ISO 14155: Clinical Investigation

of Medical Devices for Human Subjects

Karnika Singh

1  Introduction

The international standard ISO 14155 was formulated by Technical Committee

ISO/TC 194, Biological evaluation of medical devices, to define good clinical prac-
tice during clinical investigation of medical devices in human subjects. This includes
the design, conduct, recording, and reporting of clinical investigations as well as the
safety or performance of medical devices for regulatory purposes. It consists of two
parts, ISO 14155-1, which specifies procedures for the “conduct and performance,”
and ISO 14155-2 that contains prerequisites for the “preparation of Clinical
Investigation Plans (CIPs)” for the clinical investigation of medical devices. First
version of ISO 14155 was released in 2003 (ISO 14155:2003); since then it has been
modified several times, and the latest version came out in 2011 and is the standing
version till date known as the ISO 14155:2011. It should be noted that ISO 14155 is
not applicable to in  vitro diagnostic medical devices. In this chapter, we will be
discussing both parts of this ISO.

2  Structure of ISO 14155:2011

The ISO 14155:2011 is divided into several sections, namely:

1. Scope
2. Normative references (ISO 14971:2007)
3. Terms and definitions
4. Ethical considerations

K. Singh (*)
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 1

P. S. Timiri Shanmugam et al. (eds.), Medical Device Guidelines and Regulations
Handbook, https://doi.org/10.1007/978-3-030-91855-2_1
2 K. Singh

5 . Clinical investigation planning

6. Clinical investigation conduct
7. Suspension, termination, and closeout of the clinical investigation
8. Responsibilities of the sponsor
9. Responsibilities of the principal investigator
The original document also has several annexes associated with clinical investiga-
tion plan (CIP), investigator’s brochure (IB), case report form (CRF), clinical inves-
tigation report, essential clinical investigation documents, and adverse event
categorization.
In this chapter each part of ISO 14155:2011 will be discussed in the light of
above sections.

3  ISO 14155-1

3.1  Scope

As mentioned above, this part of ISO 14155 defines the “general requirements for
biological tests” aimed at protecting human subjects, assuring that clinical investi-
gation is carried out with optimal scientific conduct and helps the sponsors, moni-
tors, investigators, ethics committees, and regulatory authorities and bodies involved
in the conformity assessment of medical devices to oversee the compliance of the
standard. It specifies the requirements to plan a clinical investigation with regards to
the concerned medical device’s performance in terms of mimicking clinical use,
adverse events that might occur during normal conditions of usage, evaluation of
acceptable risks associated with the assigned performance of the medical device
and organization, conduct, monitoring, data collection, and documentation of the
clinical investigation of a medical device. All these requirements are applicable to
clinical investigations pertaining to human subjects.

3.2  Terms and Definitions

Adverse device effect: As the name suggests, it means any unexpected response to a
medical device. This could be any event as a consequence of defects or faults in
the “instructions for use” and/or arrangement of the device or simply user error.
Adverse event: This refers to the development of any unfortunate medical condition
in a subject. However it should be kept in mind that there may not be a direct
association between the adverse event and the medical device.
Case report form: Form designed to catalog all the information notified to the spon-
sor about each human subject as needed by the clinical investigation plan.
ISO 14155: Clinical Investigation of Medical Devices for Human Subjects 3

Clinical investigation: A study intended for analyzing the safety and performance of
a particular device in humans.
Clinical investigation plan: Often referred to as protocol, this document describes
all the information regarding the “rationale, objectives, design and proposed
analysis, methodology, monitoring, conduct, and record keeping of the clinical
investigation.”
Clinical investigator: Person or institution that is conducting the clinical investiga-
tion and would be liable for the good health of the human subjects that are part
of the clinical study.
Clinical investigator’s brochure: A collection of clinical and nonclinical informa-
tion about the device under investigation relevant to the human subjects of
the study.
Clinical performance: Performance or action of a medical device when used with
correct intent on suitable human subjects.
Coordinating clinical investigator: It is the person (usually appointed by the spon-
sor) who coordinates the work of a multicenter investigation.
Ethics committee: An independent panel created for ensuring the safety, well-being,
and human rights of the subjects participating in the clinical study.
Final report: Document containing the details, results, and interpretation of the con-
ducted clinical investigation.
Informed consent: A legal document confirming a subject’s voluntary participation
in a clinical study after he/she has been informed about all aspects of the clinical
investigation pertaining to their decision to participate.
Investigation center/investigation site: Site or institution of clinical investigation.
Medical device: A contraption along with the software required for its operation
used for various diagnostic purposes like prevention, monitoring, treatment, or
alleviation of disease; rectification of an injury or handicap; alteration of anat-
omy or physiology of a biological process; conception control; etc. Such a device
is not supposed to function in the human body by any pharmacological, immu-
nological, or metabolic ways. However, any such outside assistance can be taken
to improve its function.
Monitor: Person recruited by the sponsor for assessing the compliance of investiga-
tor with the clinical investigator plan, performance of source data verification,
and regular progress reporting to the sponsor.
Multicenter investigation: A clinical investigation that occurs at two or more sites
according to original clinical investigation plan.
Principal clinical investigator: A clinical investigator responsible for arranging
clinical investigation at a single site.
Serious adverse device effect: An adverse device effect resulting in a serious adverse
event or any series of events in which intervention was not possible due to vari-
ous reasons.
Serious adverse event: An adverse event leading to death or severe decline of health
of the human subject. This includes any life-threatening illness or injury, lasting
impairment of a body part, hospitalization, surgery, etc. Congenital anomalies
and fetal morbidity also fall under this category.
4 K. Singh

Source data: Original information in the records collected during the clinical inves-
tigation comprising clinical findings, observations, etc. that may be used to
reconstruct or evaluate the initial clinical investigation.
Source documents: Original data, documents, and records, for example, laboratory
notes, hospital records, pharmacy records, photographs, radiographs, etc.
Sponsor: Also known as promoter, it is the person responsible for proper institution
and/or implementation of a clinical investigation. The clinical investigator can
also carry out this role.
Subject: Human being who participates in a clinical investigation either as a receiver
of the test device or as a control.

3.3  Ethical Considerations

Declaration of Helsinki (DoH)

It was created by the World Medical Association (WMA) in 1964 as a policy state-
ment for ensuring the ethical treatment of human subjects in clinical investigation.
Since then this document has been amended seven times and the latest accepted
version was formulated in 2013. However it should be noted that this is not a legal
document, even though it is referred to at every step of a clinical investigation. The
DoH highlights the fundamentals like basic respect of the individual, their right to
informed decisions, their welfare, that the clinical investigation should be carried
out after detailed scientific investigation, and, above all, ethical considerations.

Improper Influence or Inducement

The participants of the study (subjects, officials, and other parties) should not to be
improperly influenced or induced by any means during the clinical investigation.

Compensation and Additional Health Care

This includes all the provisions decided for the compensation of subjects due to any
injury while participating in the clinical investigation. This also comprises addi-
tional healthcare provisions that would be employed during an adverse device
effect. All these occurrences if happen shall be documented.

Responsibilities

It is the responsibility of the participating parties to ensure that clinical investigation

is conducted ethically, especially as far as their role is concerned.
ISO 14155: Clinical Investigation of Medical Devices for Human Subjects 5

3.4  General Requirements

Formal Agreement

This is a written and signed agreement between the sponsor, the clinical
investigator(s), and other involved parties that describe their responsibilities.

Qualifications

This entails to the required educational qualification and experience of the person-
nel involved in the clinical investigation.

Clinical Investigation Plan

This is discussed more in part 2.

Design of the Clinical Investigation

The design of clinical investigation should center around testing the suitability of
the device for the intended medical purpose such that the results obtained shall be
authentic, supportive, and relevant to the investigation’s objective.

Confidentiality

This requires the safekeeping of patient data such as their name and identifying
information. For this, the case reports form should not use such information; the
patient data should be secured under unauthorized access and should be limited to
only reports and scientific publications.

Start of Clinical Investigation

The following things should be kept in mind before starting a clinical

investigation:
1 . A written and signed clinical investigation plan
2. Approval of the ethics committee
3. Regulatory clearance
6 K. Singh

Informed Consent

It is mandatory to obtain and document the informed consent in writing from every
subject who decides to enroll in the clinical study. It is structured in two parts: study
information and signature area. They can be together in one document or two sepa-
rate documents.
ISO 14155-1 details the “process of obtaining informed consent.” It should not
involve any pressurizing or influencing of subjects to participate. Subject’s legal
rights should not be waived. Nontechnical language should be used in the consent
form such that the subject or his/her legal representative easily understands it. The
subject should be given ample time to consider their participation in the study. The
informed consent should be signed and dated by the subject or his/her legal repre-
sentative and the clinical investigator. It should be outlined how the informed con-
sent would be obtained for cases when the subject is unable to give it. Some
circumstances could be when the subject is a fetus, child, juvenile, seriously ill,
unconscious, or mentally incapable to do so. In such conditions, a legal guardian or
representative is authorized to give informed consent. All this has to be documented
in the clinical investigation plan.
Informed consent is a really important part of a clinical investigation; therefore
the subject needs to be properly informed of certain things before obtaining their
informed consent. First, is the description and purpose of the study detailing the
involvement of research, investigation’s objective, duration of the study, how the
subject would be involved in the study, specifics about the medical device that is
being investigated, and explanation of the procedure with an emphasis on the exper-
imental part. Second, is the mentioning of any foreseeable risks that accompany the
investigation along with any side effects. The consent should also describe the
potential benefits, the subject or others might have if the study is a success (have a
positive outcome). It should also include the alternative therapies that are available
to the current medical condition/device. The consent should clearly state that the
subject’s participation would be kept confidential; his/her medical details would
only be accessible to the regulatory authorities or sponsor’s delegates; and the
results of the study may be published but the subject’s identity would not be revealed.
The consent should also state that the subject is liable to get compensation if he/she
is injured during the study and additional healthcare needs to be administered
because of an adverse device effect. The compensation can be financial and the
details of that should be outlined. The contact person needs to be clearly defined in
the consent to which the subject can ask questions about the study in general, inform
about an injury, etc. The conditions of termination of participation by the investiga-
tor should also be included in the consent. Finally, it should state that any new find-
ings related to the subject’s participation would be made available to them.
The signing of informed consent agreement means that the participating indi-
vidual or his/her legal representative would participate and comply with the clinical
investigation; they would inform their personal physician of their participation in
the study or their disagreement for this information release and that they would
allow the use of any personal data relevant to the study in the clinical investigation.
ISO 14155: Clinical Investigation of Medical Devices for Human Subjects 7

In the event of an early termination of the study, it is the sponsor’s responsibility to

promptly inform the clinical investigators and investigation centers of the termina-
tion along with the reason of termination. The ethics committee should also be
informed of the termination and its reason either by the sponsor or the investigator
or the investigation center. In some instances the subjects’ physicians may also have
to be informed.
Document and data control are critical aspects of a clinical investigation. It is
important to safeguard subject’s privacy as much as possible. A case report form
should be maintained for each patient which would record their data as required by
the clinical investigation plan. Similarly, all subjects enrolled currently or previ-
ously in the study shall be accounted for and documented. All the data obtained in
the study has to be kept confidential and only the clinical investigator would have
access to it. Monitor would only have access to source documents and other infor-
mation necessary to ensure investigator compliance with the study plan, rules, and
regulations and judge the progress of clinical investigation. The clinical investigator
should allow auditing of their clinical investigator procedures.

Documentation

Clinical investigator’s brochure and other documents like clinical investigation

plan, case report forms, etc. should be prepared before the start of clinical study. The
clinical investigator brochure should contain a summary of literature, clinical inves-
tigation design, and rationale for the planned use of the medical device. The descrip-
tion of the device should be included according to ISO 14155-2. The mechanism of
action of the device should be described along with the supporting scientific litera-
ture. The manufacturer’s instructions for use and installation and possible side
effects and contraindications should also be included if required. The expected
clinical performance of the device and materials used to manufacture the device
should be outlined. The experimental results pertaining to the device including bio-
logical, clinical, and preclinical studies should be reported. Any previous reports
regarding the device or any similar device should also be mentioned. A compiled list
of international standards and results of the risk analysis should also be included.
The clinical investigator brochure should be regularly updated with any piece of
significant information along the course of clinical investigation and shall be con-
veyed to the clinical investigators.
Other documents that should be prepared in advance, include the clinical inves-
tigation plan; the curriculum vitae that is current, signed, and dated; the institution(s)
where the clinical study would happen; written approval of the ethics committee
and related documents; all communication with authorities as needed by national
legislation; agreement between the principal investigator and the sponsor; insurance
certificates; informed consent forms and other materials provided to the subjects;
case report forms; reporting forms for adverse events and adverse device effects;
and contact information of the monitor.
8 K. Singh

Sponsor

It is the responsibility of the sponsor to design and communicate all the duties and
functions relating to the clinical study. They will ensure documentation showing
that, investigator, sponsor, and monitor comply with ISO 14155, the clinical inves-
tigation plan and subsequent amendments, and applicable regulatory requirements
through a transparent system. The responsibilities of a sponsor have been listed in
detail in the ISO 14155 document.
• Selection of investigator and the investigation center for the study and coordina-
tion of the clinical investigator if required.
• Selection and appointment of monitor for the study or acting as monitor them-
selves. The sponsor is supposed to perform this duty along with the monitor and
clearly outline the guidelines for taking care of noncompliances and missing data.
• Assemble and update the clinical investigation brochure.
• Supply the clinical investigator with clinical investigation plan, approved amend-
ments, and the clinical investigator’s brochure.
• Sign the approved clinical investigation plan.
• Provide the devices that are to be studied in the clinical investigation.
• Make sure that the clinical investigator has the appropriate information and/or
training in the use of device as per the clinical investigation plan.
• Assure that all the deviations from the original clinical investigation plan have
been reviewed with the respective clinical investigator(s) and recorded in the
case report form and the final report of the clinical investigation.
• Report and review the adverse events and adverse device effects with the clinical
investigator to the ethics committee, safety monitoring committee, and any other
relevant authorities.
• Report in writing to all clinical investigators involved in the study, the serious
adverse effects reported to them during the investigation. The report shall be sent
based on the perceived risk.
• Immediately inform the clinical investigator if the study has been prematurely
terminated or suspended along with the concerned regulatory authorities. Also
explain the reason of premature termination or suspension.
• Tell the clinical investigator(s) about the developmental status of the device, and
state the requirements essential to verify the performance of the device.
• Review and approve any departure from the original study plan, and perform any
relevant corrective or preventive actions.
• Collect, secure, store, and ensure completion by involved authorities of the listed
documents:
–– All the documents listed in the “documents” section
–– Case report forms, signed and dated
–– Records of any adverse events and adverse device effects reported to the spon-
sor during the clinical investigation
–– Final report of the clinical investigation
ISO 14155: Clinical Investigation of Medical Devices for Human Subjects 9

• Make sure that device is accountable and traceable.

Monitor

The monitor is responsible for the following:

• Verifying compliance with the clinical investigation plan is maintained and any
departure from the clinical investigation plan is reviewed and documented with
the clinical investigator and at the same time reported to the sponsor.
• Verifying that the device is being used in accordance with the clinical investiga-
tion plan and reporting to the sponsor if any modifications are needed for the
device or its methodology.
• Monitor that the clinical investigator(s) currently have the staff and facilities to
conduct the clinical study safely and effectively.
• Verify that the clinical investigators have continued access to adequate number
of subjects and clinical devices.
• Check that all consent forms obtained from the subjects at the time of enrollment
are signed and dated before any study-related procedures are started.
• See if the case report forms are complete and timed, and match the source of
the data.
• Ensure that adverse events and adverse device effects are recorded and reported
to the sponsor, followed according to respective procedure.
• Device accountability and traceability procedures are in place and are maintained.
• The equipment under study is calibrated regularly and documented at the
same time.
• There is documentation of subject withdrawal and noncompliance, regular dis-
cussion with clinical investigator, and report to the sponsor.
• Review the noncompliant findings or required modifications with the clinical
investigator, and write a monitoring report to the sponsor disclosing the above
information.

Clinical Investigator

The clinical investigator is an appropriately qualified clinician with a license to

practice medicine. He should have enough experience in the field and also training
for the device usage under investigation. He should be thorough with the back-
ground and requirements of the methods to be followed in the clinical study. The
clinical investigator should be well versed in the art of obtaining informed consent.
Like the sponsor and the monitor, the clinical investigator also has several
responsibilities to ensure the smooth day-to-day conduct of the clinical study and
safety of the human subjects involved in the study.
• The clinical investigator should have all the resources to properly conduct the
clinical study.
10 K. Singh

• He/she should also make sure that there is no conflict of interest because of
the study.
• The clinical investigator should regularly obtain important information from the
sponsor concerning the device under investigation.
• He/she should also completely go through the clinical investigation plan before
signing it.
• He/she should help the monitor and the auditor to rectify case report forms for
any inconsistencies or missing information. Also this would give the investigator
a chance to verify compliance of the two officials with the clinical investigation
plan and perform source data verification as well.
• They should discuss the possibilities of modification to the clinical investigation
plan with the sponsor and the monitor and obtain sponsor’s written approval.
• They are also responsible for making sure that the clinical investigation plan is
followed by all those involved in the study and that any departure from the plan
is documented and reported to the sponsor.
• The clinical investigator has to make the necessary arrangements for the proper
conduct and completion of the clinical study.
• They also have to make sure that necessary measures are in place for emergency
treatment to protect the subjects in the study.
• Obtaining appropriate ethics committee approval is also the responsibility of the
sponsor in order to start the clinical study at the respective center.
• Give the results from the ethics committee to the sponsor.
• Communicate to the ethics committee about any significant changes that have
been made to the study plan as approved by the sponsor along with the appropri-
ate reasons.
• Notify the ethics committee of any adverse side effects.
• Also notify the sponsor of all adverse events and adverse device effects as
they happen.
• Make sure that the subjects are recruited in an adequate manner.
• To establish that the recruited subjects were given adequate information to pro-
vide informed consent.
• Assure that informed consent is obtained and recorded.
• Ensure that clinical records clearly indicate that enrollment of subjects in respec-
tive study; if needed, the subjects shall be provided with a means to prove their
association with the study along with identification and other compliance docu-
ments. The subject’s physician may also be involved if required.
• Like the sponsor the clinical investigator also has to ensure that the subjects are
briefed with procedures to follow during an emergency situation. Under such
conditions the prior approval of sponsor shall not be required, and this would not
be considered a breach of agreement. However, these deviations would be docu-
mented and reported to the sponsor.
• Any information that is made public as a part of the clinical investigation about
the subjects and is required for clinical study’s continuation shall be conveyed to
the sponsor and if appropriate to the subject’s physician as well.
ISO 14155: Clinical Investigation of Medical Devices for Human Subjects 11

• The clinical investigator is also responsible for informing the subjects and their
physician about any premature termination or suspension of the clinical study
along with the reason of termination.
• The clinical investigator is responsible for accuracy, legibility, and security of all
data collected during the study, documents, and patient records at the investiga-
tion site both during and after clinical investigation. The clinical investigator
should sign the case report forms. Data shall be altered, initiated, and dated only
by the authorized personnel, and original data has to be retained for comparison
purposes.
• Make sure that the basic data collected during the study are retained for the mini-
mum time specified in the plan.
• The clinical investigator shall also be responsible for the supervision and assign-
ment of duties to the responsible personnel at the clinical investigation center
involved.
• Account all the devices that are part of the investigation.
The quantity of the devices received for the study should be adjusted with the
number of devices used, discarded, or returned.

Final Report

A final report of the clinical study has to be completed even when the study is pre-
maturely terminated. It has to be in a written format and signed by the sponsor and
the coordinating investigator, principal clinical investigator(s) from each center.
This document would be made available upon request to all clinical investigators
and the ethics committee. The final report should comprise a detailed identification
of the device(s), description of the methodology and design of the study, any depar-
tures from the study plan, data analysis with the statistics, and a critical assessment
of the aims of the study. The final report will include data from all the centers and
enrolled subjects. The subjects shall not be identifiable from any part of the report
or the published data. All clinical investigators would review the report and com-
ment on it. The sponsor will keep the record that all clinical investigators have been
given the final report for review and comments. If any investigator disagrees with
any part of the final report, his/her comments shall be recorded and conveyed to
other investigators. If the coordinating investigator or other investigator is unable to
or refuses to sign the report, a justification shall be given for the not signing of the
final report.
12 K. Singh

4  ISO 14155-2

4.1  Scope

This part of ISO standard details the requirements for laying out the CIP for the
clinical investigation of medical devices. A CIP compiled in accordance with this
ISO helps in establishing the validity and reproducibility of the results of a clini-
cal study.

4.2  Terms and Definitions

End point – primary: Principal indicator measured or set to evaluate the primary
objective of a clinical study
End point  – secondary: Indicator measured or set in addition to the primary end
point to determine some other aim of the study
Point of enrollment: The time at which, after recruitment, the subject signs the
informed consent forms and officially becomes the part of the study population
Follow-up period: The period of the clinical study where the effects of the medical
device under investigation are observed in the enrolled subjects
Recruitment: The process of classifying subjects who may be appropriate for the
clinical study under consideration

4.3  Requirements

All requirements for this part of ISO are same as ISO 14155-1.

4.4  Clinical Investigation Plan (CIP)

The sponsor and the clinical investigator(s) would prepare this document such that
it would be used for optimizing the scientific validity and reproducibility of the
results. All this would be done in accordance with current clinical standards relevant
to completing the aims of the study. The CIP would have information in the orga-
nized clauses. The other documents like clinical investigator’s brochure, sponsors
standard operating procedures, etc. should be referenced in the CIP and provided on
request. The sponsor can decide that any of the following requirements is not appli-
cable in a particular situation; he/she would have to provide a clear statement
explaining the omission of information in each situation.
ISO 14155: Clinical Investigation of Medical Devices for Human Subjects 13

4.5  General Information

Identification of the Clinical Investigation Plan

The CIP and any of its amended versions would be identified by the title of the study
and its reference number. It will also include the version/issue number and the date
to trace it back to the signatories. Each page would contain the version number.

 linical Investigators, Principal Clinical Investigator, Coordinating

C
Clinical Investigator, Investigation Center/Site(s)

The CIP would list the contact details (name, address, and professional position) of
the clinical investigator(s), principal investigator(s), and the coordinating clinical
investigator if applicable. Similarly, name and address would be provided for the
institutions at which the study would take place. The name and address of additional
centers or persons involved in the study in terms of patient management, testing, or
analysis would also be included.

Sponsor

The contact details of sponsor of the study would be included in the CIP whether
they are in state or a foreign country.

Monitoring Arrangements

The monitoring arrangements would be outlined in the CIP and the planned extent
of the source data verification.

Data and Quality Management

The CIP would define the protocol for database management, treatment of data,
source data verification, data archiving, retention period, and other quality control
processes.

An Overall Synopsis of the Clinical Investigation

The CIP would give a summary or outline of the clinical investigation. It can be
accompanied with graphics like flowcharts showing the key stages of the study or
other important information relevant to the study.
14 K. Singh

Approval and Agreement to the Clinical Investigation Plan

The sponsor, coordinating investigator, and the principal clinical investigator(s) in

each center shall comply with the CIP and its amendments and express their approval
and consensus by signing and dating an appropriate document.

4.6  I dentification and Description of the Medical Device

to Be Investigated

The CIP would include or reference to a brief description of the device under inves-
tigation and its designated purpose. The subsequent information shall be provided:
• The device manufacturer, its model, or type number along with software version
and accessories to allow full identification and traceability. If this information is
unknown at the time of CIP preparation, a method of traceability would be laid
down for before and after the study.
• The designated purpose of the device as declared by the manufacturer including
the contraindications and clinical implications in the study and the target
populations.
• Characterization of the device including any components that would come in
contact with tissues or body fluids. This would consist of the details of any
medicinal products, human and/or animal tissues or their derivatives, or other
biologically active substances.
• Instructions for installation and use of the device along with any necessary stor-
age and handling requirements, arrangement for use and reuse and any checking
before safety and performance, and any precautions required after use.
• A review of required training and experience needed for the use of device
under study.
• A statement of involved medical or surgical procedures in the use of the
said device.

4.7  Preliminary Investigations and Justification of the Study

Literature Review

The CIP shall contain relevant scientific literature and/or unpublished data and
reports along with a list of references that have been reviewed. The purpose of this
review is to justify the proposed study design. The review would pertain to the
intended purpose of device under investigation and prospective method of use.
ISO 14155: Clinical Investigation of Medical Devices for Human Subjects 15

Preclinical Testing

The review would recap the preclinical testing that has been done for the device
under investigation to support its use in human subjects, along with an analysis of
the results from such testing. This would include the results of the preclinical test-
ing, design calculations, in vitro tests, mechanical and electrical testing, reliability
checks, and software validation relating to the function of the device. Other results
from performance tests, ex vivo testing, biological testing and/or safety tests in ani-
mals, justification of tests done, and timeline of such results would also be included.

Previous Clinical Experience

The CIP would also include the results from the previous clinical investigations, if
any and clinical use that is pertinent to the current study. The CIP would also talk
about any previous data that is out there regarding device usage or similar devices
that are currently in use. All this comprises an evaluation of adverse device effects
and any past experiences of modification or recall.

Device Risk Analysis and Risk Assessment

The CIP shall provide results of a risk analysis and assessment. This would weigh
the balance between anticipated clinical benefit and the risks connected with the
device and its method of use as stated by the risk management. Probable interac-
tions with competent medical interventions shall be tabulated, along with a state-
ment of the expected clinical benefit. This would comprise an evaluation of adverse
device effects and any prior report of modification or recall in association with
safety and clinical performance of the device under study and similar devices.

Objectives of the Clinical Investigation

The CIP would clearly state the hypothesis and objectives, both primary and sec-
ondary, of the clinical study and populations on which the device would be tested.
These would specifically include:
• Predictions and suspected performance of the devices that are to be tested
• Risks and predictable adverse side effects that are to be evaluated
• Specific hypotheses to be tested by statistical data obtained from the study
16 K. Singh

Design of the Clinical Investigation

The scientific credibility of a clinical study lays on its design; therefore the CIP
shall supply the following information:
• Explanation of the type of investigation to be conducted (e.g., comparative
double-­blind, parallel design, with or without a control group) with appropriate
rationale for the choice
• Review of the controls
• Methods employed to reduce bias
• Primary and secondary end points with reason for this choice
• The variables to be tested with relevant reason to achieve the end points
• The methods and timing for checking, documenting, and evaluating variables
• Assess the equipment to be used for analysis of study variables and the setup for
monitoring the sustenance and calibration
• Inclusion criteria for subject election
• Exclusion criteria for subject election
• Point of enrollment
• Detailed description of the protocol that the subjects would be subjected to dur-
ing the study along with a record of other devices or medication to be utilized
during the usage of the device under investigation or during the follow-up course
• Criteria and methods for withdrawal and discontinuation of subjects from the
study and their accountability, along with the follow-up procedures of these sub-
jects, if feasible
• Number of subjects needed for the study, time required to recruit this number,
total devices needed for the study, and explanation for all these numbers. For
multicenter studies, the minimum number of subjects to be involved from each
center has to be specified and justified. If there is a chance of the validity of the
study results to get affected, the number of subjects enrolled at each center would
be taken into consideration.
• Strategy for documenting and evaluating adverse events, adverse side effects,
and/or outcomes
• Time of use of the device or its control and its follow-up time in a specific subject
of the study along with the justification
• Any known or expected factors that may impact results or their interpretation, for
example, subject baseline characteristics, concomitant medication, use of other
devices or subject-related factors (age, gender or lifestyle), etc. The means (sub-
ject selection, study design-stratified randomization, statistical analysis) of
addressing these variables in the study have to be outlined.

Statistical Considerations

The CIP will contain a description and explanation of hypothesis and statistical
design, method, and the analytical procedures to be employed. This encompasses:
ISO 14155: Clinical Investigation of Medical Devices for Human Subjects 17

• Reasoning for the sample size, significance test to be used, power of the study,
and predicted dropout rates, along with the justification of all these choices
• Pass/fail criteria to be used on the results of the study
• Plan for an interim analysis, where required, and the criteria for the cessation of
the study on the statistical grounds
• Protocols for reporting any departure(s) from the original statistical plan. All this
would be recorded in the CIP or final report.
• Criteria for choosing the subjects to be included in the study with the explanation
• Protocols for accounting of data, handling of missing, unused, or false data,
drop-outs, and withdrawals along with the explanation of leaving out particular
information from hypothesis testing

Deviations from the Clinical Investigation Plan

All the deviations from the CIP would be recorded with a justification. These devia-
tions would be communicated to the sponsor, who will analyze and evaluate its
significance. The reasons for retraction and suspension of any subject from the
study would be documented. The ethics committee or other regulatory authorities
can be involved if needed. If the reasons involve safety and lack of effectiveness,
that subject would still be followed up in the study, if feasible.

Amendments to the Clinical Investigation Plan

Any modifications to CIP shall be done only after agreement between sponsor and
the clinical investigator(s). These modifications would be recorded with required
explanations. If the list of clinical investigators and centers is changed, the list will
not be formally updated, and only sponsor would maintain the updated list and
make it available on request. The final list of all centers and investigators shall be
included in the final report.

Adverse Events and Adverse Device Effects

The CIP would contain:

• Emergency contact information for reporting of serious adverse events and seri-
ous adverse device effects
• Specifics of predictable adverse events and adverse device effects (e.g., serious/
nonserious, device-related/non-device-related, their probable incidence, meth-
ods for their management)
• Detailed procedures for reporting all adverse events and adverse device effects to
the sponsor, ethics committee, and other regulatory authorities in agreement with
18 K. Singh

relevant regulations, specifications of those types of events, device-related and

non-device-related that would be documented along with its timing

Early Termination and Suspension of the Investigation

The CIP would lay down the criteria and provisions for early termination or suspen-
sion of the study. This can apply to the whole study or one or more centers. If the
study includes blinding techniques, the rules to access and break the code have to be
described. The CIP would define the subject follow-up requirements to be consid-
ered after an early termination or suspension of the study, wherever relevant.

Publication Policy

Although all the data collected in the study should be put up for publication, still the
CIP shall state whether the results from the study would be submitted for publica-
tion or not. It would also specify the extent and the conditions under which the
results obtained from the clinical study would be proposed for publication.

Case Report Forms (CRF)

In CRF, all the information is listed that needs to be recorded during a study. The
CRF shall mirror the contents of the CIP and clearly show its version number. Any
amendments to the CRF would also contain a version number, and each page would
be marked by the study number and identification of the subjects, whose data are
present in the CRF. If the necessity of amending the CRF arises, the sponsor shall
determine whether the amendment is necessary or not by reviewing the CIP.

References

1. ISO 14155:2011 Clinical investigation of medical devices for human subjects—Part 1: General
requirements
2. ISO 14155:2011 Clinical investigation of medical devices for human subjects—Part 2: Clinical
investigation plans