Preparing for FDA BIMO Inspections

An industry expert shares tips and useful data for developing a quality-systems approach for conducting medical device clinical trials.

Susan M. Rockwell

Over the past five years, the FDA’s Division of Bioresearch Monitoring (BIMO), in the Office of Compliance at the Center for Devices and Radiological Health (CDRH), has conducted, on average, 325 to 350 inspections of medical device clinical trials each year. These inspections mainly are divided among the clinical investigators, the Institutional Review Boards (IRBs), and the medical device sponsors.

Typically, half of all BIMO inspections occur at the clinical investigational site, with the rest split between the medical device sponsors and the IRBs. A small number of inspections also occur each year at clinical laboratories.

The most important step in preparing for an FDA BIMO inspection is to develop a quality systems approach for conducting medical device clinical trials.

Inspections may occur during an active investigation (Surveillance Inspections) or at the time of a regulatory submission (Directed Inspections), pre-clearance or pre-approval. In addition, For Cause Inspections may occur at any time during the clinical trial process, in response to a complaint against the sponsor or clinical investigator.
   
Because FDA’s BIMO inspections can occur at any time during the clinical trial, it is imperative for medical device sponsors to be prepared from the very beginning. The first—and most important—step in preparing for an FDA BIMO inspection is to develop a quality-systems approach for conducting medical device clinical trials.

The agency’s BIMO division has outlined four ongoing global issues for the medical device industry to focus on (based on CDRH Compliance Actions and Inspectional Data, 2006):

• Systems to identify and/or address regulatory shortcomings
• Systems to correct and/or prevent recurring issues
• Accountable company culture
• Environment of conflict of interest

All medical device sponsors should have standard operating procedures (SOPs) in place for clinical trial functions, in order to provide internal systems for quality and consistency as part of an ongoing quality plan. If a sponsor outsources any clinical trial functions to a clincal research organization (CRO) or to a consultant, it is the sponsor’s responsibility to obtain SOPs from the subcontractor for those specific functions. The FDA typically does not inspect third parties. Instead, the agency will hold the sponsors responsible, which leads to higher numbers of deficiencies and higher noncompliance rates.

As part of a company’s quality plan, there should be systems in place to correct or prevent recurring issues.



Listed in Table 1 (above) are some of the most prevalent reported sponsor deficiencies over an eight-year period of FDA BIMO inspections.

In addition to the four deficiencies listed in Table 1, BIMO inspectors also reported the following sponsor deficiencies in 2007:

• Failure to submit Progress Reports (36%)
• Inadequate unanticipated adverse device effects analysis & reporting (27%)
• Failure to inform investigators (21%)
• Failure to obtain signed Investigator Agreement (15%)
• Unqualified monitors (12%)

In providing a corporate culture of accountability, medical device companies need to adopt better controls, and clinical trial sponsors need to be more responsive to inappropriate activities or behaviors that are identified during the course of the clinical trial. Listed in Table 2  are deficiencies that clinical investigators have reported during the past eight-year period of BIMO inspections.



In addition to the five deficiences  shown in Table 1 and Table 2, there needs to be more ownership by company officials or stakeholders in positions of authority—either within a medical device company or at a clinical investigational site. Although noncompliance rates had been improving steadily for sponsors during the past few years, noncompliance rates jumped significantly in 2007. Although the increase in noncompliance rates could be an anomaly, the FDA believes it may be due to an increase in For Cause Inspections at sponsor companies. For Cause Inspections, conducted as a follow-up to a complaint, typically find serious deficiencies or departures from the regulations. Ignoring serious deficiencies, or not taking ownership of these problems, can result in a laundry list of regulatory and administrative actions, including:

• Warning letter
• Re-inspection
• Rejection of study data
• Investigational device exemption termination or withdrawal of premarket approval application
• Disqualification of clinical investigators or IRBs
• Civil money penalties
• Prosecution

Medical device companies long have recognized that there is an environment of potential conflict of interest persistent in clinical research. Areas of conflict may include the following: There may be multiple intellectual property holders for a particular device technology or even a specific surgical technique: and institutions may be financially vested with patents and licensing issues. In addition, clinical investigators must accurately disclose financial incentives provided by medical device sponsors. Incomplete disclosure can lead to possible delays in product approval or even nonapproval.

• Medical device clinical trial sponsors need to promote a quality-system approach to the conduct of their clinical trials:
• Creating SOPs for clinical study functions
• Hiring employees with experience in conducting clinical studies
• Training employees, contractors, and clinical investigators appropriately and holding them accountable
• Conducting internal audits of clinical processes and procedures
• Increasing senior management oversight of clinical study progress

By addressing these key issues, both the sponsor and the clinical investigator(s) would be better prepared for an FDA BIMO inspection.

Susan M. Rockwell is the associate director of Clinical Development at Medical Device Consultants, Inc., n North Attleboro, MA. She has more than 25 years of experience in clinical and healthcare research. Since joining MDCI in 1988, she has held positions of clinical research associate (CRA), senior CRA, project manager, clinical trials manager, and manager of clinical trials and clinical development. Prior to joining MDCI, she coordinated cardiovascular drug trials at Boston University Medical Center and managed healthcare programs at the American Heart Association, Massachusetts Affiliate. Susan is an active member of the Association of Clinical Research Professionals (ACRP), where she currently serves on the Global Conference Planning Committee and the Device Forum Steering Committee. She is a past member of the ACRP Board of Trustees, a past chair of the Editorial Advisory Board, and a past chair of the Device Forum. Susan holds a M.Ed in Health Education from Boston University and a BA in Biology from the University of Virginia. She can be reached at [email protected].