Considerations when Mandating biopsies
as a condition for taking part in a clinical trial
An overview of what we ask of patients who take part in clinical research
owe a great debt to the patients who take part in
clinical research. Developing safer and more effective
therapies for future patients could not be done without these
heroic 'test pilots'.
Let's fully appreciate that the participants receive into their blood
a study drug about which there can be (depending on the phase
of the study) substantial uncertainty about safety
... Commonly these men, women, and
children are required to have extra tests and procedures in order
to protect their safety but also to answer study-related
questions, such as how long the drug remains in the blood, or if
a feature of the tumor sample they also provided predicts response
to the study drug.
Extra scans may be needed to see if the tumor has
responded to the study drug, and to determine how long a response has lasted.
Increasingly, tests of the tumor sample are needed to determine if
the patient is
eligible for a study -- such as to determine if the molecule
the study drug targets exists on the tumor. This test is
typically justified because it limits the risks of taking part
in the study ... to the patients who are most likely to
potentially benefit from the study drug.
... Ideally, eligibility for such studies can be determined
based on the archival tumor sample taken when the patient was
diagnosed. However, a biopsy can be needed when archival tissue
is not available or when it was stored in a way that makes the
The risk and burden of a surgical
biopsy can vary depending on location of the tumor. The
burden is also dependent on the patient's perception of the risk
and the discomfort they anticipate; and on the number of
procedures, such as when serial biopsies are
required before, during, and after treatment with the study
... The burden can increases when additional travel to
the center is required, or when the costs are not fully reimbursed by
The ethics of requiring a biopsy as a condition for taking part
in a study depends on many factors. It can be ethical,
controversial, or clearly inappropriate as briefly outlined
-- Ethical when the sample is
essential if the purpose of study, such as to determine
eligibility as described above, also improves the
prospect for the participants to benefit.
-- Strong, controversial, or inappropriate
-- when there is no prospect for direct benefit and the scientific
rationale for acquiring the samples is questionable.
The rationale is stronger when the purpose is integrative,
such as when needed to validate a promising biomarker that has a good
potential to help future patients. The rationale is weaker
if the tests are exploratory or the study size is too small to
provide meaningful information.
The IRB reviewing the study will consider if the extra procedure
involve more than minimal risk with or without
prospect for direct benefit by the participants. The review board will
also consider the burden of the tests, the purposes, and the
When might requiring a surgical procedure as a condition
for taking part in a study
be considered coercion?
threat of further harm may lead to the cooperation or obedience
of the person being coerced.” This can occur
when the required biopsy procedures provide no
prospect for direct benefit to the participant and the tests done on the
samples have a weak scientific rationale (e.g. is EXPLORATORY).
... While participation in a study is
voluntary (is not forced), a very promising study protocol could be
perceived as the patient's only chance to survive when there are
not effective standard options for their life-threatening
disease. This can lead to a perception that harm
will result if 'I am not accepted in the study.'
From the Belmont report - this section on the principle of beneficence
A difficult ethical problem remains, for example, about
research that presents more than minimal risk without
immediate prospect of direct benefit to the children involved.
Some have argued that such research is inadmissible, while
others have pointed out that this limit would rule out much
research promising great benefit to children in the future. Here
again, as with all hard cases, the different claims covered by
the principle of beneficence may come into conflict and force
Questions reviewers might ask the study team regarding
mandatory biopsies for clinical research:
tissue be used to make the assessments on the tumor?
Is the tumor
assessment integral to the study --
(the primary study
question could not be answered without it)?
Is the tumor
assessment integrative to the study?
(needed to validate a promising biomarker - based on
good preliminary evidence)
What is the prospect that
the findings will contribute to knowledge
that is meaningful
and significant to patients -- has the potential to benefit
How reliable are the
assays? Are they CLIA approved? Are the tests proven to achieve reproducible results?
Is the study size large enough (sufficiently powered) to provide
What would be a meaningful finding? What is the
next step if a meaningful finding is identified?
Will the findings be pooled with data from other
studies? If yes, please outline the plan.
What is the
burden of the extra procedure -- including the frequency of
relative to what is required for usual care?
What are the actual or perceived risks of the procedure?
Can the number of research tests be reduced in order to decrease
the burden on the patients?
Will it be feasible for all, or most, patients with this
disease to safely provide tumor samples?
What will be the impact of
the required test on accrual - the feasibility of completing the study?
Do other studies with similar promise ask less of the
Other ... (a
work in progress)
Proposal to mitigate the burden of
extra tests in close calls
When the research is deemed to be important (integrative) but
the tumor sample is not required to answer the primary endpoint,
look for other ways that the participants may benefit from
having the extra procedures – such as to test for eligibility
for the MATCH study.
This added analysis on the same tissue sample might be judged by
some parties as undue influence (a kind of payment to induce
participation) but since the patients can have this procedure
done (without cost) by entering the NCI MATCH trial it
does not seem to be undue influence to this advocate.
Karl Schwartz, research advocate, PAL
* FDA.gov: Informed Consent
Information Sheet Guidance for IRBs,
Note that coercion and undue influence may be situational.
For example, in a clinical investigation involving the surgical
insertion of an investigational device, waiting to obtain
informed consent until the potential subject is in the
preoperative area may fail to minimize the possibility of undue
In addition, statements that claim investigational test articles
are safe or effective for the purposes for which they are being
investigated are prohibited. (21 CFR 312.7(a) and 21 CFR
812.7(d).) Likewise, statements that inappropriately overstate
the possibility of benefit should be avoided because they may
unduly influence potential subjects. Careful wording is needed
in order to avoid overstating potential benefits that may
contribute to a subject’s therapeutic misconception.8
Furthermore, statements such as "FDA has given permission for
the clinical investigation to proceed" or "FDA has approved the
clinical investigation” should be avoided, because such
statements may contribute to the misimpression that the
investigation has FDA’s endorsement.
Issues Surrounding Biospecimen Collection and Use in
Allison R. Baer, RN, BSN, Mary Lou Smith, JD, MBA, Deborah
Collyar, BS, and Jeffrey Peppercorn, MD, MPH
||An advocate's presentation -
Ethics of Requiring a
Biopsy as a Condition of Trial Participation