Preparing for an FDA Audit

1
Preparing for an FDA Audit

• Jean Connor
• Heidi Moses
• Eunice Yim Newbert

2
Goals of FDA Audit

• Ensure quality and integrity of data and
  information submitted to the FDA
• - Is the data valid?
• - Was data collected under proper conditions
• To protect human research subjects
• - Was the study conducted to ensure the rights,
  safety, and welfare of subjects
• - Did Sponsor, CRO and PI/Site adhere to all
  regulations, guidelines, GCPs and approved
  protocol?

3
Types of FDA Audits/Inspections

• Bioequivalence Audits
• - when 1 study is the sole basis for approval
• Study-related Audit or ROUTINE
• - primary efficacy studies
• - studies submitted to FDA for NDA, marketing,
  license, etc
• Investigator-related Audit or FOR CAUSE
• - interest or concern regarding a specific
  investigator

4
Types of FDA Audits/Inspections

• Study-Related or ROUTINE
• Sites are randomly selected or are sites that
• - have notably high or fast enrollment
• - conducting multiple studies or large pivotal
  trials for which the majority of the
  investigational products claims are based
• - conducting studies to support a switch to
  over-the-counter status request
• Sponsors can usually predict which sites will
  be selected

5
Types of FDA Audits/Inspections

• Investigator-Related or FOR CAUSE
• Most common reasons PI selected
• - Conducts many studies or study outside their
  specialty
• - Conducts a pivotal study for NDA, license
• - Submits safety efficacy data that is
  inconsistent with other studies under the
  IND/IDE
• - Sponsor or IRB notifies FDA of problems or
  Subject complaint
• - Highly publicized in media
• - Enrollment more rapid than expected or in
  comparison with other participating sites
• - Unexpected number of subjects w/specific
  diagnosis for area

6
FDA Notification and Authority

• A Sponsor/Investigator shall, upon request
  from the FDA, at reasonable times, permit
  access to and copy and verify any records and
  reports relating to clinical investigations
  conducted under an IND.

7
FDA Notification and Authority

• Sponsor/Investigator will be notified directly
  FDA Form 482 Notice of Inspection
• FDA representative will arrange a reasonable
  time that is mutually convenient.
• - generally from a few days to a few weeks
  notice
• - be accommodating requests to delay audit
  more than 10 days without valid reason raises
  suspicion

8
FDA Notification and Authority

• FDA audit lasts 3 5 days on average.
• FDA may request an audit anytime during an
  investigation, and up to years after the study
  has been completed (e.g. PMA, 510K)
• Sponsor or Investigator cannot refuse FDA
  access to requested files for review

9
FDA Notification and Authority

• Notify your sponsor as soon as you are notified
• Notify IRB as soon as you are notified
• FDA may inspect the IRB if not previously
  inspected, or has not been inspected within
  past 5 years.

10
Preparing for an FDA Audit

• Always be Audit-Ready!!
• Listen to your monitor
• Know your study inside and out
• ? what does your approved protocol state?
• ? what does your SOP/MOO state?
• ? what does your IND/IDE application state?

11
Preparing for an FDA Audit

• Know your study staff
• ? who is responsible for each step of study
  process?
• ? ensure staff understands their on-going
  responsibilities
• ? ensure all pertinent staff is available as
  needed
• Know your study documents
• ? do you have all required documents?
• ? are documents organized, complete and current?
• ? are all documents easily available?

12
Preparing for an FDA Audit

• Study documents should be able to
• Verify study drug/device accountability
• Verify regulatory compliance, including but not
  limited to the following
• - updated FDA Form 1572/1571
• - on-going IRB review and approvals
• - IND Safety reports
• - updated Investigators Brochure and Protocol
• - Financial Disclosures
• - Communication with Sponsor and FDA

13
Preparing for an FDA Audit

• Study documents should be able to
• Verify Investigator and staff training and
  credentials, including but not limited to
• - Medical License
• - In-service training(s)
• - CVs/Resume (current within 2 years)
• - Other training records (e.g. CITI)
• Demonstrate study compliance (complete and
  accurate CRFs with supporting source
  documentation)

14
Preparing for an FDA Audit

• Study documents should be able to
• Acknowledge and explain all protocol
  deviations/exceptions and any follow-up
  corrective actions (as applicable)
• Verify identification and reporting of adverse
  and unanticipated events, and demonstrate
  adequate follow-up per approved protocol.

15
Preparing for an FDA Audit

• Study documents should be able to
• Verify subject existence
• Confirm subject eligibility at enrollment
• - Source documents, such as Medical Records
• Visit/Clinic Notes
• Shadow Charts
• Lab/Test Results
• Prescriptions
• Signed Informed Consent

16
Preparing for an FDA Audit

• Study documents should be able to
• Verify informed consent was properly obtained and
  signed prior to study participation.
• Verify data collected and submitted through
  comparison of complete and accurate case report
  forms (CRFs) with source documents (e.g. medical
  records, visit notes)

17
Preparing for an FDA Audit

• If it is not immediately clear, ask your FDA
  representative what documents should be available
  
• But have all documents available as FDA can
  expand audit as warranted.
• Check out the Compliance Program Guidance
  Manual for FDA Staff, available on-line lets
  you know what to expect!

18
During the FDA Audit

• Reserve a separate area or room with adequate
  space, and bring documents to the FDA inspector
  as requested.
• Ensure Sponsor, Investigator and pertinent staff
  are available for the duration of the FDA audit.
• Ensure FDA inspector will be accompanied at all
  times
• Ensure inspector has access to photocopier

19
During the FDA Audit

• Upon arrival, FDA Inspector presents credentials
  and FDA Form 482 Notice of Inspection
• FDA Inspector may ask to interview any staff.
  Staff should honestly answer the question asked,
  but do not offer more information.
• FDA Inspector will meet with pertinent staff at
  the end of each day to address any issues that
  can be resolved before the end of audit
• Exit Interview at end of audit to discuss and
  clarify findings

20
After the FDA Audit

• FDA Form 483 documents all inspection findings
  and deficiencies
• Response to FDA Form 483 sponsor/investigators
  response to deficiencies submitted to FDA
  inspector
• Establishment Inspection Report (EIR)
  FDA Form 483 and responses compiled into final
  report submitted to FDA headquarters
• If sponsor/investigator responses are deemed
  adequate, the corresponding finding(s) may be
  removed from the Form 483, in effect, not noted
  in the EIR

21
After the FDA Audit

• Classification of Findings
• NAI No Action Indicated
• Site is in compliance. Acknowledgment letter
  will be sent to site and no response required
• VAI Voluntary Action Indicated
• Objectionable practice having minimal effect on
  study integrity (data or/or subject protections)
  noted. A formal letter will be sent to site and
  response is required.
• OAI Official Action Indicated
• Objectionable conditions identified requiring
  sanctions. Site response/action required and
  re-inspection likely.

22
After the FDA Audit

• Warning Letters
• Inadequate response to EIR
• Significant deficiencies requiring corrective
  action to avoid further regulatory action
• Investigator/Sponsor must submit written response
  within 15 days, outlining corrective actions
• Investigator/Sponsor non-response or continued
  non-compliance will result in disqualification,
  disbarment or prosecution.

23
Indicators of Fraud

• Perfect work no mistakes or corrections,
  complete and clean CRFs
• Subjects with 100 compliance
• All subjects screened, enrolled and completed
  trial
• Questionable expertise and capability of staff,
  equipment and resources compared to quality and
  output of work.

24
Indicators of Fraud

• Unusually high volume of work compared to
  available resources
• Repeated, uniform data patterns
• Inconsistent data sources
• Consistent use of ink
• Consistent writing style
• General suspicious behavior of research staff