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...

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 bea
costs beyond those associated with usual care. Rather,
subjects generally participate without being charged fo
esearch 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 clea
guidance about their ethical and regulatory acceptability, as
well as how best to systematically examine the ethical and
egulatory issues. IRBs may face the greatest difficulty in
eview 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,
ecause 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 conside
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 conside
in the assessment of pay-to-participate research. SACHRP
acknowledges that there may be legitimate reasons to charge
esearch subjects, and that prohibiting pay-to-participate
trials could in some instances preclude valuable research. Ou
intent is to identify considerations that can be used to balance
the benefits and harms of this research funding model. We
egin 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
esearch, 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 fo
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 incu
ed 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; o
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
esearch 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
e 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 fo
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
equire 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 othe
extraordinary circumstances (e.g., resources available to a
sponsor). 21 CFR 312.8(b)(iii).
Charging for investigational devices is addressed at 21 CFR
XXXXXXXXXXThere 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
ehalf 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 fo
Investigational Drugs Under and Investigational New Drug
Application; Expanded Access to Investigational Drugs fo
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
esearch 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 XXXXXXXXXXare relevant, as are certain consent
equirements.
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
aised 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 XXXXXXXXXXa)(2) and 21 CFR XXXXXXXXXXa)(2) directs
IRBs to approve proposed research only when:
Risks to subjects are reasonable in relation to anticipated
enefits, 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
elevant 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 prio
eview by a study section or industry sponsor, it may be
lacking in scientific merit, and exposing subjects to risks and
urdens in the context of bad science is ethically
unacceptable. Scientific rigor may also be affected by the fact
that pay-to-participate trials may