Wednesday, June 9, 2010

FDA - Inspections, Compliance, Enforcement and Criminal Investigations

In 2010, a noted increase is observed in warning letters issued to pharmaceutical sponsors regarding Form FDA 483 and Investigational Device Exemptions (IDEs). The warning letters were issued by FDA to inform the the pharma sponsors of objectionable conditions observed during a FDA for cause, onsite investigation at selected clinical sites. The purpose of a 483 inspection is to determine whether the activities of the pharmaceutical sponsor/clinical investigator at clinical investigative sites comply with applicable federal regulations. A trend of increasing serious violations of Title 21, CFR Part 812, IDE was noted by FDA inspectors during unannounced onsite inspections. Inspections by FDA investigators are conducted under a regulatory program designed to ensure that data and documentation contained in requests for IDE and PMA applications, approvals and 510(k) clinical submissions are scientifically valid and accurate. Another objective of the FDA program is to ensure that human subjects are protected from undue safety hazard or risk during the course of scientific/clinical study investigations.

Most common violations issued by FDA during onsite inspections:
  • failure to obtain FDA approval prior to allowing subject participation in a clinical investigation
  • failure to ensure adequate monitoring
  • failure to complete Form FDA 1572
  • failure to complete Subject Informed Consent
  • failure to obtain IRB approval
  • failure to obtain a signed agreement from each clinical investigator that includes sufficient accurate financial disclosure
  • failure to submit complete and accurate clinical investigator certification and study disclosure statements
  • failure to qualify clinical investigators
  • failure to qualify clinical investigation sites.

Numerous violations were observed during inspections relating to adequate, quality and management at the clinical investigation sites. Sponsors are responsible for ensuring proper monitoring of the investigation and collection of data and documentation. Most common "monitoring" violations observed, but not limited to:

  • Standard Operating Procedures (SOPs)
  • Clinical Study Monitoring Procedure
  • Monitoring Visit Reports - omissions, missing laboratory tests, missing evaluations, missing conditioning logs, missing diaries
  • Monitoring Visit Reports - inc0mplete and inaccurate subject CRF
  • Monitoring Visit Reports - inaccurate, missing subject notes, copies of evaluations and exams.

The monitoring reports were noted to lack documentation for corrections and/or clarifications for the cited omissions. Immediate response from the pharmaceutical sponsor is required and expected. Within 15 working days of receiving such warning letters from FDA, it is required and expected that the pharmaceutical sponsor provide written documentation of actions taken, or to be taken to correct violations and prevent the recurrence of similar violations in current or future studies for which the pharmaceutical sponsor is involved. A corrective action plan must be submitted. The plan must be comprehensive and include projected dates of completion for each corrective action. Failure to comply and response is not recommended.

Monitor, monitor, monitor. QC data and documentation. QC process, GCP and compliance. QC SOPs and implementation at each investigation site. Review regulatory requirements,

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