While time consuming, developing and validating biomarkers will help unlock personalized medicine’s potential, an FDA researcher said.
By David Pittman
Pharmaceutical researchers can expect to spend two to three years to have new biomarkers validated, but when these biological indications of drug performance are OK’d by the Food and Drug Administration (FDA), the likelihood of new medicines’ regulatory approval skyrockets.
Biomarkers help clinicians and drug developers discover which patients may or may not respond to a particular therapy, develop a disease, or have some safety issue triggered because of a therapy. All of that information can be key to teasing out who is best suited for a treatment, which helps reduce the number of individuals needed for clinical trials and increases trial success rates.
But validating biomarkers—even when you think you have all the scientific data in your back pocket—can take years, according to Shashi Amur, Ph.D., scientific advisor in FDA’s Office of Translational Sciences in the Center for Drug Evaluation and Research (CDER).
“Many times, you may think you have all the information, but when you talk to the regulators, they tell you ‘we need this much more,’” she said during a recent American Association of Pharmaceutical Scientists webinar entitled Role of Biomarkers in Supporting Personalized Medicine Efforts. “You have to go back to the drawing board and do much more studies, and that could take much longer.”
Amur presented data from the Biotechnology Innovation Organization that showed a quarter of drugs that entered phase 1 trials with biomarkers went on to be approved, compared to 8.4 percent of drugs that entered phase 1 trials without a biomarker. At all three phases of clinical trials and submission for approval to FDA, drugs with biomarkers had a higher chance of success.
“I would say that you don’t have to have biomarkers to have a high probability of success,” Amur said. “But definitely it’s worth considering whether you can use biomarkers to increase the probably of success.”
PERSONALIZED MEDICINE
As the world of personalized or precision medicine continues to grow, biomarkers can help regulators and researchers improve their chances of gaining FDA’s seal of approval as science finds biological signs that hint at whether a drug will be successful or not for individual patients. Biomarkers also aide in identifying the correct dose of drugs. Helping across all phases of development, biomarkers can help pinpoint the right target, tissue, safety, patient, and commercial potential, Amur said.
In breast cancer, for example, tumors’ genetic biomarkers have been used to identify patients’ disease subtypes based on hormone-receptor subtypes. Treatment response was higher in tumors that had such hormone-receptor subtypes. In 2017, FDA approved its first cancer drug agnostic of site—pemrolizumab (Keytruda)—based entirely on biomarker indictors.
“Why is that possible? There was a good understanding of the biology involved” because of biomarkers used, Amur said.
Patients genetic biomarkers have been spotted to find those at risk of developing a potentially fatal skin reaction to a particular HIV drug, abacavir (Ziagen). About five percent of patients who took the drug had a severe reaction, so the drug’s developer explored the mechanism for the reaction and found it was a particular genotype. Today, the drug is contraindicated for those patients.
The submission of genomic data for FDA’s consideration has mushroomed. Amur said, “Right now, especially in the oncology area, there is a lot of genomic information which comes up for review.” In 2005, the agency saw “almost nothing.”
Biomarkers can even be used as a clinical endpoint—like a predictor of a treatment’s success—in the drug approval process, Amur said, but specifics around such work need to be discussed with FDA’s review team.
FEDERAL RESOURCES
FDA’s drug center—CDER—offers a Biomarker Qualification Program with the goal of proliferating biomarkers as drug development tools. Seven biomarkers have been validated since 2008. Once validated, recommendations are made public along with a biomarker’s reviews to help spread the word about its potential.
The 21st Century Cures Act of 2016 demanded that FDA issue guidance detailing a formal multistage process for biomarker qualification with defined timeframes for review. This summer, the agency clarified the three-stage process for validation. Developers must first submit a letter of intent about what biomarker is being studied and how. Then, FDA must accept a qualification plan that will provide greater detail on how the biomarker will be proven. Lastly, FDA must review and accept a full qualification package on all the data supporting the biomarker’s use.
Biomarkers need to be validated with a clinical assay, and researchers need to define how a biomarker would be used, such as for diagnostic, prognostic, or predictive purposes. Work needs to demonstrate that it is able to measure whatever clinical outcome is sought. “You have to show correlation, and then show the clinical validity, and then show utility,” Amur said.
Of course, biomarkers may not be available in all situations.
In 2016, FDA and the National Institutes of Health published a glossary of terminology and biomarker uses and endpoints in basic medical research and product development. The tool—the Biomarkers, Endpoints and other Tools Resource, or “BEST” for short—helps clear up confusion that might inadvertently be present in the fast-growing field.
“Hopefully, we will all speak the same language,” Amur said.
In short, biomarkers hold the key to fulfilling personalized medicine’s promise of treating the right patient with the right drug at the right time.
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David Pittman is a science and medical writer based in Washington, D.C.