Department of Health and Human Services
 
OFFICE OF 

   
INSPECTOR GENERAL 

 
 
 
 
 
 
 
 
TH  E FOOD AND DRUG 

 
A  O
DMINISTRATION S  VERSIGHT 

 
 
C T  
OF  LINICAL  RIALS 

 
 
 
 
 
 
Daniel R. Levinson 
  
Inspector General 

 
September 2007 
 
OEI-01-06-00160 
   
 
 
Office of Inspector General

http://oig.hhs.gov  
 
The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452,  
as amended, is to  protect the integrity of  the Department of Health and Human Services 
(HHS)  programs, as well as the health and welfare of beneficiaries  served by those 
programs.  This statutory mission  is  carried  out through  a nationwide network  of  audits, 
investigations, and inspections conducted by the  following operating components:  
Office of Audit Services 
The Office of Audit Services (OAS) provides all auditing services  for HHS, either by  
conducting audits with its  own audit resources or by overseeing audit work done by others.   
Audits examine the performance of HHS programs and/or its grantees and  contractors  
in carrying out  their respective responsibilities and are intended  to provide independent  
assessments of  HHS programs and operations.  These assessments help reduce waste, 
abuse, and mismanagement  and  promote economy and  efficiency throughout HHS. 
Office of Evaluation and Inspections  
The Office  of  Evaluation and Inspections (OEI)  conducts national evaluations to  provide 
HHS, Congress, and the public with timely, useful, and reliable information on 
significant issues.  Specifically, these evaluations focus on preventing fraud,  waste,  or  
abuse and promoting  economy, efficiency, and effectiveness  in departmental programs.  
To promote impact, the reports also present practical recommendations for improving 
program operations.  
Office of Investigations 
The Office of Investigations (OI) conducts criminal, civil, and administrative  
investigations  of  allegations of wrongdoing  in HHS  programs or to HHS  beneficiaries  
and of unjust enrichment by  providers.  The investigative  efforts  of OI lead to  criminal  
convictions, administrative sanctions,  or  civil monetary penalties.  
Office of Counsel to the Inspector General 
The  Office of Counsel to the Inspector General (OCIG)  provides  general legal services  to  
OIG, rendering  advice and opinions on HHS programs and operations and  providing all  
legal support in OIG's internal operations.   OCIG imposes program exclusions and civil 
monetary penalties  on health care providers and litigates  those actions  within HHS.   
OCIG also  represents OIG in the global settlement of  cases  arising under the Civil False 
Claims Act, develops and monitors corporate integrity agreements, develops compliance 
program guidances, renders advisory opinions on OIG sanctions to  the health care  
community,  and issues fraud alerts  and other industry  guidance.  
   
   
I N T R O D U C T I O N  
  E X E C U T I V E   S U M M A R Y  
OBJECTIVE 
 
1. 	  To determine the extent to which the Food and Drug Administration 
(FDA) conducted inspections of clinical trials from fiscal year       
(FY) 2000 to FY 2005. 
2. 	  To assess FDAs processes for inspecting clinical trials. 
BACKGROUND 
The Federal Food, Drug, and Cosmetic Act generally requires all new 
drugs and medical devices (hereinafter referred to as investigational 
products) to undergo clinical trials on human subjects to demonstrate 
the safety and efficacy of these products before they are approved for 
sale in the  United States.  The sponsors, clinical investigators, and 
institutional review boards (IRBs) that conduct and oversee these trials 
must comply with FDA regulations designed to protect the human 
subjects participating in them.  The Office of Inspector General (OIG) 
received a congressional request to review FDA  oversight of clinical 
trials after a series of news articles highlighted vulnerabilities. 
Three FDA centers regulate medical  investigational products for human 
use:  the Center for Drug Evaluation and Research, the Center for 
Biologics Evaluation and Research,  and the Center for Devices and  
Radiological Health.  FDAs Office of  Regulatory Affairs (ORA) conducts 
onsite bioresearch monitoring (BiMo) inspections of sponsors, clinical 
investigators, and IRBs as assigned by the centers. 
BiMo inspections are not required by Federal regulations; the centers 
decide when to assign them.  Inspections can result in one of three  
classifications: no action indicated (NAI), voluntary action indicated 
(VAI), or official action indicated (OAI).  After the inspection, BiMo  
investigators recommend a classification for the inspection, and the 
assigning center reviews the inspection report and assigns a final 
classification. Although FDA takes no additional action for inspections 
classified as NAI, it may take additional action for VAI and OAI 
inspections. 
We used seven data sources for this study:  BiMo inspections data; file 
reviews of all inspections that BiMo investigators or a center  classified  
as OAI; an e-mail survey of BiMo investigators; interviews with FDA 
officials; observations of BiMo inspections; analysis of the National 
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E X E C U T I V E   S U M M A R Y   
Institutes of Health (NIH) clinical trial registry; and reviews of FDA 
policies, procedures, and guidance documents. 
FINDINGS 
Data limitations inhibit FDAs ability  to effectively manage the BiMo 
program.  Because  FDA does not maintain a clinical trial registry, it is 
unable to identify all ongoing clinical trials and their associated trial sites.  
Further, because FDA does not maintain an IRB registry, it is unable to  
identify all IRBs.   Even though FDA maintains six databases to track 
BiMo inspections, none includes complete information needed to track all 
such inspections.  For example, ORAs database does not include complete 
information for inspection events that occur after it completes its 
inspection. The center databases do not consistently track inspection 
information. 
Other factors hinder FDAs ability  to effectively  manage the BiMo 
program.  Centers and ORA inconsistently classify OAI and NAI 
inspections.  FDA relies on voluntary compliance to correct violations of  
regulatory  significance.  Uncertainty of timing and lack of coordination 
impede FDAs ability to conduct BiMo inspections.  In addition, FDA 
guidance and regulations do not reflect current clinical trials practices.    
We estimate that FDA  inspected 1 percent of clinical trial sites 
during the  fiscal year 20002005  period.  FDA conducted 2,856 BiMo 
inspections that required a clinical trial site visit during the                 
FY 20002005 period.  Because FDA cannot identify the total number of 
clinical trial sites, we used the NIH clinical trial registry to estimate the 
proportion of clinical trial sites the  BiMo inspections reached.  The 
centers conduct more inspections that verify clinical trial data than 
inspections that focus on human subject protections.  Seventy-five 
percent of the BiMo inspections during the FY 20002005 period were 
surveillance inspections, which generally target previously completed 
trials and often focus on verifying the quality of clinical trial data.  Also, 
FDA inspected few IRBs, which offer considerable  oversight of human 
subject protections.  
RECOMMENDATIONS 
To improve the BiMo information systems and processes, FDA should 
take the following actions: 
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E X E C U T I V E   S U M M A R Y   
Improve information systems and processes.  
Develop a clinical trial database that includes all clinical trials.   FDA should 
develop a comprehensive internal database of clinical trials to more 
effectively identify and target ongoing clinical trials for inspection.    
Create an IRB registry.  This registry  would give  FDA basic information 
about IRBs that it now lacks.  By identifying all IRBs overseeing clinical 
trials, FDA could target IRBs more effectively for inspection.   
Create a cross-center database that allows complete tracking of BiMo 
inspections.    A database that includes timely and complete information 
about all BiMo inspections would help FDA better coordinate and track 
inspections.    
Establish a mechanism to provide feedback to BiMo investigators on their 
inspection reports and findings.  Improved feedback between the centers and  
BiMo investigators could lead to a common understanding of the 
regulations and guidelines that govern BiMo inspections.  
Seek legal authority to provide oversight that reflects  current clinical trial 
practices. FDA should consider seeking additional authority that covers 
all of the stakeholders in the management and conduct of clinical trials.  
In particular, FDA  could seek to expand its authority to include the 
colleagues and subordinates of a clinical investigator if they participate 
in the conduct of a clinical trial.  
AGENCY COMMENTS AND OFFICE OF INSPECTOR GENERAL  
RESPONSE 
FDA concurred with four of our five recommendations listed above.   
FDA did not address our recommendation to establish a mechanism to 
provide feedback to BiMo investigators on their inspection reports and  
findings. 
FDA pointed out that BiMo inspections make up only one part of its 
efforts to ensure human subject protections, noting that it views its 
protocol review before a clinical trial commences  as the most important 
step in protecting human subjects.  We recognize the important role  
that FDAs protocol review plays in protecting human subjects.  We  
note, however, that this report addresses another important part of the 
system for protecting human subjects:  oversight of the trials once they 
are actually underway.         
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E X E C U T I V E   S U M M A R Y   
The agency also highlighted the efforts of its Human Subject  
Protection/Bioresearch Monitoring Council and emphasized  the 
importance  of risk-based approaches to BiMo inspections. 
Where appropriate, we  made changes to the report based on FDAs 
technical comments.  
 
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  T A B L E   O F   C O N T E N T S  
EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i
  
 
 
I N T RO DUC T IO N  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  1 
  
 
 
F I N D IN G S  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  10 
  
  Data limitations inhibit FDAs ability to manage effectively . . . .  10 
  
  Other factors hinder FDAs ability to manage effectively. . . . . . .  13 
  
  We estimate that FDA inspected 1 percent of clinical trials. . . . .  18 
  
 
R E C O MMEN D A T ION S  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  22 
  
  Agency comments and Office of Inspector General response  . . . .  24 
  
 
APPENDIXES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  25 
  
  A:  Methodology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  25 
  
  B:  Agency comments  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1
   
   
A C K NO WL E D G M E N T S  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  34 
    
   
I N T R O D U C T I O N  
  I N T R O D U C T I O N
OBJECTIVE 
1. 	  To determine the extent to which the Food and Drug Administration 
(FDA) conducted inspections of clinical trials from fiscal year       
(FY) 2000 to FY 2005. 
2. 	  To assess FDAs processes for inspecting clinical trials. 
BACKGROUND 
The Federal Food, Drug, and Cosmetic Act generally requires all new 
drugs and medical devices (hereinafter referred to as investigational 
products) to undergo clinical trials on human subjects to demonstrate 
the safety and efficacy of these products before they are approved for 
sale in the United States.1  2  FDA has promulgated regulations to 
protect the rights, safety, and well-being of the human subjects who 
participate in these trials.  These regulations apply to the sponsors,  
clinical investigators, and institutional review boards (IRBs) that 
conduct or oversee clinical trials for investigational products. FDA 
inspects clinical trials to determine whether each  of these groups  
complies with the relevant regulations.   
The Office of Inspector General (OIG) received a congressional request 
to review FDAs oversight of clinical trials after a series of news articles  
highlighted vulnerabilities.3  The series identified problems with FDAs 
oversight of clinical trials, including insufficient informed consent 
procedures, inadequate training and certification requirements for 
IRBs, limited Federal regulations, and FDAs failure to enforce existing 
regulations.  
Clinical Trials 
Sponsors.  The person or entity responsible for developing and testing 
an investigational product is the products sponsor.  Sponsors of drug 
and biological products must file an investigational new drug (IND) 
application with FDA before they can begin clinical trials; device 
 
1 In some instances devices do not go through a formal approval process but go to market 
through a premarket notification and determination of substantial equivalence by FDA.  In  
these instances, clinical trials may not be necessary.  See Federal Food, Drug, and Cosmetic 
Act of 1938, P. L. No. 75-717, 52 Stat.1040 (1938) (amended 2004). 
21 U.S.C.  360(o).  
2 21 U.S.C.  355(i), 360(j). 
3 David Evans, Mike Smith, Liz Willen, Drug Industry Human Testing Masks Death,  
Injury, Compliant FDA, Bloomberg News, November 2, 2005.   
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sponsors submit investigational device exemptions (IDE).4 INDs and 
IDEs provide FDA with information on the study protocol, the 
qualifications of trial personnel, and assurances that trials will protect  
human subjects welfare, among other details.5   A sponsor may begin its 
clinical trial 30 days after FDA receives an IND or IDE, provided that 
the agency does not place the study on clinical hold.6   
FDA regulations require sponsors to  select qualified clinical 
investigators to conduct the trials needed to bring an investigational 
product to the market.7   A clinical trial generally involves many clinical 
investigators working in multiple trial sites, including sites outside the 
United States. 
Sponsors must also ensure that proper monitoring occurs throughout 
the clinical trial.8  In part, this means that sponsors must ensure that 
clinical investigators comply with the relevant FDA regulations. Key 
FDA regulations pertaining to clinical trials address informed consent  
procedures, data management practices, and clinical trial oversight 
processes.9    
If the clinical trials demonstrate the investigational product to be safe 
and effective, sponsors that wish to market a product in the United  
States must submit a new product application to FDA.10  11  Provisions 
within the Prescription  Drug User Fee Act of 1992 (PDUFA) and the 
Medical Device User Fee and Modernization Act of 2002 (MDUFMA) 
require FDA to expedite the process for the review of product  
applications.12  FDA reviews the clinical trial data and may choose to  
inspect facilities as part of the application review process.13  If FDA 
 
4 21 CFR  312.20 (drugs and biologics); 21 CFR   812.20 (medical devices). 

5 21 CFR  312.23.                    

6 21 CFR  312.40 (drugs and biologics); 21 CFR   812.30 (medical devices). 

7 21 CFR  312.50 (drugs and biologics); 21 CFR   812.40 (medical devices). 

8 Ibid. 

9 Ibid. See  also  FDA, Compliance Program  Guidance, Chapter 48:  Sponsors, Contract 

Research Organizations and Monitors Part 1Background (February 2001).  Available 
online at http://www.fda.gov/ora/compliance_ref/bimo/7348_810/default.htm.  Last accessed 
on January 16, 2006. 
10 The drug  development and approval process may take several years.  For more  
information, see Congressional Research Service, The U.S. Drug Approval Process:  A 
Primer, June 2001. 
11 21 CFR  314.50 (drugs); 21 CFR  601 (biologics); 21 CFR  814.20 (devices). 

12 21 U.S.C.  301, 379f(j). 

13 21 CFR  314 (drugs); 21 CFR  600.21 (biologics); 21 CFR  814.44 (devices).  

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approves a new product, sponsors can market and sell it in the United  
States. 
Clinical investigators.   Clinical investigators responsibilities include 
recruiting subjects, supervising clinical studies of the investigational 
product, and reporting study results to the sponsor.14 Before they begin  
drug and biological clinical trials, clinical investigators must  sign an 
FDA Form-1572 (Statement of Investigator).15 By signing this form, 
investigators agree to follow a research protocol that the sponsor 
provides to FDA, report any unexpected adverse outcomes to sponsors  
and IRBs, obtain informed consent from all subjects participating in the 
research, and comply with all relevant FDA regulations.16   
Institutional Review Boards. IRBs are committees that an institution 
designates to oversee clinical investigators and their research.17 IRBs 
are often affiliated with hospitals and academic medical centers, but 
they also exist in managed care organizations and Government agencies  
and as for-profit entities that are independent of the institution in 
which the research takes place. IRBs generally oversee many and 
varied clinical trials.18  
IRBs are intended to ensure that clinical investigators take appropriate 
steps to protect the rights and welfare of human subjects. All clinical 
trial research involving human subjects must be approved by an IRB.19   
Once an IRB approves a clinical trial, Federal regulations require it to 
reevaluate the trial at least once a year.20    
Food and Drug Administration Oversight of Clinical Trials 
Three centers within FDA individually regulate different types of 
medical investigational products for human use. These centers are the 
Center for Drug Evaluation and Research (CDER), the Center for 
Biologics Evaluation and Research (CBER), and the Center for Devices 
 
14 21 CFR  312.60 (drugs and biologics); 21 CFR   812.100 (devices). 

15 Although the Center for Devices and Radiological Health does not require a Form FDA 

1572, it does require an investigator agreement. See 21 CFR  812.43(c) (devices); 
21 CFR  312.53 (drugs and biologics). 
16 21 CFR  50.312. 
17 21 CFR  56.102. 
18 Larger IRBs may oversee more than 500 trials in a given year. See Institutional 
Review Boards Registration Requirements, 69 Fed. Reg. 40,556 (July 6, 2004). 
19 21 CFR  56.109(a). 
20 21 CFR  56.109(f). 
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and Radiological Health (CDRH).21  CDER and CBER share regulations 
for the development of investigational products; CDRH has its own 
regulations.22    
The centers use onsite inspections to  ensure that clinical investigators, 
sponsors, and IRBs comply with FDA regulations while developing 
investigational products. In 1977, FDA established the Bioresearch 
Monitoring Program (BiMo) to develop cross-center guidelines for these 
inspections of clinical investigators, sponsors, and IRBs (hereinafter 
referred to as BiMo inspections).23  BiMos objective, as it relates to  
clinical trials, is to assure the quality and integrity of data submitted 
to FDA to demonstrate the safety and efficacy of regulated products, 
and to determine that human rights and the welfare of human and  
animal research subjects are adequately protected.24  The Compliance 
Program Guidance Manual contains the current guidelines for BiMo 
inspections. 
FDAs Office of Regulatory Affairs (ORA) conducts all onsite inspection 
activities for the agency.  ORA employs about 1,300 investigators who 
conduct a total of 22,000 inspections annually.  About 200 investigators 
(hereinafter  referred to as BiMo investigators) have received  specialized  
training to conduct BiMo inspections and have conducted these 
inspections in recent years.25  BiMo investigators work out of all 19 of 
ORAs district offices.  
Types of Bioresearch Monitoring inspections.  The centers assign two 
general types of BiMo inspections:  surveillance inspections and directed 
inspections.  Most surveillance inspections target concluded clinical 
trials and retrospectively review compliance with FDA regulations.  
Many directed inspections target trials that are still treating human 
subjects (ongoing trials). The centers can assign surveillance and 
directed inspections to  ORA at any point during the development of an 
 
21 FDAs Center for Veterinary Medicine and Center for Food Safety and Applied 
Nutrition oversee investigational products as well, but are outside the scope of our 
evaluation.  
22 21 CFR  312 (drugs and biologics); 21 CFR  812 (devices).  

23 21 U.S.C.  355, 360(i). 

24 FDA, Bioresearch Monitoring  Program Coordination Background.  Available online 

at: http://www.fda.gov/ora/compliance_ref/bimo/background.html. Last accessed on   
February 5, 2007. 
25 Although some investigators conduct BiMo inspections exclusively, most investigators 
also conduct other types of inspections for FDA. 
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investigational product. Although  FDA has the authority to conduct 
surveillance and directed BiMo inspections, it is not required to do so. 
Surveillance inspections are generally routine inspections that the 
centers assign to ORA to verify that a clinical investigator, a sponsor, or 
an IRB complied with FDA regulations during clinical trials for an 
investigational product. Data verification inspections are a principal 
type of surveillance inspection.  Data verification inspections usually 
occur 2 to 3 years after the clinical trials for an investigational product 
conclude and focus on verifying the clinical trial data that a sponsor 
submitted to support a new product application.   
The centers assign directed inspections to ORA for a variety of reasons,  
including complaints about the conduct of a clinical trial from an 
interested party, problems noted during previous inspections, or 
problems identified at similar sites.   Other factors may also lead the 
centers to assign a directed inspection of a clinical trial, such as an 
unusually high number of subjects enrolled at one site under one 
clinical investigator or a treatment that may be considered higher risk.  
Directed inspections that target ongoing clinical trials allow the centers 
and BiMo investigators to review the conduct of a clinical trial and 
advise where corrective action may be needed while the trial is still 
ongoing, thereby offering further human subject protections.    
Bioresearch Monitoring inspection process. ORAs  BiMo investigators 
conduct BiMo inspections according to the Compliance Program 
Guidance Manual. Also, staff at the center that assigned a BiMo 
inspection may issue additional instructions for the BiMo investigator.  
The manuals instructions vary based on the type  of inspection           
(i.e., clinical investigator, sponsor, or IRB).26  If a BiMo investigator 
identifies violations of FDA regulations, he/she  records them on a Form 
FDA-483 (Inspectional Observations Report).  After the inspection, the 
BiMo investigator sends the assigning center a copy of the FDA-483 and 
an Establishment Inspection Report (EIR), which includes background 
 
26 FDA, Compliance Program Guidance Manual, Chapter 48.809:  Institutional Review 
Board (September 1997); Chapter 48.810:  Bioresearch MonitoringSponsors, Contract 
Research Organizations, and Monitors (February 2001); Chapter 48.111:  Clinical  
Investigators (September 2000).   
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information and copies of all inspection documents. In the EIR, the 
BiMo investigator recommends a classification for the inspection.27   
Inspection classifications and actions taken. Staff at the assigning center 
classify each inspection based on the EIR and other information they 
have about the investigational product. BiMo inspections can result in  
one of three  classifications: no action indicated (NAI), voluntary action 
indicated (VAI), or official action indicated (OAI). An NAI classification 
signifies few or no violations of FDA regulations. Generally, FDA takes 
no action in these cases.  An inspection receives a VAI classification and  
an untitled letter when the violations are serious enough to record, but 
the center does not believe the violations cross the threshold of 
regulatory significance.28 FDA does not require the clinical 
investigators, sponsors, or IRBs that receive VAI classifications to 
address the violations found during the inspection. 
Centers classify inspections as OAI and issue warning letters to the 
inspected entity when investigators find violations of regulatory 
significance.29 FDA considers warning letters an important tool in 
ensuring voluntary compliance. If the inspection subject does not take  
corrective action to address violations cited in the warning letter, FDA 
may take enforcement actions, such as disqualifying data or barring a 
clinical investigator from conducting research. Warning letters and 
enforcement actions are publicly available on FDAs Web site. 
FDA requests that the inspected entity respond to the violations listed 
in a warning letter by sending a justification or a corrective action plan 
to the assigning center. FDAs Regulatory Procedure Manual states, 
If necessary to  ensure that corrections have been implemented,     
follow-up inspections should be conducted promptly after the agreed 
upon date of completion of the promised corrections.30   
Recent Food and Drug Administration Initiatives 
Recently, FDA has taken steps to improve its BiMo inspection 
processes. In 2004, it created the BiMo Steering Committee to review 
 
27 Although most recommended classifications made by BiMo investigators are classified  
as no action indicated, voluntary action indicated, or official action indicated, BiMo 
investigators may also choose not to recommend a classification. 
28 Ibid., p. 4-27. 
29 The centers are required to get the concurrence of FDAs Office of Chief Counsel for all 
warning and untitled letters. See FDA, Regulatory Procedures Manual, Chapter 4: 
Advisory Actions, p. 4-26, March 2007. 
30 Ibid., p. 4-11. 
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BiMo processes and make recommendations for improving them.   
During the course of our study, FDA renamed that committee the 
Human Subject Protection/Bioresearch Monitoring Council. In 2006, 
the committee issued new guidance on clinical trial conduct and policy.31  
Prior Office of Inspector General Reports 
Previous OIG reports documented weaknesses in the oversight that 
FDA and IRBs provide for clinical trials. In 1998, a series of reports 
concluded that IRBs lacked the time and the expertise to sufficiently 
monitor the research taking place under their jurisdiction.32 The 
reports found that IRBs often conducted minimal review of studies after 
the initial approval of the research. Additionally, IRBs provided little 
training for investigators and board members. 
A 2000 report documented weaknesses in clinical trial oversight. The 
report found that data integrity concerns, more than human subject 
protection, drove FDAs oversight of clinical investigators and that the 
BiMo program lacked clear and specific guidelines.33  
METHODOLOGY 
Scope 
Our study focused on BiMo inspections of sponsors, clinical 
investigators, and IRBs in clinical trials from FY 2000 through FY 2005. 
We included all of the BiMo inspections conducted for CBER, CDER, 
and CDRH that are listed in FDAs inspections databases for this 6-year 
period. 
Data Sources and Analysis 
We used seven data sources for this study. See Appendix A for a 
detailed methodology. 
 
31 In 2006, FDA issued the following new guidance: Draft Guidance: Process for 
Handling Referrals to FDA Under 21 CFR  50.54; Additional Safeguards for Children in  
Clinical Investigations, May 2006; Guidance for Industry: Using a Centralized IRB Process 
in Multicenter Clinical Trials, March 2006; Guidance for Clinical Trial Sponsors: 
Establishment and Operation of Clinical Trial Data Monitoring Committees, March 2006;  
Information Sheet Guidances for IRBs, Clinical Investigators, and Sponsors, January 2006. 
32 Department of Health and Human Services, OIG, Institutional Review Boards: A 
Time for Reform, OEI-01-97-00193, June 1998;  OIG, Low-Volume Institutional Review 
Boards, OEI-01-97-00194, October 1998; Institutional Review  Boards: Their Role in 
Reviewing Approved Research, OEI-01-97-00190, June 1998. 
33 Department of  Health and Human Services, OIG, FDA Oversight of Clinical 
Investigators, OEI-05-99-00350, June 2000. 
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Food and Drug Administrations Bioresearch Monitoring inspections data. 
We analyzed FDAs BiMo inspections data to evaluate how FDA tracks  
and manages BiMo inspections.   We  also calculated the number and  
type of inspections FDA conducts.  We used data from six FDA  
databases for BiMo inspections.   The three centers maintain separate 
databases to track BiMo  inspections:  two databases each for CBER and 
CDER and one for CDRH.  ORA maintains the  Field Accomplishment 
and Compliance Tracking System (FACTS).  
From each database, we analyzed the records for BiMo inspections of 
sponsors, clinical investigators, and IRBs that BiMo investigators 
conducted for the three centers during the FY 20002005 period.  We 
excluded laboratory and bioequivalence inspections from our analysis.   
File review. Using the FDA databases, we identified and reviewed all 
BiMo inspections for which the BiMo investigator recommended OAI or 
a center classified as OAI in FY 20002005.  We reviewed 668 files, 
including 99 CBER inspection files, 248 CDER inspection files, and   
321 CDRH inspection files. 
E-mail survey of Bioresearch Monitoring investigators. We surveyed BiMo 
investigators about their experiences with FDA guidance, classification 
recommendations, inspection followup with the assigning centers, and 
challenges  conducting BiMo inspections.  We received completed 
surveys from 76 percent of the BiMo investigators (170 out of 223).  
Interviews with Food and Drug Administration officials. We conducted 
telephone interviews with all 19 ORA district directors and supervisors  
of investigation branches (hereinafter referred to as supervisors).  The 
interviews focused  on the supervisors experiences with the supervisory  
role, interactions with the BiMo investigators they supervise, 
interactions with the assigning centers, classification recommendations, 
and challenges in supervising BiMo inspections.  We also interviewed 
senior FDA  officials in the agencys  headquarters and at each center. 
Observation of Bioresearch Monitoring inspections. We  observed the 
process that BiMo investigators followed, as well as the interactions 
between the investigator(s) and the inspection subject(s).  We observed  
two clinical investigator inspections and one IRB inspection.  
Clinical trials registry site estimate. From the population of trials on the 
National Institutes of Healths (NIH) clinical trials registry as of 
February 2007, we selected a stratified random sample of 150 trials.  
Because the registry is separated by phase of the trial, the three strata 
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used for the sample were Phase I, Phase II, and Phase III of the clinical 
trial. We  excluded 43 of the sampled  trials and the final sample size to 
estimate that the number of trial sites was 107.  (See Appendix A, Table 
7, for our sample design.) 
Review of Food and Drug Administration regulations, guidance, policies, 
and procedures documents.   We obtained and reviewed all relevant FDA  
regulations, guidance, policies, and procedures documents for  
conducting BiMo inspections.  
Standards 
We conducted this review in accordance with the Quality Standards for 
Inspections issued by the Presidents Council on Integrity and 
Efficiency and the Executive Council on Integrity and Efficiency. 
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Data limitations inhibit FDAs ability to  FDA relies on BiMo inspections as 
effectively  manage the BiMo program  a principal mechanism for 
overseeing clinical trials after it 
reviews the protocol.  BiMo inspections help to ensure the quality and  
integrity of  clinical trial data, and to determine  whether sponsors, 
clinical investigators, and IRBs are complying with regulations that 
protect human subjects while they are enrolled in clinical trials.     
FDA lacks a complete clinical trial registry  
Because FDA does not maintain a clinical trial registry, it is unable to 
indentify all ongoing clinical trials and their associated trial sites.  
Limited clinical trials that are regulated by FDA can be found on a 
clinical trial registry run by NIH.34  Included within this data bank is 
information on FDA-regulated studies to treat serious or                      
life-threatening diseases and conditions.  Sponsors are not required to 
submit information on any other type of clinical trials that FDA 
regulates.    
FDA lacks an IRB registry  
Because FDA does not maintain an IRB registry, it is unable to identify 
all IRBs.  IRBs are important because their primary purpose is to 
ensure that clinical investigators take appropriate steps to  protect the 
rights and welfare of human subjects.  BiMo inspections of IRBs offer 
the centers considerable oversight of human subject protections.  
Because IRBs usually oversee many and varied clinical trials, the 
centers can  review numerous trials across the centers with each BiMo 
inspection of IRBs. 
The Office of Human Research Protections (OHRP) oversees all 
federally sponsored research that includes human subjects.35   OHRP 
maintains a database consisting of all IRBs that oversee this research.   
Although the OHRP database likely contains many IRBs that oversee 
some FDA-regulated clinical trials, it does not contain IRBs that oversee 
clinical trials regulated exclusively by FDA.     
 
34 Section 113 of the 1997 Food and Drug Administration Modernization Act directs the 
Secretary of the Department of Health and Human Services to act through NIH to establish 
and operate a databank of information on clinical trials for drugs to treat serious or life-
threatening diseases or conditions.  42 U.S.C.  282(j)(3)(A).    
35 OHRP oversees research that is conducted or supported by HHS.  See 45 CFR Part 46. 
  
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FDA has acknowledged  the importance of creating an IRB registry and  
published a proposed rule in July 2004 for the creation of one.36   
According to FDA, the benefits of such a registry would include being 
able to identify IRBs that review clinical trials regulated by FDA, 
having a complete list of IRBs for educational and outreach purposes,  
and being able to easily identify IRBs for inspection.37    
No FDA database includes complete information for all BiMo inspections, 
hindering FDAs ability to track BiMo inspections  
FDA maintains six databases to track BiMo inspections. Although 
 
ORAs database, FACTS, includes information on all BiMo inspections, 
it does not consistently include information about inspection-related  
events that occur after an investigator submits an inspection report to  
the centers. For example, 48 percent of BiMo inspection records in 
FACTS (2,557 out of 5,312 records during the FY 20002005 period) 
lack the centers final classifications. Because of these omissions, FDA  
cannot use FACTS to track inspections from assignment through a 
centers final action. 
Tracking BiMo inspections using data from the centers is challenging 
because of the number of databases involved and their inconsistencies.   
The three centers used five separate databases to track BiMo inspection 
data in the FY 20002005 period.38   
The center databases do not uniformly track inspections. First, each 
database contains different information about BiMo inspections. 
Second, when the centers track similar information, they do not do so in  
the same way. For example, each database uses different categories to 
identify the reason a center initiated an inspection.39 (See Table 1 on 
the next page.) These categories are difficult to translate across 
databases. For example, FACTS and one  of CBERs databases indicate  
whether an inspection was based on a complaint. However, the other  
databases combine complaint-based inspections with other types of 
inspections, which means that FDA cannot identify which inspections 
were prompted by complaints for all centers. Also, the databases define 
different types of inspections as surveillance and as directed. FDA  
 
36 Institutional Review Boards Registration Requirements, 69 FR 40,556 (July 6, 2004). 

37 Ibid., 40,557. 

38 CBER and CDER maintain two databases each to track inspections. 

39 None of the databases indicates whether an inspected trial was completed or ongoing. 

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cannot use these databases to track inspections across centers unless it 
controls for all of these discrepancies. 
 
Table 1: Categories Center and ORA Databases Use To Track Reason for Inspection  
 
Database   Inspections Included  Category  
 
All BiMo inspections ORA    Complaint (for cause, based on a complaint) 
conducts    Compliance (followup to previous violations)  
ORA      Surveillance (routine inspections that are not based on           
FACTS  preexisting information about a firm; includes data integrity  
  inspections)2  
CBER's IRB inspections    Text field (most entries in this field do not indicate reason for 
CBER    inspection) 
IRB  
 
CBER's clinical    Complaint 

CBER  i nvestigator and sponsor 
   Surveillance (site selected because of high risk; includes blood, 
CISM1   inspections  cell, gene, vaccine, and other)2  
 
Completed inspections of    Data audit (most are based on new product application) 
t rials for drug products     For cause (based on prior problems complaint) 
CDER 
COMIS3   
 
CDER inspections    For cause (based on previous problems or complaint)4  
 
starting in FY  2004 or    Routine data audit (based on a new product application) 
CDER  later     Information gathering 
DSI4       Surveillance2    
 
All CDRH BiMo    Routine  

inspections of IRBs, 
   For cause 

 
clinical investigators, and 
   Directed  

sponsors 
   Vulnerable population  
CDRH      Probability sampling  
  Field initiated
database  
    Center initiated 
  Expedited review  
    Surveillance2  
  Followup inspection after OAI inspection 
1CISM is clinical inve stigator, sponsor, and monitor.
 
2The databases define surveillance differently. 

3COMIS is the Cente r Office Management Information System. 

4DSI is the Division of Scientific Investigations.  In the CDER DSI database, inspections can be more than one type. 

 
Source:  OIG analysis of  ORA, CBER, CDER, and CDRH data, 2006.  
 
The five center  databases do not uniformly track other important 
inspection-related data, such as (1)  whether the inspection targets an 
ongoing or completed clinical trial, (2) ORAs recommended 
classification, and (3) follow-up inspection information. 
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Other factors hinder FDAs ability  to effectively  
 
manage the BiMo program 
 
Centers and ORA inconsistently classify OAI and NAI inspections   
According to FY 20002005 CDER and CDRH data, these centers often 
disagreed when ORA recommended  an OAI classification, the most 
serious classification category.40  (See Table 2.)  During this 6-year 
period, CDER revised 68 percent of  ORAs OAI recommendations and 
CDRH revised 23 percent of ORAs OAI recommendations.  The centers 
reclassified most of these inspections to VAI, a classification that 
neither requires the inspected  entity to formally address violations the 
center identified nor makes the classification publicly available.   
The centers do not systematically track their reasons for revising ORAs 
recommended classifications.  However, our review of 668 FDA 
inspection files identified two key reasons for changing OAI 
classifications to VAI. The most common reasons were that the  center, 
in conjunction with an Office of Chief Counsel review, determined that 
the violations were not serious enough to warrant a warning letter and 
therefore an OAI classification, and that the inspection subject promised  
corrective actions. 
   
Table 2:   CDER and CDRH Agreement  With  ORA Recommended Classifications,  FY 20002005 
Percentage of All  Percentage of  OAI   Percentage of  VAI   Percentage of  NAI 
Center  Recommendations  Recommendations Center   Recommendations Center   Recommendations 
Center Revised  Revised  Revised  Center Revised 
CDER  14%   (303 of  2,090)   68% (133  of 195)   2% (25  of 1,328)   26% (145  of 567)  
CDRH  13% (193  of 1,506)   23% (62 of  271)   7%  (47  of  688)   15% (84 of  547)  
Source:   OIG analysis  of CDER and CDRH data, 2006.   
CDER and CDRH also revised some of ORAs NAI recommendations.  In 
other words, center reviewers sometimes identified violations when a 
BiMo investigator found no significant violations at the inspection site.  
CDER reclassified 26 percent of the inspections that ORA identified as 
 
40  We could not conduct this analysis for CBER because it does not record ORAs  
recommended classification.   
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NAI. CDRH reclassified 15 percent of the inspections that ORA  
identified as NAI. 
These reclassifications suggest that ORA and the centers sometimes 
interpret the regulations and guidance for BiMo inspection 
classifications differently. Although  the centers ultimately classify 
inspections, they rely on BiMo investigators to identify violations at the  
inspection site and collect evidence to support inspection classifications. 
If BiMo investigators interpret the regulations and guidelines 
differently than center reviewers do, they may miss evidence to support 
an OAI classification when one would be appropriate. Conversely, BiMo  
investigators may spend time gathering evidence to support an OAI 
classification that the center does not support. 
BiMo supervisors and investigators reported that a lack of feedback 
from the centers and inadequate training may contribute to the 
differences in interpreting inspection classifications. Eighteen of  
nineteen BiMo supervisors we spoke with stated that the centers rarely 
or never provide feedback on the inspection reports that the districts 
submit to the centers. Further, 19 percent of the BiMo investigators we 
surveyed (32 of 170) responded that they would like more information 
on the centers final classifications or feedback on their             
inspection-related performance.   
FDA relies on  voluntary  compliance to correct violations of regulatory  
significance   
The centers send warning letters for 70 percent of inspections classified  
as OAI. The centers can respond to OAI inspections by issuing an 
untitled letter, issuing a warning letter, disqualifying a clinical 
investigator, or disqualifying data gathered in the clinical trial. Our 
analysis of center data shows that the centers chose to  respond to 
70 percent of inspections they classified as OAI during the   
FY 20002005 period by issuing warning letters. (See Table 3 on the 
next page.) The centers next most common response to OAIs was 
untitled letters, which they sent for 16 percent of OAI inspections. Less  
frequently, the centers took more formal actions, including initiating 
disqualification of inspection subjects or disqualifying data from clinical 
trials. 
Warning letters and untitled letters rely on voluntary compliance, so 
FDA must reinspect individuals who receive these letters to  ensure that 
they do not repeat violations in future clinical research. If the centers 
do not track the response to warning letters and untitled letters, they 
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cannot ensure that voluntary compliance occurs.  According to FDAs 
Regulatory Procedures  Manual, Warning Letters are issued only for 
violations of regulatory significance.  Significant violations are those 
violations that may lead to enforcement action if not promptly and  
adequately corrected.  A Warning Letter is the agencys principal means 
of achieving  prompt voluntary compliance with the Federal Food, Drug, 
and Cosmetic Act.41  
 
Table 3: Centers' Official Actions for BiMo Inspections Classified as OAI  
Percentage of  
Percentage of   Percentage of   Percentage of  
OAIs That  Resulted  
Center  OAIs That  Resulted   OAIs That  Resulted   OAIs That  Resulted   Unknown Action  
in a Disqualification 
in a Warning Letter  in an Untitled Letter  in Disqualified Data 
Letter 
CBER  82% (55 of 67)  6% (4 of 67)  12% (8 of 67)  0% (0 of 67)  0% (0 of 67) 
CDER  57% (38 of 67)  16% (11 of 67)  18% (12 of 67)  2% (1 of 67)  8% (5 of 67) 
CDRH  71% (151 of 214)   20% (42 of 214)  3% (6 of 214)  1% (1 of 214)  7% (14 of 214) 
Total  70% (244 of 348)  16% (57 of 348)   8% (26 of 348)  1% (2 of 348)  6% (19 of 348) 
Source:  OIG analysis of CDER, CDRH, and CBER inspection  files, 2006.  
 
Although CBER and CDER fail to track inspection followup, CDRH 
data show that that center conducts few follow-up inspections.  Center 
databases fail to track whether the center conducted a followup to an 
inspection classified as VAI or OAI.  CDRHs database indicates 
whether an inspection was initiated as a followup to a prior violative 
inspection. However, the database does not link the followup inspection  
to the violative inspection.  Nor does  it indicate in the record for the 
violative inspection that followup occurred.  CDRH data show that the 
center conducted 3 follow-up inspections for every 100 inspections 
classified as OAI or VAI in the FY 20002005 period (36 follow-up 
inspections for 1,048 inspections classified as OAI and VAI). 
 
 
41 FDA, Regulatory Procedures Manual, Warning Letter Procedures, p. 4-1-1, March  
2007. Available online at http://www.fda.gov/ora/compliance_ref/rpm. Last accessed     
April 9, 2007. 
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Uncertainty  and lack of coordination impede FDAs ability to conduct BiMo  
inspections 
In interviews, center and ORA staff reported that inspections triggered 
by new product applications affect the conduct and timing of other 
inspections. The centers cannot predict how many new product 
applications they will receive each year and therefore cannot plan for 
the inspections that these applications trigger.   At the beginning of each  
fiscal year, the centers plan and budget for BiMo inspections. During 
the year, the centers also receive new product applications, which 
generate BiMo inspection assignments with short due dates because of 
the overall performance  goals of PDUFA and MDUFMA.42 Assignments 
based on new product applications are usually retrospective reviews 
that focus on verifying clinical trial data used in the application. These 
assignments generally take priority over all other BiMo inspections.  
Because each center has a set budget for all inspections, an unexpected  
rise in new product applications may mean that the ORA districts have 
more inspections overall and more inspections with short due dates 
than they originally planned. 
Because of the uncertainties of timing and prioritization involved with 
BiMo inspections, districts sometimes must delay some of the other 
inspections that ORA conducts, particularly those with later due dates. 
In fact, 11 of 19 district supervisors we interviewed stated that 
assignments for inspections related to marketing applications create 
challenges for managing resources. Staff in five district offices reported 
asking the centers for additional time to complete BiMo inspections; two 
offices estimated that they request extensions for about 20 percent of 
BiMo assignments. Staff in four other districts reported that they have  
to cancel other inspections when they have too many unexpected BiMo 
assignments.  
Additionally, the centers generally fail to coordinate assignments with 
one another or the districts. When asked if they  faced any challenges 
conducting BiMo inspections, staff from 7 of the 19 district offices 
reported that lack of planning and coordination by the centers created  
challenges for the district. For example, staff in a district that oversees  
 
42 PDUFA requires pharmaceutical companies to pay fees to FDA when submitting  
Preapproval Marketing Applications and New Drug Applications. These fees are dedicated 
to expediting the review of product applications for CDER and CBER.  MDUFMA has the 
same requirement for device applications. The BiMo inspection serves as one step of the 
evaluation process. 21 U.S.C.  379g(4), 379j. 
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a large geographic area reported that inspection assignments for distant 
sites would be more manageable if they could combine multiple 
inspections in a single trip. However, this is not feasible without 
coordinating across the assigning centers.   
Failure to coordinate BiMo assignments across centers may also impede 
BiMo Steering Committee goals. In interviews,  BiMo Steering 
Committee members reported  that they want to increase the number of 
inspections of ongoing trials and inspections that focus on high-risk 
sites. One committee member we interviewed told us that the current 
system, in which each center independently issues assignments and 
tracks data, does not allow for the timely coordination necessary to 
target high-risk and ongoing inspections across centers.   
FDA guidance and regulations do not reflect current clinical trial practices  
According to interviews with center officials and ORA supervisors, 
FDAs guidance and regulations for clinical trials have fallen behind 
industry practices. FDA officials reported that when the agency 
developed clinical trial regulations, a single investigator at a single site 
ran each clinical trial. Since then, clinical trials have grown 
increasingly complex. Trials are larger and involve multiple sites 
within and outside the United States.43    
FDA officials told us that clinical investigators frequently delegate tasks 
that include direct care to human subjects to colleagues or subordinates. 
Current FDA regulations do not address colleagues or subordinates. 
When FDA  conducts an inspection and finds significant deficiencies 
related to individuals other than the clinical investigator, the agency 
may only take action against the clinical investigator. 
Finally, although sponsors increasingly conduct clinical trials outside 
the United  States, FDA authority over foreign trials remains limited.  
For example, one center official estimated that 20 to 25 percent of the  
trials for products that FDA oversees occur outside the United States. 
According to the official, centers are often unaware that foreign trials 
 
43 Regarding the increasingly complex management structures of  clinical trials, see  
Department of  Health and Human Services, OIG, The  Globalization of Clinical Trials: 
A Growing Challenge in Protecting Human Subjects, OEI-01-00-00190, September 2001. 
See also Iain M. Cockburn, The Changing  Structure of the Pharmaceutical Industry, 
Health Affairs, 23(1) pp. 1022, 2004; and R. A. Rettig, The Industrialization of Clinical 
Research, Health Affairs, 19(2), pp. 129146,  2000. Regarding the growing size and 
complexity of clinical trials, see Institute of Medicine, The Future of Drug Safety: 
Promoting and Protecting the Health of the Public, Chapters 1 and 2, 2006. 
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have taken place because FDAs investigational product regulations 
generally do not apply outside the United States.  When ORA does 
inspect foreign clinical trials and finds violations, the centers can only  
disqualify data from consideration in a new product application. 
 
As previously noted, FDA lacks a 
We estimate that FDA inspected     
complete database that includes 
1 percent of clinical trial sites during the     
information on all BiMo 
fiscal year 2000-2005 period 
inspections.  However, FDA also 
lacks registries that contain complete  clinical trial and IRB information.  
Failure to track all clinical trials and IRBs limits the centers ability to 
oversee trials through BiMo inspections.  First, the centers cannot 
assign BiMo inspections of trials and IRBs that they cannot identify.  
Second, the centers cannot identify the percentage of trials and IRBs  
that BiMo inspections reach.  To identify the percentage of trials and 
IRBs that BiMo inspections reached during the FY 20002005 period , 
we used  estimates of clinical trial and IRB populations from  
Government sources outside FDA.  
The centers reported 2,856 BiMo inspections that required a clinical 
trial site visit for the FY 20002005 period.44  (See Table 4 on the next 
page.) However, the centers do not  have data to identify the percentage 
of trial sites that these inspections reached.  Therefore, we used the 
number of INDs and IDEs the centers received as well as estimates 
from the clinical trial registry that NIH maintains to estimate the 
percentage of trial sites that the BiMo inspections reached.45    
 
44 We excluded  IRB and sponsor inspections from  this analysis because they generally do  
not take place at a clinical trial site.   
45 Section 113 of the 1997 FDAMA directs the Secretary of the Department of Health and 
Human Services to act through NIH to establish and operate a databank of information on 
clinical trials for drugs to treat serious or life-threatening diseases or conditions.  Included  
within this databank is information on studies to treat serious or life-threatening diseases 
and conditions conducted under FDA IND regulations.  Although the NIH registry does not 
include all the clinical trials FDA oversees, it provides the best available estimate of the 
average number of trial sites associated with clinical trials.  The registry is available at 
www.clinicaltrials.gov. 
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Table 4:  Centers' BiMo Inspections With Site Visits by Fiscal Year 
 
Fiscal Year  CDER  CDRH  CBER  Total 
 
2000  296  91  143  530 
 
2001  186  113  79  378 
 
2002  194  153  109  456 
 
2003  226  167  103  496 
 
2004  219  189  75  483 
 
2005  221  183  108  512 
 
Total  1,342  896  617  2,855 
Source:  OIG Analysis   of CDER, CDRH, and CBER data, 2006. 
We included only  clinical investigator, contract research organization, and sponsor monitor inspections. 
 
Although FDA cannot identify the total number of clinical trial sites 
operating during the FY 20002005 period, the centers did track the 
15,268 INDs and IDEs that they received during this period. However, 
each IND or IDE may involve many trial sites, so the number of INDs 
and IDEs cannot substitute for the total number of trial sites.  
Therefore, to estimate the total number  of trial sites, we  calculated the 
average number of clinical trial sites associated  with a random sample  
of clinical trials listed on the NIH clinical trials registry.  We found that  
clinical trials listed on that registry had an average of 23 sites per 
trial.46  Based on these figures, we estimate that the 15,268 INDs and 
IDEs the centers received included about 350,000 trial sites.   
Using the estimate of 350,000 trial sites, we estimate that FDAs    
2,855 inspections reached just under 1 percent of the trial sites 
associated with the INDs and IDEs the centers received.  
 
46 A 95-percent confidence interval for our sample is +/- 8 trial sites, or between 15 and 
31 sites per trial. Using this range, we calculate that FDAs 2,855 inspections reached at 
most just over 1 percent of trial sites associated with the 15,268 applications received by the 
centers. 
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  S  
Centers assign more surveillance inspections than directed inspections   
For the FY 20002005 period, 75 percent of BiMo inspections were 
surveillance inspections. Surveillance inspections generally focus on 
verifying the clinical trial data that sponsors submitted with their new 
product applications.  Further, most surveillance inspections target 
completed trials.  Data verification inspections serve an important 
purpose in enabling FDA to assess the quality of the data used to 
support new product applications.  However, because these inspections 
take place after trials conclude, they cannot ensure that sponsors, 
clinical investigators, and IRBs are taking the necessary actions to 
protect human subjects during the trials. 
Some of the directed inspections that the centers assigned during the  
FY 20002005 period likely focused on ongoing trials.  For example, 
CBER annually targets a high-risk category of clinical trials for 
inspection, which may include ongoing clinical trials.47 CDRH 
implemented a program in the past year to increase the number of  
inspections that focus on higher-risk clinical trials that may be ongoing.  
However, the three centers do not track whether inspections target 
ongoing trials, so we could not estimate the proportion of BiMo 
inspections that reached ongoing trials.  Several senior FDA officials 
reported to us that they recognize the need to inspect more ongoing 
clinical trials to protect  human subjects. 
Centers inspect few IRBs    
Our analysis of center data shows that in the FY 20002005 period, 
FDA conducted an average of 214 IRB inspections each year. The 
number of IRB inspections has decreased annually since 2002.  (See 
Table 5 on the next page.)  IRB inspections offer the centers 
considerable oversight of human subject protections.  Because IRBs  
usually oversee a variety of clinical trials, the centers can review 
numerous trials across the centers with each IRB inspection.   
At most, we estimate that during the FY 20002005 period, the centers 
inspected an average of about 6 percent of IRBs each year, or less than  
40 percent of all IRBs in the 6-year period we evaluated.  Because the  
centers do not track the total population of IRBs, we used the IRB 
database maintained by OHRP to estimate the population of IRBs.  
OHRP oversees all research that the Federal Government sponsors.   
 
47 Past examples include studies focusing on  pediatric populations and gene therapy 
studies.   
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The OHRP  database includes all IRBs that oversee research sponsored  
by the Government, so it likely underestimates the population of IRBs  
overseeing all clinical trial research. In February 2007, OHRP reported 
3,579 IRBs in its IRB database.48  
 
 
Table 5:   IRB  Inspections as a Percentage of  Total BiMo Inspections 
Number of IRB   Total BiMo  Percentage of Inspections That  
Fiscal Year 
Inspections  Inspections  Are IRB inspections 
2000  198  795  25% 
2001  187  633  30% 
2002  278  812  34% 
2003  251  854  29% 
2004  207  779  27% 
2005  163  769  21% 
Total  1,284  4,642  28% 
 Source:   OIG Analysis of CDER, CDRH,  and CBER data, 2006.   
IRB inspections assigned to ORA are allowed longer timeframes than 
inspections of clinical investigators or sponsors. A centers inspection 
assignment includes a due date. In many cases, the centers allow ORA 
up to 1 year to complete IRB inspections. By comparison, ORA  
generally has 30 to 90 days to complete inspections of clinical 
investigators.49    
Center data show that despite these longer timeframes, ORA frequently  
failed to meet the requested due dates for IRB inspections. ORA failed 
to meet CDRHs deadlines for 60 percent of IRB inspections (214 out of  
359); 24 percent (85 of 359) were more than 60 days late. Similarly, 
ORA failed to meet CBERs deadline for 38 percent of that centers IRB 
inspections (24 of 63).50     
 
48 OHRP oversees research that is conducted or supported by the U.S. Department of  
Health and Human Services. See 45 CFR Part 46. 
49 In some cases, IRB inspections are directed because of a past OAI or some other 
concern. In these instances, the timeframes are shorter than the timeframes presented  
here. 
50 We could  not determine the timeliness of CDER inspections because CDER does not 
include the inspection due date in its database. 
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FDA conducts BiMo inspections to ensure the quality and integrity of 
clinical trial data and to determine whether sponsors, clinical  
investigators, and IRBs are complying with regulations that protect  
human subjects enrolled in clinical trials.  Our evaluation identified a 
lack of comprehensive reporting and tracking systems, a lack of 
coordination among the centers and  ORA, and regulations that do not 
fully reflect  current clinical trial practices.  
No Federal requirements prescribe the number or type  of BiMo 
inspections FDA must conduct.  However, FDA relies on BiMo 
inspections as a principal mechanism for overseeing clinical trials after 
it reviews the protocol.  We recognize that resource limitations may be a 
factor in determining the extent of FDAs oversight of clinical trials 
using BiMo inspections.  However, to ensure its effectiveness  in meeting 
BiMo objectives, the inspection program needs comprehensive 
management and reporting systems.    
FDA has taken steps to improve the BiMo inspection program.  For 
example, in 2004 it created the BiMo Steering Committee to identify 
and address weaknesses in the BiMo program.   We identified additional 
steps that FDA can take to improve  oversight of clinical trials.  These 
changes will help FDA plan and conduct BiMo inspections more 
effectively. These changes will also help FDA meet the BiMo objective 
of determining that human rights and the welfare of human research  
subjects are adequately protected.    
FDA should:  
Improve Information Systems and Processes  
FDAs BiMo inspections are a principal mechanism to ensure the 
quality and integrity of  clinical trial data and to determine that human 
subjects are protected.   However, the weaknesses we identified in the  
BiMo information systems and management processes inhibit FDAs 
ability to effectively oversee and manage BiMo inspections across 
centers.  To  improve the effectiveness of the BiMo program, FDA should  
take the following actions: 
Develop a clinical trial database that includes all clinical trials.   FDA should 
develop a comprehensive database to use as an internal management tool 
to more effectively identify ongoing clinical trials for inspection. Although 
NIH currently maintains a clinical trial registry, that registry was not 
intended to be a comprehensive listing of clinical trials.  It was created to  
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inform the public regarding potentially new life-saving treatments. 
Because the registry contains clinical studies to treat serious or             
life-threatening diseases and conditions conducted under FDAs IND 
regulations, it excludes most other clinical trials subject to  FDA 
regulation, such as medical device studies. 
Create an Institutional Review Board registry. By identifying all IRBs 
overseeing clinical trials, FDA could  target IRBs more  effectively for  
inspection.   FDA has acknowledged  the importance of creating an IRB  
registry and published a proposed rule  in July 2004. Recently, the agency 
set a timetable of March 2008 for issuance of a final rule.51    
OHRP currently maintains an IRB registry for studies under its 
auspices.52 FDA could build upon OHRPs existing IRB registry to 
create a larger and more inclusive database while minimizing the 
administrative burden for IRBs. 
Create a cross-center database that allows complete tracking of Bioresearch 
Monitoring inspections. FDA cannot efficiently manage BiMo inspections 
across centers without a database that includes timely and complete 
information about all BiMo inspections. A single, consistent database 
would require the centers to agree about which fields are essential and  
how they should be defined. At a minimum, the database should include: 
(1) specific information on the reason for an inspection, (2) whether the 
inspection targets an ongoing or a completed clinical trial, (3) ORAs 
recommended classification, and (4) follow-up inspection information.  
Establish a mechanism to provide feedback to Bioresearch Monitoring  
investigators on their inspection reports and findings.   Improved feedback 
between the centers and BiMo investigators could lead to a common 
understanding of the regulations and guidelines.  This would minimize the 
likelihood that an investigator would miss evidence to support an OAI 
classification when one would be appropriate or  spend time gathering 
evidence to  support an OAI classification that the center does not  
corroborate.  
Seek legal authority to provide oversight that reflects  current clinical trial 
practices.   FDA should consider seeking additional authority that covers 
all of the stakeholders in the management and conduct of clinical trials. 
 
51 72 FR 22,520 (April 30, 2007).  
52 OHRP oversees research that is conducted or supported by the U.S. Department of  
Health and Human Services. See 45 CFR  46. 
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R E C O M M E N D A T I O N S  
 
In particular, FDA should consider seeking authority to include the 
colleagues and subordinates of a clinical investigator if they participate in  
the conduct of a clinical trial. 
AGENCY COMMENTS AND OFFICE OF INSPECTOR GENERAL  
RESPONSE 
FDA concurred with four of our five recommendations.  These 
recommendations aimed to improve information systems and processes 
related to the BiMo program.  FDA did not address our recommendation  
to establish a mechanism to provide feedback to  BiMo investigators on  
their inspection reports and findings.  
Specifically, FDA concurred with our recommendations to develop a 
clinical trial database that includes all clinical trials, to create an IRB 
registry, to create a cross-center database that allows complete tracking 
of BiMo inspections, and  to seek legal authority to provide oversight 
that reflects current clinical trial practices.   
FDA pointed out that BiMo inspections make up only one part of its 
efforts to ensure human subject protections, noting that it views its 
protocol review before a clinical trial commences  as the most important 
step in protecting human subjects.  We recognize the important role  
that FDAs protocol review plays in protecting human subjects and  
made several changes to  our report to reflect this point.  We do note,  
however, that this report addresses another important part of the 
system for protecting human subjects:  oversight of the trials once they 
are actually underway.         
The agency highlighted the efforts of its Human Subject 
Protection/Bioresearch Monitoring Council in identifying key issues that 
needed to be addressed, such as coordination, tracking mechanisms, 
regulations, and guidance.  FDA also emphasized the importance of 
risk-based approaches to BiMo inspections rather than committing to 
inspecting a specified percentage of clinical trials. 
Where appropriate, we  made changes to the report based on FDAs 
technical comments.  
See Appendix B for complete agency comments.  
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  A P P E N D I X   A
 
METHODOLOGY 
Scope 
Our study focused on Bioresearch Monitoring (BiMo) inspections of  
sponsors, clinical investigators, and Institutional Review Boards (IRBs) 
in clinical trials from fiscal year (FY) 2000 to FY 2005.  We reviewed all 
of the inspections that BiMo investigators conducted for the Center for  
Drug Evaluation and Research (CDER), the Center for Biologics 
Evaluation and Research (CBER), and the Center for Devices and 
Radiological Health (CDRH) that are listed in Food and Drug 
Administrations (FDA) inspections databases for this 6-year period.  
We excluded BiMo inspections that focused  on the bioequivalence and  
laboratory compliance programs.53   
Data Sources and Analysis 
We used seven data sources for this study.   
Food and Drug Administrations Bioresearch Monitoring inspections data. 
We analyzed FDA inspections data to evaluate how FDA tracks and 
manages BiMo inspections.  We also  calculated the number and type of 
inspections FDA  conducts. 
We analyzed data from six FDA databases for BiMo inspections. Each 
center we evaluated and the Office of Regulatory Affairs (ORA) 
maintain separate databases to track BiMo inspections.  CDRH and 
ORA each maintain a single database.  CBER and CDER each maintain 
two databases. 
From each database, we analyzed the records for BiMo inspections of 
clinical investigators, sponsors, and IRBs for CBER, CDER, and CDRH 
during the FY 2000 to 2005 period.   
We analyzed fields in the databases that indicate the type of inspections 
that the centers conducted in the FY 2000 to 2005 period.  (See Table 6.)  
Each center tracks inspections differently, so we could not gather 
information on every variable for all centers. 
 
53 We excluded laboratory BiMo inspections because they were not clinical in nature.  We 
excluded bioequivalence BiMo inspections because they do not necessarily follow the same  
investigational product processes described in the Background  on p. 2.  
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Using the fields listed in Table 6, we evaluated  the number and types of 
inspections that FDA conducted from FY 2000 to 2005.  We conducted 
all database analysis in SAS.  
The following is a description of each of the databases: 
  Field Accomplishment and Compliance Tracking System  (FACTS):   
We received FACTS data from ORA in July 2006.  The FACTS data 
included 5,850 records. We removed 472 records that either 
duplicated other records or targeted  subjects outside our scope (for 
example, manufacturers).  We  excluded 66 records that ORA coded as 
Cancelled or Returned or that the Center for Veterinary Medicine 
requested. Our analysis includes 5,312 FACTS records.  
	  CBER data:   We received data from CBERs two databases in         
July 2006. CBER dedicates one database to clinical investigator and 
sponsor inspections.  This database originally contained 714 records.  
We removed records that did not fall within the scope of this study, 
including five manufacturing inspections, four inspections classified  
as no inspection, three inspections classified as out of business, 
and eight inspections classified as washout.  We also removed      
11 inspections that did not include inspection start dates.  Our 
analysis includes 683 inspection records from this database. 
CBER uses a second database to track IRB inspections.  This 
database included 73 records.  We used all of these inspection records 
in our analysis. 
	  CDER data:  We received data from one CDER database, the Center 
Office Management Information System (COMIS), in October 2006.  
CDER uses COMIS to track closed inspections of CDER drug  
products trials that started before FY 2004.  The COMIS data  
originally included 4,237 inspection records.  However, many of these 
records were duplicates.  After we removed the duplicate records, 
COMIS included 1,196 inspection records. 
We received data from a second CDER database, the Division of  
Scientific Investigations database (DSI), in December 2006.  CDER 
uses the DSI database to track all inspections starting in FY 2004 or 
later. The DSI database originally included 1,137 inspection records.  
We removed records that did not fit within the scope of our study, 
including inspections that started after FY 2005 ended.  Our analysis 
included 1,107 inspection records from the DSI database. 
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	  CDRH data:  We received data from CDRH in November 2006.  
CDRHs database originally included 2,762 inspection records.  We 
excluded 1,168 inspection records, including records that ORA 
classified as no inspection made and records that CDRH classified 
as washout, out of business, or cancelled.  Our analysis included 
1,594 CDRH records.  
 
Table 6:   Variables Used To Analyze FDA  BiMo Inspections  Data 
Variable  CBER  CDRH  CDER 
Inspection Subject  Yes  Yes  Yes 
Reason for Inspection  Not  available  Yes  Yes 
ORA Recommended Classification  Not  available  Yes  Yes 
Center Final  Classification  Yes  Yes  Yes 
Database 1:  Not  
Official Actions  Yes  Yes  available 
Database 2: Yes 
Assignment Date  Yes  Yes  Yes 
Inspection Start  Date  Yes  Not available  Yes 
Inspection End Date  Yes  Yes  Not available 
Trial Status:   Ongoing or Closed  Not  available  Not available  Not available 
Source:  OIG analysis of CDER, CDRH, and CBER data,  2006. 
File review. We used FDAs databases to identify all inspections that 
either ORA or a center classified as OAI.  We reviewed 248 CDER 
inspection files, 99 CBER inspection files, and 321 CDRH inspection  
files, for a total of 668 files.   
We reviewed the files using a Microsoft Access  protocol.  Our protocol  
included inspection assignment, classification, official actions, and 
correspondence between the center and the inspection subject.  We  
analyzed data from the file reviews using SAS.  
E-mail survey of Bioresearch Monitoring investigators. ORA headquarters 
provided us with a list of the 231 ORA field investigators who had spent 
100 or more hours conducting BiMo inspections in the previous 5 years.  
We removed eight investigators from the original sample because they 
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no longer conduct inspections or had not conducted an onsite inspection  
in several years or we could not obtain contact information for them. 
Our survey solicited respondents experiences with FDA guidance, 
inspection and classification recommendations, inspection followup with 
the assigning centers, and challenges in conducting BiMo inspections. 
Before sending the survey, we solicited comments from ORA officials 
and a BiMo investigator about the surveys content and clarity. We  
incorporated their feedback into the final survey. 
We e-mailed each investigator an introductory letter explaining the 
survey and the study in August 2006. Later in the month, we e-mailed 
the survey. In September 2006, we e-mailed a second copy of the survey 
to those who had not responded. At  the end of September, we called the 
investigators who had not yet replied. We received responses from       
170 BiMo investigators for a 76-percent response rate. 
Interviews with Food and Drug Administration officials. We conducted 
telephone interviews with all 19 ORA directors of investigation (DIB) who 
oversee BiMo investigators. Several DIBs invited supervisors in their 
districts to participate in the interviews. 
The interviews focused on the DIBs experiences with the supervisory 
role, interactions with BiMo investigators, interactions with the 
assigning centers, classification recommendations, and their challenges 
in supervising BiMo inspections. Before the interviews, we solicited 
comments from ORA officials and  a DIB about the interview guides 
content and clarity. We incorporated their feedback into the final 
interview guide. We conducted the interviews in October and November 
2006. At least two OIG staff participated in each interview.   
We also interviewed senior FDA officials at FDA headquarters, ORA, 
CBER, CDER, and CDRH. 
Observation of Bioresearch Monitoring inspections. We observed three BiMo 
inspections: two clinical investigator inspections and one IRB inspection. 
FDA initiated the two clinical investigator inspections because of new 
product applications. The IRB inspection was a directed inspection.  
We based our observations on a protocol that focused on the process that 
the BiMo investigator followed as well as the interactions between the 
investigator(s) and the inspection subject(s). At  least two OIG staff 
participated in each inspection visit.  
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Clinical trial registry site estimate. To compute an estimate of the average 
number of clinical trial sites associated with a clinical trial, we used data 
from the clinical trials listed on the National Institutes of Healths clinical 
trials registry as of February 2007. We selected a stratified random 
sample of 150 trials. Because the registry is separated by trial phase, the 
three strata used for the sample were Phase I, Phase II, and Phase III of 
the clinical trial. (See Table 7 for our sample design.) 
 
Table 7: Clinical Trial Registry Site Estimate Sample Design 
 
Stratum    Population Size  Sample 
Phase I    1,866  40 
Phase II    4,566  50 
Phase III    4,863  60 
Source: Office of Inspector General analysis of the National  Institutes of Health's Clinical Trial Registry. 
 
We first counted the total number of clinical trial sites for each of the 
three clinical trial phases. This served as our population size. Using 
the OIG Office of Audit Services RAT-STATS software, we chose 
random numbers to select the clinical trial. Because each trial in the 
registry was assigned a number, we  were able to use the random 
numbers to identify the sampled trial. After sampling the trials, we 
counted the number of sites associated with each sampled trial. 
We excluded 43 of the 150 clinical trials sampled. There were three 
situations in which the sampled trials were unusable and therefore had 
to be excluded. First, some of the trials appeared in the population 
multiple times because they were named Phase I/Phase II or  
Phase II/Phase III. If a trial was listed as Phase I/Phase II, it was 
counted as Phase II. Similarly, if a trial was listed as Phase II/Phase 
III, it was counted as a Phase III. Eighteen occurrences of a Phase 
I/Phase II trial in the Phase I population were  excluded, as were seven 
occurrences of a Phase II/Phase III trial in the Phase II population. In 
addition, no sites were listed for 16 trials. Finally, terminated trials 
occurred twice in the sample. We used the remaining sample of 107 
trials to compute the average number of sites per trial. The sample was 
weighted using standard statistical formulas for a stratified sample. 
Based on these formulas, the estimated average number of sites for a 
clinical trial is 23. This estimate can vary by +/-8 trials at the 
95-percent confidence level. 
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A P P E N D I X ~ A  
Review of Food and Drug Administration policies, procedures, and guidance 
documents.   We obtained and reviewed all relevant policies, procedures, 
and guidance documents issued by FDA for conducting BiMo inspections.  
We used these documents to better understand the process for conducting  
inspections of clinical trials. 
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A P P E N D I X   ~   A  
 A P P E N D I X   B  
 
Agency Comments 
 
 
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A P P E N D I X   ~   B  
 
 
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This report was prepared under the  direction of Joyce M. Greenleaf, 
Regional Inspector General for Evaluation and Inspections in the 
Boston regional office, and Russell W. Hereford, Deputy Regional 
Inspector General.    
Danielle Fletcher served as the team leader for this study.  Other 
principal Office of Evaluation and Inspections staff from the  Boston 
regional office who contributed include Rosemary Borck, Chris Galvin, 
and Robyn Sterling, and central office staff include Ayana Everett.  
 
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