GCP Questions - Financial Disclosure

Question 1:

I have performed a cursory review of every “Reply to Inquiry” PDFs on file for the topic of Financial Disclosure and have not found a reply to my questions.

Question 1- When a covered study is outsourced to a CRO, does financial disclosure need to be obtained as it relates to both the sponsor and the CRO? (i.e. typically the industry seems to provides the investigators with a Financial Disclosure Form, a questionnaire, to gather this information; should investigators be asked if they have proprietary interest in, hold stock in, etc. the CRO as well as the sponsor?)

Question 2- Could you please provide any insight as to how this typically performed in the industry today? For example should one form be used for each the CRO and sponsor? Or is it suggested that the information captured be combined into one forms?

Question 3- It seems that the current requirement is to request financial disclosure from all persons listed on the 1572, should this include persons such as a central ECG reader (see email from Stan W. Woollen dated August 01, 2005) What if a sponsor company outsourced to an ecg company and they were to provide central reading of ecgs. There may have a small group of people doing this - whose names may or may not be known? What about a pathology lab - would that apply also? Where is the line is drawn?

Also, though I understand that a sponsor may gather the information in which it must certify to on Forms 3454 and 3455 via any means it wishes, a completed Financial Disclosure Form (questionnaire) seems the most common. Should a company that is not a publicly held company include a question coinciding with the following disclosable financial arrangement:

“Any equity interest in the sponsor of a covered study, i.e., any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices. This requirement applies to all covered studies, whether ongoing or completed.”

I.E. would FDA recommend that a question be added to the questionnaire so that the investigator may attest to this (e.g. does FDA foresee any means by which an investigator may have a disclosable financial arrangement with a privately held company in this manner)?

Answer 1:

You may also want to review our Guidance for Industry: Financial Disclosure by Clinical Investigators, available at www.fda.gov/RegulatoryInformation/Guidances/ucm126832.htm.

Investigators are required to report financial interests and arrangements with the "sponsor of the covered clinical study" defined as "the party supporting a particular study at the time it was carried out." (21 CFR § 54.2(h))

Question 7 in the guidance provides some information that may be helpful. In part, it states:

The term "sponsor" has somewhat different meanings in the regulations at 312.53/812.43 and 54.2. An applicant must report financial interests in the sponsor of the covered study. Under 21 CFR 54.2, "sponsor" is defined as the party "supporting a particular study at the time it was carried out." FDA interprets support to include those who provide "material support," e.g., monetary support or test product under study. The sponsor of an IND or IDE, as defined in 21 CFR 312 and 812 is the "party or parties who take responsibility for and initiate a clinical investigation". The term "sponsor" is also used in 312.53 and 812.43 to refer to the party who will be submitting a marketing application (who is also responsible for submitting the certification and disclosure statement required by Part 54).

Question 9 in the guidance may also be helpful and states:

9. Q. If a Contract Research Organization (CRO) is conducting a covered clinical study on behalf of another company, should the CRO collect the financial information from investigators? Is it necessary to collect financial information from investigators who have financial interests in CROs? A: With regard to CRO and commercial sponsor arrangements, the same principles as articulated in answer 6 would apply. For example, if a CRO meets the definition of an IND/IDE sponsor or has contracted to collect financial information from investigators on behalf of an IND/IDE sponsor, the CRO must collect financial information on clinical investigators' interests in Part 54 sponsors (312.53, 812.43). If the CRO provides material support for a covered study, financial information on clinical investigators' interests in the CRO is to be collected. If another entity provided material support for the study, the CRO also would collect financial information relative to that entity.

I don't have information on how industry is typically performing this data collection. The sponsor/applicant may determine which method will work best for them. Note that Question 11 in the guidance states:

11. Q. Does FDA have expectations about how the financial information should be collected? Will FDA consider it acceptable practice for a company to use a questionnaire to collect financial information from investigators rather than constructing an internal system to collect and report this information? A: FDA has no preference as to how this information is collected from investigators. Under this rule, sponsors/applicants have the flexibility to collect the information in the most efficient and least burdensome manner that will be effective, for example, through questionnaires completed by the clinical investigators or by using information already available to the sponsor. FDA does not require sponsors to establish elaborate tracking systems to collect the information.

Question 12 the guidance provides the following:

12. Q. What does FDA mean by the definition of clinical investigator and subinvestigator? Is it necessary to collect financial information on spouses and dependent children of subinvestigators? A: The definition of "clinical investigator" in Part 54 is intended to identify the individuals who should be considered investigators for purposes of reporting under the rule, generally, the people taking responsibility for the study at a given study site. For drugs, biological products and devices, it should be noted that hospital staff, including nurses, residents, or fellows and office staff who provide ancillary or intermittent care but who do not make direct and significant contribution to the data are not meant to be included under the definition of clinical investigator. For purposes of this financial disclosure regulation, the term investigator also includes the spouse and each dependent child of the investigator and subinvestigator. For drugs and biological products, clinical investigator means the individual(s) who actually conduct(s) and take(s) responsibility for an investigation, i.e. under whose immediate direction the drug or biologic is administered or dispensed to a subject or who is directly involved in the evaluation of research subjects. Where an investigation is directed by more than one person at a site, there may be more than one investigator who must report. For purposes of this rule, the terms investigators and subinvestigators include persons who fit any of these criteria: sign the Form FDA 1572, are identified as an investigator in initial submissions or protocol amendments under an IND, or are identified as an investigator in the NDA/BLA. For studies not conducted under an IND, the sponsor will need to identify the investigators and subinvestigators they consider covered by the rule in form 3454 and/or 3455. We expect that there will be at least one such person at each clinical site. If, however, there are other persons who are responsible for a study at a site, those persons should also be included as investigators. For medical devices, clinical investigators are defined as individual(s), under whose immediate direction the subject is treated and the investigational device is administered, including follow-up evaluations and treatments. Where an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. In general, investigators and subinvestigators sign "investigator agreements" in accordance with 21 CFR 812.43(c ) and it is these individuals whose interests should be reported. For studies not conducted under an FDA-approved IDE, (that is, a non-significant risk IDE or an exempt study), the sponsor would need to identify the investigators and subinvestigators they considered covered by the rule in form 3454 and 3455. We expect that there will be at least one such person at each site.

Additionally, regarding who should be listed on the Form FDA 1572, you may want to review our guidance Frequently Asked Questions - Statement of Investigator (Form FDA 1572), available at www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM214282.pdf. Question 31 states:

31. Who should be listed as a subinvestigator in Section #6?

FDA's regulation at 21 CFR 312.3(b) states: "In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. Subinvestigator includes any other individual member of that team." 21 CFR 312.53(c)(1)(viii) requires the investigator to provide "a list of the names of the subinvestigators (e.g., research fellows, residents) who will be assisting the investigator in the conduct of the investigation(s)."

The purpose of Section #6 is to capture information about individuals who, as part of an investigative team, will assist the investigator and make a direct and significant contribution to the data. The decision to list an individual in Section #6 depends on his/her level of responsibility (i.e., whether he/she is performing significant clinical investigation-related duties). In general, if an individual is directly involved in the performance of procedures required by the protocol, and the collection of data, that person should be listed on the 1572. For example, if the protocol notes that each subject needs to visit a specified internist who will perform a full physical to qualify subjects for the clinical investigation, that internist should be listed in Section #6.

As you will note in the above information, the role an individual plays in the investigation is what is important in determining whether financial disclosure is necessary. If an ECG reader is intimately involved in the study, then I would consider them as someone who needs to provide financial disclosure information, whether the individual was located at a contract facility or at the same institution. The involvement of various individuals in a trial would need to be considered on a study by study basis.

Sponsors are required to collect information on clinical investigator financial interests in a sponsor (as defined in 21 CFR § 54.2), including a sponsor for which an equity interest's value could not be determined through reference to public prices. Sponsors may determine the best way to do this, which could include adding such a question to the questionnaire being used to collect clinical investigator financial information.

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