Download UAB Comprehensive Cancer Center Clinical Trials Audit Manual

Version 10/7/09
UNIVERSITY OF ALABAMA
AT BIRMINGHAM
COMPREHENSIVE CANCER CENTER
CLINICAL TRIALS
AUDIT MANUAL
2008
PREPARED BY THE QUALITY ASSURANCE COMMITTEE
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TABLE OF CONTENTS
1.
INTRODUCTION........................................................................................................................... 3
2.
OBJECTIVES ................................................................................................................................. 3
3.
SELECTION OF PROTOCOLS FOR AUDIT ........................................................................... 3
3.1
Maintenance of Audit List .................................................................................................... 4
4.
SELECTION OF CASES FOR AUDIT ....................................................................................... 5
5.
SELECTION OF AUDIT TEAM .................................................................................................. 6
6.
SCHEDULING OF AUDIT ........................................................................................................... 6
7.
PREPARING FOR AUDIT ........................................................................................................... 6
7.1
8.
9.
10.
Flagging of Documents .......................................................................................................... 6
CONDUCTING THE AUDIT ....................................................................................................... 7
8.1
Administrative Audit ............................................................................................................ 7
8.2
Full Audit............................................................................................................................... 8
OUTCOME AND ASSESSMENT OF THE AUDIT .................................................................. 8
9.1
Regulatory Review ................................................................................................................ 9
9.2
Pharmacy Review ................................................................................................................ 10
9.3
Patient Case Review ............................................................................................................ 13
REPORT OF AUDIT FINDINGS ............................................................................................... 15
10.1 Audit Review Forms (Audit Worksheets) ......................................................................... 15
11.
FOLLOW-UP OF AUDITS ......................................................................................................... 18
12.
RETENTION OF RECORDS AND AUDIT REPORTS .......................................................... 18
13.
APPENDICES ............................................................................................................................... 18
Example of Administrative Audit Report .................................................................................. 19
Example of Full Audit Report ..................................................................................................... 20
Audit Worksheets ......................................................................................................................... 22
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1.
INTRODUCTION
The Clinical Trials Audit Manual outlines the audit policies and procedures of the Quality Assurance
Committee (QAC) of the University of Alabama at Birmingham Comprehensive Cancer Center (UAB
CCC). Oversight of clinical trials involving investigational drugs, devices, or biologics and other
clinical research perceived to involve more than a minimal risk is an essential component of the UAB
CCC Data and Safety Monitoring Plan. The Clinical Trials Audit Manual is based upon the Data and
Safety Monitoring guidelines used by the National Cancer Institute (NCI). Guidelines for NCI’s
investigator-initiated clinical trials may be found at
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines. Another useful resource is NCI’s
Cancer Therapy Evaluation Program at http://ctep.cancer.gov/.
2.
OBJECTIVES
The primary objective of an audit is to assure the accuracy of research data and to verify protocol
compliance and regulatory mandates. The Quality Assurance (QA) Office meets this objective to
maintain the high quality of care benefiting research participants, investigators, and clinical research
personnel.
Audits also serve as useful educational tools for investigators, clinical research associates, clinical trials
specialists, study coordinators, and data managers by providing opportunities for improvement in patient
care, research processes, and data systems.
3.
SELECTION OF PROTOCOLS FOR AUDIT
All UAB CCC studies are eligible for audit, including those sponsored by the National Cancer Institute
(NCI), pharmaceutical industry, or other sponsors.
Investigator-initiated studies are a high priority and are audited prior to the first IRB renewal and
annually thereafter. Investigator-initiated retrospective database studies are not audited through the
QAC since they are not clinical trials incorporating patient tissue and/or consent forms. This does not,
however, preclude retrospective database studies from IRB requirements.
Priority is given to selecting protocols to be audited in the following order: (priority scores discussed in
Section 3.1)
1. Investigator-initiated protocols in which UAB holds the IND and are actively accruing patients
(Priority Score of 1).
2. Investigator-initiated protocols in which UAB does not hold the IND but are actively accruing
patients (Priority Score of 1).
3. Investigator-initiated protocols in which UAB holds the IND and accrual has stopped but
patients are still being treated. Protocol is closed to enrollment.* (Priority Score of 1).
4. Investigator-initiated protocols in which UAB does not hold the IND and accrual has stopped
but patients are still being treated. Protocol is closed to enrollment.* (Priority Score of 1).
5. Industry sponsored Phase I protocols (Priority Score of 3).
6. Investigator-initiated non-therapeutic protocols (Priority Score of 2).
7. All other protocols
* Auditing of non-accruing studies that do not have active therapeutic intervention as part of the patient
follow-up are at the discretion of the QAC Director.
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In accordance with the UAB CCC Data Safety Monitoring Plan selection of protocols for audit will
include all protocols which do not have external monitoring with an accrual of 5 or more patients.
Protocols with accrual of less than 5 patients will be audited every other year at a minimum. “For
cause” audits may also be conducted based on concerns received by faculty, staff, patients or issues
raised by the Clinical Trials Monitoring Committee.
3.1
MAINTENANCE OF AUDIT LIST
The Quality Assurance (QA) Audit List is an ongoing list used primarily to identify active
investigator-initiated clinical trials requiring internal auditing. It also identifies other active and
inactive clinical trials not requiring internal auditing. The QA Audit List is maintained by the QA
Coordinator with input from the QAC Director. It is organized in a spreadsheet format with 4
sheets: Sheet 1 is titled Active Studies, QA Audits Needed; Sheet 2, Active Studies, No QA Audits
Needed; Sheet 3, Inactive Studies; and Sheet 4, Archived Studies. Each sheet is updated at least
monthly according to the guidelines below:
Active Studies, QA Audits Needed
A. Identification of Investigator-Initiated Protocols
Several resources are available to provide an overall assessment of active investigator-initiated
protocols. A list of these resources is as follows but is not limited to:
 A UAB Cancer Center Clinical Trials database of protocols is used to provide pertinent
information for registered and newly registered clinical trials. This database is
maintained through UAB CCC Biostatistics. While this list of Active, Closed and
Pending Protocols should include all investigator-initiated protocols, it is not fail proof
(e.g. unregistered protocols, retyped or mistyped protocols, database errors, incorrectly
marked original letter of intent from PI, etc.)
 Another valuable resource for investigator-initiated protocol confirmation is the
Clinical Trials Monitoring Committee (CTMC) reports. These are generated monthly
by each department conducting oncology-related clinical trials (e.g. HematologyOncology, Neuro-Oncology, Radiation-Oncology, etc.) The CTMC reports should
specifically identify which protocols are investigator-initiated as well as other protocol
information including the study status (currently accruing, closed to accrual or on hold).
 An Investigator-Initiated report may be accessed through the UAB Cancer Center
Clinical Trials database. This report is similar to the Active, Closed and Pending
Protocol report but should be limited to investigator-initiated protocols.
 A copy of the IRB renewal reports are submitted annually to the QA Office for review.
Renewal reports serve to reinforce the status as an investigator-initiated protocol.
 Written or verbal communication of the PI or other study personnel (e.g. research
coordinator, regulatory manager, data manager) confirming protocol designation.
Verbal confirmation is preferably followed with written documentation.
B. Protocol Type
There are three primary protocol types: investigator-initiated (II), investigator collaborative
(IC) and externally sponsored (E). Protocol types should be indicated on the QA Audit List
especially if it is investigator-initiated.
C. Priority Score Assignment
A priority score of 1, 2 or 3 is assigned for each protocol listed on Sheets 1 and 2. These
scores reflect the therapeutic impact upon patients which, in turn, dictate the significance and
importance of audits to be conducted (refer to Section 3).
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The scores are as follows:
1
High (Investigator-initiated therapeutic trial)
2
Intermediate (Investigator-initiated non-therapeutic trial)
3
Non-UAB audited
Non-therapeutic investigator initiated trials with a priority score of “2” receive an
administrative audit while a therapeutic trial with a priority score of “1” receive a full audit.
D. Protocol Accrual and Last IRB Date
An Active, Closed and Pending Protocol report may be accessed through the UAB Cancer
Center Clinical Trials database. This report provides protocol specific active study dates,
closed dates, IRB original approval dates, IRB last approval dates and total patient accrual.
Updates to the QA Audit List should primarily be made from this report at least monthly. This
is important information and assists in the audit selection and randomization process based
upon patient accrual.
Active Studies, No QA Audits Needed
Active protocols that are investigator collaborative, industry sponsored or externally monitored,
that is, not investigator-initiated, may be listed on this sheet. Typically, any protocol that is
externally monitored by other entities (NCI, MediGene, Pfizer, etc.) does not require CCC QA
internal auditing. Cooperative group studies (e.g. ECOG, CALGB, NABTT, etc.) are not
identified on the QA Audit List as they have unique and group specific auditing criteria.
Inactive Studies
Inactive protocols of any type may be listed on this sheet. These studies do not require internal
audits.
The term “inactive” has multiple meanings in reference to the QA Audit List. Inactive studies
include: studies that were never activated, closed studies with no patients in follow-up, studies that
have been stagnant for an extended period of time, terminated studies, completed studies with no
IRB continuation, and studies removed from the database. To clarify, the term “closed” may also
have a dual meaning: closed to patient accrual and/or closed to patient accrual with no patients in
follow-up. In order to be categorized as a “QA inactive study,” it must meet the latter criteria.
Otherwise, the study is still considered active and eligible for auditing.
Archived Studies
Studies that have remained inactive for an extended period of time are placed on this sheet.
4.
SELECTION OF CASES FOR AUDIT
Random selection of research participants to be audited is done through UAB CCC Biostatistics. The
QA Coordinator notifies the biostatistician of the audit to be conducted along with the registered
research participants and accession numbers to be included in the randomization. A minimum of 10%
of cases is selected for the audit. However, if problems are suspected or have been previously identified,
specific charts or a greater percentage of up to 100% of the research participants may be audited. In
these cases, audits may focus on special areas alone. For example, if problems are suspected with the
informed consent, 100% of the informed consents may be audited.
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Every effort is made to use patients chosen through the randomization process for audit selection.
However, there may be occasions requiring selection of another patient case due to chart accessibility
issues (e.g. clinic appointments) at the time of the scheduled audit. Deviations from the routine
randomization process are at the discretion of the QA Coordinator. Once the selection of case(s) has
been made, the IRB is notified.
5.
SELECTION OF AUDIT TEAM
Physicians not directly affiliated with the study to be audited are chosen to participate in the audit team.
Physicians’ participation is essential and serves as a good educational tool. Every effort will be made to
avoid selecting clinicians to serve as auditors at a time of high stress (attending responsibilities, grant
deadlines, etc.). Also equitable distribution for auditing services from a broad spectrum of clinicians is
encouraged. Research nurses, data managers, and biostatisticians will also be asked to participate as
needed. Persons are chosen who are knowledgeable of such areas as the protocol disease site, treatment
modality, etc. to be reviewed. Confidentiality of the audit team selection is routinely practiced and felt
to be of benefit to all concerned.
6.
SCHEDULING OF AUDIT
At least two weeks before the scheduled audit, the QA Coordinator will inform the Principal Investigator
(PI) and appropriate research staff of the protocol and patient case(s) selected for the audit.
Logistics of the audit such as date, time, and location are coordinated by the QA Coordinator and agreed
upon by the audit team. If an audit needs to be canceled and/or rescheduled for any reason, the QA
Coordinator will contact the audit team, PI, and research staff as soon as possible.
7.
PREPARING FOR AUDIT
The Principal Investigator or a designee is responsible for ensuring that all relevant materials are
available for review at the time of the audit. Documents on the patient chart should be labeled such as
hospital/clinic records, research notes, on-study labs, scans and imaging studies, consent forms, etc.
Either the original patient source documents or copies of the complete record must be provided. This
includes x-rays, scans, research notes, and other relevant information as needed. Regulatory documents
such as IRB correspondence and approvals and drug accountability record forms should also be made
available through appropriate personnel.
Study specific audit worksheets are prepared by the QA Coordinator. Using the current or applicable
protocol version, documents are developed outlining study specific source documentation. These
documents include eligibility criteria, treatment plans, and/or study calendar guidelines. Worksheets are
made available to the audit team for completion on the day of the audit.
7.1 FLAGGING OF DOCUMENTS
The Principal Investigator or a designee should flag the patient chart to facilitate and enhance the
accuracy of the audit review. Because the audit team is limited with time constraints, flagging helps
prevent oversights that could result in an incorrectly identified deficiency. It also serves as a good
check system for the research staff to be sure the required documents are in place. While color6
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coding is helpful for each audit category, it is not necessary. Labeling the flag produces the greatest
benefit. While not limited, flagging incorporates the protocol schema and eligibility criteria.
Possible items to be flagged:
 Signature page of the original informed consent document
 Source document for each of the eligibility criteria (i.e. pathology report, on-study labs, onstudy performance status, pregnancy status, etc.)
 Subject diaries/calendars
 All CT and other reports or source notes documenting all responses
 Chemo administration sheets for all cycles of treatment
 History and physical for each cycle
 Any hospitalizations
 Any adverse events
 Labs for each cycle
 Follow-up labs, reports, and visits
 Any other key documents (e.g. death certificate).
8.
CONDUCTING THE AUDIT
The audit process is a formal comprehensive source documentation review and evaluation of the
following elements:
1) Regulatory review of IRB compliance and informed consent requirements
2) Drug accountability, documentation and handling
3) Individual patient cases including eligibility, treatment, response, toxicity, completeness and
quality of data.
There are two types of audits: administrative and full. Investigator-initiated protocols receive one or the
other of these audits dependant upon the prioritization of the study as identified in Section 3.1.C. As
discussed, the type of audit to be performed is based upon the therapeutic impact of the study to be
audited.
8.1 ADMINISTRATIVE AUDIT
Administrative audits are performed by the QA Coordinator with no additional assistance from an
audit team. An administrative audit consists of the following:
1) regulatory review and
2) investigational drug accountability review, when applicable.
The regulatory review includes verification of documentation for:
a) Institutional Review Board (IRB) initial protocol approval
b) IRB approval of protocol amendments
c) IRB approval of annual continuing protocol reviews
d) approved informed consents including current and revised versions
e) approved current protocol version
f) Form 1572.
The majority, if not all, of this information may be found in the regulatory binders located within
each department.
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The pharmaceutical review consists primarily of investigational drug accountability and
documentation (e.g. drug disposition, usage, storage, etc.) This information is available through the
CCC UAB Research Pharmacist. If no investigational drugs are used for the protocol being audited,
the pharmaceutical review is deferred. Detailed information concerning the Pharmacy Review is
described in Section 9.2.
8.2 FULL AUDIT
A full audit is performed by both the QA Coordinator and the audit team. A full audit consists of the
following:
1) regulatory review
2) investigational drug accountability review, when applicable
3) patient case review
The QA Coordinator is responsible for the administrative component previously described while the
audit team is responsible for the patient case review(s) with follow-up by the QA Coordinator and/or
other personnel as needed. The audit team evaluates selected patient charts according to protocol
specifications for the following: informed consent, eligibility, treatment, disease outcome/response,
toxicity, and overall data quality.
During the audit, the auditors review specific source documentation to independently verify study
data. Examples of source documents may include, but are not limited to, the following:
 Inpatient and outpatient medical records
 Source documentation for each of the eligibility criteria (i.e. pathology report, on-study
history and physical exam, on-study labs, on-study CT’s, x-rays, pregnancy status, on-study
performance status, blood pressure, weight, height, etc.)
 Diagnostic reports (i.e. CT scans, x-rays, other scans, ECGs, other reports, source notes,
etc.)
 Laboratory data
 Chemotherapy administration sheets
 Progress notes (i.e. history and physical for each cycle)
 Admissions (any hospitalizations)
 Any adverse events
 Study flow sheets and other research records that are signed and dated on a real-time basis
by the health care practitioner evaluating the patient
 Post-treatment follow-up visits, labs and reports
 Subject diaries/calendars
 NCI Drug Accountability Record Forms (DARFs)
 Informed consents and IRB documents (i.e. content and signature page of the original
informed consent document)
9.
OUTCOME AND ASSESSMENT OF THE AUDIT
Each of the three audit areas, namely regulatory, pharmacy, and patient review, where applicable, will
be assessed independently based on findings at the time of the audit. Assessments are identified as:
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Acceptable, Acceptable Needs Follow-Up, or Unacceptable. A description of each assessment is
given:
Acceptable



Acceptable
Needs Follow-Up


Unacceptable



No deficiencies identified
Few lesser deficiencies identified
Major deficiencies identified during the audit that were
addressed and/or corrected prior to the audit for which
documentation exists and no further action is required
Multiple lesser deficiencies identified
Major deficiencies identified during the audit not
corrected and/or addressed prior to the audit
Multiple major deficiencies identified
A single, flagrant major deficiency identified
Multiple lesser deficiencies of a recurring nature found in
a majority of the patient cases reviewed
If an area is rated as Acceptable Needs Follow-Up or Unacceptable, a written response and/or corrective
action plan is required from the PI or appropriate personnel to the QA Office and QAC. A re-audit is
mandatory for any area rated as Unacceptable; it may or may not be required for a rating of Acceptable
Needs Follow-Up.
An inclusive and precise definition of what constitutes an unacceptable finding is difficult to construct.
Rather than developing an inclusive quantitative definition, a common set of terms or examples of
“major” and “lesser” deficiencies and a system for assessing each component of an audit, based on NCI
definitions are used. Examples under Guidelines for Monitoring of Clinical Trials for Cooperative
Groups, CCOP Research Bases, and the Clinical Trials Support Unit for the NCI Cancer Therapy
Evaluation Program (CTEP) may be found at http://ctep.cancer.gov/monitoring/. The examples are
intended to guide reviewers in their assessment and categorization of specific violations.
A major deficiency is defined as a deficiency which significantly alters the clinical effectiveness of the
treatment or the evaluation of its toxicity. A lesser deficiency occurs when the protocol is not followed
exactly but the data is useable and valid. Numerous lesser deficiencies can also constitute a major
deficiency. The grading of deficiencies as “major” or “lesser” is at the discretion of the Quality
Assurance Director and may or may not be designated.
9.1 REGULATORY REVIEW
For each protocol selected for an audit, the following regulatory areas are reviewed:
 documentation of full initial IRB approval
 documentation of full IRB annual reapproval
 documentation of IRB approval for protocol amendments
 documentation of IRB approval or reapproval prior to patient registration
 documentation of Form 1572.
The following descriptive terms are used in assessing compliance:
 Delayed reapproval: Protocol reapproval by the IRB delayed for up to one year.
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



Expired reapproval: Protocol reapproval by the IRB delayed for greater than one year.
Missing reapproval: Missing documentation of protocol reapproval (e.g. letter from
IRB, IRB minutes, etc.)
Expedited review: A review by the IRB chairperson or IRB member(s) of research
which involves no more than minimal risk or involves minor changes in previously
approved research.
Other: Issues with amendments/revisions/updates not described above.
The following are examples of major and lesser deficiencies to be considered in assessing IRB
compliance:
Major IRB deficiencies may include but are not limited to:
 Protocol never approved by IRB
 Initial IRB approval documentation missing
 Initial approval by expedited review
 Expedited reapproval for situations other than approved exceptions
 Registration and/or treatment of patient prior to full IRB approval
 Reapproval delayed more than thirty days but less than one year
 Registration of patient on protocol during a period of delayed reapproval
 Missing reapproval
 Expired reapproval
 Reportable adverse events not reported to IRB
 Lack of documentation of full IRB approval of a protocol amendment that affect more
than minimal risk.
Lesser IRB deficiencies may include but are not limited to:
 Protocol reapproval delayed less than thirty days
 Delayed reapprovals for protocols closed to accrual for which all patients have
completed therapy.
Informed Consent Content
The content of the informed consent document is checked to be sure it contains the elements
required by Federal Regulations (Title 45, Part 46). In addition, the informed consent is checked for
content to ensure it contains all appropriate risks listed in the Investigator’s Brochure.
The following are examples of major deficiencies related to informed consent content. This list is
not a comprehensive list of the major deficiencies that may be found.
 Omissions of one or more of the elements required by Federal Regulations
 Omissions of multiple risks/side effects as listed in the Investigator’s Brochure.
9.2 PHARMACY (INVESTIGATIONAL DRUG ACCOUNTABILITY) REVIEW
It is the responsibility of the investigator to maintain records that reflect appropriate dispensing of
the investigational drug. It is assumed by the QAC that the investigator of a CCC study has utilized
the services of the UAB Hospital Research Pharmacist to provide control and documentation
according to policy and procedure of the UAB Hospital Department of Pharmacy. If the UAB
Hospital Department of Pharmacy was not utilized, the policy and procedures of those providing the
service must be on file with the investigator.
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The forms provided by the NCI are acceptable to use as templates for Drug Accountability records.
These forms may be customized for study specific documentation. If the UAB CCC study is an
investigator-initiated study, additional documentation may be required in order to comply with the
Code of Federal regulations requirement to assure that a process has been established to direct the
handling of unused investigational agents.
Review of Accountability of Investigational Agents and Pharmacy Operations
Drug accountability and storage procedures described in this section are required under Federal
Regulations and NCI. Because of the difficulty categorizing major and lesser deficiencies related to
investigational drug accountability and storage, the auditor will determine the rating of this
component based on the findings of compliance to the required procedures for drug accountability
and storage.
Guidelines for Conducting the Pharmacy Review
Drug Accountability Record Forms, or DARFs, should be completely and correctly filled-out. The
following are guidelines for assessing compliance and non-compliance in regards to drug
accountability:
DARF-Specific
COMPLIANCE
NON-COMPLIANCE
 Maintain accurate records of the
 Inability to track the receipt, use, and
disposition of all supplied
disposition of supplied investigational
agents using DARFs
agents
 DARF not maintained
 Inability to track the agent due to
omissions in report
 Incorrect agent, dose, route of
administration, or dates documented
on DARF
 Registered patients who received IND
agents but are not recorded on DARF
 Systematic incorrect entries on the
DARF
 DARF not kept on timely basis
 Erasures or "whiteouts" on DARFs
 Corrections are not lined out and
initialed
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Protocol and Drug Specific
COMPLIANCE
 Agents used only for patients
entered on the audited protocol
 Each agent accounted for
separately by protocol
 An agent used for more than one
protocol has a separate DARF for
each protocol
 Multi-agent protocols have a
separate DARF for each agent
 Separate accountability forms
maintained for each different
strength or dosage form of a
particular agent
 A separate DARF is used for each
patient per double-blinded
protocol
 Appropriate documentation of
drug dispensing to multiple
patients of multi-dose medication
on separate lines of the DARF
NON-COMPLIANCE
 Patients identified on DARF are not
registered patients
 Substitution with other supplied agents,
including commercial agents
 Lack of source documentation to verify
agent supplies distributed to
investigators or administered to patients
 Each agent not accounted for separately
by protocol
 One DARF used for more than one
protocol
 One DARF for a multi-agent protocol
 One DARF used for multiple strengths
or dosage forms of an agent
 One DARF for multiple patients on a
double-blinded protocol
 Multiple-dose vials signed out to one
patient but used for multiple patients
 Multiple doses documented on one line
of the DARF
Storage Specific
COMPLIANCE



Each investigational agent stored
separately by protocol
An agent used for more than one
protocol kept in separate physical
storage for each protocol
Agent stored under proper
conditions (refrigerator, freezer,
etc.) with validation
documentation
NON-COMPLIANCE



IND not stored separately by protocol
Agents used for more than one
protocol combined in storage
Agent not stored under proper
conditions
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Security Specific
COMPLIANCE


A secure area is an area that can be
locked with a minimum number of
people with access (key or
combination)
Storage areas shall be accessible
only to an absolute minimum
number of specifically authorized
employees. When it is necessary for
unauthorized persons to be present in
or pass through, an authorized person
must provide adequate observation
of the area
NON-COMPLIANCE


Agent stored in insecure
dispensing area
Unauthorized people having access
to a secure area without
supervision
9.3 PATIENT CASE REVIEW
As part of a full audit, a minimum number of patient cases equivalent to 10% of patients accrued
since the last audit are reviewed (refer to Section 4). Each patient case is reviewed for deficiencies
in each of the following categories: properly signed and dated informed consent, eligibility, correct
treatment and treatment sequence, evaluation of disease outcome/tumor response, toxicities related
to treatment, and general quality of the data collected. Documentation identified as missing at the
time of the audit can be supplied within one week following the audit at the discretion of the audit
team and/or QA Coordinator.
Examples of Major Deficiencies
A major deficiency is a variance from protocol-specified procedures that makes the resulting data
questionable. The following examples are a representative list of major deficiencies:
A. Informed Consent
Failure to document properly obtained informed consent such as:
 Consent form missing
 Consent form not signed and dated by the patient
 Consent form signed after patient started on treatment
 Consent form does not contain all required signatures
 Consent form used was not current IRB-approved version at the time of patient
registration
 Consent form not protocol specific
 Consent form does not include updates or information required by IRB.
B. Eligibility
 Review of documentation available at the time of the audit confirms patient did not
meet all eligibility criteria as specified by the protocol
 Documentation missing. Unable to confirm eligibility.
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C. Treatment
 Incorrect agent/treatment used
 Additional agent/treatment used which is not permitted by protocol
 Dose deviations incorrect (error greater than +/- 10%)
 Dose modifications not per protocol
 Treatment doses incorrectly administered, calculated or documented
 Unjustified delays in treatment.
D. Disease Outcome/Response
Failure to evaluate response according to the protocol such as:
 Inaccurate documentation of initial sites of involvement
 Tumor measurements/evaluation of status or disease not performed according to
protocol
 Protocol-directed response criteria not being followed
 Claimed response (PR, CR, etc.) cannot be verified
 Failure to detect cancer (as in a prevention study) or failure to identify cancer
progression.
E. Toxicity
Failure to assess and report toxicities and adverse events according to the protocol such as:
 Grades, types, or dates/duration of serious toxicities inaccurately recorded.
 Toxicities cannot be substantiated
 Follow-up studies necessary to assess toxicities not performed
 Failure to report a toxicity that would require filing an Adverse Event Report
(AER)
 Recurrent under- or over-reporting of toxicities.
F. General Data Quality
 Recurrent missing documentation
 Protocol-specified laboratory tests not documented
 Protocol-specified diagnostic studies not documented
 Frequent data inaccuracies
 Errors in submitted data
 Delinquent data submission.
Examples of Lesser Deficiencies
A lesser deficiency is a deficiency that is judged to not have a significant impact on the outcome or
interpretation of the study. An unacceptable frequency of lesser deficiencies is treated as a major
deficiency in determining the final assessment of a component. The following examples are a
representative list of lesser deficiencies:
A. Informed Consent
 Consent does not have date/witness signature
 Consent does not have unique patient identifiers on each page.
B. Eligibility
 Small variations of criteria with reasonable explanation/approval
(Phase II and III only).
C. Treatment
 Wrong antiemetic given as per protocol
 Wrong doses (<25% deviation without explanation for one dose; or 25% deviation
from dose reduction indicated)
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
Wrong timing (<2 week delay with acceptable explanation such as holiday, bad
weather, etc.)
D. Disease Outcome/Response
 Missing minor measurements
 Missing one of several measurements used to assess response and scans unavailable
for review.
E. Toxicity
 Not reporting occasional grade 3 toxicities
 Frequent non-reporting of grade 1 and 2 toxicities.
F. General Data Quality
 Acceptable level of missing documentation with explanation
 Minor and sporadic missing tests
 Infrequent errors in submitted data.
10. REPORT OF AUDIT FINDINGS
The Associate Director for Clinical Research, the Cancer Center Director, the UAB IRB and other
federal, regulatory, or sponsoring agencies are notified immediately if any findings are suspected or
suggestive of intentional misrepresentation of data and/or disregard for regulatory safeguards for any
component of the audit.
A report of the audit findings is compiled by the QA Coordinator and the QAC Director who reviews the
auditors’ findings in detail. These reports are then discussed and approved by the QAC at its scheduled
quarterly meeting. Following QAC approval, the audit report is submitted electronically to the PI, the
head of the clinical study unit, the Associate Director for Clinical Research and the head of the Clinical
Trials Monitoring Committee. Other personnel directly involved with the study may also be sent a copy
of the audit report including the research nurse, data manager and/or regulatory personnel. Copies to all
other personnel will not be provided by the QA Office without written or verbal consent from the PI but
may be sent directly by the PI at his/her discretion.
If the audit requires a corrective action plan from the PI, a draft of the audit report will be sent to the
Quality Assurance Committee, the PI and the head of the Clinical Trials Monitoring Committee. The
report will be labeled as “Draft” and will have no disposition. Finalization of the report from the QAC
will be pending until a full committee meeting is held.
10.1
AUDIT REVIEW FORMS (AUDIT WORKSHEETS)
Audit Review Forms, or audit worksheets, are used by the auditor(s) to record pertinent
information that will be incorporated in the final audit report. Each element of an audit involves
the review of different medical records and data. Findings are documented on the Audit Review
Forms by the Auditor and/or QA Coordinator. A template is used for the collection of common
information (i.e. consent form content, regulatory review forms, etc.) but protocol-specific
worksheets are used for eligibility criteria and treatment (refer to Section 7). Other information
may be included in the audit worksheets as needed. Audit worksheet highlights include:
General Information
 Title, number, and principal investigator of protocol
 IRB Protocol number
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 Registration in the NIH federal registry of clinical trials at www.ClinicalTrials.gov
 Date of audit.
IRB and Informed Consent
 Title of protocol, the number of patients audited
 A history of the regulatory activity for the protocol including renewals, amendments
and suspensions
 A list of major or lesser deficiencies, if found, and a description for each
 A review of the elements required by federal regulations for informed consents
 An overall assessment for this component.
Accountability and Storage of Investigational Agents
 Title of protocol, patient and accession number being audited, identification of
investigational agent
 A review of the investigational drug use as it pertains to the maintaining of accurate
records and regulations relating to dispensing, storage, security, and inventory issues.
For any non-compliant elements, a description is given.
 The investigational drug account for the patient being audited including drug(s), date
dispensed, medication amount, dosage, agreement with the drug accountability record
forms and order on the patient chart
 An overall assessment for this component.
Patient Cases
 Number of cases audited based upon total and/or annual accrual of protocol
 Identification and medical record/accession number of patient(s) being audited
 A list of major or lesser deficiencies, if found, and a description for each (includes
review of informed consent, eligibility, treatment, follow-up, disease
outcome/response, toxicity, and general data quality)
 A review of adverse events
 An overall assessment for this component.
An extended listing of the contents of the audit worksheets is detailed below:
IRB Activation/Annual Review Information: Prior to the audit, the QA Coordinator verifies
proper IRB approval, activation, and continuing review information. The QA Coordinator also
confirms that the first patient was registered after the protocol was IRB-approved and
activated.
Identification: The Auditor obtains identifying patient information such as patient initials,
medical record and/or accession number, type of disease, and treatment to be included on the
Audit Review Forms.
Patient Entry/Randomization: Reviewing patient entry includes verifying that a signed,
informed consent was obtained prior to study enrollment and treatment. The date the patient
entered the study and the date that treatment began are recorded on the Audit Review Form.
The consent form version is also recorded.
Eligibility: The Auditor verifies patient eligibility by reviewing the patient’s eligibility
checklist from the protocol and medical records. If documentation cannot be located,
eligibility will be noted as unconfirmed due to insufficient documentation.
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Pre-therapy Requirements: Using the protocol’s list of required tests, the Auditor will verify
against source documents that all of the required tests were performed prior to the start of
treatment.
Treatment Administration: The Auditor confirms the dates of treatment and the correct
doses for each patient while reviewing the medical records. Dose modifications are included in
the review. The Auditor confirms that the correct body surface area was calculated. Proper
recording of treatment is verified. Delays in treatment or missed treatments should be noted
with explanation.
Required On-Study, Follow-up & Termination Evaluations: Using the protocol’s list of
required evaluations, the Auditor verifies against source documentation that all required
evaluations were performed at the appropriate intervals.
Adverse Events: The Auditor ensures that all adverse events recorded on the patient data
forms accurately reflect the adverse events recorded in the medical record. If an adverse event
occurred, the Auditor verifies that the event was reported accurately and to the correct entities.
The QA Coordinator also reviews the IRB protocol file containing a copy of the adverse event
report(s).
Drug Accountability: The QA Coordinator or Auditor inspects Drug Accountability Record
Forms. The NCI requires that these forms are maintained by all institutions conducting clinical
trials with NCI-supplied investigational drugs. Drug accountability is also reviewed when the
PI holds the IND. The Auditor may request documentation of storage and handling as
specified in the protocol.
The QA Coordinator or Auditor identifies the investigational drug(s) by protocol number and
checks documentation of dispensation. The NCI Drug Accountability Records may serve as
the primary transaction record. Current shelf inventories may also be compared to the balance
on the NCI Drug Accountability Records. Drug handling procedures are reviewed to assure
the return of expired drugs to the NCI drug repository with the appropriately completed form.
Proper disposal of any unused portions of drugs that have either been returned to the pharmacy
or are a result of closed protocols may also be checked. Last, the Auditor compares specific
NCI Drug Accountability Record entries to the drug administration source documentation. The
date the drug was dispensed against the dates of administration is also checked.
The UAB SPP/SCR website is the official publication source within the UAB Health System.
Previously called Standards, Policies and Procedures (SPP), the Standards & Clinical
Resources (SCR) website is a secured intranet site housing all standards of practice (policies
and procedures) and many types of references within the UAB system. The website may be
accessed at https://scr.hs.uab.edu.
Objective Tumor Response: Documentation of baseline disease status must be verified by the
patient’s medical record and Case Report Forms for both measurable and non-measurable
disease status. Response and progression must also be verified. The Auditor will check the
patient data forms to confirm that the correct data was recorded.
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Data Collection: The Auditor checks all required forms for complete and accurate data and
timely submission.
Record Keeping: The Auditor may comment on the quality of the source documentation (e.g.
the hospital and clinic records) and will note any inconsistent, incomplete, illegible, or hard to
follow records.
Additional Comments: Space is available at the end of the Audit Review Form for additional
comments and explanations. Once the Audit Review Forms are complete, the Auditor(s) signs
and dates it.
11. FOLLOW-UP OF AUDITS
Audits identified as “Unacceptable” require a re-audit before the next annual audit. Audits identified as
“Acceptable Needs Follow-Up” may or may not need a re-audit. In both instances, this will be stated in
the audit report’s Action Items section. A corrective action report should be provided by the PI or a
designee prior to the re-audit. Follow-through for submission of corrective action reports is monitored
by the QA Office. Other follow-up options include auditing a related protocol if the previously audited
protocol is closed and also closure of a protocol.
After notification of the final audit report to the PI, a compilation of all audits performed and approved
by the QAC from the previous quarter will be submitted to the Cancer Center Associate Director for
Clinical Research followed by a copy to IRB.
12. RETENTION OF RECORDS AND AUDIT REPORTS
A copy of the final audit report and audit worksheets along with other pertinent documentation and/or
study information will be retained in a locked filing cabinet maintained by the QA Coordinator. Audit
reports will be retained indefinitely in some form. All other documents will be maintained for a limited
period agreeable with the QAC Director dependant upon storage constraints.
13. APPENDICES
Example of Administrative Audit Report
Example of Full Audit Report
Audit Worksheets
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EXAMPLE OF ADMINISTRATIVE AUDIT REPORT
June 9, 2008
XXXX XXXX, M.D.
Department of Neurology
FOT 1020
Dear Dr. XXXXX,
A routine administrative audit was conducted on the following investigator-initiated protocol:
UAB XXXX – Genetic Epidemiology of Adult-Onset Brain Tumor (IRB Protocol #X050815001)
This review covered the regulatory records for this study. At the time of the audit, 24 patients from
UAB were enrolled on this protocol. Other clinical sites are participating in this study as well.
Regulatory Review
The regulatory review included IRB reapprovals and informed consent review. The consent form was
reviewed using the most recent IRB-approved consent form.
IRB Documentation: IRB approval and continuing approvals were reviewed. No deficiencies were
found.
Consent Form Review: The consent form was reviewed for content and no deficiencies were noted. A
total of 3 randomly selected patient consent forms were reviewed. No deficiencies were found.
Auditor’s Comments: All records were well-organized and the staff was most accommodating. A fast
and easy audit!
Regulatory Assessment:
ACTION ITEMS:
Acceptable
None required
__________________________________________________
John Fiveash, M.D., Quality Assurance Committee Director
__________________
Date
cc: Albert LoBuglio, M.D., Cancer Center Associate Director for Clinical Research
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EXAMPLE OF FULL AUDIT REPORT
August 26, 2008
XXXX XXXX, M.D.
Principal Investigator
University of Alabama at Birmingham
Old Hillman Building 538
Birmingham, AL 35233
Dear Dr. XXXX,
A routine internal audit was conducted on the following investigator-initiated protocol:
UAB XXXX – Extended Deep Venous Thrombosis Prophylaxis in Gynecologic Oncology Surgery
with Intermittent Compression Devices (ICD) with or without Postoperative Arixtra: A
Randomized Controlled Trial (IRB #F070727009)
The study is noted to have been registered as an “applicable clinical trial” as specified by NIH under the
expanded scope of ClinicalTrials.gov. The review covered one patient case record as well as review of
the regulatory and pharmaceutical records.
Regulatory Review
The regulatory review included informed consent content review of the most recent IRB-approved
consent and for IRB reapprovals.
IRB Documentation: IRB approval, amendments, and continuing approval were reviewed and no
deficiencies were noted.
Consent Form Content Review: The consent form was reviewed for content and no deficiencies were
noted.
Regulatory Assessment:
Acceptable
Pharmacy Review
The Drug Accountibility Record forms (DARFs) were requested but since the patient was randomized
into the standard of care management arm rather than the treatment arm, drug accountability records
were not required. Randomization records, however, were available. There were no deviations noted.
Pharmacy Assessment:
Acceptable
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UAB Patient Case Review
At the time of the audit, 6 patients were enrolled on this protocol. All 6 patients were included in the
randomization pool. A case review of one patient (Pt Initials, MRN XXXXXXX) was performed. The
patient enrolled in the study at Brookwood Hospital and was later transferred to DCH Regional Medical
Center. Records from each institution were provided. The following was found for the case review:
MRN XXXXXXX (Pt Initials)
Informed Consent:
No deficiencies found
Eligibility:
No deficiencies found
Treatment:
No deficiencies found
Disease Outcome/Response: No deficiencies found
Toxicity:
No deficiencies found
General Data Quality:
No deficiencies found
Auditor’s Comments: Flagging of the patient chart is recommended for future audits to assist in an
expeditious and accurate audit review. However, it is noted that records, though not flagged, were
complete and comprehensive.
UAB Patient Case Assessment:
Acceptable
ACTION ITEMS: Based upon communications with the Associate Director for Clinical Research,
outside hospitals will not be utilized for continued patient accrual for this study.
___________________________________________________
John Fiveash, M.D., Quality Assurance Committee Director
__________________
Date
cc: Albert LoBuglio, M.D., Cancer Center Associate Director for Clinical Research
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