CLINICAL TRIAL

AUDIT
Dr. VIJAYA KUMAR HG
Study Manager, Sanofi-aventis, India
vijaykumarhg@gmail.com
Guess who’s coming to audit?
We’re Going to be Audited !
 Overview
• Who are these auditors?
• Types of & reasons for audits
• What gets audited?
• Audit findings
• Rules of the game
• Consequences
• Advise
The Auditor
 Auditors – where do they come from?
1. Federal agency that oversees the research
• Sponsor (or their designee)
• IRB (or its designee)
• In-house (QA)

Normally auditors are independent of the

Clinical Trial team.
 Federal “oversight” auditors
•FDA (Food and Drug Administration)
–Drugs, biologics, devices, medical radiologics, etc

• Other:
–OHRP (Office of Human Research Protection)
–Office of Civil Rights (HIPAA)
–Nuclear Regulatory Agency
–DOT
–NIH
–etc.
 Sponsor’s Auditors
• Sponsor
– Pharmaceutical/biotech company
– Cooperative group
– Funding agency
– Private foundation

• Sponsor’s designee
– Contract Research Organization, or
– Individual with auditing/monitoring experience

• Auditor from regulatory department

– independent of clinical trials team.
 IRB Audits

• Human Subject Research Auditor

• IRB member (team)
• Someone designated by the IRB (with
expertise in that specific field)
 Internal Audits
• Auditor is:
– Someone on or closely associated with the Clinical
Trial team.
– Someone independent of the team/department but
reports to team and/or department.

• First line of defense

• Often conducting Quality assurance check

• Results stay within office/department

 TYPES OF AUDITS

For Cause Routine

 Routine Audits

• FDA
– To evaluate data supporting a new
drug or device application
• Sponsor
– To verify site data and conduct
– To verify how the study was monitored
• IRB or Inhouse
– To evaluate quality of research
ongoing at the institution.
 “For Cause” Audits

• FDA (Sponsor-IRB-Inhouse)
– Allegation/Suspicion of non-compliance.
– Safety or efficacy data is inconsistent with
other study sites.
– PI conducting research outside area of
specialty.
– Accrual is abnormally high for geographical
or ethnicity/race location.
 Why?
To verify :
• Records and subjects exist
• Records and study data are accurate
• Site compliance
• Quality
• Subject Safety
• To identify areas needing correction
What Gets Audited ?
 What Gets Audited – 6 Categories
• Regulatory and protocol compliance
• Subject
• Test article
Drug, device, biologic, radiologic, etc.

• Adverse events or complications

• Response
• Data management
 What Gets Audited …
1. REGULATORY
– 1572 (PI’s contract w/federal gov.)
– Protocol (amendments)
– Informed consent (assent)
– Other IRB Forms
– Communication (IRB, Sponsor, etc.)
– Other (training, etc.)
 What Gets Audited…
1. SUBJECT
(May be all subjects or only a representative sample)
– Consent
– Eligibility
– Treatment
– AEs/compliactions
– Response
– Other
 What Gets Audited…
3. TEST ARTICLE
(drug, biologic, device, radiologic, etc)

– Inventory logs (receive, dispense, return)

– Storage & handling
– Preparation
– Administered per protocol
 What Gets Audited…
4. ADVERSE EVENTS & COMPLICATIONS
– Recorded vs. Reported
– SAEs
– Other
 What Gets Audited…
5. RESPONSE
– Protocol compliant
– Documentation
 What Gets Audited…
6. DATA MANAGEMENT
– Source documents
– Case report forms
 In summary….
• The investigator (and the research team)
• The data
• The process

are all evaluated during an audit

 Audit findings
• Everything’s perfect, no problems at all
• PROBLEMS WITH:
– Protocol compliance
– Record keeping
– AE reporting/subject’s complaint
– Drug accountability
– Consent process
 How will Audit findings be
reported?
• FDA - verbal
• FDA – form 483
• OHRP - letter
• Sponsor – letter/form
• IRB – letter/form
• In-house Audit – letter/form
 Deficiency Statistics
27% - Protocol noncompliance
20% - Poor record keeping, inadequate source
documents, CRF’s, and/or IRB forms
15% - Poor AE reporting
9% - Poor drug accountability
8 % - Informed consent problems
 Examples of audit findings

• Subjects did not sign correct version of informed

consent.
• Case report forms not always accurate.
• Drug inventory forms not complete or not found
• Out of range lab values without note regarding
clinical significance or treatment relationship.
• Subject signed consent after treatment was started.
• Protocol altered without IRB approval.
• Test article dispensed by unauthorized individual
• Lack of active involvement by PI
The Blame game - Who does the PI fault ?
Per Deputy Director of CDER (FDA) June 2000:

• 9% - PI
• 91% - Someone else
– 56% - Coordinator/research nurse
– 9% - Sponsor
– 9% - Office staff
– 9% - Hospital
– 4% - Monitor
– 4% - Co-investigator
What are the rules of the game ?
 Rules of the Game
• IRB approved Protocol (Research plan)

• Federal regulations, guidelines & policies

• State regulations & policies

• IRB’s Guidelines & Policies

• IUPUI/Clarian IRB SOPs

• School/Department/Section SOPs &

policies
 Federal regulations
• Common rule (45CFR46)
– 17 federal agencies have adopted it

• FDA
– Drug/biologic
– (21CFR11, 50, 54, 56, 312, 314, or 601)
– Device
– (21CFR11, 50, 54, 56, 812, 814, 820)
 CFRs
• 21CFR11 = Electronic records & signatures
• 21CFR50 = Human Subject Protection
• 21CFR54 = Financial disclosure by clinical
investigators
• 21CFR56 = IRB structure & oversight
• 21CFR312 = IND application
• 21CFR314 = Application for FDA approval to market
a new drug
• 21CFR601 – Application for FDA approval of a
biologic
• 21CFR812 = IDE
• 21CFR814 = Premarket approval of a medical device
 CONSEQUENCES
• Letter/report (FDA form 483)
– NAI – No action indicated
– VAI – Voluntary action indicated
– OAI – Official action indicated
• Restrictions imposed
• Suspension/termination study
• Criminal/civil fines (felony in federal court)
– Investigator $250,000 (fine + restitution = $800,000)
– Coordinator $ 250,000
– Institution up to $1,000,000
• Disbarment (from Human Subject Research)
• Jail (federal prison)
 Consequences

• FDA
www.fda.gov/foi/warning.htm
www.fda.gov/ora/compliance_ref/bimo/dis_res_assur
 Consequences – example #1
• In 1997 a physician and 3 coordinator / nurses
were found to have falsified or fabricated data
in an investigational drug study (a 4th nurse
blew the whistle when she was asked to help
falsify data).
• All 4 (MD + 3 staff) plead guilty in federal
court to felony charges (conspiracy to make
false statements to a governmental agency)
• In 2002 the FDA went to court and had them
disbarred (MD 20 yrs, others 5 yrs).
 Consequences #1- disbarment
• Prohibited from providing services in any
capacity to a person with an approved or pending
drug product application (subject to civil
penalties).
• Any person with an approved or pending drug
product application who knowingly uses their
services is subject to civil penalties.
• The FDA will not accept or review any drug
application submitted by anyone who used their
services (during time of disbarment).
www.fda.gov/OHRM/DOCKETS/98fr/02-30482.htm
 Consequences – example #2
• Tenured professor (MD) at Univ.
Minnesota convicted of:
1. Falsifying information on case report forms
2. Having coordinators conduct “MD” exams

– fines & restitution to Sponsor = $214,000

– 6 months federal prison
– 6 months home probation
– 400 hours Community service
– Terminated by the university
 What’s the typical process?
(FDA)
• FDA contacts investigator directly
– 1 to 2 weeks notice
– PI or Coordinator should notify R&SP and appropriate
departmental authorities
– Determine what is to be audited and begin gathering
materials immediately
• Confirm schedules for regular office hours
• Duration: 1 – 4 days typical, but could be longer
• May be a single inspector or a team
• Upon arrival, Inspector must show credentials and
provide “Notice of Inspection” (FD-482)
 Process continued…
• Provide a comfortable, somewhat private place
to work with direct access to study records
• Upon completion, there will be an exit
interview (PI needs to be present)
– You may courteously offer evidence that corrects
inaccurate information stated by the auditor
• Auditor will send a written report of findings
• Investigator should respond promptly to written
report, factually correcting any erroneous
statements and mentioning any corrective
actions that have already been taken
 ADVISE
• Audit preparation starts when the study starts
– be knowledgeable and organized
• Make copies of everything the auditor has
requested per phone or written request (for them
and for yourself)
• Pull all records (CRFs, reg docs, drug
accountability, source docs, medical records,
sponsor training records, etc)
• Notify sponsor
• Seek advise from appropriate resources, e.g. CTP
 Advise cont…..
• Organize records – consider tagging key documents
• Conduct an internal self-audit
• Brief the PI on potential problems, if any
• Make sure the investigator will be available to meet
auditors, periodically for questions and for the exit
interview
• Provide plenty of space to work in a quiet location
• Provide a general orientation to the area and to
document organization
• Be considerate, cooperative, polite, honest
 Advise cont….
• Be brief and factual in response to questions
• Be sure of the question before answering; if not
sure or don’t know, say so
• Take immediate corrective action if possible
• Be readily available, but don’t hover; periodically
check to see if they have questions or needs
• Correct misinformation, as appropriate
• Encourage and assist the PI to respond promptly
and factually to the written report of findings
• Notify others on campus, as appropriate
 Don’t
• Panic
• Volunteer information
• Guess
• Be argumentative
• Offer opinions
• Delay responding to requests for copies or
records
 Don’ts cont…..
• Entertain hypothetical questions
• Read, sign, or listen to affidavits
• Respond to questions outside of your
expertise or that should be directed to the PI
• Provide financial information
Inspection of Clinical Trials
 Inspections
• What is an inspection?
An official review of documents, facilities, study
records
• Why?
Regulatory requirement. Routine. Pivotal. For cause
To ensure compliance with regulation and GCP
• Who?
Regulatory Authorities
• When? Anytime
 Inspections

• Where?
Where ever the study is happening-Sponsor site,
Investigator site
• How?

As with audit and inspection

 Conclusions
• We can all be audited and inspected at any
time
• All procedures focus on patient safety and
protection
• Good structured documentation is the key
Thank you
Dr. VIJAYA KUMAR HG
Study Manager, Sanofi-aventis, India
vijaykumarhg@gmail.com