What is quality assurance?

Quality Assurance (QA) in clinical trials consists of planned, systematic

activities that are conducted to ensure that a trial is performed―and that trial
data are generated, documented, and reported―in compliance with the
protocol, Good Clinical Practice (GCP) guidelines, and all other applicable
regulatory requirement(s).

Why is QA important?
Research that is not conducted according to high standards of quality yields
invalid data. It is also unethical because it may put research participants at
risk. (Protection of the safety, rights, and well-being of research participants is
discussed in the Introduction, Institutional Review Boards, Informed
Consent, and Participant Safety and Adverse Events modules.)

Audits conducted by the U.S. Food and Drug Administration (FDA) find that
several problems commonly occur in research studies.

Common problems found in FDA audits of research studies

 Failure to follow the protocol,

 Inadequate records that do not support the reported data,

 Failure to retain records for the required period of time,

 Inadequate study drug accountability,

 An inadequate informed consent process, and

 Failure to properly report adverse events.

Quality data are critical to ensure that the results of studies are interpreted
correctly. Sloppy or incorrect data can lead to misleading conclusions. Careful
attention to standards of quality also ensures that studies are completed in a
timely fashion. Timely completion of high quality studies bridges the gap
between research and practice by bringing effective new treatments to clients
more quickly.

Who is responsible for QA?

All members of the protocol team are responsible for QA.

While it is common for QA and monitoring-related duties and functions to be

transferred to a CRO, the sponsor has ultimate responsibility for
implementing and maintaining QA systems. (ICH GCP 5.1.1) This
responsibility includes oversight of all QA systems as well as any trial-related
functions performed or managed by other parties (i.e. the CRO, or a
subcontractor to the CRO) on behalf of the Sponsor (ICH GCP 5.2.2)

Investigators and every member of the protocol team are expected to perform
his or her duties diligently and thoroughly, thus ensuring that the trial is
conducted according to the highest possible standards of quality.

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QA Roles and Responsibilities in the NIDA Clinical Trials

Network

The CTN Policies and Procedures on QA

The sponsor is responsible for ensuring the trial’s integrity and for developing
a risk-based monitoring plan. As the sponsor of all studies conducted by the
network, NIDA CTN has transferred the regulatory responsibility of all
monitoring to the Clinical Coordinating Center (CCC).

The CCC develops systematic, prioritized, and risk-based (ICH GCP E6(R2)
5.18.3) monitoring plans to be utilized for each CTN study. This plan is
customized for each trial and describes the strategy, methods, responsibilities,
and requirements for monitoring the trial (ICH GCP E6(R2) 1.64).
Additionally, the plan provides operational guidelines to ensure the quality
and integrity of data collected in accordance with CTN protocols. This
document also ensures consistency in the conduct of CTN studies across
multiple sites and protocols. This monitoring plan:

 Emphasizes the monitoring of critical data and processes.

 Ensures the quality and integrity of CTN clinical studies.
 Ensures the protection of human participants.
 Advances collaboration between treatment and research staff at CTN
sites.

Roles and responsibilities of the Lead Investigator

The Lead Investigator (LI) is a CTN-specific role for the investigator that has
overall responsibility for the entire study. The LI convenes a Protocol Team
that assists with all aspects of the development and operation of the study. In
other studies outside of the CTN, this role may be considered the Principal
Investigator.

The Project Director (or Protocol Coordinator) is the LI’s “right hand.” He or
she is responsible for coordinating and carrying out day–to–day study
operations. The Project Director is a member of the Protocol Team and is the
primary contact for questions about the overall study. Other roles and
responsibilities represented on the Protocol Team usually include, but may not
be limited to, the following:

 Data Management
 Quality Assurance
 Training
 Regulatory Affairs

Roles and Responsibilities of the Node Principal

Investigator
The Node PI (or grantee) is another CTN-specific role that is responsible to
NIDA for study performance at his or her Node. He or she works with Node
staff, the Site Principal Investigator(s), and the Lead Investigator to implement
the study at that Node. The Node PI is responsible for ensuring that the study
runs smoothly at his or her Node and for taking appropriate action when
necessary to assist the Site PI(s) and the Lead Investigator. Other
responsibilities of the Node PI include:

 Appointing the Site PI and Study Coordinator.

 Managing the Node budget and staff.
 Appointing a monitor to conduct Quality Assurance visits at research
sites within the Node.
 Ensuring that study staff receives appropriate training to conduct the
study.
 Ensuring that the study receives all necessary IRB approvals and
follows all applicable regulations.
 Knowing the policies of his or her institution/university and ensuring
compliance at the Node with these policies.

The Monitoring Plan

The monitoring plan sets out monitoring strategies, the monitoring
responsibilities of all parties involved, the various monitoring methods to be
used, and the rationale for their use. It also describes monitoring procedures,
types of visits, what is involved in the conduct of those visits, and the quantity
or percentage of each type of document to be monitored. These procedures
can be further defined on a protocol basis depending on the purpose, design,
size, complexity, and primary outcome measures of the trial (ICH GCP
E6(R2) 5.18.3).

According to GCP guidelines, “the Sponsor may choose on-site monitoring, a

combination of on-site and centralized (remote) monitoring, or, where
justified, centralized monitoring alone…Centralized monitoring processes
provide additional monitoring capabilities that can complement or reduce the
extent and/or frequency of on-site monitoring and help distinguish between
reliable data and potentially unreliable data without the need for total source
data verification” (ICH GCP 5.18.3). The rationale for the chosen monitoring
strategy is documented in the monitoring plan.

In general, on-site monitoring is required and remote monitoring may occur at

any given research site before a trial begins, while it is in progress, and after it
concludes or is terminated. In many instances, study monitors may visit each
site after the first one to two participants are enrolled and then schedule
subsequent visits based on multivariate criteria, such as the rate of enrollment,
volume of data to review, site performance, and other considerations.
Study monitors conduct site visits according to the procedures describes in the
monitoring plan and in accordance with Good Clinical Practice (GCP)
guidelines.

Monitoring Role for Sponsors

The Good Clinical Practice guidelines state that the sponsor is responsible for
selecting monitors and for ensuring that the following criteria are met (see
ICH GCP 5.18.2).

 Monitors are appropriately trained and have the scientific or clinical

knowledge needed to monitor the trial adequately. Monitors
qualifications should be documented.
 Monitors are thoroughly familiar with the investigational product(s),
protocol, written informed consent form, and any other written
information about the trial to be provided to study participants, the
Sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).

Quality Assurance (QA)/Study Monitor Role

QA/study monitors perform the following study activities:

 Conduct initiation, interim, and closeout visits.

 Conduct centralized monitoring, as applicable.
 Provide training on protocol-specific issues and Good Clinical Practice,
when needed or appropriate.
 Follow-up on issues identified during earlier monitoring visits.
 File reports with the sponsor and other applicable parties, as required.
Monitoring responsibilities are described in detail in ICH GCP 5.18.4. Click
here for a summary.

Summary of monitors’ responsibilities

Monitors ensure that the trial is conducted properly by:

 Verifying that:
o Only eligible participants are being enrolled in the study.
 o Written informed consent was obtained before each participant's enrollment.

o The investigator has adequate qualifications, resources, and facilities (including laboratories,
equipment, and staff) to conduct the study.
o The investigator is following the approved protocol and any approved amendment(s).

o The investigator and trial staff are performing specified trial functions in accordance with
the protocol and have not delegated these functions to unauthorized individuals.

 For investigational product(s), verifying that:

o Storage times and conditions are acceptable and supplies adequate.

o Product(s) are supplied only to eligible participants and only at protocol-specified dose(s).

o Participants receive necessary instructions on the proper use, handling, storage, and return of
the product(s).
o Receipt, use, and return of the product(s) at study sites are adequately controlled and
documented.
o Disposition of unused product(s) at study sites complies with the applicable regulatory
requirement(s)
o The Investigator receives the current Investigator’s Brochure.

 Checking the accuracy, consistency, and completeness of entries on case report forms (CRFs), source
documents, and other trial-related records; specifically, verifying that:
o Modifications in dose or therapy are properly documented for each trial participant.

o Adverse events, concomitant medications, and intercurrent illnesses are reported in

accordance with the protocol on the CRFs.
o Missed visits, tests not conducted, and examinations not performed are clearly reported on
the CRFs.
o All withdrawals and dropouts of enrolled participants are reported and explained on the
CRFs

 Ensuring that corrections, additions, or deletions needed in the CRFs are made, dated, explained (if
necessary), and initialed by the investigator or by an authorized designee.

 Determining whether all adverse events are appropriately reported within the required time periods.

 Determining whether the investigator is maintaining essential documents for the conduct of a clinical
trial. (See the Record Keeping module for more information on essential documents.)

 Notifying the investigator of deviations from the protocol, SOPs, GCP, and applicable regulatory
requirements and taking appropriate action to prevent their recurrence.

 Notifying the investigator and sponsor of any noncompliance that significantly affects or has the
potential to significantly affect human subject protection or reliability of trial results.

 Participating in root cause analyses and ensuring that appropriate corrective and preventative actions
are implemented to correct each identified incidence of noncompliance.

 Initiation visits occur before a research site begins participant

recruitment for protocol participation and after the necessary IRB
approvals are obtained. During a site initiation visit, study monitors
review trial documents to ensure that they are complete and in order. A
listing of documents to be retained by sites before, during, and after a
trial can be found in ICH GCP Section 8. They will also inspect sites to
ensure that the facilities are appropriate, that the work and storage
 space necessary to conduct the trial are available, and that equipment,
medication, and supplies needed to start the trial are available. They
ensure that adequate staff is available and properly trained.
 Study monitors will document action items that need to be performed
by the site prior to site activation. Research sites cannot begin
participant recruitment until the Investigator(s) and sponsor have
provided their approval.

he requirements for monitoring while a trial is in progress are documented in

the Monitoring Plan. In general, monitors perform the following activities
while a trial is in progress:

 Assess the trial’s progress.

 Verify that the conduct of the trial is in compliance with the currently
approved protocol/amendment(s), with GCP guidelines, and with
applicable regulatory requirements.
 Verify that participant rights and well-being are protected.
 Verify the reported trial data (including source documents) are
attributable, legible, contemporaneous, original, accurate, and
complete. All data must be verifiable from source documents.
 Verify that the site has the adequate resources to continue the trial.
Specific monitoring functions during an interim site visit
Specific monitoring functions during an interim site visit include:

 Verifying the procedures for enrolling, assessing, treating, and following up with trial participants.
This includes reviews to ensure that:
o Informed Consent forms are properly completed and up to date

o Participants are appropriately screened and enrolled.

o Inclusion and exclusion criteria are applied properly.

o Randomization procedures are followed, and the blind is maintained.

o Trial assessments and treatment are conducted in compliance with the protocol.

o CRFs are filled out accurately, completely, legibly and verifiably based on the participant’s
source documentation.
o All source documents are attributable, legible, contemporaneous, original, accurate, and
complete.
o Medication dosing and documentation are in compliance with the protocol.

o All adverse events and serious adverse events have been documented and appropriately
reported to the Sponsor, Lead Investigator(s) and IRB.

 Reviewing drug accountability records for completeness and accuracy.

 Checking for changes in procedures or staffing that have occurred at the site since the previous visit.
For example, if a new Research Assistant or Site Coordinator has joined the research team, the
monitor must verify that he or she has received all the required training.

 Checking for protocol deviations/violations that may have occurred.

 Following up on unresolved issues from previous visits.

  Providing, or arranging for, additional staff training in problem areas.

Documents and activities that monitors may review during an interim site visit
Monitors may review any or all of the following documents and research activities during an interim site visit:

 The contents of the Regulatory, or Essential Documents, binder, especially those documents with
expiration dates.

 Site logs.

 Informed consent forms and participant enrollment records.

 Accountability records for trial drugs, as well as procedures for storing and dispensing these drugs.

 Protocol compliance.

 Reports of adverse events and serious adverse events.

 Case report forms and source documents for individual participants.

 Protocol violations, deviations and waivers.

 Staff adherence to data submission and correction rules and guidelines.

 Laboratory procedures.

 Site facilities and recruitment procedures.

 The continuing ability of the site and its staff to carry out the trial safely and in accordance with the
protocol.

 QA is the responsibility of every member of the research team. The role of

monitoring is to support and assist members of the research team in adhering to
high quality standards.
 The following list includes some helpful strategies to assist every team member
in assuring quality in clinical trials, as well as some strategies that are not
helpful. For each strategy listed, choose Yes to indicate that the strategy is
helpful for assuring quality or No if it is not.
 QUALITY ASSURANCE STRATEGIES

Thoroughly reviewing the research protocol, operations manual, standard operating procedures (SOPs),
training manuals and materials, and other relevant documents before the trial begins.

Choosing to monitor research sites arbitrarily, instead of developing and following a monitoring plan.

Following all instructions specified in the research protocol, operations manual, and SOPs, and doing so i
timely manner.

Requesting clarification of any instructions that are confusing or unclear.

Communicating openly with other members of the protocol team.

Documenting all actions.

Avoid following Good Clinical Practice guidelines.

Additionally, sponsor organizations can help to assure quality by:

 Providing all research team members with adequate training before the
trial begins.
 Monitoring progress early in the trial to assess the quality of screening,
recruitment, randomization, and documentation practices (for example,
after the first few participants have been randomly assigned to a
treatment group). This helps to ensure that any deficiencies are detected
early and at the source (i.e., at the site where the research is performed),
that inefficiencies and wasteful procedures are eliminated, and that any
necessary retraining is performed in a timely fashion. Early monitoring
also helps to reduce the likelihood that errors will occur later in the
trial, by providing additional information to help troubleshoot for future
risk mitigation strategies and risk-based monitoring of the study.
 Increasing the frequency of monitoring when necessary to correct any
deficiencies in the conduct of the trial or to provide technical support.
 Quality Assurance (QA) consists of planned, systematic activities
conducted to ensure that a trial is performed―and that trial data are
generated, documented, and reported―in compliance with the protocol
and with Good Clinical Practice (GCP) and all other applicable
regulatory requirement(s).
 QA is the responsibility of every member of the research team. The role
of QA staff is to support and assist members of the research team in
adhering to high quality standards.
 The purposes of monitoring are to verify that:
o The rights and well-being of human participants are protected.
o Reported trial data are attributable, legible, contemporaneous,
original, accurate, and complete.
o The trial is conducted in compliance with the currently approved
protocol (including any amendments), as well as with GCP and
all other applicable regulatory requirement(s).
 Monitoring can occur on-site and/or remotely (via centralized
monitoring), and it is required before, during, and after completion of a
trial.

The study protocol is a comprehensive plan of action that

contains information concerning the goals of the study, details
of subject recruitment, details of safety monitoring, and all
aspects of design, methodology, and analysis.
Monitoring is the act of overseeing the progress of a clinical trial, and of ensuring that it
is conducted, recorded, and reported in accordance with the protocol, Standard
Operating Procedures (SOPs), Good Clinical Practice (GCPs), and the applicable
regulatory requirement(s).

Good Cl P guidelines : A standard for the design, conduct, performance, monitoring,

auditing, recording, analyses, and reporting of clinical trials that provides assurance
that the data and reported results are credible and accurate, and that the rights,
integrity and confidentiality of trial subjects is protected.