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An FDA Audit: What the Investigator and Sponsor Need to Know zJoseph P. Salewski, Chief zBioresearch Monitoring Branch zCenter for Biologics Evaluation.

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Presentation on theme: "An FDA Audit: What the Investigator and Sponsor Need to Know zJoseph P. Salewski, Chief zBioresearch Monitoring Branch zCenter for Biologics Evaluation."— Presentation transcript:

1 An FDA Audit: What the Investigator and Sponsor Need to Know zJoseph P. Salewski, Chief zBioresearch Monitoring Branch zCenter for Biologics Evaluation and Research z zFAX

2 At the Beginning zRead and understand your obligations under: zForm FDA 1571 zForm FDA 1572 zProtocol

3 Form FDA 1571 zNot begin study until 30 days after FDA’s receipt of IND zNot to begin or continue studies that are placed on hold zAn IRB that complies with 21 CFR Part 56 is responsible for the initial and continuing review of the study

4 Form FDA 1571 zAn agreement to follow all other applicable requirements zName of individuals who are responsible for monitoring the conduct and progress of the study zName of individuals who are responsible for the review and evaluation of safety information

5 Form FDA 1572 zWill assure that the study will not start prior to review and approval by the IRB zWill conduct and personally supervise the study according to the relevant protocol zWill only change the protocol after notifying the sponsor and obtaining IRB approval prior to implementing the change

6 Form FDA 1572 zWill seek a properly constituted IRB and obtain initial and on-going review zWill obtain informed consent of subjects and submit progress reports to the IRB at intervals not to exceed 1 year zWill prepare and maintain adequate and accurate case histories designed to record all pertinent observations for each subject

7 Form FDA 1572 zWill prepare and maintain adequate and accurate drug accountability records zWill collect and report the data in a way to accurately and completely reflect the observations noted during the study zWill report immediately and promptly if adverse events are alarming

8 Form FDA 1572 zWill assure that the study will not start prior to review and approval by the IRB zWill conduct and personally supervise the study according to the relevant protocol zWill only change the protocol after notifying the sponsor and obtaining IRB approval prior to implementing the change

9 Form FDA 1572 zWill communicate to sub-investigators information on scientific matters of importance related to the investigation zWill 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 zWill 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 zReview Compliance Program zReview Applicable Regulations zReview Prior Inspection Record zReview Assignment Package

12 FDA Preparation: Assignment Package zBackground on: yProduct development yClinical trial ySubject population zProtocol zSigned 1572

13 FDA Preparation: Assignment Package zLine listings zAdverse event(s) zInformed Consent Form zNumber of subjects enrolled zSite specific outcome(s)

14 What Is Reviewed zAdministrative yProtocol/Informed consent forms yAmendments to protocol/consents yDrug accountability records ySponsor/IRB correspondence xIRB Approvals/Progress reports/AE reports yFD-1572s/Investigator Agreements

15 What Is Reviewed zCase Report Forms yHow data is recorded/corrected yCompared to source documents zSupporting Files(Source Documentation) yHospital Chart yClinic Chart yResearch Chart

16 What Is Reviewed zInformed Consent Forms yAre all required elements included yAre additional elements relevant yWas it approve by the IRB yWere they signed and dated by subjects yDoes FDA have current version

17 What Is Inspected zInterview study staff zTest article storage area zData Audit yExamine case report forms and compare with source documents yCompare sponsor tabulations with source documents and case report forms

18 Critical Issues zIs study entry recorded? zIs there a subject/diagnosis? zIs drug administration documented? zIs there study raw data? zDid an IRB approve all significant stages? zDid each subject provide proper informed consent prior to study entry?

19 Critical Issues zWere all screened subjects entered zDoes amount of test article used coincide with number of subjects treated zWas test article properly disposed zWas blind maintained zWas randomization scheme followed

20 Exit Interview zDiscuss inspection findings zMay issue an FD-483 yRepresents deviations from federal regulations for clinical investigators zVerbal response to FD-483

21 Common Deficiencies at Clinical Sites zProtocol non-adherence zFailure to report concomitant therapy zInadequate and inaccurate records zFailure to report adverse events zInadequate drug accountability zIRB problems zInformed consent

22 What Goes Wrong Most Often at the Clinical Site zMost commonly observed deficiencies in these areas include yFailure to follow the protocol xViolation of inclusion/exclusion criteria xFailure to perform required tests yFailure to maintain adequate and accurate records xabsence of supporting source documents xinaccurate or incomplete source documents

23 Tips for a Successful Study: Enhancing Protocol Adherence zProtocol design should be as simple as possible, promoting collection of quality data without compromising study objectives yFocus on essential data points xExplain significance in terms of study objectives (efficacy/safety) or subject protection yAvoid ambiguity and vagueness xInclusion/exclusion criteria xAdverse experiences

24 Tips for a Successful Study: Enhancing Protocol Adherence zFully understand protocol limits and the importance of strict compliance yHow much latitude is available for clinical treatment (e.G. Concomitant therapy)? yIs it ok to use the hospital or clinic protocol for performing routine procedures (e.G. Chemotherapy)? yIs it ok to skip procedures that are not medically necessary (lab tests, PEs, biopsies)? yWhich protocol procedures can be performed by non- physician study support staff?

25 Tips for a Successful Study: Enhancing Record Quality zClearly understand what records are to be maintained and how they should be completed yOriginal source data for critical study endpoints yUse your site’s indigenous record-keeping system to the maximum extent possible, discuss this with the sponsor up front yAll records should meet the ALCOA test

26 Tips for a Successful Study: Understand the Elements of Data Quality zAttributable zLegible zContemporaneous zOriginal zAccurate

27 Tips for a Successful Study: Enhancing Record Quality zMinimize the need for transcription zDon’t throw anything away especially originals zExpect the worst yFDA will be inspecting the records

28 Tips for A Successful Study: Understand Regulatory Responsibilities zRead the following before you sign-on yICH GCP Consolidated Guideline yFDA GCP Regulations yFDA Information Sheets for IRB’s and Clinical Investigators: yhttp://www.fda.gov/oc/oha/irb/toc.htmlhttp://www.fda.gov/oc/oha/irb/toc.html y21 CFR Part 312

29 Tips for A Successful Study: Communicate zWith the IRB yProtocol changes yContinuing review zWith sponsor and monitors yOpenly address problems zWith regulatory authorities yUnderstand expectations yHonor reporting obligations

30 Preparing for Site Visit zFDA investigator follows compliance program CP (clinical investigator inspections) and 21 CFR zHave available: yAll study documents yPerson knowledgeable about the study yA place to review records yAccess to a photocopier


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