building quality into clinical trials and avoiding common ...scientific misconduct percentage in...
TRANSCRIPT
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Building Quality into Clinical Trials and
Avoiding Common Pitfalls
Michael E. Marcarelli, PharmDDirector, Division of Bioresearch Monitoring
Office of ComplianceCenter for Devices and Radiological Health
US Food and Drug Administration
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Disclaimer
The contents of this presentation are my own, and do not necessarily reflect the
views and/or policies of the Food and Drug Administration or its staff. The Food and
Drug Administration will not be bound by any of the comments or information contained in
this presentation.
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OVERVIEW
• FDA Bioresearch Monitoring (BIMO)
• Data and trends
• Lessons learned…
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Bioresearch Monitoring
• Known as BIMO• Mandated by Congress in 1976• Agency-wide program • Inspection-based
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FDA BIMO INSPECTIONS
• Four (4) Areas of Focus– Sponsor/Monitor/Contract Research
Organization– Clinical Investigator (CIs)– Institutional Review Board (IRB)– Non-clinical laboratory (GLP)
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TWO UNIVERSAL GOALS
• Human Subject Protection
• High Quality Data
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Scientific MisconductPercentage in survey of US based scientists who
engaged in questionable research practices
• 15.5% Changed a study’s results to satisfy a funding source• 15.3% Dropped data from analyses based upon a “gut feeling”• 12.5% Overlooked other’s use of flawed/questionable data• 10.8% Withheld research results• 7.6% Circumventing minor rules protecting humans subjects
Source: Nature June 2005
n = 3247
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CDRH BIMO InspectionsFiscal Years 2000 - 2004
190214
357 353 350
050
100150200250300350400
FY 2000 FY01 FY02 FY03 FY04
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CDRH BIMO COMPLIANCE RATES
13%16%
12%17%
24%
0%
10%
20%
30%
40%
50%
60%
70%
10 Years FY01 FY02 FY03 FY04
NAIVAIOAI
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Global Industry Issues
• Failure to Identity and/or address issues• Failure to correct recurring issues• Failure to provide an accountable
company culture• Maintaining an environment of conflict of
interest
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CDRH Sponsor Compliance Rates
20%16%
10%
24%
31%
0%
10%
20%
30%
40%
50%
60%
70%
10 Years FY01 FY02 FY03 FY04
NAIVAIOAI
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Sponsor Deficiencies Fiscal Years 1998 - 2004
16%19%7%19%28%23%17%Inadequate device accountability
11%18%4%Obtain FDA/IRB approval
27%
65%
1999
44%
68%
2000
27%
65%
2001
21%24%19%33%Failure to secure investigator compliance
40%37%33%63%Inadequate monitoring
200420032002FY
1998
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CDRH Investigator Compliance Rates
11%16% 15% 17%
21%
0%
10%
20%
30%
40%
50%
60%
70%
10 Years FY01 FY02 FY03 FY04
NAIVAIOAI
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Investigator DeficienciesFiscal Years 1998 - 2004
13%13%8%5%11%9%11%Lack of FDA &/or IRB approval
14%18%26%27%21%17%17%Inadequate device accountability
24%21%21%28%21%19%24%Inadequate subject protection/IC
16%38%20%40%26%8%21%Protocol deviations
54%51%44%44%47%46%32%Failure to follow investigational plan/regs
200420032002200120001999FY
1998
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CDRH BIMO Complaints(Credible Allegations of Research Misconduct)
9
15
41 41
05
1015202530354045
FY01 FY02 FY03 FY04
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CDRH BIMO COMPLIANCE RATES(FY04: All Inspections vs. Complaints)
NAI
VAI
OAI
24%34%
42%
All Inspections Complaints
26%
18%
56%
133% higher OAI rate in complaint follow-ups
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Characteristics of Successful Firms
• Committed• Responsive to public• Use Risk Management• Utilize Quality Systems • Emphasize the basics
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Responsiveness to Public
• Subject safety first = TRUST• Respect for all subjects• Info to subjects• Understandable, transparent system
– COIs, IRBs watching individuals, FDA running trials• Ensure ethical conduct• Rapid resolution and recognitions of problems –
trial risk; subjects expect rapid assistance
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Risk Management
• Greater risk gets greater attention– Safety monitoring, HSP, e-recordkeeping,
pediatric subjects– Routine operations vs. serious adverse event
reporting; more control needed in certain areas
– Education enhanced websites & LDL
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Quality Systems• Difficult to inspect quality in (e.g., auditing)• Quality must be built in
– Systems approach • Consistency (e.g., automation & standardization)• Implement in a stepwise fashion
– Build upon what exists– Focus first on areas of greatest pain and risk– Develop a sustainable program and culture
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Emphasize the Basics• Research subject protection measures• Data quality?
– Fitness for use– Meets customers needs
• What will FDA look at?– ALCOA
» Attributable» Legible» Contemporaneous» Original» Accurate
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Emphasize the Basics (cont)
• Less can be more….– Ex. 80 page IC; monitoring every data point
• Documentation vs paperwork– Who is it for and why?– Lack of understanding of the regs– Value to some not others– Fear (of what or why?)
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SUGGESTIONS FOR A SUCCESSFUL STUDY
• Select qualified investigators• Obtain investigator feedback on protocol
requirements• Provide adequate training up front
– Stress importance of informed consent process• Ensure adequate monitoring• Bring investigators into compliance
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QUALIFIED INVESTIGATORS
• Skills & experience appropriate for the device & its specific use in the study
• Adequate time, staff, equipment, & access to any specialized equipment required
• Knowledge of applicable regulations
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PROTOCOL FEEDBACK
When planning a study – consult potential investigators and others!
•Inclusion/exclusion criteria appropriate & not unnecessarily restrictive
•Timing of procedures clinically appropriate•Testing, initially & at follow-up visits,
appropriate to the study endpoints•Only essential data collected – errors estimated at 3%
INTERACTIONS UP FRONT CAN AVOID COSTLY PROTOCOL VIOLATIONS
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TRAINING Before study & when essential staff
replaced• Specific study expectations• Procedures unique to the device or its use in
the study• Regulatory requirements• Clinician versus Investigator• Importance of the informed consent process
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INFORMED CONSENT PROCESS
Well-informed participants:– Understand study requirements up front– Are less likely to drop out due to
unexpected procedures – Are more likely to be compliant with
essential details– Will promote confidence in research process
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MONITORING• Early & frequent enough for specific study
– Early – ensures sites ready – Frequent– catches problems &
noncompliance before repetitive• Systemic issues can be corrected before
study integrity is jeopardized• Regular data audits avoid numerous
queries & late database cleanup• Training opportunities for new &/or non-
compliant study staff or amended protocol
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COMPLIANCE• Predetermined strategy for obtaining• Expeditious sponsor review of monitoring
reports• Immediate actions to correct
noncompliance• Where applicable, device shipments halted
until evidence of compliance• If all else fails, site’s participation in study
terminated
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To improve this picture, sponsors and institutions should:
• Seek training for their staffs • Provide training for investigators• Correct issues before they jeopardize
submissions• Focus company culture on good ethics
and research practices• Avoid potential conflicts of interest
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RESOURCES
FDA Good Clinical Practiceshttp://www.fda.gov/oc/gcp/default.htm
Device Advicewww.fda.gov/cdrh/devadvice
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CONTACT INFORMATION
Food and Drug AdministrationCenter for Devices and Radiological HealthOffice of ComplianceDivision of Bioresearch Monitoring (HFZ-310)2098 Gaither RoadRockville, MD 20850