1. Trial Master file – inspection readiness
Trial Master File & Clinical Document Management Conference
September 10, 2019
Anaheim, CA

2. speakers
JoAnn Pfeiffer, DrSC: Dr. Pfeiffer is the Director and Associate Professor, Master of Clinical Research Management & Regulatory Science Programs at Arizona State University. Co- author of multiple textbook, articles industry scientific journals, and presents nationally. She has over 15 years in clinical trial management. She has worked in both the academic and non-academic environment. She has presented on different areas in clinical research and regulatory affairs nationally and internationally.
Tina Escobedo, DNP, FNP. Dr. Escobedo earned her Registered Nurse Degree in 1987, followed by a Bachelor's of Science in 2006, Master's of Science and Family Nurse Practitioner 2008, and Doctor of Nursing Practice in 2013.  She has over 15 years experience in clinical trials management and has been actively involved in the conduct of  over 100 clinical trials. She has worked in a variety of roles including infusion nurse, certified clinical research coordinator, clinical director, and sub-investigator. Bench research in the area of dry eye and rheumatoid arthritis in the academic setting and clinical practice collaboration with associated publication(s). 

3. Agenda Regulatory Framework for Inspections Inspection Preparation
What are inspectors looking for?
Inspection findings
Responses
CAPA
Practicum
Tips for a successful inspection
Questions & Answers

4. Trial master file (TMF)
The trial master file (TMF) is the collection of essential documents which allows the conduct of a clinical trial to be reconstructed and evaluated. It is basically the story of how the trial was conducted and managed.

5. Essential documents
Essential documents are those documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements.
ICH GCP, Section 8.1
The essential documents in the ICH GCP (International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use – Good
Clinical Practice), published in 1996 [5], is the minimum list of documentation but is not a comprehensive content list for the TMF [2]. From 1996 to the present, the environment of clinical trials has changed drastically, requiring additional documentation in the TMF. All documents associated with a clinical trial that are needed to reconstruct the course and conduct of the trial are relevant for inclusion in the TMF. (Audit trail)
The EMA stated in its “Reflection paper on GCP compliance” that TMFs should be complete and accurate [2]. This raises the question:
When can a TMF be considered accurate and complete? At present, no quality characteristics have been defined to ensure a TMF is up to standard.

6. Essential Documents CRF Enrollment Logs Advertising and recruitment
Serious Adverse Event Reports
Monitoring Reports
Lab certification & lab references
Product accountability/Product destruction

7. Essential Documents - list
File – clearly labeled with study information
Correspondence
Protocol
Consent
IRB Approval, reports
Staff training
Delegation Log

8. Fda inspections Who Why What will occur When Where
Who is involved in the inspection
Internal
FDA
Why do inspections occur
End of study; ready for market approval
For cause - complaints
What should you expect at an inspection
Notice
Arrival
Access to records
Copies
Meetings
When will it occur
Regular operation hours
Days – week +
Where will it occur
Study site
Provide space
Site

9. Preparing for an inspection
How do you prepare for an FDA inspection?
Start early (as soon as receive notification)
Contact sponsor
Audit TMF, Subject Binders
Review SOPs & Training Documents (up to date)
Review previous monitoring reports for issues and make sure they have been corrected
Review previous 483s
CAPA – implemented, evaluated, results
Meetings with appropriate staff to prepare

10. What to Expect Arrival: Inspector credentials & FDA Form 482
3 days – 2 weeks
During: verify compliance with regulations, use of investigational product and human subject protection.
Inspection of subject records
Inspection of TMF (regulatory binder)
Talk to study staff
Inspect lab and pharmacy
Meet with investigator at beginning and end
Provide a summary of findings at the end with official report to follow

11. Case studies Site 1: Site 2: FDA Inspector spent 5 days at site
100% review of documents, inspected lab and pharmacy, drug accountability; Friday afternoon met with Investigator & Coordinator. Congratulated the site as they found no issues. Site receives call following week, that inspector is returning to site – regional manager instructed investigator not to leave until she found something. Spent 4 more days. Findings – IRB not notified of a subject SAE within timeline; 1 subject did not receive updated consent; delegation of authority was not current.
Site 2:
FDA inspector spent 4 days at site
100% review of study documents, inspection of facilities, met with staff
Site received following observations: the consent process was not adequate; access to subject files was lax; three SAEs had not be fully adjudicated. Resulted in development and implementation of multiple CAPAs.

12. Document management Staff Training Standard Naming Convention SOP
Follow GCPs
Timely
Random Audits

13. Data Management ALCOA Attributable Legible Contemporaneous
Original or true copy
Accurate

14. Paper vs. electronic (21 CFR 11)
The requirements for records do not differ depending on the data format; paper- based and electronic data record-keeping systems are subject to the same requirements.
Electronic Systems – 21 CFR 11
System validation
Certify meets requirements of 21 CFR 11
Limited access
Double sign-on
Electronic signatures
Track changes
Date Stamp

15. Electronic – system compliance
Sponsors and other regulated entities must ensure that procedures and processes are in place to safeguard the authenticity, integrity, and, when appropriate, the confidentiality of electronic records (§§ and 11.30).
Procedures and processes are in place to limit access to the electronic system to authorized users (§§ 11.10(d) and
External security safeguards in place to prevent, detect, and mitigate effects of computer viruses, worms, and other potentially harmful software code on study data and software (e.g., firewalls, antivirus and anti-spy software).
Electronic systems should function essentially the same way that manual typewriters or pens would function

16. Electronic systems
Obtain service agreements with the electronic service vendor. Before entering into an agreement, the sponsor or other regulated entity should evaluate and select electronic services based on the electronic service vendor’s ability to meet the part 11 requirements and data security safeguards
An electronic signature is a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature (§ 11.3(b)(7)).
Part 11 regulations require that an organization verify the identity of an individual before the organization establishes, assigns, or otherwise sanctions an individual’s electronic signature or any element of such electronic signature (§11.100(b)).

17. Principles from the paper-and-ink still apply:
§ requires that backup data are exact and complete, and secure from alteration, inadvertent erasures, or loss
§ (b) requires that data be stored to prevent deterioration or loss
§§ and require that certain activities be documented at the time of performance and that laboratory controls be scientifically sound
§ requires true copies or other accurate reproductions of the original records; and
§§ , , and (g) require complete information, complete data derived from all tests, complete record of all data, and complete records of all tests performed.

18. Why is FDA concerned with the use of shared login accounts for computer systems?
“…you must implement documentation controls that ensure actions are attributable to a specific individual.”
When login credentials are shared, a unique individual cannot be identified
On paper you would sign/initial and date your work or the review of other’s work

19. Fda Investigator inspections (2018)
FDA conducted 547 Inspector Investigations
NAI – 67.2% (368 inspections)
VAI – 31.3% (171 inspections)
OAI – 1.5% (8 inspections)

20. 2018 – FDA Inspection 483 Findings
Deficiencies (VAI)
Protocol – 29%
Records – 14%
Consent – 4%
Drug Accountability – 3%

21. 2018 – FDA Inspection Warning letter findings
Deficiencies – OAI
Records – 40%
Drug Accountability – 40%
Submission of False Information – 20%
Protocol – 20%

22. Recent fda inspections in california
Inspection No.n
Investigator
Date
Action
Deficiency Code
Institute
632210
Samer Khaled, MD
1/14/19
VAI 05
City of Hope
658671
Sourabh Kharait, MD
1/28/19
Summit Nephrology Medical Group, Inc.
695260
Robert Peters, MD
2/11/19
01, 05, 06
Profil Institute for Clinical Research
642885
Mohammed Mahmud, MD
2/25/19
05, 06
Kindred Medical Institute
3/26/18
Summit Nephrology Medical Group, Inc
642928
Tonny Tanus, MD
5/21/18
NAI 00
Kern Allergy and Medical Research, Inc.

23. Post inspection
Responses
CAPA
Learn & Plan

24. Crfs – foundation for study data
100% Inspection Readiness
Creating accurate and complete documents
Practicum
Review CRFs (accurate & complete)
Completed CRFs
Correcting Data

25. Practicum Activity one
Protocol Summary - review
Subject Case - review
Screening Visit – complete
Present

26. Practicum activity two
Protocol Summary
Subject Case
Completed Visit Two
Review for completeness & accuracy
Present

27. Practicum activity three
Protocol Summary
Subject Case
Completed Visit Eight
Review for completeness & accuracy
Present

28. Practicum activity Four
Protocol Summary
Subject Case
Completed Visit Twelve
Review for completeness & accuracy
Present

29. Challenges TMF Challenges Multiple people contributing Access
Consistency - SOP
Materials current
Responsibility – who & what r

30. Tips for success
Inspection ready at all times – regular internal audits
Complete and file forms in timely manner
SOPs – train, follow, hold accountable
Staff Training – new staff and regular staff training updates/reviews
Know the FDA & ICH requirements and guidance documents – assign one person to follow & alert to changes
Access to TMF limited to those who need it (log sheet at beginning of file)
Standard naming for files and file sections

31. questions
Thank You