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

• All – Governed by University policy–See UM HRPP OM at http://www.hrpp.umich.edu

• Most – Under OHRP jurisdiction–Common Rule, etc. at http://www.hhs.gov/ohrp/

• Some – Under FDA jurisdiction–Various regulations and guidance, start at

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm

• Others – DoD, DoEd, etc.

Important Themes for Today

• 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

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 studyEnsure the study is performed in accordance with the investigational planSubmit necessary amendments/supplements to FDAEnsure that FDA and investigators are promptly informed of significant new

adverse effects or risksMaintain adequate recordsMaintain proper control of the study drug/device

Responsibilities of Clinical Investigators

Investigator Responsibilities

Sponsor Responsibilities

Sponsor-Investigators assume both piles of

responsibilities

FDA HISTORY AT UM

FDA Inspections at UM

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”

2008-2010 (N=12) 2011-2013 (N=11)

No recent OAI Determinations!

25%OAI

VAI

NAI

VAI

NAI

UM FDA Investigations

FDA OBSERVATIONS AT UM

Clinical Investigator 483 Observations at UM (N=21 since 2008)

• Investigation was not conducted in accordance with the investigational plan (11)

• Failure to prepare or maintain adequate case histories with respect to data pertinent to the investigation (9)

• Inadequate IRB approval or notification (8)

• Problems with informed consent (7)

• Control of investigational drug or device, or inadequate return of unused drug or drug disposition records inadequate (5)

Clinical Investigator 483 Observations at UM (N=21 since 2008)

• Protocol adherence– Unreported/unapproved changes– Protocol deviations/violations– Ineligible subjects

• Informed consent– Missing– Wrong version– Signature/date irregularities– Misleading/overly technical language

Clinical Investigator 483 Observations at UM (N=21 since 2008)

• Documentation deficiencies– Incomplete/inaccurate CRFs– Missing source documents– Corrections not auditable

• 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 (N=21 since 2008)

• Poor test article accountability

• Missing or delayed reports to sponsor – AEs and protocol deviations

• 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

• Failure to obtain informed consent• Failure to follow investigational plan• Failure to report all changes to the IRB

Supervision

Factors

Inexperienced Study Staff

Very Sick Patient

Population

PI Conducting

Large Number of

Studies

Large Number of

Participants in Active

Intervention

Complexity of Study

Heavy Workload for Study

Team

Heavy Clinical

Obligations

Built a Robust CAPA

• 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

• Take advantage of training opportunities and resources– PEERRS, IRB courses, MICHR courses, sponsor training, FDA’s on-

line modules and Clinical Investigator Training Program, etc.

• Consider steps toward certification by a professional organization (SOCRA, ACRP, etc.)

• Seek an experienced mentor• If you don’t know (or don’t know that you don’t know) --

ASK!

#2 Help Your PI Supervise Well

• Communicate frequently with/between team members• Spot-check for quality of work – swap with another

team for “fresh eyes”• Identify and resolve confusion, problems, etc.• 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

• 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

How will you know?

Failure to follow the

investigational plan

Doable Protocol

#5 Test Run Protocol, Documents, and Other Systems

• Are protocol procedures and timing feasible?• Are there inconsistencies between protocol, CRFs,

investigator brochure, other study tools?• 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

• Study Drug Have you defined the roles and responsibilities for the Research Pharmacy?

– PI may delegate actions, but retains ultimate responsibility

• 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

• 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?– 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

• 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. . . • 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

• 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

• 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)…

• Inspections are usually scheduled in advance– 7-10 days notice– Will try to accommodate research team’s schedule

• Before the call comes:– Prep anyone who might take that call

• 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

• After the call -- call us!– RA and/or IRBMED– We are prepared to advise/assist you

What Do FDA Inspectors Do?

• 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?

• 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?

• 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….• Live, breathe, and follow the protocol• Be actively and fully engaged in supervising study staff• Be attentive to subject safety and rights • Make required reports to IRB, sponsor, etc.• Ensure accurate, clear documentation that fully tells the story• “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

• IRBMED Guidance http://med.umich.edu/irbmed/guidance.htm

• IRBMED Training http://med.umich.edu/irbmed/education.htm

• MICHR Training http://www.michr.umich.edu/education

• MICHR MIAP https://www.michr.umich.edu/services/regulatorysupport/miap

• PEERRS http://my.research.umich.edu/peerrs/

More Internal Resources

• Public Access Requirements (for gov’t funded research) http://orsp.umich.edu/nih/public/

• www.Clinicaltrials.gov Workshops–http://ttc.iss.lsa.umich.edu/ttc/?s=clinicaltrials.gov&

submit=Search

• Safe computing:–http://www.safecomputing.umich.edu/dataguide/

External Resources

• Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsorshttp://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf

• FDA Running Clinical Trials Pagehttp://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm

• Writing an Effective 483 Response (2009 FDA Presentation)

http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UCM102921.pdf

• FDA Warning Lettershttp://www.fda.gov/iceci/enforcementactions/warningletters/default.htm

External Resources (continued)

• WIRB Online Seminars (free)http://ie6.wirb.com/Pages/EducationServices.aspx

– 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 Practiceshttp://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf

• CDRH Learn Courseshttp://www.fda.gov/training/cdrhlearn/default.htm

Questions?

Thank you