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Regulatory Focus™ > News Articles > Advances in Sequencing Likely to Shift Paradigm in Cancer Drug Approvals, FDA Experts Say

Advances in Sequencing Likely to Shift Paradigm in Cancer Drug Approvals, FDA Experts Say

Posted 07 November 2017 | By Zachary Brennan 

Advances in Sequencing Likely to Shift Paradigm in Cancer Drug Approvals, FDA Experts Say

Experts within FDA's newly established Oncology Center of Excellence (OCE) discussed the office's role in the first site-agnostic cancer treatment approval and programs for further advancing oncology-related regulatory science and policy.

And in the concluding section of the article, the OCE experts note that FDA, which has typically approved companion diagnostics under a "one drug, one diagnostic" paradigm, is "likely to" shift to a "many drugs, a panel of diagnostic markers" paradigm because of advances in molecular sequencing.

The article comes almost a year since OCE was formally established, and almost half a year since FDA first granted approval to a treatment for patients whose cancers have a specific biomarker, rather than for a specific location in the body where the tumor originated.

"For the FDA and the field of oncology in general, this new indication represents a shift in the evaluation of therapies and changes how we may define cancer. Rather than the strict disease-site indication determined by site of origin or pathologic diagnosis, a site-agnostic indication defines the disease by the presence of a specific biomarker," co-authors including OCE Director Richard Pazdur, Gideon Blumenthal, acting deputy director of FDA's Office of Hematology and Oncology products wrote in an article published Monday in Experimental Biology and Medicine.

The authors noted that therapeutic targets are evolving from tissue- or organ-based to gene- or pathway-based, though as treatments have become more complex and cancers have been divided into hundreds of diseases defined by tumor markers or other indicators, "there cannot be a single solution for every clinical situation. This first site-agnostic approval is unlikely to be the pathway for all biomarker-identified populations, as the story of site-agnostic indications has only just begun."

The FDA leaders also note that OCE is open to working with sponsors on site-agnostic indications that are "based on a strong scientific rationale and robust clinical results. Another consideration is whether other effective therapies are available."

Other Notes

While noting the evolution of FDA oncology and hematology reviews, the authors say the agency has gone "from the traditional requirement of two randomized, controlled trials demonstrating an improvement in OS [overall survival] for approval of a new therapy" to the use of endpoints such as objective response rate (ORR) of sufficient duration and progression-free survival.

"It is not always practical or feasible to demonstrate OS in diseases where patients can live for years following treatment, such as multiple myeloma or chronic lymphocytic leukemia, because trials would be too expensive and long, and requirement of OS could delay the development and use of effective therapies to meet patients' needs," the authors add.

OS also "may be unreasonable to demonstrate with newer breakthrough therapies that target specific tumor mutations found in a limited number of patients, making randomized studies impractical. In addition, equipoise may be lost when emerging data show that a new drug demonstrates overwhelming benefit compared to available drugs used in the control arm."

The authors also say FDA is "actively exploring the use of real-world evidence for generation of clinical evidence that may provide a better understanding of chronic safety and long-term efficacy of oncology drugs."

Initiatives include FDA's Information Exchange and Data Transformation initiative and collaborations with Project Data Sphere (, Flatiron, and CancerLinQ are building technical and organizational infrastructure for big-data analytics, they say.

The FDA Oncology Center of Excellence and precision medicine


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