GCP Compliance Strategies for 2009 - Medical Device Industry

For Medical Device


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.

CDER has sharply increased the number of Warning Letters issued from previous years.

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:

  • CDRH continues to be the most enforcement minded of the three FDA Centers, but the violation rate for sponsor inspections for the most serious inspection classification (OAI Official Action Indicated) has receded from the record 33% in FY-2007.
  • CDER has sharply increased the number of warning letters issued from previous years.
  • Two of FDA's 20 district offices accounted for 27% of the Bimo warning letters issued.


This Center historically issues the most Bimo Warning Letters. It also issues the most inspection assignments for sponsors of clinical trials. Both CDER and CBER focus primarily on clinical investigator sites. There are four primary reasons that CDRH focuses on both sponsors and clinical investigators.

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.


In fiscal years 2004-2005, CDER did not issue a single warning letter to clinical investigators3. This is despite CDER historically issuing over 300 clinical investigator inspections per year. Then, in FY-2008, CDER issued 13 warning letters to clinical investigators. This corresponds to an increase of FDA resources and changes in management.

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.


This FDA Center conducts approximately 10% of the FDA Bimo inspections and is the smallest of the three Centers that have issued warning letters for clinical trials. However, some of the CBER regulated trials are vaccine studies involving thousands of subjects. Frequently the subjects are children, giving their inspections increased importance.

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


The Office of Regulatory Affairs spent the last nine months recruiting and training new CSOs to conduct inspections. Each of the 20 ORA District Offices has its own unique approach to the Bimo program, which consists of less than 5% of ORA's workplan (remember the "F" in FDA stands for food, the largest inspection program). In addition, the compliance determination for Bimo inspections takes place at FDA Centers, not in the District Office. Most FDA inspections are evaluated and classified by the ORA District Compliance Branch.

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.

What You Can Do

FDA managers stress five basic steps a sponsor can take to improve GCP compliance:
  1. Follow the GCPs and keep current with FDA Guidance Documents. If your study is a device study, follow the device regulations found in Part 812.
  2. Develop clinical SOPs and written procedures. This is particularly important for medical device monitoring plans.
  3. Monitor the data lifecycle. Put quality systems into place before the start of the trial.
  4. Conduct internal audits. Audit schedules should be conducted throughout the data lifecycle.
  5. Implement corrective and preventative action (CAPA). Correcting deficiencies is far more important than notations in a memo to file.


FDA has increased resources for conducting Bimo inspections. This, coupled with a significant change in the enforcement climate, indicates that sponsors need to renew their focus on quality systems to conduct clinical trials that will bring the benefits of new products to the market. This makes a thorough review of clinical quality assurance activities critical in 2009.


* The analysis of FY-Warning Letters was performed by the author in October 2008 in preparation for the FDAnews 2008 FDA Inspections Summit held in Bethesda,MD. It is not an official FDA analysis and additional FY-2008 Warning Letters will be posted as they are issued.1. FDA Press Release, "FDA Embarks on Major Hiring Initiative for its Public Health Mission," April 30, 20082. Anderson, C. "Trends in FDA Bioresearch Monitoring Inspections," Medical Devices Law & Industry Report, Vol. 2, No. 4, 02/27/2008.3. Presentation to the 2007 Annual Meeting of the Society of Quality Assurance by Matthew Thomas, CDER4. Anderson, C. "FDA Draft Guidance Contains Recommendations to Aid Compliance by Clinical Investigators and Sponsors Supervising Clinical Trials," Medical Research Law & Policy Report, Vol. 07, No. 06, 03/19/2008.

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 carl11anderson@yahoo.com.

Read More

FDA Link

Compliance Program Guidance Manual for FDA Staff

Additional Article

Marcarelli, Michael. "Gleaning Good Practices from Warning Letters." November 2008, MedicalDeviceLink.com. Accessed 1-12-09. http://www.devicelink.com/mddi/archive/08/11/007.html