Ct Audits

CLINICAL TRIAL

AUDIT Dr. VIJAYA KUMAR HG Study Manager, Sanofi-aventis, India [email protected]

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 [email protected]