Companies acting as sponsors of clinical trials often face challenges in recruiting enough eligible patients to participate in their trials, including for interventions related to rare diseases where, by definition, the patient population is small. In addition, due to the increasing development of newer types of therapies, such as cell and gene therapies, or with studies where the treatment process and follow-up can be complex, patients (and their caregivers) can be reluctant to participate due to the time and commitment required.
In the U.S., the FDA, which is responsible for the drug approval process, has recognized that some demographic and non-demographic characteristics of populations are underrepresented in clinical trials and has advocated for the broadening of clinical trial eligibility criteria and making participation "less burdensome" for participants.1 To that end, and to support new requirements in the Federal Food, Drug, and Cosmetic Act that require sponsors to submit a Diversity Action Plan to the FDA for certain clinical studies, the FDA has made various recommendations, including suggesting that participants be made aware of available reimbursement for expenses, such as travel and lodging expenses and to consider the use of social media recruitment strategies to assist with identification of potential subjects.2
These challenges necessitate that sponsors identify new and creative ways to enhance their recruitment potential. This article will address practical compliance considerations related to (1) how clinical trial sponsors might compensate healthcare professionals (HCPs), including clinical trial sites, investigators or staff, and patients, and (2) communications about their studies.
Payments To HCPs
While payments to clinical trial sites, investigators, or staff for their services are standard practice, clinical trial recruitment incentives like bonuses or finder's fees are generally not acceptable. Institutional review boards (IRBs) typically do not permit such payments, and many institutional policies prohibit such recruitment incentives. Although there are no laws or regulations that specifically prohibit these incentives, they are generally considered not to be appropriate since they raise potential ethical and conflict of interest issues, could create bias or compromise the integrity of the study, or otherwise put the study at risk from a regulatory perspective.
Institutions usually maintain policies addressing conflicts of interest, and some specifically include restrictions on incentive payments for clinical trial recruitment, in particular, payment structures intended to create an incentive to recruit research subjects more quickly or to drive completed enrollments. These policies often prohibit a per-subject payment schedule that increases after the enrollment of a specified number of subjects unless such increase is based on a legitimate increase in costs, payments contingent on the recruitment of a certain number of subjects, or other legitimate basis. The concern is that incentive payments could influence, or reasonably be viewed as influencing, how subjects may be recruited.
As a general matter, any payments made to clinical trial sites and investigators in connection with a clinical trial must be reasonable and tied to actual services provided by the investigator and the site staff. In certain cases, it may be reasonable to pay for specific recruitment services that are based on an identified, legitimate (and documented) need and that require additional time and effort of an investigator/site personnel. Any such services should be related to the recruitment process, screening, and other recruitment-related services that are not already covered as part of the payments outlined in the clinical trial agreement(s).
Concerning any payment for recruitment services, such payments should be fair market value for the services being provided and not based on whether a patient is ultimately enrolled, completes the study, or is otherwise tied to the outcome of the study.
Due to potential concerns raised by recruitment-related payments, it is prudent to communicate with the IRB and consider potential disclosure to research subjects in the informed consent form (ICF) for the study. Concerning disclosures in the ICF, the FDA's Informed Consent Guidance for IRBs, Clinical Investigators, and Sponsors (which refers to HHS guidance on financial relationships)3 recommends considering disclosure of financial interests, stating in part that "HHS recommends that IRBs consider whether subjects should be informed of any financial relationships or interests that are associated with the clinical investigation, such as payments for services, equity interests or intellectual property rights [footnote omitted]."4
Payments To Study Subjects
The FDA has acknowledged that payments to patients as recruitment incentives in exchange for their participation in a study are common and generally acceptable so long as they are not described as benefits for participating in the study. The FDA also has stated that such payments may raise difficult questions that an IRB should evaluate to make sure such payments are "just and fair" and do not coerce or influence the subject to participate in a study. 5
Information about any payments should be outlined in the ICF (including any applicable disclosures that payments may be considered income), and considerations to evaluate will depend on factors such as the amount, purpose, or timing of the disbursement and, as discussed in more detail below, how payments are described in recruitment materials. What is considered reasonable compensation is often fact-specific and is dependent on answers to questions such as the following: How many study visits are required? How long will each visit be? How many tests will the subject need to undergo? Will there be an inpatient hospital stay? Will the patient need to keep a diary as part of the study?
The FDA has stated that reimbursements related to reasonable travel expenses (e.g., airfare and gas) and associated costs (e.g., parking and lodging) are differentiated from payments for a subject's participation in a clinical study and do not raise coercion or undue influence issues. However, the agency has indicated that reimbursement for additional types of other costs should be considered on a case-by-case basis to assess the possibility of undue influence.6 Examples of such costs could range from lost wages to caregiver and childcare expenses to cost-sharing obligations.
While the FDA has supported certain recruitment incentives and expenses for patients, there is no safe harbor. In fact, in response to a proposal for safe harbors to the Federal Anti-Kickback Statute regarding the waivers or subsidies related to cost-sharing obligations and other incentives provided to Federal healthcare program beneficiaries, the U.S. Department of Health and Human Services, Office of Inspector General (HHS-OIG) noted that they have "long-standing concerns" regarding such remuneration.7 Advocates for these safe harbors claimed that they would not only protect the sponsor's subsidization of certain costs but also could contribute to increased diversity in clinical trials.
Given the open questions to the proposed safe harbor raised in HHS-OIG's response, to the extent clinical trial sponsors are offering any remuneration to subjects or their caregivers, in addition to considering the FDA's guidance, clinical trial sponsors should always evaluate the scope and purpose of such payments, confirm that there is documented fact-specific support and justification for any payments, and monitor ongoing developments in this area.
Clinical Trial Recruitment Communications
We have addressed the who and what you can pay for clinical trial recruitment activities, but what can you say in recruitment communications to potential research subjects? Again, although it is difficult to point to a specific law or regulation that sets forth the specific requirements and restrictions for recruitment communications, several regulatory and compliance considerations apply to these communications. Clinical trial sponsors, investigators, and clinical trial sites must be cognizant of the various issues when developing recruitment advertising and related materials.
The FDA considers clinical trial recruitment advertising to be part of the informed consent process and, consistent with the IRB's mandate to address safeguards to protect research subjects and review research-related documents and activities, FDA dictates that such materials must be reviewed by the IRB because they are seen as the start of the informed consent process.8 Concerning these materials, the IRB, consistent with their mandate, will review the content of the materials and the methods of communication to confirm that the materials are not unduly coercive or promise or imply a favorable outcome or benefits beyond what is addressed in the protocol and informed consent.
Consistent with FDA guidelines (and as a general rule), clinical trial recruitment communications should provide truthful and non-misleading information to provide potential subjects with the details of the study so that they can consider their potential interest and eligibility. It is well understood that FDA regulations prohibit the promotion of investigational drugs9, and this rule applies to clinical trial recruitment advertising/communications. This means that clinical trial recruitment communications to potential subjects should not make claims about the investigational therapy or state or imply that the investigational therapy is safe or effective or that the treatment is equivalent to or better than other treatments. Likewise, pictures, graphics, or other material used in clinical trial recruitment communications must not suggest or imply that the treatment being studied is safe or effective.
In addition, such materials should not promise or imply free medical treatment. While it is acceptable (and recommended) to include mention of compensation and/or reimbursement that may be available to research participants in connection with their participation in the study, it is not appropriate to emphasize payment as a reason to participate in the study.
In all recruitment communications, it is good practice to include a link to the study on ClinicalTrials.gov and to direct patients (and caregivers) to speak to their healthcare provider about participation in a clinical trial.
Clinical trial information related to available clinical trials may be provided to potential research subjects in several ways, such as on websites, through social media, and/or using other means. Additional considerations may need to be evaluated before pursuing these methods of communication. For example, Google, Meta (including Facebook and Instagram), and other platforms may impose certain requirements and/or restrictions related to advertising and the use of targeting techniques or character limitations that could impact the approach for recruiting on such platforms. These points should be considered before submission to the IRB.
For clinical trial recruitment activities, who and what you pay and what you say is important to the success of a clinical program and matters from a compliance perspective. For industry sponsors, a comprehensive internal evaluation of planned recruitment initiatives, including a review of recruitment communications and recruitment-related payments, is critical even before going to the IRB. Industry sponsors remain responsible for their activities and communications and cannot rely on the IRB to confirm that they are meeting all legal and regulatory requirements. Additional issues can be wide-ranging, from establishing and documenting fair market value to evaluating privacy considerations related to ICFs and online/social media activities and addressing any Physician Payments Sunshine Act or other disclosure obligations that may flow from payments made to HCPs.
Footnotes
1. See e.g., FDA Guidance, Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry (November 2020), available at https://www.fda.gov/media/127712/download; see also, FDA Draft Guidance, Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies (June 2024), available at, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-action-plans-improve-enrollment-participants-underrepresented-populations-clinical-studies.
2. Id.
3. FDA Guidance, Informed Consent Guidance for IRBs, Clinical Investigators, and Sponsors (August 2023), available at https://www.fda.gov/media/88915/download; see also Financial Conflict of Interest: HHS Guidance (2004), available at: https://www.hhs.gov/ohrp/regulations-and-policy/guidance/financial-conflict-of-interest/index.html.
4. FDA Guidance, Informed Consent Guidance for IRBs, Clinical Investigators, and Sponsors (August 2023), available at https://www.fda.gov/media/88915/download.
5. FDA Information Sheet, Guidance for Institutional Review Boards and Clinical Investigators, Payment and Reimbursement to Research Subjects (January 2018), available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/payment-and-reimbursement-research-subjects; see also FDA Guidance, Informed Consent Guidance for IRBs, Clinical Investigators, and Sponsors (August 2023), available at https://www.fda.gov/media/88915/download.
6. Id.
7. HHS-OIG Semiannual Report to Congress (Fall 2023), available at: https://oig.hhs.gov/documents/sar/1275/OIG-SAR-FALL-2023-Complete%20Report.pdf (at pages 106-107).
8. FDA Information Sheet, Recruiting Study Subjects: Guidance for Institutional Review Boards and Clinical Investigators (January 1998), available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recruiting-study-subjects (stating that it is expected that an IRB review direct advertising for prospective study subjects and that not all recruitment materials must be submitted to the IRB, including information provided on ClinicalTrials.gov and other clinical trial listings, communications directed for use only with healthcare professionals, and other materials not intended for a patient audience; see also FDA Guidance, Informed Consent Guidance for IRBs, Clinical Investigators, and Sponsors (August 2023), available at https://www.fda.gov/media/88915/download (referring to the FDA Information Sheet, Recruiting Study Subjects: Guidance for Institutional Review Boards and Clinical Investigators).
9. 21 C.F.R. §312.7(a).
Originally published by Clinical Leader.
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