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IoM: FDA, Industry Accord, Early Biomarker Research Will Aid Dx-Rx Co-Development

Early biomarker-based research and greater cooperation between the US Food and Drug Administration and the pharmaceutical industry will enhance drug-diagnostic co-development efforts for cancer indications, according to a report issued last week by the National Academies of Science’s Institute of Medicine.
The report, Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment, recommends that the federal research agencies create a single entity focused on biomarker development, support cell and tissue repositories for validating new biomarkers, and focus on identifying biomarkers with broad applicability.
It also recommends that the FDA and industry come up with new strategies, methods, and infrastructure to “leverage and integrate the available data to better inform the biology.” Since developing a diagnostic together with a therapeutic is costly, the report suggests that the FDA and industry should devise strategies to share and minimize the costs and risks of co-development.
The report can be found here.
The Biomarker Key
Cancer drugs, with their mediocre efficacy and high toxicity, make the oncology market ripe for biomarker research but also a difficult population for marketing PGx technologies.
Since cancer patients are willing to tolerate greater toxicities in exchange for a few months of additional survival, the use of genetic tests to gauge which patients will experience adverse reactions is “counter-intuitive” for many doctors who use toxicity to gauge patients’ response to treatment, Felix Frueh, associate director of genomics at the FDA, previously told Pharmacogenomics Reporter.
However, that philosophy may not always stick. Contrasting R&D experiences of two oncologics, Novartis’ Gleevec and AstraZeneca’s Iressa, illustrates the benefits of early identification of biomarkers and the pitfalls of not using such a strategy.
“The best example of where having a biomarker made all the difference in the world is with the approval of Gleevec” in Philadelphia-positive chronic myeloid leukemia patients, Harold Moses, professor of cancer biology, medicine, and pathology at Vanderbilt University School of Medicine, told Pharmacogenomics Reporter this week. Moses also chairs IoM’s Committee on Developing Biomarker-based Tools for Cancer Screening, Diagnosis, and Treatment, which authored the report.
Gleevec, which inhibits the Bcr-Abl tyrosine kinase, was approved after Phase II trials. “If you had Bcr-Abl translocation then there was a better than 90 percent probability that you would respond,” Moses said. “So that’s the hope with the development of other biomarkers and the feeling is with more complex solid tumors you are going to have to look at a panel of biomarkers, not a single one.”
In contrast, the lung cancer drug Iressa did not rely on early biomarker identification. Though the FDA put Iressa on a track for accelerated approval based on preliminary data from a Phase II study, the drug ultimately did not show a survival advantage in the Iressa Survival Evaluation in Lung Cancer trial in 2005. As a result, the agency limited its use only to those patients who were already on the drug and deriving a benefit from it.
Eventually, researchers discovered from a subgroup analyses of ISEL that Iressa yielded statistically significant increases in survival compared to placebo in Asian non-smokers. Additionally, analyses of biomarker data from ISEL have found that a high EGFR gene copy number may be a strong predictor of benefit with Iressa in pre-treated advanced non-small cell lung cancer patients.
“The oncologists putting patients in the trial knew that a subset, somewhere between 10 percent and 20 percent of patients, were having great responses, but you put them in with the regular population and it looked like a negative trial,” Moses reflected. “Had we been able, through the use of biomarkers, to enrich that trial, then it could have been approved much more easily and with less cost.”
Moses noted that by incorporating biomarkers companies can save money by doing shorter and smaller trials. “You don’t have to have the hundreds or thousands of patients if you have a response rate of 70 percent to 90 percent,” Moses said, referencing Iressa’s efficacy in the Asian sub-population.  
The IoM report acknowledges that validating a companion diagnostic can substantially add to the cost of drug development, making companies unwilling to invest in developing a genetic test without a level of certainty that the drug will garner FDA approval. “Devising strategies to share and minimize the costs and risks of co-development would foster this work,” the report suggests.
One of the messages presented in the report supports opinions held by some FDA officials that drug-diagnostic co-development is the best way to ensure that prescribers adopt PGx technologies since physicians and patients get introduced to both products simultaneously [see PGx Reporter 01-03-07].
“Diagnostics and therapeutics are currently developed separately, often by different entities,” the repot says. “Timing is key for the co-release and marketing of a diagnostic linked to a drug, but often there is a rush near the end of drug development to develop the diagnostic. As a result, the diagnostic may not be scrutinized as thoroughly” as the therapeutic.

“That’s the hope with the development of other biomarkers and the feeling is with more complex solid tumors you are going to have to look at a panel of biomarkers, not a single one.”

One recent example of a well-timed drug-diagnostic co-development partnership is the non-exclusive agreement between Monogram and Pfizer to use Monogram’s Trofile assay to identify responders to Pfizer’s HIV tropism drug maraviroc.
Pfizer used Trofile in the clinical development program for maraviroc, and invested $25 million in Monogram [see PGx Reporter 12-06-06].
The companies recently entered into a non-exclusive agreement to make the assay available to patients worldwide. The HIV tropism drug is currently undergoing an accelerated review at the US Food and Drug Administration.
Coordinated Effort
According to the IoM report, the potential of biomarkers in guiding cancer therapies is being undermined by “piecemeal and unorganized efforts” by industry and government agencies, and by confusing regulations.
The report suggests that government research agencies, including the FDA, the National Cancer Institute, the National Institutes of Health, and others, should develop a “single federal agency” that would “coordinate and oversee a more organized approach” to the discovery and development of these markers.
Diagnostic and pharmaceutical companies and federal agencies should partner to “create an international research consortia” that would “generate and share data,” the report said. It added that these companies would employ resources from different partners that would “benefit the entire field.”
“The quantity of data currently generated by any single company is likely to be inadequate for developing and validating biomarkers,” the IoM report states.
Moses echoed this sentiment, noting that although pharmaceutical companies use biomarkers in early research and drug development, they don’t necessarily share the data. A more coordinated approach would reduce “duplicative work” and streamline the process, the report notes.
Additionally, the report recommends that government agencies support cell and tissue repositories that could be used to validate new biomarkers.
Ultimately, research sponsors should focus on identifying biomarkers with broad applicability, such as “indicators of cell communication pathways that are involved in many kinds of cancer and other diseases.” According to the report, biomarkers for particular drugs are “riskier investments” because the drugs could fail.

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