Breaking Down BIMOMay 13, 2015
By James E. Valentine* –
In late April 2015, FDA’s Bioresearch Monitoring (“BIMO”) Program released its annual report on inspections from the previous fiscal year. BIMO is FDA’s multi-center compliance program for on-site inspections and data audits to monitor all aspects of FDA-regulated research, domestically and abroad. The BIMO Program assesses sponsor, investigator, and institutional review board (“IRB”) compliance with FDA regulations governing the conduct of clinical trials. The program also verifies the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications. The most common FDA enforcement activity concerning potential violations that FDA has documented during BIMO inspections is the issuance of Warning Letters. Here are the trends and highlights of BIMO’s activities in 2014.
In FY 2014, there was a modest 8% increase in the total number of BIMO inspections from FY 2013, up from 1,224 to 1,326 inspections. Table 1 provides a breakdown of the number of inspections conducted by Center. Both the Center for Biologics Evaluation and Research (“CBER”) and the Center for Drug Evaluation and Research (“CDER”) saw increases of greater than 15% from the previous year; the Center for Food Safety and Applied Nutrition (“CFSAN”) also conducted its first BIMO inspections since reorganizing the program. Meanwhile, the Center for Devices and Radiological Health (“CDRH”) had a modest decrease in BIMO inspections, and the Center for Veterinary Medicine (“CVM”) has less than half as many inspections.
Table 1. BIMO Inspections by Center: FY 2013 vs. FY 2014
*CFSAN’s BIMO program was under reorganization in FY 2013.
The BIMO program conducts inspections of clinical investigators, IRBs, sponsors, monitors, contract research organizations (“CROs”), Good Laboratory Practices (“GLPs”), and bioequivalence. In FY 2014, FDA had a marked increase in inspections of clinical investigators, increasing by 139, or about 20%. This increase is consistent with FDA’s renewed focus on clinical quality and data integrity at clinical trial sites. There was also an increase in the number of inspections of sponsors, monitors, and CROs. On the other hand, IRB, GLP, and bioequivalence inspections all decreased from FY 2013. See Table 2 for a breakdown of the number of inspections by category.
Table 2. BIMO Inspections by Category: FY 2013 vs. FY 2014
Across the board, the most common deficiencies for each category remained nearly the same from FY 2013 to FY 2014. A list of the most common deficiencies by category can be found in the annual report. In addition, the proportions of inspections classified as No Action Indicated (“NAI”), Voluntary Action Indicated (“VAI”), or Official Action Indicated (“OAI”) remained similar in FY 2014. In most inspectional categories, there appeared to be a slight decrease in OAIs and a corresponding increase in VAI and/or NAI classifications. The exception was GLP inspections, which saw a 23% decrease in NAI classifications, an 18% increase in VAI classifications, and a 5% increase in OAI classifications.
International BIMO inspections, while small in number compared to domestic inspections, also saw a modest increase from FY 2013 to FY 2015. Table 3 provides a breakdown of the number of international inspections conducted by Center. CDER and CDRH conducted slightly more inspections in FY 2014, while CBER conducted essentially the same number of inspections.
Table 3. BIMO International Inspections by Center: FY 2013 vs. FY 2014
In calendar year 2014, FDA issued 12 warning letters citing violations related to the conduct of FDA-related research (violations of 21 C.F.R. Part 312 Subpart D, 21 CFR Part 50, and/or 21 CFR Part 56). Eight warning letters were sent to clinical investigators, three to sponsors/monitors/CROs, and one to an IRB. Generally, the cited violations included failure to comply with study protocol requirements, or to keep appropriate records. Table 4 provides a breakdown of the violations cited in these 12 warning letters, as well as examples of the type of activities cited to justify the violation.
Table 4. Warning Letters Citing Violations Relating to FDA-Regulated Clinical Research: CY 2014
Failure to ensure that the investigation was conducted according to the investigational plan pursuant to 21 C.F.R. 312.60.
Failure to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation pursuant to 21 CFR 312.62(b).
Failure to retain records required to be maintained under 21 CFR Part 312 for a period of two years following the date a marketing application is approved for the drug for the indication for which the drug is being investigated; or, if no application is filed or if the application is not approved for such indication, until two years after the investigation is discontinued pursuant to21 C.F.R. 312.62(c).
Failure to protect the rights, safety, and welfare of subjects under your care pursuant to 21 C.F.R. 312.60.
Failure to obtain informed consent in accordance with the provision of 21 C.F.R. part 50 pursuant to 21 C.F.R. 312.60 and 21 C.F.R. 50.20.
Failure to personally conduct or supervise clinical investigators pursuant to 21 C.F.R. 312.60; failure to ensure proper monitoring of the investigation pursuant to 21 C.F.R.
Failure to take adequate precautions to prevent theft or diversion of an investigational drug that is subject to the Controlled Substances Act pursuant to 21 C.F.R. 312.69.
Failure to assure that an IRB that complies with the requirements set forth in 21 C.F.R. part 56 was responsible for the initial and continuing review and approval of the proposed clinical study pursuant to 21 C.F.R. 312.66.
Failure to ensure proper monitoring of the investigation and failure to ensure that the investigation is conducted in accordance with the general investigational plan and protocols contained in the IND pursuant to 21 C.F.R. 312.50 and 312.56(a).
Failure to ensure that the requirements for obtaining informed consent were met pursuant to 21 C.F.R. 50.20, 50.25(a)(4), and 50.27(a).
Failure to subject an IND application for the conduct of clinical investigations with an investigational new drug that is subject to 21 C.F.R. 312.2(a) pursuant to 21 C.F.R. 312.20(a) and 312.40(a).
Failure to maintain adequate records showing the receipt, shipment, or other disposition of the investigational drug pursuant to 21 C.F.R. 312.57(a).
Institutional Review Boards
Failure to have adequate written procedures governing the functions and operations of the IRB pursuant to 21 C.F.R. 56.115(a)(6).
Failure to require that information given to subjects as part of informed consent is in accordance with 21 C.F.R. 50.25 pursuant to 21 C.F.R. 56.109(b).
Failure to prepare and maintain adequate documentation of IRB activities pursuant to 21 C.F.R. 56.115(a)(1), (a)(2), and (a)(4).
Failure to ensure that no IRB member participated in the IRB’s initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB pursuant to 21 C.F.R. 56.107(e).
* Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.