Department of Health and Human Services 
OFFICE OF 
INSPECTOR GENERAL 
FDA Oversight of 
Clinical Investigators 
JUNE GIBBS BROWN 
Inspector General 
JUNE 2000 
OEI-05-99-00350  OFFICE OF INSPECTOR GENERAL 
The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, is to 
protect the integrity of the Department of Health and Human Services programs as well as the 
health and welfare of beneficiaries served by them.  This statutory mission is carried out through a 
nationwide program of audits, investigations, inspections, sanctions, and fraud alerts.  The 
Inspector General informs the Secretary of program and management problems and recommends 
legislative, regulatory, and operational approaches to correct them. 
Office of Evaluation and Inspections 
The Office of Evaluation and Inspections (OEI) is one of several components of the Office of

Inspector General.  It conducts short-term management and program evaluations (called

inspections) that focus on issues of concern to the Department, the Congress, and the public.  The

inspection reports provide findings and recommendations on the efficiency, vulnerability, and

effectiveness of departmental programs. 

OEI's Chicago Regional Office prepared this report under the direction of William Moran,

Regional Inspector General and Natalie Coen, Deputy Regional Inspector General.  Principal OEI

staff included:

REGION  HEADQUARTERS

Thomas Komaniecki, Team Leader  Elise Stein, Program Specialist

Nora Leibowitz

Susan Otter

To obtain copies of this report, please call the Chicago Regional Office at (312) 353-4124. 
Reports are also available on the World Wide Web at our home page address: 
http://www.dhhs.gov/progorg/oei  EE XX EE CC UU TT II VV EE     SS UU MM MM AA RR YY  
PURPOSE 
To examine the Food and Drug Administrations (FDA) selection of clinical investigators 
for inspection and FDAs discipline of those clinical investigators found in violation of 
FDAs regulations. 
BACKGROUND 
The FDA is responsible for monitoring and approving the development of new drugs, 
biologics and medical devices.  Companies develop these products with the assistance of 
clinical investigators.  Clinical investigators recruit the subjects, perform the studies and 
report the results.  The FDAs bioresearch monitoring program inspects clinical 
investigators involved in clinical research to ensure the quality and integrity of data 
submitted to the agency and to protect the rights and welfare of human subjects.  In most 
cases, these inspections occur after clinical work is complete. 
The FDA is organized into Centers and the Office of Regulatory Affairs (ORA).  Several 
of the Centers are involved in monitoring the development and testing of new human 
drugs, biologics and medical devices.  The ORA staff conduct on-site inspections as part 
of the application review process for experimental products.  The Centers assign the 
inspections, classify their results and decide what action to take. 
We reviewed the universe of 184 official actions taken by FDA since Fiscal Year (FY) 
1994.  We interviewed the staff and managers in FDAs bioresearch monitoring programs. 
We also analyzed FDAs listing of clinical investigators, as well as performed a work flow 
analysis.  We only examined FDAs bioresearch monitoring programs involved in the 
review of new human drugs, biologics and medical devices. 
FINDINGS 
Overall oversight of clinical investigators is limited 
Sponsors, Institutional Review Boards and FDA oversee clinical investigators research. 
Reviews by FDA have found serious problems with sponsors monitoring of clinical 
investigators.  Previous work by the Office of Inspector General found problems with 
Institutional Review Boards oversight of clinical research.  The FDA, in FY1999, non-
randomly inspected only 468 clinical investigators of nearly 14,000 clinical investigators 
potentially involved in clinical trials.  (The FDA could not provide the actual number of 
clinical investigators who submitted data in support of product applications.)  We 
understand that the current FDA system is not intended to provided day to day oversight 
1 
Oversight of Clinical Investigators  OEI-05-99-00350  of clinical trials.  Rather, it provides a retrospective review of clinical trials.  This report 
raises concerns about the assignment and classification of the current system of 
retrospective clinical investigator inspections. 
Data integrity concerns, more than human subject protection, drive FDAs 
oversight of clinical investigators 
Although respondents indicated that program goals are ensuring data integrity and 
protecting human subjects, FDAs monitoring of clinical investigators is more directly 
focused on verifying data.  These inspections are application driven with number of 
subjects, data issues and inspection history driving the selection.  While examining data 
integrity supports FDAs role of protecting consumers from unsafe or ineffective medical 
products, we did not find that this process protects human subjects during the research 
process.  Other programs within and outside of FDA are more geared toward human 
subject protection. 
Staff identified deliberate violations of the regulations and jeopardizing data integrity as 
the most frequent reasons to assign official action indicated to an inspection.  Fraud and 
repeated violations will often merit disqualification.  Review of official actions issued by 
FDA found the majority of official actions cited documentation and protocol violations. 
We also note that investigations are conducted after clinical research is completed, making 
oversight of human subjects protection retrospective rather than concurrent with clinical 
research. 
The bioresearch monitoring program lacks clear and specific guidelines 
The FDA regulations state that a clinical investigator may be disqualified from receiving 
investigational drugs, biologics or devices for repeatedly or deliberately failing to comply 
with the regulations.  There is no required review of complaints or clinical investigator 
inspection histories as part of the clinical investigator selection process, although 70 
percent of staff reported that they do check complaints or inspection histories.  Staff 
receive little or no formal training on how to select clinical investigators for inspection or 
how to assess what action should be taken when violations are found.  No written 
guidelines exist at a Center level for bioresearch monitoring staff on what repeated or 
deliberate violations mean.  The FDA does not have agency-wide program measures for 
the bioresearch monitoring program. 
RECOMMENDATIONS 
This report does not make any recommendations regarding the weakness found with 
sponsor or institutional review board oversight of clinical investigators, since they have 
been addressed in other studies.  Our recommendations focus on improving FDAs 
oversight of clinical investigators. 
2 
Oversight of Clinical Investigators  OEI-05-99-00350  The FDA should define cross-Center goals for the bioresearch monitoring 
program and develop criteria to determine whether the program is achieving 
those goals 
While respondents in all three Centers described similar program goals, there is currently 
no way to determine whether bioresearch monitoring is achieving those goals.  The FDA, 
through the internal working group on bioresearch monitoring, should define what an 
effective bioresearch monitoring program should accomplish.  As part of that definition, 
FDA should: 
C	 clarify how long the process should take from the conclusion of the investigation 
and submission of the report until a decision is made on the results of the 
inspection and issuance of any Agency actions; and, 
C	 clarify the criteria for selection of clinical investigators for inspection including 
looking at smaller sites and previous inspection history and compliance. 
The FDA should also recognize the limitations of the current systems ability to protect 
human subjects during clinical trials.  Currently, the vast majority of inspections are 
conducted after clinical trials are complete.  Any human subject violations identified are 
found too late to protect the human subjects involved. 
The FDA should develop internal guidance on the thresholds that violations must 
meet to justify disqualifying a clinical investigator from receiving investigational 
products 
The FDAs internal working group on bioresearch monitoring should develop guidance on 
the severity and number of violations needed to justify beginning disqualification 
proceedings.  Cross-Center guidance would insure that each of the Centers handles the 
results of clinical investigator inspections consistently.  We believe that having a written 
framework can provide structure for FDA reviewers. 
AGENCY COMMENTS 
We would like to thank the Food and Drug Administration for commenting on the draft of 
this report.  Based on FDA's general and technical comments, some changes and 
clarifications were made in this final report. 
The FDA commented that they are not responsible for providing patient care and that they 
are not currently equipped to monitor studies during the research process.  We recognize 
this.  We also understand that FDA attempts to protect human subjects and the general 
public through retrospective review of clinical investigators, research sponsors and 
institutional review boards.  See Appendix B for the text of the Agencys comments. 
3 
Oversight of Clinical Investigators  OEI-05-99-00350  T A B L E   O F   C O N T E N T S  
PAGE

EXECUTIVE SUMMARY  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  1

INTRODUCTION  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  5

FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  10

Overall Oversight Limited  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Inspections Spotlight Data Integrity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Bioresearch Monitoring Program Lacks Clear Guidelines . . . . . . . . . . . . . . . . . . . . . . . 16

RECOMMENDATIONS  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  20

AGENCY COMMENTS  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  21

APPENDIX

A: Review of FDA Official Actions  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

B: Text of Agency Comments  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

4 
Oversight of Clinical Investigators  OEI-05-99-00350  II NN TT RR OO DD UU CC TT II OO NN  
PURPOSE 
To examine the Food and Drug Administrations (FDA) selection of clinical investigators 
for inspection and FDAs discipline of those clinical investigators found in violation of 
FDAs regulations. 
BACKGROUND 
Agency structure 
The FDA is responsible for enforcing the Federal Food, Drug and Cosmetic Act as well as 
other public health laws.  To accomplish this mission, FDA is organized into Centers and 
the Office of Regulatory Affairs (ORA).  Several of the Centers are involved in monitoring 
the development and testing of new drugs, biologics and medical devices.  These Centers 
are 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), respectively.  The ORA staff conduct on-site inspections as part of the 
application review process for new drugs, biologics and medical devices.  These staff also 
conduct other inspections, such as food safety and mammography equipment. 
Clinical Investigators 
Clinical investigators perform the actual research used to support applications for new 
drugs, biologics and medical devices.  A clinical investigator may be a professional 
researcher operating out of a research institution such as a research hospital or university, 
or may be a practicing physician who also conducts clinical research.  A company 
developing a new product hires clinical investigators to recruit subjects, conduct the 
research and report the results back to the company. 
Clinical investigators are monitored by several groups:  the sponsor or company 
developing the product or a third party contracted by the sponsor; a local Institutional 
Review Board and FDA.  Clinical investigators have several responsibilities in conducting 
clinical trials, including: 
C  documenting data collection and study procedures accurately and completely; 
C  reporting to the sponsor, Institutional Review Board and FDA; 
5 
Oversight of Clinical Investigators  OEI-05-99-00350  C  protecting the safety of participating subjects;

C  following study protocols; and 

C  maintaining control of the investigational product.

Clinical investigators sign investigator agreements that attest to their knowledge of and

agreement with their responsibilities under FDA regulations as researchers.

Clinical investigator inspections 
Units within each Center review applications for new drugs, devices or biologics.  Each 
application includes a list of all clinical investigators submitting research in support of the 
application.  As part of the application process, FDA staff inspect a non-random sample of 
clinical investigators.  In addition to clinical investigator inspections, bioresearch 
monitoring selects sponsors and Institutional Review Boards for on-site inspections. 
Three quarters of inspections are initiated as part of FDAs application review process. 
The bioresearch monitoring team, in consultation with application review staff, select three 
or four clinical investigators per application for inspection.  Clinical investigators are also 
investigated due to complaints received by FDA, observations noted during previous 
inspections of the clinical investigator or analysis of data submitted to FDA. 
Once a clinical investigator is selected for an inspection, FDA bioresearch monitoring staff 
issues an inspection assignment to ORA.  The ORA investigators conduct the inspection. 
Occasionally staff from the assigning Center will accompany the field investigator on their 
inspection. 
The inspection involves interviews with the clinical investigator and study staff and a 
review of the clinical investigators processes, records, data and documentation.  Field 
investigators use a Form FDA-483 to record problems observed during the inspection.  If 
problems are observed during an inspection, the clinical investigator receives a copy of the 
FDA-483 at the end of the inspection.  The field staff sends a copy of the FDA-483 and 
the Establishment Inspection Report, which includes copies of all documents collected 
during the inspection, to the Center that issued the assignment. 
Inspection classification 
Using the information provided by the field investigator, Center staff classify the 
inspection as no action indicated, voluntary action indicated or official action indicated. 
The FDA would classify an inspection with few or no objectionable conditions or practices 
as no action indicated and the clinical investigator is not required to make any changes or 
respond to the FDA.  When FDA classifies an inspection as voluntary action indicated, the 
clinical investigator is asked to make voluntary changes.  A letter 
6 
Oversight of Clinical Investigators  OEI-05-99-00350  requesting voluntary action does not necessarily require a response from the clinical 
investigator. 
For inspections that result in an official action indicated classification, a Center can take a 
number of different official actions.  However, two official actions appear to be used in the 
vast majority of cases.  For those cases in which the violations appear less serious, a 
Center sends the clinical investigator a Warning Letter outlining violations and requesting 
a response.  The response from the clinical investigator should include the specific steps 
the clinical investigator plans to take to correct the violations, as well as what steps will be 
taken to prevent a recurrence of similar violations.  The FDA may also elect to not allow 
the clinical investigators data to be included in the application.  The FDA considers this 
decision one of their most significant controls over the activities of sponsors and 
ultimately clinical investigators. 
Disqualification proceedings 
For more serious violations, a Center can initiate the disqualification of the clinical 
investigator from future clinical research.  A disqualified investigator may not receive 
investigational products, which in effect prohibits that clinical investigator from 
conducting clinical trials. 
A Center issues the clinical investigator a Notice of Initiation of Disqualification 
Proceedings and Opportunity to Explain (NIDPOE).  This notice offers the clinical 
investigator a chance to meet informally with the Center to discuss the violations found 
during the inspection.  If the clinical investigator produces information that indicates he or 
she is taking corrective action or otherwise resolves the identified problems to the 
Centers satisfaction, this meeting may be the end of the process. 
If FDA does not agree with information presented at the informal conference, the next 
step is to issue a Notice of Opportunity for Hearing.  At this hearing, both the clinical 
investigator and FDA present their cases.  The hearing records include the investigation 
results and the clinical investigators explanation.  Legal counsel may accompany the 
clinical investigator to the hearing.  The hearing officer makes a recommendation to the 
Commissioner, who reviews the information and makes a decision.  The process often 
takes several years, during which time the clinical investigator may continue to conduct 
clinical research. 
At any point during the disqualification process, a clinical investigator can agree to be 
disqualified or restricted by signing a consent agreement.  A restriction limits the ability of 
a clinical investigator to conduct clinical trials.  A restriction can include a temporary 
disqualification for several years, specific restrictions on the type of studies a clinical 
investigator can conduct or supervision of the clinical investigator by another clinical 
investigator. 
7 
Oversight of Clinical Investigators  OEI-05-99-00350  Impact and publicity of sanctions 
The FDA maintains a list of disqualified or restricted clinical investigators on its Internet 
home page.  The list identifies the person, city and state, FDA Center, nature of sanction, 
date of sanction and limited summary information, such as whether the sanction was 
applied after a hearing or through a consent agreement.  As of January 2000, the FDA list 
included information on 133 clinical investigators.  Although FDA can repeal a 
disqualification or restriction, the names of reinstated clinical investigators remain on the 
list with a note that their sanctions have been reversed. 
The FDAs regulations require that the Center that disqualifies a clinical investigator 
review other studies to which the clinical investigator has contributed data.  The goal is to 
investigate whether data provided by a disqualified clinical investigator in support of 
another drug, biologic or medical device application was also tainted and should be 
removed from that application. 
The FDA makes Warning Letters available to the public by posting a redacted copy on its 
web site.  The Centers have expressed the intention to post Notice of Initiation of 
Disqualification Proceedings and Opportunity to Explain letters on the FDA web site as 
well, although this has not yet happened.  Currently, FDA does not list clinical 
investigators who have received a Notice of  Initiation of Disqualification Proceedings 
and Opportunity to Explain on their web site. 
Scope 
We examined FDAs bioresearch monitoring programs involved in the approval of human 
drugs, biologics and medical devices.  We did not examine FDAs bioresearch monitoring 
programs involved in approving animal drug or food products.  We also did not examine 
how district offices conduct on-site inspections of clinical investigators. 
METHODOLOGY 
We reviewed the universe of 184 warning letters, NIDPOE letters and disqualification 
communications issued by FDAs Centers between Fiscal Years (FY) 1994 and 1999.  We 
interviewed the staff (27) and managers (6) of the bioresearch monitoring programs at 
FDAs Center for Devices and Radiological Health, Center for Drug Evaluation and 
Research and Center for Biologics Evaluation and Research.  Our respondents are 
responsible for assigning investigations of clinical investigators and classifying the results 
of those inspections.  We discussed the role of bioresearch monitoring within the Centers, 
how clinical investigators are chosen for inspection and how decisions are made regarding 
case classification and disciplinary action. 
8 
Oversight of Clinical Investigators  OEI-05-99-00350  We examined the lists of clinical investigators who have received warning letters or have 
been disqualified by FDA.  In addition, we analyzed FDAs list of clinical investigators 
who have signed investigator agreements in conjunction with drug, device and biologics 
applications.  We also conducted work flow analysis and examined how FDAs 
bioresearch monitoring program fits into overall human subjects protection structures. 
We conducted our review in accordance with the Quality Standards for Inspections issued 
by the Presidents Council on Integrity and Efficiency. 
9 
Oversight of Clinical Investigators  OEI-05-99-00350  FF II NN DD II NN GG SS  
Overall oversight of clinical investigators is limited 
The activities of clinical investigators who conduct research on investigational products 
regulated by FDA are supervised by several entities.  Sponsors of clinical research are 
required to oversee the work of clinical investigators engaged in testing their products. 
Institutional Review Boards are required to review protocols and other research 
documents to make sure clinical investigators are protecting their research subjects from 
harm.  Additionally, the FDAs bioresearch monitoring program investigates clinical 
investigators as part of application reviews and on the basis of complaints to the agency. 
Monitoring by these entities appears to provide limited oversight of clinical research and 
human subject protection. 
Limited and problematic oversight of clinical investigators 
Sponsor.  A sponsor of clinical research is responsible for selecting qualified investigators, 
providing them with the information they need to conduct clinical trials and monitoring the 
clinical research.  A sponsor can transfer any or all of its obligations, including the 
monitoring of clinical investigators, to a contract research organization. 
As part of the monitoring process, sponsors try to ensure that clinical investigators 
conduct clinical research in accordance with approved protocols such as adhering to 
human subject protections.  A sponsor who finds problems with an investigator should try 
to secure compliance or end the clinical investigators participation in the investigation. 
The sponsor must notify FDA when a clinical investigators participation is terminated for 
noncompliance.  Sponsors who are reluctant to report misconduct may terminate an 
investigator for administrative reasons and are not required to report.  The FDA is 
currently looking at a way to close this loophole in their regulations. 
However, monitoring conducted by sponsors may be questionable.  According to CDRHs 
bioresearch monitoring inspections of sponsors conducted in FY 1998, over 50 percent of 
sponsors failed to ensure the proper monitoring of their clinical investigators.  In 1998, 
CDER examined recent problem clinical investigators and found significant problems with 
sponsor oversight.  They found that serious misconduct was not reported by sponsors and 
that the majority of the objectionable problems should have been detected by adequate 
monitoring.  In addition, CDER found that the Quality Assurance reports by sponsors 
were inaccessible and that monitoring plans and reports were not submitted.  The CDER 
acknowledged that they have a limited knowledge of the nature and scope of industry 
monitoring practices. 
10 
Oversight of Clinical Investigators  OEI-05-99-00350  Institutional Review Board.  Since 1971, FDA has required that any study testing new 
drugs or biologics on human subjects within an institution receive review and approval by 
an Institutional Review Board (IRB).  In 1976, FDA required IRB review for medical 
device studies.  In 1981, FDA expanded the scope of its regulations to include a 
requirement for IRB review of any study conducted outside of an institution. 
The FDA expects an IRB to conduct initial and continuing review of research involving 
human subjects.  The initial review includes examining the research protocol, the informed 
consent process, advertisements used to recruit subjects and other relevant information. 
Continuing review involves examining a study at least once a year to ensure that the risk-
benefit ratio has not changed.  During continuing review, the IRB considers study 
amendments and reports of unexpected adverse events. 
Questions have been raised about the effectiveness of IRB oversight of clinical 
investigator and clinical research.  In April 1995, the Office of Inspector General (OIG) 
found inadequacies with IRB oversight.  Problems included implantation of a device in 
three times the number of human subjects specified in the IRB approved research protocol 
and continuation of a research project for 6 weeks beyond when the IRB had suspended it. 
A 1998 OIG examination of Institutional Review Boards found problems with the IRBs 
continuing review.  This report found that continuing review by IRBs is of limited scope 
and significance. 
FDAs Bioresearch Monitoring Program.  The FDA carries out bioresearch monitoring 
inspections of clinical investigators.  The goals of the program are to ensure the quality 
and integrity of data submitted to the agency and to protect the rights and welfare of 
human subjects.  The inspections are conducted by FDA field staff with Center staff 
responsible for classifying the inspection results and identifying any needed FDA action. 
According to FDA data, there were more than 21,000 investigator agreements received in 
FY 1998 from clinical investigators involved in clinical research although not all 
investigator agreements result in data being submitted to FDA.  These applications 
represent nearly 14,000 individual clinical investigators located in more than 60 different 
countries.  In FY 1999, FDA conducted 497 non-randomly selected inspections of clinical 
investigators for a total of 468 individual clinical investigators inspected.  The number of 
clinical investigator inspections has remained fairly stable in recent years after dropping 
from a high of 627 in FY 1996. 
Three-quarters of inspections conducted in FY 1999 were not due to any suspicion of 
wrong-doing.  These were routine, or surveillance, inspections.  Such inspections normally 
occur when FDA receives an application seeking approval for a new drug, biologic or 
device.  The remaining 25 percent were directed (or compliance) inspections.  A directed 
inspection is assigned when FDA receives information suggesting there may be a problem 
with a clinical investigator.  This information could be from an analysis of 
11 
Oversight of Clinical Investigators  OEI-05-99-00350  the data submitted by the clinical investigator in an application or other information that 
FDA may have received. 
The following findings detail specific concerns about the selection and classification of 
clinical investigator inspections. 
Data integrity concerns, more than human subject 
protection, drive FDAs selection of clinical investigators for 
inspection 
Training given to FDA investigators conducting inspections of clinical investigators 
emphasize that the prime objective of a clinical investigator inspection is to verify the 
quality and integrity of significant study data in support of FDAs role of protecting 
consumers from unsafe or ineffective medical products.  Information is collected and 
assessed based on this understanding.  In the vast majority of cases, the bioresearch 
monitoring inspections occur after a clinical trial has been completed. 
Bioresearch monitoring inspections of clinical investigators are application 
driven 
Routine inspections focus on clinical investigators efforts as representative of research 
conducted in support of an application.  Clinical investigator inspections are primarily 
conducted to provide a sense of the data quality to the application review team responsible 
for approving an application for product approval. 
Inspections based on site size, inspection history, data issues 
Site size.  Bioresearch monitoring staff at all three Centers agree that the primary 
consideration in selecting clinical investigators for inspection is the size of the subject 
population at the sites. Ninety-six percent of staff respondents (all but one) named site size 
as a major criteria in selecting sites, meaning the largest sites in an application are most 
likely to be chosen.  The reason for selecting the largest site is to review the largest 
amount of data.  One respondent stated that the goal in selecting large sites is ideally to 
cover 50 percent of the subject population, but that this goal is not realized currently. 
Staff at all Centers agreed that in general, three clinical investigators are inspected per 
application. 
Respondents noted some concern that clinical investigators with small numbers of subjects 
never get visited.  Under a data validation focus this is appropriate, as smaller sites 
contribute proportionally less to the overall data.  This could be problematic in a 
12 
Oversight of Clinical Investigators  OEI-05-99-00350  protocol or human subjects protection sense, as smaller sites may be no more or less likely 
to conduct studies correctly than sites with more subjects. 
Inspection history. Respondents indicated that when information on the number of 
subjects at various sites is not enough to make selections, clinical investigator inspections 
histories will be considered.  This may also be the case when review staff have not 
recommended sites they want reviewed, especially if multiple sites have similar subject 
populations. 
There is some disagreement among staff as to how important inspection history is in the 
selection process.  Although 70 percent of staff indicated that they review the inspections 
history of clinical investigators, remaining staff indicated that they did not review the 
inspections history of clinical investigators. 
Clinical investigators may not get selected if they have had a recent inspection that found 
few problems, but may be selected if a previous inspection turned up violations.  When 
asked about warning letter follow up, many staff indicated that they reinspect a clinical 
investigator who received a warning letter when they see that the clinical investigator is 
involved with a new application.  However, this may not always happen.  Forty-seven 
clinical investigators whose official actions we reviewed submitted investigator agreements 
after receiving FDA correspondence.  Of these clinical investigators, only 17 percent were 
reinspected for any reason. 
We understand that in some cases an investigator agreement may not lead to clinical trial 
data being submitted as part of the new product application.  We did inquire whether it 
was possible to determine if the 47 clinical investigators submitted data as part of any 
product application.  We were informed by FDA that this would be a very difficult and 
time consuming task. 
Data issues.  Twenty of 27 staff indicated that they consider data issues when selecting 
clinical investigators for inspection.  Data issues include adverse events, unusual or 
suspicious data including results that look too good or bad. 
Other factors.  Almost half the staff respondents (48 percent) report working with the 
application review staff to some degree as they make their selections.  The application 
review staff may recommend certain clinical investigators for inspection based on the size 
of sites or on data issues.  Six of the 27 staff we interviewed indicated that they consider 
the workload or reputation of a district site before deciding whether to assign an 
inspection in that area.  Some districts may have a lot of competing work which could 
delay completion of a clinical investigator inspection. 
13 
Oversight of Clinical Investigators  OEI-05-99-00350  Fraud and jeopardizing data merit official action 
Most respondents indicated that an inspection will be classified as official action 
indicated when the clinical investigator is found to have deliberately disregarded 
protocols or falsified data.  While some respondents noted that multiple protocol 
violations due to sloppiness could lead to a warning letter if the volume of problems was 
large enough, this case was considered less likely than classification as official action 
indicated for deliberate falsification and fraud. 
Intent is a key reason staff will recommend classifying a clinical investigator inspection as 
an official action indicated.  Eighteen respondents indicated that whether violations 
result in a warning letter or disqualification proceedings depends in part on whether the 
investigator meant to violate the regulations.  Respondents indicated that a clinical 
investigator who fails to get some required informed consents should be educated through 
a warning letter.  Failure to get any consents signed may indicate a larger problem with the 
investigators disregard for human subject protection. 
The decision to classify a case as an official action indicated also relies heavily on the 
impact violations have on study results.  If violations call the data into question, staff are 
more likely to take stronger action than if the violations do not impact study results. 
The severity and extent of violations impact whether staff recommend that a case receive a 
voluntary or official action.  Protocol violations that may lead to voluntary action 
indicated if relatively few are found, might elicit an official action indicated response if 
the violations are numerous or show evidence of a serious disregard for study protocols. 
This is especially the case if the violations do not compromise the data or put subjects at 
direct risk.  In such cases, a high volume of violations must be found for a warning letter 
to be issued to a clinical investigator. 
Disqualification, the strongest type of official action, is usually the result of fraud 
and repeat violations 
Respondents nearly unanimously reported that fraud was the main reason that 
disqualification proceedings are initiated against a clinical investigator.  This includes data 
manipulation and falsification as well as protocol violations such as failing to collect 
required data or to record data in a specified manner.  Some respondents noted that if the 
mistakes or problems do not affect the sites data, the case will probably warrant a 
warning letter. 
If violations first noted in an initial site visit are found again in a second inspection, the 
clinical investigator will likely have disqualification proceedings initiated against him.  For 
example, when the first warning letter is written, the clinical investigator is required to 
respond to the Center indicating what steps the clinical investigator will take to correct 
14 
Oversight of Clinical Investigators  OEI-05-99-00350  identified problems.  If the same problems are found during a second site visit, the 
implication is that the clinical investigators response to the initial letter was fraudulent. 
This proof of intent would be reason to initiate disqualification proceedings. 
Review of official actions reveals that focus is primarily on data violations 
We reviewed 189 official actions the three Centers sent to clinical investigators between 
fiscal years 1994 and 1999.  The letters reviewed were warning letters, NIDPOE letters 
and letters documenting disqualifications.  The majority (107 official actions) were written 
by CDRH.  We reviewed 58 from CDER and 24 written by CBER. 
The violations noted in the correspondence the Centers sent to clinical investigators fell 
into five main categories.  Clinical investigators were routinely cited for problems with 
documentation, adherence to protocols, human subject protection, reporting and product 
(drug, device or biologic) control.  The great majority of letters enumerated reporting, 
documentation and protocol violations.  In addition, some other violations were noted, 
including promoting investigational products and failure to conduct work under federally 
required controls.  See Appendix A for further details. 
The FDA states that examining protocol criteria is the first line of defense in protecting 
human subjects.  They believe that taking investigators to task on this issue during 
inspections and highlighting the issue as part of their outreach are two effective ways of 
enhancing human subject protection.  While protocol violations can impact human subject 
protection issues, in most cases these reviews occur after a human subject completes a 
clinical trial.  These retrospective reviews by FDA do not protect the human subjects that 
are currently enrolled. 
Other programs more geared towards human subject protection 
As previously noted, bioresearch monitoring staff tend to focus their attention more on 
data concerns than on direct review of human subjects issues.  Other programs within 
FDA in general are more oriented towards human subject protection.  In its 1996 report 
Scientific Research: Continued Vigilance Critical to Protecting Human Subjects, the 
General Accounting Office notes that FDA monitors for compliance with human subject 
protections by inspecting Institutional Review Boards, reviewing researchers and 
sponsors reports and inspecting clinical studies and investigators.  The General 
Accounting Office report indicates that FDAs inspection of Institutional Review Boards 
is its primary tool for human subject protection.  While FDA does examine human subject 
protection issues during an inspection, the principal focus in such investigations is to verify 
that study data are accurate and complete and to ensure researchers adherence to study 
protocols. 
15 
Oversight of Clinical Investigators  OEI-05-99-00350  The bioresearch monitoring program lacks clear and specific 
guidelines 
Review of complaints or inspection history is not a required part of the clinical 
investigator selection process 
Complaints information is not connected to the routine inspection selection process.  Most 
staff do not routinely use complaints made about clinical investigators as a factor in the 
selection process.  Only CDER has recently instituted a complaints database.  At the other 
Centers, when a complaint comes in but does not trigger an inspection, the complaint is 
often filed with the reviewers correspondence files.  However, staff at all centers agreed 
that all complaints are followed up to some extent. 
Respondents at the three Centers said that they generally do not collect information about 
clinical investigators from the other Centers.  Some staff pointed out that few clinical 
investigators work in more than one area of drug, biologics or device trials.  Some clinical 
investigators do work in more than one area, however.  In one example, a clinical 
investigator who received a warning letter from CBER was later disqualified from CDER 
without CDER knowing about the clinical investigators previous inspection history. 
Bioresearch monitoring staff are not formally trained in classifying violations 
Most respondents indicate that they received little or no formal training on how to select 
clinical investigators for bioresearch monitoring inspections or how to assess whether 
violations necessitate voluntary action or a warning letter or the initiation of 
disqualification proceedings.  Most respondents reported that they learned how to classify 
violations from other staff, that most training was informal on the job acculturation. 
Repeated or deliberate violations: You know it when you see it 
The FDA regulations state that a clinical investigator can be disqualified from receiving 
investigational drugs or devices when the Agency has evidence that he or she has 
repeatedly or deliberately failed to comply with the applicable requirements for the 
conduct of clinical trials.  Disqualification proceedings can also be initiated if the clinical 
investigator has repeatedly or deliberately submitted false information. 
While all respondents were familiar with the phrase repeated or deliberate with regard to 
violations noted in FDA inspections at clinical trial sites, many respondents were unable to 
give a specific definition of what constitutes repeated and deliberate violations or 
what the thresholds are for these terms.  Some respondents indicated that the 
16 
Oversight of Clinical Investigators  OEI-05-99-00350  definition depends on the case, that you know it when you see it.  Staff responses to 
what repeated or deliberate means were fairly consistent, if somewhat vague. 
Many respondents defined repeated or deliberate as violations about which the clinical 
investigator had received and ignored previous warnings.  Several respondents said that a 
respondent with a warning letter has been told both what violations he needs to correct 
and what the consequences of noncompliance may be.  A clinical investigator who does 
not fix the problems cited in the warning letter deliberately violates the rules.  Other 
respondents indicated that deliberate action could be shown even if no previous warning 
letter had been issued.  An IRB could have warned the clinical investigator to correct 
problems or the inspection may produce evidence that the clinical investigator knew he 
was violating the rules.  Deliberate was also defined as fraudulent actions including 
falsification of data, forgery of consent forms or failure to report serious adverse events. 
No Guidance on Repeated or deliberate 
There is no Center-wide official definition of repeated or deliberate violations of FDA 
regulations for bioresearch monitoring staff.  No written document outlines the meaning of 
the phrase and none of the Centers provide staff with formal training on what constitutes 
repeated or deliberate violations of the regulations.  Staff members learn the working 
definition through on-the-job experience and informal discussions with more experienced 
staff. 
The FDA Commissioners office does have some guidance on what repeated or 
deliberate means based on previous decisions.  This information is used when reviewing 
disqualification cases.  However, none of the staff involved in reviewing bioresearch 
monitoring inspections were aware of this information. 
In 1976, GAO released a report entitled Federal Control of New Drug Testing is Not 
Adequately Protecting Human Test Subjects and the Public.  The report noted that FDA 
officials offered differing interpretations of the term repeatedly.  The report cited the 
Director of the Division of Scientific Investigations as saying that the meaning of the term 
is questioned because the regulation from which it comes is hard to interpret. 
While FDA has not produced an official definition of repeated or deliberate, the Agency 
has produced a guidance document which outlines acceptable standards for clinical 
investigators.  This information sheet, last revised in October 1995, provides standards of 
good clinical practice rather than legal requirements.  The document is produced for use 
by clinical investigators and IRBs, but can be utilized by Center staff as a framework 
against which violations can be identified. 
In 1997, a cross-Center bioresearch monitoring workgroup produced a draft memo on the 
thresholds for initiating disqualification of a clinical investigator.  The memo indicates 
17 
Oversight of Clinical Investigators  OEI-05-99-00350  that disqualification proceedings can be initiated against a clinical investigator who 
repeatedly or deliberately fails to comply with the requirements for the conduct of clinical 
trials or repeatedly or deliberately submits false information.  While the memo outlines the 
categories of clinical investigator misconduct, it does not define what would constitute 
repeated or deliberate wrongdoing. 
The workgroup that drafted the thresholds memo was established in 1997 to streamline 
the disqualification process.  The workgroup includes Center managers and 
representatives from the bioresearch monitoring programs Office of Enforcement, the 
Office of Chief Council and the Office of Health Affairs.  The group plans to clarify when 
and how staff should move to each step in the disciplinary process. 
Bioresearch monitorings time frames are external 
The FDA conducts bioresearch monitoring inspections after the clinical research is 
completed and an application is submitted and before a decision on approval is made. 
Inspections are intended to provide information the application review staff need to make 
decisions on application approvals.  The time frame for site selection, inspection and 
classification is short, especially for CDER and CBER.  As these Centers are subject to the 
Prescription Drug User Fee Act, bioresearch monitoring work must be completed quickly 
so that the Centers can process a full review within the required 6-12 months.  While 
deadlines are explicit for CDER and CBER, CDRH is also held to Center deadlines for 
application approvals. 
Several respondents indicated that it is important for inspections to be timely, because if 
inspection classifications and other input are not seen before an approval decision is made, 
their work is essentially useless.  In addition, faster classification of inspections and 
correspondence with clinical investigators allows the inspection to more fully act as an 
educational tool.  Officially communicating violations can alert clinical investigators to the 
scope of their misdeeds and help set them on a path toward corrective action.  The sooner 
the clinical investigator is told what is wrong and asked to respond with an improvement 
plan, the sooner he or she can make those improvements in ongoing clinical trial work. 
Several staff had concerns about the bioresearch monitoring programs effectiveness with 
regards to the timing of their work in the application process as a whole.  One respondent 
said, BIMO comes in so late in the application process, [the Office of Device Evaluation] 
is afraid we will find something wrong.  If BIMO finds something wrong [the Office of 
Device Evaluation] doesnt want to hear it unless its really extreme.  Respondents 
expressed concern that they only see information on the clinical investigators at the end of 
the application process.  One respondent stated that they arent allowed to be involved 
soon enough to be fully useful. 
18 
Oversight of Clinical Investigators  OEI-05-99-00350  Working within given time frames and the need to highlight the most serious problems , 
data validity is given priority.  Poor data has an immediately recognizable impact on 
FDAs ability to validate study results.  The effect of human subject protection problems 
or reporting violations on study results may not be as clear. 
The bioresearch monitoring program does not have Agency-wide program 
measures 
None of the bioresearch monitoring programs we reviewed have written goals nor are 
there any FDA-wide written goals.  The majority of staff and supervisors believe that the 
programs are fulfilling their goals.  However, there are no concrete criteria against which 
the programs can assess their success. 
At the Center level, some performance measures are in the early stages of development. 
Since 1997, one of the Centers has used performance measures that look at timeliness, 
overall compliance rates and compliance with specific criteria.  Another Center is using 
input measurements.  However, neither of these Centers measures are used by FDA to 
appraise the bioresearch monitoring program. 
19 
Oversight of Clinical Investigators  OEI-05-99-00350  R E C O M M E N D A T I O N S  
This report does not make any recommendations that address the weakness found with 
sponsor or institutional review board oversight of clinical investigators, since they have 
been addressed in other studies.  Our recommendations focus on improving FDAs 
oversight of clinical investigators. 
The FDA should define cross-Center goals for the Bioresearch Monitoring 
Program and develop criteria to determine whether the program is achieving 
those goals 
While respondents in all three Centers described similar program goals, there is currently 
no way to determine whether bioresearch monitoring is achieving those goals.  The FDA, 
through the internal working group on bioresearch monitoring, should define what an 
effective bioresearch monitoring program should accomplish.  As part of that definition, 
FDA should: 
C	 clarify how long the process should take from the conclusion of the investigation 
and submission of the report until a decision is made on the results of the 
inspection and issuance of any Agency actions and, 
C	 clarify the criteria for selection of clinical investigators for inspection including 
looking at smaller sites and previous inspection history and compliance. 
The FDA should also recognize the limitations of the current systems ability to protect 
human subjects.  Currently, most inspections are conducted after clinical trials are 
complete.  Any human subject violations identified are found too late to protect the human 
subjects involved. 
The FDA should develop internal guidance on the thresholds that violations must 
meet to justify disqualifying a clinical investigator from receiving investigational 
products 
The FDAs internal working group on bioresearch monitoring should develop guidance on 
the severity and number of violations needed to justify beginning disqualification 
proceedings.  Cross-Center guidance would insure that each of the Centers handles the 
results of clinical investigator inspections consistently.  We believe that having a 
framework can provide structure for FDA reviewers. 
20 
Oversight of Clinical Investigators  OEI-05-99-00350  A G E N C Y  C O M M E N T S  
We would like to thank the Food and Drug Administration for commenting on the draft of 
this report.  Based on FDA's general and technical comments, some changes and 
clarifications were made in this final report. 
The FDA commented that they are not responsible for providing patient care and that they 
are not currently equipped to monitor studies during the research process.  We recognize 
this.  We also understand that FDA attempts to protect human subjects and the general 
public through retrospective review of clinical investigators, research sponsors and 
institutional review boards.  See Appendix B for the text of the Agencys comments. 
21 
Oversight of Clinical Investigators  OEI-05-99-00350  APPENDIX A 
Review of FDA Official Actions

Table 1: Percentage of Official Actions Citing Various Types of Violations 
Issue  Documentation  Protocol  Reporting  Human  Drug/Device/ 
Subject  Biologic 
Protection  Control 
CDRH  83  (78%)  83  (78%)  85  (79%)  69  (64%)  52  (49%) 
107 official actions 
CDER  57  (98%)  51  (88%)  35  (60%)  41  (71%)  21  (36%) 
58 official actions 
CBER  20  (83%)  21  (88%)  19  (79%)  16  (67%)  10  (42%) 
24 official actions 
Total  160  (85%)  155  (82%)  139  (74%)  126  (67%)  83  (44%) 
189 official actions 
Documentation violations.  Eighty-five percent of all the official actions highlighted 
problems with documentation.  Sixty percent of all warning letters mention missing 
documentation.  Other documentation problems include missing data in submitted 
documents, discrepancies between documents, missing correspondence, documentation 
that has been altered, falsification of data and inconsistent or poor data collection. 
Protocol violations.  Protocol violations cited in official actions fall into four categories: 
enrollment violations, failure to follow protocol-required steps and instructions, problems 
with investigator agreements and authorizations and violations related to the use of a drug 
or device.  While across the three Centers 82 percent of all official actions include 
discussion of protocol violations, this number is skewed somewhat because protocol 
violations appear in relatively fewer CDRH official actions (78 percent).  As CDRH 
produced 107 official actions, this impacts the overall number.  Both CDER and CBER 
noted protocol violations in 88 percent of their official actions to clinical investigators. 
Protocol violations can significantly impact study data and human subject protection. 
Failure to follow required actions can invalidate the data collected on drug or device 
effectiveness and safety, not to mention result in death or serious injury to subjects of the 
research.  Study protocols exist to ensure that all sites conduct the study in the same way, 
that treatments are uniform and that data is collected uniformly.  While adherence to 
22 
Oversight of Clinical Investigators  OEI-05-99-00350  protocols is the first line of defense in protecting human subjects from harm, in most cases 
FDA examines protocol violations after the human subject has been enrolled in the clinical 
trial. 
Reporting violations.  Overall, 74 percent of the official actions contained descriptions of 
a clinical investigators failure to report to the appropriate IRB or study sponsor. 
Reporting violations include not submitting annual, final and other reports to the IRB or 
sponsor, not getting consent forms, protocols or advertisements approved by the IRB and 
not submitting data and substantiating documentation to the sponsor.  Failure to report 
adverse events and deaths to IRBs and sponsors and late reporting of adverse events were 
also noted in warning letters to clinical investigators. While reporting violations usually 
refer to a failure to report to an IRB or sponsor, some official actions indicate that a 
clinical investigator also did not appropriately report to FDA. 
While reporting violations appeared somewhat less often in CDERs official actions (60 
percent), both CBER and CDRH cited these violations in 79 percent of their 
correspondence.  Many of the CBER official actions focus on clinical investigators failure 
to report adverse events to IRBs and sponsors.  At CDRH, the most commonly cited 
reporting violations are failure to report adverse events and failure to submit progress, 
annual and final reports to the IRB or sponsor.  Overall, while at least one reporting 
violation appears in 79 percent of all CDRH official actions we reviewed, there were 
generally fewer total reporting violations per action than there were protocol or 
documentation violations. 
Human subjects protection violations.  The most common human subjects protection 
violation cited was the use of a deficient consent form.  Other letters noted a lack of 
signed informed consent forms, either because the subject never signed the consent or that 
the consents are missing full signatures or dates for subjects, witnesses and clinical 
investigators.  Other clinical investigators were faulted for not getting subject consent until 
after performing a surgical or other procedure on the subject.  Other violations noted 
include use of an unapproved consent form and failing to give a copy of the consent form 
to subjects.  Additionally, a few clinical investigators were found to have allowed device 
or calibration equipment to malfunction despite the potential for harm to subjects. 
Drug, device and biologic control violations.  Many official actions cited clinical 
investigators difficulties maintaining control of the receipt, use and disposition of 
investigational drugs, devices or biologics.  Often no records existed to document when 
and how many such products came in and out of the investigators control.  Other warning 
letters note discrepancies in product control records.  The Centers reported product 
control violations in 36 to almost 50 percent of their official actions; problems with 
product control are mentioned in 83 of the 184 actions we reviewed.  This is the violation 
category that is mentioned the least in FDA official actions to clinical investigators. 
23 
Oversight of Clinical Investigators  OEI-05-99-00350  APPENDIX B 
Agency Comments

24 
Oversight of Clinical Investigators  OEI-05-99-00350  25 
Oversight of Clinical Investigators  OEI-05-99-00350