ISO 11980:2012
(Main)Ophthalmic optics — Contact lenses and contact lens care products — Guidance for clinical investigations
Ophthalmic optics — Contact lenses and contact lens care products — Guidance for clinical investigations
ISO 11980:2012 gives guidelines for the clinical investigation of the safety and performance of contact lenses and contact lens care products.
Optique ophtalmique — Lentilles de contact et produits d'entretien pour lentilles de contact — Directives pour les investigations cliniques
L'ISO 11980:2012 donne des lignes directrices pour l'investigation clinique concernant la sécurité et les performances des lentilles de contact et des produits d'entretien pour lentilles de contact.
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INTERNATIONAL ISO
STANDARD 11980
Third edition
2012-11-15
Ophthalmic optics — Contact lenses and
contact lens care products — Guidance
for clinical investigations
Optique ophtalmique — Lentilles de contact et produits d’entretien pour
lentilles de contact — Directives pour les investigations cliniques
Reference number
ISO 11980:2012(E)
©
ISO 2012
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ISO 11980:2012(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2012
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means,
electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or ISO’s
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Published in Switzerland
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ISO 11980:2012(E)
Contents Page
Foreword .iv
Introduction . v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Clinical investigational requirements . 1
4.1 General . 1
4.2 Additional requirements . 1
4.3 Other considerations . 4
Annex A (informative) Elements of a clinical investigation . 5
Annex B (informative) Procedures for the evaluation of safety, physiological performance and effect on
ocular tissues .18
Annex C (informative) The evaluation of visual, refractive and lens performance and
subject acceptance .23
Bibliography .26
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ISO 11980:2012(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.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
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.
ISO 11980 was prepared by Technical Committee ISO/TC 172, Optics and photonics, Subcommittee SC 7,
Ophthalmic optics and instruments.
This third edition cancels and replaces the second edition (ISO 11980:2009), which has undergone minor
revision in order to update the normative reference to ISO 14155 and to revise 4.2.1.1 b) 6) and the fifth row of
Table A.1 (overnight wear).
This corrected version of ISO 11980:2012 incorporates the following correction:
— in Table A.12, the final equation corresponding to the total number of eyes has been inserted.
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ISO 11980:2012(E)
Introduction
Currently, contact lenses and contact lens care products are regulated in different ways in different countries.
This International Standard has been developed to encourage global harmonization. Widespread adoption
of this International Standard should represent yet another step toward mutual recognition. This International
[1]
Standard can also be used as a basis to fulfil design elements of ISO 9001 .
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INTERNATIONAL STANDARD ISO 11980:2012(E)
Ophthalmic optics — Contact lenses and contact lens care
products — Guidance for clinical investigations
1 Scope
This International Standard gives guidelines for the clinical investigation (CI) of the safety and performance of
contact lenses and contact lens care products.
NOTE This International Standard attempts to harmonize the recognized regulatory requirements for the conduct of
a CI to meet the marketing and labelling requirements for contact lenses and contact lens care products around the world.
However, national requirements vary greatly. Wherever national practice or regulations dictate some legal requirement,
this requirement takes precedence over this International Standard.
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced document
(including any amendments) applies.
ISO 14155, Clinical investigation of medical devices for human subjects — Good clinical practice
ISO 14534, Ophthalmic optics — Contact lenses and contact lens care products — Fundamental requirements
ISO 18369-1, Ophthalmic optics — Contact lenses — Part 1: Vocabulary, classification system and
recommendations for labelling specifications
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 14155, ISO 14534 and ISO 18369-1 apply.
4 Clinical investigational requirements
4.1 General
The general requirements for a CI and for a clinical investigation plan (CIP) given in ISO 14155 shall apply, with
additional requirements given below.
4.2 Additional requirements
4.2.1 Study design
4.2.1.1 General
a) The inclusion criteria for subject selection shall relate to the study objectives and should include:
1) subjects with normal eyes who are not using any ocular medications, aged 18 years or over [except
when contact lens investigations have a special indication for use in “children” (for the purposes of
this International Standard, persons less than 18 years of age) such as orthokeratology and paediatric
aphakic lenses];
2) lens powers within the range available for the test lenses;
3) the manifest cylinder less than or equal to 0,75 D (for a study with only spherical power correcting lenses);
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ISO 11980:2012(E)
4) best spectacle corrected visual acuity greater than or equal to 20/25 (less than or equal to LogMAR 0,1).
b) The exclusion criteria for subject selection shall relate to the study objectives and should include, but not
be limited to:
1) anterior segment infection, inflammation or abnormality;
2) any active anterior segment ocular disease that would contraindicate contact lens wear;
3) the use of systemic or ocular medications that would contraindicate contact lens wear;
4) history of herpetic keratitis;
5) history of refractive surgery or irregular cornea (except when the contact lenses under investigation
are indicated for irregular cornea, keratoconus or refractive surgery);
6) slit lamp findings that are more serious than grade 1;
7) corneal vascularization greater than 1 mm of penetration;
8) a pathologically dry eye;
9) participation of the subject in a contact lens or contact lens care product clinical trial within the
previous 30 days.
c) The CIP shall provide a description of the monitoring procedure to ensure consistent quality of data
collection and recording.
d) The CIP shall include a statistical analysis plan. Sample size shall be justified, calculated by a validated
statistical software package.
4.2.1.2 Contact lenses
4.2.1.2.1 General. A CI of contact lenses, including daily wear and extended wear hydrogel, silicone hydrogel,
and rigid gas-permeable contact lenses, shall be designed as one of 4.2.1.2.2 or 4.2.1.2.3.
For CIPs to demonstrate safety and performance, as well as special claims (e.g. comfort), labelling or
additional indications, the following is required: a pre-determined statistical analysis plan (including sample
size calculations) shall be specified in the clinical protocol. Where feasible, the CIP shall define objective
endpoints to help support such claims.
NOTE 1 Inter-subject controls are preferred to intra-subject controls due to the potential dependence between the two
eyes and concerns regarding subject compliance.
NOTE 2 Annex A provides guidance for the design of a CI.
4.2.1.2.2 As a prospective, concurrently controlled study. For investigations evaluating hydrogel, silicone
hydrogel or rigid gas-permeable contact lenses, a prospective, concurrent control study design shall be followed.
Either a bilateral crossover design or a contra-lateral eye (i.e. intra-subject) design or inter-subject controls shall
be utilized. If inter-subject controls are utilized, the ratio of test subjects to control subjects may be either 2:1 or
1:1. The control lens shall be a currently marketed contact lens in use for the same modality. Randomization
and masking (subject, investigator and evaluator) shall be employed where possible to minimize the potential
for bias. Subjects shall be divided evenly between study investigators.
4.2.1.2.3 As an uncontrolled study. Here, results are compared to a historical control. Alternative
investigational study designs, such as historical controls, shall be utilized when a sponsor has a clinical database
on a marketed contact lens to use as a comparator. If any historical control is used, the control group shall be
defined and adequately characterized for comparison to the test group. Compatibility of test and control groups
shall be demonstrated by comparison of the selection criteria, demographics, refractive characteristics, contact
lens wearing history and CIPs used.
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ISO 11980:2012(E)
4.2.1.3 Contact lens care products
For investigations evaluating contact lens care products, a prospective concurrent control study design shall be
followed. It is recommended that the ratio of test to control subjects be either 2:1 or 1:1. The control care product
shall be a currently marketed contact lens care product. Randomization and masking (subject, investigator and
evaluator) shall be employed where possible to minimize the potential for bias. Subjects shall be divided evenly
between study investigators. Alternative investigational study designs, such as use of historical controls, may be
utilized when a manufacturer has a clinical database on a marketed care product to use for comparison. If any
historical control is used, the control group should be defined and adequately characterized for comparison to
the test group. Compatibility of test and control groups should be demonstrated by comparison of the selection
criteria and CIPs used.
For CIPs to demonstrate safety and performance, as well as special claims (e.g. comfort), labelling or additional
indications, the following is required for the care products: a pre-determined statistical analysis plan (including
sample size calculations) shall be specified in the clinical protocol. Where feasible, the protocol should define
objective endpoints to help support such claims.
NOTE 1 Inter-subject controls are preferred to intra-subject controls due to the potential dependence between the two
eyes and concerns regarding subject compliance.
In a contact lens care product investigation, a daily wear schedule shall be followed for most products in order
to maximize the subject’s exposure to those products. However, a study of a lens or a periodic cleaner, used
at weekly intervals, may provide more valuable clinical data concerning efficacy when extended wear subjects
are enrolled than a similar investigation with daily wear subjects.
When a daily wear schedule is used and safety is a primary objective, one post-dispensing visit should be done
1 h to 2 h after lens insertion in order to permit observation of corneal and conjunctival staining caused by an
immediate toxicity reaction.
A contact lens care product with a cleaning indication shall have an objective measure of lens cleanliness on
at least one lens collected from each subject at the end of the clinical study.
If the manufacturer of a contact lens care product wishes to recommend its use with a specific type of lens in
the labelling, the compatibility with the lens type should be confirmed pre-clinically and during the clinical trial.
If the CI has not collected any data on use with a particular type of lens material (such as silicone hydrogel
lenses), the product label should clearly state this fact.
NOTE 2 Annex A provides guidance for the design of a CI.
4.2.2 Variables
4.2.2.1 Contact lenses
The following variables should be considered during the CI for contact lenses, in addition to the variables
listed in 4.2.2.2:
a) visual performance;
b) refractive performance;
c) keratometric measurements;
d) lens centration;
e) lens movement;
f) lens surface wettability;
g) lens surface deposits;
h) subject acceptance of comfort;
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ISO 11980:2012(E)
i) subject acceptance of vision;
j) subject acceptance of handling.
Additional variables can be studied in the CI to support specific claims.
NOTE Annex C provides guidance on classifications for each of these variables.
4.2.2.2 Contact lens care products
The following variables should be assessed during the CI for contact lens care products:
a) corneal oedema;
b) corneal infiltrates;
c) endothelial irregularity;
d) corneal vascularization;
e) corneal staining;
f) conjunctival observations;
g) palpebral conjunctival observations;
h) corneal ulcers;
i) corneal opacification;
j) hyphema;
k) hypopyon;
l) iritis;
m) corneal scarring.
Additional variables can be studied in the CI to support specific claims.
NOTE Annex B provides guidance on classifications for some of these variables.
4.3 Other considerations
Serious ophthalmic adverse events and all adverse device effects shall be reported using a special case report
form and forwarded to the sponsor as required. All other ophthalmic adverse events shall be reported using the
standard visit case report forms and shall be collected during monitoring.
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ISO 11980:2012(E)
Annex A
(informative)
Elements of a clinical investigation
A.1 General
The following are elements of a CIP which can assist in collecting data for the purpose of determining the
safety and performance of contact lenses and contact lens care products.
A.2 Study size and duration
A.2.1 Contact lens investigations
Table A.1 — Guide to the subject numbers (completed subjects) suggested for contact lens
clinical investigations (informative)
Subject number
Wearing modality completed per group Duration Material and design
at end of trial
Containing new or new ratio material
50 3 months
components; significant design changes
Daily wear
30 30 days All materials and designs
3 months or longer
Daily wear
50 if necessary to reach All materials and designs
orthokeratology
defined stability
Extended wear,
160 12 months All materials and designs
up to 7 days
Extended wear,
570 12 months All materials and designs
up to 30 days
Overnight wear
100 pre-market/
(may include 6 months All materials and designs
200 post-market
orthokeratology)
A.2.2 Contact lens care product investigations
A.2.2.1 Contact lens care products, including saline solutions, daily cleaners, periodic cleaners, disinfecting
solutions, neutralizers, “in-eye” solutions, conditioning solutions, and multipurpose solutions that have any new
active ingredient, or any active ingredient outside the concentration range used in a comparable marketed
product, should undergo a 3 month clinical study.
A.2.2.2 Products for use with soft (hydrophilic) lenses: sample size (completed) should be 30 subjects in the
test solution and 15 subjects in the control solution (a currently marketed solution for the same indication) for
each appropriate representative category such as:
— Group I;
— Group IV;
— A separate group for each silicone hydrogel lens. If more than one lens is made by a given manufacturer,
and they all have the same general chemistry, it is sufficient to use only the lens of highest water content.
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ISO 11980:2012(E)
A.2.2.3 Products for use with rigid lenses: sample size (completed) should be 15 or 30 subjects using the test
solution and 15 subjects using the control solution (a currently marketed solution for the same indication) for
each appropriate material group.
A.2.2.4 For a contact lens solution that does not contain any new active ingredients (as described in A.2.2.1),
but contains any active ingredient lower than the concentration range used in a comparable marketed product,
a 1 month clinical study should be conducted. In this case, the sample size should be about half of that
recommended in A.2.2.2 and A.2.2.3, using the same general distribution of subjects.
A.2.3 Statistical considerations for extended wear evaluations
A.2.3.1 General
Primary safety analysis: the key safety endpoint should be the frequency of serious and significant adverse events.
The null hypothesis, H , is that the test rate of endpoint adverse events, p , minus the control rate of endpoint
0 t
adverse events, p , is greater than or equal to the clinically insignificant difference, δ, between the two rates.
c
The alternative hypothesis, H , is that the test rate of endpoint adverse events, p , minus the control rate of
a t
endpoint adverse events, p , is less than a clinically insignificant difference, δ, between the two rates.
c
H : p − p ≥ δ
0 t c
H : p − p < δ
a t c
where
p is the proportion in the test population;
t
p is the proportion in the control population.
c
When using a 1:1 ratio of patient allocation between treatment and control, the minimum number, n, of completed
patients necessary for each treatment group is determined by:
2
()ZZ+×[(pp11−+)(pp− )]
11−−βα tt cc
n =
2
δ
where
α
is the significance level (also known as the type 1 error rate);
1 − β is the power of the test;
Z
is the standard normal quantile.
The following is an example of the calculation that makes assumptions found to be reasonable for clinical
studies of 7 day extended wear hydrogel or silicone hydrogel contact lenses. With a control rate, p , and a
c
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ISO 11980:2012(E)
test rate, p , of 0,033 (under H ), a clinically insignificant difference, δ, of 0,05, a power, 1 − β, of 0,80, and a
t a
significance level, α, of 0,05, the minimum number of completed patients per treatment group is:
2
(,0841+×,)64 [,0 033×−(,10 033),+×0 033 (,10− 033)]
n = ≈158
2
00, 5
This equation is only valid when it is assumed for the alternative hypothesis, H , that the test rate of adverse
a
events is equal to the control rate, p = p . When this is not a valid assumption, the following equation can be
t c
used to provide an approximate calculation for the sample size:
2
()ZZ+×[(pp11−+)(pp− )]
11−−βα tt cc
n =
2
()pp−−δ
tc
For clinical studies of 30 day extended wear hydrogel contact lenses, it is recommended that a 7 day extended
wear lens (worn for up to 6 nights/7 days) be used as the control. The following is an example of the calculation
that makes assumptions found to be reasonable for many clinical studies of 30 day extended wear hydrogel
contact lenses. With a control rate, p , of 0,033 and a test rate, p , of 0,053 (under H ), a clinically insignificant
c t a
difference, δ, of 0,05, a power, 1 − β, of 0,80, and a significance level, α, of 0,05, the minimum number of
completed subjects per treatment group is:
2
(,0841+×,)64 [,0 053×−(,10 053),+×0 033 (,10− 033)]
n = ≈ 562
2
(,0 053−00, 333−00,)5
Enrolment should be adjusted to compensate for drop-out which is typically 20 % to 25 % in 1 year contact
lens studies. Therefore, for the above example of a clinical study of a 7 day extended wear contact lens, the
recommended sample size would be adjusted to approximately 215 per subject group. For the above example
of a study of a 30 day extended wear lens, the recommended sample size would be approximately 760 per
subject group.
At the conclusion of the study, sensitivity analyses (e.g. multiple imputation analyses) should be conducted to
evaluate the robustness of the study result accounting for missing observations, if there is more than minimal
subject drop-out.
A.2.3.2 Daily wear hydrogel, silicone hydrogel or rigid gas-permeable contact lens evaluations
Sample sizes are designed to give reasonable assurance of obtaining at least one complication, as a function
of the expected complication rate (i.e. 5 % for a 60 subject test group, 10 % with a 30 subject test group),
with a probability of greater than 95 %. Therefore, in a subject group of 30 (completed) subjects exposed to
a short-term duration (90 days) of a test product, an adverse event occurrence in two to three subjects may
cause concern as to the biocompatibility and fundamental safety of the device being tested. Any investigation
resulting in more than one adverse reaction should include adequate justification in order to establish safety
and efficacy.
A.2.3.3 Contact lens care product evaluations
Clinical sample sizes are designed so that there is 95 % confidence that a study has at least one complication
in a material category, if the true complication rate is ≥ 10 %. This implies that a study should have at least
30 (completed) subjects exposed to a short-term duration (90 days) of a test care product, for each material
grouping. Studies should include all material groupings of interest for the product.
Any investigation resulting in more than one adverse reaction should include adequate justification in order to
establish safety and efficacy.
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ISO 11980:2012(E)
A.2.4 Adverse events and adverse device effects
A.2.4.1 General
Adverse events should be differentiated into device related and non-device related. Any corneal infiltrate, ulcer,
neovascularization, etc. shall be presumed to be device related unless the case history clearly indicates some
other origin. All corneal ulcers shall be recorded in the study report.
A.2.4.2 Serious adverse events
Serious adverse events are those events that result in, or have potential to cause, either permanent impairment
of an ocular function or damage to an ocular structure, and may necessitate medical or surgical intervention.
Serious adverse events may include any hazardous, sight-threatening conditions occurring after exposure to
test article, including but not limited to the following.
a) A presumed infectious ulcer (defined as a progressive erosion of the corneal tissue). Signs may include
irregular focal infiltrates (> 1 mm); active lesions with raised edges; significant diffuse infiltration; anterior
corneal to mid-stromal involvement; erosion with overlying staining; conjunctival and lid oedema; anterior
chamber reaction (iritis); severe bulbar and limbal redness. Symptoms associated with a presumed
infectious ulcer (microbial keratitis) may include pain of rapid onset; severe redness; purulent or muco-
purulent discharge; tearing; photophobia. For the purposes of reporting, a corneal ulcer which has any of
the following characteristics should be considered in this category:
1) central or paracentral location;
2) penetration of Bowman’s membrane;
3) infiltrate > 2 mm diameter;
4) associated with iritis ≥ grade 2;
5) associated with any increase in intraocular pressure;
6) culture positive for microorganisms;
7) increasing size or severity at subsequent visits.
b) Any central or paracentral corneal event (such as vascularization) that results in permanent opacification.
c) Any serious adverse ophthalmic events including hypopyon and hyphema.
d) Any neovascularization within the central 6 mm of the cornea.
e) The loss of two or more lines of visual acuity that fail to resolve.
f) All cases of iritis.
Significant but non-serious adverse events should include, but not be limited to:
— peripheral non-progressive non-infectious ulcers;
— all symptomatic corneal infiltrative events;
— all cases of corneal staining greater than or equal to grade 3;
— a temporary loss of two or more lines of best corrected visual acuity (for greater than or equal to 2 weeks);
— cases greater than or equal to grade 2 neovascularization;
— any ocular event that necessitates temporary lens discontinuation of greater than or equal to 2 weeks.
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ISO 11980:2012(E)
A.3 Reporting of results
Tables A.2 to A.12 give guidance for sample tables of results. Separate tables may be used for test and control
groups. Not all tables apply to studies for all product categories.
Table A.2 — Accountability by eyes enrolled in the study and distribution status
Number of eyes
Control eyes Trial eyes
Status
N N
C T
Enrolled dispensed
Completed N N
C T
Active lens wearers (visit completed)
dispensed N N
C T
1st follow-up N N
C T
2nd follow-up N N
C T
(list through nth follow-up)
Discontinued N N
C T
Lost to follow-up (no-show) N N
C T
Enrolled not dispensed N N
C T
Total enrolled N N
C T
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ISO 11980:2012(E)
Table A.3 — Tabulation of eyes by most recent lens-wearing experience and demographics
Eyes
Total
Hydrogel Silicone
Rigid lens Other Subtotal
lens hydrogel lens
Previous experience unreported
No prior lens experience
New wearers
(less than 2 months’ wear)
Previous wearers: most recent
experience
Successful:
daily wear
extended wear
Unsuccessful:
daily wear
extended wear
Total lens wearers
Total enrolled
Demographics
Age of patients: From to Average:
Sex: Female: Male: Ratio:
Lens power range: + D
(maxima)
− D
Cylinder D
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ISO 11980:2012(E)
Table A.4 — Adverse events
Non-device related
Time in
Date first
Adverse investigation Date of Subject
seen by Intervention Severity Outcome
event (from resolution discontinued?
investigator
dispensing)
1
2
3
4
etc.
Total number of non-device-related adverse events:
Device related
Time in
Adverse Date first
investigation Date of Subject
device event seen by Intervention Severity Outcome
(from resolution discontinued?
(ADE) investigator
dispensing)
1
2
3
4
etc.
Total eyes with adverse device events requiring treatment:
Table A.5 — Slit lamp findings (example: epithelial oedema) by visit,
tabulated by eyes and incidence rate
Initial Un-
dispensing Intermediate visits scheduled Final visit
visit visits
Epithelial oedema
1 2 3 4
No. % No. % No. % No. % No. % No. % No. %
0 = none
1 = trace
2 = mild
3 = moderate
4 = severe
Total eyes
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ISO 11980:2012(E)
Table A.6 — Symptoms, problems, and complaints (example: comfort) by visit,
tabulated by eyes and incidence rate
Initial Un-
Overall
dispensing Intermediate visits scheduled Final visit
total
visit visits
Total eyes at visit
1 2 3 4
No. % No. % No. % No. % No. % No. % No. % No. %
Comfort
0 = excellent, cannot be felt
1 = very comfortable, just felt
occasionally
2 = comfortable, noticeable but
not irritating
3
...
FINAL
INTERNATIONAL ISO/FDIS
DRAFT
STANDARD 11980
ISO/TC 172/SC 7
Ophthalmic optics — Contact lenses and
Secretariat: DIN
contact lens care products — Guidance
Voting begins on:
for clinical investigations
2012-07-26
Voting terminates on:
Optique ophtalmique — Lentilles de contact et produits d’entretien pour
2012-09-26
lentilles de contact — Directives pour les investigations cliniques
Please see the administrative notes on page iii
RECIPIENTS OF THIS DRAFT ARE INVITED TO
SUBMIT, WITH THEIR COMMENTS, NOTIFICATION
OF ANY RELEVANT PATENT RIGHTS OF WHICH
THEY ARE AWARE AND TO PROVIDE SUPPOR
TING DOCUMENTATION.
IN ADDITION TO THEIR EVALUATION AS
Reference number
BEING ACCEPTABLE FOR INDUSTRIAL, TECHNO
ISO/FDIS 11980:2012(E)
LOGICAL, COMMERCIAL AND USER PURPOSES,
DRAFT INTERNATIONAL STANDARDS MAY ON
OCCASION HAVE TO BE CONSIDERED IN THE
LIGHT OF THEIR POTENTIAL TO BECOME STAN
DARDS TO WHICH REFERENCE MAY BE MADE IN
©
NATIONAL REGULATIONS. ISO 2012
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ISO/FDIS 11980:2012(E)
Copyright notice
This ISO document is a Draft International Standard and is copyrightprotected by ISO. Except as permitted
under the applicable laws of the user’s country, neither this ISO draft nor any extract from it may be reproduced,
stored in a retrieval system or transmitted in any form or by any means, electronic, photocopying, recording
or otherwise, without prior written permission being secured.
Requests for permission to reproduce should be addressed to either ISO at the address below or ISO’s
member body in the country of the requester.
ISO copyright office
Case postale 56 • CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
Email copyright@iso.org
Web www.iso.org
Reproduction may be subject to royalty payments or a licensing agreement.
Violators may be prosecuted.
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ISO/FDIS 11980:2012(E)
ISO/CEN PARALLEL PROCESSING
This Minor Revision has been developed within the International Organization for Standardization (ISO),
and processed under the ISO-lead mode of collaboration as defined in the Vienna Agreement.
This final draft is hereby submitted to a parallel two-month approval vote in ISO and three-month UAP vote
in CEN.
Positive votes shall not be accompanied by comments.
Negative votes shall be accompanied by the relevant technical reasons.
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ISO/FDIS 11980:2012(E)
Contents Page
Foreword . v
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Clinical investigational requirements . 1
4.1 General . 1
4.2 Additional requirements . 1
4.3 Other considerations . 4
Annex A (informative) Elements of a clinical investigation . 5
Annex B (informative) Procedures for the evaluation of safety, physiological performance and effect on
ocular tissues .18
Annex C (informative) The evaluation of visual, refractive and lens performance and
subject acceptance .23
Bibliography .26
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ISO/FDIS 11980:2012(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
nongovernmental, 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.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
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.
ISO 11980 was prepared by Technical Committee ISO/TC 172, Optics and photonics, Subcommittee SC 7,
Ophthalmic optics and instruments.
This third edition cancels and replaces the second edition (ISO 11980:2009), which has undergone minor
revision in order to update the normative reference to ISO 14155 and to revise 4.2.1.1 b) and the fifth row of
Table A.1 (overnight wear).
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ISO/FDIS 11980:2012(E)
Introduction
Currently, contact lenses and contact lens care products are regulated in different ways in different countries.
This International Standard has been developed to encourage global harmonization. Widespread adoption
of this International Standard should represent yet another step toward mutual recognition. This International
[1]
Standard can also be used as a basis to fulfil design elements of ISO 9001 .
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FINAL DRAFT INTERNATIONAL STANDARD ISO/FDIS 11980:2012(E)
Ophthalmic optics — Contact lenses and contact lens care
products — Guidance for clinical investigations
1 Scope
This International Standard gives guidelines for the clinical investigation (CI) of the safety and performance of
contact lenses and contact lens care products.
NOTE This International Standard attempts to harmonize the recognized regulatory requirements for the conduct of
a CI to meet the marketing and labelling requirements for contact lenses and contact lens care products around the world.
However, national requirements vary greatly. Wherever national practice or regulations dictate some legal requirement,
this requirement takes precedence over this International Standard.
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced document
(including any amendments) applies.
ISO 14155, Clinical investigation of medical devices for human subjects — Good clinical practice
ISO 14534, Ophthalmic optics — Contact lenses and contact lens care products — Fundamental requirements
ISO 183691, Ophthalmic optics — Contact lenses — Part 1: Vocabulary, classification system and
recommendations for labelling specifications
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 14155, ISO 14534 and ISO 183691 apply.
4 Clinical investigational requirements
4.1 General
The general requirements for a CI and for a clinical investigation plan (CIP) given in ISO 14155 shall apply, with
additional requirements given below.
4.2 Additional requirements
4.2.1 Study design
4.2.1.1 General
a) The inclusion criteria for subject selection shall relate to the study objectives and should include:
1) subjects with normal eyes who are not using any ocular medications, aged 18 years or over [except
when contact lens investigations have a special indication for use in “children” (for the purposes of
this International Standard, persons less than 18 years of age) such as orthokeratology and paediatric
aphakic lenses];
2) lens powers within the range available for the test lenses;
3) the manifest cylinder less than or equal to 0,75 D (for a study with only spherical power correcting lenses);
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ISO/FDIS 11980:2012(E)
4) best spectacle corrected visual acuity greater than or equal to 20/25 (less than or equal to LogMAR 0,1).
b) The exclusion criteria for subject selection shall relate to the study objectives and should include, but not
be limited to:
1) anterior segment infection, inflammation or abnormality;
2) any active anterior segment ocular disease that would contraindicate contact lens wear;
3) the use of systemic or ocular medications that would contraindicate contact lens wear;
4) history of herpetic keratitis;
5) history of refractive surgery or irregular cornea (except when the contact lenses under investigation
are indicated for irregular cornea, keratoconus or refractive surgery);
6) slit lamp findings that are more serious than grade 1;
7) corneal vascularization greater than 1 mm of penetration;
8) a pathologically dry eye;
9) participation of the subject in a contact lens or contact lens care product clinical trial within the
previous 30 days.
c) The CIP shall provide a description of the monitoring procedure to ensure consistent quality of data
collection and recording.
d) The CIP shall include a statistical analysis plan. Sample size shall be justified, calculated by a validated
statistical software package.
4.2.1.2 Contact lenses
4.2.1.2.1 General. A CI of contact lenses, including daily wear and extended wear hydrogel, silicone hydrogel,
and rigid gaspermeable contact lenses, shall be designed as one of 4.2.1.2.2 or 4.2.1.2.3.
For CIPs to demonstrate safety and performance, as well as special claims (e.g. comfort), labelling or
additional indications, the following is required: a predetermined statistical analysis plan (including sample
size calculations) shall be specified in the clinical protocol. Where feasible, the CIP shall define objective
endpoints to help support such claims.
NOTE 1 Intersubject controls are preferred to intrasubject controls due to the potential dependence between the two
eyes and concerns regarding subject compliance.
NOTE 2 Annex A provides guidance for the design of a CI.
4.2.1.2.2 As a prospective, concurrently controlled study. For investigations evaluating hydrogel, silicone
hydrogel or rigid gaspermeable contact lenses, a prospective, concurrent control study design shall be followed.
Either a bilateral crossover design or a contralateral eye (i.e. intrasubject) design or intersubject controls shall
be utilized. If intersubject controls are utilized, the ratio of test subjects to control subjects may be either 2:1 or
1:1. The control lens shall be a currently marketed contact lens in use for the same modality. Randomization
and masking (subject, investigator and evaluator) shall be employed where possible to minimize the potential
for bias. Subjects shall be divided evenly between study investigators.
4.2.1.2.3 As an uncontrolled study. Here, results are compared to a historical control. Alternative
investigational study designs, such as historical controls, shall be utilized when a sponsor has a clinical database
on a marketed contact lens to use as a comparator. If any historical control is used, the control group shall be
defined and adequately characterized for comparison to the test group. Compatibility of test and control groups
shall be demonstrated by comparison of the selection criteria, demographics, refractive characteristics, contact
lens wearing history and CIPs used.
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ISO/FDIS 11980:2012(E)
4.2.1.3 Contact lens care products
For investigations evaluating contact lens care products, a prospective concurrent control study design shall be
followed. It is recommended that the ratio of test to control subjects be either 2:1 or 1:1. The control care product
shall be a currently marketed contact lens care product. Randomization and masking (subject, investigator and
evaluator) shall be employed where possible to minimize the potential for bias. Subjects shall be divided evenly
between study investigators. Alternative investigational study designs, such as use of historical controls, may be
utilized when a manufacturer has a clinical database on a marketed care product to use for comparison. If any
historical control is used, the control group should be defined and adequately characterized for comparison to
the test group. Compatibility of test and control groups should be demonstrated by comparison of the selection
criteria and CIPs used.
For CIPs to demonstrate safety and performance, as well as special claims (e.g. comfort), labelling or additional
indications, the following is required for the care products: a predetermined statistical analysis plan (including
sample size calculations) shall be specified in the clinical protocol. Where feasible, the protocol should define
objective endpoints to help support such claims.
NOTE 1 Intersubject controls are preferred to intrasubject controls due to the potential dependence between the two
eyes and concerns regarding subject compliance.
In a contact lens care product investigation, a daily wear schedule shall be followed for most products in order
to maximize the subject’s exposure to those products. However, a study of a lens or a periodic cleaner, used
at weekly intervals, may provide more valuable clinical data concerning efficacy when extended wear subjects
are enrolled than a similar investigation with daily wear subjects.
When a daily wear schedule is used and safety is a primary objective, one postdispensing visit should be done
1 h to 2 h after lens insertion in order to permit observation of corneal and conjunctival staining caused by an
immediate toxicity reaction.
A contact lens care product with a cleaning indication shall have an objective measure of lens cleanliness on
at least one lens collected from each subject at the end of the clinical study.
If the manufacturer of a contact lens care product wishes to recommend its use with a specific type of lens in
the labelling, the compatibility with the lens type should be confirmed pre-clinically and during the clinical trial.
If the CI has not collected any data on use with a particular type of lens material (such as silicone hydrogel
lenses), the product label should clearly state this fact.
NOTE 2 Annex A provides guidance for the design of a CI.
4.2.2 Variables
4.2.2.1 Contact lenses
The following variables should be considered during the CI for contact lenses, in addition to the variables
listed in 4.2.2.2:
a) visual performance;
b) refractive performance;
c) keratometric measurements;
d) lens centration;
e) lens movement;
f) lens surface wettability;
g) lens surface deposits;
h) subject acceptance of comfort;
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ISO/FDIS 11980:2012(E)
i) subject acceptance of vision;
j) subject acceptance of handling.
Additional variables can be studied in the CI to support specific claims.
NOTE Annex C provides guidance on classifications for each of these variables.
4.2.2.2 Contact lens care products
The following variables should be assessed during the CI for contact lens care products:
a) corneal oedema;
b) corneal infiltrates;
c) endothelial irregularity;
d) corneal vascularization;
e) corneal staining;
f) conjunctival observations;
g) palpebral conjunctival observations;
h) corneal ulcers;
i) corneal opacification;
j) hyphema;
k) hypopyon;
l) iritis;
m) corneal scarring.
Additional variables can be studied in the CI to support specific claims.
NOTE Annex B provides guidance on classifications for some of these variables.
4.3 Other considerations
Serious ophthalmic adverse events and all adverse device effects shall be reported using a special case report
form and forwarded to the sponsor as required. All other ophthalmic adverse events shall be reported using the
standard visit case report forms and shall be collected during monitoring.
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ISO/FDIS 11980:2012(E)
Annex A
(informative)
Elements of a clinical investigation
A.1 General
The following are elements of a CIP which can assist in collecting data for the purpose of determining the
safety and performance of contact lenses and contact lens care products.
A.2 Study size and duration
A.2.1 Contact lens investigations
Table A.1 — Guide to the subject numbers (completed subjects) suggested for contact lens
clinical investigations (informative)
Subject number
Wearing modality completed per group Duration Material and design
at end of trial
Containing new or new ratio material
50 3 months
components; significant design changes
Daily wear
30 30 days All materials and designs
3 months or longer
Daily wear
50 if necessary to reach All materials and designs
orthokeratology
defined stability
Extended wear,
160 12 months All materials and designs
up to 7 days
Extended wear,
570 12 months All materials and designs
up to 30 days
Overnight wear
100 premarket/
(may include 6 months All materials and designs
200 postmarket
orthokeratology)
A.2.2 Contact lens care product investigations
A.2.2.1 Contact lens care products, including saline solutions, daily cleaners, periodic cleaners, disinfecting
solutions, neutralizers, “ineye” solutions, conditioning solutions, and multipurpose solutions that have any new
active ingredient, or any active ingredient outside the concentration range used in a comparable marketed
product, should undergo a 3 month clinical study.
A.2.2.2 Products for use with soft (hydrophilic) lenses: sample size (completed) should be 30 subjects in the
test solution and 15 subjects in the control solution (a currently marketed solution for the same indication) for
each appropriate representative category such as:
— Group I;
— Group IV;
— A separate group for each silicone hydrogel lens. If more than one lens is made by a given manufacturer,
and they all have the same general chemistry, it is sufficient to use only the lens of highest water content.
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ISO/FDIS 11980:2012(E)
A.2.2.3 Products for use with rigid lenses: sample size (completed) should be 15 or 30 subjects using the test
solution and 15 subjects using the control solution (a currently marketed solution for the same indication) for
each appropriate material group.
A.2.2.4 For a contact lens solution that does not contain any new active ingredients (as described in A.2.2.1),
but contains any active ingredient lower than the concentration range used in a comparable marketed product,
a 1 month clinical study should be conducted. In this case, the sample size should be about half of that
recommended in A.2.2.2 and A.2.2.3, using the same general distribution of subjects.
A.2.3 Statistical considerations for extended wear evaluations
A.2.3.1 General
Primary safety analysis: the key safety endpoint should be the frequency of serious and significant adverse events.
The null hypothesis, H , is that the test rate of endpoint adverse events, p , minus the control rate of endpoint
0 t
adverse events, p , is greater than or equal to the clinically insignificant difference, δ, between the two rates.
c
The alternative hypothesis, H , is that the test rate of endpoint adverse events, p , minus the control rate of
a t
endpoint adverse events, p , is less than a clinically insignificant difference, δ, between the two rates.
c
H : p − p ≥ δ
0 t c
H : p − p < δ
a t c
where
p is the proportion in the test population;
t
p is the proportion in the control population.
c
When using a 1:1 ratio of patient allocation between treatment and control, the minimum number, n, of completed
patients necessary for each treatment group is determined by:
2
()ZZ+×[(pp11−+)(pp− )]
11−−βα tt cc
n =
2
δ
where
α
is the significance level (also known as the type 1 error rate);
1 − β is the power of the test;
Z
is the standard normal quantile.
The following is an example of the calculation that makes assumptions found to be reasonable for clinical
studies of 7 day extended wear hydrogel or silicone hydrogel contact lenses. With a control rate, p , and a
c
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ISO/FDIS 11980:2012(E)
test rate, p , of 0,033 (under H ), a clinically insignificant difference, δ, of 0,05, a power, 1 − β, of 0,80, and a
t a
significance level, α, of 0,05, the minimum number of completed patients per treatment group is:
2
(,0841+×,)64 [,0 033×−(,10 033),+×0 033 (,10− 033)]
n = ≈158
2
00, 5
This equation is only valid when it is assumed for the alternative hypothesis, H , that the test rate of adverse
a
events is equal to the control rate, p = p . When this is not a valid assumption, the following equation can be
t c
used to provide an approximate calculation for the sample size:
2
()ZZ+×[(pp11−+)(pp− )]
11−−βα tt cc
n =
2
()pp−−δ
tc
For clinical studies of 30 day extended wear hydrogel contact lenses, it is recommended that a 7 day extended
wear lens (worn for up to 6 nights/7 days) be used as the control. The following is an example of the calculation
that makes assumptions found to be reasonable for many clinical studies of 30 day extended wear hydrogel
contact lenses. With a control rate, p , of 0,033 and a test rate, p , of 0,053 (under H ), a clinically insignificant
c t a
difference, δ, of 0,05, a power, 1 − β, of 0,80, and a significance level, α, of 0,05, the minimum number of
completed subjects per treatment group is:
2
(,0841+×,)64 [,0 053×−(,10 053),+×0 033 (,10− 033)]
n = ≈ 562
2
(,0 053−00, 333−00,)5
Enrolment should be adjusted to compensate for dropout which is typically 20 % to 25 % in 1 year contact
lens studies. Therefore, for the above example of a clinical study of a 7 day extended wear contact lens, the
recommended sample size would be adjusted to approximately 215 per subject group. For the above example
of a study of a 30 day extended wear lens, the recommended sample size would be approximately 760 per
subject group.
At the conclusion of the study, sensitivity analyses (e.g. multiple imputation analyses) should be conducted to
evaluate the robustness of the study result accounting for missing observations, if there is more than minimal
subject dropout.
A.2.3.2 Daily wear hydrogel, silicone hydrogel or rigid gas-permeable contact lens evaluations
Sample sizes are designed to give reasonable assurance of obtaining at least one complication, as a function
of the expected complication rate (i.e. 5 % for a 60 subject test group, 10 % with a 30 subject test group),
with a probability of greater than 95 %. Therefore, in a subject group of 30 (completed) subjects exposed to
a shortterm duration (90 days) of a test product, an adverse event occurrence in two to three subjects may
cause concern as to the biocompatibility and fundamental safety of the device being tested. Any investigation
resulting in more than one adverse reaction should include adequate justification in order to establish safety
and efficacy.
A.2.3.3 Contact lens care product evaluations
Clinical sample sizes are designed so that there is 95 % confidence that a study has at least one complication
in a material category, if the true complication rate is ≥ 10 %. This implies that a study should have at least
30 (completed) subjects exposed to a shortterm duration (90 days) of a test care product, for each material
grouping. Studies should include all material groupings of interest for the product.
Any investigation resulting in more than one adverse reaction should include adequate justification in order to
establish safety and efficacy.
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ISO/FDIS 11980:2012(E)
A.2.4 Adverse events and adverse device effects
A.2.4.1 General
Adverse events should be differentiated into device related and non-device related. Any corneal infiltrate, ulcer,
neovascularization, etc. shall be presumed to be device related unless the case history clearly indicates some
other origin. All corneal ulcers shall be recorded in the study report.
A.2.4.2 Serious adverse events
Serious adverse events are those events that result in, or have potential to cause, either permanent impairment
of an ocular function or damage to an ocular structure, and may necessitate medical or surgical intervention.
Serious adverse events may include any hazardous, sightthreatening conditions occurring after exposure to
test article, including but not limited to the following.
a) A presumed infectious ulcer (defined as a progressive erosion of the corneal tissue). Signs may include
irregular focal infiltrates (> 1 mm); active lesions with raised edges; significant diffuse infiltration; anterior
corneal to midstromal involvement; erosion with overlying staining; conjunctival and lid oedema; anterior
chamber reaction (iritis); severe bulbar and limbal redness. Symptoms associated with a presumed
infectious ulcer (microbial keratitis) may include pain of rapid onset; severe redness; purulent or muco
purulent discharge; tearing; photophobia. For the purposes of reporting, a corneal ulcer which has any of
the following characteristics should be considered in this category:
1) central or paracentral location;
2) penetration of Bowman’s membrane;
3) infiltrate > 2 mm diameter;
4) associated with iritis ≥ grade 2;
5) associated with any increase in intraocular pressure;
6) culture positive for microorganisms;
7) increasing size or severity at subsequent visits.
b) Any central or paracentral corneal event (such as vascularization) that results in permanent opacification.
c) Any serious adverse ophthalmic events including hypopyon and hyphema.
d) Any neovascularization within the central 6 mm of the cornea.
e) The loss of two or more lines of visual acuity that fail to resolve.
f) All cases of iritis.
Significant but non-serious adverse events should include, but not be limited to:
— peripheral nonprogressive noninfectious ulcers;
— all symptomatic corneal infiltrative events;
— all cases of corneal staining greater than or equal to grade 3;
— a temporary loss of two or more lines of best corrected visual acuity (for greater than or equal to 2 weeks);
— cases greater than or equal to grade 2 neovascularization;
— any ocular event that necessitates temporary lens discontinuation of greater than or equal to 2 weeks.
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ISO/FDIS 11980:2012(E)
A.3 Reporting of results
Tables A.2 to A.12 give guidance for sample tables of results. Separate tables may be used for test and control
groups. Not all tables apply to studies for all product categories.
Table A.2 — Accountability by eyes enrolled in the study and distribution status
Number of eyes
Control eyes Trial eyes
Status
N N
C T
Enrolled dispensed
Completed N N
C T
Active lens wearers (visit completed)
dispensed N N
C T
1st followup N N
C T
2nd followup N N
C T
(list through nth followup)
Discontinued N N
C T
Lost to followup (noshow) N N
C T
Enrolled not dispensed N N
C T
Total enrolled N N
C T
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ISO/FDIS 11980:2012(E)
Table A.3 — Tabulation of eyes by most recent lens-wearing experience and demographics
Eyes
Total
Hydrogel Silicone
Rigid lens Other Subtotal
lens hydrogel lens
Previous experience unreported
No prior lens experience
New wearers
(less than 2 months’ wear)
Previous wearers: most recent
experience
Successful:
daily wear
extended wear
Unsuccessful:
daily wear
extended wear
Total lens wearers
Total enrolled
Demographics
Age of patients: From to Average:
Sex: Female: Male: Ratio:
Lens power range: + D
(maxima)
− D
Cylinder D
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ISO/FDIS 11980:2012(E)
Table A.4 — Adverse events
Non-device related
Time
...
NORME ISO
INTERNATIONALE 11980
Troisième édition
2012-11-15
Optique ophtalmique — Lentilles de
contact et produits d’entretien pour
lentilles de contact — Directives pour
les investigations cliniques
Ophthalmic optics — Contact lenses and contact lens care products —
Guidance for clinical investigations
Numéro de référence
ISO 11980:2012(F)
©
ISO 2012
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ISO 11980:2012(F)
DOCUMENT PROTÉGÉ PAR COPYRIGHT
© ISO 2012
Droits de reproduction réservés. Sauf prescription différente, aucune partie de cette publication ne peut être reproduite ni utilisée sous
quelque forme que ce soit et par aucun procédé, électronique ou mécanique, y compris la photocopie et les microfilms, sans l’accord écrit
de l’ISO à l’adresse ci-après ou du comité membre de l’ISO dans le pays du demandeur.
ISO copyright office
Case postale 56 • CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Publié en Suisse
ii © ISO 2012 – Tous droits réservés
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ISO 11980:2012(F)
Sommaire Page
Avant-propos .iv
Introduction . v
1 Domaine d’application . 1
2 Références normatives . 1
3 Termes et définitions . 1
4 Exigences relatives à l’investigation clinique . 1
4.1 Généralités . 1
4.2 Exigences supplémentaires . 1
4.3 Autres éléments pris en considération . 5
Annexe A (informative) Éléments d’une investigation clinique . 6
Annexe B (informative) Modes opératoires d’évaluation de la sécurité, des performances
physiologiques et des effets sur les tissus oculaires .19
Annexe C (informative) Évaluation des performances visuelles et réfractives, de l’efficacité des lentilles
et de leur degré de tolérance chez le sujet .24
Bibliographie .27
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ISO 11980:2012(F)
Avant-propos
L’ISO (Organisation internationale de normalisation) est une fédération mondiale d’organismes nationaux de
normalisation (comités membres de l’ISO). L’élaboration des Normes internationales est en général confiée aux
comités techniques de l’ISO. Chaque comité membre intéressé par une étude a le droit de faire partie du comité
technique créé à cet effet. Les organisations internationales, gouvernementales et non gouvernementales,
en liaison avec l’ISO participent également aux travaux. L’ISO collabore étroitement avec la Commission
électrotechnique internationale (CEI) en ce qui concerne la normalisation électrotechnique.
Les Normes internationales sont rédigées conformément aux règles données dans les Directives ISO/CEI, Partie 2.
La tâche principale des comités techniques est d’élaborer les Normes internationales. Les projets de Normes
internationales adoptés par les comités techniques sont soumis aux comités membres pour vote. Leur publication
comme Normes internationales requiert l’approbation de 75 % au moins des comités membres votants.
L’attention est appelée sur le fait que certains des éléments du présent document peuvent faire l’objet de droits
de propriété intellectuelle ou de droits analogues. L’ISO ne saurait être tenue pour responsable de ne pas avoir
identifié de tels droits de propriété et averti de leur existence.
L’ISO 11980 a été élaborée par le comité technique ISO/TC 172, Optique et photonique, sous-comité SC 7,
Optique et instruments ophtalmiques.
Cette troisième édition annule et remplace la deuxième édition (ISO 11980:2009), qui a subi des modifications
e
mineures afin d’actualiser la référence normative ISO 14155, et de réviser 4.2.1.1 b) et la 5 rangée du
Tableau A.1, «Port nocturne».
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ISO 11980:2012(F)
Introduction
Actuellement, les lentilles de contact et les produits d’entretien pour lentilles de contact font l’objet de
réglementations différentes selon les pays. La présente Norme internationale a été élaborée pour encourager
une harmonisation globale. Il convient que l’adoption de la présente Norme internationale constitue une étape
supplémentaire vers une reconnaissance mutuelle. La présente Norme internationale peut également servir
[1]
de base pour satisfaire aux éléments de conception de l’ISO 9001 .
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NORME INTERNATIONALE ISO 11980:2012(F)
Optique ophtalmique — Lentilles de contact et produits
d’entretien pour lentilles de contact — Directives pour
les investigations cliniques
1 Domaine d’application
La présente Norme internationale donne des lignes directrices pour l’investigation clinique concernant la
sécurité et les performances des lentilles de contact et des produits d’entretien pour lentilles de contact.
NOTE La présente Norme internationale a pour objet d’harmoniser les exigences réglementaires reconnues pour
l’élaboration des données cliniques afin de répondre aux exigences de commercialisation et d’étiquetage des lentilles de
contact et des produits d’entretien pour lentilles de contact au niveau mondial. Cependant, les exigences nationales varient
considérablement. Partout où les pratiques ou réglementations nationales déterminent certaines exigences légales, ces
exigences priment sur la présente Norme internationale.
2 Références normatives
Les documents de référence suivants sont indispensables à l’application du présent document. Pour les
références datées, seule l’édition citée s’applique. Pour les références non datées, la dernière édition du
document de référence s’applique (y compris les éventuels amendements).
ISO 14155, Investigation clinique des dispositifs médicaux pour sujets humains — Bonnes pratiques cliniques
ISO 14534, Optique ophtalmique — Lentilles de contact et produits d’entretien des lentilles de contact —
Exigences fondamentales
ISO 18369-1, Optique ophtalmique — Lentilles de contact — Partie 1: Vocabulaire, système de classification
et recommandations pour l’étiquetage des spécifications
3 Termes et définitions
Pour les besoins du présent document, les termes et définitions donnés dans l’ISO 14155, l’ISO 14534 et
l’ISO 18369-1 s’appliquent.
4 Exigences relatives à l’investigation clinique
4.1 Généralités
Les exigences générales relatives à l’investigation clinique (IC) et au plan d’investigation clinique (PIC) données
dans l’ISO 14155 doivent s’appliquer, avec les exigences supplémentaires mentionnées ci-dessous.
4.2 Exigences supplémentaires
4.2.1 Conception de l’étude
4.2.1.1 Généralités
a) Les critères d’inclusion relatifs au choix des sujets doivent être liés aux objectifs de l’étude et il convient d’inclure:
1) les sujets aux yeux normaux ne faisant pas usage de traitement médical oculaire, âgés de 18 ans
ou plus [sauf lorsque les investigations cliniques de lentilles de contact indiquent spécifiquement que
l’optique ophtalmique et les produits associés peuvent être utilisés avec des sujets mineurs (donc,
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ISO 11980:2012(F)
pour les besoins de la présente Norme internationale, âgés de moins de 18 ans), par exemple dans le
cas de l’orthokératologie et des lentilles de correction de l’aphakie à usage pédiatrique];
2) les lentilles relevant de la gamme disponible pour les lentilles d’essai;
3) un cylindre de réfraction inférieur ou égal à 0,75 D (pour une étude avec uniquement des lentilles de
correction sphériques);
4) une meilleure acuité visuelle corrigée des lunettes supérieure ou égale à 20/25 (inférieure ou égale
à LogMAR 0,1).
b) Les critères d’exclusion relatifs au choix des sujets doivent être liés aux objectifs de l’étude et il convient
d’inclure sans toutefois s’y limiter:
1) toute infection, inflammation ou anormalité des segments antérieurs;
2) tout trouble oculaire évolutif des segments antérieurs pour lequel le port de lentilles de contact
serait déconseillé;
3) l’utilisation de produits de traitement systémique ou oculaire pour laquelle le port de lentilles de contact
serait déconseillé;
4) les antécédents de toute kératite herpétique;
5) les antécédents de toute chirurgie réfractive ou de toute cornée irrégulière (sauf dans les cas où les
lentilles de contact examinées peuvent être portées par un sujet ayant une cornée irrégulière, atteint
de kératocône ou ayant subi une opération de chirurgie réfractive);
6) des observations à la lampe à fente de gravité supérieure au grade 1;
7) une vascularisation de la cornée d’une pénétration supérieure à 1 mm;
8) les cas de sécheresse oculaire pathologique;
9) les cas où un sujet a participé à un test clinique sur des lentilles de contact ou des produits d’entretien
pour lentilles de contact au cours des 30 derniers jours.
c) Le plan d’investigation clinique (PIC) doit fournir une description de la procédure de surveillance qui permet
de garantir une cohérence de la qualité de collecte et d’enregistrement des données.
d) Le PIC doit comporter un plan d’analyse statistique. L’effectif de l’échantillon doit être justifié, calculé par
un logiciel de statistique validé.
4.2.1.2 Lentilles de contact
4.2.1.2.1 Généralités. Une investigation clinique des lentilles de contact, y compris les lentilles de contact à
port quotidien et les lentilles de contact en hydrogel, en silicone-hydrogel et rigides perméables au gaz à port
prolongé, doit revêtir l’une des formes décrites en 4.2.1.2.2 ou 4.2.1.2.3.
Un plan d’analyse statistique prédéterminé (comportant les calculs de l’effectif d’échantillon) doit être spécifié
dans le protocole clinique afin que le PIC puisse démontrer que la sécurité et les performances des lentilles,
ainsi que les revendications spéciales (par exemple confort), l’étiquetage ou des indications complémentaires
font l’objet de propositions. Le PIC doit définir, lorsque la pratique le permet, des résultats objectifs permettant
de satisfaire à ces revendications.
NOTE 1 Les témoins inter-sujets sont préférés aux témoins intra-sujets en raison de la dépendance éventuelle entre
les deux yeux et des préoccupations relatives à la conformité des témoins.
NOTE 2 L’Annexe A fournit des recommandations pour la conception d’une investigation clinique.
4.2.1.2.2 Étude prospective à contrôle simultané. Une étude prospective à contrôle simultané doit être
adoptée pour les investigations qui se proposent d’évaluer les lentilles de contact en hydrogel, en silicone-
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ISO 11980:2012(F)
hydrogel et rigides perméables au gaz. Une étude croisée bilatérale ou des témoins avec yeux controlatéraux
[c’est-à-dire que les sujets inclus dans l’étude sont aussi les témoins (témoins intra-sujets)], des témoins de
contrôle ou des témoins inter-sujets (c’est-à-dire que les témoins ne sont pas inclus dans l’étude) doivent être
utilisés. Si les témoins inter-sujets sont utilisés, le rapport sujets d’essai-sujets témoins peut être de 2:1 ou 1:1.
La lentille témoin doit être une lentille de contact, actuellement disponible dans le commerce, employée pour
la même modalité. Une répartition aléatoire et un masquage (sujet, examinateur et évaluateur) doivent être
appliqués dans toute la mesure du possible afin de réduire le risque d’erreur au minimum. Les sujets doivent
être répartis de manière égale entre les examinateurs de l’étude.
4.2.1.2.3 Étude non soumise à contrôle. Dans ce cas, les résultats sont comparés à un contrôle antérieur.
Des études d’investigation alternatives, telles que des contrôles d’antécédents, doivent être appliquées lorsqu’un
promoteur dispose d’une base de données clinique sur une lentille de contact commercialisée destinée à être
utilisée comme comparateur. Lorsqu’il est procédé à un contrôle antérieur, le groupe témoin doit être défini et
caractérisé de manière appropriée afin d’être comparé au groupe expérimental. La compatibilité des groupes
expérimentaux et des groupes témoins doit être démontrée par une comparaison des critères de sélection, des
données démographiques, des caractéristiques de réfraction, des antécédents de port des lentilles de contact
et des PIC utilisés.
4.2.1.3 Produits d’entretien pour lentilles de contact
Une étude prospective à contrôle simultané doit être adoptée pour les investigations qui se proposent d’évaluer
les produits d’entretien pour lentilles de contact. Il est recommandé que le rapport sujets d’essai-sujets témoins
soit égal à 2:1 ou 1:1. Le produit d’entretien témoin doit être un produit d’entretien pour lentilles de contact
actuellement disponible dans le commerce. Une répartition aléatoire et un masquage (sujet, examinateur et
évaluateur) doivent être appliqués dans toute la mesure du possible afin de réduire le risque d’erreur au
minimum. Les sujets doivent être répartis de manière égale entre les examinateurs de l’étude. Des études
d’investigation alternatives, telles que des contrôles antérieurs, peuvent être appliquées lorsqu’un fabricant
dispose d’une base de données clinique sur un produit d’entretien commercialisé destiné à être utilisé à des
fins de comparaison. Lorsqu’il est procédé à un contrôle antérieur, il convient de définir le groupe témoin et de
le caractériser de manière appropriée afin d’être comparé au groupe expérimental. Il convient de démontrer
la compatibilité des groupes expérimentaux et des groupes témoins par une comparaison des critères de
sélection et des PIC utilisés.
Un plan d’analyse statistique prédéterminé (comportant les calculs de l’effectif d’échantillon) doit être spécifié
dans le protocole clinique afin que le PIC puisse démontrer que la sécurité et les performances des produits
d’entretien, ainsi que les revendications spéciales (par exemple confort), l’étiquetage ou des indications
complémentaires font l’objet de propositions pour les produits d’entretien. Il convient que le protocole définisse,
lorsque la pratique le permet, des résultats objectifs permettant de satisfaire à ces revendications.
NOTE 1 Il est préférable d’utiliser des témoins inter-sujets plutôt que des témoins intra-sujets en raison de la dépendance
potentielle entre les deux yeux et des préoccupations relatives à la conformité des sujets.
Dans le cas d’une investigation portant sur un produit d’entretien pour lentilles de contact, un calendrier de port
quotidien doit être respecté pour la plupart des produits, afin que la durée d’exposition du sujet à ces produits
soit maximale. Toutefois, l’étude d’une lentille ou d’un produit de nettoyage périodique, utilisés à intervalles
hebdomadaires, peut fournir des données cliniques plus valables concernant l’efficacité de l’objet, lorsque des
sujets soumis à un port prolongé sont concernés, qu’une investigation similaire avec des sujets soumis à un
port quotidien.
Lorsqu’un calendrier de port quotidien est appliqué, et que la sécurité est un objectif primaire, il convient
d’effectuer une visite après mise à disposition du produit dans un délai de une à deux heures après l’insertion
des lentilles afin de pouvoir observer la coloration de la cornée ou de la conjonctive suite à une réaction de
toxicité immédiate.
Un produit d’entretien pour lentilles de contact comportant une indication de nettoyage doit faire l’objet d’une
mesure objective de la propreté sur au moins une des lentilles de chaque sujet à la fin de l’étude clinique.
Si le fabricant d’un produit d’entretien pour lentilles de contact souhaite recommander, dans l’étiquetage,
son utilisation avec un type de lentille spécifique, il convient de confirmer la compatibilité du type de lentille
préalablement et au cours de l’essai clinique.
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ISO 11980:2012(F)
Si l’investigation clinique n’a pas permis de recueillir des données concernant l’utilisation du produit avec un
type particulier de lentille (par exemple lentilles en silicone-hydrogel), il convient que l’étiquette du produit
l’indique clairement.
NOTE 2 L’Annexe A fournit des recommandations pour la conception d’une investigation clinique.
4.2.2 Variables
4.2.2.1 Lentilles de contact
Il convient de considérer les variables suivantes lors de l’investigation clinique relative aux lentilles de contact,
outre les variables énumérées en 4.2.2.2:
a) performances visuelles;
b) performances réfractives;
c) kératométrie;
d) centrage des lentilles;
e) mobilité des lentilles;
f) mouillabilité de la surface antérieure des lentilles;
g) dépôts sur la surface postérieure;
h) appréciation du confort par le sujet;
i) agrément de la vision par le sujet;
j) agrément de la manipulation par le sujet.
Des variables supplémentaires peuvent être étudiées dans l’investigation clinique afin de satisfaire à des
revendications spécifiques.
NOTE L’Annexe C fournit des recommandations concernant les classifications de chacune de ces variables.
4.2.2.2 Produits d’entretien pour lentilles de contact
Il convient d’évaluer les variables suivantes lors de l’investigation clinique relative aux produits d’entretien pour
lentilles de contact:
a) œdème de la cornée;
b) infiltrats cornéens;
c) irrégularité endothéliale;
d) vascularisation de la cornée;
e) piquetés de la cornée;
f) observations conjonctivales;
g) observations de la conjonctive palpébrale;
h) ulcères de la cornée;
i) opacification de la cornée;
j) hyphéma;
k) hypopion;
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ISO 11980:2012(F)
l) iritis;
m) cicatrices de la cornée.
Des variables supplémentaires peuvent être étudiées dans l’investigation clinique afin de satisfaire à des
revendications spécifiques.
NOTE L’Annexe B fournit des recommandations concernant les classifications de certaines de ces variables.
4.3 Autres éléments pris en considération
Les événements ophtalmiques indésirables sévères et tous les effets indésirables du dispositif doivent être
consignés dans une fiche d’observations spéciale et transmis au promoteur si nécessaire. Tous les autres
événements ophtalmiques indésirables doivent être consignés dans les fiches d’observations de visite types
et doivent être recueillis au cours de la surveillance.
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ISO 11980:2012(F)
Annexe A
(informative)
Éléments d’une investigation clinique
A.1 Généralités
Les éléments décrits ci-dessous sont les éléments constitutifs d’un plan d’investigation clinique qui peut être
utilisé pour recueillir les données permettant de déterminer la sécurité et les performances des lentilles de
contact et des produits d’entretien pour lentilles de contact.
A.2 Effectif et durée de l’étude
A.2.1 Investigations portant sur les lentilles de contact
Tableau A.1 — Guide concernant le nombre de sujets (sujets sur lesquels l’étude a été réalisée) pour
les investigations cliniques portant sur les lentilles de contact (informatif)
Nombre total de sujets par
Modalité de port Durée Matériau et géométrie
groupe à la fin de l’étude
Comportant de nouveaux composants
ou de nouvelles proportions des
50 3 mois
composants ou des modifications
Port quotidien
importantes de géométrie
Tous les matériaux/toutes les
30 30 jours
géométries
3 mois ou plus si
Port quotidien nécessaire pour Tous les matériaux/toutes les
50
orthokératologie atteindre une stabilité géométries
définie
Port prolongé, Tous les matériaux/toutes les
160 12 mois
jusqu’à 7 jours géométries
Port prolongé, Tous les matériaux/toutes les
570 12 mois
jusqu’à 30 jours géométries
100 avant la mise sur le
Port nocturne
marché/ Tous les matériaux/toutes les
(peut inclure 6 mois
200 après la mise sur le géométries
l’orthokératologie)
marché
A.2.2 Investigations portant sur les produits d’entretien pour lentilles de contact
A.2.2.1 Il convient que les produits d’entretien pour lentilles de contact, y compris les solutions salines, produits
de nettoyage quotidiens et périodiques, solutions désinfectantes, agents neutralisants, solutions «oculaires»,
solutions de conditionnement et solutions polyvalentes comportant tout nouvel ingrédient actif, ou tout ingrédient
actif non compris dans la plage de concentration utilisée dans le cas d’un produit commercialisé comparable,
fassent l’objet d’une étude clinique d’une durée de trois mois.
A.2.2.2 Dans le cas de produits destinés à être utilisés avec des lentilles souples (hydrophiles), il convient que
l’effectif d’échantillon (exhaustif) soit de 30 sujets dans le cas de la solution pour essai et de 15 sujets dans le
cas de la solution de contrôle (une solution actuellement commercialisée pour la même indication) pour chaque
catégorie représentative appropriée telle que:
6 © ISO 2012 – Tous droits réservés
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ISO 11980:2012(F)
— Groupe I;
— Groupe IV;
— Un groupe distinct pour chaque lentille en silicone-hydrogel. Si un fabricant donné produit deux lentilles ou
plus, et si toutes les lentilles ainsi produites présentent toutes la même composition chimique générale, il
suffit d’utiliser uniquement la lentille ayant la plus forte teneur en eau.
A.2.2.3 Produits destinés à être utilisés avec des lentilles rigides: il convient que l’effectif d’échantillon (sur
lequel l’étude a été réalisée) soit de 15 ou de 30 sujets utilisant la solution pour essai et de 15 sujets utilisant la
solution de contrôle (une solution actuellement commercialisée pour la même indication) pour chaque catégorie
d’équipement appropriée.
A.2.2.4 Il convient de réaliser une étude clinique d’une durée de un mois dans le cas d’une solution de lentilles
de contact ne contenant aucun nouvel ingrédient actif (tel que décrit en A.2.2.1), mais contenant en revanche
tout ingrédient actif dont la concentration est inférieure à la plage de concentration utilisée dans le cas d’un
produit commercialisé comparable. Dans ce cas, il convient que l’effectif d’échantillon corresponde à la moitié
de celui recommandé en A.2.2.2 et A.2.2.3, en utilisant la même répartition générale des sujets.
A.2.3 Éléments statistiques pour les évaluations dans le cas d’un port prolongé
A.2.3.1 Généralités
Analyse de sécurité primaire: il convient que la fréquence des événements indésirables sévères et importants
constitue le résultat de sécurité essentiel.
L’hypothèse de différence nulle, H , part du principe que le taux d’essai des événements indésirables résultant,
0
p , moins le taux de contrôle des événements indésirables résultant, p , est supérieur ou égal à la différence
t c
sans intérêt clinique, d, entre les deux taux.
L’hypothèse alternative, H , part du principe que le taux d’essai des événements indésirables résultant, p ,
a t
moins le taux de contrôle des événements indésirables résultant, p , est inférieur à une différence sans intérêt
c
clinique, d, entre les deux taux.
H : p - p ≥ d
0 t c
H : p - p < d
a t c
où
p est le pourcentage de la population d’essai;
t
p est le pourcentage de la population témoin.
c
Dans le cas d’un rapport d’affectation de patients égal à 1:1 entre les opérations de traitement et de contrôle,
le nombre minimum, n, de patients, sur lesquels l’étude a été réalisée, nécessaire pour chaque groupe de
traitement est déterminé par:
2
()ZZ+×[(pp11−+)(pp− )]
11−−βα tt cc
n =
2
δ
où
a est le niveau de signification (également appelé taux d’erreur de type 1);
1 - b est la puissance du test;
Z est le quantile normal type.
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ISO 11980:2012(F)
L’exemple suivant illustre un calcul d’applicabilité des hypothèses formulées pour des études cliniques
consacrées à des lentilles de contact en hydrogel ou en silicone-hydrogel faisant l’objet d’un port prolongé
d’une durée de 7 jours. Avec un taux de contrôle, p , et un taux d’essai, p , de 0,033 (sous H ), une différence
c t a
sans intérêt clinique, d, de 0,05, une puissance (1 - b) de 0,80 et un niveau de signification, a, de 0,05, le
nombre minimal de patients sur lesquels l’étude a été réalisée par groupe de traitement est le suivant:
2
(,0841+×,)64 [,0 033×−(,10 033),+×0 033 (,10− 033)]
n = ≅158
2
00, 5
L’équation ci-dessus est valable uniquement lorsqu’il est supposé, pour l’hypothèse alternative, H , que le taux
a
d’essai des événements indésirables est égal au taux de contrôle, p = p . Dans le cas d’une hypothèse non
t c
valable, l’équation suivante peut être utilisée pour obtenir un calcul approché de l’effectif d’échantillon:
2
()ZZ+×[(pp11−+)(pp− )]
11−−βα tt cc
n =
2
()pp−−δ
tc
Pour les études cliniques consacrées aux lentilles de contact hydrogel faisant l’objet d’un port prolongé
d’une durée de 30 jours, il est recommandé d’utiliser comme lentille témoin, une lentille faisant l’objet d’un
port prolongé d’une durée de 7 jours (6 nuits/7 jours). L’exemple suivant illustre un calcul d’applicabilité des
hypothèses formulées pour de nombreuses études cliniques consacrées à des lentilles de contact hydrogel
faisant l’objet d’un port prolongé d’une durée de 30 jours. Avec un taux de contrôle, p , de 0,033 et un taux
c
d’essai, p de 0,053 (sous H ), une différence sans intérêt clinique, d, de 0,05, une puissance (1 - b) de 0,80
t, a
et un niveau de signification, a, de 0,05, le nombre minimal de patients sur lesquels l’étude a été réalisée par
groupe de traitement est le suivant:
2
(,0841+×,)64 [,0 053×−(,10 053),+×0 033 (,10− 033)]
n = ≅ 562
2
(,0 053−00, 333−00,)5
Il convient d’ajuster le nombre de patients soumis à l’investigation clinique afin de compenser le taux d’exclusion
généralement compris entre 20 % et 25 % dans les études consacrées aux lentilles de contact sur une année.
Par conséquent, dans le cas de l’exemple susmentionné portant sur l’étude clinique d’une lentille de contact
dont la durée de port prolongée est de 7 jours, l’effectif d’échantillon recommandé serait ajusté à environ 215
par groupe de sujets. Dans le cas de l’exemple susmentionné portant sur l’étude d’une lentille dont la durée de
port prolongée est de 30 jours, l’effectif d’échantillon recommandé serait environ de 760 par groupe de sujets.
Il convient, à la fin de l’étude, d’effectuer des analyses de sensibilité (par exemple analyses à plusieurs
imputations) afin d’évaluer la robustesse du résultat de l’étude, en tenant compte des observations manquantes,
dans le cas d’un taux d’exclusion des sujets supérieur au taux minimal.
A.2.3.2 Évaluations des lentilles de contact en hydrogel, en silicone-hydrogel ou rigides perméables
au gaz faisant l’objet d’un port quotidien
Les effectifs d’échantillons sont calculés de manière à obtenir, avec une certitude raisonnable, au moins une
complication, en fonction du taux de complication attendu (c’est-à-dire 5 % pour un groupe expérimental
de 60 sujets, 10 % avec un groupe expérimental de 30 sujets), avec une probabilité supérieure à 95 %. Par
conséquent, dans un groupe de 30 sujets (sur lesquels l’étude a été réalisée) exposés à un produit pour essai
pendant une courte durée (90 jours), l’occurrence d’un événement indésirable avec deux à trois sujets peut
constituer une source de préoccupation concernant la biocompatibilité et la sécurité fondamentale du dispositif
soumis à l’essai. Il convient que toute investigation entraînant deux réactions indésirables ou plus comporte
une justification appropriée permettant de déterminer la sécurité et l’efficacité.
A.2.3.3 Évaluations des produits d’entretien pour lentilles de contact
Les effectifs d’échantillons cliniques sont calculés de sorte qu’une étude comporte au moins une complication
dans une catégorie d’équipement (taux de confiance de 95 %), si le taux vrai de complication est ≥10 %. Cela
implique qu’une étude comprenne l’exposition d’au moins 30 sujets (sur lesquels l’étude a été réalisée) à un
produit d’entretien pour essai, pendant une courte durée (90 jours), et ce, pour chaque groupe de matériaux. Il
convient que les études incluent tous les groupes de matériaux qui concernent le produit.
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ISO 11980:2012(F)
Il convient que toute investigation entraînant deux réactions indésirables ou plu
...
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