How to Make FDA Inspections as Painless as Possible

How to Make FDA Inspections As Painless As Possible.  What To Expect, What to Do, And What Not to Do.  A Site’s Perspective

Janet Lewis, RN, CCRP

Janet has presented at MAGI’s Clinical Research Conferences and ACRP’s Global Conferences, most recently during ACRP’s 2015 conference in Salt Lake City.  Janet has completed 20 FDA audits and over 125 sponsor audits.  She is available for consulting services, including how to prepare a site for an FDA audit.

The FDA conducts inspections of clinical research sites to determine if the clinical investigators are conducting research studies in compliance with applicable statutory and regulatory requirements.  A site may anticipate an audit for the following reasons:

  • Top enroller
  • Pivotal study
  • Unusual amount of AEs or SAEs
  • Working outside the scope of practice
  • For cause initiated by sponsor, CRO, IRB, employee, or patient

What are FDA investigators looking for at a site?

  • Compliance with protocol
  • PI oversight
  • Appropriate ICF procedures
  • Compliance with randomization/blinding procedures
  • Appropriate delegation of authority
  • Adequacy of study personnel
  • Site procedures, including emergency procedures
  • Safety of subjects maintained
  • All SAE events reported to IRB
  • IRB oversight, approval and communication
  • Drug accountability
  • Cold chain maintained for IP and samples
  • Source documentation is adequate
  • Equipment calibrated
  • Data is accurate
  • Record retention
  • Data correction procedures
  • Was the study conducted as designed

Sites contacted for an upcoming inspection will need to notify the principal investigator, sponsor and IRB for the study, and all other sponsors they are currently working with.  Sites should make sure to ask:

  • What is the scope and nature?
  • How many investigators should the site expect?
  • What is the expected length of the visit?
  • Is there a list of subject documents they would like to review?

The best way to ensure the inspection goes as smoothly as possible is to be prepared.  Sites anticipating an audit should have at least the following ready for the FDA investigator:

  • SOP for FDA inspections
  • 100% of consents, sources and eCRFs, and clinic charts (paper or electronic) audited
  • X-rays (if applicable)
  • Regulatory and laboratory binders
  • RDE manual (if applicable)
  • CD ROM and computer (if applicable)
  • Other relevant forms, contracts, and certificates

When the FDA investigator arrives at a site they should present identification along with the FDA Form 482.  Site orientation as well as a pre-meeting should be arranged with the PI and key contact person from the site.  The key contact person should check in regularly with the investigator and document their responses to the investigator’s questions.

Common findings in FDA audits include:

  • Cross-outs or write-overs that are not lined through, dated and initialed
  • Incorrect visit windows
  • Source and eCRF that do not match
  • Medical history that doesn’t match medications
  • Inaccurate age and birthdates
  • Inclusion / exclusion criteria not met
  • Not following the protocol as written

Once an inspection is finished the FDA investigator will conduct an exit interview with the site to discuss their findings.  If deficiencies are found, the FDA investigator will issue a written Form FDA 483.  The 483 describes any observations that, in the opinion of the FDA investigator, represent deviations from applicable statutes and regulations.  Deficiencies that have been found by FDA investigators include:

  • failure to follow the investigational plan and signed investigator statement or agreement
  • protocol deviations
  • inadequate recordkeeping
  • inadequate accountability for the investigational product
  • inadequate subject protection, including informed consent issues

Following the inspection, the FDA investigator who conducted the inspection will prepare a written Establishment Inspection Report (EIR).  A site should then receive one of the following types of letters (although sites with no significant deviations might not receive a letter):

  1. A letter stating that basic compliance was met
  2. An Informational or Untitled Letter that identifies deviations that are not significant for a Warning Letter
  3. A Warning Letter that identifies serious deviations and requests a written response outlining how a site will make corrections
  4. A Notice of Initiation of Disqualification Proceedings and Opportunity to Explain.  The clinical investigator may be provided with the opportunity to explain the situation.  If the explanation is accepted by the agency then a corrective action plan may be considered.  If the explanation is rejected or the investigator has repeatedly or deliberately failed to comply then they will be disqualified from conducting future clinical trials.

The FDA posts final clinical investigator inspection classifications as well as warning letters on its website.

FDA Warning Letters

FDA Inspections of Clinical Investigators: Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors