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MAGI's Clinical Research Conference

Site Visit Follow- Up: Notes to File, Visit Reports and

Corrective Action Plans Presented by:

Stacey Basham RN, RQAP-GCP President, Rialto Quality Group LLC

Brigid Flanagan, MS, RN, CCRC Senior Manager of Clinical Studies, Fresenius Medical Care

2 MAGI’s Clinical Research Conference

Agenda

Discuss role of Investigator and Monitor in:

Site Visit Reports/Follow-up communications

Notes to File (NTF)

Corrective and Preventive Actions (CAPAs)

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Regulatory Review

MAGI’s Clinical Research Conference

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Regulatory Requirements - Sponsor

21 CFR § 11, § 50, § 54, § 56

21 CFR § 312, § 812

312.50, 812.40

Sponsor to ensure adequate information to conduct the study is provided to the investigator

Sponsor to ensure proper monitoring of study

312.56, 812.46 Sponsor shall monitor the progress of the study


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Regulatory Requirements – Sponsor (continued)

ICH-GCP 5.18 - Monitoring

5.18.6 ---Monitoring Report

A written report after each visit

5.18.4(q) deviations from the protocol, SOPs, GCP, and regulations are to be communicated to the investigator along with corrective action


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Regulatory Requirements – Sponsor (continued)

Guidance for Industry – Guideline for The Monitoring of Clinical Investigations (Jan1988) (Minor editorial and formatting changes Nov1998)

Record of On-Site Visits: The Sponsor should maintain a record of the findings, conclusions and actions taken to correct deficiencies…

Source: http://www.fda.gov/RegulatoryInformation/Guidances/ucm126400.htm


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Regulatory Requirements - Investigator

21 CFR § 312

21 CFR § 312.60 – ―…investigator is

responsible for ensuring that an investigation is conducted according … applicable regulations‖

21 CFR § 812

21 CFR § 812.100 – ―investigator is

responsible for ensuring that an investigation is conducted according to … applicable FDA regulations…‖


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Regulatory Requirements – Investigator (continued)

FDA Form 1572

21 CFR § 11, § 50, § 54, § 56, §

312, and § 812

Guidance for Industry Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects (Oct2009)


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Visit Communications


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Site Visit Reports/Communications

Site Visit Reports

Monitor‘s communication of site visit findings

To the Sponsor (site visit report)

To the Investigator (site visit follow up letter)

Should be temporal to the site visit, e.g. within 10 business days from last date of visit


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Visit Reports – What We Are Hearing…

Comment Rationale

No follow-up letters • Not required per Sponsor SOPs

Late receipt of follow-up letter

• Tight timelines to complete numerous visits • SOP does not dictate timeline for submission of follow-up communications

Incomplete follow-up letters

• Was not generated after completed Sponsor report • Sponsor approved follow-up template set format.


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Visit reports – What We Are Hearing… continued

Comment Rationale

Inaccurate letters • Inadequate time for review of letter, e.g. letter went out before final sponsor report

Letter covered events for another site

• Lack of QC • Inadequate time for review

Format of follow-up letter ‗buries the lead‘

• Sponsor approved template does not allow for amending format of letters


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Suggested Follow-up Letter Formatting


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Examples of Outcomes of Inadequate Communications

PI cited for ―…failing to investigate for additional acts of falsification within the same clinical investigation or in other clinical investigations in which the study coordinator was involved…‘‖

―Regardless of your corrective actions, as the principal investigator you were ultimately responsible for the conduct of this study, including the fact that false information was submitted to the sponsor…‖


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It’s A Two-Way Street!

Investigator should have a plan for supervision and oversight of the trial…includes:

Routine Meetings with the sponsor‘s monitors

A procedure for dealing with data queries and discrepancies identified by the study monitor

CRA should document those meetings in follow up letter

PI should review and sign; respond in writing with any corrective actions taken.


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Expectations From Study Start – Clear Communication

At study start, make communication expectations clear.

For action items, respond in writing.

Remember, site visit communications are a permanent study record

Records measurement of compliance

Communications Should reflect collaborative effort


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Notes to File


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Notes to File

When used properly, they can be a positive practice.

A problem is identified

A corrective action is identified to prevent recurrence

Procedure is instituted


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Notes to File - continued

FDA will still cite you for the initial problem but the change in procedure mitigates the citation.

The NTF itself is not a corrective action. The corrective action taken and whether the action worked is what should be documented.


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Notes to File - continued

NTFs become part of the study record.

NTFs are a road map for any inspector.

FDA wrote ―Our investigation found (the sponsor) failed to take action except to generate numerous notes to file after all the subjects completed the study‖

Keep NTFs few and far between.


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Notes to File - example

NOTE TO FILE (example taken from actual NTF)

Date: 9 January 2010

RE: Protocol 012010

PI: Dr. XYZ

Our site was counseled and trained on the completion of study questionnaires. Dr. XYZ did the counsel 9Jan2010 @

site training meeting S. Coordinator 2/12/2010 B. CRA counseled via phone 22Jan2010 on all questionnaires. S. Coordinator

2/13/2010 A. XYZ, MD, 1/9/2010


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Notes to File - example

NOTE TO FILE (example taken from actual NTF)

Date: 9 January 2010

RE: Protocol 012010

PI: Dr. XYZ

The subject was seen on 10 November 2009 for Visit 7. The patient did not have labs drawn due to not fasting. Patient did not return for lab draw as scheduled. This has been reported as a protocol deviation.

Savvy Writer

Study Coordinator


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Corrective and Preventive

Action Plans


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Corrective and Preventive Action Plan (CAPA)

CAPA is the quality system used to identify, implement, track and evaluate effectiveness of actions taken as a result of deviations identified

CAPAs are another form of oversight to ensure compliance


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Corrective and Preventive Action Plan (CAPA) - continued

Identification of the deviation

Identification of the root cause

Corrective action/s to be taken to correct (when possible) the deviation

Preventive actions to be taken to prevent reoccurrence of the deviation

Measurement of preventive actions


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Corrective and Preventive Action Plan (CAPA) - continued

Site monitoring and follow-up communications—How do they compare to CAPAs?

Identify problems and deviations

Provide corrective action plans

Provide measurements of compliance with corrective action

Review of findings cited in a site visit follow-up communication

A CAPA may be initiated by site or by monitor


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Wrap-up


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Wrap-up

Communication, communication, communication

Role of Investigator and Monitor:

Site Visit Reports/Follow-up communications

Two-way street

Monitor to generate

Not receiving, ask why not!

Notes to File (NTF)

Over used

Corrective and Preventive Actions (CAPAs)

Need for may be identified from site visit communications

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Questions??


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References

FDA – www.fda.gov

CFR - http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

GCP - http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm

Warning Letters - http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

ICH E6 – Good Clinical Practice

http://www.ich.org/LOB/media/MEDIA482.pdf


http://www.fda.gov/

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm

http://www.ich.org/LOB/media/MEDIA482.pdf

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References - continued

FDA Guidance Documents

Devices - http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm

Drugs - http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

Biologics - http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm


http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm



http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm



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References-continued

Anderson, C. ‗Note to Self: No More Notes to File‘. Applied Clinical Trials. March 1, 2008
