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Clinical Trial Data Integrity: Bioresearch Monitoring Program Jur Strobos MD JD FACEP Olsson Frank Weeda Terman Matz 240-472-9665.

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Presentation on theme: "Clinical Trial Data Integrity: Bioresearch Monitoring Program Jur Strobos MD JD FACEP Olsson Frank Weeda Terman Matz 240-472-9665."— Presentation transcript:

1 Clinical Trial Data Integrity: Bioresearch Monitoring Program Jur Strobos MD JD FACEP Olsson Frank Weeda Terman Matz

2 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

3 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

4 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

5 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 § )

6 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, §§ ,.62,.64,.68) –Sponsor delegated responsibilities Signed FDA Form 1572, protocol and clinical site or investigator agreements (§ )

7 Administrative Remedies Investigator disqualification § (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 § Loss of NIH funding 42 CFR 74.61,.62 Data exclusion § (d)

8 Preparation for an Inspection Investigator Operations Manual –Chapter 1, 2, 5 Compliance Policy Guide Manual –CPMG Regulatory Procedure Manual –Chapter 5, § FDA Guidance –Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors –Protecting the Rights, Safety and Welfare of Study Subjects

9 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)

10 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

11 Thanks!

12 Data Falsification: Legal Framework and Potential Concerns Eve Brunts Ropes & Gray LLP

13 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

14 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

15 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

16 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

17 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)

18 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

19 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

20 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)

21 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

22 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

23 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

24 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

25 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

26 Clinical Trial Data Integrity: The Investigative Site A Systems Based Approach

27 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

28 FDA Quality System Requirements Requires Quality Systems : –Good Laboratory Practices (cGLPs) –Good Manufacturing Practices (cGMPs) No Quality System Requirement: –Good Clinical Practices (cGCPs)

29 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

30 Conflict of Interest Barrier 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 FDA Design-Reviewed Processes completed under Quality Systems

31 cGMP-like processes at Investigative Sites: the Site Specific Research Organization (“SSRO”)

32 cGMP-like Protocol Specific Processes at INVESTIGATIVE SITE cGMP-like Protocol Specific Processes at INVESTIGATIVE SITE SSRO Adaptive Investigative Site Management Conflict of Interest Barrier 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 FDA Design-Reviewed Processes completed under Quality Systems

33 Case Study #1 Site Specific Research Organization (“SSRO”) brought in after study stalled

34 Now small market of patients Adjust to Higher $$ for “Orphan” Product = Successful Sponsor, Patients and Investigators Now small market of patients Adjust to Higher $$ 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 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 160 PT Study for Resistant Patients = Moderate Sized Market- Moderate Price Expected SSRO 3 Sites = Skin Toxicity SSRO 3 Sites = Skin Toxicity No issues Drug Resistant Condition SSRO 3 sites x 3 months = 30 patients

35 SSRO and traditional CRO each contracted to enroll half of Phase III study patients (240 patients total) Case #2 Phase 3 Study for High Risk CV patients

36 Traditional CRO Managed Physician Sites SSRO Managed Physician Sites Investigative Sites 807 Patients Enrolled 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

37 Case #3--ADHD Study Traditional CRO Managed Physician Sites SSRO Managed Physician Site Investigative Sites 151 Patients Enrolled 120 in 36 months40 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


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