An FDA Audit: What the Investigator Needs to Know
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Transcript An FDA Audit: What the Investigator Needs to Know
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