Econogenomics 2007: When Does the Inclusion of Biomarkers in Oncology Drug Development Make Economic Sense?
Authors: Thomas Roberts
Journal: Clinical Cancer Research (2007)

ED03-04   Over the past 5-10 years, cancer drug development has entered an especially dynamic time. By 2006, there were at least 600 cancer drugs being studied in more than 6,000 clinical trials. Cancer drugs in development now outnumber (by a wide margin) those in any other therapeutic class of medicine. Once the sole dominion of the U.S. government and one or two drug companies, every large pharmaceutical company now has a major cancer drug discovery effort, not to mention a countless number of smaller biotechnology companies focusing in cancer drug development. Pfizer, the world’s largest pharmaceutical company, now spends 20% of its research budget each year on cancer projects. The effort has paid off: we are now averaging 3-4 new cancer drug approvals per year compared to just 1-2 new drugs per year just 15 years ago. Most recent cancer drug approvals are part of the newer class of molecularly targeted agents which allow for the prospect of selecting subsets of patients most likely to receive a clinical benefit. The hope of developing the next imatinib, bevacizumab, or lenalidomide has in turn fueled ample capital investment in cancer drug development by venture capitalists, hedge funds, and the broader investment community. [ ]  Despite notable successes, serious challenges remain. Fewer than 10% of cancer drugs entering phase I clinical trials ultimately make it to FDA approval. The majority of phase III cancer trials fail to show a benefit of the experimental arm over the reference regimen. Even the successful trials often demonstrate improved survival times (or other surrogates of clinical benefit) by relatively modest amounts, sparking debate in the popular press and in some European countries about the benefit to cost ratios. For their part, biopharmaceutical companies point to the rising cost of cancer drug development, driven in large part by late-phase failures and by the need for large-scale clinical trials powered to demonstrate modest improvements in clinical benefit. The investment community has also begun to grow skeptical as a series of high-profile molecularly-targeted agents have failed to demonstrate benefit in late-stage testing. Finally, achieving accelerated approvals in cancer, which are available only for areas of unmet medical need, are likely to become more difficult to achieve as more indications fill up with approved agents. [ ]  Two fundamental problems appear to dominate modern cancer drug development. First, far too many cancer drugs fail at late stages of clinical testing. For example, canfosfamide (Telcyta), an investigational cancer cell-activated chemotherapeutic agent, recently failed to demonstrate a clinical benefit in ovarian and lung cancer in three phase III registration trials after completing more than ten “positive” earlier-phase trials. Hundreds of millions of dollars of investment capital was employed in this effort, which to date has not yielded any substantial evidence of success. Several matrix metalloproteinase inhibitors met a similar fate in phase III trials. The list of late-stage failures in cancer is long and distinguished: only drugs targeting the central nervous system have lower success rates in late-stage testing. [ ]  The second problem is that even the successes have demonstrated a relatively modest benefit on the outcomes of many of the common epithelial cancers. Drugs such as trastuzumab, bevacizumab, cetuximab, sunitinib, and erlotinib have proven to increase survival from 2 months to a year in clinical trials, but in no instance has an epithelial cancer yielded to a cure from the new agents outside of the adjuvant setting. The approval of many other targeted agents has been supported by improvements in response rate or progression free survival without definite evidence of clinical benefit. The failure of the new agents to change the natural history of most cancers outside of a few notable examples (e.g., CML, GIST, EGFR mutant-positive NSCLC) and the many failure have led to a re-examination of clinical development process in cancer. One of the innovations that has gained the most interest over the past few years is the integration of biomarkers into the clinical trials process. [ ]  Biomarkers are clinical tests that offer the prospect of stratifying patients within histopathologic diagnoses into subsets most likely to receive a clinical benefit from a particular targeted therapy. A stratified approach to cancer drug development can have both positive and negative elements from an economic perspective. On the negative side, biomarkers may add to the cost of earlier-stage testing. Adding a functional imaging scan or an advanced pathology test requiring a tissue biopsy to a phase I trial may increase the cost per patient by 10-50%. The results of a biomarker test may also mislead clinical scientists if the agent happens to work through a mechanism not captured by the biomarker. Biomarkers may also reduce a sponsor’s ultimate on-label market size if the approach is successful in stratifying patients into those most likely to receive a clinical benefit, and if the molecular basis of the stratification does not generalize to other cancer types. [ ]  Several positive elements of a stratified approach to cancer drug development may offset these limitations. First, biomarkers may help drug developers improve the therapeutic ratio for certain patient subsets. Such a boost to the benefit to risk ratio can improve the ultimate success rate for drugs under development and may change powering assumptions, thus allowing for smaller and potentially faster registrational trials. Second, sponsors that develop agents under a stratified approach may be more likely to receive orphan drug status, which can lead to longer periods of marketing exclusivity and a reduction in regulatory fees. Third, cancer drugs with highly effective profiles, which would be expected under a stratified approach, can demand premium pricing. Recent targeted agents approved under a stratified approach can cost $5,000-$10,000 per month. Finally, a stratified approach may allow certain agents to gain approval which would have otherwise been rejected by the FDA due to insufficient clinical activity in an unselected population. [ ]  Surprisingly little academic work has focused on pharmacoeconomic aspects of biomarkers, despite their promise of effecting the most radical change in the approach to cancer drug development in more than a generation. The author’s talk will focus on presenting an economic framework for measuring the impact of biomarkers on the net present value of cancer drugs in development. A variety of sensitivity analyses will be presented to highlight under what scenarios a stratified approach to cancer drug development is likely to provide an economic benefit.