Legal and Ethical Considerations for Offering Clinical Trial Recruitment Payments and Enrollment Incentives

By Anna Zhao 

I. Introduction

Recruiting clinical trial participants is an important yet challenging step for any clinical trial. Studies show that 85% of clinical trials fail to retain enough participants, and up to 50% of clinical trial sites fail to enroll any participant in their trials.[1] Failure to recruit or retain a sufficient number of participants may lead to stagnation or termination of clinical trials and further delay marketing application filing, which is estimated to result in a potential loss of $8 million per day for drug developers.[2]

Facing recruitment challenges, drug developers, i.e., clinical trials sponsors, may consider offering recruitment payments and enrollment incentives to spur investigators to invest more time and resources in recruiting trial participants. For example, certain practices may include paying investigators—in forms such as recruitment payments, milestone payments, or bonuses—when the investigators recruit a certain number of participants or complete the enrollment goal early. In addition, sponsors and investigators may consider rewarding non-investigator healthcare professionals (HCPs) for identifying their patients as potentially eligible for clinical trials.

These recruitment payments and incentives have long raised intriguing legal and ethical quandaries and require renewed consideration as the legal and regulatory environment and clinical trial landscape evolve. This article analyzes the legal and ethical considerations for offering such recruitment payments and enrollment incentives to investigators and non-investigator referring HCPs and provides practical recommendations.

II. Background on Clinical Trial Participant Recruitment

Recruiting clinical trial participants is a crucial step in drug development. Under the Federal Food, Drug, and Cosmetic Act (FDCA), the U.S. Food and Drug Administration (FDA) will approve a marketing application—either a new drug application (NDA) or a biologics license application (BLA)—provided that the applicant must demonstrate that the drug is safe and effective through appropriate evidence generated by clinical investigations, among other things.[3] Conversely, FDA must withhold approval of a marketing application if the applicant fails to submit substantial evidence to show that the drug has the purported effect.[4] This generally means an applicant must conduct adequate and well-controlled clinical investigations on an appropriate clinical trial population and generate sufficient safety and efficacy data to support the application.

Typically, clinical trial participant recruitment involves three core parties: the sponsor, the investigator and study personnel, and the institutional review board (IRB). A sponsor is responsible for the design and conduct of a clinical trial, including devising the appropriate participant selection criteria, providing information to investigators, monitoring the trial, and submitting safety and other reports to FDA in an investigational new drug application (IND).[5]

Investigators are responsible for recruiting trial participants and protecting participants’ rights, safety, and welfare.[6] Specifically, investigators must review and evaluate the prospective participants’ eligibility to enroll in a trial pursuant to the study protocol, obtain adequate and effective informed consent, and perform necessary procedures and tests to confirm participants are eligible to take part in the trial prior to enrollment.[7]

While investigators may delegate some of the recruitment-related tasks to study personnel, investigators must maintain adequate oversight of the activities and take the ultimate responsibility.[8] Recruiting inappropriate or ineligible participants is considered as failure to adhere to the study protocol and violates an investigator’s responsibilities, which could result in inspectional observations, advisory or enforcement actions, and penalties, including disqualification of investigators.[9] It may also lead to the underlying data being disqualified or rejected by FDA and, in serious cases, potential delay in or refusal of approval of a marketing application.[10]

IRBs oversee trials and have authority to approve, require modification in, or disapprove all research activities covered by FDA’s regulations and to conduct continuing review of such activities.[11] To approve a clinical trial, an IRB must determine that the risks to participants are minimized, the selection of participants is equitable, and proper informed consent is sought.[12] As part of this authority, an IRB reviews the participant recruitment and selection materials and processes.

FDA has maintained a guidance, titled “Recruiting Study Subjects,” that sets forth considerations for IRBs when reviewing participant recruitment activities.[13] For example, the guidance provides that an IRB should review “the methods and material[s] that investigators propose to use to recruit subjects.”[14] However, the guidance does not address the practice of offering investigators and other HCPs recruitment payments and enrollment incentives.[15] It leaves IRBs with discretion to review the appropriateness of such practices and requires sponsors and investigators to conduct appropriate review and exercise prudence when engaging in such practices to ensure compliance.

III. Clinical Trial Diversity and Inclusiveness

Clinical trial diversity and inclusiveness has been an increasingly significant consideration for clinical trial participant recruitment. Generally, FDA expects that sponsors enroll trial participants that reflect the characteristics of clinically relevant populations regarding age, gender, race, and ethnicity.[16] FDA has issued a suite of guidance documents in recent years to encourage sponsors to increase the diversity of clinical trial participants and to include those historically underrepresented racial and ethnic populations, such as Black, Hispanic/Latino, and Asian populations.[17] To further this effort, FDA encourages sponsors to consider innovative clinical trial designs and decentralized clinical trial models by, among others, engaging local clinics and HCPs and using digital health technologies to access more diverse populations.[18]

The Food and Drug Omnibus Reform Act, passed in December 2022, further mandates that sponsors submit a diversity action plan to FDA when submitting a phase 3 or another pivotal clinical trial protocol.[19] The diversity action plan must describe the sponsor’s enrollment goals to recruit diverse study participants, the rationale of such goals, and the strategies the sponsor will use to achieve the goals, including demographic-specific outreach and enrollment strategies, study-site selection, clinical study inclusion and exclusion practices, and diversity training for study personnel.[20] These would likely call for increased efforts by sponsors in participant recruitment, including devising appropriate strategies such as offering recruitment payments and enrollment incentives to engage investigators and local HCPs to identify and recruit diverse participants into clinical trials. Against this backdrop, offering recruitment payments and enrollment incentives may have broader implications and require renewed considerations.

IV. Anti-Kickback Statute and Physician Payments Sunshine Act Considerations

  1. Anti-Kickback Statute

As a starting point, there is risk that recruitment payments and enrollment incentives might be considered as “kickbacks” under the Federal Anti-Kickback Statute (AKS), depending on the circumstances. The AKS prohibits a person from knowingly and willfully offering or paying any renumeration (including any kickbacks, bribes, or rebates) to induce or reward patient referrals or services reimbursable by federally funded healthcare programs.[21] Generally, the government has advised drug manufacturers to structure payments to HCPs for clinical research to fit into one of the safe harbors known as the personal services safe harbor whenever possible.[22]

To qualify for this safe harbor, the arrangement must meet the following criteria: 1) the arrangement is set out in a written agreement and signed by the parties; 2) the agreement specifies all the services to be provided by HCPs during the term of the agreement; 3) the term of the agreement is not less than one year; 4) the methodology for determining the compensation over the term of the agreement is set in advance, is consistent with fair market value in arm’s-length transaction, and does not take into account referrals or business generated between the parties; and, among others, 5) the aggregate services contracted for are reasonable necessary to accomplish the commercially reasonable business scope.[23]

Typically, ensuring the compensation to HCPs is consistent with fair market value and can be appropriately substantiated is a key criterion to meet this safe harbor requirement. For biotech companies who do not have a commercial product, there is a potential argument that the AKS does not apply if there is no good or service being covered by a federal healthcare program. However, there remains conceivable risk that payments made to the investigators could be viewed as intending to influence future use of a drug product upon commercial availability. States often have similar anti-kickback statutes that prohibit similar activities.

To mitigate the AKS risk, recruitment payments and enrollment incentives should be structured to meet the above safe harbor criteria. The payments should be based on legitimate needs and intended to compensate the HCPs’ bona fide recruitment efforts such as screening, chart review, discussion with prospective participants regarding clinical trials, and collection of biological samples. Such payments should be consistent with the fair market value, substantiated, necessary and reasonable, and documented in a written agreement such as a clinical trial agreement or amendment.

2. Physician Payments Sunshine Act

Recruitment payments and enrollment incentives may also be subject to the reporting requirements under the federal Physician Payments Sunshine Act (the Sunshine Act). The Sunshine Act generally requires medical product manufacturers report annually to the Centers for Medicare and Medicaid Services (CMS) any payments or other transfers of value made to physicians or teaching hospitals for inclusion in a publicly available database.[24] Payments and other transfers of value subject to reporting include, among others, research payments.[25] The term “research” is defined to cover both basic and applied research and product development, including nonclinical studies and FDA-regulated phase 1–4 clinical studies, as well as investigator-initiated investigations.[26]

Accordingly, recruitment-related payments may fall under this broad category. The purpose of the reporting requirement is to promote transparency regarding the relationship between manufacturers and HCPs and to avoid conflicts of interest.[27] It applies to manufacturers of drugs, devices, biologics, or medical supplies covered by Medicare, Medicaid, or the State Children’s Health Insurance Program.[28] Thus, manufacturers should take the recruitment payments and enrollment incentives into account when making annual reports to CMS. Many emerging companies that conduct clinical trials for their first drug product may not be immediately subject to this requirement, but it applies once the drug receives approval and coverage.

V. FDA Regulatory Considerations

As discussed above, FDA’s regulations do not directly address recruitment payments and enrollment incentives to investigators and other HCPs. However, the practice requires prudent considerations under FDA’s regulations as it may impact the integrity of the trial conduct and affect trial participants’ rights, safety, and wellbeing. In particular, the agency has commented on offering recruitment incentives in the contexts of investigator financial disclosure, informed consent, IRB, and Good Clinical Practices requirements.

1. Financial Disclosure

FDA’s financial disclosure regulation requires that an applicant submit to FDA certain information concerning the compensation made to, or financial interests and arrangement of, investigators who conducted a clinical study covered by the regulation.[29] A “covered clinical study” means any human study of a drug submitted in a marketing application that the applicant or FDA relies on to establish that the product is effective or any study in which a single investigator makes a significant contribution to the demonstration of safety.[30]

Financial interests subject to disclosure include compensation, equity interests in the sponsor, proprietary interests in the product, and significant payments of other sorts (SPOOS), which is defined to mean payments made by a sponsor to an investigator or an institution to support activities of the investigator that “have a monetary value of more than $25,000, exclusive of the costs of conducting the clinical study . . . during the time the clinical investigator is carrying out the study and for 1 year following the completion of the study.”[31] Investigators must provide accurate information relating to these financial interests to allow subsequent disclosure or certification by the applicant.[32] The purpose of this requirement is to assist FDA in evaluating the reliability of the study data to ensure that the clinical trial data supporting a marketing application are adequate and that potential bias is minimized.[33]

One potential source of bias in clinical studies that FDA considers is the investigator’s financial interest in the outcome of the study “because of the way payments are arranged.”[34] In particular, FDA has noted that recruitment payments and enrollment incentives can introduce bias from investigators and affect an investigator’s professional judgement in making enrollment decisions.

In 2016, a sponsor sought FDA’s advice regarding whether it was acceptable to pay an investigator to enroll study participants—in that case $1,500 per participant randomized into the study and $1,500 monthly retainer if the investigator enrolled two participants per month.[35] The agency responded that “FDA is aware that recruitment payments and incentives are sometimes paid to a clinical investigator, especially when enrollment is particularly challenging for a clinical trial. . . . Such payments and incentives can present a risk of bias, by affecting an investigator’s professional judgment in making enrollment decision.”[36] The agency further recommended that recruitment payments and incentives be included in the calculation of SPOOS.[37] Therefore, sponsors should ensure that they capture investigator recruitment payments and enrollment incentives in the SPOOS calculation and further evaluate any steps needed to mitigate potential bias to make appropriate disclosure and certification to FDA.

2. IRB Oversight

As stated above, an IRB has the authority to review the appropriateness of the recruitment payments and enrollment incentives. The aim of this IRB review is to ensure adequate protection of participants’ rights and welfare. In an inquiry where FDA was asked whether it was appropriate to pay investigators or physicians who are not associated with the study referral or finder’s fees for referring potential study participants into clinical trials to be further checked for their potential eligibility, FDA stated that the regulations do not prohibit such payments, but the payments should be submitted to and reviewed by the IRB.[38]

That said, no uniform rule exists among IRBs in reviewing and approving recruitment payments and enrollment incentives. Many IRBs have policies that prohibit payments solely for referring patients or recruiting prospective participants, known as referral fees or finder’s fees.[39] Some other IRBs also prohibit incentive payments to investigators based on the number of participants recruited or the attainment of enrollment goals.[40] Other IRBs may determine the magnitude of the payments and assess such payments on a case-by-case basis. The main concern behind these policies is that recruitment payments may create a conflict of interest and provide an appearance that HCPs’ professional judgement in patients’ welfare or validity of the research could be compromised by financial interests.[41] Practically speaking, these IRB requirements pose a potential hurdle, often prohibiting offering recruitment payments or enrollment incentives. Sponsors should ensure that recruitment-related payments and incentives align with IRB policies.

3. Informed Consent

Sponsors and investigators should also obtain adequate consent from potential participants regarding recruitment payments and enrollment incentives. While FDA’s informed consent regulation does not specifically address the practice, the regulation requires that an informed consent document include, among other things, “a description of any benefits to the subject or others which may reasonably be expected from the research.”[42] FDA’s older guidance on informed consent provides that it may be an issue when benefits accruing to the investigator, the sponsor, or others are different than normally expected to result from conducting research,” and suggests that “[i]f these benefits may be materially relevant to the subject’s decision to participate, they should be disclosed in the informed consent document.”[43]

The latest final guidance on informed consent issued by FDA in August 2023 specifically recommends that investigators consider including in the informed consent form: 1) the source of funding and funding arrangements for the conduct and review of the clinical investigations, or 2) the financial interest and arrangement of an investigator or institution and how it is being managed.[44] Further, consistent with an IRB’s authority as discussed above, the guidance provides that IRBs should retain final responsibility to determine whether participants should be provided with the information relating to the source of funding, funding arrangement, or financial arrangement of parties in the informed consent process.[45] IRBs should also determine the kind, amount, and level of detail of information to be provided by study participants.[46] In other words, only including the financial information in an informed consent form is not sufficient, and the level of the disclosure also needs to be appropriate as determined by the IRB.

4. Good Clinical Practice (GCP)

Finally, recruitment payments and enrollment incentives could raise risks of jeopardizing the safety of the trial participants and the integrity of the clinical trial conduct, thereby violating the Good Clinical Practice (GCP). The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) defines GCP as “a standard for the planning, initiating, performing, recording, oversight, evaluation, analysis, and reporting of clinical trials that provides assurance that the data and reported results are reliable and that the rights, safety and well-being of trial participants are protected.”[47]

The GCP requirements are considered to have been embedded in FDA’s clinical trial regulations in 21 C.F.R. Part 312, among others, and FDA has also adopted ICH’s GCP E6(R3) as a guidance.[48] The requirements in GCP E6(R3) and FDA’s regulations do not specifically call out recruitment payments to investigators and other HCPs. However, improper payment incentives could lead the investigators and study personnel not to apply the inclusion and exclusion criteria properly and enroll participants that are ineligible for the trial, which could further compromise participants’ safety and welfare as well as the integrity of the study conduct and outcome, thereby violating the GCP.

FDA conducts inspections of sponsors, CROs, and investigators to review the trial conduct and assess compliance with FDA’s regulations, including the GCP requirements. For instance, FDA’s compliance program requires inspectors to review the process to recruit participants and to document any process that appears to be coercive in nature.[49] In the past, FDA has issued inspectional observations relating to enrollment of participants in trials that should not have been enrolled, and some of these instances were linked to the use of incentive payments to address enrollment challenges.[50] To prevent such risks, sponsors should consider conducting audits and exercise more intensified oversight such as monitoring over the clinical trial sites where recruitment payments and incentives are offered to ensure such recruitment payments and incentives do not compromise the participants’ rights, safety and wellbeing, or the integrity of the trial conduct.

VI. Ethical Quandaries: Finder’s Fees, Referral Fees, or Not?

Recruitment payments and enrollment incentives to HCPs have long raised ethical issues. Many IRBs and medical organizations prohibit payments known as “finder’s fees” or “referral fees” where physicians would be rewarded for identifying or referring their patients to research. The primary ethical concern is such payments may give rise to a conflict of interest where a physician’s professional judgment regarding the validity of research and patients’ wellbeing may be jeopardized by financial interests.[51] It may also erode patients’ trust in physicians as they rely on the physicians’ judgments in making decisions to participate in clinical trials.[52]

The American Medical Association’s (AMA’s) Code of Medical Ethics provides that physicians should not accept payments “solely for referring patients to research studies.”[53] The American College of Physicians (ACP) Ethics Manual similarly provides that “giving or accepting finder’s fees for referring patients to a research study generates an unethical conflict of interest for physicians.”[54] In addition, the International Code of Medical Ethics of the World Medical Association provides that “[a] physician shall not receive any financial benefits or other incentives solely for referring patients.”[55]

However, it may be reasonable to draw a distinction between recruitment-related payments intended to compensate for the time and resources invested by physicians in identifying or recruiting study participants from mere finder’s fees or referral fees.[56] One may argue that what the medical ethics rules intend to prevent regarding these fees is the potential bias in research integrity and undue influence on patients’ wellbeing—not the fair reimbursement for performance of services by physicians.

FDA appears to have noted such distinction in a GCP inquiry where FDA was asked whether it is acceptable to reward physicians with cash for referring their patients to a clinical trial.[57] The agency stated: “[t]here is a difference between the amount of resources it takes for a physician to simply refer the name of a patient who might be eligible to the investigator vs. the physician who actually performs a service to identify potentially eligible patients by reviewing their patient charts, assessing patients in accordance with the inclusion/exclusion criteria of the study protocol, contacting a patient/potential subject to discuss the study and assessing that patient’s interest in being referred to the investigator for more information on the proposed study.”[58] This suggests that recruitment-related payments may be permissible if they are offered to compensate a physician for the time and effort in identifying potential eligible participants and reflect the actual time and effort the physician spent in carrying out the relevant recruitment activities.

Indeed, the ACP Ethics Manual provides that “compensation for the actual time, effort, and expense involved in research or recruiting patients is acceptable; any compensation above that level represents a profit and constitutes or can be perceived as an unethical conflict of interest.”[59] The AMA similarly advises that physicians who engage in research should decline financial compensation that awards “in excess of the physician’s research efforts and does not reflect fair market value.”[60]

Another troubling ethical issue is offering incentives to investigators such as milestone payments or bonuses based on the number of the participants recruited or the rate and timing of attaining the enrollment goal.[61] One may view that this practice raises heightened risk that HCPs may stretch enrollment criteria and recruit inappropriate patients to obtain the additional financial benefits. Thus, like finder’s fees, offering bonus payments contingent upon completion of certain enrollment goals could provide an appearance of impropriety unless they can be appropriately substantiated otherwise by HCPs’ heightened recruitment efforts.

VII. Practical Recommendations

Sponsors should be conscientious when offering recruitment payments and enrollment incentives to investigators and other HCPs. At minimum, payments should not be offered to reward HCPs—either investigators or non-investigators—for merely finding or referring participants. Recruitment payments and enrollment incentives, if offered, should be based on legitimate needs, negotiated in arm’s-length transactions and documented in a clinical trial agreement or amendment. The level of the payments should be fair, reasonable, appropriately substantiated, and should not exceed fair market value. In addition, such payments need to be reviewed and approved by an IRB in advance, appropriately considered for FDA financial disclosure and other reporting purposes, and disclosed in the informed consent forms. Below are key guardrails and recommendations for some of the common practices of offering recruitment payments and enrollment incentives. Further considerations may be needed depending on the specific type and nature of the payments.

Recruitment Payments to Investigators. Recruitment payments to investigators should reflect the investigators’ performance of recruitment activities such as screening, chart review, and sample collection, and align with fair market value. Ideally, recruitment payments should be structured per activity or on an hourly basis at an appropriate rate. The ultimate payments should not exceed the level of the actual time, efforts, and expenses invested by investigators and study personnel. In addition, it is advisable that the clinical trial agreement clarify that recruitment payments made to investigators are not intended to reward or induce, and are not related to, any past or future prescriptions of the sponsor’s drug products, and that they are not a finder’s fee or referral fee and should not be contingent upon whether the prospective participants would ultimately enroll in or complete the trial or not.

Milestone Payments or Bonuses to Investigators. Generally, it is disfavored to offer payments including milestone payments or bonuses that are linked to the rate and timing of participant enrollment or contingent upon the investigators’ completion of the enrollment target due to the heightened risk that HCPs may pursue the extra financial incentives at the expense of the participants’ wellbeing. As stated above, some IRB policies and medical associations prohibit these incentive payments.

That said, milestone payments or bonuses could be permissible in certain instances if they are based on legitimate needs and appropriately structured based on the time and resources invested by investigators and study personnel. For example, if a sponsor expects that additional hours or efforts are required to achieve the enrollment goal within the expected timeline (e.g., 50 hours/week in reviewing patient charts or screening a certain number of patients within a quarter), it may be reasonable to pay an additional amount when the investigator/site hits that hours’/efforts’ milestone. Alternatively, if additional personnel are needed to support heightened recruitment activity within the expected timeline, there could be payment for the additional personnel’s work. These payments may be arguably permissible so long as they are commensurate with the time and efforts by the investigators and study personnel, consistent with IRB policies and do not exceed fair market value. The payments generally should not be contingent on whether the potential participants ultimately enroll in the clinical trial.

Increasing Payment Levels. In addition, as the trial progresses, sponsors and investigators may realize that certain recruitment activity requires more time and effort than previously anticipated. In principle, increasing the initial recruitment payments to compensate for the extra time and effort needed from the investigators and study personnel may be proper so long as the increase can be appropriately justified and substantiated.

Payments to Non-Investigator Referring HCPs. As stated above, sponsors and investigators may consider paying non-investigator HCPs, such as community physicians, for identifying their patients for clinical trials. Engaging local clinics and HCPs can expand the potential trial participant pool and has increasingly been becoming a valuable recruitment strategy to recruit diverse participants.[62] However, because non-investigator referring HCPs and their institutions do not typically provide clinical trial services to sponsors, payments to non-investigator referring HCPs may face heightened risks of being considered as inappropriate referral fees or finder’s fees.

To mitigate such risks, sponsors and/or investigators should consider entering into a patient identification or referral agreement or the like with the referring HCPs or institutions to elucidate the rationale of the payments. The agreement should: 1) specify the patient identification and referral services that the referring HCPs perform on behalf of the sponsor or investigator (e.g., reviewing patient charts and records and discussing with the patients regarding their interest in participating in clinical trial), and 2) clarify the payments made to the referring HCPs are intended to compensate them for performing such services and are not finder’s fees or referral fees.

In light of the limited role of non-investigator referring HCPs and the nature of the arrangement, the agreement should also include proper guardrails such as that 1) the referring HCPs should limit the discussions with their patients to the clinical trial and their potential eligibility to participate in the trial; 2) the referring HCPs should not promise, either explicitly or impliedly, that the patients are eligible to participate in the clinical trial; 3) the referring HCPs should not promote the investigational drug as safe or effective;[63] and 4) any payments made to referring HCPs should not be contingent upon ultimate enrollment of or completion of the clinical trial by potential participants referred by the HCPs.

These guardrails would set boundaries between the referring HCPs’ patients identification activities and the investigators’ clinical trial activities, preserve the investigators’ roles and responsibilities, and ensure compliance with FDA’s regulations. Moreover, as clinical trials often involve vulnerable patient population (e.g., elderly, non-English speaking population) who may lack adequate resources or information, these guardrails are critically important to protect their rights and welfare and to mitigate the potential risks of coercion and undue influence.

VIII. Conclusions

Overall, recruitment payments and enrollment incentives raise many thorny legal and ethical issues. Sponsors should be cognizant of different considerations and exercise proper review and judgement when offering these payments and incentives. Sponsors should also consider increasing the oversight such as prioritizing monitoring and GCP audits of clinical trial sites where incentive payments are being offered to ensure that such payments do not compromise the protection of human subjects and integrity of the clinical trial conduct, yet at the same time serve as appropriate incentives to accelerate the clinical trial and promote diversity in clinical trial enrollment.

 

[1] Considerations for Improving Patient Recruitment Into Clinical Trials, Clinical Leader, https://www.clinicalleader.com/doc/considerations-for-improving-patient-0001.

[2] Id.

[3] FDCA § 505(d); Public Health Service Act § 351(a); 21 C.F.R. § 600.3(s); Food and Drug Administration Modernization Act § 123(f).

[4] Id.

[5] 21 C.F.R. §§ 312.23(a)(6)(iii)(c); 312.33(a)(2); 314.50(d)(5)(v), (vi). Sponsors may transfer all or some of their responsibilities to a contract research organization (CRO). See 21 C.F.R. § 312.52.

[6] Id. §§ 312.56, 312.60, 312.66.

[7] Id. § 50.20.

[8] 21 C.F.R. § 312.60. See also U.S. Food & Drug Admin., Investigator Responsibilities—Protecting the Rights, Safety, and Welfare of Study Subjects: Guidance for Industry 2 (Oct. 2009), https://www.fda.gov/media/77765/download.

[9] See, e.g., Warning Letter to R. Hayashi, U.S. Food & Drug Admin. (Mar. 14, 2023), https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/robert-j-hayashi-mdwashington-university-school-medicine-department-pediatrics-654873-03142023; see also Warning Letter to Mobeen Mazhar, U.S. Food & Drug Admin. (May 31, 2023), https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/mobeen-mazhar-md-660335-05312023.

[10] See, e.g., Annalee Armstrong, Pfizer, Valneva Push Back Lyme Disease Vaccine Filing to 2026 After Cutting Half of Participants, Fierce Biotech (May 4, 2023), https://www.fiercebiotech.com/biotech/pfizer-valneva-push-back-lyme-disease-vaccine-filing-2026-after-cutting-half-participants; Paul Schlosser, Clinical Trial Coordinators Sentenced to Prison After Data Falsification Scheme, Endpoint News (Oct. 19, 2022), https://endpts.com/clinical-trial-coordinators-sentenced-to-prison-after-data-falsification-scheme/.

[11] 21 C.F.R. § 56.109(a), (f).

[12] Id. § 56.111.

[13] Recruiting Study Subjects, Guidance for Institutional Review Boards and Clinical Investigators, U.S. Food & Drug Admin. (Jan. 1998), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recruiting-study-subjects.

[14] Id. See also U.S. Food & Drug Admin., E6(R3) Good Clinical Practice: Guidance for Industry 7 (June 2023), https://www.fda.gov/media/169090/download [hereinafter FDA, E6(R3) Good Clinical Practice].

[15] In 2000, the U.S. Department of Health and Human Services (HHS) issued a report which noted the practice that sponsors offer financial incentives to boost enrollment and recommended developing guidance to IRBs regarding the appropriateness of such practice. See U.S. Dep’t of Health & Hum. Servs., Off. of Inspector Gen., Recruiting Human Subjects, Pressures in Industry-Sponsored Clinical Research 2–5, 32–33 (June 2000), https://oig.hhs.gov/oei/reports/oei-01-97-00195.pdf.

[16] FDCA § 505(d); see also 21 C.F.R. § 314.126 (b)(3); U.S. Food & Drug Admin., Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices, and Trial Designs: Guidance for Industry 5 (Nov. 2020), https://www.fda.gov/media/127712/download [hereinafter FDA, Enhancing the Diversity of Clinical Trial Populations].

[17] See, e.g., FDA, Enhancing the Diversity of Clinical Trial Populations, supra note 16; U.S. Food & Drug Admin., Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials: Draft Guidance for Industry (April 2022), https://www.fda.gov/media/157635/download.

[18] U.S. Food & Drug Admin., Decentralized Clinical Trials for Drugs, Biological Products, and Devices: Draft Guidance for Industry 6 (May 2023), https://www.fda.gov/media/167696/download [hereinafter FDA, Decentralized Clinical Trials].

[19] Food and Drug Omnibus Reform Act of 2022, Pub. Law. No. 117-328, §§ 3601, 3602 (codified as amended in the FDCA § 505(z)).

[20] Id. § 3602.

[21] 42 U.S.C. § 1320a-7b(b)(2).

[22] 68 Fed. Reg. 23,731, 23,735–36 (May 5, 2003).

[23] 42 C.F.R. § 1001.952(d)(1).

[24] 42 U.S.C. § 1320a-7h(a), (c); 42 C.F.R. § 403.904.

[25] 42 U.S.C. § 1320a-7h(a)(1)(A)(vi); 42 C.F.R. § 403.904(d)(2).

[26] 42 C.F.R. § 403.902; see also 78 Fed. Reg. 9,458, 9,482 (Feb. 8, 2013).

[27] 78 Fed. Reg. 9,458, 9,482 (Feb. 8, 2013).

[28] 42 U.S.C. § 1320a-7h(e); 42 C.F.R. § 403.902.

[29] 21 C.F.R. § 54.4(a).

[30] Id. § 54.2(e).

[31] Id. § 54.4(a)(3), 54.2. U.S. Food & Drug Admin., Financial Disclosure by Clinical Investigators: Guidance for Clinical Investigators, Industry, and FDA Staff 4, 11–15 (Feb. 2013), https://www.fda.gov/media/85293/download.

[32] 21 C.F.R. § 54.4.

[33] Id. § 54.1(b).

[34] Id.

[35] FDA, Reply to GCP Inquiry re: Financial Disclosure–Recruitment Incentives & Other Payments (Dec. 19, 2016).

[36] Id.

[37] Id.

[38] U.S. Food & Drug Admin., Reply to GCP Inquiry re: Referral Fees and Finder’s Fees of Study Subjects (June 29, 2016).

[39] See, e.g., Univ. of Pa., Payments in Human Research Subjects: Guidance and Requirements (Feb. 2023), https://irb.upenn.edu/wp-content/uploads/2023/02/Payments-to-Human-Research-Subjects.pdf.

[40] See, e.g., Finder’s Fees and Recruitment Incentives, Univ. of Pittsburgh Hum. Rsch. Prot. Off. (Apr. 23, 2021), https://www.hrpo.pitt.edu/finders-fees-and-recruitment-incentives.

[41] Supra notes 40–41.

[42] 21 C.F.R. § 50.25(a)(3) (emphasis added).

[43] U.S. Food & Drug Admin., FDA Information Sheet, A Guide to Informed Consent: Guidance for Institutional Review Boards and Clinical Investigators (Jan. 1998).

[44] U.S. Food & Drug Admin., Informed Consent: Guidance for IRBs, Clinical Investigators, and Sponsors 37(Aug. 2023), https://www.fda.gov/media/88915/download.

[45] Id. at 31, 37.

[46] Id.

[47] ICH, E6(R3) Good Clinical Practice (GCP) (Draft Version) 52 (May 19, 2023), https://database.ich.org/sites/default/files/ICH_E6%28R3%29_DraftGuideline_2023_0519.pdf.

[48] FDA, E6(R3) Good Clinical Practice, supra note 14.

[49] U.S. Food & Drug Admin., Compliance Program 7348.811: Clinical Investigators and Sponsor-Investigators 20 (July 22, 2020).

[50] See, e.g., supra note 9.

[51] Ethical and Regulatory Aspects of Clinical Research 369–72, 377–78 (Ezekiel J. Emanuel et al. eds., 2003).

[52] Id. at 377.

[53] Conflicts of Interest in Research, Opinion 7.1.4, Am. Med. Ass’n, https://code-medical-ethics.ama-assn.org/ethics-opinions/conflicts-interest-research; Fee Splitting, Opinion 11.3.4,  Am. Med. Ass’n, https://code-medical-ethics.ama-assn.org/ethics-opinions/fee-splitting.

[54] Lois Snyder Sulmasy & Thomas Bledsoe, American College of Physicians Ethics Manual (7th Edition), Annals Internal Med. (Jan. 15, 2019) (¶ “Protection of Human Subjects”).

[55] WMA International Code of Medical Ethics, World Med. Ass’n (Apr. 14, 2023), https://www.wma.net/policies-post/wma-international-code-of-medical-ethics/.

[56] U.S. Food & Drug Admin., GCP Office, Reply to GCP Question RE: Fee for Referrals to a Clinical Trial (Oct. 14, 2014).

[57] Id.

[58] Id.

[59] Supra note 55.

[60] Conflicts of Interest in Research, Opinion 7.1.4, supra note 53.

[61] Supra notes 40–41.

[62] See, e.g., FDA, Decentralized Clinical Trials, supra note 18, at 6; see also Janet Woodcock, Richardae Araojo, Twyla Thompson & Gary A. Puckrein, Integrating Research into Community Practice—Toward Increased Diversity in Clinical Trials, 385 New Eng. J. Med. 1351 (Oct. 7, 2021).

[63] 21 C.F.R. § 312.7.