Adaptive clinical trials, in which data are used as they become available to adjust the allocation of future patients and other aspects of the study design, appear closer to adoption following the recent launch of a large clinical trial to test multiple neoadjuvant therapies for women undergoing standard chemotherapy for high-risk, fast-growing breast cancers.
The adaptive trial, called I-SPY 2, will make extensive use of biomarker data combined with molecular and MRI imaging to screen up to 12 different cancer drugs from various companies under a master Investigational New Drug approval issued by the U.S. Food and Drug Administration (FDA). Researchers will use early patient data to graduate, drop, and/or add drugs seamlessly throughout the course of the trial without having to stop and write new protocols. The goal is to shave off several years and save hundreds of millions of dollars compared to conventional drug discovery and development methods.
“The I-SPY 2 trial explores a whole new way to rapidly screen new cancer treatments and match the therapy to specific markers,” said Janet Woodcock, MD, director of the at the FDA’s Center for Drug Evaluation and Research. “Developing individualized medicines needs a solution bigger than any one group can generate,” she said.
I-SPY 2—which loosely stands for Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2—will enroll patients at up to 20 university hospitals and cancer centers nationwide over five years at a cost of about $26 million. Announced in March, the project is managed by the non-profit Foundation for the National Institutes of Health (FNIH) in association with the Biomarkers Consortium, a public-private partnership that includes FDA, National Institutes of Health (NIH), the Pharmaceutical Research and Manufacturers of America, the Biotechnology Industry Organization, major drug companies, and other corporations and numerous non-profit organizations.
I-SPY 2 will use whole genome expression profiling technology developed by Agendia (Huntington Beach, Calif.) and MRI imaging systems from Sentinelle Medical Inc. (Toronto, Canada). In the first phase, five new investigational drugs donated by three companies will be tested. Tumors will be imaged to determine the extent of shrinkage and novel biomarker data will be collected to help match disease subtypes and treatments. The idea is to quickly identify those drugs that are likely to be beneficial and to halt testing of those that are not.
The first five drugs to be tested are veliparib (ABT-888), a PARP inhibitor from Abbott Laboratories, Abbott Park, Ill.; conatumumab (AMG 655 and AMG 386), an APO/TRAIL inhibitor and angiogenesis inhibitor, respectively, from Amgen Inc., Thousand Oaks, Calif.; and figitumumab (CP-751,871) and neratinib (HKI-272), IGFR and Pan ErbB inhibitors, respectively, from Pfizer Inc., New York. Each represents a different anti-cancer drug class or type of chemical mechanism. All trial results will be published and data will be maintained at the University of California-San Francisco. Drugs showing promise will likely move into Phase 3 tests sponsored by the private companies.
“We have set up a system where everyone can learn faster and, together, we can dramatically reduce the amount of time and the cost to bring those drugs to market that can make a difference in whether women live or die,” said Laura Esserman, MD, MBA, co-principal I-SPY 2 investigator and director of the Carol Franc Buck Breast Care Center at UCSF. “The collaborative power behind this trial is truly transformational for breast cancer patients and for cancer research as a whole.”
Adaptive clinical trials are part of FDA’s “Critical Path” initiative designed to speed development and approval of new therapies and drugs. In February, the FDA published nonbinding, draft guidance for industry on adaptive design clinical trials. The agency acknowledged several potential benefits from adaptive trials, including greater efficiency through use of fewer subjects, increased likelihood of meeting statistically significant endpoints, and better understanding of subgroup treatment effects. But the FDA also noted challenges, including the potential for errors and biases due to unblinded interim analyses, the risk of false positives, and difficulties in statistical analysis due to fewer subjects and multiple treatment adaptations.
To help compensate for potential statistical limitations in I SPY-2, Donald Berry, PhD, co-principal investigator and chair of biostatistics at the University of Texas M.D. Anderson Cancer Center, oversaw the development of an adaptive Bayesian design. Such complex statistical simulations and scenario analyses are necessary but also time-consuming parts of adaptive trial designs, and can take many months to properly fashion.
Several major drug manufacturers have previously tested the waters of adaptive trial design, including Eli Lilly and Co., which conducted an early-stage adaptive drug trial for an investigational diabetes drug, and Merck & Co., which is involved in a separate adaptive trial called BATTLE, which seeks to combine biomarker data with various targeted drugs to fight lung cancer.
Despite researchers’ optimism, both the FDA and the European Medicines Agency (EMEA), which issued its own guidance on adaptive clinical trials in 2007, have cautioned against adaptive trials when conventional trials are available. Nevertheless, the number of adaptive trials, although small, is growing. Three or fewer adaptive clinical trials were begun each year from 2003 to 2006. In 2007, following the publication of EMEA guidance, there were 13, according to survey results published in the April issue of Clinical Trials.
Still, the potential is real. Anna D. Barker, PhD, deputy director of the National Cancer Institute and cochair of the Biomarkers Consortium Cancer Steering Committee said, I SPY-2 “will allow us to finally design advanced, smaller, and less expensive Phase 3 trials that test the right drugs in the right patients.”
About the Author
Contributing editor Ted Agres, MBA, is a veteran science writer in Washington, DC. He writes frequently about the policy, politics, and business aspects of life sciences.
Filed Under: Drug Discovery