FDA Audits and Guidelines

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FDA Audits and Guidelines
Andrea D. Buchmeier, CCRCUniversity of Colorado
Cancer Center
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Objectives

• Background
• What to expect during the Audit
• After Audit Follow up
• Examples of 483 and Warning Letter Citations
• Lessons Learned

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Federal Regulation and ICH Guidelines

• Federal Regulations
• CFR 21.11-Electronic Records and Electronic
  Signature
• CFR 21.50-Protection of Human Subjects
• CFR21.54-Financial Disclosure
• CFR 21.56-Instituional Review Boards
• CFR 21.812-Investigational Device Exemptions
• CFR 21.312-Investigational New Drug Application
• ICH Guidelines-
• E6-Good Clinical Practices
• E2A-Clinical Safety Data Management

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Reference Web Sites and other Reading

• www.fda.gov
• www.fda.gov/cder/
• www.fda.gov/cber/
• www.fda.gov/cdrh/
• www.fda.gov/fdac
• www.os.dhhs.gov
• www.hhs.gov/ohrp
• Belmont Report
• Declaration of Helsinki
• FDA Guidance Documents

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Types of Audits

• Routine
• Pivotal studies
• Prior to drug approval
• May choose high enrolling sites or sites that
  conduct a large number of studies
• Geographical Area

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Types of Audits

• Investigator Oriented (For Cause)
• Can be an extension of a study specific audit
• Investigator conducting research outside of
  his/her therapeutic area
• Suspicious Data
• Investigator reports few or no AEs in relation
  to other sites
• Investigator reports higher efficacy results than
  other investigators

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Types of Audits

• Investigator Oriented
• As a result of some type of complaint (The FDA
  investigates ALL complaints)
• Patient
• Employee
• Sponsor

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How many audits per year?

• FDA has a Performance Plan that is updated
  annually
• One goal To increase the number of inspections

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Bioresearch Monitoring Inspections FY
2008Source FDA.gov
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• CONDUCT EVERY STUDY AS IF IT WILL BE AUDITED!

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Inspection Objectives

• Routine
• Assure integrity of scientific testing and
  reliability of data submitted to FDA
• To determine that human rights and welfare of
  human subjects are adequately protected
• To assess whether data submitted to FDA is
  substantiated by records
• Assure compliance of clinical investigators with
  the regulations
• Routine IRB audits-every three years

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Inspection Objectives

• Investigator/For Cause
• The Consumer Safety Officers (CSO) will have a
  specific assignment related to the complaint
• PI and staff training?
• Data manipulation/falsification?
• PI Involvement?
• Subject Safety?
• Adequate Informed Consent?

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Initial Call From the FDA

• Who might receive the call?
• PI
• CRC
• Administrative Assistant
• Site Director

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Initial Call From the FDA

• What to ask?
• The Consumer Safety Officers (CSO) name
• What study does the CSO want to review
• Type of Audit
• Timeline When would they like to come?
• They will generally work around your schedule but
  you need to schedule it as soon as possible!

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Initial Call From the FDA

• Anticipated length of inspection
• Typical Audit is 3-5 days
• Who will be coming with CSO
• For an investigator oriented audit, someone from
  Headquarters may attend with CSO
• What records will they review?

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ARE YOU READY?

• Notify all Study Staff
• P.I., sub-investigators, CRCs, IRB, Pharmacist,
• Notify Sponsor
• Institutional Official
• Pull all ORIGINAL research records
• CRF and source documents including signed
  informed consents
• Clinic charts if applicable
• Regulatory Binder-IRB approvals, correspondence,
  drug shipping and return information, site
  signature log, monitor visit log, 1572, CVs, etc

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ARE YOU READY?

• May need Subject and staff schedules, telephone
  logs, subject sign-in sheets, temperature logs,
  calibration logs
• Review Protocol
• Review CRF/Source documents and informed consents
  for all subjects
• Review SAEs

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ARE YOU READY?

• Review regulatory binder especially
  correspondence
• Organize documents if necessary

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ARE YOU READY?

• Identify a conference room or private space for
  the CSO
• Appoint a point person to make copies and escort
  the the CSO
• Familiarize the CSO with the surroundings
  restroom, phone, cafeteria, etc.

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The Inspection..

• The CSO will introduce themselves and show
  credentials. If they do not show credentials
  ASK!
• CSO will review notice of inspection Form 482
  and give the PI/IRB Director the original
• CSO will review why the audit is being audited,
  the inspection process, what they will look at,
  and projected timeline

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The Inspection..

• Check in with the CSO from time to time. They
  may have some questions regarding data,
  organization, procedures, etc.
• Make duplicate copies one for CSO, one for you
• This will give you an idea of what they are
  focusing on and will assist you in your follow up
  response.

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The Inspection..

• Call your sponsor/institutional official at the
  end of each inspection day or as agreed upon
• Meet with the CSO at the end of each day. The
  CSO may have items for you to address before the
  next inspection day
• Confirm the day and time for the next days visit

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The Interview Dos and Donts

• Listen carefully and repeat the question or ask
  it to be repeated if necessary
• Answer completely, directly, and honestly
• Do not guess or make up the answer
• Do not provide your opinion, only the facts
• What do you think? What is your best guess?
• Do not volunteer more information than necessary

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The Interview Dos and Donts

• Never question the CSOs authority (remember,
  they have a badge!)
• Never argue or raise your voice
• Do not answer for someone else
• Do not agree or volunteer to change a policy
  without first discussing with PI and/or site
  director

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The Interview Dos and Donts

• There is no such thing as off the record
• It is OK to say I do not know or I do not
  remember
• Take notes of questions asked
• Expect what you say to be documented in a FDA
  field notebook
• Leave as soon as the interview is over

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Interview Questions for the PI

• How many studies have you been involved in?
• How many other studies were you involved in
  during this trial?
• What of time did you devote to this project?
• How did the sponsor choose you?
• How were you trained on the protocol?

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Interview Questions for the PI

• How did the sponsor communicate your
  responsibilities?
• As PI, what are your responsibilities?
• How were sub-investigators and CRCs trained on
  protocol?
• How do you delegate responsibility?
• How did you recruit subjects?
• What did the consent process involve?

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Interview Questions for the PI

• Where was study drug stored?
• Who had access to the study drug?
• Did you see subjects at each visit?
• When did you review the source docs and CRFs?
• Who determined subject eligibility?

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Interview Questions for the PI

• How many subjects did you enroll?
• Who assessed AEs?
• Any SAEs?
• How often did the monitor visit?
• Did you meet with the monitor at every visit?

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Interview Questions for the PI

• Study Specific Questions and Findings
• This will give you an opportunity to address
  issues and MAYBE keep them off the 483
• Were you aware of.
• I found 3 missing consents, etc.

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Interview Questions for the CRC

• How were you trained on this protocol?
• Was the PI Available when needed?
• Who determined eligibility?
• Who assessed AEs?
• Can you see a pattern???

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Communication

• Keep the lines of communication open between the
  PI, the CRC, and the sponsor/institutional
  official
• The PI, sponsor and/or institutional official may
  request a daily update

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Inspection Close-Out

• Exit Interview will go over findings
• 71 of sites receive a Form 483
• This will go over in detail the results of the
  CSOs findings
• Make sure you understand what the 483 contains
• Send a copy of the 483 to your sponsor

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Response Letter

• You are not required to respond to a Form 483
  HOWEVER, any comments received from the PI will
  be considered in evaluating the PIs compliance
  status i.e. it is in you best interest to
  respond in a timely manner!

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Is it over?

• NO!

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Inspection Results

• The CSO will write and Establishment Inspection
  Report (EIR)
• The EIR will be used by the FDA District Office
  to classify the sites compliance and details the
  inspection, exit interview and items listed on
  the Form 483
• A copy of the EIR will be sent to you shortly
  (3-6 months!) after the inspection

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Inspection Results

• There are three possible classifications for a
  site on an EIR

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Inspection Results

• NAI (No Action Indicated)
• This indicates that the PI is in compliance with
  all applicable Federal Regulations. A letter may
  be issued, but no response by the PI is necessary

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Inspection Results

• VAI (Voluntary Action Indicated)
• This indicates that a condition, practice or
  facility is not in compliance with applicable
  Federal Regulations. A letter may be issued
  depending on the severity of the violations or
  the potential impact on the reliability and
  validity of the study data. A response is
  normally required within 30 days unless the
  written response to the 483 is so complete that
  it requires no further comment.

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Inspection Results

• OAI (Official Action Indicated)
• This indicates objectionable conditions are such
  that regulatory and/or administrative action will
  be recommended due to noncompliance with
  applicable Federal Regulations.

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Classifications of Clinical Investigator
Inspections during FY 2008
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Classifications of IRB Inspections during FY 2008
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Classifications of Sponsor Inspections during FY
2008
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Inspection Results

• The FDA may respond to an OAI classification in a
  number of ways
• Warning letter-requires written response from PI
  within 15 days. Warning letter may contain items
  not listed on the 483. Follow up or expansion of
  inspection.
• Informing sponsor that the PIs data is not
  acceptable to support their NDA.
• Administrative action including termination of
  the IND.

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Inspection Results

• Disqualification Investigator or IRB
• Injunction, prosecution, or referral to other
  agencies
• Withhold IRB approval of new studies
• No new subjects enrolled to ongoing studies
• Terminate studies
• Notification of interested third parties

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Most Common Citations

• Informed Consent Inadequate
• Protocol Nonadherance
• Records Inaccurate/Inadequate
• Drug Accountability Inadequate

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Example 483

• TURBO FDA 483
• canned text to standardize citation
• Problem does not always fit the issue

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Example 483 Citations

• An investigation was not conducted in accordance
  with the signed statement of investigator and
  investigational plan.
• Specifically, Dr. X did not have control over
  personnel involved in the study as evidenced by
  the following
• All employees assisting in the investigation were
  not included on the FDA-1572 as
  sub-investigators. Four out of four CRCs
  conducting spirometry were not listed. Five
  radiology physicians were involved in the study
  by administering the investigational drug to a
  subject, but were not listed as Sub-Is on the
  1572.

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Example 483 Citations

• The ECG for subject 123 on 2/4/02 documents that
  CRC Jane was the technician, however, CRC Jane
  was no longer working at the research center at
  that time.
• Out of all lung exams reviewed for each of the 6
  visits for 10 subjects, 2 were not done.

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Example 483 Citations

• Specifically, Dr. X did not always personally
  conduct or supervise the investigation as
  evidenced by the following
• One of ten subjects completed CRFs were not
  reviewed by Dr. X in a timely manner. Final
  contact with subject 123 was 9/29/02, however,
  the CRF was not reviewed until 1/27/03.
• Of the six CRCs who worked on this protocol,
  three were not on the site signature log.
  Training??

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Example 483 Citations

• In order to continue to the baseline visit,
  subjects must meet eligibility at the screening
  visit. For subjects 123 and 234, Dr. X did not
  confirm eligibility, as required by the protocol,
  until after subjects randomization visit.
• Subject 53301 had no temperatures recorded for
  visits 1,2,3 and 5
• Subject 53301 had no blood pressure recorded for
  visits 2, 3 and 5 (120 minutes post injection)

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Examples of 483 Citations

• Failure to Obtain Informed Consent in accordance
  with 21 CFR Part 50 from each human subject prior
  to conducting study related tests
• Specifically
• 483 listed subjects by initials and screen date.
  These subjects never received study drug (screen
  failures)
• Out of 35 subjects screened, 3 subjects did not
  sign the updated version of the IRB approved
  informed consent

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Examples of 483 Citations

• Investigational Drug disposition records are not
  adequate with respect to dates and quantity
• Specifically
• A MTF dated 1/30/04 documents that the study drug
  returned by subject 123 on 61103 (7 tablets),
  could not be accounted for in drug inventory.
• Drug dispensing records could not be located for
  three subjects.

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Examples of 483 Citations

• Failure to prepare or maintain adequate and
  accurate case histories with respect to
  observations and data pertinent to the
  investigation
• Specifically
• CRF for subject 890 document two adverse events.
  URI was documented as possibly related to study
  drug and Thrush was documented as related to
  study drug. However, source documents record the
  two adverse events as URI-related and
  Thrush-possibly related

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Examples of 483 Citations

• All CRFs and source data for five out of thirty
  subject s screened could not be found
• Source documents on two subjects for v-3 could
  not be found
• Source documents for subject 678 record the last
  dose of study drug on 7/2/02 at 6pm, however, the
  subject diary records zero doses taken between
  4pm and 1159pm on 7/2/02

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• Review of 483 and subsequent warning letter
• Review of Sanofi Warning Letter

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Lessons Learned..

• General study conduct/ Training and SOPs
• All CRCs and study personnel with significant
  role in study should be listed on the 1572 OR you
  must have written documentation (SOP, sponsor
  instructions) detailing who is and who is not to
  be listed on 1582.
• Physical exams If you need to add an
  investigator to the 1572 because they performed a
  physical, make sure they are properly trained
  on the protocol and document that training.

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Lessons Learned..

• Properly document all training general and
  protocol specific. This includes protocol
  hand-off.
• Make sure anyone who touches a subject or the
  data are on the site signature log and are
  trained on the protocol .
• Periodic review of the source documents and CRFs
  by the PI is HIGHLY recommended.
• Investigator review and sign off on CRFs within
  30 days of subject completion. This may mean
  that the PI may need to review and sign off twice
  or more depending on monitor visits and query
  resolution.

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Lessons Learned..

• If your site has the capability, perform periodic
  internal QA.
• Archive completed studies in a timely manner.
  This will assist in avoiding the loss of study
  data.
• Be proactive not reactive

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Lessons Learned..

• CRC should initial any procedure performed.
• PI review and sign off on all procedures
  performed by CRC.
• Keep current and accurate temperature logs.
  NEVER discard these logs!

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Lessons Learned..

• Diary cards
• You must review the diaries with the subject
  before the subject leaves the unit
• Date and initial each diary card after review
• Double check study drug dosing and rescue med
  times against what the subject tells you

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Lessons Learned..

• PI involvement
• Meet with monitor at every visit. If
  unavailable, follow-up with a documented phone
  call or email.
• PI to review and date/sign on all monitor
  follow-up letters.

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Lessons Learned..

• Informed Consent
• Consider different color copies for different
  consent versions.
• Effective communication between regulatory staff
  and clinical staff. Make sure everyone knows
  what has changed and is able to properly explain
  these changes to the subject.

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Remember.

• If it is not documented
• it did not happen!

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THANK YOU!!!!!