Download - Auditing & Quality Assurance
Auditing & Quality Assurance
Igor Espinoza-Delgado, M.D.Gary Smith M.Sc.Cancer Therapy Evaluation Program
Health CareDelivery Research
Good ClinicalPractice
Clinical Trials
Good Clinical Practice (GCP)•An internationally recognized standard
for the design, conduct, performance, monitoring, auditing, recording,
analyses, and reporting of clinical trials. • GCP provides assurance
that the data and reported results are credible and accurate, and that the
rights, integrity, and confidentiality of trial subjects are protected.
Regulatory Basis forMonitoring and Auditing
1962 Harris-Kefauver amendments to the food, drug, and cosmetic act required that FDA regulate the testing of new drugs as an investigational new
drug (IND) prior to drug approvalDemonstration of efficacy and safety in well-
controlled clinical investigations
Regulatory Basis forMonitoring and Auditing (Cont.)
FDA IND regulations (21CFR 312.50) requires sponsors to ensure proper monitoring of
investigation(s), ensure that investigations are conducted in accordance with approved protocols as contained in the IND, and ensure that the FDA
and all participating investigators are promptly informed of significant new adverse effects or risks
with respect to the drug.
All those planned and systematic actions that are established to ensure that the
trial is performed and the data are generated, documented (recorded), and
reported in compliance with GCP and applicable regulatory requirements.
Quality Assurance
Patient Safety/Ethical Considerations-Respect for Persons
-Beneficence: maximize possible benefits and minimize possible harms
Regulatory Considerations-Delay in product approval
-Approval withdrawals-Sanctions
Why Be Concerned With Quality?
Monetary Considerations-$802 million: total average preclinical and
clinical costs up to the time of receiving FDA marketing approval
-$897 million fully capitalized cost to develop a new drug, including cost of conducting post
marketing surveillance studies after receiving regulatory approval
(Tufts Center for the Study of Drug Development)
Why Be Concerned With Quality?
Public Trust
Why Be Concerned With Quality?
Staff training/mentoringQuality control
Data safety and monitoringStudy monitoring
Auditing
Components of Quality Assurance
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), GCP, and applicable regulatory
requirements.
Monitoring
A systematic and independent examination of trial related activities and
documents to determine whether the evaluated trial related activities were conducted, and the data recorded, analyzed and accurately reported
according to the protocol, sponsor’s standard operating procedures, GCP, and
the applicable regulatory requirements.
Audit
Auditing: Snapshot in time On-site process Subset of patients
on a trial
Monitoring: Continuous process On-site and/or off-site Includes all patients on
a trial
Quality AssuranceAuditing vs. Monitoring
Objectives:
Assure accuracy and quality of dataAssure compliance with Federal regulations
Assure compliance with sponsor’s policies and procedures
Assure compliance with GCPServes as an educational tool
On-Site Audit Program
Phase of Study
Study Monitoring ReportingMechanism
Auditing
Phase 1 &Select Phase 2
CTMS + CTEP Bi-weekly CRFs to CTMSMonthly CTMS reports, downloads to CDUS
CTMS Pharm.D./M.D. once per yearCTMS/CRATwice per year
Phase 2 & 3 Cooperative Group
Cooperative Group + CTEP
CDUS quarterly
Group physicians, CRAs, nurses once every 3 years
Phase 2 & 3 Cancer Center/Single Inst.
CTEP CDUS quarterly
CTEP + CTMS + peer physicians once every 3 years
CTEP Monitoring and Auditing
Special audits:
-For cause audits
-Response audits
Other Types of Audits
NCI model:
Phase 1 CTMS monitored trials
Phase 2 & 3 trials:
- Monitoring via electronic submission of data quarterly via the clinical data update system (CDUS) and adverse event expedited reporting system (AdEERS).
Industry Model:
Similar to NCI model Phase 2 & 3 trials:
- Sites undergo on-site monitoring visits every 6 weeks with 100% of Case Report Forms included in source data verification during monitoring visit.
Key Differences Between NCI and Industry Model
NCI model: Audit unit is institution
based >10% of patient cases
are audited Scientific incentives
Industry Model: Audit unit is protocol
based >10% of sites are
audited Financial incentives
Key Differences Between NCI and Industry Model (Cont.)
On the day of the audit:
Provide overview of research procedures (scientific review committee, IRB)
Provide overview of organization of the medical records and research charts
Have data management staff available throughout the process if questions arise
Audit Preparation
Audit Preparation
On the day of the audit (cont.):
Meeting with principal investigator to review status of studyPharmacy inspection
Exit interview with P.I. and staff
Regulatory:
-Documentation of initial IRB approval-Documentation of continuing reviews-Documentation of IRB approval of all
amendments-Documentation of IRB review of reportable
adverse events and IND safety reports-Documentation of other IRB
correspondence pertaining to protocol
Audit PreparationWhat Is Needed?
Regulatory (cont.):
-1572s for Principal Investigator and Co-Investigator*-Investigator CV/Medical License*-IRB Membership List*-Office of Human Research Protections (OHRP) Assurance Number-Laboratory Certification* and Lab Normal Ranges
*primarily industry requirement
Audit PreparationWhat Is Needed?
Pharmacy:
-Drug Accountability Records as provided by the sponsor along with
shipping receipts, return receipts, and transfer forms when applicable-Appointment with pharmacy to
conduct inspection
Audit PreparationWhat Is Needed?
Patient medical records:
-ORIGINAL signed and dated informed consent (at time of enrollment as well as at time of re-
consent, if applicable)-Baseline history and physical exam
-Prior therapies including start and stop dates-Pathology report
-Protocol required parameters (labs, x-rays, scans, EKG, etc.)-Physician orders
Audit PreparationWhat Is Needed?
Patient medical records (cont.):-Medication administration records
-Nursing and physician progress notes-Off-study note
Research Records:-Eligibility checklist
-Confirmation of registration including arm and/or dose assignment
-Documentation of collection/submission of research tests (pharmacokinetics, marker studies, etc.)
-Documentation of tumor measurements
Audit PreparationWhat Is Needed?
Research Records (cont.):-Outside labs and other study parameters
-Outside physician records and correspondence -Appointment books
-Subject diaries/calendars-Study flow sheets and other research records that are signed and dated on a real time basis by the
health practitioner evaluating the patient-Protocol or study road maps
Audit PreparationWhat Is Needed?
Classification of deficiencies:
Major: any variance from protocol-specified procedures that makes the resulting data
questionableLesser: any variance that is judged to not have a significant impact on the outcome or interpretation
of the study data
Cooperative Group On-siteAudit Program
Possible Actions:
Re-auditSuspension of patient registrationSuspension of Investigator’s 1572Problematic audit findings may be referred to other agencies, such as the FDA, the Office for Human Research Protections (OHRP), or the Office of Research Integrity (ORI) when warranted
Unacceptable Audits
Reapproval delayed less than 30 daysReapproval delayed greater than 30 days but
less than one yearLack of documentation of full IRB approval of a
protocol amendment that affect more than minimal risk
Delayed reapprovals for protocols closed to accrual for which all patients have completed
therapyMissing reapproval
Most Frequently Occurring Deficiencies: IRB
Most Frequently Occurring Deficiencies: Consent Content
Lack of disclosure of all risks or side effects contained in model informed consent approved by NCILack of disclosure of approximate number of
participantsLack of disclosure of extent of confidentiality of recordsLack of disclosure of the contact person for research
questions, information regarding subject’s rights, and/or contact for research-related injury
Failure to disclose circumstances in which subject’s participation may be terminated by investigator without
subject’s consent
NCI drug accountability record forms (DARFs) incomplete or inaccurate
NCI DARFs not protocol and drug specificSatellite NCI DARFs not accounted for
NCI DARFs not kept as primary transaction record
Most Frequently Occurring Deficiencies: Pharmacy
Consent form does not contain all required signatures or dates
Consent form does not include updates or information required by IRB
Consent form used was not current IRB-approved version at time of patient registrationConsent form not signed and dated by patientConsent form signed after patient started on
treatment
Most Frequently Occurring Deficiencies: Informed Consent
Documentation missing; Unable to confirm eligibility
Review of documentation confirms patient did not meet all eligibility criteria as specified by the protocol
Most Frequently Occurring Deficiencies: Eligibility
Treatment doses incorrectly administered, calculated or documentedDose deviations incorrect
(greater than +/- 10%)Dose modifications unjustifiedUnjustified delays in treatment
Additional agent(s)/ treatment given prohibited by protocol
Most Frequently Occurring Deficiencies: Treatment
Tumor measurements/evaluation of status or disease not performed according to protocol
Claimed response (partial response, complete response, etc.) cannot be verified
Protocol-directed response criteria not followedInaccurate documentation of initial sites of involvementFailure to detect cancer (as in a prevention study) or
failure to identify cancer progression
Most Frequently Occurring Deficiencies: Response
Follow-up studies necessary to assess toxicities not performed
Grades, types or dates/duration of serious toxicities inaccurately recorded
Recurrent under or over reporting of toxicitiesFailure to report a toxicity that would require
filing an adverse event reportReported toxicities cannot be substantiated
in source documents
Most Frequently Occurring Deficiencies: Toxicity
Most Frequently Occurring Deficiencies: General Data Quality
Errors in submitted dataDelinquent data submission
Recurrent missing documentation, e.g., chartsProtocol-specified laboratory tests
not documented
Quality Improvement
General Record Keeping:
Remember, if it is not documented, it cannot be verified as being done
Follow standard procedures for documentation and error correction, including dating
and initialing entries
Quality Improvement
“The myth of perfect performance of the health care worker is unrealistic. We must change to an
engineering mode of thinking that things will always go wrong. We need to protect the patient from results of errors, or failure of safe design. We not only need a
‘fail-safe’ design, but redundancy in the system, because a backup system protects the process. The
system must possess two independent redundant steps, not interdependent steps.”
(Quote from Richard J. Croteau, M.D., JCAHO executive director for strategic initiatives)9