Biotechnology Healthcare - June 2008 - (Page 34) Payers should understand cancer trial endpoints and their clinical relevance, while allowing for individual variations that may affect patient care. likely to inhibit tumor growth than cause tumor regression, it does appear to convey some clinical benefit in this difficult-to-treat population. It would be hard for payers to make coverage decisions based solely on the response data. Time to progression of symptoms. Time to progression (TTP) is the time from randomization until objective tumor progression. TTP of symptoms is a direct measure of clinical benefit rather than of subjective factors. It is difficult to differentiate symptoms resulting from tumor progression from those resulting from drug toxicity. If the measures used to compare efficacy among drugs are not carefully evaluated, a drug that is less toxic may appear to be more efficacious (FDA 2007). TTP can be a useful measurement in cancers that have low partial or CR rates. Taxanes have recently reemerged as chemotherapy agents with significant treatment potential for patients with metastatic breast cancer. Nabholtz (2003) studied the efficacy of docetaxel (Taxotere), a taxane, and doxorubicin (Adriamycin) compared with doxorubicin and cyclophosphamide (Cytoxan) as firstline chemotherapy for metastatic breast cancer patients. The primary endpoint was TTP of symptoms, and a secondary endpoint was timeto-treatment failure. Although both TTP of symptoms and time-totreatment failure were shown to be significantly longer with docetaxel and doxorubicin, overall survival was comparable in both arms (Nabholtz 2003). Simply evaluating TTP of symptoms and time-to-treatment failure may lead to the presumption that one treatment is superior to another, but further data would be needed to come to this conclusion. OS rates may indicate that the docetaxel and doxorubicin regimen had a lower rate of toxic effects than the doxorubicin and cyclophosphamide arm that led to superior TTP of symptoms and time-to-treatment failure rates. To reach a conclusion about the efficacy of these therapeutic regimens, payers need a detailed analysis of adverse events in both clinical arms, as well as an evaluation of information from other trials of these agents. Progression-free survival. PFS differs from TTP in that PFS represents the time from randomization until objective tumor progression or until death occurs. This method is typically preferred over TTP of symptoms as a regulatory endpoint because in a TTP analysis, the deaths are censored (FDA 2007). In rare cases, such as metastatic breast cancer, PFS may be preferable to OS. Patients with metastatic breast cancer frequently rotate through many different chemotherapy regimens; as such, the value of OS may be limited because it is difficult to tell which regimen contributed to OS and which did not. Although PFS can demonstrate direct patient benefit, the trial should have a control arm and be blinded to minimize bias (FDA 2007). PFS may have more value in phase 2 trials, where the purpose is to determine effective agents that are worthy of more indepth study (Michaelis 2006). Payers should be extremely cautious when making coverage decisions in which PFS data are the only data available. The use of PFS is appropriate in select situations, however. For example, PFS is often used as an endpoint in diseases with very low survival rates, such as advanced metastatic colorectal cancer (FDA 2007) In these cases, PFS may be helpful in comparing treatment regimens. Venook (2005) recently assessed several different agents used to treat metastatic colorectal cancer. Although multiple endpoints were used in the clinical trials that were compared, PFS provided a useful comparator across different trial designs and study populations (Figure 3). In the absence of other data, payers can use PFS to find the context within which other treatments can be used for the same cancer. SUGGESTIONS FOR PAYERS The careful evaluation of clinical studies, based on an understanding of cancer trial endpoints, is crucial to the effective management of oncology agents in the managed care context. Payers must not only understand the many oncology clinical trial endpoints and their clinical relevance, they also must allow for individual variations that may be necessary in the care of the patient with cancer. Expert reviews of the available data, therefore, would be useful in placing into perspective the value of the various cancer therapies available. Oncology remains a specialty in which treatment regimens are carefully tailored to individual patients. Therefore, conversations with experts knowledgeable about trial end- 34 BIOTECHNOLOGY HEALTHCARE ยท MAY/JUNE 2008
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