Pharmaceutical research has brought few biologic drugs to market, despite scores of basic scientific discoveries keying off the sequencing of the human genome. In the U.S., submissions of new molecular entities to the FDA fell from 30 to 20 between 2000 and 2002. Meanwhile, the cost of launching a new drug has increased 55% in the last five years.
The drug development process continues to stall, largely because assessments of the safety and efficacy of experimental therapeutic compounds are antiquated. Makers of oncologic agents rely on guidelines for measuring changes in tumor size, such as the Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization standards for calculating tumor dimensions on CT or MR scans.
But these guidelines don't tell pharmaceutical researchers how to evaluate pockets, cystic structures, or tumors that necrose or cavitate in the lung, said Dr. Theresa McShane, worldwide clinical technical director for Pfizer Global Research and Development. She spoke at the 2004 meeting of the International Society for Magnetic Resonance in Medicine in Kyoto, Japan.
Nor can conventional measurements of tumor shrinkage provide a timely determination of treatment response from new classes of therapeutic agents, such as antiangiogenic compounds, which attack not tumor tissue but the blood vessels that feed the tumor, said Dr. Greg Sorensen, director of the Center for Biomarker Imaging at Massachusetts General Hospital.
To avoid financially disastrous drug failures in phase III trials, pharmaceutical companies are optimizing their choices of clinical imaging techniques to facilitate go/no-go decisions in phase I and phase II studies. Even a 10% improvement in predicting failures before entering into phase III trials could save an estimated $100 million in development costs per drug, according to the FDA.
Oncology drug manufacturers are beginning to apply structural, molecular, and functional imaging modalities as quantitative research tools in clinical trials to examine apoptosis, tumor vasculature, and viable tumor volumes and to quantify a drug's mechanism of action, said Dr. Patricia Cole of Novartis Pharmaceutical, at the ISMRM meeting.
In trials of its oncologic agents, Novartis is imaging properties of tumor tissue known as hallmarks of cancer: proangiogenesis, hypermetabolism, hyperproliferation, invasion, and metastases.
"If there is a major alteration in a cancer hallmark, that drug is more likely to show efficacy in larger numbers of patients in later phase trials," Cole said. "So imaging that shows a major perturbation in a cancer hallmark can be very useful in decision making."
In testing an antiangiogenic drug directed at a tyrosine kinase inhibitor at the vascular endothelial growth factor (VEGF) receptor, Novartis employed dynamic contrast-enhanced (DCE) MR to examine colorectal cancer metastases in the liver. After one dose of the drug, imaging revealed a marked reduction in the baseline contrast enhancement of a tumor mass located at the dome of the liver in one patient. On study day two, imaging across all patients showed a change in the baseline transfer coefficient of Ktrans, which was consistent with a dose response. At two months, patients had stable disease.
These findings allowed Novartis to make two important decisions. First was to take the drug forward. If trials had indicated only that patients had stable disease with no evidence of a pharmacodynamic effect, the company would have given up on the drug. Second was to pick an optimal biologic dose. The dose of 1000 mg not only produced significant changes on MR imaging; it also correlated with the actual plasma concentration of the drug.
Four clinical oncology drug development programs at Pfizer have successfully employed DCE MR to studies of drugs in the pipeline. In a dose-escalation phase I trial of Pfizer's VEGF tyrosine kinase inhibitor targeted at tumor vasculature, company investigators performed DCE at baseline, on day two, at the end of the first 28-day treatment cycle, and at week eight. They calculated changes in Ktrans as well as the area under the curve over time (see related story on page 6).
Imaging is becoming such an important aspect of drug development that the FDA, Harvard University, and the Massachusetts Institute of Technology are reviewing its use in pharmaceutical decision making to find specific technologies that could improve or accelerate the process, said Dr. Jerry Collins, director of the Laboratory of Clinical Pharmacology in the FDA's Center for Drug Evaluation and Research.
Researchers from Mass General and the FDA are analyzing data from the published literature and new drug applications to determine how imaging can be used to choose the optimal dose for a drug, based on its presumed mechanism of action. This work is leading to examples that clinical trial sites may follow when conducting phase III investigations.
"There has been an explosion in the number of sites that have molecular imaging technologies, so the technical ability to do these kinds of studies is taking off," Collins said. "We can sit and wait until that translates into NDAs or get ready now and help shape the field."