WASHINGTON—The U.S. Food and Drug Administration hopes within the next six months to issue a finalized guidance document on the co-development of new therapies intended for use with companion diagnostic tests, according to Janet Woodcock, MD, Director of the FDA's Center for Drug Evaluation and Research.
The agency released a draft guidance document on the co-development of drugs and companion diagnostics in 2011. That document defined a companion diagnostic as an in vitro diagnostic device that provides information considered essential for the safe and effective use of a corresponding therapeutic product.
“The oncology community really is going at this double-barreled,” Woodcock said of drugs and companion diagnostics, speaking here at a keynote address at the National Press Club during the ninth annual luncheon on personalized medicine hosted by the Personalized Medicine Coalition (PMC). “Oncology is just on fire about this; we literally can't get them in their hands fast enough.”
A classic example of a diagnostic for use with a targeted therapy is a test that reveals whether a patient's breast cancer cells over-express the HER2 protein; if they do, the patient can be considered a candidate for the targeted therapies trastuzumab or lapatinib. The PMC released a white paper, “Personalized Medicine Regulation: Pathways for Oversight of Diagnostics,” earlier this year.
“I'm here to declare victory… targeted therapies have reached the mainstream,” Woodcock said. “Cancer and certain infectious diseases are leading the way.”
These new targeted therapies are the result of the fact that “ever smaller subsets of disease are being identified,” she added. And to ensure that these population subsets receive the most appropriate and effective targeted therapies, reliable companion diagnostic tests will be required.
“Diagnosis is the foundation of therapy and of personalized medicine,” noted Woodcock, who introduced FDA's Critical Path Initiative in 2004, a program designed to move medical discoveries from the laboratory to the bedside more efficiently.
Woodcock said that about one-third of FDA-approved new medical entities in 2012 contained some biomarker genomic information, reflecting a trend toward increasingly targeted therapeutics, which includes personalizing a drug's dose by genotype. “Many of the new 'breakthrough therapy' designations have involved targeted approaches,” she said, and the agency expects there to be more such drugs—which will potentially have a rapid development path.
“The new challenge will be to assist the larger health care community in dealing with this medical and scientific transition,” she added.
For about a decade, noted Woodcock, the FDA has been urging the adoption of pharmacogenomic strategies and the pursuit of targeted therapies on the part of the pharmaceutical industry. She said that initially the agency received pushback from industry on providing genomic data with its new drug applications, ostensibly because industry representatives believed that FDA reviewers lacked the sophisticated scientific background to properly evaluate genomic information.
“It just shows how far we've come how quickly,” she said of the trend toward providing genomic data on New Drug Applications (NDAs) to identify disease subpopulations. From 2008 to 2010, the FDA saw nearly a four-fold increase in review work on NDAs containing data on biomarkers and pharmacogenetics, she said.
Co-development of a drug and a companion diagnostic would solve some logistical problems and clinical issues, she noted. Today, some targeted drugs are developed “very fast,” and development of the diagnostic tests for use with those new targeted drugs lags behind—leaving physicians without necessary tools for optimal use of the new therapies.
Conversely, she said, some diagnostic tests are developed very fast compared with a slower pace of drug development. Ideally, a companion diagnostic test would be available immediately to aid clinicians using a new targeted therapy in disease prediction, prognosis, patient selection, dosing, and monitoring. If a diagnostic test is developed separately from the targeted therapy, it might not be adequately discriminatory of data, she noted.
Woodcock emphasized that in the era of targeted therapies, a new approach to drug development will have to evolve. Today, she said, “we have subgroup-driven drug development” due to the rapid evolution in diagnostic testing, especially genomic testing. She added, “Our future is targeting the molecular basis of disease… we are going to have to change how drugs are developed, period.”
One pressing challenge, she noted—a challenge she termed a “wonderful consequence” of the price of success—is this: when does a disease subpopulation get so small that it cannot be studied in a randomized clinical trial? Put another way, how can researchers study a rare genotype?
New Definition Needed
“We need a new definition of a clinical trial,” Woodcock said. “Because it will be impossible to do a separate, single trial to answer each question raised by each biomarker and candidate therapy, we need to turn the [current] paradigm on its head.”
The way clinical trials are currently conducted is too expensive, too non-informative, and takes too long. The goal of new trial designs will be to intervene early with combination therapy; as an example of an adaptive new trial design that uses that strategy, Woodcock cited the breast cancer I-SPY2 trial, which has a broad intake and many treatment strata based on biomarkers.
She said new trial designs for candidate therapies will evolve, which will focus on biomarkers that are major pathophysiological drivers of a disease and are known molecular targets of the proposed therapies. Investigators using new trial designs will have to consider seriously whether to enroll only subjects with those biomarkers or whether to enroll biomarker-negative subjects as well; Woodcock said it could be considered unethical to put biomarker-negative subjects on such trials.
Overwhelming Volume of Information
Another major challenge in the age of targeted therapies, said Woodcock, is how to make sense of the large volume of information, especially genomic information, which can be overwhelming to practicing clinicians. Practicing physicians “want clarity” in how to use a therapy and its companion diagnostic in clinical practice, not “an in-depth post-graduate education on science,” she said.
And finally, she said, a very real question is whether health insurers will pay for new targeted therapies, including those intended for use with a companion diagnostic. “We're seeing some resistance in paying for this,” said Woodcock. “We're going to have to focus on adding value.”
Because there is a perception that targeted interventions are “high-tech” and “expensive,” the challenge is going to be showing that new targeted therapies actually do cure or control disease, thus making them cost-effective. “We're only in the early stages of this therapeutic revolution, but this is the ultimate goal,” she said. “I think we're going into uncharted waters here.”
Stephen Eck, MD, Head of Clinical Oncology at Astellas Pharma US, Inc., which sponsored the luncheon, said in his introduction that medicine is clearly in transition from the old model of diagnosis on the basis of disease symptoms to diagnosis on the basis of the underlying biology of the disease. But, “these changes are not going to happen by themselves,” he emphasized.
“For those of us who are proponents of personalized medicine, this brings new responsibility—the responsibility of educating academic, industry, patient, provider, and payer communities about the value of molecular diagnostics and the proper choice of medicines, an essential component of our personalized medicine future.”