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

Joseph P. Salewski, ChiefBioresearch Monitoring BranchCenter for Biologics Evaluation and Research301-827-6220FAX 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 listingsAdverse event(s)Informed Consent FormNumber of subjects enrolledSite 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 staffTest article storage areaData 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 enteredDoes amount of test article used

coincide with number of subjects treated

Was test article properly disposedWas blind maintainedWas randomization scheme followed

Exit Interview

Discuss inspection findingsMay issue an FD-483

Represents deviations from federal regulations for clinical investigators

Verbal response to FD-483

Common Deficiencies at Clinical Sites

Protocol non-adherenceFailure to report concomitant therapy Inadequate and inaccurate recordsFailure 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 criteriaFailure to perform required tests

Failure to maintain adequate and accurate recordsabsence of supporting source documentsinaccurate 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 vaguenessInclusion/exclusion criteriaAdverse 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 non-physician 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

Tips for a Successful Study:Understand the Elements of Data Quality

AttributableLegibleContemporaneousOriginalAccurate

Tips for a Successful Study:Enhancing Record Quality

Minimize the need for transcriptionDon’t throw anything away

especially originalsExpect 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 312http://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