Department of Health and Human Services

OFFICE OF 

INSPECTOR GENERAL 

 

Daniel R. Levinson 

Inspector General 

January 2009 

OEI-05-07-00730 

 

THE FOOD AND DRUG 

ADMINISTRATION’S OVERSIGHT 

OF CLINICAL INVESTIGATORS’ 

FINANCIAL INFORMATION 
Office of Inspector General 

http://oig.hhs.gov 

The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, as 

amended, is to protect the integrity of the Department of Health and Human Services 

(HHS) programs, as well as the health and welfare of beneficiaries served by those 

programs. This statutory mission is carried out through a nationwide network of audits, 

investigations, and inspections conducted by the following operating components: 

Office of Audit Services 

The Office of Audit Services (OAS) provides auditing services for HHS, either by conducting 

audits with its own audit resources or by overseeing audit work done by others. Audits 

examine the performance of HHS programs and/or its grantees and contractors in carrying 

out their respective responsibilities and are intended to provide independent assessments of 

HHS programs and operations. These assessments help reduce waste, abuse, and 

mismanagement and promote economy and efficiency throughout HHS. 

Office of Evaluation and Inspections 

The Office of Evaluation and Inspections (OEI) conducts national evaluations to provide 

HHS, Congress, and the public with timely, useful, and reliable information on significant 

issues. These evaluations focus on preventing fraud, waste, or abuse and promoting 

economy, efficiency, and effectiveness of departmental programs. To promote impact, OEI 

reports also present practical recommendations for improving program operations. 

Office of Investigations 

The Office of Investigations (OI) conducts criminal, civil, and administrative investigations 

of fraud and misconduct related to HHS programs, operations, and beneficiaries. With 

investigators working in all 50 States and the District of Columbia, OI utilizes its resources 

by actively coordinating with the Department of Justice and other Federal, State, and local 

law enforcement authorities. The investigative efforts of OI often lead to criminal 

convictions, administrative sanctions, and/or civil monetary penalties. 

Office of Counsel to the Inspector General 

The Office of Counsel to the Inspector General (OCIG) provides general legal services to 

OIG, rendering advice and opinions on HHS programs and operations and providing all 

legal support for OIG’s internal operations. OCIG represents OIG in all civil and 

administrative fraud and abuse cases involving HHS programs, including False Claims Act, 

program exclusion, and civil monetary penalty cases. In connection with these cases, OCIG 

also negotiates and monitors corporate integrity agreements. OCIG renders advisory 

opinions, issues compliance program guidance, publishes fraud alerts, and provides other 

guidance to the health care industry concerning the anti-kickback statute and other OIG 

enforcement authorities. 
 

Δ EXECUTIVE SUMMARY 

OBJECTIVE

1. To describe the extent and nature of clinical investigators’ disclosed 

financial interests reported to the Food and Drug Administration 

(FDA) for marketing applications approved in fiscal year (FY) 2007. 

2. To assess FDA’s oversight of clinical investigators’ financial 

information. 

BACKGROUND 

Most new drugs, biological products, and medical devices undergo 

clinical trials on human subjects before they are marketed in the United 

States. Sponsors, generally pharmaceutical or device companies, 

oversee clinical trials conducted by clinical investigators. Before clinical 

trials begin, sponsors submit a pretrial application to FDA outlining 

their study design. After clinical trials are completed, sponsors wishing 

to market their product submit a marketing application to FDA. 

Sponsors must collect financial information from clinical investigators 

before clinical trials. However, sponsors submit financial information to 

FDA only when they submit their marketing application after clinical 

trials end. For each clinical investigator, sponsors submit a financial 

form either certifying that the investigator does not have a financial 

interest or disclosing the financial interest. Federal regulations also 

allow sponsors to indicate that they acted with due diligence but were 

unable to obtain financial information from a clinical investigator. For 

each disclosed financial interest, sponsors must attach details of the 

financial interest and a record of their actions to minimize potential 

bias toward clinical trial results. 

FDA assigns marketing applications to a multidisciplinary team for 

review. Reviewers evaluate financial information as well as sponsors’ 

actions to minimize any potential bias related to clinical investigators’ 

disclosed financial interests. Reviewers provide written notes that are 

used to determine whether a marketing application should be approved 

by FDA. If reviewers suspect that disclosed financial interests 

compromised data integrity, they are required to take action to ensure 

the reliability of the data. 

We reviewed financial forms, attachments, and accompanying FDA 

review notes for all 118 marketing applications approved by FDA in 

FY 2007. We also reviewed FDA regulations and guidance, conducted 

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EXECUTIVE SUMMARY 

structured interviews with FDA officials, and sent an electronic survey 

to FDA reviewers. 

FINDINGS 

One percent of clinical investigators disclosed a financial interest. 

Among clinical investigators listed in financial forms, 1 percent 

disclosed at least one financial interest. This represents 206 of the 

29,691 clinical investigators listed in financial interest forms. Of these 

206 clinical investigators, almost all disclosed only one financial 

interest, with a few disclosing two or three financial interests. 

FDA cannot determine whether sponsors have submitted financial 

information for all clinical investigators. FDA cannot determine 

whether sponsors have submitted complete financial information for all 

clinical investigators because it does not have a complete list of clinical 

investigators. In addition, FDA does not use onsite inspections to 

confirm that submitted financial information is complete. 

Forty-two percent of FDA-approved marketing applications were 

missing financial information. Twenty-three percent of approved 

marketing applications were missing a certification or disclosure form 

or required attachments. In 28 percent of marketing applications, 

sponsors used the due diligence exemption to indicate that they were 

unable to provide complete financial information. Although allowed by 

regulation, sponsors’ use of the diligence exemption results in no 

financial information for FDA reviewers. Some marketing applications 

had both missing attachments and the due diligence exemption was 

marked. 

FDA did not document a review of any financial information for 

31 percent of marketing applications. When FDA reviewers used a 

review template, they were more likely to document a review of 

financial information. 

Neither FDA nor sponsors took action for 20 percent of marketing 

applications with disclosed financial interests. In 20 percent of 

marketing applications, FDA reviewers did not take action and sponsors 

did not indicate that they minimized potential bias during the clinical 

trials. For over half of these marketing applications, reviewers did not 

document a review of financial information. In addition, when FDA did 

take action, their actions were inconsistent. 

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E XECUTIVE SUMMARY 

RECOMMENDATIONS 

FDA should ensure that sponsors submit complete financial 

information for all clinical investigators. 

• FDA should use a complete list of clinical investigators to check 

that sponsors have submitted financial information for all 

clinical investigators. 

• FDA should check that sponsors have submitted all required 

attachments to financial forms. 

• FDA should update guidance to sponsors regarding the due 

diligence exemption. 

• FDA should add a review of financial information to the onsite 

inspection protocol. 

FDA should ensure that reviewers consistently review financial 

information and take action in response to disclosed financial 

interests. 

• FDA should require that all centers consistently use a template 

that includes a prompt to document a review of financial 

information. 

• FDA should provide additional guidance and training to 

reviewers. 

FDA should require that sponsors submit financial information for 

clinical investigators as part of the pretrial application process. 

AGENCY COMMENTS AND OFFICE OF INSPECTOR GENERAL 

RESPONSE 

FDA expressed concerns about elements of our analysis in three of our 

findings. In response to FDA’s concerns, we removed employees from 

our analysis of disclosed financial interests. For FDA’s remaining 

concerns, we maintain that our analysis is accurate. 

FDA agreed with all of our recommendations except our final 

recommendation that FDA require sponsors to submit financial 

information for clinical investigators as part of the pretrial application 

process. FDA emphasized that collecting financial information before a 

clinical trial starts is the sponsors’ responsibility. However, despite this 

important role for sponsors, FDA has no mechanism in place to ensure 

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EXECUTIVE SUMMARY 

that sponsors are in fact collecting financial information before 

beginning clinical trials. 

FDA also stated that it would take significant additional effort for both 

industry and FDA to collect and review financial information during the 

pretrial application process. However, pursuant to regulation, FDA 

already requires sponsors to collect financial information before the 

start of clinical trials. In addition, basic information on clinical 

investigators is submitted to FDA as they are added to clinical trials. 

Further, FDA asserted that this additional effort would not be 

worthwhile because financial interests are only one form of potential 

bias and not all clinical trials are presented in the marketing 

application. Receiving financial information during the pretrial 

application process would allow FDA to have information on all 

potential sources of financial bias. FDA could then work effectively with 

sponsors to identify potential bias. In addition, receiving financial 

information related to ongoing clinical trials is in keeping with FDA’s 

stated intention to improve its oversight of ongoing clinical trials. 

We continue to recommend that FDA require sponsors to submit 

financial information as part of the pretrial application process. 

Acknowledging the burden to FDA’s administrative and review staff, we 

encourage FDA to develop a review of financial information that best 

balances the additional effort with the potential benefits. 
Δ TABLE OF CONTENTS 

EXECUTIVE SUMMARY .....................................i

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 

FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 

 One percent of clinical investigators disclosed a financial 

 interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 

FDA cannot determine whether sponsors have submitted 

complete financial information. . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 

 FDA approved applications missing financial information . . . . . . 17 

 FDA did not always note a review of financial information . . . . . 18 

 No action taken in 20 percent of applications with disclosures . . 20 

 

RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 

 Agency Comments and Office of Inspector General Response . . . 26 

APPENDIXES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 

 A: Certification of No Financial Interests, Form 3454 . . . . . . . . . 30 

 B: Disclosure of Financial Interests, Form 3455. . . . . . . . . . . . . . 31 

 C: Financial Forms Submitted to Each Center in 

Fiscal Year 2007. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 

 D: Response Rates for Reviewer Survey . . . . . . . . . . . . . . . . . . . . 33 

 E: Description of Food and Drug Administration Action . . . . . . . 34 

 F: Agency Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 

ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 
 

ΔINTRODUCTION INTRODUCTION 

OBJECTIVE 

1. To describe the extent and nature of clinical investigators’ disclosed 

financial interests reported to the Food and Drug Administration 

(FDA) for marketing applications approved in fiscal year (FY) 2007. 

2. To assess FDA’s oversight of clinical investigators’ financial 

information. 

BACKGROUND 

Research has shown that financial relationships exist between medical 

companies and researchers, including researchers conducting clinical 

trials for the approval of new drugs, biological products, and medical 

devices. For example, the Journal of the American Medical Association 

reported that between 23 percent and 28 percent of academic 

researchers had financial interests in medical companies.1 

Financial relationships between researchers and medical companies 

may compromise the safety of human subjects and the integrity of 

research data. After a teenager died while undergoing experimental 

treatment in 1999, the President encouraged agencies to develop steps 

to address financial relationships. An investigation into the case found 

that many of the clinical investigators had financial interests in the 

sponsor of that clinical trial.2 In another case, study results from a 

medical device trial may have been “cast in an overly flattering light,” 

potentially because researchers at about half the clinical trial sites had 

financial interests in the device company.3 

The Office of Inspector General (OIG) has worked to ensure that 

financial interests do not compromise clinical trials. FDA developed its 

1999 regulations regarding the disclosure of clinical investigators’ 

financial interests after OIG officials reported that FDA’s failure to 

collect information about clinical investigators’ financial interests could 

constitute a material weakness under the Federal Manager’s Financial 

1 Justin E. Bekelman, et al., 2003. “Scope and Impact of Financial Conflicts of Interest in 

Biomedical Research,” Journal of the American Medical Association, vol. 289(4), p. 456. 

Available online at http://jama.ama-assn.org/cgi/reprint/289/4/454?ijkey= 

9e08192f3f85916bd89686c6af4713ad33b514ea. Accessed on May 30, 2008. 

2 FDA, “Human Gene Therapy: Harsh Lessons, High Hopes.” Available online at 

http://www.fda.gov/fdac/features/2000/500_gene.html. Accessed on May 5, 2008. 

3 Abelson, Reed, “Financial Ties Cited as Issue in Spine Study.” The New York Times, 

January 30, 2008, p. 2. 

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INTRODUCTION 

Integrity Act.4 Although FDA determined that a material weakness did 

not exist, FDA concluded that there was a need to address this issue 

through rulemaking.5

The Food and Drug Administration 

2 

r 

vices. 

Among other activities, FDA is responsible for protecting the public 

health by ensuring the safety, efficacy, and security of human drugs, 

biological products, and medical devices (hereinafter referred to as 

investigational products).6 Within FDA, the Center for Drug 

Evaluation and Research (CDER) regulates drugs, the Center fo

Biologics Evaluation and Research (CBER) regulates biological products 

that come from living sources (such as vaccines or gene therapies), and

the Center for Devices and Radiological Health (CDRH) regulates 

medical de

Clinical Trials 

The Federal Food, Drug, and Cosmetic Act generally requires that most 

new investigational products undergo clinical trials on human subjects 

to demonstrate their safety and efficacy before they are approved for 

sale in the United States.7 Sponsors, clinical investigators, and 

institutional review boards (IRB) play a role in clinical trials. 

Sponsors. Sponsors, often pharmaceutical or device companies, are 

responsible for developing and testing investigational products in 

clinical trials. 

Clinical investigators. Sponsors hire clinical investigators to conduct 

clinical trials. Clinical investigators may be researchers at academic 

institutions or practicing physicians. Typically, there are many clinical 

investigators working in multiple clinical trial sites, including outside 

the United States, for each clinical trial. 

There are both primary investigators and subinvestigators. Primary 

investigators recruit subjects, supervise clinical studies, collect data, 

4 21 CFR § 54.4; FDA, “Guidance Financial Disclosure by Clinical Investigators.” 

Available online at http://www.fda.gov/oc/guidance/financialdis.html. Accessed on 

March 11, 2008. 

5 63 Fed. Reg. 5233 (Feb. 2, 1998). 

6 FDA, “FDA’s Mission Statement.” Available online at 

http://www.fda.gov/opacom/morechoices/mission.html. Accessed on April 3, 2008. 

7 21 U.S.C. § 355; 21 CFR § 812.20(b)(2); FDA, “The FDA’s Drug Review Process: 

Ensuring Drugs Are Safe and Effective.” Available online at 

http://www.fda.gov/fdac/features/2002/402_drug.html. Accessed on March 11, 2008. 

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INTRODUCTION 

and report study results to the sponsor.8 Primary investigators must 

sign investigator agreements stating that they will comply with all 

relevant FDA regulations.9 Subinvestigators assist primary 

investigators with their responsibilities. 

Institutional Review Boards. IRBs are committees that oversee clinical 

investigators’ research to ensure that all steps are taken to protect the 

rights and welfare of human subjects.10 IRBs must include members 

from varying backgrounds and often are composed of physicians, 

scientists, lawyers, and ethicists.11 An IRB must approve all clinical 

trials involving human subjects before clinical trials can begin.12 

During their reviews of clinical trials, IRBs are not required to review 

clinical investigators’ financial information. Yet, the Department of 

Health and Human Services (HHS) strongly urges IRBs to look at 

financial information.13 It has been estimated that a quarter of IRBs 

routinely conduct such a review.14 

FDA’s Oversight of Clinical Trials 

FDA requires that sponsors file a pretrial application before beginning 

clinical trials.15 16 Pretrial applications include the study protocol, the 

8 21 CFR § 312.60 (drugs and biologics); 21 CFR § 812.100 (devices). FDA, “Guidance on 

Clinical Trials,” p. 18. Available online at http://www.fda.gov/cder/guidance/959fnl.pdf. 

Accessed on May 5, 2008. 

9 Pretrial applications submitted to CDRH include investigator agreements for 

subinvestigators. (21 CFR § 312.53 (drugs and biologics); 21 CFR § 812.43(c) (devices)). 

10 21 CFR § 56. 

11 21 CFR § 56.107. 

12 21 CFR § 56.101. 

13 HHS, “Financial Relationships and Interests in Research Involving Human Subjects: 

Guidance for Human Subject Protection.” May 12, 2004. Available online at 

http://www.hhs.gov/ohrp/humansubjects/finreltn/finalguid.pdf. Accessed on May 30, 2008. 

14 National Institutes of Health (NIH), “Financial Conflicts of Interest and Research 

Objectivity: Issues for Investigators and Institutional Review Boards.” June 5, 2000. 

Available online at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-040.html. 

Accessed on March 25, 2008. 

15 Sponsors submit an Investigational New Drug Application to CDER or CBER per 

21 CFR § 312.20. Sponsors submit an Investigational Device Exemption to CDRH per 

21 CFR § 812.20. 

16 FDA uses the term “sponsor” and “applicant” at different times in the regulations. 

FDA states that generally “the sponsor of the covered study, and the applicant company are 

the same party.” For the purpose of this report, we refer to sponsors and applicants 

collectively as “sponsors.” Question Seven, FDA, “Guidance Financial Disclosure by Clinical 

Investigators.” Available online at http://www.fda.gov/oc/guidance/financialdis.html. 

Accessed on March 11, 2008. 

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INTRODUCTION 

chosen IRB(s), and assurances that human subjects will be protected.17 

As part of the pretrial application to FDA, sponsors submit the names, 

addresses, and qualifications of all primary investigators. They must 

also list all subinvestigators. Pretrial applications do not include 

financial information about clinical investigators. 

Upon successful completion of clinical trials, sponsors that wish to 

market a product must submit a marketing application to FDA.18 

Marketing applications include clinical trial results, descriptions of the 

investigational products’ components, proposed labeling, and financial 

information about clinical investigators’ relationship to sponsors. 

FDA assigns the marketing application to a multidisciplinary team of 

reviewers. Reviewers represent a variety of scientific disciplines, 

including medicine, pharmacology, statistics, and chemistry. Reviewers 

evaluate information in the marketing application relevant to their 

expertise.19 These reviews help determine whether FDA will approve a 

marketing application. 

Onsite inspections. During and after clinical trials, FDA performs onsite 

inspections of clinical investigators, sponsors, and IRBs through the 

Bioresearch Monitoring Program (BiMo).20 The purpose of the BiMo 

program is to ensure the protection of research subjects and the 

integrity of clinical trial data.21 BiMo officials work in each of the three 

FDA centers. 

BiMo conducts both surveillance and directed inspections to determine 

compliance with FDA regulations. Surveillance inspections are 

typically routine inspections that occur after FDA receives a marketing 

application and target completed clinical trials. Directed inspections 

typically target ongoing clinical trials and occur because of specific 

concerns about data integrity. These concerns could include clinical 

investigators’ financial interests.

17 21 CFR § 312.23. 

18 21 CFR § 314.50 (drugs); 21 CFR § 601.2 (biologics); 21 CFR § 814.20 (devices). 

19 FDA, “The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective.” 

Available online at http://www.fda.gov/fdac/features/2002/402_drug.html. Accessed on 

March 27, 2008. 

20 21 U.S.C. §§ 355 and 360i. FDA, “Compliance Program Guidance Manual,” 

Chapter 48: Bioresearch Monitoring Background. 

21 FDA, “Bioresearch Monitoring Program.” Available online at 

http://www.fda.gov/oc/gcp/compliance.html. Accessed on October 30, 2008. 

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INTRODUCTION 

Sponsors’ Financial Disclosure Requirements 

Beginning in 1999, FDA required sponsors submitting marketing 

applications to disclose the financial interests of primary investigators 

and subinvestigators (hereinafter referred to as clinical investigators) 

who contributed data for a “covered clinical study.”22 In 2001, FDA 

issued guidance to sponsors providing additional details about the 

requirements. The guidance defines terms included in the regulations 

and addresses questions from the industry.23

Pursuant to regulations, sponsors must obtain financial information 

from clinical investigators before clinical trials.24 This is done so 

sponsors can consult with FDA early on regarding “any potentially 

problematic financial interest,” and take action to minimize any 

potential study bias.25 Sponsors can collect financial information from 

clinical investigators using any format or process. 

After their initial submission, clinical investigators are required to 

provide updates to sponsors with any changes in their financial status 

during clinical trials and in the year after clinical trials are complete. 26 

Sponsors must maintain complete records detailing clinical 

investigators’ financial information during clinical trials and for 2 years 

after FDA approves a marketing application.27 

Sponsors are required to submit financial information on clinical 

investigators to FDA only when they submit the marketing application 

after clinical trials are complete. 

FDA requires that sponsors disclose the following financial interests for 

all clinical investigators, their spouses, and their dependent children: 

(1) any financial arrangement between the sponsor whereby the value 

of the compensation could be influenced by the study outcome; 

5 

22 FDA defines a “covered clinical study” as any study submitted in a marketing 

application relied upon to show a product is effective or any study to which a single 

investigator significantly contributes to the demonstration of safety. For purposes of this 

report, we refer to covered clinical studies as clinical trials. 21 CFR §§ 54.4 and 54.2(e). 

23 FDA, “Guidance Financial Disclosure by Clinical Investigators.” Available online at 

http://www.fda.gov/oc/guidance/financialdis.html. Accessed on March 11, 2008. 

24 21 CFR § 312.53(c)(4) (drugs and biologics); 21 CFR § 812.43(c) (devices). 

25 67 Fed. Reg. 6042 (Feb. 8, 2002); Question 6, FDA, “Guidance Financial Disclosure by 

Clinical Investigators.” Available online at 

http://www.fda.gov/oc/guidance/financialdis.html. Accessed on March 11, 2008. 

26 21 CFR § 312.53 (drugs and biologics); 21 CFR § 812.43(c) (devices). 

27 21 CFR § 54.6. 

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INTRODUCTION 

(2) a sum of all significant payments exceeding $25,000 made on or 

after February 2, 1999, from the sponsor. Payments include research 

grants, retainers for ongoing consultation, or a general honorarium. 

They do not include the payments, such as salaries, associated with 

conducting the clinical trial; 

(3) any proprietary interest in the tested product, including patents, 

trademarks, or licensing agreements; and 

(4) equity in the sponsor’s public company exceeding $50,000, or equity 

for which the value cannot be determined through public prices.28

Certification: Financial Interests and Arrangements of Clinical 

Investigators, Form 3454. Sponsors use Form 3454 to list clinical 

investigators who have no financial interest with the sponsor. Sponsors 

can submit a single certification form for multiple clinical investigators 

involved with clinical trials. If sponsors cannot obtain financial 

information from a clinical investigator, they can indicate on the 

certification form that they acted with due diligence to collect the 

information.29 

FDA’s 2001 guidance defines due diligence as “a measure of activity 

expected from a reasonable and prudent person under a particular 

circumstance.”30 In 2002, in comments to a Federal Register notice, 

FDA was asked to define what constitutes due diligence. In response, 

FDA advised sponsors to try to locate clinical investigators through at 

least two telephone calls, and document notes of the calls. In addition, 

FDA recommended that sponsors follow up in writing, sending at least 

two certified letters.31 

If sponsors indicate due diligence, they are expected to describe why 

they were unable to obtain the financial information and document 

28 21 CFR §§ 54.2 and 54.4(a)(3); FDA, “Guidance Financial Disclosure by Clinical 

Investigators.” Available online at http://www.fda.gov/oc/guidance/financialdis.html. 

Accessed on March 11, 2008. We combined the regulations’ two equity disclosures in this 

list because they are combined on the form that sponsors complete when disclosing a 

clinical investigator’s financial interests. 

29 21 CFR § 54.4. 

30 Question Three, FDA, “Guidance Financial Disclosure by Clinical Investigators.” 

Available online at http://www.fda.gov/oc/guidance/financialdis.html. Accessed on 

March 11, 2008. 

31 67 Fed. Reg. 6041 (Feb. 8, 2002). 

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INTRODUCTION 

their attempts to obtain the information.32 Sponsors are required to 

provide the reasons why they were unable to obtain the information 

when they claim the due diligence exemption on the certification form. 

Sponsors are not required to submit documentation of their attempts to 

contact clinical investigators nor describe their attempts. See 

Appendix A for a copy of the certification form. 

Disclosure: Financial Interests and Arrangements of Clinical Investigators, 

Form 3455. Sponsors use Form 3455 to disclose clinical investigators’ 

financial interests. The form lists FDA’s four financial disclosure 

categories. Sponsors must submit a separate disclosure form for each 

clinical investigator with financial interests. 

Sponsors must include two attachments with each disclosure form. The 

first must provide specific details about the financial interest. The 

second must describe any steps taken to minimize the potential bias 

resulting from disclosed financial interests.33 FDA does not specify the 

actions sponsors must take to minimize potential bias. See Appendix B 

for a copy of the disclosure form. 

FDA’s Oversight of Financial Information 

When FDA receives a marketing application, it performs an 

administrative check to ensure that sponsors have included the required 

information, including financial forms. If sponsors neglect to submit 

financial forms, FDA can refuse to accept a marketing application for 

review.34 When FDA accepts a marketing application for review, FDA 

reviewers evaluate the application and clinical trial data, including 

whether disclosed financial interests compromised the integrity of the 

trial data.

Marketing application review. Among other things, the marketing 

application review includes an evaluation of clinical investigators’ 

disclosed financial interests to determine their potential effect on data 

integrity. FDA reviewers provide written notes regarding their reviews. 

32 FDA, Form 3455, “Disclosure: Financial Interests and Arrangements of Clinical 

Investigators.” Available online at http://www.fda.gov/opacom/morechoices/fdaforms/FDA3455.pdf. Accessed on October 11, 2007. FDA, “Guidance Financial Disclosure by Clinical 

Investigators.” Available online at http://www.fda.gov/oc/guidance/financialdis.html. 

Accessed on March 11, 2008. 

33 21 CFR § 54.4(a)(3)(v). 

34 21 CFR § 54.4(c). 

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INTRODUCTION 

Division directors35 read these review notes to determine whether to 

recommend approval for a marketing application.36

The process for reviewing financial information within the marketing 

application differs by center. CDER has a review template that 

reviewers are required to use to review various aspects of marketing 

applications, including financial information. CBER has a draft review 

template that reviewers may use, and that includes a review of financial 

information. CDRH does not have a review template. 

FDA action in response to disclosed financial interests. If FDA determines 

that clinical investigators’ disclosed financial interests raise a serious 

question about the integrity of the data, FDA is required to take action 

to ensure the reliability of the data.37 For example, FDA reviewers may 

take action if they discover that results from clinical trial sites managed 

by clinical investigators with disclosed financial interests were more 

favorable than average. 

Regulations do not stipulate specific actions, but offer examples of 

possible actions.38 Suggested actions include requesting an onsite 

inspection, requesting that the sponsor submit further data analyses or 

conduct additional independent studies, and refusing to review clinical 

trial results.39 

Related Reports 

An OIG report issued in 2000 found that FDA’s overall oversight of 

clinical investigators was limited.40 Additionally, a 2007 OIG report 

found that FDA had limited ability to effectively manage BiMo.41 The 

35 Centers may refer to this position under various titles, including office director and 

team leader. For this report, we use the term division director to indicate the FDA official 

who provides recommendations to the FDA Commissioner on whether to approve a 

marketing application. 

36 FDA, “The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective.” 

Available online at http://www.fda.gov/fdac/features/2002/402_drug.html. Accessed on 

March 27, 2008. 

37 21 CFR § 54.5(c). 

38 Ibid. 

39 Ibid. 

40 OIG, “FDA Oversight of Clinical Investigators,” OEI-05-99-00350, June 2000. 

41 OIG, “The Food and Drug Administration’s Oversight of Clinical Trials,” 

OEI-01-06-00160, September 2007. 

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I NTRODUCTION DUCTION 

evaluation estimated that FDA inspected 1 percent of clinical trial sites 

between 2000 and 2005.42

In 2001, the Government Accountability Office (GAO) issued a report 

that compared financial disclosure requirements of FDA and NIH. GAO 

found that, unlike NIH, FDA is not notified of clinical investigators’ 

financial information until after clinical trials are complete. GAO 

recommended that HHS develop specific guidance or policy concerning 

financial information. In response, HHS stated that to the extent 

specific guidance or policy was developed, it would be coordinated 

throughout the Department.43 

In 2001, the Government Accountability Office (GAO) issued a report 

that compared financial disclosure requirements of FDA and NIH. GAO 

found that, unlike NIH, FDA is not notified of clinical investigators’ 

financial information until after clinical trials are complete. GAO 

recommended that HHS develop specific guidance or policy concerning 

financial information. In response, HHS stated that to the extent 

specific guidance or policy was developed, it would be coordinated 

throughout the Department.43 

METHODOLOGY 

Scope 

To describe the extent and nature of clinical investigators’ financial 

interests, we reviewed disclosed financial interests from marketing 

applications approved in FY 2007. We did not review other types of 

applications approved by FDA; for instance, applications for generic 

products. By limiting our study to marketing applications, we focused 

on products that have been newly released to the public. 

This evaluation reviewed FDA’s oversight of clinical investigators’ 

financial interests. We did not review FDA’s oversight of the financial 

interests of FDA employees or FDA advisory board members. 

Data Collection 

We collected financial forms and attachments from all 118 marketing 

applications approved in FY 2007. This includes 73 marketing 

applications approved by CDER, 32 approved by CDRH, and 

13 approved by CBER. See Appendix C for financial forms submitted to 

each center in FY 2007. 

We also conducted six structured group interviews with FDA center 

officials and FDA BiMo officials from each of the three centers between 

January and March 2008. We discussed FDA’s process for overseeing 

financial information, guidance to sponsors and reviewers, action taken 

in response to disclosed financial interests, and BiMo reviews of 

financial information. 

42 Ibid. 

43 GAO, “Biomedical Research: HHS Direction Needed to Address Financial Conflicts of 

Interest,” GAO-02-89, p. 39, November 2001. 

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I NTRODUCTION 

To assess FDA’s review of financial information and actions taken in 

response to this review, we collected FDA reviewers’ notes, completed 

review templates, and summary review documents (hereinafter referred 

to as review notes) corresponding to their evaluation of financial 

information in the marketing applications. 

To assess FDA’s review of financial information and actions taken in 

response to this review, we collected FDA reviewers’ notes, completed 

review templates, and summary review documents (hereinafter referred 

to as review notes) corresponding to their evaluation of financial 

information in the marketing applications. 

To further understand FDA’s review process, we sent an electronic 

survey to FDA reviewers in January 2008. Survey questions pertained 

to reviewers’ process for evaluating financial information, any 

instructions they received, and whether they had ever taken action in 

response to disclosed financial interests. 

To further understand FDA’s review process, we sent an electronic 

survey to FDA reviewers in January 2008. Survey questions pertained 

to reviewers’ process for evaluating financial information, any 

instructions they received, and whether they had ever taken action in 

response to disclosed financial interests. 

We sent the survey to 790 potential reviewers identified by FDA center 

officials. Of those, 337 reviewers responded and, of these, 162 indicated 

that they had reviewed financial information in the past 3 years. We do 

not project the responses to all FDA reviewers and present survey data 

only from the 162 reviewers as secondary evidence in our findings. See 

Appendix D for a breakdown of survey responses by FDA center. 

We sent the survey to 790 potential reviewers identified by FDA center 

officials. Of those, 337 reviewers responded and, of these, 162 indicated 

that they had reviewed financial information in the past 3 years. We do 

not project the responses to all FDA reviewers and present survey data 

only from the 162 reviewers as secondary evidence in our findings. See 

Appendix D for a breakdown of survey responses by FDA center. 

Data Analysis 

Describing the extent and nature of disclosed financial interests. To 

describe the extent of disclosed financial interests, we reviewed all 

financial forms in marketing applications to classify each clinical 

investigator as: (1) having no financial interest, (2) disclosing a 

financial interest, or (3) unable to provide financial information. In 

total, sponsors listed 29,691 clinical investigators on financial forms. 

We did not include clinical investigators that the sponsor identified as 

employees because it was ambiguous whether sponsors were disclosing 

a financial arrangement for these employees. Sponsors are exempt from 

submitting financial information for employees.44 

We also described the extent of disclosed financial interests by 

calculating the percentage of marketing applications with at least one 

disclosed financial interest. 

To describe the nature of clinical investigators’ disclosed financial 

interests, we categorized financial interests using FDA’s four financial 

disclosure categories listed on the disclosure form. We used disclosed 

financial interests as the unit of analysis for this assessment because 

clinical investigators could disclose multiple financial interests in a 

marketing application. 

44 21 CFR § 54.4. 

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I NTRODUCTION 

In four marketing applications, sponsors disclosed 12 financial interests 

that fell below the federally defined threshold. We still categorized 

these as disclosed financial interests because sponsors informed FDA of 

financial relationships with clinical investigators. 

In four marketing applications, sponsors disclosed 12 financial interests 

that fell below the federally defined threshold. We still categorized 

these as disclosed financial interests because sponsors informed FDA of 

financial relationships with clinical investigators. 

Assessing whether marketing applications contained complete financial 

information. We assessed whether marketing applications had complete 

financial information by reviewing submitted financial forms and 

attachments. We categorized a marketing application as having 

complete financial information if it met four criteria: (1) included either 

a certification or disclosure form, (2) included an attachment with a 

description of steps taken to minimize potential bias with each 

disclosure form, (3) included an attachment detailing descriptions of 

disclosed financial interests with each disclosure form, and (4) did not 

claim the due diligence exemption indicating that at least one clinical 

investigator did not provide financial information. We categorized a 

marketing application as having incomplete financial information if it 

failed to meet any of these four criteria. 

Assessing FDA’s review of financial information. To assess FDA’s review 

of financial information in FY 2007, we analyzed FDA’s review notes. 

We calculated the percentage of marketing applications with any 

mention of financial information in the review notes. For this analysis, 

we excluded administrative checklists that are used to check for 

financial interests forms. Checklists help ensure that sponsors submit 

forms, but do not indicate whether FDA reviewers read and evaluated 

the forms.

We also calculated the percentage of marketing applications with 

disclosed financial interests that had detailed review notes. We 

categorized review notes as detailed if they mention any of four things: 

(1) the sponsors’ actions to decrease potential bias, (2) aspects of the 

study design that may have minimized potential bias, (3) action taken 

to ensure data reliability, or (4) a request for additional financial 

information from sponsors. 

Assessing sponsors’ and FDA actions in response to disclosed financial 

interests. To assess the extent of sponsors’ actions, we calculated the 

percentage of marketing applications on which sponsors indicated that 

they took action to minimize potential bias for all clinical investigators 

with disclosed financial interests. Regulations require that sponsors 

report their actions to minimize potential bias for all disclosed financial 

interests. Thus, we did not count two marketing applications on which 

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 INTRODUCTION 

sponsors reported their steps for only some disclosed financial interests 

as sponsors taking actions. 

To assess the extent of FDA reviewers’ actions, we calculated the 

percentage of marketing applications with review notes indicating any 

action taken or requested by an FDA reviewer. To assess the nature of 

FDA reviewers’ actions, we reviewed FDA’s review notes. We 

categorized FDA’s actions based on the examples listed in FDA 

regulation. Because the regulations do not provide an exhaustive list, 

we also considered reanalyzing clinical trial results from clinical 

investigators with disclosed financial interests as an action. 

Limitations 

The number of clinical investigators listed on financial forms from 

marketing applications may be slightly inflated. Sponsors often listed 

clinical investigators without financial interests, as an attachment to 

the certification form, by their clinical trial site. Because clinical 

investigators may work on multiple clinical trial sites, investigators 

may have been listed more than once. We attempted to address this by 

conducting electronic searches for duplicate names. As a result, we 

expect any potential overestimation to be minimal. 

We relied solely on review notes as an indication that FDA reviewers 

evaluated financial information. FDA reviewers are required to 

evaluate financial information but are not required to provide written 

documentation of this review. Therefore, FDA reviewers may have 

evaluated financial information but failed to note their review. 

Nonetheless, written notes remain the most reliable evidence of an FDA 

review. Division directors review these written notes when determining 

whether to recommend that FDA approve a marketing application.45

We also relied solely on review notes as an indication that FDA 

reviewers took action in response to disclosed financial interests. FDA 

reviewers may have taken action in response to disclosed financial 

interests but failed to note their action. Similar to assessing whether 

FDA reviewers evaluated financial information, written notes remain 

the most reliable evidence of FDA action. 

12 

45 FDA, “The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective.” 

Available online at http://www.fda.gov/fdac/features/2002/402_drug.html. Accessed on 

March 27, 2008. 

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INTRODUCTION 

Standards 

This study was conducted in accordance with the “Quality Standards for 

Inspections” issued by the President’s Council on Integrity and 

Efficiency and the Executive Council on Integrity and Efficiency. 

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FINDINGS 

Among clinical investigators 

listed in financial forms, 

1 percent disclosed at least one 

financial interest. This represents 206 of the 29,691 clinical 

investigators. Of the 206 clinical investigators, almost all disclosed only 

one financial interest, with a few disclosing two or three financial 

interests. Four clinical investigators disclosed two financial interests 

and two clinical investigators disclosed three financial interests. 

One percent of clinical investigators disclosed a 

financial interest 

Δ FINDINGS 

Disclosed financial interests were associated with almost half of marketing 

applications 

Forty-two percent of marketing applications included at least one 

clinical investigator with a disclosed financial interest. This represents 

49 of 118 marketing applications. 

Although most applications had few disclosed financial interests, some 

applications had numerous clinical investigators with disclosed 

financial interests. Sixty-seven percent of the 49 marketing 

applications with disclosed financial interests had one or two clinical 

investigators with a disclosed financial interest. On the other hand, 

12 percent of these 49 marketing applications included 10 or more 

clinical investigators with a disclosed financial interest. The application 

with the most disclosed financial interests had 38 clinical investigators 

with financial interests. 

Most disclosed financial interests were payments from sponsors 

Seventy-seven percent of disclosed financial interests were for payments 

from sponsors. Most payments were for consulting services or general 

honoraria. Though not required, 53 percent of payment disclosures 

included a specific dollar amount. The median reported payment was 

$47,252, almost twice the $25,000 minimum payment reporting 

threshold. The highest reported payment was a sponsors’ payment of 

$3.9 million to a clinical investigator’s affiliated institution. 

Nineteen percent of disclosed financial interests were for equity 

interests, primarily stock options. Though not required, 46 percent of 

equity disclosures included a specific dollar amount. The median 

reported equity interest was $65,000. This exceeds the $50,000 

minimum equity reporting threshold by $15,000. The highest reported 

equity interest was $148,751. 

Two percent of disclosed financial interests were for proprietary 

interests. Most of the marketing applications that included proprietary 

interests were for medical devices. 

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FINDINGS 

Lastly, 1 percent of disclosed financial interests were “financial 

arrangements that could influence the study outcome.” Sponsors 

included additional descriptions of only one of these disclosed financial 

interests. This clinical investigator was a patent owner of the product. 

See Table 1 for a list of clinical investigators’ disclosed financial 

interests by FDA’s financial disclosure categories. 

 

Table 1: Disclosed Financial Interests 

FDA Financial Disclosure Category 

Number of Disclosed 

Financial Interests 

Percentage of Total 

Disclosed Financial 

Interests

Payments from sponsors 165 77 percent 

Equity interests 41 19 percent 

Proprietary interests in tested product 5 2 percent 

Financial arrangements that could influence 

the study outcome 3 1 percent 

 Total 214* 99 percent** 

* Clinical investigators can disclose more than one financial interest. There were 206 clinical investigators with 

214 disclosed financial interests. 

** Total does not equal 100 percent because of rounding. 

Source: OIG analysis of marketing applications, 2008.

FDA cannot determine whether 

sponsors have submitted financial 

information for all clinical 

investigators because it does not 

have a complete list of clinical investigators. In addition, FDA does not 

use onsite BiMo inspections as a mechanism to confirm that submitted 

financial information is complete. These limitations could result in FDA 

being unaware of a clinical investigator’s financial interest and thus 

unable to gauge its potential bias on clinical trial results. 

FDA cannot determine whether sponsors have 

submitted financial information for all clinical 

investigators 

FDA does not have a complete list of clinical investigators 

FDA cannot systematically check whether marketing applications have 

financial information for all clinical investigators because FDA does not 

maintain a complete list of clinical investigators. FDA was able to 

provide a complete list of clinical investigators for only 7 percent of 

marketing applications approved in FY 2007. 

Although FDA maintains a database that captures demographic and 

inspection information on clinical investigators, it currently cannot be 

used to easily compile a complete list of clinical investigators per 

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FINDINGS 

marketing application. FDA’s Bioresearch Monitoring Information 

System database contains information for some clinical investigators. 

However, the database does not list subinvestigators for two FDA 

centers. In addition, the database only includes clinical investigators 

listed in pretrial applications, and does not include any clinical 

investigators who might have been recruited once the clinical trials 

were underway. 

BiMo inspections do not routinely review financial information 

BiMo inspectors are not instructed to routinely review financial 

information as part of their inspection protocol. Currently, BiMo 

inspectors review financial information only when an FDA reviewer 

specifically requests it or when an inspector takes personal initiative. 

Although BiMo inspects only a small portion of all clinical trial sites, 

these inspections are FDA’s only onsite and indepth tool for reviewing 

sponsors and clinical investigators. 

When BiMo inspectors reviewed financial information in the recent 

past, they found that sponsors had submitted incomplete financial 

information to FDA. For instance, in 2005, an inspection found that a 

clinical investigator did not submit financial information for a 

subinvestigator. As a result, FDA issued a letter to the clinical 

investigator suggesting areas of improvement. 

In another example, FDA reviewers, in 2006, requested an inspection of 

clinical investigators and a sponsor because of concerns about financial 

interests. BiMo inspectors found that a clinical investigator violated 

regulations by failing to disclose financial interests to the sponsor. 

BiMo inspectors also found that the sponsor failed to disclose the 

financial interests of an additional five clinical investigators to FDA. 

FDA issued the sponsor a letter suggesting areas of improvement. 

Moreover, when BiMo inspectors reviewed a sponsor in 2005, they found 

that the sponsor collected financial information shortly before the 

submission of the marketing application and not before beginning the 

clinical trial. According to regulation, sponsors are required to collect 

financial information from clinical investigators before beginning 

clinical trials. 

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FINDINGS 

Forty-two percent of 

approved marketing 

applications did not include 

complete financial 

information. Twenty-three percent of these marketing applications 

were missing required financial forms or attachments. Twenty-eight 

percent were missing financial information because sponsors used the 

due diligence exemption to indicate that they were unable to provide 

financial information. Although allowed by regulation, sponsors’ use of 

the diligence exemption results in no financial information for FDA 

reviewers. Some marketing applications had both missing attachments 

and the due diligence exemption marked. 

Forty-two percent of FDA-approved marketing 

applications were missing financial information 

Twenty-three percent of approved marketing applications did not include 

required financial forms or attachments 

Twenty-three percent of all 118 marketing applications approved in 

FY 2007 were missing financial interest forms or required attachments 

with disclosed financial interests. Of these, 7 percent did not include 

any certification or disclosure forms for any clinical investigators. 

Among marketing applications with disclosed financial interests, 

24 percent were missing the sponsors’ actions to minimize potential bias 

resulting from disclosed financial interests. In addition, 18 percent of 

marketing applications with disclosed financial interests were missing 

detailed descriptions of the financial interests. 

Twenty-eight percent of marketing applications indicated that sponsors 

were unable to provide complete financial information 

Twenty-eight percent of marketing applications included certification 

forms on which sponsors used the due diligence exemption to claim that 

they were unable to obtain complete financial information. As 

previously stated, Federal regulations allow sponsors to indicate that 

they acted with due diligence but were unable to obtain financial 

information from a clinical investigator. In total, sponsors indicated 

that they were unable to provide financial information for 1,123 clinical 

investigators. This is more than five times the 206 clinical investigators 

who disclosed financial interests. 

If sponsors use the due diligence exemption, regulations require them to 

explain why they were unable to obtain the information. In 18 percent 

of marketing applications indicating due diligence, sponsors did not 

explain why they were unable to obtain financial information from all 

clinical investigators, as required. When sponsors did include this 

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FINDINGS 

explanation, they most often reported that clinical investigators could 

not be located or failed to return the financial form. 

FDA reviewers did not document a 

review of financial information for 

31 percent of marketing 

applications. Over one-third of 

these marketing applications included disclosed financial interests. If 

FDA reviewers fail to document a review, division directors may 

overlook disclosed financial interests and their potential impact on data 

integrity. 

FDA did not document a review of any financial 

information for 31 percent of marketing 

applications 

Review templates increased the likelihood of a documented review of 

financial information 

Reviewers from CDER, the only center to consistently use a review 

template, documented a review of financial information for 95 percent of 

marketing applications. CDER reviewers used a review template 

94 percent of the time when documenting a review of financial 

information. 

Reviewers from CBER documented a review of financial information in 

23 percent of marketing applications. CBER is in the process of 

finalizing a review template similar to CDER’s template. When CBER 

reviewers documented a review of financial information, they always 

used a template. 

The CDER review template and CBER’s draft template prompt 

reviewers to “discuss whether the applicant adequately disclosed 

financial arrangements with clinical investigators and whether these 

arrangements raise questions about the integrity of the data.”46 The 

review template assigns a specific member of the review team the 

responsibility of reviewing financial information. 

Reviewers from CDRH documented a review of financial information in 

28 percent of marketing applications. CDRH reviewers do not use a 

review template. 

18 

46 FDA, “Manual of Policies and Procedures: Clinical Review Template,” July 9, 2004, 

p. 17. Available online at http://www.fda.gov/cder/mapp/6010.3.pdf. Accessed on 

March 28, 2008. 

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FINDINGS 

See Table 2 for FDA reviewers’ documented reviews of financial 

information by center. 

Table 2: FDA Reviewers’ Documented Reviews 

FDA Center Marketing Applications 

Percentage of Marketing 

Applications With 

Documented Reviews of 

Financial Information 

Percentage of 

Documented Reviews 

Found in a Template 

CDER 73 95 percent 94 percent 

CDRH 32 28 percent 0 percent* 

CBER 13 23 percent 100 percent 

 Total 118 69 percent 63 percent 

* CDRH reviewers do not use a template. 

Source: OIG analysis of FDA review notes, 2008. 

Most documented reviews of marketing applications with disclosed financial 

interests were detailed 

Seventy-three percent of marketing applications with disclosed financial 

interests had documented reviews. Among these documented reviews, 

72 percent of review notes were detailed and the remaining 28 percent 

were nondetailed. 

Detailed notes provided evidence of more complete analyses of how 

disclosed financial interests might affect clinical trial results. For 

example, one detailed note stated that Dr. X “received more than 

$25,000 in honoraria and travel expenses for educational activities. Any 

bias was minimized by the independent data monitoring, by the use of 

multiple investigators, and by the use of double-blind placebo-controlled 

trials.” 

Nondetailed notes indicated that a more cursory review may have been 

undertaken. Most commonly, nondetailed notes either mentioned that 

financial information was included or summarized the financial 

information. For example, one nondetailed note stated that 

“Certificates of financial disclosure were submitted in compliance with 

the Final Rule on Financial Disclosure by Clinical Investigators.” 

Division directors reading nondetailed notes may overlook or 

underestimate the impact of disclosed financial interests on clinical trial 

results. On the other hand, division directors can use detailed notes to 

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FINDINGS 

determine financial interests’ potential impact on data integrity before 

recommending possible approval of a marketing application. 

Neither FDA reviewers nor 

sponsors noted taking action in 

response to disclosed financial 

interests for 20 percent of 

marketing applications with disclosed financial interests. FDA 

reviewers did not take action on 88 percent47 of marketing applications 

with disclosed financial interests. However, in 67 percent of marketing 

applications with disclosed financial interests, sponsors indicated that 

they acted to minimize potential bias during the clinical trials. For 

example, sponsors hired independent observers to monitor clinical trial 

sites. Sponsors also prevented clinical investigators with financial 

interests from knowing whether subjects were in the experimental or 

the control group. When sponsors took action, FDA reviewers may have 

judged sponsors’ actions to be sufficient, and have seen no need for 

further action. 

Neither FDA nor sponsors took action for 

20 percent of marketing applications with 

disclosed financial interests 

On the other hand, FDA reviewers did not take action on 20 percent of 

marketing applications with disclosed financial interests upon which 

sponsors did not indicate taking action to minimize potential bias. To 

protect data integrity, sponsors are required to describe their actions to 

minimize potential bias related to all disclosed financial interests. 

Although FDA reviewers may have had other reasons to believe that 

disclosed financial interests did not compromise data integrity, FDA 

reviewers did not have the assurance that sponsors acted to minimize 

potential bias during the clinical trials. 

In addition, there was no documented FDA review of financial 

information in more than half of the marketing applications upon which 

no action was taken. Because FDA reviewers may have not reviewed 

financial information, they may not have had sufficient information to 

judge whether action to address potential bias was warranted. 

See Table 3 on the next page for sponsors’ and FDA reviewers’ action in 

response to marketing applications with disclosed financial interests. 

20 

47 FDA reviewers did not review 87.7 percent of marketing applications with disclosed 

financial interests, which we have rounded to 88 percent. 

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FINDINGS 

Table 3: Sponsors’ and FDA Reviewers’ Actions 

Number of Marketing 

Applications 

Percentage of Marketing Applications 

With Disclosed Financial Interests 

No sponsor action; no FDA action 10 20 percent 

No sponsor action; FDA action 3 6 percent 

Sponsor action; no FDA action 33 67 percent 

Sponsor action; FDA action 3 6 percent 

 Total 49 99 percent* 

* Total does not equal 100 percent because of rounding. 

Source: OIG analysis of marketing applications and FDA review notes, 2008.

FDA reviewers did not consistently take action in response to disclosed 

financial interests 

Based on FDA reviewers’ documented notes, FDA reviewers took action 

inconsistently. FDA reviewers took action on 12 percent of marketing 

applications with disclosed financial interests. However, FDA reviewers 

did not take action on other marketing applications with disclosed 

financial interests. In the cases in which FDA reviewers did not take 

action, they may have determined that other aspects of the marketing 

application mitigated the need for action, despite the disclosed financial 

interests. However, if this was the case, FDA reviewers did not 

document this assessment in their review notes. See Appendix E for a 

description of FDA actions taken in response to disclosed financial 

interests. 

Marketing applications upon which FDA took action had disclosed 

financial interests similar to marketing applications upon which FDA 

reviewers took no action. In one marketing application, an FDA 

reviewer took action when sponsors failed to provide any financial 

forms. Yet FDA approved 7 percent of marketing applications without 

any financial forms. 

In another marketing application, an FDA reviewer took action when a 

clinical investigator with disclosed financial interests enrolled a large 

number of patients. However, a different FDA reviewer took no action 

although two clinical investigators with disclosed financial interests 

enrolled a quarter of all patients. 

In a third marketing application, an FDA reviewer took action because 

over a quarter of clinical investigators disclosed financial interests. Yet 

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FINDINGS 

on two other marketing applications, over a quarter of clinical 

investigators disclosed financial interests, but no FDA action was taken. 

Reviewer discretion may explain why action was taken in some 

instances and not others. FDA states that reviewers should be given 

the flexibility to consider financial information and steps taken to 

minimize bias on a case-by-case basis.48 

Despite being given such discretion, only 10 percent of surveyed FDA 

reviewers reported receiving instruction from FDA regarding how to 

review financial information. In addition, 70 percent of surveyed 

reviewers indicated that further instructions would be helpful. 

Most FDA action can only occur after clinical trials are complete because 

FDA receives financial information only with the marketing application 

Most FDA action to ensure that disclosed financial interests do not 

affect data integrity can occur only after clinical trials are complete 

because FDA does not receive financial information before the 

marketing application. FDA could take action during clinical trials, 

such as conducting a BiMo inspection, if it were alerted to potential 

issues related to financial interests. FDA encourages sponsors to 

engage in early consultation with FDA if they are concerned about their 

financial arrangements with clinical investigators.49 However, all cases 

of FDA reviewers’ actions in response to disclosed financial interests in 

FY 2007 took place after the clinical trials were complete. 

When sponsors submit financial information to FDA with the marketing 

application, reviewers face time constraints. FDA’s review of marketing 

applications is subject to nonbinding timelines, per Federal law.50 

Consequentially, FDA reviewers have limited time to take action to 

determine how disclosed financial interests may have affected data 

integrity. In fact, a previous OIG report found that 58 percent of CDER 

reviewers had concerns about time constraints for approving marketing 

applications.51

22 

48 63 Fed. Reg. 5236 (Feb. 2, 1998). 

49 Ibid. 

50 The Prescription Drug User Fee Act, 21 U.S.C. §§ 379g-h and the Medical Device User 

Fee and Modernization Act, 21 U.S.C. § 379j authorize FDA to collect user fees from 

manufacturers in an effort to streamline and improve the timeliness of the review and 

approval of new drugs and medical devices. 

51 OIG, “FDA’s Review Process for New Drug Applications,” OEI-01-01-00590, 

March 2003. 

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Δ RECOMMENDATIONS 

Financial interests between clinical investigators and sponsors create a 

potential for bias that may compromise the safety of human subjects 

and the integrity of research data. Sponsors are required to disclose all 

clinical investigators’ financial interests to FDA in the marketing 

application. In FY 2007, only 1 percent of clinical investigators 

disclosed a financial interest. By way of comparison, the Journal of the 

American Medical Association reported that between 23 percent and 

28 percent of academic researchers had financial interests in medical 

companies.52 Further, we found a number of limitations in FDA’s 

oversight, leaving FDA unable to determine whether sponsors submit 

financial information for all clinical investigators. 

In addition, FDA approved 42 percent of marketing applications in 

FY 2007 that were missing financial information. FDA did not 

document a review of financial information for 31 percent of marketing 

applications. 

Finally, neither FDA nor sponsors took action for 20 percent of 

marketing applications with disclosed financial interests. When FDA 

did act, it did not consistently take action in response to disclosed 

financial interests. These findings lead us to the following 

recommendations: 

FDA Should Ensure That Sponsors Submit Complete Financial Information 

for All Clinical Investigators

To ensure that sponsors submit complete financial information for all 

clinical investigators, we recommend the following: 

FDA should use a complete list of clinical investigators to check that 

sponsors have submitted financial information for all clinical investigators. 

To check that sponsors have submitted financial information for all 

clinical investigators, FDA should create a complete list of clinical 

investigators for each marketing application. This could be done in a 

variety of ways, including: 

• requiring that sponsors submit an updated list of clinical 

 investigators with the marketing application, 

52 Justin E. Bekelman, et al., 2003. “Scope and Impact of Financial Conflicts of Interest 

in Biomedical Research,” Journal of the American Medical Association, vol. 289(4), p. 456. 

Available online at http://jama.ama-assn.org/cgi/reprint/289/4/454?ijkey= 

9e08192f3f85916bd89686c6af4713ad33b514ea. Accessed on May 30, 2008. 

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RECOMMENDATIONS 

• modifying the Bioresearch Monitoring Information System to 

 identify all clinical investigators, or 

• modifying other FDA databases to capture information on clinical 

 investigators and link it to marketing applications. 

FDA should check that sponsors have submitted all required attachments to

financial forms. To ensure that sponsors have submitted required 

attachments to financial forms, FDA centers should use a checklist that 

includes a check for attachments to financial forms during the 

administrative filing of marketing applications. 

FDA should update guidance to sponsors regarding the due diligence 

exemption. FDA should update guidance stressing that sponsors should 

only rarely use the due diligence exemption. Given that sponsors are 

required to obtain financial information from clinical investigators 

before starting clinical trials, sponsors should always have the 

information they need to submit to FDA. 

In addition, FDA should update guidance to sponsors incorporating its 

2002 explanation of due diligence, which is currently provided only in 

Federal Register comments. This would clarify that due diligence is 

making at least two telephone calls and sending two certified letters. 

This sets a higher threshold for sponsors to meet before claiming the 

due diligence exemption than the current threshold of “a reasonable 

judgment made by the sponsor.” 

FDA should add a review of financial information to the onsite inspection 

protocol. To help identify previously unknown financial interests, FDA 

should add a review of financial information to sponsor and clinical 

investigator BiMo inspection protocols. 

FDA Should Ensure That Reviewers Consistently Review Financial 

Information and Take Action in Response to Disclosed Financial Interests 

To ensure that reviewers consistently review and take action in 

response to financial information, we recommend the following: 

FDA should require that all centers consistently use a template that 

includes a prompt to document a review of financial information. To help 

ensure that reviews of financial information are completed and 

documented, CBER should finalize its draft Clinical Review Template. 

CDRH should develop a review template that includes a prompt to 

document a review of financial information. 

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RECOMMENDATIONS 

FDA should provide additional guidance and training to reviewers. The 

guidance and training could address how to review financial 

information, how to identify bias, and how and when to take action to 

ensure data integrity. 

FDA Should Require That Sponsors Submit Financial Information for 

Clinical Investigators as Part of the Pretrial Application Process 

We recommend that the pretrial application process be amended to 

require that sponsors submit financial information for clinical 

investigators. As each clinical investigator begins work on a clinical 

trial, sponsors should be required to either certify that clinical 

investigators do not have a financial interest with the sponsor or 

disclose a financial interest. For disclosed financial interests, sponsors 

should describe the financial interest and sponsors’ actions to minimize 

any potential bias these financial interests may cause. 

Implementing this recommendation would require only minimal 

changes to FDA’s current process. Sponsors are already required to 

collect financial information from clinical investigators prior to 

beginning clinical trials. Further, FDA already engages with sponsors 

during the clinical trials. First, FDA approves the clinical trial protocol 

as part of the pretrial application. Then, as clinical trials get underway, 

sponsors are required to submit information on each clinical 

investigator they hire. Financial information for each clinical 

investigator could be included with these submissions. However, we 

recognize that FDA reviewers face time and resource constraints. Thus, 

we recommend that FDA build this review into the pretrial application 

process in the best way it sees fit, perhaps focusing most attention on 

disclosed financial interests. 

If FDA received financial information before clinical trials, FDA could 

ensure that sponsors are collecting financial information before trials 

and are taking action to ensure that disclosed financial interests do not 

threaten human subjects or compromise data integrity. In addition, 

FDA is now devoting one-third of BiMo resources to ongoing clinical 

trials, as opposed to focusing solely on completed trials, according to 

FDA officials. Having information about a clinical investigator’s 

financial interest could help FDA target which clinical trial sites are 

chosen for BiMo inspections. Finally, FDA has acknowledged the 

importance of obtaining this information before a clinical trial. FDA 

asserts that receiving clinical investigators’ financial information before 

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RECOMMENDATIONS 

a trial allows sponsors the opportunity to consult with FDA and take 

action to minimize any potential study bias.53 

In addition to requiring that sponsors submit financial information 

during the pretrial application process, sponsors should still be required 

to submit financial information with the marketing application. This 

ensures that FDA can review updated financial information for clinical 

investigators. It also ensures that financial information will be 

submitted for any clinical investigators whose information was not 

submitted as part of the pretrial application process. 

AGENCY COMMENTS AND OFFICE OF INSPECTOR GENERAL 

RESPONSE 

FDA expressed concerns about elements of our analysis in three of our 

findings. In addition, FDA agreed with all of our recommendations 

except the recommendation that FDA require sponsors to submit 

financial information for clinical investigators as part of the pretrial 

application process. 

With respect to the first finding that 1 percent of clinical investigators 

disclosed a financial interest, FDA disagreed with our decision to report 

36 disclosures for employees of the sponsor. Based on FDA’s concern, 

we removed 34 disclosures for employees from our analysis because it 

was ambiguous whether sponsors were disclosing a financial interest for 

these employees. Two employees had clearly disclosed financial 

interests and thus were kept in our analysis. FDA also objected to our 

decision to report 12 disclosures that fell below the defined threshold. 

We continue to include these disclosures because it was our intention to 

describe all disclosures in FY 2007, even those not required by 

regulation. We assumed that sponsors purposefully disclosed these 

financial interests to FDA and did not question the validity of the 

disclosures. 

In our second finding, we state that FDA cannot determine whether 

sponsors have submitted financial information for all clinical 

investigators because it does not have a complete list of clinical 

investigators. FDA took exception to our statement that FDA could 

provide complete lists of clinical investigators for only 7 percent of 

marketing applications. FDA believed that we did not clearly ask for 

53 67 Fed. Reg. 6042 (Feb. 8, 2002) 

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RECOMMENDATIONS 

this information. However, we submitted an official written request to 

FDA for a list of clinical investigators from approved marketing 

applications. From discussions with FDA, we understood that there is 

often no list of clinical investigators in marketing applications but that 

FDA would provide us these lists when found. In fact, subsequently 

FDA did provide us with some lists of clinical investigators, but we 

could not validate the accuracy or completeness of the lists provided. 

Finally, FDA did not agree with our decision to consider applications 

indicating due diligence as incomplete. We acknowledge that 

regulations allow sponsors to claim the due diligence exemption, but we 

maintain that sponsors’ failure to submit financial information for all 

clinical investigators, whether they indicated due diligence or not, 

constitutes missing financial information. In these cases, FDA 

reviewers have incomplete knowledge of clinical investigators’ financial 

information. 

In response to our recommendation that FDA ensure that sponsors 

submit complete financial information, FDA stated that it is considering 

revising its guidance to industry to instruct sponsors to provide a table 

listing all clinical investigators and indicating whether a certification 

form, a disclosure form, or the due diligence exemption is being 

provided. FDA also stated that it is reviewing its procedures to 

determine whether modifications are needed to ensure that all required 

attachments are submitted. In addition, FDA stated that it is 

considering providing additional advice to sponsors on the use of the due 

diligence exemption. Finally, FDA stated that it has updated its onsite 

inspection protocol to include a closer inspection of financial 

information. 

In response to our recommendation that FDA reviewers consistently 

review financial information, FDA indicated that it is evaluating its 

review procedures and templates. In addition, FDA is considering 

developing additional guidance and training for reviewers on the review 

of financial disclosure information. 

For many reasons, FDA did not agree with our final recommendation 

that FDA require sponsors to submit financial information for clinical 

investigators as part of the pretrial application process. 

FDA emphasized that collecting financial information before a clinical 

trial starts is the sponsors’ responsibility. However, FDA has no 

mechanism to ensure that sponsors are collecting financial information 

before beginning clinical trials. In fact, FDA commented that sponsors 

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RECOMMENDATIONS 

may find obtaining financial information difficult because there can be a 

significant amount of time between completion of a clinical trial and 

submission of the marketing application. However, if sponsors were 

collecting financial information for all clinical investigators before they 

participated in a clinical trial as required, the lag time between when 

the clinical trial ended and when the marketing application was 

submitted would be irrelevant. Receiving financial information during 

the pretrial application process would allow FDA to ensure that 

sponsors were collecting financial information before beginning clinical 

trials, as required. 

FDA also stated that financial interests are only one potential source of 

bias of clinical trials, emphasizing the importance of proper study 

design as a means for minimizing bias. Although it is true that there 

are multiple sources of potential bias, FDA acknowledged that sponsors 

are required to collect financial information before beginning a clinical 

trial so that they can identify and manage all potential sources of bias to 

ensure that human subjects are protected and data are reliable. 

Similarly, FDA could use information on all potential sources of bias, 

including financial information, to help sponsors identify potential bias 

before beginning clinical trials. 

FDA also believes that for industry to collect and submit financial 

information and for FDA to review this information during the pretrial 

application process would represent significant additional work. 

However, pursuant to regulation, FDA already requires sponsors to 

collect financial information from clinical investigators before starting a 

clinical trial. In addition, basic information on clinical investigators is 

submitted to FDA as they are added to clinical trials. Thus, it is unclear 

how submitting financial information that is already collected, as well 

as the other information on clinical investigators that sponsors submit 

to FDA, would be a significant addition of effort on sponsors’ part. 

Further, FDA stated that it intends to improve its oversight of ongoing 

clinical trials. Therefore, receiving financial information about ongoing 

clinical trials adds to an oversight initiative that is presently underway. 

FDA also pointed out that many clinical trials are ultimately not 

submitted in a marketing application, thus making a review of financial 

information in the pretrial application process a potential waste of time. 

However, FDA stated its intention to improve its oversight of ongoing 

trials. Further, even if clinical trials do not result in a marketing 

application, the investigational products are still being tested on human 

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RECOMMENDATIONS 

subjects. To protect human subjects, FDA should take a proactive 

approach to ensure that clinical investigators are not biased when 

recruiting and testing investigational products on human subjects. 

We continue to recommend that FDA require sponsors to submit 

financial information as part of the pretrial application process. 

Acknowledging the added burden to FDA’s administrative and review 

staff, we encourage FDA to develop a review of financial information 

that best balances the additional effort with the potential benefits. 

For the full text of FDA’s comments, see Appendix F. FDA’s technical 

comments are not included, but we made changes in the report where 

appropriate. 

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Δ APPENDIX ~ A 

 CERTIFICATION OF NO FINANCIAL INTERESTS, FORM 3454 

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Δ APPENDIX ~ B 

DISCLOSURE OF FINANCIAL INTERESTS, FORM 3455 

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32 

FINANCIAL FORMS SUBMITTED TO EACH CENTER IN FISCAL 

YEAR 2007 

 

 Chart 1: Financial Forms Submitted to Each Food and Drug Administration Center in FY 2007 

12 11

38

17

1

31

3

4

1

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

 Center for 

Drug Evaluation and Research 

 Center for 

Device and Radiological Health 

 Center for 

Biologics Evaluation and Research

Food and Drug Administration Center

Number of Marketing Applications

Does Not Include Any Financial Information

Includes Forms That Disclose Financial Interests 

Includes Only Forms Certifying No Financial Interests

Δ APPENDIX ~ C 

Source: Office of Inspector General analysis of marketing applications, 2008. 

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RESPONSE RATES FOR REVIEWER SURVEY 

Our goal was to survey the Food and Drug Administration (FDA) 

reviewers who evaluated financial information within the past 3 years. 

However, not all centers could identify a specific population of reviewers 

that evaluate financial information. Therefore, for two centers, we sent 

surveys to all reviewers who reviewed a marketing application in the 

last 3 years. Thus, we distributed our survey to a high proportion of 

reviewers who did not evaluate financial information in the past 

3 years. See Table 4 for survey responses by FDA center. 

33 

Table 4: Survey Responses by FDA Center 

Center Survey Recipients 

Total Surveys 

Sent 

Total 

Respondents 

Respondents Who 

Reported Evaluating 

Financial Information 

Center for Drug 

Evaluation and 

Research (CDER)* Medical officers 308 109 87 

Center for Devices and 

Radiological Health 

(CDRH)** 

Reviewers who 

reviewed a marketing 

application in the last 

3 years 305 176 61 

Center for Biologics 

Evaluation and 

Research (CBER)** 

Reviewers who 

reviewed a marketing 

application in the last 

3 years 177 52 14 

 Total 790 337 162 

* CDER identified medical officers as the discipline of reviewers who routinely evaluate financial information. 

** CDRH and CBER could not identify a specific discipline of reviewers who routinely evaluate financial information. Therefore, the 

centers identified all reviewers who reviewed a marketing application in the last 3 years, regardless of whether they evaluated

financial information. 

Source: Office of the Inspector General analysis of electronic survey respondents, 2008. 

Δ APPENDIX ~ D 

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DESCRIPTION OF FOOD AND DRUG ADMINISTRATION 

ACTION 

When the Food and Drug Administration (FDA) reviewers took action in 

response to disclosed financial interests, they most often conducted their 

own analyses to identify potential bias. Additionally, two reviewers 

requested inspections from the Bioresearch Monitoring Program (BiMo) 

and one reviewer requested additional analysis from the sponsor. As a 

result of their actions, FDA reviewers determined that the disclosed 

financial interests did not compromise the integrity of the data. See 

Table 5 for details of FDA action for the six marketing applications on 

which FDA took action. 

Table 5: Details of FDA Actions in Response to Marketing Applications 

With Disclosed Financial Interests 

 FDA Action Per Marketing Application Reason Action Was Taken 

Compared outcomes from investigators with 

financial interests against those without 

Over a quarter of clinical investigators had 

disclosed financial interests 

Compared outcomes from investigators with 

financial interests against study mean* 

Some clinical investigators with disclosed 

financial interests had very favorable results 

Compared outcomes from investigators with 

financial interests against study mean* Unspecified 

Requested a BiMo inspection of an investigator 

with a financial interest 

Investigator disclosed a financial interest and 

had a large number of patients 

Requested a BiMo inspection of the sponsor The sponsor originally did not submit any 

financial forms 

Requested that the sponsor submit reanalysis 

of study outcomes excluding clinical 

investigators with financial interests* 

Unspecified 

* Indicates marketing applications upon which sponsors also took action to decrease bias. 

Source: Office of Inspector General analysis of marketing applications and FDA review notes, 2008. 

Δ APPENDIX ~ E 

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AGENCY COMMENTS 

Δ APPENDIX ~ F 

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APPENDIX ~ F 

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APPENDIX ~ F 

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APPENDIX ~ F 

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APPENDIX ~ F 

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APPENDIX ~ F 

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APPENDIX ~ F 

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APPENDIX ~ F 

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APPENDIX ~ F 

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ΔAPPENDIX ~ D APPENDIX ~ A ACKNOWLEDGMENTS ACKNOWLEDGEMENTS 

This report was prepared under the direction of Ann Maxwell, Regional 

Inspector General for Evaluation and Inspections in the Chicago 

regional office, and Thomas Komaniecki, Deputy Regional Inspector 

General. 

Anne Bracken led this study and Beth McDowell served as the lead 

analyst. Other principal Office of Evaluation and Inspections staff from 

the Chicago regional office who contributed to the report include Abby 

Lopez; central office staff who contributed include Robert Gibbons, 

Ayana Everett, Matthew McMullen, and Talisha Searcy.