Research · 6 min read
What a Trial Investigator Has to Disclose About Money
There is a regulation devoted to one specific worry: that a doctor running a study stands to gain from the answer. It sets two dollar thresholds, names four kinds of interest, and tells the agency what to do when one turns up.
Key takeaways
- 21 CFR part 54 exists because FDA treats an investigator's financial interest in a study's outcome as a potential source of bias affecting data reliability.
- Four categories are disclosable: compensation that could be higher for a favorable outcome, a significant equity interest in the sponsor, a proprietary interest such as a patent, and significant payments of other sorts.
- The thresholds are $50,000 for equity in a publicly traded sponsor and $25,000 for other payments, each measured during the study and for one year after it ends.
- The definition of clinical investigator includes the investigator's spouse and each dependent child.
- The disclosure form asks not only what the interest was but what steps were taken to minimize the potential for bias.
- FDA weighs a disclosed interest against the study design, and may audit, request further analyses or independent confirmation, or refuse to treat the study as supporting data.
Answer first: the rule exists because a financial interest is a source of bias
21 CFR 54.1 states the reasoning in the agency's own words. FDA may consider clinical studies inadequate, and the data inadequate, if appropriate steps have not been taken in the design, conduct, reporting and analysis of the studies to minimize bias. It then names one such source: a financial interest of the clinical investigator in the outcome of the study, because of the way payment is arranged — its example is a royalty — or because the investigator has a proprietary interest in the product, such as a patent, or an equity interest in the sponsor.
The regulation is careful about how the disclosed information is used. FDA will use it, the section says, in conjunction with information about the design and purpose of the study, as well as information obtained through on-site inspections, in the agency's assessment of the reliability of the data.
That is a narrow and specific claim. Disclosure is an input into a reliability assessment. It is not a finding of misconduct, and the regulation never treats it as one.
The four kinds of interest, and the two dollar figures
Section 54.2 defines the terms, and the definitions are where the substance is.
Compensation affected by the outcome of clinical studies means compensation that could be higher for a favorable outcome than for an unfavorable outcome — the regulation gives as examples compensation explicitly greater for a favorable result, compensation in the form of an equity interest in the sponsor, and compensation tied to sales of the product, such as a royalty interest.
A significant equity interest in the sponsor means any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices — generally, interests in a nonpublicly traded corporation — or any equity interest in a publicly traded corporation that exceeds $50,000 during the time the investigator is carrying out the study and for one year following its completion.
A proprietary interest in the tested product means property or other financial interest in the product including, but not limited to, a patent, trademark, copyright or licensing agreement.
Significant payments of other sorts means payments by the sponsor to the investigator or the institution to support the investigator's activities having a monetary value of more than $25,000, exclusive of the costs of conducting the study — the regulation's examples are a grant to fund ongoing research, compensation in the form of equipment, retainers for ongoing consultation, or honoraria — again during the study and for one year after completion.
Two definitions widen the scope more than most readers expect. Clinical investigator means only a listed or identified investigator or subinvestigator directly involved in the treatment or evaluation of research subjects — and the term also includes the spouse and each dependent child of the investigator. And the one-year tail on both dollar thresholds means an interest acquired after the study ends can still be disclosable.
Which studies are covered, and which are not
A covered clinical study, under 54.2(e), is any study of a drug or device in humans submitted in a marketing application that the applicant or FDA relies on to establish that the product is effective — including studies showing equivalence to an effective product — or any study in which a single investigator makes a significant contribution to the demonstration of safety.
The definition then lists what this would in general not include: phase 1 tolerance studies, pharmacokinetic studies, most clinical pharmacology studies unless they are critical to an efficacy determination, large open safety studies conducted at multiple sites, treatment protocols, and parallel track protocols. An applicant may consult FDA about which studies count.
The logic behind that list is visible in it. The rule concentrates on the studies whose result decides an approval, and on studies where one person's contribution to a safety demonstration is large enough to matter on its own. A large multi-site safety study is exactly the design in which no single investigator's interest could swing the answer.
Certify or disclose, and the information flows upward from the site
Section 54.4 sets out the mechanics. An applicant must submit a list of all clinical investigators who conducted covered studies, identifying those who are full-time or part-time employees of the sponsor. For every investigator who is not such an employee, the applicant must, for each covered study, submit either a certification that none of the defined financial arrangements exist, or a disclosure statement.
The disclosure statement must set out, completely and accurately: any financial arrangement between the sponsor and the investigator whereby the value of the investigator's compensation could be influenced by the outcome of the study; any significant payments of other sorts; any proprietary interest in the tested product held by any investigator involved in a study; any significant equity interest in the sponsor held by any investigator involved in any clinical study; and any steps taken to minimize the potential for bias resulting from those arrangements, interests or payments.
That last element is the one people miss. The form does not only ask what the interest was. It asks what was done about it.
The information originates at the trial site. Under 54.4(b) the investigator must provide the sponsor with sufficient accurate financial information to allow complete and accurate certification or disclosure, and must promptly update it if relevant changes occur during the investigation or for one year following completion. The same duty appears twice more in the research regulations: 21 CFR 312.53 requires a sponsor to obtain that information, and a commitment to update it, before permitting an investigator to begin, and 21 CFR 312.64(d) states the investigator's parallel duty.
There is also a consequence for an incomplete file. Under 54.4(c), FDA may refuse to file a marketing application that does not contain the required information, or a certification that the applicant acted with due diligence to obtain it and could not, stating the reason.
What the agency does when an interest is disclosed
Section 54.5 is the part that keeps this proportionate, and it is worth knowing because it explains why a disclosed interest is not automatically a scandal.
FDA will evaluate the disclosed information for each covered study to determine the impact of any disclosed financial interests on the reliability of the study. It may consider both the size and nature of the interest — including the potential increase in its value if the product is approved — and the steps taken to minimize the potential for bias.
Then comes a paragraph headed effect of study design. In assessing the potential of an investigator's financial interests to bias a study, FDA will take into account the design and purpose of the study. Study designs that use approaches such as multiple investigators, most of whom do not have a disclosable interest, blinding, objective endpoints, or measurement of endpoints by someone other than the investigator, may adequately protect against any bias created by a disclosable financial interest.
That sentence is the practical bridge between this regulation and everything else about trial design. A design can absorb an individual's conflict. A single-investigator study measuring a subjective endpoint cannot.
Where the agency does conclude that financial interests raise a serious question about the integrity of the data, 54.5(c) lists what it may do: initiate audits of the data derived from the investigator in question; request further analyses, for example to evaluate the effect of that investigator's data on the overall study outcome; request that the applicant conduct additional independent studies to confirm the results; and refuse to treat the covered study as providing data that can be the basis for an agency action.
For anyone reading a company's account of its evidence, the transferable question is the one 54.5(b) asks. Not merely who paid, but whether the study was built so that the answer did not depend on any one interested person's judgment.
Sources
- 21 CFR 54.1 — Purpose, and 21 CFR 54.2 — DefinitionsThe stated purpose and the treatment of an investigator's financial interest as a potential source of bias; the statement that FDA uses the information alongside study design and purpose and on-site inspection findings to assess data reliability; and the definitions of compensation affected by the outcome, significant equity interest with the $50,000 threshold, proprietary interest, significant payments of other sorts with the $25,000 threshold, the one-year tail on both, the inclusion of the spouse and each dependent child in clinical investigator, and the scope and exclusions of covered clinical study.
- 21 CFR 54.4 — Certification and disclosure requirementsThe requirement to list all investigators who conducted covered studies and identify sponsor employees; the choice between certification and disclosure for non-employees; the five items a disclosure statement must contain, including any steps taken to minimize the potential for bias; the investigator's duty to supply and promptly update financial information during the study and for one year after; and FDA's ability to refuse to file an application lacking the required information or a due-diligence certification.
- 21 CFR 54.5 — Agency evaluation of financial interestsThat FDA evaluates disclosed interests for their impact on study reliability considering size, nature and mitigating steps; that it takes study design into account, naming multiple investigators, blinding, objective endpoints and endpoint measurement by someone other than the investigator as protections; and the four actions available where financial interests raise a serious question about data integrity.
- 21 CFR 312.53 — Selecting investigators and monitors, and 21 CFR 312.64 — Investigator reportsThat before permitting an investigator to begin, a sponsor must obtain sufficient accurate financial information for part 54 certification or disclosure together with a commitment to update it promptly during the investigation and for one year after completion, and that the investigator carries the same duty under part 312.
Frequently asked questions
Why is there a financial disclosure rule for trial investigators at all?
21 CFR 54.1 explains that FDA may consider studies and data inadequate if appropriate steps were not taken to minimize bias, and names an investigator's financial interest in the outcome as one potential source — through payment arrangements such as royalties, a proprietary interest such as a patent, or an equity interest in the sponsor.
What dollar thresholds does the regulation use?
Two. An equity interest in a publicly traded corporation counts as significant if it exceeds $50,000 during the study and for one year after completion. Payments of other sorts to support the investigator's activities count if they exceed $25,000, exclusive of the costs of conducting the study, over the same period. Interests whose value cannot be readily determined from public prices count regardless of amount.
Does the rule cover an investigator's family?
Yes. The definition of clinical investigator at 21 CFR 54.2(d) covers a listed or identified investigator or subinvestigator directly involved in the treatment or evaluation of research subjects, and states that the term also includes the spouse and each dependent child of the investigator.
Which studies does it apply to?
Covered clinical studies: any study of a drug or device in humans submitted in a marketing application that is relied on to establish effectiveness, including equivalence studies, or any study in which a single investigator makes a significant contribution to a safety demonstration. It generally excludes phase 1 tolerance and pharmacokinetic studies, most clinical pharmacology studies, large open multi-site safety studies, treatment protocols and parallel track protocols.
Does a disclosed financial interest mean the data are unreliable?
No. Under 21 CFR 54.5, FDA evaluates the size and nature of the interest and the steps taken to minimize bias, and takes the study design into account — noting that multiple investigators most of whom have no disclosable interest, blinding, objective endpoints, or measurement of endpoints by someone other than the investigator may adequately protect against bias.
What can FDA do if it is not satisfied?
Section 54.5(c) lists four actions: audit the data from the investigator in question, request further analyses such as the effect of that investigator's data on the overall outcome, request additional independent studies to confirm the results, and refuse to treat the covered study as data that can support an agency action.