The FDA press release dated April 30, 2008 should have caught the eye of every regulatory affairs and quality assurance professional responsible for compliance to the FDA. "FDA Embarks on Major Hiring Initiative for its Public Health Mission" the press release blared. "Agency will fill more than 1,300 positions within the next several months," it continued. That is more than triple the number of positions the agency filled in fiscal years 2005-20071.
In the subsequent months after the press release, managers at the FDA Centers in Montgomery County Maryland (Center for Drug Evaluation and Research (CDER); Center for Devices and Radiological Health (CDRH); and Center for Biological Research and Evaluation) as well additional regulatory professional at field offices around the country (e.g., in the Office of Regulatory Affairs (ORA)) have interviewed thousands of applicants for the next generation of FDA officials.
These include hundreds of new Consumer Safety Officers (i.e., CSOs or the FDA's field investigators) to staff ORA's 200 district offices, resident posts, and newly created FDA overseas offices. Increased public and Congressional concerns over the safety of food, drugs and medical devices have led to increased scrutiny and enforcement actions. A look at FDA warning letters issued in FY-2008 by the FDA Bioresearch Monitoring Program shows the direction that FDA is heading in 2009.
On September 30, 2008 the FDA website listed 44 warning letters for the Bioresearch Monitoring (Bimo) Program's GCP inspection programs. These include inspections of clinical investigators, sponsors/CROs, and institutional review boards (IRBs). The federal fiscal year ends on September 30 and FDA maintains warning letters on their website for one year*. A review of these warning letters sheds light on three new developments:
The first is the nature of the medical device industry. Most of the industry's sponsors of clinical trials are small companies. In fact, 89% of the nearly 15,000 medical device manufacturers had fewer than 60 employees2. Smaller firms have fewer resources to devote to the quality systems necessary for conducting GCP compliant clinical trials.
Second, approximately 70% of FDA's Bimo inspections are conducted for drug- or biologics-related trials. The GCP regulations for these studies are found in 21 CFR 312, the Investigational New Drug (IND) application regulations. Medical device studies fall under 21 CFR 812, the Investigational Device Exemption (IDE) regulations. Many research professionals and CROs are more familiar with Part 312 and are unaware of the differences. One important difference is that Part 812 requires sponsors to have a written monitoring plan. The failure to do so will result in a warning letter.
Third, medical device sponsors are required to make a determination of "significant risk," requiring an IDE, or "non-significant risk," which doesn't. Making the wrong determination also results in a warning letter.
Finally, there is a smaller body of knowledge in the medical device industry than the biopharmaceutical industry regarding FDA inspections. Because 70% of the inspections use the IND regulations, there is more experience in results and expectations, leading to increased compliance.
CDER also issues warning letters to sponsors of clinical research. In a warning letter dated October 27, 2007 CDER charged: "Failure to Secure Investigator Compliance" and "Failure to Ensure Proper Monitoring" although the sponsor had transferred responsibilities to a CRO. This tells us that FDA ultimately holds the sponsor responsible for serious violations. In fact, CRO inspections are a rare occurrence even though they are officially part of the Bimo program.
An important area of concern for CBER is the appropriate delegation of authority and supervision at clinical sites. Some studies include the use of sub-investigators at remote clinical sites, sometimes in different states than the study's principal investigator. For that reason CBER points to the recent draft guidance document, Supervisory Responsibilities of Investigators, as a resource for the protection of subjects in CBER regulated research4. The guidance is found at: http://www.fda.gov/OHRMS/DOCKETS/98fr/07d-0173-gdl0001.pdf
For this reason, many ORA districts don't emphasize the Bimo program. However, several District Offices give the Bimo program the same high level of emphasis as other programs. The Florida District Office and the Cincinnati District Office (comprising the state of Ohio) conducted Bimo inspections that resulted in 27% of the Bimo Warning Letters issued in FY-2008. The Cincinnati office was also a top performer in FY-2007. Industry has long complained of different inspection approaches in different parts of the country. The culture-specific districts may have some influence on this.
Carl Anderson is a Tacoma, WA based regulatory affairs and quality assurance consultant in the field of FDA health product approvals including drugs, biologics, and medical devices. From 1987 to 2005 he worked for the United States Food and Drug Administration. In 1994 he began conducting inspections in the Bioresearch Monitoring program and inspected clinical investigators, institutional review boards, nonclinical laboratories, and sponsors of clinical research.
Anderson's experience also includes postmarketing surveillance of adverse drug experiences and good manufacturing practice of drug products. He was on the FDA's international inspection cadre and has conducted audits and inspections in Canada, Europe, the Middle East, and East Asia. Since leaving FDA he has focused on assisting clinical trial sponsors develop clinical quality assurance systems and preparing sponsors and clinical sites for FDA Bioresearch Monitoring inspections.
Anderson has made frequent public presentations on good clinical practice, quality assurance, and FDA regulations to professional and industry organizations including the Society of Quality Assurance, Drug Information Association, Regulatory Affairs Professional Society, and Association for Clinical Research Professionals. He also conducts training for private industry as well as public agencies such as the Centers for Disease Control and Prevention (CDC) and university extension services.
Anderson may be reached by phone at 253-307-6513 or via email at email@example.com.
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