Everyday Preparedness for the
Challenges of
FDA-Regulated Research
Pat Ward & Diane Wilson
UMMS Regulatory Affairs
With special thanks to Kara Morgenstern, HSLO
Human Subject Research at UM
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All – Governed by University policy
– See UM HRPP OM at http://www.hrpp.umich.edu
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Most – Under OHRP jurisdiction
– Common Rule, etc. at http://www.hhs.gov/ohrp/
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Some – Under FDA jurisdiction
– Various regulations and guidance, start at
http://www.fda.gov/ScienceResearch/SpecialTopics
/RunningClinicalTrials/default.htm
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Others – DoD, DoEd, etc.
Important Themes for Today
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Clinical research is a good thing for UMMS and its patients
UMMS clinical research is a part of the University’s overall HRPP
program
FDA-regulated research as a Clinical Investigator team is hard
FDA-regulated research as a SPONSOR-Investigator team is VERY Hard
Compliant research takes infrastructure, supervision, and commitment
Mistakes happen
FDA investigators are VERY good at their jobs - if there are mistakes or
concerns, the FDA will find them
Most mistakes and concerns can be satisfactorily addressed
Proactive preparations can help avoid mistakes and improve an
inspection’s outcome
Advice and assistance are available!
RESPONSIBILITIES
Responsibilities of Clinical Investigators
and their teams
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Follow investigational plan
Obtain and document informed consent
Clinical investigator personally conducts or supervises the investigation
Protect rights, safety, and welfare of participants
Ensure adequate medical care for the study participants
Obtain and maintain necessary approvals from IRB
Maintain and retain drug/device disposition
Maintain documentation of patient case history records
Provide written reports to the IRB and sponsor, as required
Ensure changes are not implemented without prior IRB and sponsor approval
Promptly report serious adverse events to the IRB and sponsor
Furnish progress and other reports, as required
Ensure all study team members are informed about their obligations noted above
Additional Responsibilities of
Sponsor-Investigators
(a.k.a. IND/IDE Holders)
 Select qualified clinical investigators
 Secure written agreements and financial disclosures
 Provide information to other investigators and study staff to ensure study
performed properly
 Ensure proper monitoring of the study
 Ensure the study is performed in accordance with the investigational plan
 Submit necessary amendments/supplements to FDA
 Ensure that FDA and investigators are promptly informed of significant new
adverse effects or risks
 Maintain adequate records
 Maintain proper control of the study drug/device
Responsibilities
of Clinical Investigators
Sponsor-Investigators
assume both piles of
responsibilities
Investigator
Responsibilities
Sponsor
Responsibilities
FDA HISTORY AT UM
FDA Inspections at UM
12
10
8
6
4
2
0
2005-2007
2008-2010
2011-2013
2014-
Possible FDA Determinations
–NAI – No Action Indicated
–VAI – Voluntary Action Indicated
–OAI – Official Action Indicated
• Untitled Letter
• Warning Letter
• NIDPO Letter
“Notice of Initiation of
Disqualification Proceedings and
Opportunity to Explain”
UM FDA Investigations
2008-2010 (N=12)
25%
OAI
2011-2013 (N=11)
NAI
VAI
NAI
VAI
No recent OAI Determinations!
FDA OBSERVATIONS AT UM
Clinical Investigator
483 Observations at UM
(N=21 since 2008)
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Investigation was not conducted in accordance with the
investigational plan (11)
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Failure to prepare or maintain adequate case histories with
respect to data pertinent to the investigation (9)
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Inadequate IRB approval or notification (8)
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Problems with informed consent (7)
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Control of investigational drug or device, or inadequate
return of unused drug or drug disposition records
inadequate (5)
Clinical Investigator
483 Observations at UM
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Protocol adherence
– Unreported/unapproved changes
– Protocol deviations/violations
– Ineligible subjects
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Informed consent
– Missing
– Wrong version
– Signature/date irregularities
– Misleading/overly technical language
(N=21 since 2008)
Clinical Investigator
483 Observations at UM
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(N=21 since 2008)
Documentation deficiencies
– Incomplete/inaccurate CRFs
– Missing source documents
– Corrections not auditable
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Missing or delayed IRB approval/reporting
– Amendment implemented before approval
– Missing or late reports
– Lapse in IRB approval
Auditable = ALCOA
Clinical Investigator
483 Observations at UM
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Poor test article accountability
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Missing or delayed reports to sponsor
(N=21 since 2008)
– AEs and protocol deviations
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Special issues for FDA Sponsor-Investigators
– Inadequate monitoring
– Missing or delayed reports to FDA
OAI EXAMPLE :
BUSY CLINICIAN & CLINICAL
INVESTIGATOR
Busy clinician ends up with multiple
“observations” on a Form 483
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Failure to obtain informed consent
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Failure to follow investigational plan
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Failure to report all changes to the IRB
Inexperienced
Study Staff
Heavy
Clinical
Obligations
Heavy
Workload
for Study
Team
Very Sick
Patient
Population
Supervision
Factors
Complexity
of Study
Large
Number of
Participants
in Active
Intervention
PI
Conducting
Large
Number of
Studies
Built a Robust CAPA
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PI self-imposed moratorium on clinical research
Certification training in FDA’s Clinical Investigator course
Adopt departmental QA program
– New QA position
– Enhanced SOPs
– Documented training to SOPs
– Weekly supervisory meetings with study team
Experienced colleague serving in advisory/mentor capacity
Oversight committee
Re-allocated some industry studies to other faculty
Successful external audit required before research allowed to resume
Prepare for FDA follow-up inspection
GENERAL LESSONS LEARNED:
“All men make mistakes,
but only WISE men
learn from their mistakes”
Winston Churchill
FDA-Regulated Research…
Top Tips for
Everyday Preparedness
From lessons we learned the hard way
#1 Train Well
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Take advantage of training opportunities and resources
– PEERRS, IRB courses, MICHR courses, sponsor training, FDA’s online modules and Clinical Investigator Training Program, etc.
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Consider steps toward certification by a professional
organization (SOCRA, ACRP, etc.)
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Seek an experienced mentor
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If you don’t know (or don’t know that you don’t know) -ASK!
#2 Help Your PI Supervise Well
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Communicate frequently with/between team members
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Spot-check for quality of work – swap with another
team for “fresh eyes”
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Identify and resolve confusion, problems, etc.
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Stay organized and current on documentation
The buck may stop at the PI’s desk, but s/he needs your
support to stay ahead of potential problems
#3 Qualifications of Study Team
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Identify all qualified Co-Is and staff needed and
complete paperwork
– Are study team members properly credentialed to complete
medical procedures in protocol?
– Has all training (including study-specific training) of study team
members been completed and documented?
– Are Co-Is on the FDA 1572 (drug study) or investigator
agreement (device study), if applicable?
– Is the delegation log accurate and up-to-date?
– Are any conflicts of interests identified and managed?
#4 Have a well-written,“doable” protocol
Failure to
follow the
investigational
plan
Doable
Protocol
How will you know?
#5 Test Run Protocol, Documents,
and Other Systems
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Are protocol procedures and timing feasible?
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Are there inconsistencies between protocol, CRFs,
investigator brochure, other study tools?
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Do alerts and
alarms work?
If not…
#6 Once You Commit to a Protocol…
The protocol
is not just a
“guideline”
If you feel
like
something is
outside the
bounds,
speak up!
#7 Implement Controls for
Study Article Accountability
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Study Drug
Have you defined the roles and responsibilities for the
Research Pharmacy?
– PI may delegate actions, but retains ultimate responsibility
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Study Device
Are all components of the investigational device strictly
tracked and controlled (locked down) to avoid access by
unauthorized users?
#8 Use Study Monitors Effectively
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Whether a S-I or CI industry trial, ask yourself:
– Can I rely on my monitor?
– Does sponsor/monitor’s advice make sense?
– Does my regulatory file document directions
given by sponsor/monitor and addressed by my team?
#9 Document To Tell Entire Story
Ask yourself:
• If you ran off to the Fiji Islands, would the
documentation you left behind tell the
entire story?
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Why you deviated from the protocol?
Who from sponsor approved the deviation?
When and why a CRF value was corrected?
Who made the changes?
Why any CRF data are inconsistent with source
documents?
#10 Ongoing Quality Assessment
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Know how things are going! Share this with your PI!
– Has there been staff turnover?
– Are research participants withdrawing or complaining?
– Are IRB submissions of good quality and submitted timely?
– What is outcome of monitoring reports?
– What is outcome of In-house audits reports?
• Office of Human Research Compliance Review (OHRCR)
– If issues are arising. . .
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Consider putting the project on hold to protect participants and data integrity
Report to IRB
Conduct root cause analysis (“5 Whys”)
Implement corrective and preventive actions
WILL FDA INSPECTION
LIGHTNING STRIKE YOU?
Objectives of FDA Inspections
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FDA Biomedical Monitoring (BIMO) Program Objectives
– To protect the rights, safety, and welfare of subjects
– To verify the accuracy and reliability of clinical trial data
– To assess compliance with FDA's regulations governing the
conduct of clinical trials
Triggers for FDA Inspections
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PI conducts many studies
PI is high enroller
Rapid or late enrollment
Pivotal trial for new drug application
Test article of focused FDA interest
PI conducts study outside his/her specialty area
Inconsistent data or unusual safety profile
Complaints
Non-compliance reported to FDA
When FDA Calls (or appears)…
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Inspections are usually scheduled in advance
– 7-10 days notice
– Will try to accommodate research team’s schedule
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Before the call comes:
– Prep anyone who might take that call
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During the call, also politely ask:
– Reason for inspection (data audit, for-cause, particular study?)
– Names of inspectors coming
– What would they like prepared in advance
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After the call -- call us!
– RA and/or IRBMED
– We are prepared to advise/assist you
What Do FDA Inspectors Do?
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Hold you to…
– FDA regulations
– Sponsor’s protocol
– IRB approval
– Your own (and University) policies and procedures
Keep to the code.
The code is the law…
What do FDA Inspectors Do?
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Compare CRFs to source documents to verify…
– Subjects met inclusion/exclusion criteria
– IRB review/approval obtained
– Informed consent obtained from subjects
– Study was conducted according to the protocol
– Primary efficacy measures
– Adverse events reported
– Safety data (labs, etc.)
– Accountability of investigational agent
What do FDA Inspectors Do?
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Interview members of the study team and
key institutional representatives (IRB, etc.)
– Who did what?
– What was the practice/expectation
at time X?
– Do interviewees understand their
respective responsibilities?
FDA’s View of Principal Investigator
A PI should….
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Live, breathe, and follow the protocol
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Be actively and fully engaged in supervising study staff
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Be attentive to subject safety and rights
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Make required reports to IRB, sponsor, etc.
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Ensure accurate, clear documentation that fully tells the story
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“Get It”
With FDA….
It’s all about the PI !
When we inspire their
confidence, the FDA
can go from this…
…to this!
Internal Resources
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IRBMED Guidance
http://med.umich.edu/irbmed/guidance.htm
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IRBMED Training
http://med.umich.edu/irbmed/education.htm
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MICHR Training
http://www.michr.umich.edu/education
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MICHR MIAP
https://www.michr.umich.edu/services/regulato
rysupport/miap
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PEERRS http://my.research.umich.edu/peerrs/
More Internal Resources
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Public Access Requirements (for gov’t funded
research) http://orsp.umich.edu/nih/public/
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www.Clinicaltrials.gov Workshops
– http://ttc.iss.lsa.umich.edu/ttc/?s=clinicaltrials.gov&
submit=Search
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Safe computing:
– http://www.safecomputing.umich.edu/dataguide/
External Resources
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Information Sheet Guidance For IRBs, Clinical
Investigators, and Sponsors
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.p
df
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FDA Running Clinical Trials Page
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm
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Writing an Effective 483 Response (2009 FDA
Presentation)
http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/Works
hopsMeetingsConferences/UCM102921.pdf
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FDA Warning Letters
http://www.fda.gov/iceci/enforcementactions/warningletters/default.htm
External Resources (continued)
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WIRB Online Seminars (free)
http://ie6.wirb.com/Pages/EducationServices.aspx
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Importance of an effective corrective and preventive action program
How to survive an FDA inspection of your clinical trial site
Feasibility issues – should I agree to do this trial?
Many other topics
ICH Guideline E6: Good Clinical Practices
http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf
• CDRH Learn Courses
http://www.fda.gov/training/cdrhlearn/default.htm
Questions?
Thank you