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The Food and Drug Administration (FDA) is providing a progress report on the agency's Human Subject Protection (HSP)/Bioresearch Monitoring (BIMO) Initiative.1 Launched in 2006 as a part of the Critical Path Initiative,2 the HSP/BIMO Initiative is aimed at modernizing and strengthening the agency's oversight and protection of subjects in clinical trials and the integrity of resulting data. The HSP/BIMO Initiative encompasses all FDA-regulated clinical trials, that is, those related to human drugs and biological drug products, devices, foods, and veterinary medicine. The overarching goals of the agency's BIMO program are to protect the rights, safety, and welfare of subjects involved in FDA-regulated clinical trials; to determine the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications; and to assess compliance with FDA's regulations governing the conduct of clinical trials, including those for informed consent and ethical review.
After performing an inventory of its programs, FDA engaged the participation of internal and external stakeholders, conducted workshops, and created other opportunities for public input. During the past two years, the agency has been working diligently to develop and issue new regulations and guidance to further improve the conduct of clinical trials and enhance the protection of participating human subjects. Some of these documents are addressed to study sponsors, clinical investigators, and institutional review boards; others focus on FDA's internal procedures and oversight activities. The agency has also revamped its processes for taking regulatory actions against clinical investigators who repeatedly or deliberately fail to comply with FDA's regulations governing the conduct of clinical trials. Discussed below are the major accomplishments to date.
New Regulations
New Guidance
Improvements to FDA's Internal Procedures
FDA established an internal task force to ensure that all pending and future recommendations related to the agency's oversight of clinical trials raised by Congress, the HHS Office of the Inspector General (OIG)10 and the General Accounting Office (GAO) are fully addressed. As recommended, FDA established procedures to enhance communication between its field and headquarters staff, developed criteria for initiating certain regulatory actions, and provided additional training to its staff in a number of areas. Specifically, FDA:
While FDA has already implemented a number of changes to its clinical trial oversight activities, the agency continues to look for new approaches to these responsibilities. The agency has been striving to implement a quality systems approach that will provide for continuous process improvements, thus building quality into the clinical trial upfront rather than assessing it at trial completion. To further this effort, FDA co-sponsored two public meetings where in-depth discussions of quality systems in clinical trials were held.
Clinical Trial Transformation Initiative (CTTI)14
Recognizing the need to modernize the clinical trials enterprise, FDA and Duke University formed a public-private partnership that aims to identify practices that through broad adoption will increase the quality and efficiency of clinical trials. CTTI includes representation from government, industry, patient advocacy groups, professional societies, and academia. Current projects include the assessment of various clinical trial monitoring methods to assist sponsors in selecting the most appropriate techniques for a specific trial and development of “best practices” for analyzing and reporting results of clinical trials.
International harmonization, capacity-building, and outreach activities
Guidance in Development
Modernizing our Regulations
At the direction of the HSP/BIMO Council, FDA convened a working group to discuss the need for updating the agency's Good Laboratory Practice for Nonclinical Laboratory Studies regulation (21 CFR Part 58) to better reflect current practices. This agency-wide working group, which includes representatives from the Center BIMO programs, the National Center for Toxicological Research, ORA, and the Office of the Commissioner, has conducted a thorough review of the regulation, discussed stakeholder input, and will soon present its suggestions for modernizing the regulation to the HSP/BIMO Council.
Each year, FDA's field staff conduct on-site inspections of BIMO facilities, including sponsors, monitors, clinical investigators, IRBs, and laboratories that conduct nonclinical safety studies (including animal toxicity studies) to support FDA-regulated research. The agency performs these inspections to evaluate the inspected party's practices and procedures to determine compliance with applicable regulations. FDA has generally conducted the majority of its BIMO inspections in association with the submission of a marketing application or as a part of its investigation of a complaint. Recently, the agency has been shifting more of its resources to inspections of ongoing studies. This will allow the agency to identify potential problems while the study is still going on, thus enabling the implementation of corrective actions to minimize risks to human subjects and preserve the integrity of the clinical trial. FDA has also been improving its follow-up of violative inspections and working to identify alternative methods to select clinical investigator sites for inspection, such as risk-based approaches and using statistical evaluations to identify sites of interest.
Summary information about FDA's domestic inspectional activities for fiscal year 2008 is presented in the following:.
Figure 1
Figure 1 depicts the total number of inspections that were completed by the Office of Regulatory Affairs' field investigators as well as the numbers completed for each of the assigning Centers. (BEQ denotes bioequivalence studies.)
Figure 2
Figure 2 depicts the compliance classification of Establishment Inspection Reports (EIRs) for inspections of clinical investigators that were classified by the assigning Center in FY 2008. (NAI denotes No Action Indicated, VAI denotes Voluntary Action Indicated, and OAI denotes Official Action Indicated.)
Figure 3
Figure 3 depicts the compliance classification of EIRs for inspections of IRBs that were classified by the assigning Center in FY 2008.
Figure 4
Figure 4 depicts the compliance classification of EIRs for inspections of sponsors that were classified by the assigning Center in FY 2008.
Figure 5
Figure 5 depicts the compliance classification of EIRs for inspections of bioequivalence studies that were classified in FY 2008.
1 The HSP/BIMO Council, which is overseeing this initiative, includes representatives from each of FDA's Centers, the Office of Regulatory Affairs (ORA), and the Office of the Commissioner (OC).
2 www.fda.gov/bbs/topics/NEWS/2006/NEW01396.html
3 http://edocket.access.gpo.gov/2009/E9-682.htm
4www.regulations.gov/fdmspublic/component/main?main=DocumentDetail&o=0900006480537f08
5 www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2007-D-0202-gdl.pdf
6 www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0576-gdl.pdf
7 www.fda.gov/cdrh/ode/guidance/1668.html
8 www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0406-gdl.pdf
9 www.fda.gov/OHRMS/DOCKETS/98fr/04d-0440-gdl0002.pdf
10 Examples of recent OIG reports include FDA Oversight of Clinical Investigators (June 2000; www.oig.hhs.gov/oei/reports/oei-05-99-00350.pdf ); The Food and Drug Administration's Oversight of Clinical Trials (September 2007, www.oig.hhs.gov/oei/reports/oei-01-06-00160.pdf ); FDA's Oversight of Clinical Investigators' Financial Information (January 2009, www.oig.hhs.gov/oei/reports/oei-05-07-00730.pdf ).
11 www.fda.gov/ora/compliance_ref/bimo/7348_811/default.htm
12 www.fda.gov/ora/compliance_ref/rpm/
13 www.fda.gov/smg/vol4/7000/7711.html
14 www.trialstransformation.org
15 For example, Pan American Health Organization's GCP Working Group.
16 Examples include Asia Pacific Economic Cooperation, Bangkok, May 2008; India, September 2008 and May-June 2009; Multinational Clinical Trial Symposium for Middle East/North African States, Jordan, October 2008.
17 Draft guidance is available at:: www.fda.gov/OHRMS/DOCKETS/98fr/07d-0173-gdl0001.pdf
18 Draft guidance is available at:: www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0406-gdl.pdf
19 Draft guidance is available at: www.fda.gov/oc/ohrt/irbs/review.html
20 Draft guidance is available at:: www.fda.gov/OHRMS/DOCKETS/98fr/06d-0331-gdl0001.pdf