Copper-bearing intrauterine contraceptive devices -- Guidance on the design, execution, analysis and interpretation of clinical studies

ISO 11249:2018 provides guidance on the design and conduct of clinical studies to determine the performance characteristics of new intrauterine devices. It also provides advice on the analysis of data when the study is completed, as well as interpretation of these results by manufacturers, researchers and regulatory bodies. ISO 11249:2018 is intended to ensure the scientific conduct of the clinical investigation and the credibility of the clinical investigation results, and to assist sponsors, monitors, investigators, ethics committees, regulatory authorities and other bodies involved in the conformity assessment of medical devices. Certain clinical trial concerns are not addressed in this document, including subject compensation, confidentiality of subjects and their records, use of local ethics committees, etc. These and many other clinical trial design issues are covered in great detail in ISO 14155.

Dispositif intra-utérin au cuivre à but contraceptif -- Recommandations relatives à la méthodologie, la réalisation, l'analyse et l'interprétation des résultats des études cliniques

General Information

Status
Published
Publication Date
31-Jan-2018
Current Stage
6060 - International Standard published
Start Date
13-Dec-2017
Completion Date
01-Feb-2018
Ref Project

Buy Standard

Standard
ISO 11249:2018 - Copper-bearing intrauterine contraceptive devices -- Guidance on the design, execution, analysis and interpretation of clinical studies
English language
23 pages
sale 15% off
Preview
sale 15% off
Preview

Standards Content (sample)

INTERNATIONAL ISO
STANDARD 11249
First edition
2018-02
Copper-bearing intrauterine
contraceptive devices — Guidance on
the design, execution, analysis and
interpretation of clinical studies
Dispositif intra-utérin au cuivre à but contraceptif —
Recommandations relatives à la méthodologie, la réalisation,
l'analyse et l'interprétation des résultats des études cliniques
Reference number
ISO 11249:2018(E)
ISO 2018
---------------------- Page: 1 ----------------------
ISO 11249:2018(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2018

All rights reserved. Unless otherwise specified, or required in the context of its implementation, 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 prior written permission. Permission can be requested from either ISO at the address

below or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva, Switzerland
Tel. +41 22 749 01 11
Fax +41 22 749 09 47
copyright@iso.org
www.iso.org
Published in Switzerland
ii © ISO 2018 – All rights reserved
---------------------- Page: 2 ----------------------
ISO 11249:2018(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

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

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

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

4 Planning an IUD trial — Good clinical practice .................................................................................................................... 6

5 Ethics ................................................................................................................................................................................................................................. 6

5.1 General ........................................................................................................................................................................................................... 6

5.2 Ethics of IUD trials ............................................................................................................................................................................... 6

5.3 Informed consent .................................................................................................................................................................................. 6

5.3.1 General...................................................................................................................................................................................... 6

5.3.2 Process of obtaining informed consent ........................................................................................................ 7

5.3.3 Information to be provided to the subject ................................................................................................. 7

6 Identification and description of the investigational device .................................................................................. 7

7 Preliminary investigations and justification for the design of the clinical investigation .........7

7.1 Literature review .................................................................................................................................................................................. 7

7.2 Preclinical testing ................................................................................................................................................................................. 8

7.3 Previous clinical experience ........................................................................................................................................................ 8

7.4 Investigational device and clinical investigation risks and benefits ......................................................... 8

8 Objectives and hypotheses of the clinical investigation .............................................................................................. 8

9 Design of the clinical investigation .................................................................................................................................................... 9

9.1 General ........................................................................................................................................................................................................... 9

9.2 Investigational device(s) and comparator(s) ............................................................................................................13

9.3 Subjects ......................................................................................................................................................................................................14

9.4 Procedures ...............................................................................................................................................................................................15

9.5 Statistical considerations ............................................................................................................................................................16

10 Adverse events, adverse device effects and non-medical complaints ........................................................18

11 Early termination or suspension of the clinical investigation ...........................................................................18

12 Publication policy .............................................................................................................................................................................................18

Annex A (informative) Exclusion and inclusion criteria for IUD trials ..........................................................................19

Annex B (informative) Timing of insertion of IUD: When can an IUD be inserted? ..........................................21

Bibliography .............................................................................................................................................................................................................................22

© ISO 2018 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO 11249:2018(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: www .iso .org/ iso/ foreword .html.

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

barrier prophylactics.
iv © ISO 2018 – All rights reserved
---------------------- Page: 4 ----------------------
ISO 11249:2018(E)
Introduction

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

clinical studies conducted in accordance with the requirements of ISO 7439.

Intrauterine devices (IUD) are highly effective at preventing pregnancy. A new device aims at maintaining

or improving the efficacy of intrauterine contraception and/or reducing the side effects associated with

IUDs, such as excessive menstrual bleeding. Trials evaluating new or modified IUDs should be conducted

to the highest standards and this guidance will help those preparing for an IUD trial.

This guidance is based on the structure and content of a clinical investigation plan (CIP) as described in

ISO 14155 to assist in the writing of a CIP and includes sections of the CIP that are of special relevance

to IUD trials.

This guidance also draws on the experience gained in preparing the Cochrane systematic review of

trials of copper-containing IUDs, which has been used to inform the updating of the WHO/UNFPA

Specification for TCu380A IUD.

It is important that persons designing, running, and analysing clinical studies of new IUDs are familiar

with all relevant standards for research designed to protect the rights, safety and well-being of human

subjects.
This guidance should be read in conjunction with ISO 14155.

Clinical studies are also subject to local regulations and, in most countries, require prior approval from

the local regulatory body.
© ISO 2018 – All rights reserved v
---------------------- Page: 5 ----------------------
INTERNATIONAL STANDARD ISO 11249:2018(E)
Copper-bearing intrauterine contraceptive devices —
Guidance on the design, execution, analysis and
interpretation of clinical studies
1 Scope

This document provides guidance on the design and conduct of clinical studies to determine the

performance characteristics of new intrauterine devices. It also provides advice on the analysis of data

when the study is completed, as well as interpretation of these results by manufacturers, researchers

and regulatory bodies.

It is intended to ensure the scientific conduct of the clinical investigation and the credibility of the

clinical investigation results, and to assist sponsors, monitors, investigators, ethics committees,

regulatory authorities and other bodies involved in the conformity assessment of medical devices.

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

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

clinical trial design issues are covered in great 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:

— IEC Electropedia: available at http:// www .electropedia .org/
— ISO Online browsing platform: available at https:// www .iso .org/ obp
3.1
adverse device effect
ADE
adverse event (3.2) related to the use of a medical device (3.27)

Note 1 to entry: This includes any adverse event resulting from insufficiencies or inadequacies in the

instructions for use, the deployment, the implantation, the installation, the operation, or any malfunction (3.26)

of the medical device.

Note 2 to entry: This includes any event that is a result of a use error or intentional misuse.

3.2
adverse event

any untoward medical occurrence, unintended disease or injury or any untoward clinical signs

(including an abnormal laboratory finding) in subjects (3.35), users or other persons whether or not

related to the investigational device (3.25)

Note 1 to entry: This includes events related to the investigational device or the comparator (3.10).

Note 2 to entry: This includes events related to the procedures involved.
© ISO 2018 – All rights reserved 1
---------------------- Page: 6 ----------------------
ISO 11249:2018(E)

Note 3 to entry: For users or other persons, this is restricted to events related to the investigational device.

3.3
audit

systematic examination of clinical investigation (3.6) related activities and documents performed by an

independent entity not involved in the conduct of the clinical investigation

Note 1 to entry: The examination will determine whether the clinical investigation related activities were

conducted, and the data were recorded, analysed and accurately reported, according to the clinical investigation

plan (3.7), standard operating procedures, this document and applicable regulatory requirements.

3.4
blinding/masking

procedure in which one or more parties to the clinical investigation (3.6) are kept unaware of the

treatment assignment(s)

Note 1 to entry: Single-blinding usually refers to the subject(s) (3.35) being unaware of the treatment

assignment(s). Double-blinding usually refers to the subject(s), clinical investigator(s), monitor, and, in some

cases, centralized assessors being unaware of the treatment assignment(s).
3.5
case report form
CRF

set of printed, optical or electronic documents for each subject (3.35) on which information to be

reported to the sponsor (3.34) is recorded as required by the CIP
Note 1 to entry: There may be more than one case report form per subject.
3.6
clinical investigation

systematic investigation in or on one or more human subjects (3.35), undertaken to assess the safety

and/or efficacy of a medical device (3.27)

Note 1 to entry: “Clinical trial” or “clinical study” are synonymous with “clinical investigation”.

3.7
clinical investigation plan
CIP

document that states the rationale, objectives (3.28), design and proposed analysis, methodology,

monitoring, conduct and record-keeping of the clinical investigation (3.6)

Note 1 to entry: The term “protocol” is synonymous to “CIP”. However, protocol has many different meanings,

some not related to clinical investigations, and these can differ from country to country. Therefore, the term CIP

is used in this document.
3.8
clinical investigation report

written document summarizing the design, execution, statistical analysis and results of a clinical

investigation (3.6)
3.9
clinical performance

behaviour of a medical device (3.27) and/or the response of the subject (3.35) to that medical device in

relation to its intended use when correctly applied to appropriate subjects
3.10
comparator

medical device (3.27), therapy (e.g. active control), placebo or no treatment, used in the reference group

in a clinical investigation (3.6)
2 © ISO 2018 – All rights reserved
---------------------- Page: 7 ----------------------
ISO 11249:2018(E)
3.11
deviation

instance(s) of failure to follow, intentionally or unintentionally, the requirements of the CIP

3.12
ectopic pregnancy
pregnancy located outside the uterine cavity
3.13
primary end point

indicator to assess the primary hypothesis (3.17) of a clinical investigation (3.6)

Note 1 to entry: There might be more than one primary end point.
3.14
secondary end point

indicator to assess the secondary hypotheses (3.17) of a clinical investigation (3.6)

Note 1 to entry: There might be more than one secondary end point.
3.15
ethics committee

independent body whose responsibility is to review clinical investigations (3.6), protocols and

procedures in order to protect the rights, safety and well-being of human subjects (3.35) participating

in a clinical investigation

Note 1 to entry: For the purposes of this document, “ethics committee” is synonymous with “research ethics

committee”, “independent ethics committee”, or “institutional review board”. The regulatory requirements

pertaining to ethics committees or similar institutions can differ by country or region.

3.16
expulsion

inadvertent movement of the IUD into or from the vagina, including partial expulsion, requiring removal

of the IUD from the cervix
3.17
hypothesis

testable biostatistical statement, derived from the study objective (3.28), for evaluating the

investigational device (3.25) safety and/or performance

Note 1 to entry: The hypothesis is used to design the clinical investigation (3.6) and stipulates the statistic(s) used

to accept or reject the results of the clinical investigation.

Note 2 to entry: The primary hypothesis is the determinant of the investigational device safety and/or

performance parameters and is usually used to calculate the sample size. Secondary hypotheses concerning

other points of interest can also be evaluated.
3.18
independent party

party not involved in the conduct of a clinical investigation (3.6), except for their specifically assigned

responsibilities in order to avoid bias or a conflict of interest
3.19
informed consent process

process by which an individual is asked to voluntarily participate in a clinical investigation (3.6) having

been provided with information about the clinical investigation

Note 1 to entry: Informed consent is documented by means of a written, signed and dated informed consent form.

© ISO 2018 – All rights reserved 3
---------------------- Page: 8 ----------------------
ISO 11249:2018(E)
3.20
intrauterine pregnancy
normally sited pregnancy within the uterine cavity
3.21
insertion instrument
instrument designed to place an IUD in the uterine cavity
3.22
intrauterine contraceptive device
IUD
device placed in the uterine cavity for the purpose of preventing pregnancy
Note 1 to entry: The abbreviation IUCD may be used in some publications.
3.23
investigator

any individual member of the investigation site (3.24) team designated and supervised by the principal

investigator at an investigation site to perform critical clinical investigation-related procedures and/or

to make important clinical investigation-related decisions

Note 1 to entry: An individual member of the investigation site team can also be called “sub-investigator” or “co-

investigator”.
3.24
investigation site
institution or site where the clinical investigation (3.6) is carried out

Note 1 to entry: For the purpose of this document, “investigation site” is synonymous with “investigation centre”.

3.25
investigational device

medical device (3.27) being assessed for safety and performance in a clinical investigation (3.6)

Note 1 to entry: This includes marketed medical devices that are being evaluated for new intended uses, new

populations, new materials or design changes.
3.26
malfunction

failure of a device to perform in accordance with its intended purpose when used in accordance with

the instructions for use or CIP
3.27
medical device

any instrument, apparatus, implement, machine, appliance, implant, software, material, or other similar

or related article intended by the manufacturer to be used, alone or in combination, for human beings

for one or more of the specific purpose(s) of
— diagnosis, prevention, monitoring, treatment or alleviation of disease,

— diagnosis, monitoring, treatment, alleviation of or compensation for an injury,

— investigation, replacement, modification, or support of the anatomy or of a physiological process,

— supporting or sustaining life,
— control of conception,
— disinfection of medical devices, and

— providing information for medical purposes by means of in vitro examination of specimens derived

from the human body
4 © ISO 2018 – All rights reserved
---------------------- Page: 9 ----------------------
ISO 11249:2018(E)

and which does not achieve its primary intended action in or on the human body by pharmacological,

immunological or metabolic means, but which may be assisted in its intended function by such means

3.28
objective
major purpose(s) for conducting the clinical investigation (3.6)
3.29
perforation

puncture of the uterus, as may be caused by a uterine sound or insertion tube or by an intrauterine

contraceptive device (3.22)
3.30
point of enrolment

date at which, following recruitment (3.31) and signing and dating the informed consent form, a subject

(3.35) is enrolled in a study
3.31
recruitment

active efforts to identify subjects (3.35) who might be suitable for enrolment into the clinical

investigation (3.6)
3.32
serious adverse device effect
SADE

adverse device effect (3.1) that has resulted in any of the consequences characteristic of a serious adverse

event (3.33)
3.33
serious adverse event
SAE
adverse event (3.2) that
a) led to a death,
b) led to a serious deterioration in the health of the subject (3.35) that
— resulted in a life-threatening illness or injury,
— resulted in a permanent impairment of a body structure or a body function,

— required in-patient hospitalization or prolongation of existing hospitalization,

— resulted in medical or surgical intervention to prevent life threatening illness or injury or

permanent impairment to a body structure or a body function, or

c) led to foetal distress, foetal death or a congenital abnormality or birth defect

Note 1 to entry: A planned hospitalization for pre-existing condition, or a procedure required by the CIP, without

a serious deterioration in health, is not considered to be a serious adverse event.

3.34
sponsor

individual or organization taking responsibility and liability for the initiation and/or implementation of

a clinical investigation (3.6)

Note 1 to entry: When an investigator (3.23) initiates, implements and takes full responsibility for the clinical

investigation, the investigator also assumes the role of the sponsor and is identified as the sponsor-investigator.

© ISO 2018 – All rights reserved 5
---------------------- Page: 10 ----------------------
ISO 11249:2018(E)
3.35
subject
individual who participates in a clinical investigation (3.6)
Note 1 to entry: A subject can be either a healthy volunteer or a patient.
3.36
thread

attachment to an IUD for the purpose of verifying the presence of and enabling the removal of the IUD

Note 1 to entry: The thread is intended to lie in the cervical canal and the vagina when the body of the device is

placed correctly in the uterine cavity.
3.37
unanticipated serious adverse device effect
USADE

serious adverse device effect (3.32) which by its nature, incidence, severity or outcome has not been

identified in the current version of the risk analysis report

Note 1 to entry: There should be a distinction in the report between anticipated and unanticipated serious

adverse device effects.
4 Planning an IUD trial — Good clinical practice

ISO 14155 addresses good clinical practice for the design, conduct, recording and reporting of clinical

investigations carried out in human subjects to assess the safety or performance of medical devices for

regulatory purposes.

The principles set forth in ISO 14155 should apply to all trials conducted on IUDs. ISO 14155 specifies

general requirements intended to protect the rights, safety and well-being of human subjects and

ensure the scientific conduct of the clinical investigation and the credibility of the results. It defines

the responsibilities of the sponsor and principal investigator, and assist sponsors, investigators, ethics

committees, regulatory authorities and other bodies involved in the conformity assessment of medical

devices.
5 Ethics
5.1 General

Clinical investigations should be conducted in accordance with the ethical principles that have their

[24]

origin in the Declaration of Helsinki . This protects the rights, safety and well-being of clinical

investigation subjects, which are the most important considerations and are required by the Declaration

to prevail over interests of science and society. This should be understood, observed, and applied at

every step in the clinical investigation.
5.2 Ethics of IUD trials

Trials of a new IUD are justified if they are likely to demonstrate improved performance, whether by

improving efficacy, reducing side-effects or improved bleeding pattern, or potentially reducing costs

when compared to standard IUDs such as TCu380A.
5.3 Informed consent
5.3.1 General

Informed consent should be obtained in writing and documented before any procedure specific to the

clinical investigation is applied to a subject. The informed consent form consists of an information form

and an informed consent signature form.
6 © ISO 2018 – All rights reserved
---------------------- Page: 11 ----------------------
ISO 11249:2018(E)
5.3.2 Process of obtaining informed consent

The procedures specified in ISO 14155 should be followed when obtaining informed consent.

5.3.3 Information to be provided to the subject

The procedures relating to information to be provided to the subject specified in ISO 14155 should be

followed. The risks relating to pregnancy should be clearly pointed out.

The procedures specified in ISO 14155 should be followed when obtaining informed consent signature.

The subject’s signature should be obtained before enrolling into the study and an IUD is inserted.

6 Identification and description of the investigational device
The CIP should contain:
a) a summary description of the intrauterine device and its intended purpose;
b) the manufacturer of the device;

c) the model or type name and/or number and accessories, if any, to permit full identification;

d) a description as to how traceability will be achieved during and after the clinical investigation, for

example, assignment of lot numbers, batch numbers, or serial numbers;

e) the intended purpose of the intrauterine device in the proposed clinical investigation. If purposes

other than contraception are intended, these should be described;

f) the populations and indications for which the intrauterine device is intended when in general use;

g) a description of the intrauterine device including any materials that will be in contact with tissues

or body fluids;

h) instructions for insertion and use of the IUD including any necessary storage and handling

requirements, preparation for use and any precautions to be taken after use, e.g. disposal;

i) a summary of necessary training and experience needed for the use of the IUD;

j) a description of the necessary medical or surgical procedures involved in the use of the

investigational device.
7 Preliminary investigations and justification for the design of the clinical
investigation
7.1 Literature review

Although the clinical requirements for copper bearing IUDs are specified in ISO 7439, it is nevertheless

recommended that a literature review is undertaken during the planning stage for any clinical trials

on IUDs.
The CIP should contain:

a) the conclusions of a critical review of the relevant scientific literature and/or unpublished data and

reports;
b) a list of the literature reviewed.

The conclusions from this literature review may impact on the design of the proposed clinical

investigations. The review should be relevant to the intended purpose of the IUD and the proposed

© ISO 2018 – All rights reserved 7
---------------------- Page: 12 ----------------------
ISO 11249:2018(E)

method of use. It should also help in the identification of relevant end-points and confounding factors

that should be considered, and the choice and justification of comparator(s).
7.2 Preclinical testing

The CIP should contain a summary of the relevant preclinical testing that has been performed on the

IUD to justify its use in human subjects, together with an evaluation of the results of such testing.

7.3 Previous clinical experience
The CIP should contain:

a) a summary of the results from previous clinical investigations and clinical usage, if any, that are

relevant to the proposed clinical investigation;

b) relevant experience, if any, with the IUD, or medical devices with similar features, including that

relating to other indications for use of the IUD;

c) an analysis of adverse device effects and any history of modification or recall.

7.4 Investigational device and clinical investigation risks and benefits
The CIP should contain:
a) anticipated clinical benefits;

b) residual risks associated with the IUD, as identified in the risk analysis report;

c) risks associated with participation in the clinical investigation;
d) anticipated adverse device effects;
e) possible interactions with concomitant medical treatments;
f) steps that will be taken to control or mitigate the risks;
g) risk/benefit rationale.
NOTE The risk management process, which includes risk analysis, risk/benefit a
...

Questions, Comments and Discussion

Ask us and Technical Secretary will try to provide an answer. You can facilitate discussion about the standard in here.