Attachment A - Charging Subjects for Clinical Trial Participation

Background

Most clinical trials conducted in the United States are funded either by the federal government, particularly the National Institutes of Health (NIH), or by private drug and device companies.  In these clinical trials, it is unusual for the sponsor, institution, or investigators to ask subjects to bear costs beyond those associated with usual care.  Rather, subjects generally participate without being charged for research interventions and associated care, and conversely, are often reimbursed for study-related expenses, offered compensation for time and burden, and/or paid incentives to encourage enrollment and retention.^[1]   Sometimes, however, potential subjects are asked to pay to participate in research.   For the purposes of this recommendation, SACHRP will use the terms “pay to participate” and “pay-to-participate trials” to describe this situation.

SACHRP’s Goals

Anecdotally, SACHRP is aware that IRBs are increasingly asked to review pay-to-participate trials, but lack clear guidance about their ethical and regulatory acceptability, as well as how best to systematically examine the ethical and regulatory issues. IRBs may face the greatest difficulty in review and oversight when pay-to-participate trials involve medical products that are not clearly regulated by FDA as drugs, biologics or devices – for example, nutritional supplements, surgical procedures, autologous stem cell transplants meeting minimal manipulation and homologous use criteria, and novel applications of standard treatments.  However, the relevant issues are not limited to those contexts. 

Investigators and sponsors conducting pay-to-participate trials may also face conflicts between optimal study design and conduct and the expectations of those subjects who, because they are bearing the financial costs of the research, consequently expect individual benefit.

Prospective subjects considering pay-to-participate trials are also in need of guidance. NIH has asked SACHRP to consider whether there are questions that prospective subjects should ask, or objective criteria that they should consider, that are unique to pay-to-participate trials and that would facilitate understanding of any implications of participating. 

SACHRP’s goal is to provide IRBs, sponsors, investigators, institutions, and prospective subjects with points to consider in the assessment of pay-to-participate research.  SACHRP acknowledges that there may be legitimate reasons to charge research subjects, and that prohibiting pay-to-participate trials could in some instances preclude valuable research.  Our intent is to identify considerations that can be used to balance the benefits and harms of this research funding model.  We begin from the position that whenever possible, it is best to avoid charging for research participation; use of traditional funding models increases access to clinical trials, helps ensure the generalizability of the knowledge generated from research, honors subjects’ contributions to the socially valuable endeavor of research, and accords with the ethical standards normally applied by the regulated research community.  We discuss issues applicable to pay-to-participate trials, make recommendations appropriate for case-by-case review, and provide questions for potential subjects to ask about pay-to-participate trials. 

Scope of this Recommendation

Broadly speaking, there are two variations of pay-to-participate trials.  Both of them diverge from the most common funding model in the United States, which involves a single sponsor, whether public or private, that provides all funding for a clinical trial.  We have adopted two terms to describe these variations, “full pay-to-participate trials” and “partial pay-to-participate trials.”  In full pay-to-participate trials, the subjects provide the funding for the entire trial, including the study article, associated study interventions and data collection, administrative costs, and payments to investigators and staff.  In partial pay-to-participate trials, the subjects are charged only for certain costs, such as the study article, a procedure, or a diagnostic test, or some combination.  The unifying factor in partial pay-to-participate trials is that the subjects are expected to pay for some percentage of the research costs, short of the entire budget.  Although there may be some differences between full and partial pay-to-participate trials, many of the considerations will be similar.

There are several additional issues that fall outside of the scope of this recommendation: 

• Routine billing for medical costs normally incurred in clinical care that are also billed to patients in clinical trials, such as the cost of anti-emetics in oncology care and oncology clinical trials;
• Circumstances in which study subjects may be expected to bear the costs of study-related injury, should it occur;
• Expanded Access or Right to Try; or
• Social and behavioral research because SACHRP is not aware of any pay-to-participate studies being proposed in that category.

Sponsors’ Motivation for Proposing Pay-To-Participate Trials 

The most compelling reason for proposing a pay-to-participate trial is difficulty in securing funds through traditional government and industry mechanisms. When research cannot secure funding through traditional mechanisms, investigators may ask research subjects to shoulder the burden, in whole or in part. The federal government funds research through a competitive process that aims to allocate public research dollars to projects designated as highest priority. Many proposed studies will not secure government funding, sometimes because they are low quality but often because there is simply not enough money to fund all worthwhile projects.  On the industry side, the development costs of an investigational drug or device may be prohibitive to the conduct of a clinical trial absent charging for an investigational product. A sponsor may not be willing to donate an investigational product to an investigator-initiated trial, leading to the need for the investigator to charge for participation. Lastly, some pay-to-participate trials may be initiated by patient advocacy groups and “citizen scientists” with reduced access to traditional funding sources or a desire to eschew them.

However, another possible motivation for asking subjects to pay the costs of a trial is profit-seeking. It appears that some pay-to-participate trials are not intended to generate important scientific knowledge, but rather are a pretext to circumvent regulatory prohibitions against marketing investigational products.   Because not all pay-to-participate studies are profit-seeking, it is important to distinguish the motive for charging subjects.  It is also important to recognize that the motives for proposing pay-to-participate research may be mixed.

Subjects’ Motivation for Joining Pay-to-Participate Trials

As in traditionally funded research, potential subjects might be interested in pay-to-participate trials because they anticipate (or hope) that participation could help them and/or because they have an interest in advancing science. In addition, as in traditionally funded research, subjects solely motivated by the possibility of direct medical benefit do not suffer from the therapeutic misconception so long as they understand that the benefit they seek is not certain, and do not misestimate the probability or magnitude of benefit and harm.  How the trial is explained to potential subjects is therefore key. This is true for all clinical research, but is even more critical when subjects are charged for their participation.

Regulatory and Ethical Issues

FDA permits one category of partial pay-to-participate trials; its regulations address the circumstances in which charging for investigational products is permissible in a clinical trial. FDA applies the relevant criteria directly as part of its review of the regulatory submission, rather than requiring other parties, such as investigators or IRBs, to do so. 

When a sponsor proposes to charge for investigational drugs and biologics under an IND, regulations at 21 CFR 312.8 require the sponsor to:

Demonstrate that the clinical trial could not be conducted without charging because the cost of the drug is extraordinary to the sponsor. The cost may be extraordinary due to manufacturing complexity, scarcity of a natural resource, the large quantity of drug needed (e.g., due to the size or duration of the trial), or some combination of these or other extraordinary circumstances (e.g., resources available to a sponsor).  21 CFR 312.8(b)(iii).

Charging for investigational devices is addressed at 21 CFR 812.7.  There is more latitude for device manufacturers to charge for investigational devices.  This regulation provides:

A sponsor, investigator, or any other person acting for or on behalf of a sponsor or investigator shall not:

(b) Commercialize an investigational device by charging the subjects or investigators for a device a price larger than that necessary to recover costs of manufacture, research, development, and handling.

The preamble to 21 CFR Part 312 and 316 “Charging for Investigational Drugs Under and Investigational New Drug Application; Expanded Access to Investigational Drugs for Treatment Use; Final Rules,” states the following:

General Requirements for Charging:

First, charging should be allowed only to facilitate development of a promising new drug or indication that might not otherwise be developed, or to obtain important safety information that might not otherwise be obtained. The preamble to the 1987 charging rule made clear that there should be compelling justification for taking the unusual step of allowing charging for unproven therapy during its development, stating that 'cost recovery is justified in clinical trials only when necessary to further the study and development of promising drugs that might otherwise be lost to the medical armamentarium'. ^[2]

These FDA regulations provide reasoning that could be adopted by IRBs to assist in the analysis of pay-to-participate research proposals. Most importantly, the FDA approach acknowledges that pay-to-participate trials should be unusual and require compelling justification.

No other U.S. regulations governing human subjects research directly address the issue of pay-to-participate trials.  However, some of the IRB criteria for approval at 45 CFR 46.111 and 21 CFR 56.111 are relevant, as are certain consent requirements.

SACHRP acknowledges that there will be proposed research that is unregulated because it is not federally funded and does not involve an FDA-regulated drug, device or biologic. The committee believes that, because of the particular issues raised by trials that require participants to pay, such trials should be voluntarily submitted to an IRB even when there is no regulatory requirement.

Beneficence

First, 45 CFR 46.111(a)(2) and 21 CFR 56.111(a)(2) directs IRBs to approve proposed research only when:

Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research).

The validity of the science supporting a research proposal is relevant to the “knowledge that may reasonably be expected to result,” which in turn influences whether it is appropriate to expose subjects to the burdens and risks of harm associated with the research. There are several reasons why a pay-to-participate trial may not have an acceptable level of scientific validity.  First, if a study has not been vetted through traditional funding and peer review mechanisms, such as prior review by a study section or industry sponsor, it may be lacking in scientific merit, and exposing subjects to risks and burdens in the context of bad science is ethically unacceptable. Scientific rigor may also be affected by the fact that pay-to-participate trials may entail an incentive to use less rigorous study design and avoid research methods such as randomization and blinding so that the paying subjects can be ensured access to the desired investigational product. Moreover, there may be a conflict in favor of including paying subjects who can help meet funding goals even though they should be excluded for reasons of scientific validity or safety.

Finally, some subjects who are so motivated to enroll that they are willing to pay may have reason to deceive the researcher about eligibility, study adverse events, and other such issues to avoid jeopardizing their enrollment and continued participation, especially when their motivation is the expectation of direct medical benefit. Failure to provide accurate information to researchers could create risks both to those subjects and to other participants.  Conversely, some subjects who are required to pay to participate might be more invested and engaged in the research and thus might comply more closely with the trial requirements. These empirical considerations should be evaluated with evidence.

Justice

Regulations at 45 CFR 46.111(a)(3) and 21 CFR 56.111(a)(3) address the principle of justice, directing IRBs to assess whether:

Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted.  The IRB should be particularly cognizant of the special problems of research that involves a category of subjects who are vulnerable to coercion or undue influence, such as children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons.

One purpose of this regulatory provision aims at avoiding the inclusion of subject populations solely on the basis of convenience and control, which could result in unfairly concentrating research risks and burdens in certain vulnerable populations. Rather than targeting individuals who are economically disadvantaged, however, which may be of concern in some research, pay-to-participate trials are likely to selectively include individuals who are economically able to pay or raise the required funds. These individuals may be vulnerable in other ways. For example, they may be desperate if they have exhausted all available treatments for a serious condition, and thus may be vulnerable to exploitation.

The regulatory provision’s reference to consideration of whether the selection of subjects is equitable means that not only should the risks and burdens of research be fairly distributed, but so should the potential benefits. To the limited extent that pay-to-participate research offers the prospect of direct benefit to participants, the possibility of benefit as a participant should not be concentrated only in certain advantaged groups. This concern about pay-to-participate trials is different from the concern about fair distribution of benefits after an experimental intervention has been shown to be a successful treatment, but it should still be considered, since those who cannot afford to pay will be excluded from potential benefits in both instances. The economically disadvantaged may also go to great lengths to gather the resources needed to participate, for example through crowdfunding and perhaps undertaking debt, if the potential for benefits appears sufficiently great.

Whether it is appropriate to concentrate the potential benefits of pay-to-participate trials only in the economically advantaged raises an additional concern relating to scientific validity: Are those who are economically advantaged enough to pay the costs of participation sufficiently representative and diverse so that study results will not be inappropriately biased by the exclusion of those unable to pay? That is, will the research data be broadly applicable to a diverse cohort of future recipients?  To address this concern, IRBs will need to consider the likely study population as part of its evaluation of the proposal’s scientific validity. If that is acceptable, then special consideration should be given to subject vulnerability and inclusion. Importantly, efforts to make recruitment fairer should also help promote generalizability and scientific validity.

Finally, pay-to-participate trials may also reduce trust in science by fostering the perception that research participation is a valuable commodity made unfairly available to those individuals with more resources.  Furthermore, these trials might divert resources (both financial and human capital) from better research proposals or better treatments for subjects. 

Autonomy and Informed Consent

Regulations at 45 CFR 46.116(a) and 21 CFR 50.20 require that investigators seek informed consent “under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence.”  In addition, 45 CFR 46.116(c)(3) and 21 CFR 50.25(b)(3) require that informed consent disclose “any additional costs to the subject that may result from participation in the research.”  This has clear applicability to pay-to-participate trials, as the costs must be disclosed to subjects.

Because the primary goal of research is to create generalizable knowledge that may benefit patients in the future, subjects in pay-to-participate trials are asked to contribute to societal benefit both by their data and by their financial payment. Subjects have many and often mixed reasons to enroll in research studies, including altruism and a desire for anticipated direct clinical benefit. The requirement to pay in order to participate in research will probably be a disincentive to many potential subjects, either because they are aware that research is usually cost-free to subjects and may even involve payment to them, or because they do not have sufficient funds. 

However, pay-to-participate trials pose a heightened risk of fostering the therapeutic misconception, either intentionally or not, as compared with traditionally funded studies.  When subjects are asked to pay to participate, they may view the amount charged as a signal that participation itself is valuable – and because price often connotes value, higher prices may signal higher value. Moreover, because asking subjects to pay to participate is unusual among clinical trials, subjects may be more likely to view participation as something desirable and payment as an exchange for some benefit.

In particular, pay-to-participate trials may exploit vulnerable patients, those for whom clinical care options may have been exhausted and who are understandably desperate to find something that works. Asking them to pay may not only confuse research with clinical care and encourage therapeutic misconception; it may also encourage financial risk-taking in hopes of a highly unlikely medical outcome. 

In pay-to-participate trials, as in all research, outcomes are uncertain and benefit is far from guaranteed. It is important for subjects to understand that they are not paying for access to a proven intervention, that they may experience no direct benefit, and that they may even be harmed by research participation. They must be given explicit information about scientific uncertainty, the nature, magnitude, and likelihood of direct benefit, the benefit-related implications of the particular study design (e.g., dose escalation, randomization, adaptive designs, post-trial access, etc.) and available alternatives.

Nonetheless, pay-to-participate trials may be the only way to conduct research on worthwhile projects that are not able to secure funding through traditional mechanisms. Subjects’ decisions to spend their money to participate is one way they can exercise their autonomy. Individuals have the right to spend their money on many activities and products that might not be regarded as benefitting them directly, such as charitable and political contributions or gifts to others.  Thus, subjects willing to pay to participate may decide to be altruistic; they may also choose to take a chance on an improbable outcome, as long as they are not misinformed and are given sufficient information in the consent form and process.

Recommendations

The ethical acceptability of pay-to-participate trials is highly fact-specific. Therefore, SACHRP does not recommend a default presumption against pay-to-participate trials, even though in general, research subjects should not be expected to pay to contribute to socially valuable research. Instead we recommend a careful review of each trial, based on consideration of the questions discussed below and satisfaction of all regulatory criteria for approval.  These recommendations are framed in terms of the IRB’s role, but investigators and sponsors have comparable duties in regard to charging subjects, based on their roles in helping to conduct sound science and to protect the rights, interests and welfare of research subjects. 

(1) Does the study meet relevant thresholds of scientific quality?

The question of a study’s scientific validity is integral to the IRB’s assessment of whether a study’s benefits justify its risks and burdens. Because pay-to-participate studies typically lack the well-established peer review processes that generally precede IRB review, the IRB’s responsibility to evaluate the evidence of scientific validity of such proposals is heightened.  The IRB should be prepared to confirm the scientific validity and value of the proposed study and its design, either directly when they have the expertise to do so, or through reliance on expert consultants or other institutional committees. An IRB that lacks access to sufficient expertise to conduct the necessary review of scientific quality may of course decline to review any study, including a pay-to-participate trial. 

(2) Is the risk-benefit balance justifiable?

Assuming the threshold of scientific quality has been confirmed, the IRB must continue to evaluate the study’s risks in relation to its benefits to subjects and society. Just as payment to subjects is not to be considered as a benefit that could balance research risks, payment to participate should not be considered as a harm in the risk-benefit assessment. Instead, the IRB should evaluate a study’s risks and benefits first without considering payment. If the balance is unacceptable on that account, the study should not be approved. If, however, the balance appears to be acceptable independent of any payment to participate, the IRB should next consider whether payment raises other concerns that need to be addressed to satisfy ethical and regulatory criteria for approval.  

(3) Why are traditional research funding sources not being used? Could the study potentially be funded by means other than charging subjects?

The IRB should require investigators to specifically explain and justify the rationale for charging subjects, including whether traditional funding was sought and why other funding sources are not available or appropriate. Although it should not be necessary for investigators to demonstrate that all other funding options have been exhausted, they should demonstrate an adequate and reasonable justification for charging subjects. In particular, IRBs should examine each trial’s potential to exploit subjects for profit-seeking motives.

Investigators should be expected to provide a detailed breakdown of the amount charged and a description of what exactly subjects will pay for.  They should also explain whether the payment is expected as a lump sum or in installments, as well as the conditions under which a subject would receive a partial or complete refund, if any (e.g., what will happen if a subject withdraws part way through the research or the investigator removes a subject from the study for medical or noncompliance reasons).  This information should be included in the consent form.

The IRB should review sufficient information to promote confidence that the payment required is minimized and reflects the actual costs of making possible the development of a potentially valuable intervention or the gathering of important information.  The FDA regulations detailed above may provide IRBs with useful guidance in this regard.  If the justification for charging subjects is not compelling, then IRBs should not approve the trial.

(4) Will requiring payment for participation influence equitable subject selection?

Where the justification for charging is deemed acceptable, the IRB should then consider whether and how study results may be affected by an expectation of payment by subjects. Investigators should be expected to make efforts to mitigate concerns regarding generalizability and inequitable subject selection, potentially considering efforts to include some subjects who are unable to pay their own way (e.g., a sliding payment scale or an approach where economically disadvantaged subjects are subsidized by those who are able to pay).

(5) Is requiring payment from subjects likely to exacerbate the possibility of therapeutic misconception? If so, how can that concern be mitigated?

If a pay-to-participate study has appropriate scientific validity, an acceptable harm-benefit ratio, a strong rationale for charging subjects, and a plan for equitable subject selection, the next question is how to minimize the potential for a payment requirement to interfere with subjects’ informed decision-making process. When subjects are charged for participation, they may be more likely to expect direct benefit, or to regard trial participation as a means of gaining early access to a promising new treatment. This raises concerns about their adequate consideration of and reflection about important study features, such as risks, burdens, discomforts, and uncertainty.

IRBs (and investigators and sponsors) should therefore pay special attention to whether the informed consent process will provide clear and complete information about the study and support adequate consideration and comprehension of that information.  Similar consideration should be given to any recruitment materials.  Although individuals are free to make decisions outside the research setting that reflect misunderstanding or insufficient consideration of key information (for example, when accepting a job offer or making a purchase), IRBs and investigators fail to fulfill their responsibilities for subject protection if they do not strive to assist potential subjects in reasoned decision-making. IRBs need not monitor the enrollment process of each individual subject, but rather should encourage investigators to adopt approaches that will support high-quality decision-making. These may include:

• Setting aside sufficient time for knowledgeable study staff to review the entire consent form with potential subjects and answer any questions, rather than permitting a passive consent process in which potential subjects are expected to review materials on their own.
• Including tests of comprehension or “teach-back” methods that will provide an indication that potential subjects are aware of and understand key information about the study, such as the difference between research and clinical care, the uncertainty of benefit, and the amount they will be required to pay.
• Incorporating a waiting period for potential subjects to reflect on their desire to participate and potentially discuss the study with trusted others.
• Facilitating prospective subjects’ explicit consideration of their interests (for example, asking for reflection about the possibility that the intervention may have no beneficial effects or may be harmful or that available alternative treatments may be preferable).
• Providing further support for any individual who expresses that he or she “has no choice” but to enroll, because of his or her medical circumstances.

SACHRP notes that the “key information” requirement in the revised Common Rule may also promote these goals.

Questions Potential Subjects Should Consider Asking about Pay-to-Participate Trials

The informed consent form and process offer an important source of information for prospective research subjects. Potential subjects may also find it helpful to seek information about particular studies, perhaps especially when they are considering enrollment in a pay-to-participate trial. OHRP provides excellent educational resources about research in general for potential subjects, including questions to ask [https://www.hhs.gov/ohrp/education-and-outreach/about-research-participation/index.html]. So does NIH [https://clinicaltrials.gov/ct2/about-studies/learn#Considerations].

However, individuals considering enrollment in pay-to-participate trials may also seek more specific information. The following questions are intended to help potential subjects in pay-to-participate trials ask questions focusing on key attributes of such trials. Many of the questions apply to all research, but should be addressed so that questions specific to payment-to-participate can be understood in the context of the whole trial. This list is not exhaustive and is offered only as a starting point for IRBs, investigators, and sponsors to develop best practices for communicating effectively with potential subjects in the consent form and process for pay-to-participate trials.

• Who has reviewed this research and said it is OK to do?  Has there been ethical and scientific review of the research?
• Why do the researchers think that what is being tested might help people like me? What do they think it might do, if it works?
•  Has it been tested before? If so, how many people has it been tested on?
• Why am I being asked to pay to join this research?
• How much will the researchers charge me to be in this research?
• What exactly will I be paying for (e.g., diagnostic tests, the study intervention)?
• What are some reasons I might be willing to pay to join this research? What are some reasons I might not be willing to pay to join this research?
• Besides the people like me who join this research, are any other people or groups also paying for this research? If so, what exactly are they paying for?
• If I am injured, who will pay for the treatment of that injury?
• When will I be expected to pay?  If paid in installments, what happens if a payment it missed?
• If I quit the research, will I get any of my money back?
• If the researchers make me leave the research, will I get any of my money back?
• What other costs might I have to pay if I join this research?
• Will being in this research affect my health insurance coverage? Will my health insurance cover any part of what I am being charged for this research?