When is it Ethical to Require Biospecimens
from the Participants in
Further below: Laboratory Correlates -
considerations for researchers:
Requiring that patients provide biospecimens (tumor tissue, blood,
urine, and so on) for entry into a clinical trial is a contentious area …
some stakeholders arguing that it can sometimes be a form of coercion
… as in: sorry, no tissue, no trial.
In a treatment study, the rationale for the need to acquire
additional tissue (such as by biopsy) should be
presented clearly, because it may not be a minor or risk-free
procedure. Further, the need for a biopsy should be stated up
front before the patient travels to the center and it should be
a core part of the research study if required.
Patients should look for eligibility criteria
in the study protocol such as:
"Measurable disease by CT scan, defined as at least 2
lesions that measure >1.5 cm in a single dimension (one of
which is superficial and easily accessible for biopsy)."
consent form should clearly indicate whether the new biopsy
is required to make the treatment decision in the trial
itself, or whether it is only done to provide information
leading to future decision making (benefiting the future,
but not the patient him/herself), a more altruistic decision
to make." (Hans, advisor to PAL)
behind the requirement drives the ethics of whether a biopsy
should be taken.
Does the biopsy help to safeguard the patient’s health?
It should be made clear to the
patient that NOT giving consent for additional uses of the
tissue -- beyond the trial -- will not exclude you from
may be necessary to examine it to confirm
the diagnosis or the grade of the disease – both of which may be
critical in accepting the patient for the
(Similarly a bone marrow biopsy is required to make sure
that you are eligible for radioimmunotherapy in regular
In a clinical trial,
researchers often need to know more than if you responded – the actual
mechanism by which the experimental treatment is working
[can be important to making additional progress against the
Considering the woefully small participation in clinical
trials overall, it is to researchers benefit to reduce the
number of barriers erected to potential participants, and to
collect only the tissue that is necessary to protect
the patient and to validate the study results."
There are many
dedicated people involved in the approval of trial protocols,
such as the Institution Review Board, the FDA and in many cases
a team of experts, which will often include patient advocates
involved in the vetting of the protocol.
So in most cases
when biospecimen is required it will be based on sound research
principles, needs, and also attention to patient safety.
For example, tissue might be required when there's a
need to make sure that you are eligible for the trial protocol,
or for studies of targeted drugs when it can be important to
make sure that the drug that you will receive is appropriate -- that
the target exists in the tumor, in order to avoid giving you a drug that is
unlikely to be effective but sure to have side effects.
NOTE: The existence of the target in the tumor cells improves
only the plausibility that the drug can have an effect on the
tumor, but it in no way assures that you will benefit - that you
will live longer or better because of it.
Can tissue from a prior biopsy be used instead?
It depends on what kind of information is needed from the tissue
and how that tissue was captured, fixed, and stored; and perhaps
how long ago it was acquired – because the lymphoma cells can
change over time. It may also depend on the willingness of the
center that stores the tissue to release it to another center.
We cannot make progress against lymphoma (the purpose of
research) without examination of the genetics and underlying
biology of the cells, which can be unique to each patient, which
needs to be correlated with clinical outcomes to help one day
personalize our care.
Most patients will appreciate the importance of this aspect of
clinical research when it is explained well. After all,
who better than patients understand how important it is to avoid
unproductive therapies that will only harm us?
Laboratory Correlates - considerations for researchers:
There are practical and ethical consideration in the design of a
study that include laboratory correlates. Here's our
Requiring biospecimen seems appropriate for these reasons:
eligibility in the trial
(such as the diagnosis, validated biomarkers for safety or
or if the target of the drug exists in the tumor).
the safety of a new drug
(such as to determine how long it stays in the blood and
where it accumulates).
To assess the
efficacy of a new drug
(such as to determine if the drug is active in the bone
prospectively validate biomarkers that appear to predict
harm or benefit from the study intervention,
when this is a primary or secondary objective of the study.
Questions that can
help researchers to decide if providing biospecimen should be
required or optional include:
What is the
risk of the procedure, and how does the risk compare to the
risks of competing protocols?
discomfort or fear (or perception of risk) is associated
with the procedure,
and how likely is this to work against enrollment in your
are the laboratory findings to helping to address an urgent
for the indication being studied?
How strong is
the biological rationale for the proposed correlative study?
How likely are
the laboratory findings in your study to influence clinical
or to make important new discoveries?
How large is
your study - is it sufficiently powered to do meaningful
For a small
study, can the laboratory correlates be pooled with the
findings from other trials?
Are you using
standardized assays and procedures that makes it feasible to
your findings with other studies?
Many thanks for
the informed comments of advisors on this topic, which we've
copied directly into the text.
~ Karl (advocate's