Bioresearch Monitoring Program FDA Inspection of Clinical

Investigators

Quynh-Van Tran, PharmD., BCPP, RACLCDR, U.S. Public Health Service

Division of Clinical Compliance EvaluationOffice of Scientific Investigations

Office of ComplianceCenter for Drug Evaluation and Research

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OutlineResponsibilities of the Clinical Investigator (CI)

Bioresearch Monitoring Program (BIMO) CI Inspection

o What to expect during the inspection

o FDA Form 483

o Response to FDA Form 483

Trends in FDA BIMO CI Inspections

Most Common CI Deficiencies

Collaboration with International Regulators

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General CI Responsibilities [ 21 CFR 312.60]

Ensuring that an investigation is conducted according to the– Signed investigator statement (Form 1572)– Investigational plan– Applicable regulationsProtecting the rights, safety, and welfare of subjects under the investigator's careControl of drugs under investigationEnsuring that informed consent is adequately obtained according to 21 CFR 50Ensuring IRB review, approval and reporting requirements are met per 21 CFR 56

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CI Responsibilities  (cont.)Control of investigational drug (312.61)Record keeping and retention (312.62)– An investigator is responsible for: 

Maintaining adequate records of the disposition of the drugAccurate case histories that record all observations, and

other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation

– An investigator is required to maintain study records for:2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated2 years after the investigation is discontinued and FDA is notified if no application is to be filed or if the application has not been approved for such indication

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CI Responsibilities (cont.)

Investigator reports (312.64)– Progress reports to sponsor– Safety reports

Immediately report any adverse event that is alarming (e.g. an unexpected event that is serious or life‐threatening)Record non‐serious adverse events and report them to the sponsor according to the timetable for reporting specified in the protocol

– Final report to sponsor– Financial disclosure to sponsor

Promptly update as needed during the course of the investigation and for 1 year following study completion

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Risk Factors for Noncompliance for CIs

• Poor supervision & training of study staff• Insufficient investigator involvement in study conduct

• Inappropriate delegation of study tasks to unqualified persons

• Overworked investigator & study staff  (e.g., too many subjects, complex study with large amount of data collection, too many concurrent studies)

BIMO CI Inspection

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BIMO Program Objectives

• To ensure that the rights and welfare of human research subjects are protected

• To verify the quality and integrity of research data

• To ensure that FDA‐regulated research is conducted in compliance with applicable regulations

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Shared Goals

Public—Drug Developers—Regulators

Safe and effective medical products

Confidence in the clinical trial process

– Valid and generalizable knowledge about product

• Good decisions regarding approval of product

• Good information in product label

– Protection of participants’ rights, safety, and welfare

“Clear path” – predictability and efficiency in drug development and regulatory oversight

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ClinicalInvestigatorIRB

FDA‐Regulated Research

Sponsor/CRO

Human Subject Protection & Data Integrity

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Types of BIMO Inspections• For‐Cause Inspections – “Complaints”

– Based on allegations (referrals) from any source– Allegations that raise concerns regarding data integrity or the rights, welfare, and safety of study subjects have been compromised

• PDUFA‐Related Inspections (NDA/BLA)– FDA receives a Marketing Application– Drug is typically a new molecular entity (NME)– Pivotal studies not conducted under IND (foreign)– Data in support of application from foreign sites only – Also may be referred to as “routine” inspections

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Inspection at CI site 

• Inspection of site to “re‐create” the trial• Verification of data submitted to FDA(Source        CRF        Data submitted to FDA)

• Human subject protection: IRB review and Informed Consent process

• Location of study procedures• Protocol adherence• Safety reporting• Investigator oversight

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Inspection at CI site 

• Date of IRB approval of documents• Staff training records• Protocol responsibilities:  Inclusion/exclusion criteria, 

enrollment, randomization, administration of product, frequency of observations, required procedures & evaluations, adverse events

• Communications with monitors• Process for recording subject data: Enrollment log, CRFs, 

ICFs, medical records, study records (accurate, legible, contemporaneous, original, & attributable)

• Accountability for the test article

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Electronic Data

• If electronic data and collection methods are defined in the protocol– Procedures for creating, modifying, maintaining and transmitting e‐records

– Record retention procedure• Inspect electronic records

– Accessibility– Audit trail

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Inspectional OutcomesForm FDA 483 issued or not

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Form FDA 483 Inspection Observations

List of inspection observations Language:

“This document lists observations made by the FDA representative during the inspection of your facility.  They are inspectional observations, and do not represent a final Agency determination regarding your compliance.”†

• Additional 483 information available from FDA Investigations Operations Manual (IOM) 5.2.3 at www.fda.gov/ora/inspect_ref/iom/ † Form FDA 483 

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Closeout DiscussionCI will be asked at the time of the closeout discussion to respond* to the 483 CI may choose not to respond– CI may dispute any or all points– CI may agree with any or all points – CI may suggest corrective action*CI’s responses included in the Establishment Inspection Report

The CI is not required to respond to the 483 at the time of the inspection or afterward.

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Responding to FDA 483or Warning Letter

Three subsections: Response basics

Four reasons to submit a well‐reasoned, complete, and timely written response

Suggestions for an effective written response 

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483 Responses

There is no regulatory requirement for you to respond to the FDA 483.  

However, a well‐reasoned, complete, and timely 483 response is in your best interest.

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Four Reasons to Submit  a Complete and Timely Written Response

1. A complete and timely response could mitigate an FDA compliance decision. It MAYmake a difference in the final classification or in the 

type of regulatory correspondence issued. “As a general rule, a Warning Letter should not be issued if 

the agency concludes that a firm’s corrective actions are adequate and that the violations that would have supported the letter have been corrected.”

Regulatory Procedures Manual at www.fda.gov/ora/compliance_ref/rpm/pdf/ch4.pdf

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Four Reasons to Submit  a Complete and Timely Written Response

2. A complete and timely response demonstrates your acknowledgment and understanding of the observations to the FDA.

3. A complete and timely response demonstrates your commitment to correct the observations to the FDA.

4. A complete and timely response establishes credibility with the FDA. Initial response & follow‐up

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Suggestions for 483 Responses

1. Address each observation separately.2. Note whether you agree or disagree [documents?].3. Provide both corrective and preventive actions.4. Provide both completed and planned actions.5. Provide timelines for completion. 6. Provide a method of verification or monitoring the 

effectiveness of the actions.7. Submit documentation (training, SOPs, CAP, records). 8. SUBMIT THE RESPONSE WITHIN 15 WORKING DAYS.

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Example of an Inadequate Response

Verbal Response: “… I signed the Investigator Agreement, but I never read it… during a real estate settlement, do you read all those documents before signing them?”

Failure of the clinical investigator to obtain informed consent, follow the study protocol, and comply with the commitments of FDA‐regulated research

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Example of an Inadequate Response

Failure to obtain informed consent properly

Response: “As to the [forged] signatures of four persons out of eighty patients, suffice it to say … we are talking of a margin of error of 5% … this is well within recognized statistical limits.”

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Example of an ADEQUATE Response

• Failure to follow the investigational plan

Response: “We prepared and adopted a written procedure that will help staff to assure compliance with written study protocols and the obligations we accept as clinical investigators for FDA-regulated trials. A copy of the approved SOP is attached. We have reviewed this new procedure at a meeting held on _____ with all research staff (attendance sign-in sheet attached) and implemented it on _____. After 3 months, we will evaluate these new practices to determine if this corrective action assists with protocol adherence.”

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After InspectionORA field investigator prepares Establishment Inspection Report (EIR) and submits to Center.Relevant Center evaluates the EIR, determines final classification (NAI, VAI or OAI), and issues correspondence to inspected partyWhere applicable, the Center provides recommendations on data reliability to CDER’s Office of New Drugs

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Compliance Classifications

• No Action Indicated• No violations of FDA regulations foundNAI• Voluntary Action Indicated• Regulatory violations do not rise to

level warranting OAI classificationVAI

• Official Action Indicated• Serious noncompliance• Repeated or deliberate failure to

comply with the regulationsOAI

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Potential Outcomes of OAI classifications

Warning LetterNotice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE)Disqualification of clinical investigatorCriminal investigation by Office of Criminal InvestigationsDebarment

Trends in FDA BIMO

CI Inspections

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*Based on inspection start date – [Complis database as of December 20, 2016]• Sponsor (GCP) includes Sponsor/CRO/Sponsor-Investigator• BEQ Application-Inspections accomplished with 280 FY16 Site Visits• Good Laboratory Practice and Bioequivalence inspection programs operated by OSIS as of January 2015

Application‐Inspections Overseen by OSI/OSIS*(CDER, FY 2007 ‐ FY 2016)

31*Based on inspection start date – [Complis database as of December 20, 2016]

Bioresearch Monitoring Program Inspections* (CDER, FY 2016)

* Based on inspection start date – [Complis database as of December 20, 2016] • Referrals include Complaints, Required Reports, IRB/Sponsor Notifications, and other referrals-internal and external for All OSI Branches

Clinical Investigator: Data Audit versus Referral* (CDER, FY 2016)

Clinical Investigator Inspections* (CDER, FY 2007 – FY 2016)

*Based on inspection start date – [Complis database as of December 20, 2016]

*Based on inspection start date – [Complis database as of December 20, 2016]

Clinical Investigator Inspections by Location*(CDER, FY 2016)

International Clinical Investigator Inspections*(CDER, FY 2007 - FY 2016)

*Based on inspection start date – [Complis database as of December 20, 2016]

*Based on inspection start date – [Complis database as of December 20, 2016]

International Clinical Investigator Inspections by Location* (CDER, FY 2016)

*Based on Letter Issue date; Includes OAI Untitled Letters, [Complis database as of December 20, 2016]

Clinical Investigator Inspections Final Classification*(CDER, FY 2016)

International Clinical Investigator Inspections Final Class*(CDER, FY 2016)

*Based on Letter Issue date; Includes OAI Untitled Letters, [Complis database as of December 20, 2016]

*Includes Complaints, Required Reports, IRB/Sponsor Notifications, and internal/external referrals for all branches where evaluation may result in inspection.[Complis database as of December 20, 2016]

Referrals Received by OSI* (CDER, FY 2007 - FY 2016)

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*Based on inspection start date; Referrals include Complaints, Required Reports, IRB/Sponsor Notifications, and other referrals-internal and external for All Branches [Complis database as of December 20, 2016]

Referral-Related Clinical Investigator Inspections* (CDER, FY 2007 - FY 2016)

Most Common CI Deficiencies

Frequency of Clinical Investigator-Related Deficiencies Based on Post-Inspection Correspondence Issued*

(CDER, FY 2016)

*Based on letter issue date. Inspections may have multiple deficiencies. Includes OAI untitled letters. [Complis database as of December20, 2016]Note: this does not denote number of inspections completed, but rather number of inspection reports evaluated and closed.

Domestic CI Deficiencies Foreign CI Deficiencies

43*Based on letter issue date. Inspections may have multiple deficiencies. Includes OAI untitled letters. [Complis database as of December 20, 2016]Note: this does not denote number of inspections completed, but rather number of inspection reports evaluated and closed.

Frequency of Clinical Investigator Related Deficiencies Based on Post-Inspectional Correspondence Issued:

Official Action Indicated (OAI) Final classification* (CDER, FY 2016)

Collaboration with International Regulators

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Collaboration with International Regulators

• FDA‐EMA GCP initiative:– Inspections: joint, parallel and sequential

• Confidence building exercise• Comparison of practices

– Information sharing on marketing applications– Sharing information on best practices/guidances 

• Goal: harmonization where possible, leveraging of finite resources

• Extension of collaboration efforts to other regulatory authorities

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Information Exchanges/Meetings

Information Exchange

• Inspection plans & findings

• Lists of current applications

• Advisory Committee briefing documents

• Policies • Guidances• Procedures• Templates

Meetings/ Conferences

• Minimized duplication of inspections

• Influenced inspection decision‐making process (triggering/ canceling inspections)

• Better understanding of each other’s inspection procedures & processes

• Improved inspection coverage

Results

• Participation in annual EMA Inspectors Working Group training 

• Basic & Advanced GCP Inspectors Training

• Inspectors’ local & teleconference presentations

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FDA’s Use of EMA Inspection Reports• If an EMA inspection report shows no serious problems, we may choose not to  inspect the same site.  Instead, we may inspect other sites to widen our coverage.

• If EMA’s inspection report shows serious problems, we may re‐inspect the site or use the information to select additional sites. 

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Benefits of Collaboration 

We gain a better understanding of each other’s inspection procedures & processes

We improve our inspection coverage, exchange inspection reports, & avoid duplications

We provide more efficient use of resources in   support of a risk‐based approach

We create greater consistency in regulatory approaches

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The Way Forward

• Strengthen collaboration to help us identify & improve gaps

• Strengthen confidence building to reach mutual recognition & mutual reliance on each other’s inspection findings

• Expand the initiative outside the U.S. & E.U.

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Questions?