Perspectives on Fraud in Clinical Research - Views from the Sponsor, Investigator, IRB & FDA

Background Information & General History

Advancements in medical treatments and healing have been achieved as a result of gaining new knowledge and applying it for the good of humanity. In attaining and utilizing groundbreaking knowledge, research and experimentation have been a prime source of development. In the medical realm of the scientific community, clinical trials have been the key to discovering the effects of various pathological disease conditions and how they can be treated. For the pioneers who have made our current medicines and treatment therapies possible, they are rewarded with high respect and regard for their contribution to science and medicine. Indeed, there is a deep sense of value for those who are involved in clinical research, especially the clinical investigators who test and study new drug therapies for safety and effectiveness. The world relies on these individuals to establish sound scientific evidence to confirm a drug’s safety and efficacy. Many of these investigators are driven and passionate about their work for the sake of alleviating people’s suffering. However, not all investigators are driven by good intentions. The purpose of this paper is to explore accuracy and fraud as well as how it effects all who are involved in research including the clinical investigator, the sponsor, the Institutional Review Board, and the FDA.

Throughout the history of experimentation many old beliefs in medicine have been discredited while others have been confirmed and well established based on scientific principles. With time, clinical researchers have gained the trust of the general public as they discovered and presented them with innovative clinical solutions. The world has come to place its faith on research for the pursuit of improving modern medicine. Yet in retrospect of medical and scientific accomplishments gained, the clinical research community has also witnessed less ideal situations in research studies. Generally, these situations manifest as different forms of inaccuracy in studies due to a variety of reasons ranging from simple inadvertent errors to deliberate, dishonest acts of misconduct and fraud.

It is normal to have errors in trials and most are unintentional as they are usually caused by misunderstanding or inattention to detail. The impacts of errors on study results are not as significant since they are traceable and easily corrected once they are caught. Errors can be eliminated, or at least reduced, through various means of monitoring, reviewing, and analysis of statistical data. Misconduct, unlike error, is a more serious situation and is not taken lightly. This is because it involves intentional wrongdoing (Woodin & Schneider, 2003). Perhaps even worse than misconduct, the most unethical form of dishonesty in clinical trials is fraud. This is the more serious offense since it entails willful deception and tampering with study materials by fabricating, falsifying, or mishandling of data for gaining some form of reward or benefit (Sheehan, 2007). Misconduct and fraud can have major impact on a trial leading to serious consequences in compromising data accuracy and validity. Regardless of the differences between errors, misconduct, and fraud; they all lead to deviation from the truth.

Key Issues & Perspectives

The clinical research industry is one of the most heavily regulated industries that exist. One cannot function in this industry in a compliant manner without knowing the regulations and the responsibilities they are expected to maintain. Good Clinical Practice, or GCP, is a set of guidelines for the design, performance, monitoring, recording, analysis, and reporting of clinical trials (Woodin & Schneider, 2003). These guidelines are recognized as overall standard operating procedures in conducting clinical research. Compliance with GCP standards ensures proper and ethical conduct of trials while preventing, or at least reducing, the chances of misconduct and fraud. This is why it is crucial for all research professionals to understand and be familiar with GCP. In essence, GCP can be viewed as a system of shared responsibilities between sponsors, clinical investigators, Institutional Review Boards, and the FDA; all working together to preserve the integrity of clinical research (Woollen, 2000). When questionable accuracy or fraud infects a trial, the affects become contagious.

Investigator Perspective:

Investigators are the primary individuals in charge of clinical studies since they hold ultimate accountability in conducting and supervising a trial. They are well-qualified professionals who hold the proper credentials, experience, and training necessary to meet the challenges and enormous responsibilities associated with undertaking a clinical research study. Having a good investigator enables the research process to run smoothly and avoid potential problems of inaccuracy due to fraud and misconduct. Besides fulfilling the general commitments noted in the Code of Federal Regulations and in Form 1572 (FDA Selecting Investigators and Monitors, 2006), investigators are also expected to maintain accurate records and data throughout the duration of a trial (FDA Investigator Recordkeeping and Record Retention, 2006). These records include patient charts, consent forms, case report forms, case histories, progress notes, laboratory reports, and all other supporting documents. This helps to keep track of study progress and to preserve quality and accuracy of gathered information in relation to the trial.

Furthermore, another requirement of investigators is that they must certify that they have no financial interests. Medical treatments are always in demand so long as disease continues to exist; and where there is demand, there is business, and where there is business there is money. Those involved in clinical research, including investigators, are human and thus they are not immune to the temptations which lead to conflicts of interest. If there is financial interest, investigators must disclose this information as it may cause bias in the outcome of the clinical trial being conducted (FDA Financial Disclosure by Clinical Investigators, 2006). This can be through financial interest in the company or patent interest if the drug should become approved. Otherwise, the validity of trial is jeopardized. Taking all of this into consideration, it is no wonder that investigators deal with enormous liability in leading a clinical trial. Thus, they must do everything they can to remain in compliance with the regulations governing clinical research. Failure to do so means the risk of disqualification from future studies (FDA Disqualification of a Clinical Investigator, 2006) and being forever listed on the FDA’s List of Disqualified and Restricted Investigators, otherwise known as the infamous “black list” (Woodin & Schneider, 2003). In the worst cases, investigators may face legal troubles, heavy fines, or even be sent to prison. Indeed, investigator fraud is a serious offense that holds severe consequences and must be dealt with accordingly.

The nature of science necessitates that researchers have an obligation to check their data meticulously for thoroughness and accuracy and to draw only valid conclusions from them. Falsifying data, fabricating reports, allowing bias due to conflict of interest, and other elements that may compromise the integrity of a study should be prevented by all means possible. Some may argue that acts of misconduct and fraud should not go unpunished. Otherwise, scientist and researchers will grow tolerant of such behavior, which would lead to more occurrences of inaccuracy.

The only ethical principle which has made science possible is that the truth shall be told all the time. If we do not penalize false statements made in error, we open up the way, don't you see, for false statements by intention. And of course a false statement of fact made deliberately, is the most serious crime a scientist can commit. (Snow, 2000, p.74)

Sponsor Perspective:

Sponsors put in a great deal of investing in terms of time, money, and energy into developing a drug and having it tested in a clinical trial. They use experienced investigators to run the trial, well trained research personnel to spot and eliminate errors, and a solid protocol containing all the information needed to complete the study correctly. With so much at stake sponsors are careful to make certain that everything is done properly to gain approval for their drug to reach the market. Hence, it would be wise of them if they occasionally audit their own investigative sites to ensure compliance and quality assurance (Ginsberg, 2005). In fact, not doing so would be reckless, especially if an incident of misconduct or fraud was actually going on. In this case, it may not be discovered until it is too late wherein the sponsor would confront a devastating nightmare.

When faced with misconduct or fraud, the consequences can be disastrous for a sponsor. The data from the fraudulent site would no longer be useable, the study itself would be ineffective, and the site may even be ultimately terminated (Woodin & Schneider, 2003). This would mean a huge loss in finances and time because such incidents would delay the New Drug Application, or NDA process, and the drug would not reach the market. If such an event were to occur, the sponsor would be set back several years in the drug development program. To avoid significant losses due to fraudulent activity, it is imperative that sponsors promptly report any information they have if they detect any possible research misconduct (Woollen, 2000). Sponsors should have any events of fraud and misconduct be reported as soon as it is suspected. They should not wait until the damage becomes irreversible.

Institutional Review Board (IRB) Perspective:

The primary purpose of Institutional Review Boards, or IRBs, is to review and approve quality research involving human subjects. In other words, they watch over a study to see that it is carried out smoothly with no ethical infringement or exploitation. IRBs are required by regulation to follow written procedures in reviewing and approving a trial. They must carefully document their review of the research study and retain the documentation appropriately (Woodin, 2004). This can be viewed as a safeguard for protecting not only the research subjects in the trial, but also the integrity of the trial. However, there are rare instances when IRB’s may contribute to the problems of fraud and misconduct. Among the leading problems evoking official action include (Woollen, 2000)

Failure to prepare and/or follow written procedures.

Failure to adequately document activities.

Failure to conduct adequate continuing review.

Failure to fulfill requirements for expedited review.

Failure to fulfill the requirements of informed consent.

Sometimes even when an IRB does everything they can, fraudulent activity still manages to break through. This may be by no fault of the IRB but by fault of the sponsor or the study site. Some of the causes that can lead to these problems include: failure to request and obtain IRB approval, failure to notify IRB of protocol changes, and failure to comply with subject disclosure and protections (Sheehan, 2007). Consequently, the IRB is in a position of oversight and it must use its position to question and inquire about the activities of researchers and their departments. If the IRB is unable to perform this function, or if the researcher evades the regulations in place, then a government agency such as the FDA must intervene to assure that compliance is enforced.

FDA Perspective:

The FDA is known for its mission of maintaining high standards in the conduct of drug research. They serve as the government watchdogs by conducting occasional audits and inspections of investigative sites with certain criteria in mind; to determine the validity and integrity of data and to assess adherence to regulations and guidelines (Ginsberg, 2005). Interestingly, since 1999 the FDA has noticed a large increase in the number of complaints filed with regards to fraud and misconduct. Since then, the FDA’s Division of Scientific Investigations, or DSI, reports that that the number of complaints filed against investigative sites for failure to comply with GCP in 2000 were 10% higher than what was filed in 1999 (Gamache, 2001). These complaints come from various sources including research staff and personnel, sponsors, IRBs, and others. The DSI examines these complaints very closely and has an aggressive tracking system in place to follow-up and thoroughly investigate irregularities and issues of noncompliance.

The U.S. Department of Health & Human Services has set up regulations and guidelines to help researchers properly conduct ethical trials. They even provide documents such as the Guidelines for the Monitoring of Clinical Trials (1988) so that the principles of standard practice in monitoring a clinical investigation may be recognized. Thus with all these efforts it is not surprising that the FDA does not look kindly upon any form of misconduct or fraud. When it discovers such activity, the results are severe. The FDA places strict penalties for fraud and misconduct, even if it means having to close down a site, blacklisting an investigator, and causing a sponsor to repeat a study which may take several years (Ginsberg, 2005).

Problems & Proposed Solutions

The reasons for conducting fraudulent studies and presenting falsified dishonest research for scientific publication are complex. Some leading factors may be due to the mounting pressures of competition, achieving fame and prestige within the scientific community, or attaining wealth and professional advancement through deceitful ways of career progression. All of these may be considered as contributing factors, and when they are present the signs of fraud begin to set in motion. Thus, it is important to recognize and look for signs of research inaccuracy. Fabrication of study subjects, absence of source documents, deviating from the approved protocol, and having study staff perform duties which they are unqualified to do are all warning signs to be cautious of (Woollen, 2000). In a study on menopause and aging conducted at the University of Vermont by Dr. Eric Poehlman, it was discovered that much of the research data had been either falsified or fabricated (Sheehan, 2007). It was exposed that Dr. Poehlman manipulated the data on several spreadsheets and misrepresented the number of subjects participating in the study. Furthermore, he was also guilty of submitting 17 falsified grant applications and fabricating data in 10 papers submitted for publication. As a result of his deceitful actions, he was sentenced to serve one year in jail and had been permanently barred from receiving any federal research grants. Since his misconduct affected many other studies, he was also ordered by the court to write letters of retraction and correction to several scientific journals (Office of Research Integrity, 2005).

Not disclosing risks or reporting adverse events also warrants suspicion of fraud. In 1999, 18-year-old Jesse Gelsinger participated in a gene therapy study led by Dr. James Wilson at the University of Pennsylvania. She died as a result of serious toxicity but even so, the study went on without having the adverse event reported or disclosing the risks to participants (US Attorney’s Office, 2005). Upon investigation of this case it was later revealed that the study team refused to stop the study since they were too eager to be the first to achieve success in providing a gene therapy solution for a rare disease (Sheehan, 2007).

Questionable integrity in research can come in many forms. Martinson, Anderson, and De Vries (2006) note some of the following ways in which misconduct takes place:

Manipulating or concocting research data.

Failing to disclose financial interest or not properly disclosing conflict of interest.

Plagiarizing or using another’s ideas without obtaining permission or giving due credit.

Failing to present data that contradict one’s own previous research.

Overlooking the use of flawed data or questionable interpretation of data.

Circumventing certain minor aspects of human-subject requirements (e.g. related to informed consent, confidentiality, etc.).

Changing the design, methodology or results of a study in response to pressure from a funding source.

Ignoring details or cutting corners to meet a deadline.

Considering the causes of inaccuracy and the ways in which fraud and misconduct can manifest in research, the scientific community cannot be complacent towards these actions. Even with the regulations and policies currently in place, there is still a strong need to find and implement solutions to address these problems. In spite of the desired belief that scientific misconduct may be rare, the problem exists and its occurrence holds a significant impact nonetheless. It manages to shake public confidence in the clinical trial process, while raising concerns as to what steps are being taken to uphold effectiveness in trial monitoring. In the recent years, the need to preserve the integrity of clinical research has been apparent now more than ever.

Detecting fraud and misconduct may seem daunting and difficult but through diligence and intelligent observation it can be accomplished. Thorough monitoring and recognizing suspicious activities during reviews and evaluation of a site is essential, but it has to be done right. Thus, knowing how to discriminate between good quality data and false fabricated data can mean the difference between valid research and fraud. As noted by Woodin (2004), the general characteristics of good quality data include logical information with values that are within range and have the correct units for measurement. They can be evaluated and analyzed with ease. Good quality data in a study is gained by having subjects who meet the entry criteria and source documents that are accurate with all fields filled out accordingly. There should be no need to query data and all data should show consistency. A site that is run smoothly will be able to generate reliable data which would allow for valid conclusions to be drawn. As long as these characteristics are met, then they should lead to high quality data with valid results that can be reproduced. This helps eliminate errors and generate good, usable data. With this in mind, it helps to question any missing information and retrieve records to fill in the blanks. If for some reason there seems to be a great deal of blame shifting, then this might be a sign of hiding misconduct and could be a cause for alarm.

There have been several efforts and initiatives to reinforce ethical practice in clinical research. Among them, the FDA publishes many guidelines and information sheets pertaining to the appropriate conduct of clinical trials. It also provides Compliance Program Guidance Manuals, or CPGM. In attempts to ensure accuracy while combating misconduct and fraud, the FDA has placed significant efforts in establishing departments supporting the Bioresearch Monitoring Information System (BMIS). This program consists of comprehensive on-site inspections and data audits intended to monitor all aspects of the conduct and reporting of FDA regulated research. In doing so, it not only maintains the rights and welfare of research subjects but it is also able to verify the quality and integrity of research data submitted to the FDA (Woollen, 2000). In addition, the American Association of Medical Colleges has taken notice of the need to reinforce integrity in research and has collaborated with the Centers for Education and Research in Therapeutics and the Blue Cross Blue Shield Association to develop a set of principles, recommendations, and guidelines to standardize the process of analyzing and reporting the results of sponsored clinical research, especially clinical trials sponsored by industry (Ehringhaus & Korn, 2006).

On a larger scale, various national committees and working parties have been set up in some countries to help tackle the issues resulting from inaccuracy and fraud. In Britain, the Committee of Publication Ethics (COPE) has been established to serve in a manner similar to the FDA’s Office of Research Integrity in the United States (Fenton, 2002). COPE is a voluntary organization, which aims to find practical ways of dealing with issues of misconduct and develop good practice. It is an advisory association that places the responsibility on individual institutions to deal with fraudulent research emanating from their facilities. Many multidisciplinary and specialty journals have subscribed to the evolving principles of COPE by editorial comment or by reproducing the relevant guidelines.

Conclusion

Complex issues demand complex solutions. Addressing research fraud and dishonesty requires comprehensive focus on informing researchers and staff personnel on reporting and dealing with unethical research practices. Considering the competitive environment between researchers within the scientific community, there should be a greater focus on the quality of research rather than quantity. Although targeting inaccuracy and research fraud requires continuous effort from all members of the research industry, ethical practice ultimately depends on the ethical investigator. Thus clinical investigators must be held accountable for intentional misconduct and for undisclosed conflicts of interest that threaten their objectivity as researchers and their ability to protect the rights and welfare of research subjects. Researchers who are caught cheating are devastated by the consequences to the point that often their lives and careers are ruined. However, this is the price they pay because crucial values are at stake: honesty, integrity, and accuracy in research as well as the public’s trust.

References

Ehringhaus, S., & Korn D. (2006, January 6). Principles for Protecting Integrity in the Conduct and Reporting of Clinical Trials. Retrieved April 25, 2007, from http://www.aamc.org/research/clinicaltrialsreporting/clinicaltrialsreporting.pdf

FDA Disqualification of a Clinical Investigator, 21 C.F.R. § 312.70 (2006, April 1). Retrieved April 25, 2007, from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.70

FDA Financial Disclosure by Clinical Investigators, 21 C.F.R. § 54.4 (2006, April 1). Retrieved April 25, 2007, from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=54.4

FDA Investigator Recordkeeping and Record Retention, 21 C.F.R. § 312.62 (2006, April 1). Retrieved April 25, 2007, from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.62

FDA Selecting Investigators and Monitors, 21 C.F.R. § 312.53 (2006, April 1). Retrieved April 25, 2007, from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.53

Fenton, J. E. (2002). Integrity in medical research and publication. [Electronic version]. Clinical otolaryngology and allied sciences, 27(6), 436-439. Retrieved April 20, 2007, from ALADIN database.

Gamache, V. (2001, June). FDA Complaints against investigative sites still rising. Newsletter: CenterWatch, 8(6), 14.

Ginsberg, D. (2005). Becoming a Successful Clinical Research Investigator. Boston, MA: CenterWatch.

Martinson, B. C., Anderson, M. S., & De Vries, R. G. (2006). Scientists’ perceptions of organizational justice and self reported misbehaviors. [Electronic version]. Journal of Empirical Research on Human Research Ethics, 1(1), 51-66.

Office of Research Integrity. (2005, March 24). Case Study – Eric T. Poehlman. Federal Register, 70(56). Retrieved April 26, 2007, from http://ori.dhhs.gov/misconduct/cases/poehlman_notice.shtml

Sheehan, J. (2007, March 2). Fraud, conflict of interest, and other enforcement issues in clinical research. [Electronic version]. Cleveland Clinic Journal of Medicine, 74(2), S63-S67.

Snow, C. P. (2000, January). The Search. North Yorkshire, UK: House of Stratus.

Woodin, K. E., & Schneider, J. C. (2003). The CRA’s Guide to Monitoring Clinical Research. Boston, MA: CenterWatch.

Woodin, K. E. (2004). The CRC’s Guide to Coordinating Clinical Research. Boston, MA: CenterWatch.

Woollen, S. W. (2000, June 14). Patient Misuse and Investigator Fraud in Clinical Trials: What Can Be Done? Part I. Retrieved April 23, 2007 from http://www.fda.gov/cder/present/dia-62000/woolen1/index.htm

U.S. Attorney’s Office Eastern District of Pennsylvania. (2005, February 9). U.S. settles case of gene therapy study that ended with teen’s death. Retrieved April 24, 2007, from http://www.usdoj.gov/usao/pae/News/Pr/2005/feb/UofPSettlement%20release.html

U.S. Department of Health & Human Services. (1988, January). Guideline for the monitoring of clinical investigations. Retrieved April 24, 2007, from http://www.fda.gov/ora/compliance_ref/bimo/clinguid.html

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