August 25, 2011 marked the day when the 1995 version of U.S. Financial Conflict of Interests (FCOI) regulations (42 CFR Part 50 Subpart F, 45 CFR Part 94) was changed. The major changes are listed as follows (click on the table to magnify view):
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| Source: http://grants.nih.gov/grants/policy/coi/summary_of_major_changes.doc |
Online training on FCOI
1. NIH FCOI Reporting Requirements Webinar (August 14, 2012, audio-video, 1 hr. 27 mins.)
2. The 2011 Regulation FCOI Tutorial on 42 CFR Part 50 subpart F (Responsibility of Applicants for Promoting Objectivity in Research for Which Public Health Service (PHS) Funding Is Sought and Responsible Prospective Contractors; Final Rule). The tutorial consists of interactive slides where user's knowledge is tested with multiple choice quizzes. Upon successful completion of the tutorial a printable certificate will be awarded to the user. According to the UBC FCOI policy page, the tutorial takes 45 minutes to complete (http://ethics.research.ubc.ca/ore/us-financial-coi).
3. NIH FCOI Webinar (Nov. 30, 2011, audio-video and slides, 1 hr. 24 mins.)
View video below by clicking on the play (➢) button
View video with slide presentation here.
Included in the above webinar is a question and answer section that is essential to determining whether the audience have understood the regulations enough to apply them to actual situations. It is useful to test knowledge of rules against scenarios so that the audience can compare these examples to situations they may encounter in their research. One good example of a scenario-approach to FCOI training is the Case Scenarios document posted by University of Washington on August 23, 2012.
4. UBC produced its own 17-minute FCOI audio-video tutorial and slide presentation.
View video below by clicking on the play (➢) button
Significant Financial Interests (SFIs)
According to the current and final version of the regulation, the Significant Financial Interest (SFI) threshold is 5,000 USD, i.e. if the SFI exceeds that amount, then it is considered SFI for disclosure for FCOI determination purposes.
Included SFIs are:
1. remuneration from publicly traded entity that 'reasonably appears' to be related to institutional responsibility of which value exceeds 5,000 USD in the preceding 12 months,
2. remuneration from non-publicly traded entity related to institutional responsibility of which value exceeds 5,000 USD in the preceding 12 months,
3. income from intellectual property rights,
4. reimbursed or sponsored travel paid by organizations other than excluded sources (e.g. governments, institutions of higher learning and affiliated institutes, academic teaching hospital, medical centre),
5. income from teaching paid by organizations other than excluded sources (e.g. governments, institutions of higher learning and affiliated institutes, academic teaching hospital, medical centre),
6. income from service in committees paid by organizations other than excluded sources (e.g. governments, institutions of higher learning and affiliated institutes, academic teaching hospital, medical centre).
Note that that regulation (42 CFR 50.603) requires remuneration to only "reasonably appear" related to the Investigator's institutional responsibility. It does not require proof that it is actually related or actually influence the performance of institutional responsibility, which is the Investigator's primary interest, for it to be covered by SFI disclosure requirement.
Excluded from SFI disclosure requirement are the Investigator's institutional income, teaching income, committee membership income, income from investment vehicles e.g. mutual funds and retirement account investments not under Investigator's control, IPR assigned to institution and shared royalties, ownership interests in the Institution held by the Investigator, and travel costs that are reimbursed by excluded sources.
According to Dr. Jeffrey Toward (video time 7:21 - 7:46; 8:47 - 57), UBC at that time is still confirming with NIH if the disclosure requirement also does not apply to Canadian Investigators' travel reimbursements from Government and institutions of higher education and income from teaching and committee service in the same way as it does not apply to U.S.-based Investigators (see above video published May 7, 2014). NIH allows stricter rules than the minimum stipulated in the FCOI regulations. When such stricter rules are adopted by institutions, their investigators should follow these. After all, the point of having these rules in place is to promote objectivity in research and institutions can impose higher standards that they deem appropriate.
SFI is only FCOI when the designated institutional official (DIO) reasonably determines that the SFI could directly and significantly affect the design, conduct and reporting of the PHS funded research. SFI disclosure is a necessary step to make this determination.
The Investigator responsible for SFI disclosure according to 42 CFR 50.603 include "the Project Director/Principal Investigator (PD/PI) as well as any other person, regardless of title or position, who is responsible for the design, conduct, or reporting of research funded by the PHS, or proposed for such funding, which may include, for example, collaborators or consultants." The disclosure must include SFIs of spouse and dependents.
In addition to following her own Institution's FCOI policies and procedures, the Investigator is also required to undergo FCOI training every 4 years and immediately if:
1. her Institution revises its FCOI policies and procedures;
2. the Investigator is new to the institution; or
3. when the Institution finds the Investigator not in compliance with the Institution's FCOI policy or management plan.
Within 30 days of acquisition or discovery of new SFIs during the period of award and annually, financial disclosures to the Institution must be updated.
Investigators who are awarded NIH funding for clinical research projects that evaluate safety or effectiveness of a drug, medical device or treatment with an FCOI that was not managed or reported by an Institution, shall be required to disclose her FCOI in every public presentation of the results of the research project and to request for an addendum of such FCOI in previously published presentations.
The case of Dr. Wilson and the University of Pennsylvania Gene Therapy Clinical Trial
The widely known case of Dr. Wilson, often cited in relation to FCOI, involved the death of clinical trial volunteer Jesse Gelsinger in 1999 while participating in a gene therapy clinical trial (Wilson 2010 cf. Wilson 2009). One of the Penn researchers that had a study-related SFI had stakes in a company called Genovo valued by the Wall Street Journal at 13.5 million USD and between 28.5 and 33.3 million USD by the University of Pennsylvania's Conflict of Interest Standing Committee (CISC) (Wilson 2010: 308). Those amounts are way above the 10,000 USD SFI threshold set by the U.S. PHS at that time and so was referred to the Penn's CISC. The current PHS SFI threshold is set to 5,000 USD.
Penn's CISC took the following steps in response to the magnitude of SFI involved in the study:
1. One of the CISC members, Arthur Caplan, recused himself from the CISC's deliberations because of a conflict of interest or the appearance of one-namely, that Dr. Wilson chaired the department in which Caplan had tenure (Wilson 2010: 309).
2. The committee met 4 times and asked the following questions in relation to deciding whether to authorize a stake of such magnitude (CISC draft question from March 3, 1995 meeting, Wilson 2010: 310):
- 5. How can Dr. Wilson and the University avoid liability for any damages if a patient died from any products produced or studied at the University?
- 15. Once a research course has been chosen, what steps will be taken to assure the University that the results of studies will not be biased by the financial interests of Dr. Wilson or his staff?
- 16. Since Dr. Wilson's research efforts will be directed towards the solution of aproblem in which he has a financial interest in the outcome, how can Dr.Wilson assure the University that he will not be conflicted when maling decisions that could have an impact on either Genovo, Biogen or the further development of his intellectual property?
3. Consulted a top health law firm and thought long and hard on how to protect clinical trial participants.
4. The committee asked Dr. Wilson whether he will be involved in the evaluation of the clinical data. Dr. Wilson responded that he will not be involved in the design of the study.
5. The committee imposed a number of conditions to Dr. Wilson, including:
forbidding him to serve in a management role or on the Scientific Advisory Board for Genovo or Biogen, capping his equity holdings in Genovo at 30%, limiting his consulting (for all organizations, including Genovo) to "one day in seven," and prohibiting him from receiving compensation when consulting with Genovo or Biogen...required Wilson to disclose his financial interests in "publications and public presentations" and to all "current" and "prospective" members of Wilson's lab, to be available "to discuss with members of your laboratory any concerns or questions ... regarding Genovo-sponsored research," and to provide information annually to lab members about an oversight committee that Penn established. (Wilson 2010: 314)
6. The committee decided to approve the FCOI and allow Dr. Wilson to participate in the design of the study while proscribing "direct" involvement. The committee "...directed Wilson to: Avoid direct participation in the conduct of clinical studies in which Genovo or Biogen has an interest. You are allowed to participate in the design of such studies but shall not be responsible for the analysis of data resulting from such studies." (Wilson 2010: 314)
The basis of this decision is "unusual circumstances," including:
the possible benefit of Wilson's research to the public, the possibility for opening a wide range of research at Penn, the need to get a timely start on research in a rapidly changing scientific environment, the fact that nascent technologies developed by Wilson were already under license to Genovo and that Wilson's involvement was important for the new research's likely success, together with the likely lack of available funding from other sources, like NIH. (Wilson 2010: 311)
After the CISC approved the FCOI, it was later discovered that Dr. Wilson had an influence in removing important information (that animals died in prior studies) approved by the RAC and IRB to be included in the informed consent forms (Wilson 2010: 316). Such information could have influenced the decision of participants to enroll in the study. Such unauthorized removal of information from the consent form could have been prevented if a post-approval monitoring procedure had been conducted (Wilson 2010: 322-325).
The lawsuit that was filed by the Gelsinger family was settled out of court so no publicly available determination through the courts were made as to what FCOI arose from this controversial clinical trial.
Enhancing compliance to FCOI regulations
The US PHS and NIH require compliance to FCOI regulations. It is therefore unlikely that Investigators applying for funding and intending to continue receiving funds from the US PHS will not want to comply with FCOI regulations. They may unintentionally miss some details that undermine the quality of compliance but if they are given accurate guidance by their institution's designated FCOI official, they should be able to fulfill all FCOI regulation requirements.
It is interesting to note that clinical trials not funded by the US PHS may have less incentive to evaluate their SFI for possible FCOI. Fulfilling FCOI requirements is a relatively demanding task and one reason that the US PHS exempted Small Business Innovation Research (SBIR)/ Small Business Technology Transfer research (SBTTR) phase I (safety study) applications (42 CFR 50.602, 45 CFR 94.2).
One survey (Rochon, et al. 2011) that evaluated adherence to FCOI disclosure requirements that are designed to promote the objectivity of research show variance across trial stages. The same study found that of the 844 investigators that responded to the email survey, 269 (37%) personally experienced or witnessed FCOI situations, and over 70% of these situations related to industry trials. The most frequent theme related to personal financial incentives (24%) and "180 (76%) of respondents indicated that the situations they witnessed were in relation to industry-funded trials" (Rochon, et al. 2011: 3). Perhaps, a way to avoid this tendency, if institutionally feasible, is to impose SFI disclosure requirements to all clinical trials regardless of funding source.
References
4. The committee asked Dr. Wilson whether he will be involved in the evaluation of the clinical data. Dr. Wilson responded that he will not be involved in the design of the study.
5. The committee imposed a number of conditions to Dr. Wilson, including:
forbidding him to serve in a management role or on the Scientific Advisory Board for Genovo or Biogen, capping his equity holdings in Genovo at 30%, limiting his consulting (for all organizations, including Genovo) to "one day in seven," and prohibiting him from receiving compensation when consulting with Genovo or Biogen...required Wilson to disclose his financial interests in "publications and public presentations" and to all "current" and "prospective" members of Wilson's lab, to be available "to discuss with members of your laboratory any concerns or questions ... regarding Genovo-sponsored research," and to provide information annually to lab members about an oversight committee that Penn established. (Wilson 2010: 314)
6. The committee decided to approve the FCOI and allow Dr. Wilson to participate in the design of the study while proscribing "direct" involvement. The committee "...directed Wilson to: Avoid direct participation in the conduct of clinical studies in which Genovo or Biogen has an interest. You are allowed to participate in the design of such studies but shall not be responsible for the analysis of data resulting from such studies." (Wilson 2010: 314)
The basis of this decision is "unusual circumstances," including:
the possible benefit of Wilson's research to the public, the possibility for opening a wide range of research at Penn, the need to get a timely start on research in a rapidly changing scientific environment, the fact that nascent technologies developed by Wilson were already under license to Genovo and that Wilson's involvement was important for the new research's likely success, together with the likely lack of available funding from other sources, like NIH. (Wilson 2010: 311)
After the CISC approved the FCOI, it was later discovered that Dr. Wilson had an influence in removing important information (that animals died in prior studies) approved by the RAC and IRB to be included in the informed consent forms (Wilson 2010: 316). Such information could have influenced the decision of participants to enroll in the study. Such unauthorized removal of information from the consent form could have been prevented if a post-approval monitoring procedure had been conducted (Wilson 2010: 322-325).
The lawsuit that was filed by the Gelsinger family was settled out of court so no publicly available determination through the courts were made as to what FCOI arose from this controversial clinical trial.
Enhancing compliance to FCOI regulations
The US PHS and NIH require compliance to FCOI regulations. It is therefore unlikely that Investigators applying for funding and intending to continue receiving funds from the US PHS will not want to comply with FCOI regulations. They may unintentionally miss some details that undermine the quality of compliance but if they are given accurate guidance by their institution's designated FCOI official, they should be able to fulfill all FCOI regulation requirements.
It is interesting to note that clinical trials not funded by the US PHS may have less incentive to evaluate their SFI for possible FCOI. Fulfilling FCOI requirements is a relatively demanding task and one reason that the US PHS exempted Small Business Innovation Research (SBIR)/ Small Business Technology Transfer research (SBTTR) phase I (safety study) applications (42 CFR 50.602, 45 CFR 94.2).
One survey (Rochon, et al. 2011) that evaluated adherence to FCOI disclosure requirements that are designed to promote the objectivity of research show variance across trial stages. The same study found that of the 844 investigators that responded to the email survey, 269 (37%) personally experienced or witnessed FCOI situations, and over 70% of these situations related to industry trials. The most frequent theme related to personal financial incentives (24%) and "180 (76%) of respondents indicated that the situations they witnessed were in relation to industry-funded trials" (Rochon, et al. 2011: 3). Perhaps, a way to avoid this tendency, if institutionally feasible, is to impose SFI disclosure requirements to all clinical trials regardless of funding source.
References
Rochon, P. A., Sekeres, M., Hoey, J., Lexchin, J., Ferris, L. E., Moher, D., ... & Gold, J. (2011). Investigator experiences with financial conflicts of interest in clinical trials. Trials, 12(9), 6215-12. http://dx.doi.org/10.1186/1745-6215-12-9
Wilson, J. M. (2009). Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Molecular genetics and metabolism, 96(4), 151-157. http://dx.doi.org/10.1016/j.ymgme.2008.12.016
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