An FDA Audit: What the Investigator and Sponsor Need to Know

1
An FDA Audit What the Investigator and Sponsor
Need to Know

• Joseph P. Salewski, Chief
• Bioresearch Monitoring Branch
• Center for Biologics Evaluation and Research
• 301-827-6220
• FAX [phone]

2
At the Beginning

• Read and understand your obligations under
• Form FDA 1571
• Form FDA 1572
• Protocol

3
Form FDA 1571

• Not begin study until 30 days after FDAs receipt
  of IND
• Not to begin or continue studies that are placed
  on hold
• An IRB that complies with 21 CFR Part 56 is
  responsible for the initial and continuing review
  of the study

4
Form FDA 1571

• An agreement to follow all other applicable
  requirements
• Name of individuals who are responsible for
  monitoring the conduct and progress of the study
• Name of individuals who are responsible for the
  review and evaluation of safety information

5
Form FDA 1572

• Will assure that the study will not start prior
  to review and approval by the IRB
• Will conduct and personally supervise the study
  according to the relevant protocol
• Will only change the protocol after notifying the
  sponsor and obtaining IRB approval prior to
  implementing the change

6
Form FDA 1572

• Will seek a properly constituted IRB and obtain
  initial and on-going review
• Will obtain informed consent of subjects and
  submit progress reports to the IRB at intervals
  not to exceed 1 year
• Will prepare and maintain adequate and accurate
  case histories designed to record all pertinent
  observations for each subject

7
Form FDA 1572

• Will prepare and maintain adequate and accurate
  drug accountability records
• Will collect and report the data in a way to
  accurately and completely reflect the
  observations noted during the study
• Will report immediately and promptly if adverse
  events are alarming

8
Form FDA 1572

• Will assure that the study will not start prior
  to review and approval by the IRB
• Will conduct and personally supervise the study
  according to the relevant protocol
• Will only change the protocol after notifying the
  sponsor and obtaining IRB approval prior to
  implementing the change

9
Form FDA 1572

• Will communicate to sub-investigators information
  on scientific matters of importance related to
  the investigation
• Will ensure that the drug is administered
  according to the stated dosing regime, including
  dose, route, rate, and duration, and maintains
  records documenting such facts

10
Form FDA 1572

• Will certify that the drugs are being tested for
  investigational purposes and will obtain informed
  consent of subjects or their representative prior
  to enrollment

11
FDA Preparation

• Review Compliance Program
• Review Applicable Regulations
• Review Prior Inspection Record
• Review Assignment Package

12
FDA Preparation Assignment Package

• Background on
• Product development
• Clinical trial
• Subject population
• Protocol
• Signed 1572

13
FDA Preparation Assignment Package

• Line listings
• Adverse event(s)
• Informed Consent Form
• Number of subjects enrolled
• Site specific outcome(s)

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What Is Reviewed

• Administrative
• Protocol/Informed consent forms
• Amendments to protocol/consents
• Drug accountability records
• Sponsor/IRB correspondence
• IRB Approvals/Progress reports/AE reports
• FD-1572s/Investigator Agreements

15
What Is Reviewed

• Case Report Forms
• How data is recorded/corrected
• Compared to source documents
• Supporting Files(Source Documentation)
• Hospital Chart
• Clinic Chart
• Research Chart

16
What Is Reviewed

• Informed Consent Forms
• Are all required elements included
• Are additional elements relevant
• Was it approve by the IRB
• Were they signed and dated by subjects
• Does FDA have current version

17
What Is Inspected

• Interview study staff
• Test article storage area
• Data Audit
• Examine case report forms and compare with source
  documents
• Compare sponsor tabulations with source documents
  and case report forms

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Critical Issues

• Is study entry recorded?
• Is there a subject/diagnosis?
• Is drug administration documented?
• Is there study raw data?
• Did an IRB approve all significant stages?
• Did each subject provide proper informed consent
  prior to study entry?

19
Critical Issues

• Were all screened subjects entered
• Does amount of test article used coincide with
  number of subjects treated
• Was test article properly disposed
• Was blind maintained
• Was randomization scheme followed

20
Exit Interview

• Discuss inspection findings
• May issue an FD-483
• Represents deviations from federal regulations
  for clinical investigators
• Verbal response to FD-483

21
Common Deficiencies at Clinical Sites

• Protocol non-adherence
• Failure to report concomitant therapy
• Inadequate and inaccurate records
• Failure to report adverse events
• Inadequate drug accountability
• IRB problems
• Informed consent

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What Goes Wrong Most Often at the Clinical Site

• Most commonly observed deficiencies in these
  areas include
• Failure to follow the protocol
• Violation of inclusion/exclusion criteria
• Failure to perform required tests
• Failure to maintain adequate and accurate records
• absence of supporting source documents
• inaccurate or incomplete source documents

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Tips for a Successful StudyEnhancing Protocol
Adherence

• Protocol design should be as simple as possible,
  promoting collection of quality data without
  compromising study objectives
• Focus on essential data points
• Explain significance in terms of study objectives
  (efficacy/safety) or subject protection
• Avoid ambiguity and vagueness
• Inclusion/exclusion criteria
• Adverse experiences

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Tips for a Successful StudyEnhancing Protocol
Adherence

• Fully understand protocol limits and the
  importance of strict compliance
• How much latitude is available for clinical
  treatment (e.G. Concomitant therapy)?
• Is it ok to use the hospital or clinic protocol
  for performing routine procedures (e.G.
  Chemotherapy)?
• Is it ok to skip procedures that are not
  medically necessary (lab tests, PEs, biopsies)?
• Which protocol procedures can be performed by
  non-physician study support staff?

25
Tips for a Successful StudyEnhancing Record
Quality

• Clearly understand what records are to be
  maintained and how they should be completed
• Original source data for critical study endpoints
• Use your sites indigenous record-keeping system
  to the maximum extent possible, discuss this with
  the sponsor up front
• All records should meet the ALCOA test

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Tips for a Successful StudyUnderstand the
Elements of Data Quality

• Attributable
• Legible
• Contemporaneous
• Original
• Accurate

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Tips for a Successful StudyEnhancing Record
Quality

• Minimize the need for transcription
• Dont throw anything away especially originals
• Expect the worst
• FDA will be inspecting the records

28
Tips for A Successful StudyUnderstand
Regulatory Responsibilities

• Read the following before you sign-on
• ICH GCP Consolidated Guideline
• FDA GCP Regulations
• FDA Information Sheets for IRBs and Clinical
  Investigators
• http//www.fda.gov/oc/oha/irb/toc.html
• 21 CFR Part 312 http//www.access.gpo.gov/nara/cfr
  /index.html

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Tips for A Successful StudyCommunicate

• With the IRB
• Protocol changes
• Continuing review
• With sponsor and monitors
• Openly address problems
• With regulatory authorities
• Understand expectations
• Honor reporting obligations

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Preparing for Site Visit

• FDA investigator follows compliance program CP
  7348.811 (clinical investigator inspections) and
  21 CFR 312.60
• Have available
• All study documents
• Person knowledgeable about the study
• A place to review records
• Access to a photocopier