Investigator's Qualifications and Agreements
The investigator(s) should be qualified by education, training, and
experience to assume responsibility for the proper conduct of the
trial, should meet all the qualifications specified by the applicable
regulatory requirement(s), and should provide evidence of such qualifications
through up-to-date curriculum vitae and/or other relevant documentation
requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).
The investigator should be thoroughly familiar with the appropriate
use of the investigational product(s), as described in the protocol,
in the current Investigator's Brochure, in the product information
and in other information sources provided by the sponsor.
The investigator should be aware of, and should comply with, GCP and
the applicable regulatory requirements.
The investigator/institution should permit monitoring and auditing
by the sponsor, and inspection by the appropriate regulatory authority(ies).
The investigator should maintain a list of appropriately qualified
persons to whom the investigator has delegated significant trial-related
The investigator should be able to demonstrate (e.g., based on retrospective
data) a potential for recruiting the required number of suitable subjects
within the agreed recruitment period.
The investigator should have sufficient time to properly conduct and
complete the trial within the agreed trial period.
The investigator should have available an adequate number of qualified
staff and adequate facilities for the foreseen duration of the trial
to conduct the trial properly and safely.
The investigator should ensure that all persons assisting with the
trial are adequately informed about the protocol, the investigational
product(s), and their trial-related duties and functions.
Medical Care of Trial Subjects
A qualified physician (or dentist, when appropriate), who is an investigator
or a sub-investigator for the trial, should be responsible for all
trial-related medical (or dental) decisions.
During and following a subject's participation in a trial, the investigator/institution
should ensure that adequate medical care is provided to a subject
for any adverse events, including clinically significant laboratory
values, related to the trial. The investigator/institution should
inform a subject when medical care is needed for intercurrent illness(es)
of which the investigator becomes aware.
It is recommended that the investigator inform the subject's primary
physician about the subject's participation in the trial if the subject
has a primary physician and if the subject agrees to the primary physician
Although a subject is not obliged to give his/her reason(s) for withdrawing
prematurely from a trial, the investigator should make a reasonable
effort to ascertain the reason(s), while fully respecting the subject's
Communication with IRB/IEC
Before initiating a trial, the investigator/institution should have
written and dated approval/favourable opinion from the IRB/IEC for
the trial protocol, written informed consent form, consent form updates,
subject recruitment procedures (e.g., advertisements), and any other
written information to be provided to subjects.
As part of the investigator's/institution's written application to
the IRB/IEC, the investigator/institution should provide the IRB/IEC
with a current copy of the Investigator's Brochure. If the Investigator's
Brochure is updated during the trial, the investigator/institution
should supply a copy of the updated Investigator's Brochure to the
During the trial the investigator/institution should provide to the
IRB/IEC all documents subject to review.
Compliance with Protocol
The investigator/institution should conduct the trial in compliance
with the protocol agreed to by the sponsor and, if required, by the
regulatory authority(ies) and which was given approval/favourable
opinion by the IRB/IEC. The investigator/institution and the sponsor
should sign the protocol, or an alternative contract, to confirm agreement.
The investigator should not implement any deviation from, or changes
of the protocol without agreement by the sponsor and prior review
and documented approval/favourable opinion from the IRB/IEC of an
amendment, except where necessary to eliminate an immediate hazard(s)
to trial subjects, or when the change(s) involves only logistical
or administrative aspects of the trial (e.g., change in monitor(s),
change of telephone number(s)).
The investigator, or person designated by the investigator, should
document and explain any deviation from the approved protocol.
The investigator may implement a deviation from, or a change of, the
protocol to eliminate an immediate hazard(s) to trial subjects without
prior IRB/IEC approval/favourable opinion. As soon as possible, the
implemented deviation or change, the reasons for it, and, if appropriate,
the proposed protocol amendment(s) should be submitted:
to the IRB/IEC for review and approval/favourable opinion,
to the sponsor for agreement and, if required,
to the regulatory authority(ies).
Responsibility for investigational product(s) accountability at the
trial site(s) rests with the investigator/institution.
Where allowed/required, the investigator/institution may/should assign
some or all of the investigator's/institution's duties for investigational
product(s) accountability at the trial site(s) to an appropriate pharmacist
or another appropriate individual who is under the supervision of
The investigator/institution and/or a pharmacist or other appropriate
individual, who is designated by the investigator/institution, should
maintain records of the product's delivery to the trial site, the
inventory at the site, the use by each subject, and the return to
the sponsor or alternative disposition of unused product(s). These
records should include dates, quantities, batch/serial numbers, expiration
dates (if applicable), and the unique code numbers assigned to the
investigational product(s) and trial subjects. Investigators should
maintain records that document adequately that the subjects were provided
the doses specified by the protocol and reconcile all investigational
product(s) received from the sponsor.
The investigational product(s) should be stored as specified by the
sponsor (see 5.13.2 and 5.14.3) and in accordance with applicable
The investigator should ensure that the investigational product(s)
are used only in accordance with the approved protocol.
The investigator, or a person designated by the investigator/institution,
should explain the correct use of the investigational product(s) to
each subject and should check, at intervals appropriate for the trial,
that each subject is following the instructions properly.
Randomization Procedures and Unblinding
investigator should follow the trial's randomization procedures, if
any, and should ensure that the code is broken only in accordance with
the protocol. If the trial is blinded, the investigator should promptly
document and explain to the sponsor any premature unblinding (e.g.,
accidental unblinding, unblinding due to a serious adverse event) of
the investigational product(s).
Informed Consent of Trial Subjects
In obtaining and documenting informed consent, the investigator should
comply with the applicable regulatory requirement(s), and should adhere
to GCP and to the ethical principles that have their origin in the
Declaration of Helsinki. Prior to the beginning of the trial, the
investigator should have the IRB/IEC's written approval/favourable
opinion of the written informed consent form and any other written
information to be provided to subjects.
The written informed consent form and any other written information
to be provided to subjects should be revised whenever important new
information becomes available that may be relevant to the subject's
consent. Any revised written informed consent form, and written information
should receive the IRB/IEC's approval/favourable opinion in advance
of use. The subject or the subject's legally acceptable representative
should be informed in a timely manner if new information becomes available
that may be relevant to the subject's willingness to continue participation
in the trial. The communication of this information should be documented.
Neither the investigator, nor the trial staff, should coerce or unduly
influence a subject to participate or to continue to participate in
None of the oral and written information concerning the trial, including
the written informed consent form, should contain any language that
causes the subject or the subject's legally acceptable representative
to waive or to appear to waive any legal rights, or that releases
or appears to release the investigator, the institution, the sponsor,
or their agents from liability for negligence.
The investigator, or a person designated by the investigator, should
fully inform the subject or, if the subject is unable to provide informed
consent, the subject's legally acceptable representative, of all pertinent
aspects of the trial including the written information given approval/favourable
opinion by the IRB/IEC.
The language used in the oral and written information about the trial,
including the written informed consent form, should be as non-technical
as practical and should be understandable to the subject or the subject's
legally acceptable representative and the impartial witness, where
Before informed consent may be obtained, the investigator, or a person
designated by the investigator, should provide the subject or the
subject's legally acceptable representative ample time and opportunity
to inquire about details of the trial and to decide whether or not
to participate in the trial. All questions about the trial should
be answered to the satisfaction of the subject or the subject's legally
Prior to a subject's participation in the trial, the written informed
consent form should be signed and personally dated by the subject
or by the subject's legally acceptable representative, and by the
person who conducted the informed consent discussion.
If a subject is unable to read or if a legally acceptable representative
is unable to read, an impartial witness should be present during the
entire informed consent discussion. After the written informed consent
form and any other written information to be provided to subjects,
is read and explained to the subject or the subject's legally acceptable
representative, and after the subject or the subject's legally acceptable
representative has orally consented to the subject's participation
in the trial and, if capable of doing so, has signed and personally
dated the informed consent form, the witness should sign and personally
date the consent form. By signing the consent form, the witness attests
that the information in the consent form and any other written information
was accurately explained to, and apparently understood by, the subject
or the subject's legally acceptable representative, and that informed
consent was freely given by the subject or the subject's legally acceptable
Both the informed consent discussion and the written informed consent
form and any other written information to be provided to subjects
should include explanations of the following:
That the trial involves research.
The purpose of the trial.
The trial treatment(s) and the probability for random assignment
to each treatment.
The trial procedures to be followed, including all invasive procedures.
The subject's responsibilities.
Those aspects of the trial that are experimental.
The reasonably foreseeable risks or inconveniences to the subject
and, when plicable, to an embryo, fetus, or nursing infant.
The reasonably expected benefits. When there is no intended clinical
benefit to the subject, the subject should be made aware of this.
The alternative procedure(s) or course(s) of treatment that may
be available to the subject, and their important potential benefits
The compensation and/or treatment available to the subject in the
event of trial-related injury.
The anticipated prorated payment, if any, to the subject for participating
in the trial.
The anticipated expenses, if any, to the subject for participating
in the trial.
That the subject's participation in the trial is voluntary and that
the subject may refuse to participate or withdraw from the trial,
at any time, without penalty or loss of benefits to which the subject
is otherwise entitled.
That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory
authority(ies) will be granted direct access to the subject's original
medical records for verification of clinical trial procedures and/or
data, without violating the confidentiality of the subject, to the
extent permitted by the applicable laws and regulations and that,
by signing a written informed consent form, the subject or the subject's
legally acceptable representative is authorizing such access.
That records identifying the subject will be kept confidential and,
to the extent permitted by the applicable laws and/or regulations,
will not be made publicly available. If the results of the trial
are published, the subject's identity will remain confidential.
That the subject or the subject's legally acceptable representative
will be informed in a timely manner if information becomes available
that may be relevant to the subject's willingness to continue participation
in the trial.
The person(s) to contact for further information regarding the trial
and the rights of trial subjects, and whom to contact in the event
of trial-related injury.
The foreseeable circumstances and/or reasons under which the subject's
participation in the trial may be terminated.
The expected duration of the subject's participation in the trial.
The approximate number of subjects involved in the trial.
Prior to participation in the trial, the subject or the subject's
legally acceptable representative should receive a copy of the signed
and dated written informed consent form and any other written information
provided to the subjects. During a subject's participation in the
trial, the subject or the subject's legally acceptable representative
should receive a copy of the signed and dated consent form updates
and a copy of any amendments to the written information provided to
When a clinical trial (therapeutic or non-therapeutic) includes subjects
who can only be enrolled in the trial with the consent of the subject's
legally acceptable representative (e.g., minors, or patients with
severe dementia), the subject should be informed about the trial to
the extent compatible with the subject's understanding and, if capable,
the subject should sign and personally date the written informed consent.
Except as described in 4.8.14, a non-therapeutic trial (i.e., a trial
in which there is no anticipated direct clinical benefit to the subject),
should be conducted in subjects who personally give consent and who
sign and date the written informed consent form.
Non-therapeutic trials may be conducted in subjects with consent of
a legally acceptable representative provided the following conditions
The objectives of the trial can not be met by means of a trial in
subjects who can give informed consent personally.
The foreseeable risks to the subjects are low.
The negative impact on the subject's well-being is minimized and
The trial is not prohibited by law.
The approval/favourable opinion of the IRB/IEC is expressly sought
on the inclusion of such subjects, and the written approval/favourable
opinion covers this aspect.
Such trials, unless an exception is justified, should be conducted
in patients having a disease or condition for which the investigational
product is intended. Subjects in these trials should be particularly
closely monitored and should be withdrawn if they appear to be unduly
In emergency situations, when prior consent of the subject is not
possible, the consent of the subject's legally acceptable representative,
if present, should be requested. When prior consent of the subject
is not possible, and the subject's legally acceptable representative
is not available, enrollment of the subject should require measures
described in the protocol and/or elsewhere, with documented approval/favourable
opinion by the IRB/IEC, to protect the rights, safety and well-being
of the subject and to ensure compliance with applicable regulatory
requirements. The subject or the subject's legally acceptable representative
should be informed about the trial as soon as possible and consent
to continue and other consent as appropriate (see 4.8.10) should be
Records and Reports
The investigator should ensure the accuracy, completeness, legibility,
and timeliness of the data reported to the sponsor in the CRFs and
in all required reports.
Data reported on the CRF, that are derived from source documents,
should be consistent with the source documents or the discrepancies
should be explained.
Any change or correction to a CRF should be dated, initialed, and
explained (if necessary) and should not obscure the original entry
(i.e., an audit trail should be maintained); this applies to both
written and electronic changes or corrections (see 5.18.4 (n)). Sponsors
should provide guidance to investigators and/or the investigators'
designated representatives on making such corrections. Sponsors should
have written procedures to assure that changes or corrections in CRFs
made by sponsor's designated representatives are documented, are necessary,
and are endorsed by the investigator. The investigator should retain
records of the changes and corrections.
The investigator/institution should maintain the trial documents as
specified in Essential Documents for the Conduct of a Clinical Trial
(see 8.) and as required by the applicable regulatory requirement(s).
The investigator/institution should take measures to prevent accidental
or premature destruction of these documents.
Essential documents should be retained until at least 2 years after
the last approval of a marketing application in an ICH region and
until there are no pending or contemplated marketing applications
in an ICH region or at least 2 years have elapsed since the formal
discontinuation of clinical development of the investigational product.
These documents should be retained for a longer period however if
required by the applicable regulatory requirements or by an agreement
with the sponsor. It is the responsibility of the sponsor to inform
the investigator/institution as to when these documents no longer
need to be retained (see 5.5.12).
The financial aspects of the trial should be documented in an agreement
between the sponsor and the investigator/institution.
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority,
the investigator/institution should make available for direct access
all requested trial-related records.
The investigator should submit written summaries of the trial status
to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.
The investigator should promptly provide written reports to the sponsor,
the IRB/IEC (see 3.3.8) and, where applicable, the institution on
any changes significantly affecting the conduct of the trial, and/or
increasing the risk to subjects.
All serious adverse events (SAEs) should be reported immediately to
the sponsor except for those SAEs that the protocol or other document
(e.g., Investigator's Brochure) identifies as not needing immediate
reporting. The immediate reports should be followed promptly by detailed,
written reports. The immediate and follow-up reports should identify
subjects by unique code numbers assigned to the trial subjects rather
than by the subjects' names, personal identification numbers, and/or
addresses. The investigator should also comply with the applicable
regulatory requirement(s) related to the reporting of unexpected serious
adverse drug reactions to the regulatory authority(ies) and the IRB/IEC.
Adverse events and/or laboratory abnormalities identified in the protocol
as critical to safety evaluations should be reported to the sponsor
according to the reporting requirements and within the time periods
specified by the sponsor in the protocol.
For reported deaths, the investigator should supply the sponsor and
the IRB/IEC with any additional requested information (e.g., autopsy
reports and terminal medical reports).
Premature Termination or Suspension of a Trial
the trial is prematurely terminated or suspended for any reason, the
investigator/institution should promptly inform the trial subjects,
should assure appropriate therapy and follow-up for the subjects, and,
where required by the applicable regulatory requirement(s), should inform
the regulatory authority(ies). In addition:
If the investigator terminates or suspends a trial without prior agreement
of the sponsor, the investigator should inform the institution where
applicable, and the investigator/institution should promptly inform
the sponsor and the IRB/IEC, and should provide the sponsor and the
IRB/IEC a detailed written explanation of the termination or suspension.
If the sponsor terminates or suspends a trial (see 5.21), the investigator
should promptly inform the institution where applicable and the investigator/institution
should promptly inform the IRB/IEC and provide the IRB/IEC a detailed
written explanation of the termination or suspension.
If the IRB/IEC terminates or suspends its approval/favourable opinion
of a trial (see 3.1.2 and 3.3.9), the investigator should inform the
institution where applicable and the investigator/institution should
promptly notify the sponsor and provide the sponsor with a detailed
written explanation of the termination or suspension.
Final Report(s) by Investigator
completion of the trial, the investigator, where applicable, should
inform the institution; the investigator/institution should provide
the IRB/IEC with a summary of the trial's outcome, and the regulatory
authority(ies) with any reports required.