Breaking Down BIMO

May 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.

Domestic Inspections

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

Center

FY’13

FY’14

Change

CBER

104

121

+ 16%

CDER

729

865

+ 18%

CDRH

332

313

– 6%

CFSAN

0*

2

+ 200%

CVM

59

25

– 58%

Totals

1224

1326

+ 8%

*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

 

FY’13

FY’14

Change

Clinical Investigator

664

803

+ 20%

IRB

174

152

– 13%

Sponsor/Monitor/CRO

120

138

+ 15%

GLPs

61

43

– 30%

Bioequivalence

205

190

– 7%

Total

1224

1326

+ 8%

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 Inspections

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 

Center

FY’13

FY’14

Change

CBER

24

23

– 4%

CDER

202

214

+ 6%

CDRH

12

18

+ 50%

Total

246

255

+ 4%

Enforcement Actions

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

Violation

Examples Cited

Clinical Investigators

Failure to ensure that the investigation was conducted according to the investigational plan pursuant to 21 C.F.R. 312.60.

  • Failure to perform certain study procedures, such as physical examinations, bone scans, and specified laboratory tests, at specific times.
  • Failing to properly screen subjects to ensure they were eligible for study protocols.
  • Failing to adjust the dose of study drug within the timeframe specified.
  • SOPs conflicting with directions contained in study protocols.
  • Study staff recording the primary efficacy endpoint when the protocol specified subjects should self-record.
  • Improper dose correction to the eligible dose regimen after screening of study subject, rather than prior to screening as prescribed.
  • Study visits occurring outside of the specified timeframe.
  • Increasing dose of study drug when not prescribed.
  • Taking subject PK blood samples at the same visit as study drug administration, when it is specified that samples are to be taken 2 days after receiving study drug.
  • Failing to report all SAEs to the sponsor within 24 hours, the timeframe specified in the protocol.
  • Failing to perform laboratory assessments at rescue visits as specified.
  • Failing to collect all unused medication from subjects as specified.
  • Conflicts between the dosing log and Progress Note Addendum as to whether subjects received appropriate dosing. 
  • Failing to hold or adjust the dose of the investigational drug in managing specific drug-related adverse events.
  • Failing to follow specific procedures for reporting adverse events.
  • Failing to complete hypersensitivity assessment forms as prescribed.
  • Not excluding family members of study staff personnel from enrolling as subjects as prescribed.

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).

  • Changing determination of lab results from “not clinically significant” to “clinically significant” almost three years later with no explanation for the change.
  • Signed and dated hypersensitivity assessment forms missing subject identification or any other information with regard to hypersensitivity signs and symptoms.
  • Changing determination of adverse event from “yes” for possibly drug related to “no” three years later with no explanation for the change.
  • Discrepancies in Source Document Worksheet as to whether a subject a fundoscopy exam was performed.
  • Documents with late entries and/or undated entries.
  • Failure to record subjects’ consent to optional studies in the subjects’ study registration forms.
  • Discrepancies as to informed consent in two versions of the same document.
  • Signs and symptoms of hypersensitivity were not recorded on the hypersensitivity assessment forms for certain subjects.
  • Missing records, including completed hypersensitivity assessments forms, telemetry records, and electrocardiograms.

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). 

  • Not retaining records of the disposition of the drug, including dates, quantity, and use by subjects.
  • Not retaining adequate and accurate case histories, including signed and dated informed consent forms, case report forms, and all supporting data.

Failure to protect the rights, safety, and welfare of subjects under your care pursuant to 21 C.F.R. 312.60.

  • Failing to ensure diabetic subjects who were experiencing persistent hyperglycemia received a timely rescue treatment.
  • Failing to ensure that subjects received the correct dose of the investigational drug.

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.

  • Failing to obtain informed consent from subjects who were enrolled.
  • Enrolling subjects and giving them investigational drug before each signed the informed consent document.

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.

  • Failing to adequately supervise individuals to whom she delegated study tasks, leading to the other violations cited in the letter.

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. 

  • Failing to store a Schedule II controlled substance in a securely locked enclosure, resulting in approximately 900 tablets being stolen from the investigator’s site.

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.

  • Enrolling subjects during a lapsed period in the IRB approval.

Sponsors

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).

  • Failing to identify and correct the clinical investigator’s failure to obtain informed consent for enrolled subjects.
  • Not identifying and correcting a clinical investigator’s failure to ensure that an IRB reviews and approves a proposed clinical investigation.
  • Failing to ensure that the investigation was conducted in accordance with the investigational plan, including a clinical investigator’s failure to administer the correct dose and failure to collect study subjects’ data on protocol-specific case report forms.

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).

  • The “Alternatives” section of the informed consent form was inadequate, not sharing availability of appropriate alternative procedures.
  • The informed consent forms used were not submitted to and approved by an IRB.
  • Informed consent forms contained impermissible exculpatory language.

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).

  • Conducting a clinical investigation before submitting an IND.

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).

  • Not maintaining any records showing the shipment or other disposition of the investigational drug.

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).

  • Procedures manual lacked written procedures for certain IRB activities.

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).

  • Approving an informed consent document that did not include required information, including the purpose of the research, the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures that were experimental.

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).

  • Failing to maintain:
    • copies of the original protocol that was reviewed during a convened IRB meeting;
    • meeting minutes in sufficient detail to show the votes on actions for convened IRB meetings;
    • documentation of a discussion held between the IRB Chairman and the clinical investigator pertaining to the closing of the study.

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).

  • Failing to ensure that IRB members with conflicting interests in the project being reviewed do not participate.

* Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.