Department of Health and Human Services 

OFFICE OF 

INSPECTOR GENERAL 

JUNE GIBBS BROWN 

Inspector General 

JUNE 2000 

OEI-05-99-00350 

FDA Oversight of 

Clinical Investigators 
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 
EXECUTIVE EXECUTIVE SUMMARY SUMMARY 

PURPOSE 

To examine the Food and Drug Administration’s (FDA) selection of clinical investigators 

for inspection and FDA’s discipline of those clinical investigators found in violation of 

FDA’s 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 FDA’s 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 FDA’s bioresearch monitoring programs. 

We also analyzed FDA’s listing of clinical investigators, as well as performed a work flow 

analysis. We only examined FDA’s 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, nonrandomly 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 

Oversight of Clinical Investigators 1 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 FDA’s 

oversight of clinical investigators 

Although respondents indicated that program goals are ensuring data integrity and 

protecting human subjects, FDA’s 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 FDA’s 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 FDA’s 

oversight of clinical investigators. 

Oversight of Clinical Investigators 2 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 system’s 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 FDA’s 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 Agency’s comments. 

Oversight of Clinical Investigators 3 OEI-05-99-00350 
TABLE OF CONTENTS 

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

Oversight of Clinical Investigators 4 OEI-05-99-00350 
INTRODUCTION INTRODUCTION 

PURPOSE 

To examine the Food and Drug Administration’s (FDA) selection of clinical investigators 

for inspection and FDA’s discipline of those clinical investigators found in violation of 

FDA’s 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; 

Oversight of Clinical Investigators 5 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 FDA’s 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 investigator’s 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 

Oversight of Clinical Investigators 6 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 investigator’s 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 

Center’s 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 investigator’s 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. 

Oversight of Clinical Investigators 7 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 FDA’s 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 FDA’s bioresearch monitoring programs involved in the approval of human 

drugs, biologics and medical devices. We did not examine FDA’s 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 FDA’s Centers between Fiscal Years (FY) 1994 and 1999. We 

interviewed the staff (27) and managers (6) of the bioresearch monitoring programs at 

FDA’s 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. 

Oversight of Clinical Investigators 8 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 FDA’s 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 FDA’s 

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 President’s Council on Integrity and Efficiency. 

Oversight of Clinical Investigators 9 OEI-05-99-00350 
FINDINGS FINDINGS 

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 FDA’s 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 investigator’s participation in the investigation. 

The sponsor must notify FDA when a clinical investigator’s 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 CDRH’s 

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. 

Oversight of Clinical Investigators 10 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 riskbenefit 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. 

FDA’s 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 

Oversight of Clinical Investigators 11 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 FDA’s 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 FDA’s 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 

Oversight of Clinical Investigators 12 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. 

Oversight of Clinical Investigators 13 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 

investigator’s 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 site’s 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 

Oversight of Clinical Investigators 14 OEI-05-99-00350 
identified problems. If the same problems are found during a second site visit, the 

implication is that the clinical investigator’s 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 FDA’s 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. 

Oversight of Clinical Investigators 15 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 reviewer’s 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 investigator’s 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 

Oversight of Clinical Investigators 16 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 Commissioner’s 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 

Oversight of Clinical Investigators 17 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 program’s 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 monitoring’s 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 program’s 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] doesn’t want to hear it unless it’s 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 “aren’t allowed to be involved 

soon enough to be fully useful.” 

Oversight of Clinical Investigators 18 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 

FDA’s 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. 

Oversight of Clinical Investigators 19 OEI-05-99-00350 
RECOMMENDATIONS 

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 FDA’s 

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 system’s 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 FDA’s 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. 

Oversight of Clinical Investigators 20 OEI-05-99-00350 
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 Agency’s comments. 

Oversight of Clinical Investigators 21 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 

Subject 

Protection 

Drug/Device/ 

Biologic 

Control 

CDRH 

107 official actions 

83 (78%) 83 (78%) 85 (79%) 69 (64%) 52 (49%) 

CDER 

58 official actions 

57 (98%) 51 (88%) 35 (60%) 41 (71%) 21 (36%) 

CBER 

24 official actions 

20 (83%) 21 (88%) 19 (79%) 16 (67%) 10 (42%) 

Total 

189 official actions 

160 (85%) 155 (82%) 139 (74%) 126 (67%) 83 (44%) 

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 

Oversight of Clinical Investigators 22 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 investigator’s 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 CDER’s 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 investigator’s 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. 

Oversight of Clinical Investigators 23 OEI-05-99-00350 
APPENDIX B 

Agency Comments

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