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:
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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 patient's 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 routine 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
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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