“The Facility’s Perspective” (FDA) Inspections

Patrick R. Ayd RN, MBA

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The Speaker

How to prepare for an FDA Inspection

Understanding the Goal of the Auditor

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The Facility‘s Perspective

Why Does the FDA Conduct Inspections?

• Assess adherence to federal laws and regulations

• Determine that the safety, rights and welfare of subjects were protected through consent and IRB/EC procedures

• Confirm validity of data supporting INDs and NDAs

• Determine whether the trial was well controlled and conducted according to the trial protocol/SOPs/ contracts/regulatory guidelines/CFRs

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Electronic Records; Electronic Signatures: Part 11

Protection of Human Subjects: Part 50

Financial Disclosure by Clinical Investigators: Part 54

Institutional Review Boards: Part 56

Investigational New Drug Applications: Part 312

(Subpart D), Responsibilities of Clinical Investigators

and Sponsor

New Drug Applications: Part 314

Major Federal Regulations Governing Clinical Research

Title 21, Code of Federal Regulations

Inspection of Clinical Investigators

• Does the principal investigator retain control of the trial and has any authority been delegated?

• If authority has been delegated, has the principal investigator retained control of the trial or has he/she given full or partial control to someone else who FDA may not be aware of until they initiate their inspection?

• FDA inspectors will conduct interviews and review documentation in effort to identify all other physicians, assistants, and any other personnel who are, or were, associated with the trial; and to assess compliance to protocol/SOPs/regulations

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Three Types of Inspections of Clinical Investigators

Trial Oriented Inspection• Primary focus is on verification of reported trial data related to an

NDA submission (pivotal trials)

Investigator Oriented Inspection• Investigator Oriented: an inspection in which the focus is related

to suspicious behavior by the clinical investigator

Bioequivalence/Bioavailability Inspection• Focus is mainly related to the conduct of the trial and collection

of data

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Routine Inspections

Advance Notice

Usually Inspect trials That Were Completed and Reported in NDA

Inspections Usually Last 3-4 Days

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Why is “My” Site Being Audited

Investigator is conducting a significant # of clinical trials

Investigator is conducting clinical trials outside his/her field of specialization

The investigator reports efficacy for a drug that appears to be too good compared with the results of other investigators conducting the same trial

The investigator reports few adverse drug reactions as compared with other investigators conducting the same trial

Luck

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“For Cause” Inspections

No Advance Notice (1 day if lucky)

More Stressful Than Routine Inspections

Can Last for Weeks or Months with Intermittent Visits

May Involve FDA HQ Personnel

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What Could Prompt a “For Cause” Audit

Complaint Related To Safety, Informed Consent, Coercion

The Investigator Is Conducting Clinical Trials Outside His/Her Field Of Specialization

The FDA has received complaints from a patient or the sponsor that the investigator is in alleged violation of the regulations, protocol, or human rights

The Investigator Reports Few Adverse Drug Reactions As Compared With Other Investigators Conducting The Same Trial

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Four Major Segments of an FDA Inspection

Announcement of an Inspection

Conduct of the Inspection

Exit Interview

Post Inspection

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They’re Here!

Now what?????

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Upon Arrival of the Auditor

Contact Appropriate Personnel

Confirm Credentials

Receive FDA Form 482

Determine Purpose

Request Guidelines/expectations (Schedule, Debriefing, Etc.)

Assign an Appropriate Room

FDA Inspection SOP

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Notify sponsor

Establish roles• primary/secondary

contacts

• documentation

• making copies

Retrieve & review trial file & trial protocol

Retrieve CRFs for each subject

Gather source documents

Alert & prepare support staff

Visit/alert ancillary facilities ( pharmacy, clinical laboratory, etc.)

Upon Announcement of an Inspection, cont.

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Conduct of Inspection

Tour/Facility Inspection

Accompany At All Times

• Allow Inspector Quiet Time To Work

• Set Expectations

• Check Periodically To Answer Questions

Staff Interviews

Data Reviews

Daily Debriefing

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Investigator Interview and Facility Inspection

People-Related Issues Who assisted in performing the trial?

What were each person’s specific duties?

How were the trial subjects recruited?

Describe the monitoring (quality control) procedures & your interaction with the monitor

• frequency of visits• frequency of telephone calls• information provided by monitor

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Investigator Interview and Facility Inspection, cont.

Facility-Related Issues Where was the trial conducted?

What protocol specific equipment was used? Where is it located?

How and where were data recorded and stored?

Where was investigational drug stored?

What records provide documentation of drug accountability to and from the sponsor?

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Review of Investigator Trial File

• Protocol

• Investigators Brochure

• 1572 with CV(s)

• IRB/EC approval letter(s) & correspondence

• Sample IRB/IEC approved informed consent form

• Randomization schedule

• Monitoring documentation

• IND Safety Reports

• Drug Accountability records

• Lab Certification/CV(s)

• Notification of trial end to IRB/IEC & sponsor

• Signed consent form for each subject

• Copies of completed CRFs

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Review of the Subjects’ Consent Forms

• Review of the Signed Original And/or Revised Consent Forms for Selected trial Subjects

• Verify Who Obtained or Witnessed Consent Process

• Verify Date of Consent to Ensure the Process Was Before the Date of the First Trial Procedure

• Verify That Subjects Were Consented With the IRB-Approved Form

• Verify That Each Subject Received a Copy of the Original Signed Consent Form

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Audit of Subjects’ Records

• Review of Organization, Completeness, Condition, and Location of Subjects’ Records

• Review of Documentation to Assure That the Trial Subjects Did Exist and Were Alive and Available for Trial Participation

• Review and Cross-comparison of Selected Case Report Forms With Corresponding Source Documentation

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• Review and evaluation of Serious Adverse Events, and how and when they were reported to the IRB/IEC and Sponsor

• Review for subject Drop-Outs

• Are they being reported to the sponsor?

• What are the reported reasons for Drop-Outs?

• Did patient move, experience some type of adverse event, or decide to voluntarily withdraw?

Audit of Subjects’ Records, cont.

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Examples of Areas Reviewed

• Compare adherence to practices & procedures to Contract/SOPs/ protocol/guidelines

• Review contractual agreement

• Organization charts

• Names/titles of responsible persons

• Facility

• Identify departments/functions/key personnel

• Authority delegated

• Authority to review & approve reports & data tables, evaluations , AE’s

• Job descriptions, CV’s, training records

• Subject records

• Drug accountability23

Be Prepared to Discuss

• Responsibilities

• SOPs

• Organization Chart

• Roles/Functions

• Training• general• trial specific

• Transfer of obligations

• Tracking of activities

• Central Files

• Source Documents

• Trial Documentation

• Problem Resolution

• Subject Screening/Decisions

• AE Reporting

• Validation

• Equipment

• Quality Assurance

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Be Prepared to Discuss

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Essentially,anything related to your job, internal processes and the project

be able to clearly & succinctly explain your job responsibilities, processes (know your job description, SOPs, contracts, protocol, etc.)

think before you speak

make sure you understand the question

• DON’T ASSUME• clarify if necessary

During the Interview…...

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answer ONLY questions asked• don’t volunteer • get comfortable with ‘pregnant

pause’

answer ONLY questions related to your position

answer ONLY questions you know, otherwise

• I don’t know• I will/someone else will follow up

answer truthfully

During the Interview…… cont.

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Correct Erroneous Information Provided

Know & Refer Back to Processes Refer Back to Protocol, Reports, and

Other Documents Know Contract & Protocol

Expectations Be Positive Be Polite Be Prepared Be Alert to Hallway Talk

During the Interview…… cont.

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Do Not Argue

Do Not Deny the Obvious

Do Not Get Hooked on ‘Fishing Expeditions’

Do Not Comment on Quality

Do Not Respond to Casual Comments

During the Interview…… cont.

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Do Not Express Frustrations or Editorialize

Do Not Respond to Questions Unless QA/Management Is Present

Do Not Read or Sign Affidavits or Statements

Do Not Provide Copies of Any Documents (QA/Management)

During the Interview…… cont.

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FDA is trained in interviewing & interrogation techniques

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Conclusion

Know & Follow SOPs, Protocol, Contract, Plans, etc.

Ensure Your CV, Training Records Are Current

Document & Follow up With Problems

Be Aware of Quality Trends

Ensure Documentation Is Adequate & Accurately Reflects Activities

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Most Common Reasons for FDA to Reject a Trial

• Source Documentation Not Available

• Failed to Follow the Protocol

• Unreported Concomitant Medications That Might Interfere With Evaluation of the Drug

• Unreported Adverse Experiences That Could Be Associated With the Investigational Drug

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Inadequate andinaccurate records 52%

failure to adhere to protocol 52%

Inadequate subject consent form 44%

inadequate record of drug accountability 28%

Failure to inform IRB/IEC of changes / progress 14%

Investigator-Oriented Inspections Results (FDA)

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Investigator-Oriented Inspections Results (FDA), cont.

Deficiency 451 InspectionsUnapproved Concomitant Therapy 11%

Submission of False Data 11%

Problems With Records Availability 9%

Inappropriate Follow-up of Adverse Reactions 7%

Inappropriate Delegation of Authority 5%

Failure to Obtain IRB Approval 3%

Sub-investigators Not Listed 4%

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June, 2008 to October, 2009

Trial Oriented Inspections Results (FDA)

Deficiency 483 InspectionsInadequate Consent Form 49%

Failure to Adhere to Protocol 31%

Inadequate and Inaccurate Records 26%

Inadequate Drug Accountability 20%

Failure to Inform IRB of Changes / Progress 7%

Inappropriate Follow-up of Adverse Reactions 3%

Unapproved Concomitant Therapy 3%

Failure to Obtain IRB Approval 3%

Problems With Record Availability 3%

Sub-investigators Not Listed 2%

Failure to Obtain Informed Consent 1%

June, 2008 to October, 2009

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Possible Adverse Consequences of FDA’s Observation of Deficient Clinical Research

• Restrictive Sanctions

• Disqualification

• Criminal Prosecution

• Rejection of Invalid Data

• Delay of NDA Review and Approval

• Unapproved NDA

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