Clinical Trial Data Integrity:
Bioresearch Monitoring
Program
Jur Strobos MD JD FACEP
Olsson Frank Weeda Terman Matz
jur.strobos@ofwlaw.com
240-472-9665
BiMo Investigations
• Statutory jurisdiction and penalties
• Regulatory scope of inspection and
agency remedies
• Preparing for a clinical site investigation
• Top five FDA Form 483 observations
FDA Inspections of Clinical Sites
• § 704(a)(1) of the Food, Drug, and Cosmetic
Act, authorizes FDA officials to:
– Enter [and] inspect ... any establishment ... in which
prescription drugs are ... held, [and] inspection shall
extend to all things therein or otherwise bearing on
violation of this Act
• Presentation of credentials to responsible
corporate official
– Five day pre-announcement, reasonable time/manner
– FDA Form 482
3
Penalties Under § 704(a)
• FDCA § 303(a)(1) provides for misdemeanor
conviction for prohibited acts
• FDCA § 306 individual or organizational debarment
– (a) mandatory for FDCA-related felony conviction
– (b)(2) permissive for FDCA-related misdemeanor
conviction
• FDCA § 301 prohibited acts include
– (d) [R]efusal to permit access to or copying of any
record required by ... § 704(a)
– (ii) [F]alsification of a report of a serious adverse event
jur.strobos@ofwlaw.com
240-472-9665
4
Scope of Documents
• Anything related to 21 CFR Parts 50, 56,
312 compliance
• Excludes financial, sales, pricing,
personnel, research data except:
– Related to qualification of technical and professional personnel
performing functions subject to this Act
– Related to new drug ... subject to reporting and inspection under
regulations lawfully issued pursuant to section 505(i) = studies
conducted under IND
• Pre-approval or routine IRB inspection
• Identifiable patient records if the “records of particular
individuals require a more detailed study” (21 CFR § 312.68)
During the Inspection
• Federal criminal code (18 USC § 1001)
provides felony penalties for ‘wilfully false
statements’ to the FDA investigator
• 21 CFR Part 50 – informed consent
• 21 CFR Part 56 – institutional review board
• Note that Part 312 obligations extend to
– Clinical investigators (eg, §§ 312.60, .62, .64, .68)
– Sponsor delegated responsibilities
• Signed FDA Form 1572, protocol and clinical site or
investigator agreements (§ 312.52)
jur.strobos@ofwlaw.com
240-472-9665
6
Administrative Remedies
• Investigator disqualification § 312.70(b)
– “[H]as repeatedly or deliberately failed to comply”
– Notice of Initiation of Disqualification Proceedings
and Opportunity to Explain (NIDPOE)
– Part 16 regulatory hearing
• IRB or institutional disqualification § 56.121
• Loss of NIH funding 42 CFR 74.61, .62
• Data exclusion § 312.70(d)
jur.strobos@ofwlaw.com
240-472-9665
7
Preparation for an Inspection
• Investigator Operations Manual
– Chapter 1, 2, 5
• Compliance Policy Guide Manual
– CPMG 7348.811
• Regulatory Procedure Manual
– Chapter 5, § 5-9-3
• FDA Guidance
– Information Sheet Guidance for IRBs, Clinical
Investigators, and Sponsors
– Protecting the Rights, Safety and Welfare of
Study Subjects
jur.strobos@ofwlaw.com
240-472-9665
8
Steps
• Presentation of FDA Form 482
• Request and review of pertinent
documents
– Copying as requested
• Daily oral close-out
• FDA Form 483 Observations, if any
• Follow-up Establishment Inspection
Report (EIR)
Top Form 483 Observations
• Protection of patient rights
– Written, contemporaneous, signed informed
consent
• Protection of patient safety, safety, safety
– Adverse events documentation and reporting
– Patient eligibility requirements
– Failure to maintain accountability of
investigational new drug
– Failure to supervise
jur.strobos@ofwlaw.com
240-472-9665
10
Thanks!
jur.strobos@ofwlaw.com
240-472-9665
11
Data Falsification:
Legal Framework and Potential Concerns
Eve Brunts
Ropes & Gray LLP
eve.brunts@ropesgray.com
617.951.7911
Legal Framework:
FDA Regulations and Guidance
• U.S. Food and Drug Administration (FDA) expects that
sponsors and investigators will assist the FDA in
detecting data falsification
− No express affirmative obligation on sponsor or investigators to
report data falsification when detected
− FDA 2010 proposed rule would create affirmative obligation
• FDA requirements related to monitoring, recordkeeping
and data submission requirements can give rise to
obligations to detect and address data falsification
• Submission of falsified data can expose sponsor and
investigator to administrative and enforcement action
Legal Framework:
FDA Regulations and Guidance
• Sponsor Obligations
− Monitor progress of clinical investigations
• FDA Guidance for Industry Oversight of Clinical Investigations – A RiskBased Approach to Monitoring (2013)
− Respond to identified investigator non-compliance by securing
compliance or terminating investigator participation
• Termination investigator participation reported in information amendment
− Submit annual reports on progress of clinical trial
− Review data for every subject enrolled in clinical trial whether
subject withdraws or clinical trial terminated
• FDA Guidance for Sponsors, Clinical Investigators and IRBS: Data
Retention when Subjects Withdraw from FDA-Regulated Clinical Trials
(2008)
− Submit data on every subject in clinical trial in new drug
application absent advance agreement with FDA to omit data as
not pertinent to a review of a drug’s safety or effectiveness
Legal Framework:
FDA Regulations and Guidance
• Investigator
− Conduct the clinical trial in accordance with protocol
− Supervise other personnel involved in the clinical trial
− Prepare detailed case history forms for each subject with all
pertinent data and observations
− Provide sponsor with progress reports that contain all pertinent
data and observations
− Maintain adequate and accurate records
Legal Framework:
FDA Proposed Regulation
• In 2010, FDA issued proposed rule that would amend
investigational new drug application and investigational
device exemption regulations to require sponsors to
report to FDA suspected data falsification
− Ensure data integrity and protect study subjects
− Proposed rule intended to “clarify” sponsor reporting
requirements
Legal Framework:
FDA Proposed Regulation
• General Requirement
− Sponsor must report when “any person has, or may have,
engaged in the falsification of data in the course of reporting
study results, or in the course of proposing, designing,
performing, recording, supervising, or reviewing studies
conducted by or on behalf of a sponsor or relied on by a
sponsor”
•
•
•
•
Obligation to report “possible” falsification
No particular “information threshold” established
No need to determine intent
No reporting of errors (typos)
Legal Framework:
FDA Proposed Regulation
• Process
− Report to applicable FDA center (e.g., Center for Drug
Evaluation and Research)
− Report “promptly” but no later than 45 calendar days after the
sponsor becomes aware of the information (before, during or
after completion of study)
− Report information about person potentially falsifying data and
nature of falsification
Legal Framework:
FDA Proposed Regulation
• Key Terms
− Falsification of data means creating, altering, recording, or
omitting data in such a way that the data do not represent what
actually occurred
• Making up data, altering data, misrepresenting data, or omitting data
− Data includes individual facts, tests, specimens, samples,
results, statistics, items of information, or statements made by
individuals
Legal Framework:
FDA Proposed Regulation
• Response and Penalty
− Reports may lead to administrative actions (e.g., disqualifying
an investigator) or enforcement actions (e.g., criminal
proceedings)
− Failure to report possible falsification of data might constitute a
violation of Section 301(e) of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. § 331(e)) (concerning failure to make
a required report) or 18 U.S.C. § 1001 (concerning the
submission of a false statement to the federal government)
Legal Framework:
Office of Research Integrity/Clinical Sites
• Clinical sites that engage in research funded by the
Public Health Service (PHS) must implement a research
misconduct policy consistent with federal regulations (42
C.F.R. Part 93)
− Research misconduct includes fabrication, falsification, or
plagiarism in proposing, performing, or reviewing PHS-funded
research, or in reporting results from PHS-funded research
• Fabrication is making up data or results and recording or reporting them
• Falsification is manipulating research materials, equipment, or processes, or
changing or omitting data or results such that the research is not accurately
represented in the research record
• Plagiarism is the appropriation of another person's ideas, processes, results,
or words without giving appropriate credit
• Research misconduct does not include honest error or differences of opinion
Legal Framework:
Office of Research Integrity/Clinical Sites
• Research misconduct policy establishes process and
allocation of responsibilities for responding to potential
research misconduct
− Initial inquiry, investigation, appeal and report to federal agency
(HHS Office of Research Integrity)
− Specific confidentiality requirements apply
• Final agency findings of research misconduct are published
• Clinical sites may implement scientific misconduct
policies with expanded scope or more stringent
requirements
Potential Concerns
• General
− Source
• Characteristics of data
• Conduct of/communications from investigator, study personnel or clinical site
− Identification
• Reports
• Data
• Data analysis
– Includes statistical analysis
Potential Concerns
• Potential Issues
− Consistent data
• Example: Drug administered at same time to multiple subjects by same
person
• Example: Similar lab values for numerous subjects
− Inconsistent data
• Example: Discrepancies with drug delivered during or after administration
− Unlikely data
• Example: Numerous subjects randomized in short period of time
− Incomplete data
• No response or inadequate response from investigator on follow-up
− Inadequate documentation
• Example: Inability to verify data reported in case report forms with source
documentation
• Example: Altered records
Potential Concerns
• Potential Issues
− Implementation Anomalies
• Example: High screen failure rates
• Example: Relatively high enrollment rates
− Regulatory anomalies
• Regulatory anomalies may be indicative of more systematic non-compliance
• Example: High frequency of protocol deviations
• Example: IRB/consent non-compliance
− Unexplained request from clinical site to withdraw investigator
from clinical trial or refusal to provide clinical trial data
Clinical Trial Data Integrity:
The Investigative Site
A Systems Based Approach
Quality Systems are
Required for Data Integrity
• A Quality Product– one that performs as
intended (per specifications)
• Quality Systems– materials, procedures,
and personnel that together ensure the
product/service performs as intended
• Data must be obtained using validated
processes and point-of-process review to
ensure integrity
FDA Quality System
Requirements
• Requires Quality Systems :
– Good Laboratory Practices (cGLPs)
– Good Manufacturing Practices (cGMPs)
• No Quality System Requirement:
– Good Clinical Practices (cGCPs)
Data Integrity at Investigative
Sites is NOT Assured
• Data generated without site and protocol
specific processes
• No quality system review as data obtained
• Result: Impacts on completion
timelines, costs, data
integrity/interpretability, and FDA
approval decision timeline
Conflict of Interest Barrier
Typical structure
FDA
Design-Reviewed Processes
completed under Quality Systems
INVESTIGATIVE
SITE
PI
Clinical
Group or
Sponsor
CRO
SPONSOR
Design-Reviewed
Processes completed under
Quality Systems
No Design-Reviewed Processes
and no Quality Systems at Site
Credible Data
Queries
cGMP-like processes at Investigative Sites:
the Site Specific Research Organization (“SSRO”)
Conflict of Interest Barrier
SSRO Adaptive Investigative
Site Management
FDA
Design-Reviewed Processes
completed under Quality Systems
cGMP-like Protocol Specific
INVESTIGATIVE
Processes at
SITE
INVESTIGATIVE
SITE
PI
Clinical
Group or
Sponsor
CRO
SPONSOR
Design-Reviewed
Processes completed under
Quality Systems
Design-Reviewed Processes
completed under Quality Systems
Ensures what is intended is
actually done
Credible Data
Queries
Case Study #1
Site Specific Research Organization (“SSRO”) brought in after
study stalled
Drug Resistant Condition
160 PT Study
for Resistant Patients =
Moderate Sized MarketModerate Price Expected
Traditional CRO 80 Sites X 20 months = 120 pts
SSRO 3 sites x 3 months = 30 patients
Now small market of patients
Adjust to Higher $$ for
“Orphan” Product =
Successful Sponsor, Patients and
Investigators
Reassess the Market:
Homozygous pts. safe AND
have highest NEED
SPONSOR
breaks blind and
determines that only
homozygous pts do NOT
have toxicity
No issues
SSRO
3 Sites =
Skin
Toxicity
Case #2
Phase 3 Study for High Risk CV patients
•
SSRO and traditional CRO each contracted to enroll half of Phase III
study patients (240 patients total)
High Risk CV Patient Study
Traditional CRO Managed
Physician Sites
SSRO Managed
Physician Sites
Contracted
Patients
120 in six months
120 in six months
Investigative
Sites
80
7
Patients Enrolled
100
125 after 4.5 months
Data Quality
~80% of patients in one arm were
enrolled in violation of I/E criteria
All SSRO enrolled patients fit I/E criteria
Sponsor
Actual Cost — $32 million for 100
patients
Actual Cost — $11 million of which $3.6
million to SSRO and sites for 125 pts
Cost to enroll all 240 patients — $82
million
Cost to enroll all 240 patients — $18
million
CRO vs SSRO
Costs
Case #3--ADHD Study
SSRO Managed
Physician Site
Traditional CRO Managed
Physician Sites
Investigative
Sites
15
1
Patients Enrolled
120 in 36 months
40 patients in 4.5 months (capped)
Data Quality
FDA Audit
•
After 3 years, study was closed
with multiple sites losing data.
•
High rate of protocol violations
extended enrollment timelines from
5 months to 3 years
?
•
Found EDC was Part 11 noncompliant early, notified Sponsor,
and duplicated entries on paper
to protect data integrity.
•
Doubled contracted patient number
all fitting I/E criteria
FDA Auditor recommended, “No Action
Indicated” as Data Integrity was ensured
through SSRO Systems