Quality Assurance and Quality Control
The sponsor is responsible for implementing and maintaining quality
assurance and quality control systems with written SOPs to ensure
that trials are conducted and data are generated, documented (recorded),
and reported in compliance with the protocol, GCP, and the applicable
The sponsor is responsible for securing agreement from all involved
parties to ensure direct access (see 1.21) to all trial related sites,
source data/documents, and reports for the purpose of monitoring and
auditing by the sponsor, and inspection by domestic and foreign regulatory
Quality control should be applied to each stage of data handling to
ensure that all data are reliable and have been processed correctly.
Agreements, made by the sponsor with the investigator/institution
and any other parties involved with the clinical trial, should be
in writing, as part of the protocol or in a separate agreement.
Contract Research Organization (CRO)
A sponsor may transfer any or all of the sponsor's trial-related duties
and functions to a CRO, but the ultimate responsibility for the quality
and integrity of the trial data always resides with the sponsor. The
CRO should implement quality assurance and quality control.
Any trial-related duty and function that is transferred to and assumed
by a CRO should be specified in writing.
Any trial-related duties and functions not specifically transferred
to and assumed by a CRO are retained by the sponsor.
All references to a sponsor in this guideline also apply to a CRO
to the extent that a CRO has assumed the trial related duties and
functions of a sponsor.
sponsor should designate appropriately qualified medical personnel who
will be readily available to advise on trial related medical questions
or problems. If necessary, outside consultant(s) may be appointed for
The sponsor should utilize qualified individuals (e.g. biostatisticians,
clinical pharmacologists, and physicians) as appropriate, throughout
all stages of the trial process, from designing the protocol and CRFs
and planning the analyses to analyzing and preparing interim and final
clinical trial reports.
For further guidance: Clinical Trial Protocol and Protocol Amendment(s)
(see 6.), the ICH Guideline for Structure and Content of Clinical
Study Reports, and other appropriate ICH guidance on trial design,
protocol and conduct.
Trial Management, Data Handling, and Record Keeping
The sponsor should utilize appropriately qualified individuals to
supervise the overall conduct of the trial, to handle the data, to
verify the data, to conduct the statistical analyses, and to prepare
the trial reports.
The sponsor may consider establishing an independent data-monitoring
committee (IDMC) to assess the progress of a clinical trial, including
the safety data and the critical efficacy endpoints at intervals,
and to recommend to the sponsor whether to continue, modify, or stop
a trial. The IDMC should have written operating procedures and maintain
written records of all its meetings.
When using electronic trial data handling and/or remote electronic
trial data systems, the sponsor should:
Ensure and document that the electronic data processing system(s)
conforms to the sponsor's established requirements for completeness,
accuracy, reliability, and consistent intended performance (i.e.,
Maintains SOPs for using these systems.
Ensure that the systems are designed to permit data changes in such
a way that the data changes are documented and that there is no
deletion of entered data (i.e., maintain an audit trail, data trail,
Maintain a security system that prevents unauthorized access to
Maintain a list of the individuals who are authorized to make data
changes (see 4.1.5 and 4.9.3).
Maintain adequate backup of the data.
Safeguard the blinding, if any (e.g., maintain the blinding during
data entry and processing).
If data are transformed during processing, it should always be possible
to compare the original data and observations with the processed data.
The sponsor should use an unambiguous subject identification code
(see 1.58) that allows identification of all the data reported for
The sponsor, or other owners of the data, should retain all of the
sponsor-specific essential documents pertaining to the trial (see
8. Essential Documents for the Conduct of a Clinical Trial).
The sponsor should retain all sponsor-specific essential documents
in conformance with the applicable regulatory requirement(s) of the
country(ies) where the product is approved, and/or where the sponsor
intends to apply for approval(s).
If the sponsor discontinues the clinical development of an investigational
product (i.e., for any or all indications, routes of administration,
or dosage forms), the sponsor should maintain all sponsor-specific
essential documents for at least 2 years after formal discontinuation
or in conformance with the applicable regulatory requirement(s).
If the sponsor discontinues the clinical development of an investigational
product, the sponsor should notify all the trial investigators/institutions
and all the regulatory authorities.
Any transfer of ownership of the data should be reported to the appropriate
authority(ies), as required by the applicable regulatory requirement(s).
The sponsor-specific 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 requirement(s) or if needed
by the sponsor.
The sponsor should inform the investigator(s)/institution(s) in writing
of the need for record retention and should notify the investigator(s)/institution(s)
in writing when the trial related records are no longer needed.
The sponsor is responsible for selecting the investigator(s)/institution(s).
Each investigator should be qualified by training and experience and
should have adequate resources (see 4.1, 4.2) to properly conduct
the trial for which the investigator is selected. If organization
of a coordinating committee and/or selection of coordinating investigator(s)
are to be utilized in multicentre trials, their organization and/or
selection are the sponsor's responsibility.
Before entering an agreement with an investigator/institution to conduct
a trial, the sponsor should provide the investigator(s)/institution(s)
with the protocol and an up-to-date Investigator's Brochure, and should
provide sufficient time for the investigator/institution to review
the protocol and the information provided.
The sponsor should obtain the investigator's/institution's agreement:
to conduct the trial in compliance with GCP, with the applicable
regulatory requirement(s) (see 4.1.3), and with the protocol agreed
to by the sponsor and given approval/favourable opinion by the IRB/IEC
to comply with procedures for data recording/reporting;
to permit monitoring, auditing and inspection (see 4.1.4) and
to retain the trial related essential documents until the sponsor
informs the investigator/institution these documents are no longer
needed (see 4.9.4 and 5.5.12).
sponsor and the investigator/institution should sign the protocol,
or an alternative document, to confirm this agreement.
Allocation of Duties and Functions
to initiating a trial, the sponsor should define, establish, and allocate
all trial-related duties and functions.
Compensation to Subjects and Investigators
If required by the applicable regulatory requirement(s), the sponsor
should provide insurance or should indemnify (legal and financial
coverage) the investigator/the institution against claims arising
from the trial, except for claims that arise from malpractice and/or
The sponsor's policies and procedures should address the costs of
treatment of trial subjects in the event of trial-related injuries
in accordance with the applicable regulatory requirement(s).
When trial subjects receive compensation, the method and manner of
compensation should comply with applicable regulatory requirement(s).
financial aspects of the trial should be documented in an agreement
between the sponsor and the investigator/institution.
Notification/Submission to Regulatory Authority(ies)
initiating the clinical trial(s), the sponsor (or the sponsor and the
investigator, if required by the applicable regulatory requirement(s))
should submit any required application(s) to the appropriate authority(ies)
for review, acceptance, and/or permission (as required by the applicable
regulatory requirement(s))to begin the trial(s). Any notification/submission
should be dated and contain sufficient information to identify the protocol.
Confirmation of Review by IRB/IEC
The sponsor should obtain from the investigator/institution:
The name and address of the investigator's/institution's IRB/IEC.
A statement obtained from the IRB/IEC that it is organized and operates
according to GCP and the applicable laws and regulations.
Documented IRB/IEC approval/favourable opinion and, if requested
by the sponsor, a current copy of protocol, written informed consent
form(s) and any other written information to be provided to subjects,
subject recruiting procedures, and documents related to payments
and compensation available to the subjects, and any other documents
that the IRB/IEC may have requested.
If the IRB/IEC conditions its approval/favourable opinion upon change(s)
in any aspect of the trial, such as modification(s) of the protocol,
written informed consent form and any other written information to
be provided to subjects, and/or other procedures, the sponsor should
obtain from the investigator/ institution a copy of the modification(s)
made and the date approval/favourable opinion was given by the IRB/IEC
The sponsor should obtain from the investigator/institution documentation
and dates of any IRB/IEC re-approvals/re-evaluations with favourable
opinion, and of any withdrawals or suspensions of approval/ favourable
Information on Investigational Product(s)
When planning trials, the sponsor should ensure that sufficient safety
and efficacy data from nonclinical studies and/or clinical trials
are available to support human exposure by the route, at the dosages,
for the duration, and in the trial population to be studied.
The sponsor should update the Investigator's Brochure as significant
new information becomes available (see 7. Investigator's Brochure).
Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)
The sponsor should ensure that the investigational product(s) (including
active comparator(s) and placebo, if applicable) is characterized
as appropriate to the stage of development of the product(s), is manufactured
in accordance with any applicable GMP, and is coded and labelled in
a manner that protects the blinding, if applicable. In addition, the
labelling should comply with applicable regulatory requirement(s).
The sponsor should determine, for the investigational product(s),
acceptable storage temperatures, storage conditions (e.g., protection
from light), storage times, reconstitution fluids and procedures,
and devices for product infusion, if any. The sponsor should inform
all involved parties (e.g., monitors, investigators, pharmacists,
storage managers) of these determinations.
The investigational product(s) should be packaged to prevent contamination
and unacceptable deterioration during transport and storage.
In blinded trials, the coding system for the investigational product(s)
should include a mechanism that permits rapid identification of the
product(s) in case of a medical emergency, but does not permit undetectable
breaks of the blinding.
If significant formulation changes are made in the investigational
or comparator product(s) during the course of clinical development,
the results of any additional studies of the formulated product(s)
(e.g., stability, dissolution rate, bioavailability) needed to assess
whether these changes would significantly alter the pharmacokinetic
profile of the product should be available prior to the use of the
new formulation in clinical trials.
Supplying and Handling Investigational Product(s)
The sponsor is responsible for supplying the investigator(s)/institution(s)
with the investigational product(s).
The sponsor should not supply an investigator/institution with the
investigational product(s) until the sponsor obtains all required
documentation (e.g., approval/favourable opinion from IRB/IEC and
The sponsor should ensure that written procedures include instructions
that the investigator/institution should follow for the handling and
storage of investigational product(s) for the trial and documentation
thereof. The procedures should address adequate and safe receipt,
handling, storage, dispensing, retrieval of unused product from subjects,
and return of unused investigational product(s) to the sponsor (or
alternative disposition if authorized by the sponsor and in compliance
with the applicable regulatory requirement(s)).
The sponsor should:
Ensure timely delivery of investigational product(s) to the investigator(s).
Maintain records that document shipment, receipt, disposition, return,
and destruction of the investigational product(s) (see 8. Essential
Documents for the Conduct of a Clinical Trial).
Maintain a system for retrieving investigational products and documenting
this retrieval (e.g., for deficient product recall, reclaim after
trial completion, expired product reclaim).
Maintain a system for the position of unused investigational product(s)
and for the documentation of this disposition.
The sponsor should:
Take steps to ensure that the investigational product(s) are stable
over the period of use.
Maintain sufficient quantities of the investigational product(s)
used in the trials to reconfirm specifications, should this become
necessary, and maintain records of batch sample analyses and characteristics.
To the extent stability permits, samples should be retained either
until the analyses of the trial data are complete or as required
by the applicable regulatory requirement(s), whichever represents
the longer retention period.
The sponsor should ensure that it is specified in the protocol or
other written agreement that the investigator(s)/institution(s) provide
direct access to source data/documents for trial-related monitoring,
audits, IRB/IEC review, and regulatory inspection.
The sponsor should verify that each subject has consented, in writing,
to direct access to his/her original medical records for trial-related
monitoring, audit, IRB/IEC review, and regulatory inspection.
The sponsor is responsible for the ongoing safety evaluation of the
The sponsor should promptly notify all concerned investigator(s)/institution(s)
and the regulatory authority(ies) of findings that could affect adversely
the safety of subjects, impact the conduct of the trial, or alter
the IRB/IEC's approval/favourable opinion to continue the trial.
Adverse Drug Reaction Reporting
The sponsor should expedite the reporting to all concerned investigator(s)/institution(s),
to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies)
of all adverse drug reactions (ADRs) that are both serious and unexpected.
Such expedited reports should comply with the applicable regulatory
requirement(s) and with the ICH Guideline for Clinical Safety Data
Management: Definitions and Standards for Expedited Reporting.
The sponsor should submit to the regulatory authority(ies) all safety
updates and periodic reports, as required by applicable regulatory
The purposes of trial monitoring are to verify that:
The rights and well-being of human subjects are protected.
The reported trial data are accurate, complete, and verifiable from
The conduct of the trial is in compliance with the currently approved
protocol/amendment(s), with GCP, and with the applicable regulatory
Selection and Qualifications of Monitors
Monitors should be appointed by the sponsor.
Monitors should be appropriately trained, and should have the scientific
and/or clinical knowledge needed to monitor the trial adequately.
A monitor's qualifications should be documented.
Monitors should be thoroughly familiar with the investigational
product(s), the protocol, written informed consent form and any
other written information to be provided to subjects, the sponsor's
SOPs, GCP, and the applicable regulatory requirement(s).
Extent and Nature of Monitoring
The sponsor should ensure that the trials are adequately monitored.
The sponsor should determine the appropriate extent and nature of
monitoring. The determination of the extent and nature of monitoring
should be based on considerations such as the objective, purpose,
design, complexity, blinding, size, and endpoints of the trial. In
general there is a need for on-site monitoring, before, during, and
after the trial; however in exceptional circumstances the sponsor
may determine that central monitoring in conjunction with procedures
such as investigators' training and meetings, and extensive written
guidance can assure appropriate conduct of the trial in accordance
with GCP. Statistically controlled sampling may be an acceptable method
for selecting the data to be verified.
The monitor(s) in accordance with the sponsor's requirements should
ensure that the trial is conducted and documented properly by carrying
out the following activities when relevant and necessary to the trial
and the trial site:
Acting as the main line of communication between the sponsor and
Verifying that the investigator has adequate qualifications and
resources (see 4.1, 4.2, 5.6) and remain adequate throughout the
trial period, that facilities, including laboratories, equipment,
and staff, are adequate to safely and properly conduct the trial
and remain adequate throughout the trial period.
Verifying, for the investigational product(s):
That storage times and conditions are acceptable, and that supplies
are sufficient throughout the trial
That the investigational product(s) are supplied only to subjects
who are eligible to receive it and at the protocol specified dose(s).
That subjects are provided with necessary instruction on properly
using, handling, storing, and returning the investigational product(s).
That the receipt, use, and return of the investigational product(s)
at the trial sites are controlled and documented adequately.
That the disposition of unused investigational product(s) at the
trial sites complies with applicable regulatory requirement(s)
and is in accordance with the sponsor.
Verifying that the investigator follows the approved protocol and
all approved amendment(s), if any.
Verifying that written informed consent was obtained before each
subject's participation in the trial.
Ensuring that the investigator receives the current Investigator's
Brochure, all documents, and all trial supplies needed to conduct
the trial properly and to comply with the applicable regulatory
Ensuring that the investigator and the investigator's trial staff
are adequately informed about the trial.
Verifying that the investigator and the investigator's trial staff
are performing the specified trial functions, in accordance with
the protocol and any other written agreement between the sponsor
and the investigator/institution, and have not delegated these functions
to unauthorized individuals.
Verifying that the investigator is enrolling only eligible subjects.
Reporting the subject recruitment rate.
Verifying that source documents and other trial records are accurate,
complete, kept up-to-date and maintained.
Verifying that the investigator provides all the required reports,
notifications, applications, and submissions, and that these documents
are accurate, complete, timely, legible, dated, and identify the
Checking the accuracy and completeness of the CRF entries, source
documents and other trial-related records against each other. The
monitor specifically should verify that:
The data required by the protocol are reported accurately on the
CRFs and are consistent with the source documents.
Any dose and/or therapy modifications are well documented for
each of the trial subjects.
Adverse events, concomitant medications and intercurrent illnesses
are reported in accordance with the protocol on the CRFs.
Visits that the subjects fail to make, tests that are not conducted,
and examinations that are not performed are clearly reported as
such on the CRFs.
All withdrawals and dropouts of enrolled subjects from the trial
are reported and explained on the CRFs.
Informing the investigator of any CRF entry error, omission, or
illegibility. The monitor should ensure that appropriate corrections,
additions, or deletions are made, dated, explained (if necessary),
and initialled by the investigator or by a member of the investigator's
trial staff who is authorized to initial CRF changes for the investigator.
This authorization should be documented.
Determining whether all adverse events (AEs) are appropriately reported
within the time periods required by GCP, the protocol, the IRB/IEC,
the sponsor, and the applicable regulatory requirement(s).
Determining whether the investigator is maintaining the essential
documents (see 8. Essential Documents for the Conduct of a Clinical
Communicating deviations from the protocol, SOPs, GCP, and the applicable
regulatory requirements to the investigator and taking appropriate
action designed to prevent recurrence of the detected deviations.
The monitor(s) should follow the sponsor's established written SOPs
as well as those procedures that are specified by the sponsor for
monitoring a specific trial.
The monitor should submit a written report to the sponsor after
each trial-site visit or trial-related communication.
Reports should include the date, site, name of the monitor, and
name of the investigator or other individual(s) contacted.
Reports should include a summary of what the monitor reviewed and
the monitor's statements concerning the significant findings/facts,
deviations and deficiencies, conclusions, actions taken or to be
taken and/or actions recommended to secure compliance.
The review and follow-up of the monitoring report with the sponsor
should be documented by the sponsor's designated representative.
If or when sponsors perform audits, as part of implementing quality
assurance, they should consider:
The purpose of a sponsor's audit, which is independent of and separate
from routine monitoring or quality control functions, should be to
evaluate trial conduct and compliance with the protocol, SOPs, GCP,
and the applicable regulatory requirements.
Selection and Qualification of Auditors
The sponsor should appoint individuals, who are independent of the
clinical trials/systems, to conduct audits.
The sponsor should ensure that the auditors are qualified by training
and experience to conduct audits properly. An auditor's qualifications
should be documented.
The sponsor should ensure that the auditing of clinical trials/systems
is conducted in accordance with the sponsor's written procedures
on what to audit, how to audit, the frequency of audits, and the
form and content of audit reports.
The sponsor's audit plan and procedures for a trial audit should
be guided by the importance of the trial to submissions to regulatory
authorities, the number of subjects in the trial, the type and complexity
of the trial, the level of risks to the trial subjects, and any
The observations and findings of the auditor(s) should be documented.
preserve the independence and value of the audit function, the regulatory
authority(ies) should not routinely request the audit reports. Regulatory
authority(ies) may seek access to an audit report on a case by case
basis when evidence of serious GCP non-compliance exists, or in
the course of legal proceedings.
When required by applicable law or regulation, the sponsor should
provide an audit certificate.
Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory
requirement(s) by an investigator/institution, or by member(s) of
the sponsor's staff should lead to prompt action by the sponsor to
If the monitoring and/or auditing identifies serious and/or persistent
noncompliance on the part of an investigator/institution, the sponsor
should terminate the investigator's/institution's participation in
the trial. When an investigator's/institution's participation is terminated
because of noncompliance, the sponsor should notify promptly the regulatory
Premature Termination or Suspension of a Trial
a trial is prematurely terminated or suspended, the sponsor should promptly
inform the investigators/institutions, and the regulatory authority(ies)
of the termination or suspension and the reason(s) for the termination
or suspension. The IRB/IEC should also be informed promptly and provided
the reason(s) for the termination or suspension by the sponsor or by
the investigator/institution, as specified by the applicable regulatory
Clinical Trial/Study Reports
the trial is completed or prematurely terminated, the sponsor should
ensure that the clinical trial reports are prepared and provided to
the regulatory agency(ies) as required by the applicable regulatory
requirement(s). The sponsor should also ensure that the clinical trial
reports in marketing applications meet the standards of the ICH Guideline
for Structure and Content of Clinical Study Reports. (NOTE: The ICH
Guideline for Structure and Content of Clinical Study Reports specifies
that abbreviated study reports may be acceptable in certain cases.)
multicentre trials, the sponsor should ensure that:
All investigators conduct the trial in strict compliance with the
protocol agreed to by the sponsor and, if required, by the regulatory
authority(ies), and given approval/favourable opinion by the IRB/IEC.
The CRFs are designed to capture the required data at all multicentre
trial sites. For those investigators who are collecting additional
data, supplemental CRFs should also be provided that are designed
to capture the additional data.
The responsibilities of coordinating investigator(s) and the other
participating investigators are documented prior to the start of the
All investigators are given instructions on following the protocol,
on complying with a uniform set of standards for the assessment of
clinical and laboratory findings, and on completing the CRFs.
Communication between investigators is facilitated.