A Regulatory Compliance Perspectives on Improving Clinical

Trial Quality, Protection of Trial Participants, and Data Integrity

Jean MulindeMedical Officer, Policy AdvisorDivision of Clinical Compliance EvaluationOffice of Scientific InvestigationsCDER, FDA

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FDA Disclaimer

The views and opinions presented here represent those of the speaker and should not be considered to represent advice or guidance on behalf of the U.S. Food and Drug Administration.

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Today’s Topics

•Quality in clinical product development•COVID-19 pandemic •CDER bioresearch monitoring (BIMO) requests• Inspectional findings

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Reminder: Clinical Trials of Quality• Scientific question is important; there is a need to produce

high-quality evidence to inform decision making on use of a preventive, diagnostic, or therapeutic intervention

• Trial design is adequate to answer this scientific question; if study well conducted the results will be credible

• Data produced are sufficiently accurate and reliable (fit for purpose) so that they may be used for decision making

• The rights, safety, and welfare of trial participants have been adequately protected

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Proactive Quality & Risk Based Approaches

Quality Management System

Quality by Design

An integrated system through which organizations can systematically plan and achieve quality objectives linked to their broader strategic goals

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Quality by Design

• Premise: Quality in clinical trials is defined as the absence of errors that matter.

What do we really need to get right to ensure reliability of results and patient protection?

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Quality by Design• Careful consideration of factors

critical to quality • Identification and evaluation the

risks to critical processes and data• Proactively addressing risk control

(mitigate, track, accept)• Ensuring risk communication,

review, and reporting processes are built in and utilized throughout course of study

https://www.ctti-clinicaltrials.org/toolkit/qbd/introduce-qbd/qbd-principles/explore-ctq-factors

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Draft ICH E8(R1)• E8(R1) provides an overall introduction to

other clinical development efficacy guidelines

• Overarching theme being need to design quality into clinical studies and focus on those factors critical to the quality of the studies.

• Draws from pre-existing work done by the Clinical Trials Transformation Initiative, Quality by Design working group composed of multiple industry, patient, investigator, academic, and regulatory groups

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Proactive Quality & Risk Based Approaches

Quality Management System

Quality by Design

ProtocolVendor Quality and Oversight PlansRisk Based MonitoringSafety Monitoring PlanData Management PlanPlans, Plans, Plans, etc.

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Further Topical FDA Guidance

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Absence of Proactive Quality & Risk Based Approaches …

• Fire fighting mentality addressing issues that may have been prevented or may have been addressed before reaching critical mass, with variable effectiveness at great cost (dollars, time, reputation, trial participant safety)

• Loss data integrity resulting in rejection of study to support regulatory and therapeutic decisions

• Discontinued development of potentially beneficial therapy?

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Sponsors Progressing on Quality Journey

Overarching Quality Management Systems

Risk Assessment Processes

Quality by Design

Risk-Based Monitoring

Overarching Data Governance Model

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COVID19 Pandemic

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• Created to provide FDA current thinking on general issues impacting clinical trial conduct during the COVID-19 public health emergency

• Safety of trial participants paramount• All decisions should be guided by good risk assessment

and management practices

• Q&A Appendix• Protocol deviation vs need for amendment• Remote visits, safety monitoring, direct to participant IP• Informed consent in pandemic settings• Electronic signatures• Remote monitoring

https://www.fda.gov/media/136238/downloadClinicaltrialconduct-COVID19@fda.hhs.gov

FDA Guidance During COVID-19 Pandemic

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Site Monitoring• Travel and local pandemic related restrictions prevent

planned on-site monitoring (in-person evaluation carried out by sponsor personnel or representatives at the investigation site).

• Limited experience with remote monitoring (off-site evaluation performed by the monitor away from the site at which the clinical investigation is being conducted).

• Immature centralized monitoring capabilities (analytical evaluation carried out by sponsor personnel or representatives at a central location other than the site at which the clinical investigation is being conducted).

• Immature quality and risk management systems, QbD, Risk-Based Monitoring

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Remote Monitoring Considerations• Is there a compelling reason to

replace on-site visit with remote assessment? (Risk-Based Monitoring)

• Historical information available about site

• Centralized data analytics

• Trial participants’ informed consent permits remote review of records

• Procedures for remote monitoring in place – focus on critical data and procedures

• Technology in place to permit site and monitor to engage in meaningful remote monitoring process

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FDA Recommendations on Remote Monitoring Methods

Establish a secure remote viewing portal that would permit site staff to provide access to the site’s study documentation and/or trial participants’ source documents for the study monitor’s review.

<a href="https://www.freepik.com/photos/computer">Computer photo created by diana.grytsku -www.freepik.com</a>

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FDA Recommendations on Remote Monitoring Methods

Sites upload certified copies of source records to a sponsor-controlled electronic system or other cloud-based repository that contains appropriate security controls.

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FDA Recommendations on Remote Monitoring Methods

Cautions• Access controls• Security controls• When source documents contain potentially unblinding

information, controls to protect the study blind should be in place prior to view or transfer of source documents

• Other regional regulatory limitations

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FDA Guidance During COVID-19 Pandemic

https://www.fda.gov/emergency-preparedness-and-response/counterterrorism-and-emerging-threats/coronavirus-disease-2019-covid-19

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Bioresearch Monitoring (BIMO) Inspections• March 2020 - routine surveillance domestic and foreign BIMO

inspections placed on hold. Pre-approval inspections FDA uses other tools and approaches, including requests for:

• Inspection reports from other trusted foreign regulatory partners through mutual recognition and confidentiality agreements

• Information from applicants, and records and other information directly from facilities and other inspected entities

• Limited on-site inspections

• July 20, 2020 - resumption prioritized domestic inspections guided by FDA’s COVID-19 Advisory Rating system to determine what categories of regulatory activity can take place in a given geographic region

• Domestic “mission-critical” inspections, and on case-by-case basis some foreign inspections

• Prioritized domestic inspections, which may include pre-approval and surveillance inspections

https://www.fda.gov/media/141312/download

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Mission Critical Inspections

• Products with breakthrough therapy designation or regenerative medicine advanced therapy designation

• Products used to diagnose, treat, or prevent a serious disease or medical condition for which there is no other appropriate substitute

• Both for-cause and pre-approval inspections can be deemed mission-critical

• Selection of sites for BIMO inspections will continue to be risk-based, considering application and site-specific factors

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CDER 21st Century Review ProcessIdentification of Sites for Inspection

Recommendations on Adequacy Subject Protections and Data Integrity Due to OND

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CDER’s BIMO Inspection Related Requests

• Clinical Study-Level Information• Listing Clinical Sites• Identify Entities Contracted by to Perform Study

Related Activities• Protocol and Amendments, Annotated Case Report

Form

• Subject-Level Line Listing by Clinical Site• Summary-Level Clinical Site Dataset

https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/UCM332466.pdf

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CDER’s BIMO Inspection Related Requests(August 2020 BIMO Conformance Guide Updates)

• Subject-Level Line Listing by Clinical Site• Clarified and more specifically defined requests

• Summary-Level Clinical Site Dataset (clinsite.xpt)

• Deleted request for SITEFFE and SITEFFS variables in clinsite.xpt• Added COHORT variable for clinsite.xpt• Revised PROTVIOL variable to IMPDEV and NOIMPDEV variables

for clinsite.xpt

• Provided additional instructions for placement of files per eCTD format

https://www.fda.gov/media/85061/download

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CDER’s Clinical Investigator Site Selection Tool• Risk ranking of sites provides a framework for site

selection• Provides standard data exploration methodology• Assembles many site characteristics in one tool and

gives the user the ability to choose sites based on site views of:

• Data Irregularities• Outliers analysis with filters • Inspection history and Investigator experience• Clinical investigator cross-study participation• Regional and country-specific summaries• Comparison of variables across treatment arms• Raw data versus converted data views

• Easy navigation and functionalities• Improves data analysis time• Automated documentation and form generation

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CISST Support Metrics

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Benefits Realized • Clinical sites identified earlier in review clock

• Enhanced identification of clinical sites with GCP non-compliance

• Archived clinsite data available for data mining

Initiate inspection process earlier

Inspection results sooner

Increased time within review cycle for resolution of issues identified

during inspections

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Inspections Overseen by Office of Scientific Investigations and Office of Study Integrity and Surveillance

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Inspectional Outcomes – Clinical Investigator

NAI = No Action Indicated

VAI = Voluntary Action Indicated

OAI = Official Action Indicated

Data derived from publicly published yearly OSI/OSIS BIMO Metrics

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Inspectional Outcomes – Sponsor/CRO

Data derived from publicly published yearly OSI/OSIS BIMO Metrics

NAI = No Action Indicated

VAI = Voluntary Action Indicated

OAI = Official Action Indicated

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Inspectional Classification versus Regulatory Impact

• Ongoing study led by David Burrow, OSI Office Director with review and analysis by OSI’s Michelle Foringer

• Review of > 400 Office of Scientific clinical inspection summaries (CIS) for NDA and BLA applications and supplements

• CIS recommendations classified as • Active • Not Active

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CIS Active Recommendations

• Recommendation to CDER’s Office of New Drugs following a OSI review of the inspection(s) reports. Active recommendations include one or more of the following:

• Recommend a sensitivity analysis (data reliability concerns)• Recommend need for additional inspections to verify outstanding issues• Recommend excluding data generated from all or individual inspected

sites• Descriptions of violations (isolated vs pattern) impact on interpretability• Subject safety concerns or inadequate safety reporting

• May have multiple recommendations per CIS

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OSI Active Recommendations to OND

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CIS with Active Recommendations

101 of 478 CIS with OSI Active Recommendation to OND

= 21%

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Active Recommendations (FY15-18)

31%

9%

10%

50%

Sensitivity Analysis Data Exclusion

Additional Inspection Other

“Other” recommendations include:• Safety/Efficacy concerns• Third-party audits• Request additional studies• Additional analyses

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Inspection Classifications

A CIS with an active recommendation does not correlate with OAI inspection classifications –tremendous value found with NAI and VAI

inspections!

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Persevering on the Quality Journey

Overarching Quality Management Systems

Risk Assessment Processes

Quality by Design

Risk-Based Monitoring

Overarching Data Governance Model

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Case Example – When the “Quality Journey” You Embarked on Saves the Day

• Large randomized, blinded, placebo-controlled cardiovascular outcomes study

• > 600 Global clinical investigator sites • > 10,000 Subjects enrolled• Independent adjudication committee for primary endpoint

(MACE - Major Adverse Cardiovascular Events)• Multiple sponsor changes over course of 7 year study

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Case Example – Site “A” Selection

• CDER’s Clinical Investigator Site Selection Tool utilized

• Site “A” chosen based on:• Enrollment (approximately 5% subjects in study)• Data trends suggesting under reporting of events (efficacy and

safety)

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Case Example – Site “A” Inspection

• MACE events • Based on source record review multiple examples identified that appeared

consistent with MACE event, but that were adjudicated negatively by independent adjudication committee

• Per CI, if a subject had an event and was seen at facility outside of the site’s network that it was almost impossible for site staff to obtain requested records due to litigious climate of community

• SAE Reporting• Unclear how negatively adjudicated MACE events captured – not present on

SAE eCRF by design • Unreported SAEs identified?

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Case Example – Sponsor Inspection

• Risk-based monitoring of CI sites evolved throughout study to eventually include risk-based monitoring including centralized statistical monitoring methods by final sponsor

• Formal risk assessment and risk management implemented by sponsors 2/3

• MACE adjudication committee charter nonspecific as to required source documentation in adjudication packages

• Per protocol, and safety data management plans, MACE events considered clinical events and were not to be collected as SAEs

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Case Example – Sponsor Inspection

• Site “A” Follow-up• Final sponsor instituted RBM had flagged site during centralized

monitoring for potential under reporting of clinical events (MACE and secondary efficacy endpoints). Well documented follow-up:

• Increase on-site monitoring• Increase source document review• Reissue requests for additional source documentation to support

adjudication packages

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Case Example – Sponsor Inspection

• Site “A” Follow-up – Adequacy of Monitoring?• Missed SAEs – Risk-based monitoring plan did not require SDV/SDR

for these subjects/visits• Documentation of prespecified subjects/visits for SDV/SDR present

(including implemented increased monitoring) and SDV/SDR conducted

• Monitoring considered adequate, no regulatory violation cited (no 483)

• Inspectional findings related to several missed SAEs conveyed to review division, but overall monitoring and data quality considered adequate to support regulatory decision

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Case Example - Lessons

• Importance of QbD• Site selection process more than site’s ability to randomize eligible

patients, consider site’s delivery of other critical data elements• Need to identify critical data and risks to that data in order to mitigate

impacts when possible, develop tracking/intervention plans when accept risk (define tolerance limits)

• Importance of Risk-Based Monitoring • Value Centralized Analytic Procedures - Earlier identification of issues

and intervention at Site “A” (and similar sites) may have resulted in less missing endpoint data and avoided need to expand sample size

• Value of documentation - tracking, assessment, and interventions taken

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Please Consider…

A SHIFTIN

THINKING

What if we shift the way we do things and implement things like risk based monitoring and FDA investigators find something on inspection that we didn’t monitor or identify?

What if we don’t shift the way we do things by implementing QbD and risk based monitoring and FDA raises a data integrity issue that our study oversight and monitoring methods did not identify?

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COVID-19 Related Resources

1. For general questions on clinical trial conduct during the COVID-19 public health emergency, email Clinicaltrialconduct-COVID19@fda.hhs.gov

2. For Review Division/IND/IDE specific questions contact:• CDER: https://www.fda.gov/about-fda/center-drug-evaluation-and- research-

cder/office-new-drugs • CBER: https://www.fda.gov/about-fda/center-biologics-evaluation-and- research-

cber/contacts-center-biologics-evaluation-research- cber#indcont• CDRH: https://www.fda.gov/about-fda/cdrh-offices/cdrh-management-

directory-organization

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“Quality is never an accident; it is always the result of high intention, sincere effort, intelligent direction and skillful execution; it represents the wise choice of many alternatives”

- William A. Foster