Critical Path Initiative
Many tests currently used for diagnostic purposes and drug evaluations are over 100 years old. This is primarily because there is not yet an FDA guidance document for the regulation or approval of a method. Recognizing the problem, the FDA established the Critical Path Initiative (C-Path) in 2004. Its mission statement is “to create innovative collaborations in research and education that enable the safe acceleration of the process for developing new medical products.”
According to Raymond Woosley, Ph.D., the president and CEO of the Critical Path Institute, it is focused on “trying to address the process of getting science into commercialization.” It wants to make sure that “better, more modern methods and tools are qualified for use in drug development.” He stressed that it does not deal with products, only processes.
Dr. Woosley will review a few examples of biomarkers being used clinically in oncology. C-Path would like to expedite the development of diagnostic and other assays to follow these.
Irinotecan, marketed by Pfizer as Camptosar, is a topoisomerase I inhibitor used clinically against colon cancer. Its active metabolite is inactivated in the body by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). Patients with the otherwise benign Gilbert’s syndrome have insufficient UGT1A1, and therefore, when treated with irinotecan receive an effectively higher dose and suffer toxicity. An invader assay has been developed to detect this genotype in colon cancer patients, making irinotecan the first chemotherapy agent individually dosed by genotype.
Approximately 15–20% of breast cancers overexpress HER2/neu. Trastuzumab (Herceptin, Genentech) is only effective in these cancers, so breast tumors are routinely tested for this overexpression to determine the appropriate course of treatment.
Erlotinib hydrochloride, marketed as Tarceva (Genentech, OSI Pharmaceuticals), is used to treat non-small-cell lung cancer. As it targets the EGF receptor, a test for EGFR mutations in cancer patients would probably help predict who will best respond to it and similar kinase inhibitors.
As an independent third party, C-Path has induced 18 pharmaceutical companies to share their methodologies, then summarized and compared them. This cooperation will determine if EGFR is in fact a valuable biomarker and, just as importantly, which test is best for predicting efficacy of drugs targeting it. Speeding up the trial process in this way could reduce the number of costly failed drugs and lower the price of prescription drugs in general.
Dr. Woosley opines that “biomarkers are not being fully utilized for drug development.” They could be used to predict, and thereby prevent, a new drug’s side effects and to account for variability in efficacy.
The representative examples mentioned here are only that; the uses for biomarkers need be limited only by researchers’ creativity. For instance, a group at the Technion in Israel recently described a novel technology for cancer biomarker discovery that they dubbed “humoral proteomics,” based on the fact that cancer patients have expanded antibody repertoires with abnormal specificities. Biomarkers have the potential to make medicine more like it should be: more personalized, more predictive, more preemptive, and ultimately more effective.