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 301-827-6748
At the Beginning
Read and understand your obligations
under:
Form FDA 1571
Form FDA 1572
Protocol
Form FDA 1571
Not begin study until 30 days after FDA’s
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
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
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
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
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
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
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
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
FDA Preparation
Review Compliance Program
Review Applicable Regulations
Review Prior Inspection Record
Review Assignment Package
FDA Preparation:
Assignment Package
Background on:
Product development
Clinical trial
Subject population
Protocol
Signed 1572
FDA Preparation:
Assignment Package
Line listings
Adverse event(s)
Informed Consent Form
Number of subjects enrolled
Site specific outcome(s)
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
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
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
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
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?
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
Exit Interview
Discuss inspection findings
May issue an FD-483
Represents deviations from federal
regulations for clinical investigators
Verbal response to FD-483
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
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
Tips for a Successful Study:
Enhancing 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
Tips for a Successful Study:
Enhancing 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 nonphysician study support staff?
Tips for a Successful Study:
Enhancing 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 site’s indigenous record-keeping
system to the maximum extent possible,
discuss this with the sponsor up front
All records should meet the ALCOA test
Tips for a Successful Study:
Understand the Elements of
Data Quality
Attributable
Legible
Contemporaneous
Original
Accurate
Tips for a Successful Study:
Enhancing Record Quality
Minimize the need for transcription
Don’t throw anything away especially
originals
Expect the worst
FDA will be inspecting the records
Tips for A Successful Study:
Understand Regulatory
Responsibilities
Read the following before you sign-on
ICH GCP Consolidated Guideline
FDA GCP Regulations
FDA Information Sheets for IRB’s 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
Tips for A Successful Study:
Communicate
With the IRB
Protocol changes
Continuing review
With sponsor and monitors
Openly address problems
With regulatory authorities
Understand expectations
Honor reporting obligations
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