword vIntroduction vi1 Scope . 12 Normative references 13 Terms and definitions . 14 Risk assessment 35 Pilot clinical studies 36 Clinical validation investigation . 46.1 Objectives of clinical validation investigation 46.2 Outcome measures 46.3 Study subjects 46.3.
9、1 General 46.3.2 Enrolment of study subjects 56.4 Informed consent 66.5 Test and control condoms . 66.5.1 General 66.5.2 Test condom . 76.5.3 Control condom 76.5.4 Trial duration exceeds one year . 76.5.5 Sampling of control condoms for bench testing . 86.6 Randomization 86.7 Allocation concealment
10、and study masking 86.8 Use of additional lubricant . 86.9 Instructions and interactions with study couples 86.10 Interviews and data collection 96.10.1 Schedule for interviews and condom distribution . 96.10.2 Enrolment interview 96.10.3 Individual condom use CRF . 106.10.4 Mid-study CRF, crossover
11、trial 106.10.5 Compiling data from CRFs 116.11 Data integrity . 116.11.1 General. 116.11.2 Interactive voice response systems (IVRS) 116.11.3 Mail-in and web-based data reporting 116.11.4 Web-based data collection systems, additional suggestions 126.12 Control of distribution chain 136.13 Analysis o
12、f returned condoms 136.14 Other methodological details 136.15 Statistical analysis plan . 146.15.1 General. 146.15.2 Primary study hypothesis . 146.15.3 Secondary study hypotheses 156.15.4 Study design 156.15.5 Statistical analysis 156.15.6 Additional statistical comments and concerns .166.16 Clinic
13、al study results: Review and interpretation .166.16.1 General. 166.16.2 Total clinical failure rates for control condom 166.16.3 Non-inferiority 166.16.4 Superiority . 176.16.5 Safety (adverse events) . 176.16.6 What happens if one is unable to conclude non-inferiority? 17 ISO 2017 All rights reserv
14、ed iiiContents PageBS ISO 299432:2017ISO 29943-2:2017(E)Annex A (informative) Formula for power calculation .18Annex B (informative) Pilot clinical investigation (sample outline) 19Annex C (informative) Time and events schedule for individual study subject (sample) .21Annex D (informative) CRF Study
15、 entry (sample) 22Annex E (informative) CRF Mid-study (sample) .25Annex F (informative) CRF Single use of female condom (sample)27Annex G (informative) CRF Adverse event (sample) 31Annex H (informative) Protocol for evaluation of returned used condoms .33Bibliography .39iv ISO 2017 All rights reserv
16、edBS ISO 299432:2017ISO 29943-2:2017(E)ForewordISO (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
17、 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 Electrotec
18、hnical 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
19、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 respo
20、nsible 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
21、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 ISOs adherence to the World Trade Organization (WTO) principle
22、s in the Technical Barriers to Trade (TBT) see the following URL: www.iso.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
23、rights reserved vBS ISO 299432:2017ISO 29943-2:2017(E)IntroductionThere 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 o
24、f 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 valid
25、ation 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 mat
26、erials. 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 misd
27、irection. 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 re
28、garding 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
29、(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 f
30、or 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 typicall
31、y 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
32、 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
33、 research involving human subjects, including ethical considerations. For additional information, refer to ISO 14155.vi ISO 2017 All rights reservedBS ISO 299432:2017Condoms Guidance on clinical studies Part 2: Female condoms, clinical function studies based on self-reports1 ScopeThis document is in
34、tended 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 interc
35、ourse (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 clini
36、cal 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 referencesThere are no normat
37、ive references in this document.3 Terms and definitionsFor 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 IE
38、C 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.3.1clinical breakagebreakage or tearing of the condom during inte
39、rcourse or withdrawal from the vaginaNote 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
40、the package).3.2clinical breakage ratenumber of female condoms broken or torn during intercourse or withdrawal divided by the number of female condoms used during intercourseNote 1 to entry: The clinical breakage rate is typically reported as a percentage.INTERNATIONAL STANDARD ISO 29943-2:2017(E) I
41、SO 2017 All rights reserved 1BS ISO 299432:2017ISO 29943-2:2017(E)3.3clinical slippagecondom slipping completely out of the vagina during intercourseNote 1 to entry: If a condom slips off primarily as a result of breakage, do not count that as a slippage event.3.4clinical slippage ratenumber of fema
42、le condoms that slipped completely out of the vagina divided by the number of female condoms used during intercourseNote 1 to entry: The clinical slippage rate is typically reported as a percentage.3.5clinical misdirectioninsertion of the penis between the female condom and the vaginal wall3.6clinic
43、al misdirection ratenumber of female condoms that misdirect divided by the number of female condoms used during intercourseNote 1 to entry: The clinical misdirection rate is typically reported as a percentage.3.7clinical invaginationexternal retention feature of the female condom that is partially o
44、r fully pushed into the vagina during intercourse3.8clinical invagination ratenumber of female condoms that invaginate divided by the number of female condoms used during intercourseNote 1 to entry: The clinical invagination rate is typically reported as a percentage.3.9clinical failure eventclinica
45、l breakage (3.1), clinical slippage (3.3), clinical misdirection (3.5) or clinical invagination (3.7) 3.10total clinical failurenumber of female condoms with at least one acute failure event that results in potential vaginal exposure to semen and other penile dischargeNote 1 to entry: Any condom tha
46、t 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
47、 Clause 4.3.11total clinical failure ratenumber of female condoms with clinical failure divided by the number of female condoms used during intercourseNote 1 to entry: The total clinical failure rate is typically reported as a percentage.2 ISO 2017 All rights reservedBS ISO 299432:2017ISO 29943-2:20
48、17(E)3.12biassystematic error caused by a variable not considered in the calculation of resultsNote 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 b
49、ias, 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.3.13non-inferiority margin statistical term used to identify a clinically meaningful difference between productsNot
