The Oncologist, Vol. 8, No. 6, 500–500,
December 2003
© 2003 AlphaMed Press
The Dilemma of Drug Development and Approval
Bruce A. Chabner, M.D., Editor-in-Chief
The Oncologist
In an accompanying editorial, Schein, Scheffler, and Carter provide an insightful and comprehensive assessment of the current status of cancer drug development in the U.S. They point out that, despite the great progress that has been made in understanding cancer biology and in the identification of new "targets" for drug discovery, the rate of cancer drug approvals remains distressingly low. Not counting monoclonal antibodies, only two new "targeted" small molecules have won approval in the past decade: imatinib mesylate and gefitinib, and the latter after a difficult and controversial debate. They point out that the accelerated approval mechanism of the U.S. Food and Drug Administration (FDA) has hastened the marketing of few new chemical entities in its 13-year history. In the past several months, a minor flurry of new agents (imatinib mesylate for gastrointestinal stromal tumors, bortezomib for myeloma, gefitinib for non-small cell lung cancer [NSCLC], and tositumomab & iodine I 131 tositumomab for lymphoma) have been granted accelerated approval, but with postmarketing requirements for additional trials. Only two (bortezomib and gefitinib) represent new chemical entities, and neither are a true "breakthrough" agent at this point.
As Schein and colleagues point out, there clearly is a need for more creative and encouraging responses from the FDA. It is not sufficient to declare a new drug with modest activity too early for marketing. We have known for many years that most cancer drugs work for only a subset of patients. Under the existing criteria for full approval, drugs with modest levels of phase II activity may languish in phase III trials for years (as did oxaliplatin), or the sponsors may just admit defeat. The problem is particularly critical for biotechnology companies, the future of which may depend on a single product. And it is critical for patients with incurable diseases who want and deserve access to new agents.
However, the problem is not primarily a regulatory issue. Even if the FDA moves to a greater emphasis on early response rates, the bar may be too high for most innovative new agents. The field of cancer drug discovery clearly needs to turn greater attention to the problem of identifying responsive subsets of patients early in the development process and needs to utilize the tools of genomics as a standard part of drug development. It would greatly simplify the problem of early drug approval to know which 10% of the patients with NSCLC would respond to gefitinib or similar new agents. Why not require the sponsor to conduct such studies as part of the quid pro quo for early drug approval?
To be honest, there are major scientific hurdles to rational drug discovery and development. We depend on imperfect systems for validating targets, for using animals to predict activity in humans, and for selecting appropriate patients for treatment with "targeted" drugs. The idea of molecular targets is no doubt valid, but may be ahead of its time, given the gaps in implementation. Little did we imagine that the target might be clear, and the design of an inhibitor straightforward, but finding the right patient to treat might defeat the effort.
