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...

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(1) What are the most important pros and cons of paying and charging clinical subjects (and why)?




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. SACHRPʼs 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. SACHRPʼs 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 subjectsʼ 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. Sponsorsʼ 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. Subjectsʼ 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
Answered Same DayFeb 01, 2022

Answer To: Attachment A - Charging Subjects for Clinical Trial Participation Background Most clinical trials...

Garima answered on Feb 02 2022
117 Votes
What are the most important pros and cons of paying and charging clinical subjects (and why)?
Clinical trials are conducted to find a new treatment for a disease or improvise on an existing treatment. In United States, clinical trials are either funded by a fed
eral agency like National Institute of Health (NIH) or by private drug and device companies. Benefits of clinical trials include building new treatments for incurable diseases, however, such trials also pose risks to the subjects who participate in such trials like side effects or irritations/ discomfort or the new treatment might not be better than standard care. To make sure that participants are protected and to make clinical trials safer, investigators/ researchers are required to follow certain rules which are enforced by the Federal Government (HHS policy 45CFR46, 2018). These rules include informed consent from the participants, reviewing of the clinical trial project proposal by Institutional Review Boards (IRBs) to make sure participants are exposed to minimal risk and periodically checking of results of clinical trials by Data and Safety Monitoring Committee. Generally, subjects are not charged for their participation in clinical trials, conversely, they may even get paid to encourage participation or to compensate for time and burden/ discomfort associated with the trials.
Charging clinical subjects:
But recently, a new research funding model is becoming more evident, where, clinical trial proposals ask participants to pay (pay-to-participate trials) especially for drugs, devices and biologics (nutritional supplements, surgery, stem cell transplantation etc) that are not regulated by Food and Drug Administration (FDA). IRBs face problems in reviewing such clinical trial proposals due to lack of clear ethical and regulatory guidelines. Since participants pay and bear the financial cost of research, they expect individual benefit and this brings conflict between research team and sponsors related to optimal study design. Prospective subjects who want to pay and participate lack proper guidance from the IRBs as to what criteria should be considered for participation and the risks involved.
The goal of SACHRP (Secretary's Advisory Committee on Human Research Protections) is to provide expert recommendations to the secretary of HHS (Department of Health and Human Services) for issues that come up regarding ethical and regulatory guidelines. And one such issue is pay-to-participate trials where SACHRP provides recommendations for case-by-case review, provides questions to prospective subjects that they must ask the...
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