The new drugs advent: clinical or economic outcomes?

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in both men and women. Despite the introduction of newer cytotoxic agents during the last decade the survival rates still remain low. New strategies are clearly needed to improve treatment outcomes. Chemotherapy is under investigation as neoadjuvant and adjuvant strategy in early stage, and same progress has been achieved in the treatment of locally advanced and metastatic disease; however treatment outcomes for NSCLC are yet to be considered disappointing. New hope comes from improved knowledge of tumour biology and mechanisms of oncogenesis, with identification of several new potential targets. Randomized studies conducted over the past decade have shown that cisplatin-based chemotherapy provides a survival advantage over supportive care alone, that two drug chemotherapy regimens are superior to single agent regimens, and that two drug combinations should contain at least one new agent (gemcitabine, paclitaxel, vinorelbine, docetaxel). Advances in our understanding of cancer biology have led to the discovery of several potential molecular targets and to the development of novel agents that, unlike conventional cytotoxic agents, specifically target tumour cells. Three such agents are the small molecules, inhibitors of the intracellular tyrosine kinase, gefitinib (G) and erlotinib (E), and the monoclonal antibody anti-EGFR cetuximab, that are being extensively evaluated in NSCLC. EGFR-inhibitors demonstrate significant clinical activity in approximately 10–20% of pretreated NSCLC patients [1, 2]. However, four large phase III randomised, placebo-controlled trials of G and E in combination with standard platinum-based first-line chemotherapy failed to show any survival benefit in patients receiving the experimental drugs [3–6]. Possible reasons include patient selection, drug dose or scheduling, trial design or other factors. Active research is ongoing to improve the efficacy of EGFR inhibitors as monotherapy or in combination with other treatment modalities. A major concern with the clinical employment of new drugs is the economic burden for the society due to the increased costs of the therapy. Cancer is among the most significant contributors of health care spending in the United States. The National Institute of Health estimated its cost in 2002 at $171.6 billion, $60.9 billion of which was attributed to direct medical costs, $15 billion of which to indirect morbidity costs and $95 billion to indirect mortality costs [7]. Lung cancer in particular is estimated as the second highest cost pathology among seven other analyzed cancers in a retrospective matched-cohort analysis [7]. The mean monthly costs for antineoplastic drug therapy-related office-visits being US$553 and the incremental monthly direct costs US$6181. It is important to note that none of the new biological agents recently developed for lung cancer were included in this analysis. Clearly, the cost of new drugs raises crucial moral and policy questions [8]. Indeed, much attention is being paid to economic analyses as an instrument for establishing a formal link between costs of therapy and outcomes, to create a rationale basis for approval and commercial distribution of new drugs. Furthermore, clinical trials have been designed to evaluate both clinical and economic outcomes for new drug [9–11] and many countries, like Canada and Australia, require evidence of safety, efficacy and cost-effectiveness (CE) before they approve a new drugs for routine clinical use [12, 13]. However, pharmacoeconomics analyses are a complex, and their practical use is not easy. Hill et al. [14], infact, describe problems with the evaluation and the interpretation of 326 submissions to the Department of Health and Aged Care (DHAC) for funding made under the Australian Pharmaceutical Benefits Scheme. Out of 326 submissions, 218 (67%) were considered to present ‘serious problems of interpretation’. Sometimes no randomized controlled trial (RCT) was available or the RCTs were of poor quality or low power. Other problems were found in the analysis of the interpretation of the trial results, uncertainty about choice of comparator or inappropriate comparator. Similar methodological pitfalls with pharmacoeconomic analyses were also found in Italy [15] with the experience of the Comitato Interministeriale Programmazione Economica (CIPE) of the Italian Ministry of Health (the structure responsible for national drug reimbursement negotiations). Other limitations and source of bias of the pharmacoeconomic analyses are worthy of interest. Friedberg et al. [16] investigated the financial conflict of interest of economic analyses of oncologic drugs and showed that pharmaceutical company sponsorship of economic analyses is associated with reduced likelihood of reporting of unfavourable results over noprofit-sponsored studies (5% versus 38%, respectively, P = 0.04). Therefore, it is normal to look with suspicion at such analysis and even if the publication of guidelines [17] has provided an important contribution to standardizing CE research, some methodological points still remain unclear. s y m p o s iu m