Site Regulatory Document Management: Best Practices

1. Site Regulatory Document Management: Best Practices Patrice H. Pompa April 11, 2012

2. Agenda • Refresher: Purpose of Site Regulatory Documents • Collection vs Review • Recommended Approach • Tools • Key Docs • Tracking • Files • Lessons Learned and Training • Summary

3. Clinical Trial Activities

4. Clinical Trial Activities Form 1572- Investigator CVs - Protocol Signatures -Medical Licenses - IRB Approval Letter -Investigator Brochure – IRB Approved Consent – IRB Approved Assent- ICF Translations -IRB membership list- Lab Certification/Accreditation - Lab Director CV - Laboratory Normal Ranges - Financial Disclosure - FDA Investigator debar list - FDA compliance checks -IRB & FWA #s - DEA #s - Clinical Trial Agreement Negotiation- Budget Development - Patient Advertisements - Tracking -Program planning - INDs - Protocol Design - Case Report Form Setup - User Acceptance Testing - Validation - Study Budgeting - Study County Allocation - Investigator Recruitment - Site Feasibility Assessments - Randomization Schemes - FDA Reviews - Site Recruitment - IVRS/ IWRS - PGx -PD - Special Labs - Phase I-IV - Central IRB - Investigator Meetings - ICH – GCP - EEC - Payment Schedule - Global Collaboration - Investigational Product - Study Supplies - RFPs - Vendors - electronic Data Capture setup - eData Management - ePRO (electronic Patient Reported Outcomes) - Training – Timelines - First Patient In - Patient Recruitment - multiple Guidelines - - Metrics - Data Queries - Budget Tracking - Follow-up - Study Management - Risk Assessments - - Field Monitoring - Site Data - Source Documents - electronic Medical Records - Protocol Amendments - Site Management - Investigators - Study Coordinators - Clinical Laboratories - Adverse Events - Safety Letters - Investigator Brochure Updates - Data Safety Monitoring Boards - Clinical Events Committees - Key Opinion Leaders - Portals - Systems - User Access - Biostatistics - Sponsor Study Records Management - Audits - CAPAs - Helpdesks - Tickets – HD Knowledgebases - Tracking - Milestones - Reports - Coding Database Freeze - Analysis - Clinical Summaries - NDAs - TMFs/ eTMFs - Study Closeout - Archiving

5. WHATSite Regulatory Documents are needed to start a Clinical Trial? Form 1572- Investigator CVs - Protocol Signatures -Medical Licenses - IRB Approval Letter -Investigator Brochure – IRB Approved Consent – IRB Approved Assent- ICF Translations -IRB membership list- Lab Certification/Accreditation - Lab Director CV - Laboratory Normal Ranges - Financial Disclosure - FDA Investigator debar list - FDA compliance checks -IRB & FWA #s - DEA #s - Clinical Trial Agreement Negotiation- Budget Development - Patient Advertisements - Tracking -Program planning - INDs - Protocol Design - Case Report Form Setup - User Acceptance Testing - Validation - Study Budgeting - Study County Allocation - Investigator Recruitment - Site Feasibility Assessments - Randomization Schemes - FDA Reviews - Site Recruitment - IVRS/ IWRS - PGx -PD - Special Labs - Phase I-IV - Central IRB - Investigator Meetings - ICH – GCP - EEC - Payment Schedule - Global Collaboration - Investigational Product - Study Supplies - RFPs - Vendors - electronic Data Capture setup - eData Management - ePRO (electronic Patient Reported Outcomes) - Training – Timelines - First Patient In - Patient Recruitment - multiple Guidelines - - Metrics - Data Queries - Budget Tracking - Follow-up - Study Management - Risk Assessments - - Field Monitoring - Site Data - Source Documents - electronic Medical Records - Protocol Amendments - Site Management - Investigators - Study Coordinators - Clinical Laboratories - Adverse Events - Safety Letters - Investigator Brochure Updates - Data Safety Monitoring Boards - Clinical Events Committees - Key Opinion Leaders - Portals - Systems - User Access - Biostatistics - Sponsor Study Records Management - Audits - CAPAs - Helpdesks - Tickets – HD Knowledgebases - Tracking - Milestones - Reports - Coding Database Freeze - Analysis - Clinical Summaries - NDAs - TMFs/ eTMFs - Study Closeout - Archiving

6. Clinical Research Trials: • Are highly regulated by the FDA and other global regulatory bodies • May also be influenced by state law • Investigational New Drug (IND) application • Requires information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound • To assess whether they are qualified to fulfill their clinical trial duties • Zero tolerance for fraud – as applied to investigator credentials as well as study data • Subject to FDA Regulatory Inspections / Audits

7. Regulatory Documents

8. WHYare Site Regulatory Documents Needed? Title 21: Part 11 – Electronic Records; Electronic Signatures Title 21: Part 50 - Protection of Human Subjects Title 21: Part 54 – Financial Disclosure by Clinical Investigators Title 21: Part 56 – Institutional Review Boards Title 21: Part 312 – Investigational New Drug Application (IND) Title 21: Part 314 – Applications for FDA Approval to Market a New Drug ICH Guidelines – E6- Good Clinical Practices (GCP) EU Directives (Clinical Trials and GCP)

9. Other Requirements Some local states have additional/differing requirements Examples Include: • Researcher Registration- Massachusetts • PatientBill of Rights- California, Oregon, Florida • Lab Licensure- NY and Washington are exempt from CLIA; state laboratory inspection in lieu of CLIA Country requirements • Seek counsel with local experts - Are there special local regulatory documents needed? • Do you need to increase emphasis on GCPs in CTA?

10. WHOis impacted?

11. Regulatory Documents:Most Common Deficiencies per FDA Bioresearch Monitoring (BIMO) Metrics FDA Clinical Investigator Inspections – FY ‘08, ‘09, ‘10:

12. Consequences • Possible consequences of deficient regulatory documents: • Regulatory Inspector audit findings (included in 483s, Warning Letters). • Most noted: • Failure to document, document, document • Failure to comply with specified processes • Failure to take corrective action • Failure to avoid risk (e.g. protect human subjects) • Unnecessary backtracking & rework to recollect documents • Delayed Filing: • Sponsor may = longer review of all investigator site Regulatory Documents when preparing for NDA submission!

13. Collection vs. Review If you don’t have a license, you can’t drive the car. = If you don’t have quality RegDocs, you can’t start the study. EXPIRED Good Site Activation Practices Drive Subject Enrollment & Data Quality: Must confirm that the investigator & their participating staff have appropriate, current qualifications and credentials, experience, and facilities before they can start the study.

14. RegDoc Collection Current Scenario • Necessary chore to get study initiated • Collected as quickly as possible • Cursory checks performed • Quality can vary from person to person

15. Site: Case Study • Principal Investigator was approved by Sponsor • PI was listed as Dr. and “MD” on 1572 & other docs • Medical license could not be found on website • Requests made to site for Medical License • CV education section revealed PI was a Veterinarian and “MD” was PI’s first and middle name initials • Sponsor was notified • A M.D. physician PI had to be added

16. Highly Dynamic RegDoc Logistics Financial Disclosure Due Diligence: PIs, Sub-Is, Dependents CRA Data Management Sponsor/ CRO RegDocs (posted or issued to sites) Investigator Site Electronic verification checks IRB Electronic & Manual RegDoc Reviews Patient Informed Consent Files eFiles & Tracking Systems

17. HOW do we manage all these documents? Establish a systematic, comprehensive, in- stream regdoc review process

18. Focused RegDoc Review Benefits of conducting a focused and efficient RegDocReview • Meet all governing regulatory requirements • Meet protocol specific needs • RegDocs are correct, current, appropriate • Produce auditable, high quality study initiation documentation

19. Structured Approach

20. Define the Core Process • Develop a core regulatory document review Quality Management System • Establish primary standards for RegDoc Review

21. Define the Study-Specific Requirements Review the study protocol & proactively ask questions: • Participating countries? i.e. # subjects, # sites/country, study timelines, etc. • Special Informed Consent requirements? • Central and/or local IRBs? • Central, local, &/or specialized labs? • Custom tracking reports? • Investigator Brochure (distributed by drug project, not by study)? • How are Protocol Amendments managed?

22. Understand RegDoc Handoffs • Define the Workflow & Communication Process • Agree on Roles & Responsibilities of study startup team • How will you coordinate/partner with Monitors, other CROs, eTMFs, contractors, etc.? • Who is communicating with the sites? • Who must approve documents prior to finalizing them? • Where will the regdocs reside during and at the end of the process?

23. Good Communication Practices 23

24. Good Communication Practices Sites: • Provide assistance where needed • Repeat requests: Site first concerns is seeing their patients! • Don’t ask for information you may already have elsewhere (or on several different forms…tracker, surveys, etc.) • Find out site preferences • Is it better to call the site or email the site? • Which days of the week are better? (i.e. Mondays may be terrible due to patient voicemails, office visits, drug shipments, etc.) 24

25. Prepare RegDoc Study Project Plan All RegDoc team members ID whose SOPs are to be utilized Any special regdocs for review and review specifications Schedule for team meetings Team communication and escalation plan RegDoc Work Flow Agreed routine & customized reports Timelines & Metrics Systems to be used Document handling and archiving process (Document Management System) Maintain all new agreements or revisions throughout study life cycle. RegDoc Project Plan Study Team: Document key agreements & activities throughout study!

26. RegDoc Review Tools Create review aids to promote understanding of each RegDoc. • Highlight any RegDoc interdependencies/cross checks • Facilitate consistent & expeditious reviews • Employs a detailed QC process for each investigator site RegDoc file reviewed • Can be used for future training purposes • Define the purpose of each document in detail • Give samples of each RegDoc with detailed review tips • Utilize a standard RegDoc Review Checklist • Transfer issues captured on checklist to an Issue Log • Resolve issues & discrepancies with site until resolved

27. RegDoc Review Checks

28. Informed Consent • New Rules • New studies must include ClinicalTrials.gov • in patient Informed Consent • Effective March 12, 2011 (with 1 year grace period): see FDA’s 21 C.F.R. Part 50.25 (c) Q&A • Suggestions: • See Informed Consent Q&A • Check if ICFs are combined (e.g. Consents/Assents, • HIPAA) • Compare ICF against Clinical Trial Agreement • (CTA) subject compensation & injury language • Define special review checkpoints • Plan for ICF translations • Know who provides legal counsel & how it is accessed • Check both pre and post IRB approval • Check state and local laws for any special requirements (e.g. Patient Bill of Rights, etc.) Informed Consent is often a separate SOP

29. IRBs • Recommendations • Membership Rosters • Needs to identify the institution by their letterhead • Needs to have a current date or version date • Compare against IRB approval letter timeline • Obtain new IRB roster with each approval to • make sure that the membership did not change • The PI/Sub-I can not vote on study. If listed, need proof that they abstained from voting • Be Aware of the type of IRB Review Occurring • Fullor partial committee review; expedited, etc. • Initial &/or Continuing IRB Review • Track IRB submission & approval expiration dates • Make sure you have copies of the most current approval docs filed at each site & with sponsor

30. Financial Disclosure • New Rules • May 2011 - New Draft Guidance: Financial • Disclosure by Clinical Investigators (see exemptions) • http://www.fda.gov/RegulatoryInformation/Guidances/ucm126832.htm • Applies to both domestic & international trials • Financial Disclosure Questionnaires (FDQs) • must be collected “before allowing the clinical • Investigator to participate in a covered clinical • study.” 21 CFR 312.53(c), 812.20(b)(5) and • 812.43(c). ..Complete disclosure or certification • “and to update this information if any relevant • changes occur during the study and for one year • following its completion.” • See FDA’s Financial Disclosure Questions & Answers • FDQ update is needed if Sponsor changes during study • Sponsors may have to take steps to minimize any potential bias Due Diligence

31. Financial Disclosure: Case Study • Global medical device company- $3 billion annual sales • Consulting contracts & gifts of company stock given to participating investigators • Financial Disclosure Forms not closely reviewed • Some signed and dated but otherwise blank • Others disclosed an equity interest but offered no details • FDA missed this, but Attorney General in NJ did not • Assurance of Voluntary Compliance Agreement executed • Stringent reporting requirements • Forbidden from compensating physicians with stock • Paid $236,000 in fines, penalties and legal fees

32. RegDoc Review Tracking Utilize an effective, flexible document tracking system • That can be modified for the study • Tracks document dates, IRB submission dates, pending expirations, and receipt/sent logistics, site status, etc. • Know how to keep track of document versions • Useful for tracking issue trends • Sends red flag alerts • Provides key reports (i.e. tracking/summary reports, metrics) • Use systems to pre-populate forms with site PI name, addresses, email where possible • Provide future access to site information to avoid rework later RegDoc tracking system + good work processes= Best Practice

33. File Maintenance • Have a Document Management Quality System SOP • Centralize access to RegDoc files & relevant correspondence • A Investigator Site File Index should be created for investigator files • Define TMF process flow: Know rules for maintaining regulatory documents both electronically and in paper format e.g. Trial Master File • Scan in ALL hard copy files into designated study repository • Establish a clear standardized file naming convention & file folder structure • “Wet Ink” documents should be defined in the RegDoc Project Plan • Ensure required original “Wet Ink” signatures are present on designated paper documents • Original paper documents must be filed in a secure locked area until release to designated archivist • Ensure RegDoc files are ready for audit

34. Lessons Learned Debrief At the end of the trial, assess the following: • Were RegDoc processing timelines & deliverables met? If not, why? • Were there any communication, escalation, or logistical issues that could have been avoided? • What are best practices and lessons-learned? • Any required CAPAs (Corrective and Preventive Actions)? • Capture experiences in a Risk Management Plan with well thought out contingencies • Enhance SOPs, working practices as needed • Incorporate new processes into next RegDoc Study Project Plan

35. Qualifications & Training • Reviewer qualifications should align with job descriptions • Ensure all reviewers are trained to • SOPs, protocol, & other resources • Employ Hands-On RegDoc review exercises • Conduct periodic internal audits • Maintain complete Training Records • Indicate specific documents training • Specify all training dates • Re-train staff when process changes occur

36. IRB Approval Letters, IRB Approved ICF/Assents, Ads, other Patient Materials Weeks -21 -20 -19 -18 -17 -16 -15 -14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 Concurrent Review Process: Balancing Quality & Speed Study Initiation Site Contract Clinical Trial Agreement (CTA) & Budget Negotiation Confidentiality Agreement • Check against CTA InFormed Consent Study ICF Template ICF Template/ICF/Assent Checklist Reviews RegDoc Maintenance IRB Approvals IRB Submission Site Selection & Finalization Other RegDocs B Collection of all other RegDocs, Filing, System Tracker/Updates, Communications /Interactions Feasibility Provision Country Allocation Project Kickoff Mtg RegDoc Project Plan weeks First Center Initiated Key Milestones Concept Protocol Approval Final Protocol Approval 36

37. Summary • Develop both core and study-specific RegDoc Review processes • Include RegDocs in your study’s Project Planning • Centralize access to appropriate & current review resources • Establish an effective tracking system that can also capture issue trending • Use a clear, standard document management system • Conduct process checks & enhance SOPs when needed • Be proactive - Do it right up front to avoid rework! • Work within study timelines

39. Thank You Patrice H. Pompa Director – Regulatory Document Management (RDM) ppompa@cfsclinical.com April 11, 2012 www.cfsclinical.com