clinical trial data integrity: bioresearch monitoring program jur strobos md jd facep olsson frank...
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Clinical Trial Data Integrity:Bioresearch Monitoring
Program
Jur Strobos MD JD FACEP
Olsson Frank Weeda Terman Matz
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
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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)
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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)
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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
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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
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Data Falsification:
Legal Framework and Potential Concerns
Eve Brunts
Ropes & Gray LLP
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 Risk-Based 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 areRequired 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
Co
nflict o
f Inte
rest B
arrie
r
SPONSOR
Design-Reviewed
Processes completed under
Quality Systems
Clinical
Group or
Sponsor
CRO
No Design-Reviewed Processes
and no Quality Systems at Site
Typical structure
INVESTIGATIVE
SITE
PI
Credible Data
Queries
FDA
Design-Reviewed Processes
completed under Quality Systems
cGMP-like processes at Investigative Sites: the Site Specific Research Organization (“SSRO”)
cGMP-like Protocol Specific
Processes at
INVESTIGATIVE
SITE
SSRO Adaptive Investigative Site Management
Co
nflict o
f Inte
rest B
arrie
r
SPONSOR
Design-Reviewed
Processes completed under
Quality Systems
Clinical
Group or
Sponsor
CRO
Design-Reviewed Processes
completed under Quality Systems
Ensures what is intended is
actually done
INVESTIGATIVE
SITE
PI
Credible Data
Queries
FDA
Design-Reviewed Processes
completed under Quality Systems
Case Study #1
Site Specific Research Organization (“SSRO”) brought in after study stalled
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
Traditional CRO 80 Sites X 20 months = 120 pts
160 PT Study
for Resistant Patients =
Moderate Sized Market-Moderate
Price Expected
SSRO
3 Sites =
Skin
Toxicity
No issues
Drug Resistant Condition
SSRO 3 sites x 3 months = 30 patients
• SSRO and traditional CRO each contracted to enroll half of Phase III study
patients (240 patients total)
Case #2Phase 3 Study for High Risk CV patients
Traditional CRO Managed Physician Sites
SSRO Managed Physician Sites
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
CRO vs SSRO
Costs
Actual Cost — $32 million for 100 patients
Cost to enroll all 240 patients — $82 million
Actual Cost — $11 million of which $3.6 million to SSRO and sites for 125 pts
Cost to enroll all 240 patients — $18 million
High Risk CV Patient Study
Contracted Patients
120 in six months 120 in six months
Case #3--ADHD StudyTraditional CRO Managed
Physician SitesSSRO Managed
Physician Site
Investigative Sites
15 1
Patients Enrolled 120 in 36 months 40 patients in 4.5 months (capped)
Data Quality
• 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 non-compliant early, notified Sponsor,and duplicated entries on paper to protect data integrity.
• Doubled contracted patient number all fitting I/E criteria
FDA Audit ?FDA Auditor recommended, “No Action
Indicated” as Data Integrity was ensured through SSRO Systems