ISO 11249:2018

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 2018
© ISO 2018
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Published in Switzerland
ii © ISO 2018 – All rights reserved

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
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

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.
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
AE
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.
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

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
EC
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.
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

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.
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

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
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 assessment and risk control,
is described in ISO 14971.
8 Objectives and hypotheses of the clinical investigation
The CIP should contain:
a) Claims and intended performance of the IUD that are to be verified
ISO 7439 describes three requirements that the IUD will be judged against:
1) the upper limit of the 95 % two-sided confidence interval for the one-year pregnancy rate
computed using life table methods (ISO 7439 specifies ≤ 2 %);
2) one-year expulsion rates computed using life table methods (ISO 7439 specifies ≤ 10 %);
3) one-year discontinuation rates for clinical reasons computed using life table methods (ISO 7439
specifies ≤ 35 %).
NOTE 1 Regulatory bodies from some countries can require analysis of the clinical data in more than one
way in order to evaluate outcomes of interest in different ways. For instance, besides the requirement for
life table analysis, referenced above, a regulatory body can require a primary analysis applying the Kaplan
Meier statistic. The regulatory body can additionally ask that the cumulative Pearl Index be calculated. See
[16][17][18]
Bibliography for additional information on the use of these various statistics .
8 © ISO 2018 – All rights reserved

NOTE 2 Typically, the life table analysis is used to evaluate each individual year of use, as well as
evaluating the full duration of use covered by the entire study.
NOTE 3 There can be subsets from the data analysis where the limits cited above can be exceeded.
b) Risks and anticipated adverse device effects that are to be assessed
See 9.1 c) below.
NOTE 4 When analysing the outcome of the study, it is useful to report results for specific subsets of the
population such as nulliparous subjects.
When calculating discontinuation rates, the discontinuations should be device related only.
9 Design of the clinical investigation
9.1 General
The scientific integrity of, and the validity of, the data from the clinical investigation depend
substantially on its design.
The CIP should contain the following.
a) A description of the type of clinical investigation to be performed (e.g. comparative, blinded,
parallel design, without a comparator group) with rationale for the choice.
ISO 7439 requires that contraceptive efficacy rates should be determined in a randomized trial
using TCu380A, if possible, as a comparator device. If not, another IUD with a well-established
pregnancy rate that complies with the requirements in ISO 7439:2015, 4.2, shall be used as the
comparator.
NOTE 1 The comparator arm using TCu380A is included in the trial to confirm that no bias is introduced
due to the study methodology and/or the population using the index device. This can be demonstrated if an
average of 360 women in the comparator arm are followed during the first year of use.
b) A description of the measures to be taken to minimize or avoid bias, including randomization and
blinding/masking. Specifically,
1) a true randomization schedule should be used, and
2) as far as is practical, it is recommended that the type of device should be masked to the
participants, those providing the care at follow-up, and those doing the analysis.
NOTE 2 Depending on the study design, masking is not necessary.
c) The primary and secondary end points
1) The primary end points for IUD studies are:
i) the upper 95 % confidence level, two-sided confidence interval for the one-year pregnanc
...