Should We Pay Patients In Clinical Trials For Their Time?
By Kamila Novak, KAN Consulting
For years, I have been bothered by the practice of payment, or, more accurately, the absence of payment in Greece and other European countries, to patients for participating in clinical studies, meaning a reimbursement for their time and inconvenience. Should we pay them or should we not? Is it ethical or is it not?
Consider patients’ burdens while participating in a study. They travel to study sites, sometimes significant distances, and suffer inconveniences from examinations. Have you ever done a bone marrow biopsy? It is not an experience you would like to repeat every few weeks. They may take a leave from work and pay babysitters or caregivers for elderly parents; sometimes they need somebody to accompany them, and this companion then carries some of the same burdens. Every study visit consumes at least half a day, possibly the whole day. Such visits are still numerous. While decentralized clinical trials (DCTs) may eliminate a significant part of the burden, we cannot see DCTs as the solution. Not all studies are, will be, or can be decentralized. Last year, I audited a study in Greece in which each patient visit lasted 13 hours, and the protocol required four such visits within two months. The patients got nothing, not even a meal or a meal voucher or a comfortable place to stay between the examinations; they just had to hang around. Would you volunteer for such study? I doubt I would.
Patients are participants, not subjects. They participate in research just like other players, give their time, efforts, body fluids, and tissues, and they undertake risks, especially in early phase studies, when we know little about the risks and benefits of a potential new therapy. In every informed consent, we tell them they may not benefit from their participation, and we cannot promise them they will get better. Reimbursement for their time, inconvenience, and lost income feels fair.
By the way, healthy volunteers participating in bioequivalence (BE) and Phase 1 studies are always paid. Everywhere. Hardly anybody would question payments to volunteers in Phase 1 studies with novel products. These people take risks; they are the first ones to test a product we know little about, apart from the preclinical data. However, in BE studies, the volunteers receive two doses of a generic product – a copycat of the brand drug with a well-established safety profile. These studies are routinely conducted during weekends, so there are no lost wages, and the payments may significantly exceed the minimum monthly wages (I’ve seen the numbers during BE study audits), so no wonder some volunteers have it as a nice side job. This is outside of the main scope of this article; I am using it to illustrate a double standard.
However, we should not be guided by feelings of “fairness” independent of what the regulators say. I searched different regulations and, for the past 12 months, asked investigators and clinical research professionals in different countries about their practices.
Surprisingly, despite all harmonization efforts, regulators approach this matter differently.
Regulatory Authority Perspectives
In January 2018, the FDA issued the final guidance Payment and Reimbursement to Research Subjects.1 It says:
Paying research subjects in exchange for their participation is a common and, in general, acceptable practice. Payment to research subjects for participation in studies is not considered a benefit that would be part of the weighing of benefits or risks; it is a recruitment incentive. FDA recognizes that payment for participation may raise difficult questions that should be addressed by the IRB. For example, how much money should research subjects receive, and for what should subjects receive payment, such as their time, inconvenience, discomfort, or some other consideration. In contrast to payment for participation, FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence. Other than reimbursement for reasonable travel and lodging expenses, IRBs should be sensitive to whether other aspects of proposed payment for participation could present an undue influence, thus interfering with the potential subjects’ ability to give voluntary informed consent. Payment for participation in research should be just and fair. The amount and schedule of all payments should be presented to the IRB at the time of initial review. The IRB should review both the amount of payment and the proposed method and timing of disbursement to assure that neither are coercive or present undue influence.
So, the FDA clearly allows payment for participation that is proportionate, non-coercive, pro-rated (i.e., not paid entirely at the study end), and approved by the Institutional Review Boards (IRBs).
The European Medicines Agency (EMA) says very little about the matter; there are no Reflection Papers or Questions & Answers documents. The European Clinical Trial Regulation 536/2014 mentions compensation for lost earnings for pregnant and breast-feeding women, incapacitated subjects, and minors and their legal representatives.2 While I wholeheartedly agree special attention should be paid to protecting these participants, I do not understand the logic behind why these participants are allowed to be compensated for lost earnings and others, potentially participating in the same studies, are excluded. Not to mention that minors in the European Union (EU) do not lose earnings since they cannot have a regular full-time job (some exceptions exist once the minor is at least 15 years of age).
Other regulatory authorities, e.g., in Greece, prohibit such payments entirely as unethical and coercive (I wonder what the reason behind that is and whether there was any misuse historically), allowing only reimbursement of direct travel costs. Even these reimbursements are usually not provided since the payment system through the Hellenic Investment Organizations (ELKE/ELKEA) and Regional Departments of Health (YPE) does not have mechanisms to do so. A possible workaround, such as contracting a travel agency or a taxi company by a contract research organization (CRO) that then processes these third-party vendors’ invoices as pass-through costs, depends on the goodwill of the CRO to undertake extra work and get sponsors’ agreements.
Years ago, when I was clinical project manager of large global projects, I witnessed another strange situation. Patients in Hungary were prohibited to get money as their travel cost reimbursement, so they received some meal vouchers. Regrettably, there were only a few places they could use them. Frankly, they received worthless papers they could use as wallpaper or a decoration in their houses to remind them of their study participation.
How about other regions? The approach of regulators in the Middle East countries mostly resembles the EMA’s approach. They say little about payments for participation. However, since many of them quote Good Clinical Practice (GCP)3 and sometimes reference it verbatim in their regulations, and since GCP talks about these payments positively, as we will see a bit later, there is perhaps a window of opportunity, at least to try to include the payments in the study submission dossier.
Regulators in all sub-Saharan countries I have visited recently allow payments for participation, and participants are commonly paid. Some research centers have dedicated staff and offices to pay their participants. When I asked investigators in these centers my usual question: “Do you pay your participants for their time?” The typical answer was: “Yes, of course. They would be normally working and earning money for their family.” I could see the unspoken in their eyes: “How come you ask such a question?”
In contrast, a few months ago, when I asked a CRO in one of the Baltic countries the same question, the answer was: “It is allowed, but we do not do that. Nobody does.” Interesting.
At the same time, the regulators ask the industry to ensure patient diversity in clinical studies, i.e., a good representation of different ethnic, racial, and social groups. Not all participants should be middle class white men about 35-45 years old, the statistical “average patient.”
Do We Slide Into Complacency Or Can We Find A Common Ground?
Now, imagine a clinical study conducted worldwide. Apart from their disease, patients carry all the burdens mentioned earlier. A U.S. patient is paid, a Greek patient is not. The logic is lame, and common sense cries in the corner. Do we wonder why patients, except for those with life-threatening diseases, often refuse to participate?
In Europe, it has been like this for decades, and everybody has settled with it. When I started as a clinical research associate (CRA) in the ’90s, we were told during our training that payments to study participants are prohibited since they are coercive and generally wrong, since the study drugs are provided free of charge. It is less work without dealing with payments, after all. But is it ethical? Is it fair? Does it represent the best interest of potential study participants? Does it promote diversity of the study population or makes it worse? Are payments for study participation essentially non-ethical? If so, how come the FDA would miss that? Or is perhaps the lack of uniform and transparent compensation to study participants across studies around the globe the problem we should be calling out?
I dare to say we see a kind of complacency with an unfair situation. Some regulators labeled payments generally unethical, while some sponsors and CROs got comfortable with refusing payments. The longer the situation lasts, the more normal it is perceived. In some places, the “evil of payments” became dogma and an unquestioned truth. In addition, sponsors and CROs alike aim to shrink the study start-up timelines to the necessary minimum, and any additional negotiation or submission means more time, hence, a cost increase. Last but not least, the traditional conservative approach of the industry is driven by concerns of regulatory inspection findings, often resulting in over-interpreting regulations and guidance documents or the sit-and-wait strategy – let someone else try it first and we will see what happens.
Somewhere lost and forgotten is the patient.
Do we need another regulation on payments? No, we should go back to the GCP we all accept as the basis of clinical research in humans. It says: “The IRB should ensure that information regarding payment to participants, including the methods, amounts, and schedule of payment is set forth in the written informed consent form and any other written information to be provided to participants. The way payment will be prorated should be specified.”3 The “research ground rule” foresees payments for participation and mandates their IRB approval. Of course, a non-coercive payment will be different in Burkina Faso, Greece, and the United States.
What can we do? And do we want to do something? Are we ready to allow the inequality in approaching payments for participation to bother us? To bother us to the extent that we take actions?
I hope so. Let me dream.
4 Steps To Create Change
We have organizations such as the Drug Information Association (DIA) providing an impartial forum for discussions, raising awareness, and educating stakeholders. We have bioethics groups and academic initiatives. So far, there has been little collaboration among the lonely “voices in the desert.” How can we change it?
Step 1: Raising Awareness
We need to clearly say there is a problem, bring it into the light, and shake up the status quo. Admitting the problem brings us halfway to a solution. Part of it is explaining that the current non-payment situation is unethical and unfair and that safeguards exist against using payments for coercion, as well as sharing best practices from geographies with long experience with making the payments.
Step 2: Building Coalitions
Once the issue starts to be discussed, interested parties will learn about one another and can build coalitions, e.g., patients’ organizations and advocacy groups, bioethicists from academia, the DIA Bioethics Community, etc. They can meet and get to know and understand one another.
Step 3: Design Strategy
With the goal in mind of changing the approach to payments for participation in restrictive geographies, representatives of interested coalitions can organize educational webinars and mini conferences, publish white papers, engage more stakeholders, especially representatives of pharma and biotech companies, CROs, etc., and initiate a dialogue with regulators.
Step 4: Engage Regulators
The dialogue will likely clarify their concerns and once articulated, they can be addressed. Every problem wants to be solved.
I hope to witness a new regulatory framework providing a transparent and universal approach to study participants’ payments (much as it exists regarding investigator payments), which will convince the laggards to accept and allow the practice. This will benefit all stakeholders and open doors to better and more inclusive study participation, improving patients’ access to clinical studies.
- Payment and Reimbursement to Research Subjects, FDA, Jan 2018
- Regulation (EU) No 536/2014 of the European Parliament and of the Council, EMA, effective since January 31, 2022 (Articles 31, 32, 33)
- ICH E6 – GCP (R2) (article 3.1.9)
About The Author:
Kamila Novak, MSc, got her degree in molecular genetics. Since 1995, she has been involved in clinical research in various positions in pharma and CROs. Since 2010, she has been working as an independent consultant focusing on QA and QC, as a certified auditor for several ISO standards, risk management, medical writing, and training. She is a member of the Society of Quality Assurance (SQA), the World Medical Device Organisation (WMDO), the European Medical Writers’ Association (EMWA), the Drug Information Association (DIA), the Continuing Professional Development (CPD) UK, and other professional societies.