Clinical Research Qa Audit Checklist - PDF by emt12705

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									              PEER REVIEWED

                                                                                                                   I S S U E S
                                 Florence Noël, PhD, CCRC, CCRP | Bambi Grilley, RPh, CCRP, CCRC, CIP

                                 A Peer-reviewed

                                                                                                                   I N
                                                                                                                   C L I N I C A L
                                 Quality Assurance Program
                                 at a Clinical Research Site

                                                                                                                   R E S E A R C H
                                   mplementation of Good Clinical Practice (GCP) at clinical research sites has
                                   been a challenge. Problems such as incomplete and inaccurate medical
                                 records, failure to adhere to experimental protocols, poor drug accountability,
                                 inadequate documentation of informed consent, and insufficient reporting of
                                 adverse events led the Food and Drug Administration (FDA) to develop guide-
                                 lines mandating Quality Assurance (QA) for clinical research.1,2 The develop-
                                 ment, by clinical research sites, of site-based QA programs could proactively
                                 address these problems and provide a guarantee to ensure data integrity and
                                 regulatory compliance. Such programs are starting to appear nationwide.3 We
The goal of our QA program is    describe here the implementation of a QA program at Texas Children’s Cancer
                                 Center (TCCC) and the Center for Cell and Gene Therapy (CAGT). The goal of
to ensure the accuracy and       our QA program is to ensure the accuracy and integrity of clinical research
                                 activities and compliance with FDA regulations, the International Conference
integrity of clinical research   of Harmonization (ICH) Good Clinical Practice: Consolidated Guideline, and
                                 institutional standard operating procedures (SOPs) with the ultimate goal of
activities.                      achieving a high-quality clinical research operation (Table 1).
                                    The article reviews the design and steps of development of our QA program,
                                 as well as the nuts and bolts of a QA audit. The challenges encountered during
                                 the development and implementation of this program are also discussed, along
                                 with the benefits of a site-based peer reviewed QA program.

                                 Design and Development

                                 As the central component of our QA program, a peer-review system was devel-
                                 oped to review all program activities (Figure 1).

                                 Peer Review

                                 An oversight committee consisting of seven peer investigators guides the QA
                                 activities. The committee developed a policy and procedure manual and devel-
                                 oped institutional SOPs. The committee also reviews the results of QA audits
                                 and makes decisions on the proper course of action to be taken if issues remain
                                 unresolved during and after a QA audit.

                                                                                         PEER REVIEWED     R 31
   Table 1. Goals of Peer-reviewed            the QA analyst works independently               ●   the components of the audit chart
            Quality Assurance                 from the institution clinical research           ●   the method to notify the study
            Program                           operations and is neither an investigator            team of an upcoming audit
 i. Ensure accuracy and integrity of          nor a clinical study coordinator to ensure       ●   specifications regarding which
      clinical research activities            a complete absence of conflict of interest.           documents will be reviewed as part
 ii. Ensure compliance with FDA                                                                    of the audit
      regulations                                                                              ●   the format of the audit report
                                              Policy and Procedures and SOPs
 iii. Ensure compliance with ICH GCP:                                                          ●   the conduct of the exit interview
      Consolidated Guideline                  The first step in developing the QA pro-          ●   the distribution of the audit report
 iv. Ensure compliance with institutional     gram was writing the policy and pro-             ●   the format and timeframe for
      standard operating procedures           cedures and SOPs. The QA analyst, in                 response to the audit report, and
                                              collaboration with the institution’s             ●   the review by the oversight com-
                                              investigators and under the guidance of              mittee of both the audit report and
                                              the oversight committee, developed a
Quality Assurance Analyst                                                                          the response to the audit report.
                                              policy and procedure manual. This man-
The QA analyst is responsible for execut-     ual details the purpose, scope, responsi-        We distributed a draft of the QA Pol-
ing QA audits. The QA analyst is familiar     bilities, selection criteria, and audit       icy and Procedures, as well as the QA
with all processes involved in performing     process. The final version was presented       SOP, to the investigators and clinical
clinical studies at the institution includ-   to the institution’s lawyers for review and   research staff for review and comment.
ing regulatory requirements, protocol         approval. One outcome of the collabora-
                                                                                            The oversight committee then has final
requirements, protocol-specific proce-        tion with the legal department was that
                                                                                            approval over both documents. Fol-
dures, the process of accountability of       the QA program became part of the
                                                                                            lowing approval, we initiated the QA
investigational drugs/biologics, study        physician peer review process for the
coordination, medical records, and data       institution; as a result, findings from QA
capture and recording. The QA analyst         audits are considered confidential.
must establish a relationship with all            As a second step, an SOP was written      The Quality Assurance
personnel involved in each clinical trial     to detail technical matters of the audit      Audit Process
operation in order to facilitate the audit    process. Included in the SOP are the
process. The QA analyst and oversight         following:                                    The chronological steps of a QA audit
committee meet regularly to review                                                          are detailed below (Table 2).
results of QA audits and discuss QA              ●    a description of how studies to be
activities. It is important to stress that            audited are selected                  Selection of Study

                                                                                            Selection of the study to be audited is the
     Figure 1. A Peer-review System Developed to Review All Program Activities
                                                                                            first step of a QA audit. All investigator-
                                                                                            initiated clinical studies involving treat-
                                      Peer-review                                           ment can be subjected to the QA audit.
                                  Oversight Committee                                       We use a computer-generated random-
                                                                                            ization system to select the studies to be
                                               ● Audit reviews
                                                                                            audited. In addition to random audits,
                                               ● Corrective action
                                                                                            we have audited all investigator-initiated
                                        Quality                                             studies involving an Investigational New
                                    Assurance Audit                                         Drug Application after enrollment of the
                                                                                            first subject.
            ● Response to audit                            ● Performs audit
            ● Corrective action                            ● Coordinates audit review
                                                                                            Setup of a QA Audit
                      Principal                        Quality
                                                                                            Once a study has been chosen, the QA
                    Investigator                  Assurance Analyst
                                                                                            analyst formally notifies the principal
                                                                                            investigator and staff (e.g., research

       Table 2. Chronological Steps of a       according to GCP and institutional SOPs        Randomization. If the study is random-
                Quality Assurance Audit        is also verified.                               ized, subject randomization should be
 i.      Random selection of audited study                                                    documented in the subject medical
 ii.     Audit performed by quality assur-     Review of Study Conduct                        records and should follow the randomiza-
         ance analyst                                                                         tion process as described in the protocol.
                                               As a first step toward reviewing study
 iii.    Exit interview (quality assurance
         analyst and principal investigator)   data, subject medical records, research/       Study treatment and treatment modifi-
 iv.     Principal investigator responds to    shadow charts, and access to databases         cations. The QA analyst verifies that med-
         audit findings                         and case report forms are obtained. The        ication administration and treatment
 v.      Principal investigator sets up cor-   QA analyst must be familiar with the           modifications are documented and follow
         rective actions                       protocol and determine protocol re-            the protocol treatment plan. These can be
 vi.     Oversight committee reviews audit     quirements in order to verify that each        extensive in oncology studies.
         findings and response from princi-     protocol requirement is respected.
         pal investigator                      Thorough review of the study material          Study evaluations and response as-
 vii.    Oversight committee recommends        includes the following elements (Table 3).     sessments. Pre-study and on-study
         corrective action to principal                                                       evaluations as well as assessment of
         investigator                          Consent. Signed informed consent
                                               forms are located and reviewed. It is          treatment response are critical data in
                                               determined whether an IRB approved             the outcome of a study. The QA analyst
                                               and protocol-specific consent form was         verifies evaluations for protocol adher-
nurse, protocol coordinator, data man-         signed by the subject or legal guardian        ence. Missing evaluations are considered
ager or clinical research coordinator) of      and by the investigator. Documentation         deficiencies unless they are documented
the date the audit will start; notification     of the consenting conference should be         in subject medical records or in variance
is usually made two weeks prior to the         found in the subject’s medical record.         reports.
start of the audit. The notification letter
                                               Eligibility. Does the subject fit all eligi-   Recording and reporting of adverse
requests that a list of enrolled subjects be
                                               bility criteria? All inclusion and exclu-      events. As a first step in the review of
provided to the QA analyst so that he can
                                               sion criteria should be documented in          adverse event recording, the QA analyst
select subjects that include a minimum
                                               the subject’s medical records. The QA          reviews the criteria for selecting adverse
of 10% of the total enrolled subjects for
                                               analyst will verify subject eligibility by     events critical to safety evaluation. Such
review. The QA analyst informs the prin-
                                               matching each eligibility criteria with        criteria for a given study in the protocol
cipal investigator and necessary staff
                                               source documents. In addition, the             or for a type of study (e.g., bone marrow
which subjects have been selected for QA
                                               investigator should complete, sign, and        transplant, Phase I) are described in the
audit. On the day the audit is scheduled
                                               date an eligibility checklist.                 institution’s SOPs. The QA analyst gath-
to begin, the QA analyst should obtain or
have access to all regulatory documents                                                       ers all source documents such as prog-
and all study data (e.g., research charts,                                                    ress notes, nursing notes, phone notes,
                                                  Table 3. Elements of Study                  results of laboratory tests, diagnostic-
study databases, source documentation,
                                                           Conduct Review
and subject medical records). At this                                                         imaging reports, and other documents to
stage a positive interaction between the        i.  Regulatory documents                      confirm due diligence in the capture of
study staff and the QA analyst is critical.     ii. Submissions to regulatory agencies        adverse events according to study crite-
                                                iii.Informed signed consent                   ria. The adverse events identified by the
                                                iv. Patient eligibility                       QA analyst must match the adverse
Review of Regulatory Documents                  v.  Study treatment                           events entered on case report forms or
                                                vi. Study evaluation
The QA analyst reviews all regulatory                                                         into the study database.
                                                vii.Response assessment
documents for completeness, accuracy,                                                            Reporting of adverse events to regula-
                                                    Adverse event recording and
and compliance with protocol and reg-                                                         tory agencies is also reviewed. Criteria
ulatory requirements. The timeliness of                                                       for reporting adverse events should be
                                                ix. Case report forms
documentation submission and regu-              x. Databases
                                                                                              described in the protocol or in the insti-
latory agencies’ approvals is also re-          xi. Investigational drug pharmacy             tution SOPs. Failure to report adverse
viewed. Proper filing of documents                                                            events will be considered a deficiency.

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Case report forms and databases. All            do not require action are qualified as       the attention of the oversight committee.
data captured on case report forms and          “Note.”                                      If there no response from the PI, the
in databases are compared with source                                                        oversight committee may suspend the
documents and reviewed for complete-                                                         clinical study until an appropriate re-
ness and clarity. Blanks, corrections             The QA analyst describes all               sponse is obtained.
missing initials and date, inaccurate
entries, and missing source documents             findings of the detailed                    Review of the Audit Report
are reported as deficiencies.                                                                 and PI Response
                                                  review of regulatory
Investigational drug pharmacy. The QA                                                        Once the audit response has been
analyst reviews investigational drug              documents and study data in                obtained from the PI, both the audit
accountability logs for completeness and                                                     report and the response are presented to
clarity. Dispensing of drug from the              the audit report.                          the oversight committee which reviews
pharmacy is compared with physician’s                                                        both documents and decides on any
orders and administration records. If                                                        action to be taken. The audit response is
drug has been discarded for any reason,         Exit Interview                               assessed as acceptable, acceptable—
records should account for it and the                                                        needs follow-up, or unacceptable. An
conditions of disposal should match that        Once the audit report is completed, the      acceptable audit does not require further
described in the protocol. Conditions of        QA analyst schedules a meeting with the      action and is deemed complete. An audit
investigational agent storage are re-           principal investigator to review the find-    is noted as acceptable—needs follow-up
viewed to ensure that the investigational       ings detailed in the audit report. The QA    when issues are not addressed in the
                                                analyst should be ready to provide evi-      principal investigator’s response. As an
agents are stored in a secured area and
                                                dence of findings (e.g., an incomplete       example, if staff training seems needed
that the storage conditions (e.g., temper-
                                                case report form or an error in docu-        but is not proposed as a plan of action by
ature, etc.) match the conditions de-
                                                mentation). Having clear documen-            the PI, the oversight committee would
scribed in the protocol or investigator’s
                                                tation of the deficiencies can improve       make a request to the PI that such train-
                                                communication between the two parties        ing should be provided. An audit re-
                                                and help expedite the principal investi-     sponse is deemed unacceptable if there is
Audit Report                                    gator’s response.                            any indication that subject safety is at
                                                                                             risk, in which case the oversight commit-
The QA analyst describes all findings of                                                     tee may suspend the clinical study. At
the detailed review of regulatory docu-         Response to the Audit
                                                                                             this step of the QA audit process, the
ments and study data in the audit report.       The QA analyst asks the principal inves-     oversight committee is responsible for
The audit report has to be clear and            tigator (PI) to reply to the audit report    meeting with the PI to discuss the audit
thorough, as it becomes a tool to estab-        within two weeks of the exit interview.      findings and reinforce corrective actions.
lish communication between the QA               The PI must address each deficiency
analyst, principal investigator, study staff,   listed in the audit report by providing an
and oversight committee. The report                                                          Confidentiality
                                                explanation or a corrective action when
should itemize and describe in detail all       possible. For example, when case report      Special effort is made to keep the audit
findings such as missing documents,             forms are incomplete, the PI should          report and audit response confidential.
data entry errors, and missing study            complete and include those forms as          As stated above, the QA process is part of
evaluations.                                    part of the response to the report. Miss-    the physician peer review process for the
    We assign each finding or deficiency a        ing documents should be located and          institution. Audit reports and responses
qualitative rank according to whether it        unreported AEs collected/reported as         are stored on a secure, limited-access
is a significant deficiency (Major) or a        appropriate.                                 drive on the computer and all paper
less significant deficiency (Lesser). The           If the PI does not provide a response    documents are stored in locked file cabi-
Major/Lesser scale was derived from the         within two weeks, she is reminded of the     nets. Such documents are not filed in
National Cancer Institute quality assur-        requirement. A sustained lack of re-         subject’s research charts or with regula-
ance audit manual.4 Finally, findings that       sponse up to two months is brought to        tory documents.

Summary Report                                they were performed during the first           addressed immediately. Furthermore,
                                              months of protocol enrollment, because         effective solutions to problems found for
An annual report compiling all findings
                                              corrective actions such as training are        one study can be extended to other stud-
from the QA audits allows for monitor-
                                              still taking place and improper or in-         ies which broadens the impact made by
ing of trends and is a critical aspect for
                                              complete documentation is not com-             each individual audit. Thus, an institu-
documenting the effectiveness of the QA
                                              pounded over time. Conversely, QA              tional QA process impacts the entire
program. This summary report allows
                                              audits that are performed years after          clinical research operation, beyond just
the oversight committee to determine
                                              subject enrollment were found less use-        the study being audited.
the most frequent deficiencies and the
                                              ful as practices and personnel of the              Finally, the timing of internal QA
associated weaknesses of the clinical
                                              study team have changed and because            audits is essential so that problems iden-
research operations. For example, if case
                                              errors were difficult or impossible to         tified in the process of a study can be
report forms were often found to have
                                              correct.                                       corrected as early as possible. Ideally, the
numerous blank fields, or proof of IRB
                                                  A significant drawback of a QA audit        QA audits should occur after the enroll-
review of adverse event reports was often
                                              is the additional work for investigators       ment of the first subject. Correcting
found missing, such deficiencies could
                                              and study staff with already busy sched-       errors early in the course of a clinical
routinely be corrected with training of
                                              ules. In some cases the tasks related to       trial also allows teaching clinical research
study staff and improving the global
                                              responding to a QA audit and setting up        staff and investigators to avoid similar
quality of study documents.
                                              corrective actions can be extensive.           errors in the future. This leads to a con-
                                                  For the QA analyst, obtaining an           tinuous improvement of the entire clini-
Benefits and Challenges                        audit response from a busy principal           cal research program.
                                              investigator can be difficult. Delays in
Our QA program was quickly rewarded           obtaining responses within the two-week
by positive feedback. The investigators       period were usually explained by busy          References
subjected to QA audits were asked to give     schedules, business travel, or summer
                                                                                             1. Lepay D. GCP Compliance, FDA expectations
their opinion on how the QA program           vacations. However, in these rare cases,          and recent findings, June 9, 1998.
had affected their clinical research. The     reminders from the QA analyst and then         2. Lepay DA. GCP Quality Assurance: Then and
principal investigators agreed that QA        the oversight committee members have              Now, Fall 2001.
audits are a useful experience. They                                                         3. Maloy J, et al. Tipping the scale toward success,
                                              always led to a satisfactory outcome.
                                                                                                The Monitor, Summer 2003, 17(2).
found that interaction with study staff
                                                                                             4. Clinical Trials Monitoring Branch, Cancer
and their performance were improved by                                                          Therapy Evaluation Program, Division of Can-
                                              Advantages to the Site
the audits. Charting practice has also                                                          cer Treatment and Diagnosis, National Cancer
improved. For example, documenta-             The members of the clinical research              Institute, Guidelines for monitoring of clinical
                                                                                                trials for cooperative groups, CCOP research
tion of performance score, consenting         oversight committee reviewing QA
                                                                                                bases, and the cancer trials support unit
process, and eligibility criteria have all    audits are peers of principal investiga-          (CTSU), August 2001.
improved since implementation of the          tors. Oversight by peers allows a dynamic
QA program. In addition, we believe that      process, from QA audit to PI response
compliance with regulatory requirements       and execution of corrective actions.           Florence Noël, PhD, CCRC, CCRP, is a Clinical
                                                                                             Research Quality Control Manager at Texas Chil-
has been improved and the program has         When problems, such as weaknesses in
                                                                                             dren’s Cancer Center and Center for Cell and Gene
better prepared the institution for outside   the process of a clinical study, are identi-   Therapy. She can be contacted at
audits. Finally, we are encouraged by the     fied during a QA audit, they are quickly
fact that investigators feel more confident    brought to the attention of the con-           Bambi Grilley, RPh, CCRP, CCRC, CIP, is the
                                                                                             Director, Clinical Protocol Research and Regula-
in the quality of study data.                 cerned parties and addressed rapidly.
                                                                                             tory Affairs at Texas Children’s Cancer Center and
    We found that usefulness of QA            Similarly, the need for staff training can     Center for Cell and Gene Therapy. She can be con-
audits was especially noticeable when         be recognized during a QA audit and            tacted at

                                                                                                                    PEER REVIEWED         R 35

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