Personalized medicine in oncology

Emerging insights into the basic biology of cancer have led to the development of novel, tailored treatments for patients based on existing specific genetic profiles and other biomarkers. Several of these, such as trastuzumab and imatinib, have shown considerable commercial success. Recent scientific developments have introduced a ”second-generation” of personalized medicines, and several agents in late-stage clinical development are being studied in patient populations that are segmented by either existing or novel biomarkers. Key new drug launches targeting the EML4–ALK fusion protein (crizotinib) and the BRAF pathway (vemurafenib) are expected to deliver significant efficacy improvements for patients with these mutations. However, tying a new product to a new companion diagnostic test for an unprecedented target is a unique challenge that increases strategic complexity and risk for the drug developer, wrote analysts Alex Chiang and Ryan Million on 1 December in the Nature Reviews Drug Discovery.

Managing complexity and risk:  The development of targeted drugs requires a number of decisions, in particular for clinical trial design and biomarker selection. Choosing to develop an agent with an established versus novel biomarker can affect the trade-offs between clinical and commercial risks. For example, PARP inhibition is thought to be ideally suited for BRCA1 and BRCA2 mutated breast and ovarian cancers, because of a mechanistic link between these mutations and DNA damage repair via PARP1. However, the failure of iniparib highlights the clinical risk of such a strategy, and follow-up studies in patients with BRCA mutations may be appropriate.

The most straightforward route is the development of a novel biomarker, as pursued in the development of crizotinib and vemurafenib. However, launching a new drug with a novel biomarker and companion diagnostic results in significant commercial complexities and risk; specifically, marketing an agent that utilizes a novel pathway also requires marketing the pathway. Encouraging scientific awareness through guidelines, conferences and publications is crucial as physicians must update familiar treatment paradigms. The clinical merits of the agent as well as of the diagnostic to which they are attached need to be demonstrated. The new agent may be completely dependent on the test, so the test's performance (false positives and/or negatives) is associated with the agent as well.

To streamline adoption of the novel companion diagnostic, manufacturers need to have a full understanding of the physician ordering and usage experience for the new biomarker's test. This includes considerations before testing (for example, epidemiology), sample requirements, timing, as well as test sensitivity and specificity. Accurately communicating the strengths, weaknesses and logistics of the diagnostic is as important to the agent's success as the merits of the agent itself.

Perhaps the greatest commercial challenge for pharmaceutical firms, however, is accurately forecasting the sales potential of their newest products. Biomarker-driven agents necessarily lower the potential patient population. Although clinical trial experiences will give a leading indicator of biomarker prevalence and mutation frequencies, only commercialization in the entire patient population will yield actual results.

Pricing of personalized medicine:  Prices of novel agents in oncology have steadily risen in the past decades. Recently, the launch of ipilimumab has grabbed headlines with prices of around 100,000 USD per year per patient. The pricing of oral agents such as erlotinib, imatinib, capecitabine, sunetinib and sorafenib shows an average increase in price of over 76% since 2006. From the reimbursement point of view, the prior authorization requirement typically associated with the appropriate companion diagnostic is used as a stage–gate requirement for prescribing these novel therapies. In this way, payers are being assured that novel agents are only prescribed in populations in which a therapeutic benefit has been proven. Payment for the diagnostic tests is typically already viewed as cost effective as these tests are driving a clinical decision with an expensive, specific drug therapy. Finally, once patients test positive, these novel agents are likely to be by far the most appropriate clinical treatment option. These factors are thought to justify premium prices in open markets such as the United States as well as government-driven markets in Europe.

Novel companion diagnostics: next steps:  By lowering clinical risk with the chance of breakthrough efficacy results, increasing the speed to market and reducing overall development costs (via accelerated approval following a small phase I/II trial), companion-diagnostic based strategies can present a value-creating, science-driven approach to drug development. At a minimum, the inclusion of biomarker analysis is now standard in clinical trials to drive an understanding of which patients are responding to therapy.

For the future development of companion-based targeted agents, drug developers will need to proactively address the strategic and tactical issues confronting companion diagnostic-linked therapies. Solving these issues successfully prior to launch will help to minimize the commercial risk imposed by adding the extra diagnostic step needed in product adoption.