purpose of clinical trials from the scientist's perspective is
to test new therapies in a way that reliably guides the care of
future patients or advances clinical science. Patients
considering participation, however, have a different purpose:
the hope to address our unmet clinical needs.
Here is an overview of the phases of clinical studies and how we
patients might think about them, with a focus on when phase I
study participation might be considered a reasonable clinical
decision -- guided by our treating physicians.
The phases of studies focus on different questions.
Phase I – what is the highest dose of the study drug that’s safe?
"The dose is usually increased a little at a time in
order to find the highest
dose that does not cause harmful side effects"
Phase II – does the study drug have clinical activity at that dose?
Phase III – does it provide meaningful clinical benefit?
Testing if the activity
against the disease exceed the
side effects … compared to?
There are overlapping purposes for each phase:
A phase I study will also
look for signals of clinical activity
A phase II study will
continue to look for and record rates of side effects.
A phase III study
assesses both good and bad effects and also
asks if the net effect provides meaningful clinical
compared to the regular approach.
Comparative studies are needed to advance and inform best
practice – and to test the study approach against the current standard of care.
The words “activity” and “benefit”
have special meanings in clinical research.
Clinical activity (in this discussion) refers to a response of the tumors – such
as if the tumor shrinks in size, or remains stable when it was
previously increasing, or if it goes away (a complete response).
It's important to emphasize that clinical activity does not mean benefit.
A tumor might shrink for a short while and then grow faster. The bad
effects of the study drug might be more significant overall than the
good effects. The study drug showing "activity" in preclinical
studies might not be safe to give to people at an active dose.
Benefit is when the activity of the drug against the tumors
offsets the risks and toxicities. Here the study drug demonstrated by
well designed studies a positive risk/benefit effect. Meaningful
clinical benefit also requires that the good effects are lasting.
To demonstrate that a study drug provides benefit is very challenging
and takes time. It generally requires a large comparative study -- where
the assignment to the study and control arms is randomized to ensure
that risks factors of the participants are balanced (by age, stage,
* Exceptions can be made for “breakthrough drugs”,
where the activity in phase II studies is compelling relative to the
* TERMINOLOGY DISCUSSION:
I’ve defined the word activity as a response by the tumor.
This could be a nonstandard use of the word; efficacy is also used for
this purpose. I’ve stayed clear of the word efficacy
intentionally, because it suggests benefit more than the word activity.
The FDA defines clinical benefit as the result of an intervention that
improves survival or quality of life. Tumor shrinkage (a response) is
sometimes used as a surrogate endpoint that might reasonably predict
benefit in some cases, depending on the duration of the response and the
side effects of the treatment. See
When might we patients reasonably consider taking part in a phase I
That we are eligible for a phase I study does not mean it's a good fit
for us -- as each patient will have unique clinical circumstances and
preferences. The potential benefits and risks of each study
can also be unique.
Phase I studies may be considered:
standard therapies are not considered appropriate due to
resistance or toxicities.
When the study drug has a
mechanism of action and standard approaches
are not working for
(if we have treatment refractory lymphoma).
When the study drug is given with a
standard drug AND the standard drug is appropriate for us,
and, perhaps, when the
science suggests that the study drug might enhance the standard
type (class) of study drug seems promising and unlikely to have serious toxicities -
(participation is unlikely to burn treatment bridges).
Some phase I studies test different doses of the
study drug in the same patient (intra-patient dose escalations). This design
improves the odds of getting a clinically active dose of the study drug, but
this design also increases the risk of toxicity.
Increasingly, phase I studies will select patients based on biomarkers that may predict response to the study drug, increasing the odds that the study drug
will be active.
(Your tumor has this genetic change. This drug was designed to target that.
However, it should be emphasized that mechanism of action is not evidence of
benefit ... or even that the active dose of the study drug can be given safely
-- which is the question the phase I study is asking.)
Some phase I studies will test new compounds that *appear* to have a unique
potential to inhibit key drivers of the disease involved in resistance to
standard therapies. The preliminary science might suggests that this could help
overcome treatment-resistant disease and this is your situation.
Historically, phase I studies uncommonly helped the patient directly. The
purpose was to
help advance clinical science. But as drug design is based increasingly on
insights into the biology of tumors, the odds of benefiting in phase I studies is increasing. Some patients,
for example, in the earliest phases of CART 19 studies apparently benefited
from taking part.
Overall, the chance of benefiting
in phase I studies is low 2, even if improving. However, it should be noted that lymphoma and CLL (blood
cell cancers) appear to have a greater intrinsic potential to be treated
effectively with single agents -- even when at an advanced stage - compared to many other types of
cancer. Arguably, this improves the odds
that lymphoma patients can benefit from
a novel study approaches in safety studies.
... It's also important to note that every approved therapy was first studied
for safety, and that additional progress against lymphoma depends on
participation in early-phase studies.
Finally the risks and potential benefits from participation in a phase I study
must be weighed against comfort care (palliative care) - which is given not to
treat the lymphoma but to improve how we feel and our quality of life. Our
performance, age, and general health also enters into the decision about study
How to decide?
It's very important to seek independent expert guidance on trial
participation. That we are eligible for a study is not in itself a reason
to take part. When you consult a specialist, he or she will have first-hand
information about your clinical circumstances, your treatment goals, your
preferences, and also knowledge of available standard and investigational
For this reason, we provide the Trial Talk list below.
Trial Talk - experts to
consult for second opinions and to inquire about clinical trials