FY 2012 Clinical Investigation Objectionable Activities/Enforcement Trends

Forewarned is forearmed. For FDA-regulated clinical investigations, knowledge of the most common violations cited by the agency upon inspection is a useful tool for examining one’s own procedures and practices. It helps ensure they are not vulnerable to the same deficiencies before FDA arrives at your investigational site.

Pursuant to its Bioresearch Monitoring (“BIMO”) Program, FDA visits clinical research sites to conduct inspections of clinical investigations. The agency’s purpose in doing so is to determine if the clinical investigations are operating in compliance with applicable statutory and regulatory requirements governing the conduct of clinical trials. These on-site inspections are intended to document how the study is actually being conducted at the clinical site. Depending on the circumstances, these on-site inspections can be announced or unannounced for reasons such as verifying the accuracy and reliability of data that has been submitted to the agency, to follow-up on a complaint to FDA about the conduct of the study, to provide FDA with a real-time assessment of the investigator’s conduct of the trial and protection of human subjects, and in response to the concerns of the study’s sponsor, among others.

Such inspections often involve inspecting investigational records and interviewing individuals involved in the conduct of the study. Occasionally, the investigator also reviews the actual study data, potentially including case report forms, informed consent forms and medical records, e.g., progress notes, subject charts, and nurse’s notes. The FDA inspector’s observations are captured on a Form FDA-483 and can be used as the basis for a potential FDA enforcement action, if warranted.

A review of FDA’s cited observations for Fiscal Year 2012 indicates that investigators and sponsors are making avoidable mistakes that unnecessarily expose them to regulatory (and potentially criminal) sanctions. The most frequently cited observations include:

  1. Non-Compliance With the Protocol – The failure to comply with the study protocol was the most common type of observation involving clinical investigations in FY 2012. Often times, these types of violations occur when investigators do not adequately familiarize themselves with the investigational requirements or their own FDA regulatory obligations as investigators. In other instances, these violations occur when investigators intentionally deviate from the investigational requirements based on preliminary results without seeking the approvals necessary to do so. Simply put, investigators must understand and adhere to these requirements.
  2. Inadequate Case History Records – Investigators are required to prepare and maintain adequate and accurate case histories, recording all observations and other data pertinent to the study about each subject treated with the investigational article or enrolled as a control. It is especially important to have procedures in place to ensure that case history records are complete and up to date because they are often audited by FDA to verify the validity and completeness of the case report data submitted to the agency.
  3. Inadequate Investigational Article Accountability Records – The next most common observation involves an investigator’s failure to control and keep track of the investigational articles entrusted to his or her care for the purpose of conducting the study. It is important to establish and closely adhere to appropriate recordkeeping procedures for the receipt, use, and disposal/disposition of each study article.
  4. Inadequate Informed Consent Records – FDA continues to uncover problems with the adequacy of informed consent documentation prepared and maintained by investigators. Typical problems include use of consent forms that have not been approved by the IRB, forms that have not been signed by the subject (or their legally authorized representative), forms that were not properly dated when consent was given. In other instances, investigators fail to properly update consent forms and “re-consent” subjects when consent requirements change while the study is in progress.
  5. Sponsors’ Compliance with their General Responsibilities – This observation was used when, among other things, study sponsors failed: to meet their obligations to ensure that they have selected qualified investigators; to provide the selected investigators with the information that they need to conduct the investigation properly; to seek and receive IRB approval; to submit an IND/IDE application to FDA for a significant risk study; and to promptly inform FDA/IRB of significant new information about an investigation. Sponsors must work hand-in-hand with FDA, the IRB, and investigators to assure compliance.

Investigators, sponsors, and IRBs would be well advised to re-examine their own policies and procedures for the conduct of clinical investigations to ensure that they are not vulnerable to these common deficiencies.

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