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EUROPEAN COMMISSION
DIRECTORATE GENERAL for HEALTH and CONSUMERS
Consumer Affairs
Cosmetics and Medical Devices
MEDDEV 2.7/4
December 2010
GUIDELINES ON MEDICAL DEVICES
GUIDELINES ON CLINICAL INVESTIGATION:
A GUIDE FOR MANUFACTURERS AND NOTIFIED
BODIES
Note
The present Guidelines are part of a set of Guidelines relating to questions of application of EC-
Directives on medical Devices. They are legally not binding. The Guidelines have been carefully drafted
through a process of intensive consultation of the various interest parties (competent authorities,
Commission services, industries, other interested parties) during which intermediate drafts where
circulated and comments were taken up in the document. Therefore, this document reflects positions
taken by representatives of interest parties in the medical devices sector.
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CONTENTS
1 Introduction........................................................................................................... 3
2 Scope ................................................................................................................... 3
3 References ........................................................................................................... 4
4 Definitions............................................................................................................. 5
5 General Principles When Considering the Need for a Clinical Investigation ........ 6
6 General Principles of Clinical Investigation Design .............................................. 7
7 Ethical Considerations for Clinical Investigations ............................................... 10
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1 Introduction
These guidelines are based on the guidance document SG5/N3:2010 of the Global
Harmonization Task Force. They are adapted to the requirements on clinical
investigations laid out in annex 7 of directive 90/385/EEC and in annex X of directive
93/42/EEC as amended by directive 2007/47/EC. The clinical investigations shall be
performed as described in these annexes.
They reflect the consensus view of the various interested parties with regard to
clinical investigations under the above-mentioned medical devices directives.
What is a clinical investigation?
A clinical investigation is defined as “any systematic investigation or study in or on
one or more human subjects, undertaken to assess the safety and/or performance
of a medical device.” (SG5/N1:2007).
The undertaking of a clinical investigation is a scientific process that represents one
method of generating clinical data.
What is the objective of a clinical investigation?
The objective of a clinical investigation is to assess the safety and clinical
performance of the device in question and evaluate whether the device is suitable
for the purpose(s) and the population(s) for which it is intended (EN ISO 14155-
1:2009).
How is a clinical investigation conducted?
EN ISO 14155-1:2009 Clinical Investigation of Medical Devices for Human Subjects
- General Requirements details the general requirements for the conduct of clinical
investigations and EN ISO 14155-2:2009 Clinical Investigation of Medical Devices
for Human Subjects - Clinical Investigation Plan contains detailed information about
the procedure and contents of a clinical investigation plan. Clinical investigations
must take into account scientific principles underlying the collection of clinical data
along with accepted ethical standards surrounding the use of human subjects. The
clinical investigation objectives and design should be documented in a clinical
investigation plan.
2 Scope
The primary purpose of this document is to provide guidance in relation to:
• when a clinical investigation should be undertaken for a medical device to
demonstrate compliance with the relevant Essential Requirements; and
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• the general principles of clinical investigations involving medical devices.
Given the wide diversity of medical devices and their associated risks, this document
is not intended to provide comprehensive guidance for clinical investigations of
specific medical devices.
The guidance contained within this document is intended to apply to medical devices
generally and to combination products regulated as medical devices. It is not
intended to cover in vitro diagnostic medical devices. Additionally, this document
was drafted primarily to address the use of Clinical Investigations to support clinical
evaluation and a conformity assessment procedure. Some aspects of this document
may apply to studies conducted following commercial release of a device. A
separate guidance document specifically addresses post-market clinical follow-up
(MEDDEV 2.12/2: Clinical Evaluation - Post Market Clinical Follow-up).
3 References
Directive 90/385/EEC, as amended by Directive 2007/47/EC
Directive 93/42/EEC, as amended by Directive 2007/47/EC
Interpretative Documents
MEDDEV 2.7.1 Rev. 3; December 2009
Clinical Evaluation: A Guide for Manufacturers and Notified
Bodies
MEDDEV 2.7.1, Appendix 1; December 2008
Evaluation of Clinical Data – A Guide for Manufacturers and
Notified Bodies – Appendix 1: Clinical Evaluation of Coronary
Stents
MEDDEV 2.7.2; December 2008
Guide for Competent Authorities in Making an Assessment of
Clinical Investigations Notification
MEDDEV 2.12/2; May 2004
Clinical Evaluation - Post Market Clinical Follow-up
GHTF final documents
SG5/N1:2007 Clinical Evidence – Key definitions and Concepts
SG5/N2:2007 Clinical Evaluation
Harmonized/International standards
EN ISO 14155-1: 2009
Clinical investigation of medical devices for human subjects – Part
1 General requirements
EN ISO 14155-2: 2009
Clinical investigation of medical devices for human subjects – Part
2 Clinical investigation plans
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EN ISO 14971: 2009
Application of risk management to medical devices
Other References
World Medical Association – Declaration of Helsinki - Ethical
principles for medical research involving human subjects
4 Definitions
Clinical Data:
The safety and/or performance information that is generated from
the use of a device. Clinical data are sourced from:
— clinical investigation(s) of the device concerned; or
— clinical investigation(s) or other studies reported in the
scientific literature, of a similar device for which equivalence
to the device in question can be demonstrated; or
— published and/or unpublished reports on other clinical
experience of either the device in question or a similar device
for which equivalence to the device in question can be
demonstrated.
Clinical Evaluation:
The assessment and analysis of clinical data pertaining to a medical
device to verify the clinical safety and performance of the device
when used as intended by the manufacturer.
Clinical Evidence:
The clinical data and the clinical evaluation report pertaining to a
medical device.
Clinical Investigation:
Any systematic investigation or study in or on one or more human
subjects, undertaken to assess the safety and/or performance of a
medical device.
Clinical Investigation Plan:
Document that states the rationale, objectives, design and proposed
analysis, methodology, monitoring, conduct and record-keeping of
the clinical investigation.
Clinical Performance:
The ability of a medical device to achieve its intended purpose as
claimed by the manufacturer.
Clinical Safety:
The absence of unacceptable clinical risks, when using the device
according to the manufacturer’s Instructions for Use.
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Conformity Assessment:
The systematic examination of evidence generated and procedures
undertaken by the manufacturer, according to Article 9 of directive
90/385/EEC and Article 11 of directive 93/42/EEC, to determine that
a medical device is safe and performs as intended by the
manufacturer and, therefore, conforms to the Essential
Requirements according to Annex 1 of directive 90/385/EEC and
Annex I of directive 93/42/EEC.
Device intended for Clinical Investigation:
any device intended for use by a duly qualified medical practitioner
when conducting investigations as referred to in Sections 2.1 of
Annex 7 of directive 90/385/EEC and section 2.1 of Annex X of
directive 93/42/EEC in an adequate human clinical environment.
Endpoint: Indicators measured or determined to assess the objectives of a
clinical investigation, prospectively specified in the clinical
investigation plan. (EN ISO 14155_2:2009, modified)
Residual Risk: Risk remaining after risk control measures has been taken (EN ISO
14971:2009).
Risk Management:
The systematic application of management policies, procedures and
practices to the tasks of analysing, evaluating, controlling and
monitoring risk (EN ISO 14971:2009).
5 General Principles When Considering the Need for a Clinical
Investigation
Clinical Evaluation
According to Annex 1.I.5a of directive 90/385/EEC and Annex I.I.6a of directive
93/42/EEC demonstration of conformity with the essential requirements must
include a clinical evaluation in accordance with Annex 7/Annex X of the respective
directive.
As a general rule, confirmation of conformity with the requirements concerning the
characteristics and performances referred to in sections I.1 and I.3 of annex I of
directive 90/385/EEC and in sections I.1 and I.2 of annex I of directive 93/42/EEC
under the normal conditions of use of the device, and the evaluation of the side-
effects and of the acceptability of the benefit/risk ratio referred to in Section I.5/I.6 of
Annex I of directives 90/385/EEC and 93/42/EEC respectively, must be based on
clinical data.
The kind and amount of clinical data needed will primarily depend on the specifics of
the clinical claims with regard to clinical performance, considerations of clinical
safety, including determination of undesirable side-effects and on risk management
output, namely determination of residual risks and favorable benefit/risk ratio.
Some factors that may typically influence the specificity/extent of clinical data
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requirements are listed in section 6 of this guidance.
Different clinical claims/intended purposes of a device may often necessitate
different clinical data. For example, in the case of the closure of the heart defect
patent foramen ovale, clinical performance/safety data and benefit/risk-
considerations may vary in different intended purposes such as stroke prevention or
migraine crisis prevention.
Conducting a proper clinical evaluation will demonstrate which clinical data are
necessary, which clinical data can be adequately supplemented by other methods,
such as literature search, prior clinical investigations, clinical experience or by using
suitable clinical data from equivalent1 devices, and which clinical data remain to be
delivered by clinical investigations (see MEDDEV 2.7.1 Rev.3: “Clinical Evaluation: A
Guide for Manufacturers and Notified Bodies”).
The clinical evaluation and its documentation must be actively updated with data
obtained from the post-market surveillance. New such data as well as considerations
for new or changed intended purposes need updating of the clinical evaluation and
may indicate necessity of additional clinical investigations.
When must/should a clinical investigation be undertaken?
The Conformity Assessment process for active implantable medical devices as well
as for class III and implantable medical devices requires that a clinical investigation
is undertaken unless it is duly justified to rely on existing data (section 1.2 of Annex
7 of directive 90/385/EEC and section I.1a of Annex X of directive 93/42/EEC ). Any
such justification will have to be based on a proper clinical evaluation.
Depending on clinical claims, risk management outcome and on the results of the
clinical evaluation, clinical investigations may also have to be performed for non-
implantable medical devices of classes I, IIa and IIb.
Additional clinical investigations may be feasible to corroborate the existing clinical
evidence with regard to aspects of clinical performance, safety, benefit/risk-ratio or
to determine relative effectiveness and safety with suitable comparators.
6 General Principles of Clinical Investigation Design
Any clinical investigation must:
• be part of the clinical evaluation process;
• follow a proper risk management procedure to avoid undue risks;
• be compliant with all relevant legal and regulatory requirements;
• be appropriately designed (see below);
• follow appropriate ethical principles (see Section 7).
1
The concept of equivalency encompasses technical, biological and clinical equivalency.
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Basic legal and administrative provisions given in directives 90/385/EEC and
93/42/EEC
Art. 4 of the two directives require that Member States shall not create any obstacle
to devices intended for clinical investigation being made available to medical
practitioners or authorized persons for that purpose if they meet the conditions laid
down in Article 10/15 and in Annex 6/VIII of the respective directives. These devices
shall not bear the CE marking.
Art. 10/15 of the directives contain the administrative provisions for clinical
investigations, Annex 6/VIII respectively the contents and provisions for the
statement and documentation required.
Annexes 7/X, sections 2.2 relate to ethical provisions, sections 2.3 specify basic
methodological aspects of clinical investigations.
Further legal and regulatory/administrative requirements may be valid at
national/regional level.
Factors to Influence Clinical Data Requirements
The design of the clinical investigation, including the study objectives and statistical
considerations, should provide the clinical data necessary to address relevant
aspects of clinical performance, safety, including undesirable side-effects as well as
the residual risks identified in the risk management process. Some factors that may
influence the extent of clinical data requirements include, but are not limited to, the
following:
• type of device and/or regulatory classification;
• novel technology/relevant previous experience;
• clinical application/indications;
• nature of exposure to the product, e.g.: surface contact, implantation,
ingestion;
• risks inherent in the use of the product, e.g.: risk associated with the
procedure;
• performance claims made in the device labeling (including instructions for
use);
• component materials and substances;
• disease process (including severity) and patient population being treated;
• demographic, geographic and cultural considerations (e.g.: age, race, gender,
etc.);
• potential impact of device failure;
• period of exposure to the device;
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• expected lifetime of the device;
• availability of alternative treatments and current standard of care; and
• ethical considerations.
Considerations for Device Study Designs
Some of the factors that need to be considered in the study design include, for
example:
• clear statement of objectives
• appropriate subject population(s)
• minimization of bias (e.g., randomization, blinding)
• identification of confounding factors (e.g., concurrent medications, co-
morbidities)
• choice of appropriate controls (e.g., cohort, sham, historical), where
necessary
• design configuration (e.g., parallel, crossover, factorial)
• type of comparison (e.g., superiority, non-inferiority, equivalence)
Investigations should be planned in such a way as to maximize the clinical relevance
of the data while minimizing confounding factors. Possible study designs include:
• randomized controlled trials
• cohort studies
• case-control studies
• case series
These are further explained in Appendix C of the document MEDDEV 2.7.1 Rev. 3
on Clinical Evaluation.
In designing the study, statistical considerations should be prospectively specified
and should be based on sound scientific principles and methodology. Care must be
taken in developing a statistical plan that includes consideration of, for example, the
following:
• endpoints that are clinically relevant, clearly defined and assessed at a
specified time point
2
• a testable hypothesis
• statistical significance levels, power
• sample size justification
2
See e.g. critical aspects of end point definition for regulatory trials [D.B. Kramer et al, American Journal of
Therapeutics 17, 2-7 (2010)]
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• analysis methodology (including sensitivity and poolability analysis)
The design should ensure that the statistical evaluation derived from the
investigation reflects a meaningful, clinically significant outcome.
Discussion with a competent authority or a notified body may be appropriate when
there is uncertainty as to whether the proposed clinical investigation plan is
sufficient.
Conduct of Clinical Investigations
A properly conducted clinical investigation, including compliance to the clinical
investigation plan and local laws and regulations, ensures the protection of subjects,
the integrity of the data and that the data obtained is acceptable for the purpose of
demonstrating conformity to the Essential Requirements. EN ISO 14155 outlines
good clinical practice for clinical investigations of medical devices.
Final Study Report
The outcome of a clinical investigation has to be documented in a final study report
(Annex 7/X, section 2.3.7 of directives 90/385/EEC and 93/42/EEC) This then forms
part of the clinical data that is included in the clinical evaluation process and
ultimately becomes integrated into the clinical evaluation report (see MEDDEV 2.7.1
Rev. 3) for the purposes of conformity assessment. The structure of a final study
report is proposed in EN ISO 14155-1:2009.
7 Ethical Considerations for Clinical Investigations
In their sections 2.2 of Annex 7/Annex X, directives 90/385/EEC and 93/42/EEC
require: “Clinical investigations must be carried out in accordance with the Helsinki
Declaration adopted by the 18th World Medical Assembly in Helsinki, Finland, in
1964, as last amended by the World Medical Assembly. It is mandatory that all
measures relating to the protection of human subjects are carried out in the spirit of
the Helsinki Declaration. This includes every step in the clinical investigation from
first consideration of the need and justification of the study to publication of the
results.”
As a general principle, “the rights, safety and wellbeing of clinical investigation
subjects shall be protected consistent with the ethical principles laid down in the
Declaration of Helsinki” (EN ISO 14155-1:2009).
It is ethically important in deciding to conduct a clinical investigation that it should
generate new data and answer specific safety and/or performance questions that
remain unanswered by the current body of knowledge. The desire to protect human
subjects from unnecessary or inappropriate experimentation must be balanced with
the need to protect public health through the use of clinical investigations where they
are indicated. In all cases, however, care must be taken to ensure that the
necessary data are obtained through a scientific and ethical investigational process
that does not expose subjects to undue risks or
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