Johns Hopkins Masters Project: Clinical Trials

1. Preparing for FDA/BIMO Site
Inspection
Prepared by Vice President
PharmaABCD Inc
Shubhda Roy

2. Agenda
• Current situation
• FDA Inspection Process
• Key Regulations covered
• RISK Analysis & Mitigation
• Before Audit
• During Audit
• Post Audit
• Mock Audit Check-List

3. Current Situation
• Hypertension drug in PHASE III
• Clinical trials being conducted in India
• CROs conducting trial in India
• Clinical Investigator sites in India
• All Documentation captured electronically
• Consent Form being captured electronically
o 25% subjects illiterate
• CI had to follow all local laws governing ethical
oversight

4. FDA Inspection Process
http://www.slideshare.net/PrashantBodhe/audit-monitoring-and-inspections-cro-perspectives

5. Key Regulations covered
• 21 CFR 58: Good Laboratory Practices:
• 21 CFR 312 : Good Clinical Practices:
• 21 CFR 312.120 : Non-U.S : Non-IND studies FOR PURPOSES OF
REVIEW in support of an application (NDA) for marketing in the U.S
• Compliance Program Guidance Manual
• Non US GCP Inspectors from India (India (CDSCO)
• 21 CFR 312.62(b) : Investigator recordkeeping
• 21 CFR 312.64 : Investigator reports
• 21 CFR 312.66 : Assurance of IRB review
• 21 CFR 312.62 : Investigator recordkeeping and record retention
• 21 CFR 312.60 : General responsibilities of investigators
• 21 CFR Part 11: Electronic records and electronic signatures
• 21 CFR Part 820.30(g): Design Controls
• 21 CFR Part 820.70(i): Automated Processes
• 21 CFR Part 58: Good Laboratory Practices
• FDA will accept non-U.S., non-IND studies FOR PURPOSES OF REVIEW
in support of an application (NDA) for marketing in the U.S., if the conditions
in are met

6. Risk Analysis & Mitigation
• Risks
o English is not a native language for the subjects
o 25% of the subjects are illiterate
o How is the data being electronically captured, verified and maintained
• Mitigation
o 10% English speaking subjects directly making data entry with help of trained site staff who can help
them with logistics of computers.
o 55% of Marathi speaking subjects (commonly spoken in Mumbai )are making direct entries with help of
trained site staff who can translate and help them with logistics of computers.
o 25% illiterate subjects are not making direct data entry. Site staff is translating and making entries on
their behalf. Computer system can directly take fingerprints of subjects for verification.
o All entries for marathi speaking and illiterate subjects are being video-recorded, which is part of the e-
source data.
o Clinical Data Liaisons (CDLs) are conducting real-time data review in Mumbai to ensure the wrong data
is not being collected.
o Patient consent and additional clinical information being collected from subjects is directly being
integrated using HL7 standards.
o Information is being send to send to backup servers located in USA.
o The servers are located in three different locations.
o Next day in USA, EHR (Electronic Data Record) staff is performs an interim analysis and verifies the
quality, and integrity of data .

7. Risk Analysis & Mitigation
• Risks
o Personnel not trained on computers properly
• Mitigation
• Need to assign qualified trainers for a quick
refresher course for all personnel for use
of computerized systems
• Have documentation of the computer
education, training available in clear sight

8. Risk Analysis & Mitigation
• Risks
o Dependency on an international CRO based in India
o Reliability of Clinical Sites being monitored by CRO
o CRO need to follow local & National law for the following:
• Need to follow the local & National Law for the following
• Human Subject Protections
• Adverse Event Reporting
• Registration and Approval of Clinical Investigations
• Continued Ethical Oversight
• Mitigation
o Working with a very reputed CRO
o Has global footprint in many countries including India
o Vendor who has earned trust
o Preferred vendor with a record of similar partnerships
o Contract Provisions with CRO includes:
• Right to monitor & audit any time
• Document retention
o Clear lines of Communication with Vendors:Who does the vendor call with compliance questions?
o CRO Understand & protect the attorney-client privilege
o Trainers from both sponsor and vendor collaborate on development of training curriculum and materials
o “Train the trainer” model – vendor’s project-dedicated
o CRO has worked on multiple clinical trials in India and understands the local and National Laws
• Clear accountability for Compliance/policy/legal violations in place with CRO
http://www.ehcca.com/presentations/pharmacongress9/kelly_t2_pm.pdf

9. Risk Analysis & Mitigation
o Risk
• Delegation of responsibility/CI personal involvement
• Monitoring (frequency; follow-up)
o Mitigation
• To Remedy these issues following happens:-
o Mock audits are conducted every few months.
o Continuous training of the site staff is undergoing on the process and
Systems
o There is hierarchy of staff and rotational program, in place
o Medical Monitor monthly rotations and monthly “call” notations
o Monitoring Chart (in next slide)
o Governance structure with communication plan and issue escalation
pathway (next slide)
Lecture Notes:

10. Risk Analysis & Mitigation
http://www.ehcca.com/presentations/pharmacongress9/kelly_t2_pm.pdf
CRO Monitoring chart

11. Governance Structure
Executive Steering Committee
Operational Committee
Line managers, team leads or subject matter experts for
concerned functional areas
Sponsor Program Director
Vendor Program Director
Functional Lead
Functional Unit Member
Escalation
and
Communicati
on
Pathway
http://www.ehcca.com/presentations/pharmacongress9/kelly_t2_pm.pdf

12. Risk Analysis & Mitigation
o Risk
• Availability of original data
• Consent document/process
• Traceability of data and samples
o Mitigation
Refer E-source flowchart in next slide
Lecture Notes

13. Esource in Placehttp://www.scdm.org/sitecore/content/be-ga/scdm/Publications/~/media/be%20bruga/scdm/documents/eSource%20White%20Paper%2006122014%20FINAL.ashx
E-source Flow Chart
o 10% English speaking subjects directly making data
entry with help of trained site staff who can help them
with logistics of computers.
o 55% of Marathi speaking subjects (commonly spoken in
Mubai )are making direct entries with help of trained site
staff who can translate and help them with logistics of
computers.
o 25% illiterate subjects are not making direct data entry.
Site staff is translating and making enteries on their
behalf. Computer system can directly take fingerprints of
subjects for verification.
o All entries for marathi speaking and illiterate subjects are
being video-recorded, which is part of the e-source data.
o Clinical Data Liaisons (CDLs) are conducting real-time
data review in Mubai to ensure the wrong data is not
being collected.
o Patient consent and additional clinical information being
collected from subjects is directly being integrated using
HL7 standards.
o Information is being send to send to backup servers
located in USA.
o The servers are located in three different locations.
o Next day in USA, EHR (Electronic Data Record) staff is
performs an interim analysis and verifies the quality, and
integrity of data .

14. Risk Analysis & Mitigation
• Risk
o The protocol for gathering and maintaining source
data should ensure that the data is being captured
accurately and not altered
o Source Documentation and Retention
• Mitigation
o Provide a detailed schematic data flow diagram
(e.g.-eCRF in XML format from clinical site→
Sponsor/CRO/IRB/Monitor/DSMB→ Data Lock→
Statistical Review→ Clinical Report→ Submission to
FDA)

15. Risk Analysis & Mitigation
• Risk
o Proof of a fail safe electronic system in place at CRO/Clinical Site which is fully automated.
o Proof of Clinical Documentation from source to finish
• Mitigation
o Clinical Data Management Plan (CDM)
• Documents all CDM Activities
• One repository for all documents
• Great tool for FDA inspections
o System operating manual (User’s Manual)
o Validation summary report for computerized system
• Data validation template
• Data Validation specification
• Data Management Plan Template (given in next slide)
o It is taken from the lecture notes.
o Documentation on User Acceptance Testing
o Data collection and handling documented in detail via flow charts
o System maintenance (Service/Upgrade Logs)
o Report listing all computer and software components with product names and versions
o Backup servers/ Redundant Servers or Hard-Drives placed in Mumbai, Delhi and Boston
o Audit Trails for every entry, modification with date stamp of created by, Created, Updated by, Updated, data
old and data new. The audit trail cannot be changed
o Clinical Data Liaisons (CDLs) to conduct Real-Time data review facilitating centralized control and
monitoring of clinical studies
From Lecture

17. Risk Analysis & Mitigation
• Risk
o Clinical sites must also meet IT specification requirements
• Mitigation
o Metrics for collecting and evaluating clinical data is consistent and documented at
the CRO
• Language (English Vs. Hindi/Marathi)
• Dates (e.g.- 8/12/08 Vs. 12/8/08)
• Times (e.g.- 21:00 Vs. 9:00 PM)
• Lab Values

18. General Guidelines Training for all
• Always answer truthfully
• Do not answer a question until you have heard and understood the whole
question.
• Answer only the question asked
• Answer questions with yes or no whenever possible
• Do not answer questions outside your area of responsibility
• Speak clearly and slowly
• Do not panic or be nervous
• Do not answer that you may think or assume
• Dress professionally
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371552/
https://www.uthsc.edu/research/research_compliance/OHSP/docs/How%20to%20Survive%20an%20FDA%2
0Inspection.ppt.

19. Before Audit
• Ask the Inspector
o How many inspectors are coming, how long will they stay, list of items they need
to review
• Identify the time they will arrive and set that time for the
introductory meeting.
• Notify your sponsor of the inspection
• Inform the CRO, prepare staff
• Prepare for Mock interviews, role plays so everyone in
the facility can answer the three questions.
o What you do, how you do it, show me
• Assign specific responsibilities for the audit

20. Before Audit
• Need to assign a escort/Facilitator
• Need to define a protocol - “SOP” for meeting with the
interactions from start to exit
• Need to gather and bring all study documents in one
place
• Need to put together a list of investigator’s studies
• Need to review the CDC plan
• Need to get a photocopier in place
• Need to get an allocated space for auditor
http://www.slideshare.net/PrashantBodhe/audit-monitoring-and-inspections-cro-perspectives

21. Before Audit
1. PI
2. Clinical Research
Coordinator
3. Research Staff
If notified of an FDA audit, notify the sponsor and
IRB as soon as possible.
Ensure that all documentation, including informed
consent forms, source documents, CRFs, and the
regulatory binder for the study identified as the
focus of the audit are accurate, complete and
available for review by the auditor (Attachment A,
Preparing for an Audit Checklist).
1. Clinical Research
Coordinator
Ensure that the study drug dispensing records are
accurate, complete and available for review. If there
were any instances in which emergency breaking of
the blind was required, have that documentation
available.
Ensure that drug accountability records are
accurate, complete and available for review.
1. Director, Research &
Innovation
2. Clinical Research
Coordinator
Ensure that records of staff qualifications and
training are available for review by the auditor.
https://www.mercyhealth.com/documents/Investigative%20Site%20SOPs/qa601audits.doc

22. During Audit
o All personnel access should be recorded and controlled
o Should be readily available – All Requested documentation, facility area
o Access should be controlled when the auditor arrives
http://www.phmacn.com/2008files/20110624153333-0.pdf
1. PI
2. Director, Research &
Innovation
3. Clinical Research
Coordinator
Meet with the auditor or inspector. Request to see
identification, and if this is an FDA audit, request
Form FDA 482.
Provide orientation and access to the study records
and files.
Provide copies of requested study-related
documents.
Ensure that questions posed by the auditor or
inspector are answered by appropriate study
personnel.
https://www.mercyhealth.com/documents/Investigative%20Site%20SOPs/qa601audits.doc

23. Post Audit
https://www.mercyhealth.com/documents/Investigative%20Site%20SOPs/qa601audits.doc
1. PI
2. Clinical Research
Coordinator
Participate in the exit interview with the auditor or
inspector. If this was an FDA audit, request Form
FDA 483, if available.
1. Clinical Research
Coordinator
2. Investigator
Respond to the audit report as soon as possible after
its receipt. Reply to each item in the report,
providing clarification or steps that will be taken to
institute corrective action. Supply a copy of the
final report to the IRB.

24. MOCK Audit CheckList