Should
we increase access to emerging treatment outside of clinical trials?
Many informed patient advocates agree
that clinical trials are preferable to single-patient INDs (Investigational
New Drug application), both for the
individual and for the patient community as this way is more apt to
increase our understanding of how the new therapy works. We also agree that our primary
focus should be on providing guidance on how to conduct useful and ethical
clinical trials, and encouraging patients to participate. However, as we
know, patients are often ineligible for clinical trials because they have
or have not received previous treatment, or because they do not meet other
standards. Also, suitable trials might not be open or accessible when the
pt needs treatment.
I believe
that the perspective that some pts will not participate in trials if
single patient INDs are made available is invalid for phase II trials,
because patients will take the easier path (choose the trial) if it were
open.
The
perspective that patients will not participate in randomized studies
requires additional thought. If the randomized trial is seen as a risk to
the patient, then the trial design must be addressed and changed. Randomized studies should only compare agents with equivalent
potentials and risks, in which there is genuine uncertainty about
which treatment is superior. If
the trial meets this criterion, pts will not seek treatment INDs as an
alternative.
Importantly,
when standard treatments don’t cure or improve survival, it’s not
always in the patient’s best interest to use them when less toxic
investigational agents are available—especially for agents that have
demonstrated clinical benefit in well-designed phase II trials.
It is important to distinguish between media hype and results of
well-conducted studies. While
it may be true that phase II results can sometimes be misleading, the
following profound disadvantages of standard treatments (chemotherapies)
for some cancers should also be considered:
 | Special considerations must be made for
patients with cancers for which Standard treatments merely regress
tumors without providing meaningful clinical benefit (improving
survival).
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| Standard treatments are more likely to
harm the pts chances of benefiting from subsequent treatments,
including investigational targeted treatments, than the other way
around (see abstract below). Perhaps
we may need to encourage pts to avoid standard treatments in some
settings, and to first participate in clinical trials.
For example: Pts who try a vaccine as front line therapy, can still
often benefit optimally from chemo, but the reverse is probably not
true, unless the chemo is followed immediately by the vaccine--which
is still an option for the pt who tries the vaccine first.
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| Standard treatments are more likely to
be toxic than targeted and biological treatments. If the choice is
between a standard treatment, like CVP, and a low toxic combination of
investigational antibodies, the latter might be more suitable. It
would be unethical to deny pts to try options like this in a
circumstance where a trial is not open to them.
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| Toxicity for emerging treatments is not
very difficult to determine in phase I & phase II studies. In
general, we can expect targeted agents to be less toxic. The
toxicity of standard cytotoxic treatments is well known and more
likely to cause cross-resistance than the majority of therapies that
target malignant cells. The
mechanism of action can be telling.
If the new agent binds to an antigen on cancer cells, for
example, we can expect that if it does not cause the malignant cells
to die, it is not likely to make them more resistant as an alkylating agent is likely to do.
Example1: Only Rituxan, a targeted treatment, has resulted in longer
durations of response when given a second time to responding pts.
Example 2: Pts who do not respond to Rituxan, often do respond to
subsequent chemotherapy, and radiotherapy. There are some indications that non-responders still
benefit from Rituxan if followed closely by chemotherapy. |
In
conclusion, "patients have one life to experiment with."
Therefore, we must look very
closely at the casual use of standard treatments that do not provide
meaningful benefit. We must not say to patients that they must first try a
toxic standard treatment (that does not improve survival) before trying
less toxic therapies. This is
especially relevant when the investigational agent is less likely to
preclude them from benefiting from subsequent treatments.
We also need to provide objective guidance about treatment options,
and make new agents available to pts when they and their doctors can
provide rational reasons for their use over approved therapies. We should
ask the scientific community to design clinical trials that test low
toxicity agents for pts in a variety of treatment settings, to remove the
demand for treatment INDs so that we can practice good medicine and
conduct good studies simultaneously.
We must carefully design randomized clinical trials, and seek
alternatives to them in cases where ethical designs are not possible to
create.
Sincerely,
Karl
Schwartz
Patient Consultant, FDA ODAC
See ASCO
abstract about standard treatments for indolent NHL below.
ASCO 1165
Each Subsequent Therapy Results in Diminishing Response Rate and
Duration of Response in Low Grade or Transformed Low Grade Non-Hodgkin's
Lymphoma.
Richard Wahl, Mark Kaminski, Andrew
Zelenetz, Julie Vose, Oliver Press, Stanley Goldsmith, Louis Fehrenbacher,
Kathleen J. Clapp, Richard Fisher, Johns Hopkins Medical Inst., Baltimore,
MD; Univ. of Michigan, Ann Arbor, MI; Memorial Sloan-Kettering, New York,
NY; Univ. of Nebraska Medical Center, Omaha, NE; Univ. of Washington
Medical Center, Seattle, WA; Cornell Medical Center, New York, NY; Kasier
Permanente, Vallejo, CA; Coulter Pharmaceutical, So. San Francisco, CA;
Loyola Univ. Medical Center, Maywod, IL.
Chemotherapeutic regimens used in the
treatment of Low Grade Non-Hodgkin's Lymphoma (LGNHL) result in an initial
response in the majority of patients. However, relapse ultimately occurs.
Attempts at retreatment with the same or different drug combinations can
lead to responses, but as drug resistance develops response rate and
duration of response declines with each subsequent therapy.
These findings were previously reported
by Gallagher, et al, in a predominantly chlorambucil treated patient
population Sixty patients were treated in a Phase III multicenter trial
evaluating the safety and efficacy of the radioimmunotherapy Bexxar™ (tositumomab,
iodine I-131 tositumomab) in the treatment of LGNHL and transformed LGNHL.
The majority of the patients received a cyclophosphamide-containing
regimen (35%). Other regimens included Fludarabine (25%), combinations
such as DHAP, ESHAP, DICE, MINE, EPOCH and ICE (23%), other combinations
(13%) and single agent cyclohosphamide (3%). All patients received a
median of 4 (range 2-13) prior treatment regimens. Evaluation of response
and duration of response in these sixty patients to all prior
chemotherapies re-confirmed the previously published experience showing
diminished response and duration of response with each subsequent
chemotherapy. In this same patient population the duration of response to
the most recent chemotherapy was 4 months. However, upon relapse,
subsequent treatment with Bexxar provided a 10 month duration of response
(p=<0.001 ). An independent radiology and oncology review panel
confirmed these findings.
The high incidence of multiple relapses
and the enduring decrease in both response and duration of response to
subsequent therapy further reinforces the need for novel therapies for the
treatment of LG or Transformed LG NHL. New treatment options are necessary
to provide greater clinical benefit evidenced by both response and
duration of response.
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