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Good Clinical Practice and Audit Preparedness


Good Clinical Practice and Audit Preparedness IUPU Symposium - October 2010 Michael R. Hamrell, Ph.D. MORIAH Consultants FDA Inspection Follow-up FDA Follow-up ... – PowerPoint PPT presentation

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Title: Good Clinical Practice and Audit Preparedness

Good Clinical Practice and Audit Preparedness
  • IUPU Symposium - October 2010

Michael R. Hamrell, Ph.D. MORIAH Consultants
What is Clinical Research?
  • The essential piece to demonstrate that a new
    product is safe and effective
  • The most costly part of development
  • 60 of cost spent on clinical
  • The most time-consuming part of product

Quality Concepts in Clinical Trials
  • Sponsor Responsibilities
  • Ensure proper monitoring of investigations (21
    CFR 312.50)
  • Monitor the progress of all clinical
    investigations being conducted under its IND (21
    CFR 312.56(a))
  • Correct and/or report serious non-compliance to
    the FDA (812.46(a))

Quality Concepts in Clinical Trials
  • Clinical Investigator Responsibilities
  • Conduct study according to the protocol
    (21 CFR 312.60 812.100)
  • Maintain adequate and accurate case histories (21
    CFR 312.62(b) 812.140)

Role of the Coordinator
  • Clinical Research Coordinator (CRC)
  • Works under the direction of the Principal
  • Expected to perform many of the tasks in the
    clinical study
  • need to be qualified (and trained) to perform the
  • PI still responsible for all patients

Role of the Coordinator
  • Often is the key person for the successful
    conduct of a trial
  • Typically has the most patient contact and direct
    role in many key tasks
  • Usually the person who fills out the CRFs, lab
    slips, etc.
  • Tasks will depend on professional qualifications
    and training

Safety Reports
  • Investigator is required to report all adverse
    events to Sponsor
  • timing depends on nature and severity
  • has major impact on subject safety

21 CFR 312.64(b) 812.150
Quality Concepts in Clinical Trials
  • IRB Responsibilities
  • Organization and Personnel through review of IRB
    membership list (21 CFR 56.107)
  • Functions and Operations through evidence of
    written SOPs (21 CFR 56.108)
  • Review of Research through sufficient details of
    IRB meeting minutes (21 CFR 56.109)

Product Accountability
  • Focus on complete picture
  • Shipping
  • Receipt
  • Use
  • Returns
  • Reconciliation

Product Accountability
Test Articles Reconciled By Sponsor
Investigator Timepoint A
Investigator Timepoint B
Test Article FDA Comment
  • Although the sites personnel have been
    delegated the responsibility for test article
    accountability, it is the Principal Investigator
    who is ultimately responsible for the this task.
  • Even when a research pharmacist is involved in a
    study at a site, the clinical investigator
    retains responsibility for ensuring that the test
    article was appropriately prepared, dispensed and

FDA Viewpoint on Auditing
  • FDA takes no official position on whether
    companies should conduct clinical audits
  • FDA viewpoint on sponsor responsibilities
    Sponsors are responsible for selecting qualified
    investigators ensuring that the investigation(s)
    is conducted in accordance with the general
    investigational plan and protocols contained in
    the IND 21 CFR 312.50 812.40

Whats the Chance of an Audit
  • According to the Inspector Generals Report on
    The FDA Oversight of Clinical Trials (Sept
  • FDA only inspects less than 1 of all clinical
    trial sites
  • 75 of inspections overall were routine

How would you characterize your site?
  • How would you characterize the staff
  • What is the commitment/focus to research relative
    to medical practice
  • How is their research performance perceived?

Some fun examples
Reality Check
  • How many of you do multiple clinical trials each
  • Investigator initiated vs. sponsor
  • How many of your sites/groups have SOPs?
  • How many of your sites use electronic medical
  • How many of you have experience with eCRFs?
  • How do you communicate with your IRB (paper or

Should a Site have SOPs?
  • Reiterates role of PI in all studies including
    delegation of responsibilities to study staff and
  • Defines role of PI and staff in study oversight
  • Suggests the need for site SOPs

The investigator should develop a plan for the
supervision and oversight of the clinical trial
at the site. Supervision and oversight should be
provided even for individuals who are highly
qualified and experienced. A plan might include
the following elements, to the extent they apply
to a particular trial
From Guidance Document
ICH GCP Viewpoint
  • The auditing of clinical trials is conducted in
    accordance with the Sponsors written procedures
    of what to audit, how to audit, the frequency of
    audits and the form and content of audit
    reports. Section 5.19.3

FDA Role in GCP Compliance
  • Determine compliance with regulations
  • Verify integrity of data

FDA GCP Inspections
  • FDA will routinely inspect some or all of the
    data for pivotal studies in support of an
  • FDA choice of sites are based on a variety of
  • number of sites
  • Number of studies at site
  • importance of data
  • type of study
  • Geographic location

Role of FDA Inspection
  • Essential part of PMA/510K/NDA/BLA review process
  • Know your rights
  • Use sponsor/CRO/consultants help to prepare
  • Build quality into your work

FDA Role in Clinical Investigations
  • Bioresearch Monitoring Program
  • An on-going audit program managed by the Division
    of BIMO in each Center
  • To determine the adherence of sponsors, CROs,
    monitors, IRBs and clinical investigators to
    current regulations and official guidelines
  • To assess through audit procedures whether data
    submitted to FDA are substantiated by records

FDA Inspection of Clinical Research
  • FDA Conducts Two Types of Inspections
  • Routine data audits (study oriented)
  • Audit of key pivotal data from NDAs, BLAs,
    510(k)s, PMAs, etc. to verify data and procedures
  • 'For-cause' audits (investigator oriented)
  • Targeted audit of data or investigators as a
    result of prior knowledge or suspicion or alleged
    violations of the regulations

The Facts About Source Documents
  • FDA Requirements Related to source documents in
    clinical trials
  • 312.62(b) An investigator is required to prepare
    and maintain adequate and accurate case histories
    that record all observations and other data
    pertinent to the investigations on each
    individual administered the investigational drug
    or employed as a control
  • Similar requirement in 812.140 for devices

Preparing for the Inspection
  • Before you start, make sure you are prepared
  • (re)Familiarize with protocol, CRFs, other study
  • Review Study archives
  • Check FOI for other inspection results

Plan for FDA Inspection
  • FDA Arrival
  • Who is to be called
  • Check FDA inspector credentials
  • Accept Notice of Inspection (Form 482)
  • Confirm purpose of FDA inspection

FDA Form 482
Site Policy
  • Main Contact
  • Identify who is to be notified at the time
    inspection commences and how
  • Identify who is authorized to receive and
    accompany FDA inspector
  • Plan how oral inquiries and requests for
    documents are processed

General Dos and Donts
  • DO !
  • Greet FDA and ask for identification and FDA Form
  • Provide work area that affords privacy
  • Make available phone/internet/power
  • Offer coffee, tea, water, bathroom
  • Provide visitor pass or parking pass
  • Keep conversation polite and professional
  • Extend common courtesy

General Dos and Donts
  • Dont even think about !
  • Pay for meals
  • Offer any monetary compensation
  • Offer gifts (even at holiday time)
  • Photograph, record or tape things
  • Socialize with FDA after work hours
  • Ask personal questions
  • Look over the inspectors shoulder
  • Complain about government, taxes, FDA

Company/Site Policy
  • Document Production

Company/Site Policy
  • Document Marking and Duplication
  • Do not permit marking of documents by FDA
  • Make copies for FDA and retain a copy of each
    document provided to FDA
  • Mark documents containing trade secret or
    confidential information before providing
  • If confidential information is conveyed orally,
    establish these facts to FDA use witness

Company/Site Policy
  • Affidavits
  • Establish policy on whether to review FDA
    prepared affidavits
  • Circumstances under which
  • an affidavit could be signed
  • Do not sign affidavit or volunteer any
    information unless such disclosure is consistent
    with company policy

Plan for FDA Inspection
  • During Inspection
  • Company/site representative should accompany FDA
    Inspector at all times, to ensure access only to
    information and those parts of the premises under
    the FDC Act

Plan for FDA Inspection
  • Keep an accurate written record of
  • Areas of the site visited and to whom he/she
  • Accurate and complete record of all comments and
    suggestions made by inspector, unanswered
    questions and site commitments
  • Any commitments made to FDA should have
    concurrence of top management

Plan for FDA Inspection
  • A daily summation with FDA, and separately with
    site staff is helpful
  • If additional inspection days are required,
    prepare an agenda for next day with FDA
  • Prepare daily report to management

Company/Site Policy
  • Corrections during Inspection
  • If a change is made during the inspection, decide
    whether the change/correction will be conveyed to
    the FDA inspector and, if so, in what manner

Correction to 483
The Inspection Process
What will the Inspectors ask me to produce for
the audit
  • Source Documentation
  • All of the source documents should cover the
    entire period of the study and be present at the
    time of the audit to allow the auditor(s) to
    properly conduct the audit
  • A standard GCP site inspection will include a
    tour of the facility and a thorough review of the

What will the Inspectors ask me to produce for
the audit
  • Documents in the project notebook filed during
    the course of the trial
  • List of the study subjects and their
    corresponding study numbers
  • Should the FDA investigator ask for the
    identities and demographics of your study
    subjects because of some concern, you are
    required to comply with the request

Warning Letter
What will the Inspectors ask me to produce for
the audit
  • Two-way correspondence with the IRB,
  • Original signed consent forms for all the
  • Case Report Forms (CRFs) for all the patients
  • Source Documentation (Patient medical records,
    clinic and hospital charts)

What will the Inspectors ask me to produce for
the audit
  • Records of patients who were study drop outs
  • Product storage facilities and accountability
  • Serious Adverse Event Reports and documentation
  • Monitor visit log

Data Inspection Process
  • Subject Records
  • Did the Investigator maintain records that are
    supportive of each entry in CRFs for each subject
  • Were all CRFs completed in a timely fashion

Could you recreate CRF from source?
Data Inspection Process
  • For eCRF situations
  • Were all regulations and requirements followed
    relative to 21 CFR 11
  • Do source documents support any
    changes/corrections to the e-CRF

Data Inspection Process
  • Reporting of Study Progress
  • Did investigator terminate or discontinue the
    study before completion
  • Incidence and reports of SAEs to Sponsor and IRB
    handled properly
  • Did Investigator maintain copies of all reports
    submitted to sponsor and IRB

Data Inspection Process
  • Records Retention
  • Who maintains custody of required records
  • Data storage media
  • Record storage conditions
  • Investigator aware of FDA record retention

Data Inspection Process
  • Data Audit Procedures
  • Subject study data
  • Number and type of subjects
  • Existence and availability of subjects
  • Documentation of prior conditions
  • Subject inclusion/exclusion criteria
  • Screen log/failures

Data Inspection Process
  • Protocol Adherence
  • Enrollment of subjects who did not meet the
    inclusion/exclusion criteria
  • Changes in the protocol in dosage, frequency,
    time of dosing, or method of dosing of the test
  • Failure to report serious adverse events promptly
    to the IRB and the sponsor

Data Inspection Process
  • Protocol Adherence
  • Failure to document illnesses, hospitalizations,
    and other significant problems concurrent with
    the study
  • Failure to perform critical tests, examinations,
    or assessments at the protocol-specific time or

Data Inspection Process
  • Protocol Adherence
  • Administration of concomitant therapy that could
    compromise the study results
  • Failure to report concomitant therapy
  • Entering more subjects into the study than
    originally approved by the IRB or the sponsor

Data Inspection Process
  • Product Accountability
  • Did the sponsor maintain accounting procedures
    for the test article
  • Were all unused supplies returned to sponsor or
    disposed of properly
  • Limitations of test article access and
  • Route of administration and proper use

Data Inspection Process
  • Medical/Clinical Laboratory Facilities
  • Are the facilities adequate, and proper
    diagnostic equipment available, to fulfill
    protocol requirements?
  • Is the equipment in good working order?
  • Does the equipment require calibration and are
    there records documenting the required equipment
  • Is the laboratory accreditation/license
    documentation current?
  • Is there proper documentation and storage of
    trial samples?

Data Inspection Process
  • Safety Information
  • How does sponsor assure that the Investigator
    notifies promptly of SAEs
  • Is monitor involved in reporting
  • Is timeframe consistent with regulations
  • Does source data support SAEs
  • Any deaths or dropouts due to SAEs

Data Inspection Process
  • IRB Communication
  • Proper approval and documentation for protocol
    and informed consent
  • Documentation of IRB qualifications
  • Communication/correspondence between Investigator
    and IRB
  • Continuing review performed

Its Over Now What??
FDA Inspection Follow-up
  • At the end of the inspection a discussion is
    scheduled with key personnel to discuss the
    findings (exit interview)
  • May issue Form 483
  • May note observations (annotate)
  • Will record any verbal responses and promised

What is a 483 Observation?
Plan for FDA Inspection
  • Exit Interview
  • Report of FDA inspector findings with appropriate
    site management
  • Opportunity for site to correct any
    misunderstandings incorrect deficiencies
  • If Form 483 is issued, each observation should be
    reviewed with the Inspector and understood
  • Commitment to FDA
  • Plans to correct deficiencies
  • Timetable for future actions (answer will be
    recorded by FDA)

Plan for FDA Inspection
  • After Inspection
  • All items on FDA 483 should be responded to in a
    letter to appropriate FDA Office
  • Follow-up report to appropriate company/site

Plan for FDA Inspection
  • After Inspection
  • Form 483 items should be reviewed by company/CRO
    regulatory, technical, or legal personnel
  • work with Sponsor to address issues
  • State how and when you expect to make corrections
    to FDA

Some items can appear in a letter that were not
on the 483
Warning Letter
What Happens to Inspection Findings?
FDA Inspection Follow-up
  • FDA Follow-up
  • Investigator reviews notes, observations,
    documents collected, etc.
  • All records collected during inspection are
    attached as exhibits

FDA Inspection Process
  • Completion of Inspection
  • Inspector returns to office and prepares written
    report of findings an Establishment Inspection
    Report (EIR)
  • Audit classification is determined and submitted
    to FDA Headquarters for concurrence

FDA Inspection Follow-up
  • FDA Follow-up
  • A recommendations for classification is made
  • Headquarters agrees with Field most of the time
  • EIR and exhibits are forwarded to assigning
    office at HQ (BIMO) for final review and

FDA Inspection Process
  • Completion of Inspection
  • Based on Classification of Inspection follow-up
    letter usually sent
  • Additional Courses of Action
  • as needed or required

FDA Inspection Follow-up
  • Follow-Up Letters
  • Acknowledgement Letter NAI
  • No problems thank you for cooperation
  • Information Letter - VAI
  • letter may point out deviations from the
    regulations and a written response may or may not
    be requested

FDA Inspection Follow-up
  • Follow-Up Letters
  • Warning Letter - OAI
  • Significant deviations from the regulations and
    written response is required within 15 days
  • Letter may also include an invitation to an
    informal conference if deviations are major
  • may be signal of other regulatory action

FDA New Policy on WL
  • More rigid internal timelines for issuing 483 and
    follow-up letters
  • Send response to 483 within 15 days
  • Speedier enforcement following an inspection, if
  • A Warning Letter response can be followed with a
    Closeout Letter, after evaluating the corrective
    action taken, not based on just promised action

FDA Inspection Follow-up
  • Other Follow-Up Letters
  • NIDPOE Letter - Notice of Initiation of
    Disqualification Proceeding and Opportunity to
  • Most serious deviations from the regulations
    where additional administrative actions are being
  • No further use in studies while under

BIMO Inspections CompletedFY 2009
Center CI IRB Spon/Mon GLP Total CBER 83
15 11 6 115
CDER 458 102 73 36
669 CDRH 163 79 59 4 305
CFSAN 0 0 0 1 1 CVM
26 na 4 15 45 All
Centers 730 196 147 53 1135
137 BEQ inspections (CDER specific) 1272 total
International Inspections - 2009
  • Center total
  • CBER 3 (2 CI, 1 sponsor)
  • CDER 119
  • CDRH 12 (10 CI, 2 sponsor)
  • CVM 0
  • Total 134

FY09 CI Inspection Classified All Centers
n 867
FY09 Sponsor/Monitor Inspection Classified
All Centers
n 116
CDRH BIMO Compliance Rates
10-Year CDER OAI rate 3-5
FY09 IRB Inspections Classified All Centers
n 179
Top ten ways to tell your FDA inspection is going
  • 10. FDA sets up temporary housing in your parking
  • 9. The FDA inspector mutters uh-oh each time
    he enters a different department, or opens a
    different folder
  • 8. A 60 Minutes crew asks to film the
  • 7. The FDA inspector wont even enter the room
    where the test article is stored
  • 6. The Congressman you called for help wont
    return your call, but returns your campaign

Top ten ways to tell your FDA inspection is going
  • 5. Instead of a Form 482, the FDA Inspector
    begins with, You have the right to remain
  • 4. The FDA inspector comes to audit a specific
    study, but its not one you completed
  • 3. The FDA inspector knows all of your
    employees by their first names
  • 2. The FDA inspector is a former employee that
    you fired
  • 1. The FDA Commissioner conducts the exit

FDAs Purpose for Inspections
  • Remember, the FDA is both a Public Health
    Consumer Protection Agency and must assure the
    people that the products it approves meet the
    required standards
  • For the government, that means they and you) need
    to AUDIT!

Any Questions ?
Michael Hamrell, Ph.D. MORIAH Consultants 714-970-
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