FDA Officials Question Lack of New Cancer Drugs Developed in Combination With Radiation

Posted 13 April 2017 By Zachary Brennan

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Although almost half of patients with cancer who are cured will have received radiation therapy as a component of their care, there is still a dearth of new therapies being developed in combination with radiation, officials from the US Food and Drug Administration (FDA) wrote in an article published this week.

The authors, including Richard Pazdur, director of FDA's Oncology Center of Excellence, and FDA medical officer Amanda Walker, say that since 2006 there have been more than 250 new drugs and biologics approved by FDA's Office of Hematology and Oncology Products but only one cancer therapy, Eli Lilly's Erbitux (cetuximab), has been approved for use with radiation.

"The reasons for this discrepancy are complex and multifactorial, including limited regulatory precedent for drugs developed specifically for use with radiation therapy, as well as perceived challenges in trial design with radiation," the authors claim.

But they also say that there is a need for more of these combination therapies, noting that it is critical for sponsors to work with the agency through the development process.

"There is a significant unmet need in the oncology community for the development of successful drug–radiation therapy combinations, given the opportunity to improve long-term control rates and survival," they write. "Because of the limited regulatory precedent for the development of drugs specifically for use with radiation therapy, it is critical that sponsors engage with the FDA early and often in the process of drug development through meeting requests and special protocol assessments."

The article also discusses the regulatory framework under which cancer drugs in combination with radiation therapy may be developed and it describes how sponsors can obtain feedback from FDA during the drug development process.

Unmet Need?

Vinay Prasad, a hematologist-oncologist and assistant professor of medicine at the Oregon Health and Sciences University, told Focus via email that he thinks the lack of enthusiasm on combining new drugs and radiation is that "external beam radiotherapy feels antiquated to many in cancer. It is non-specific, hits off target tissues, has side effects. It just seems old and boring. Isn't the purpose of drug development to free us of radiation and surgery and bad older drugs? I think many have this intuitive belief. The FDA may be right that this feeling is not strictly based on evidence, and might be something we need to get over."

But Prasad also said he strongly disagrees with FDA on the claim that there is an unmet need in oncology to develop successful drug–radiation therapy combinations.

"Here, the FDA is perverting the definition of unmet need, in my opinion. Unmet need refers to characteristics of a disease that make patients more willing to tolerate greater uncertainty about efficacy. Some such characteristics include: a dire cancer, or a cancer that has few treatment options. But simply lacking a radiation-drug option is probably not enough," he said.

On the unmet need claim, Prasad also gives the analogy "of saying I am so hungry I would eat anything (and not being picky). You can say that if you 1. are very hungry or 2. have literally nothing in your house that is edible, but if you start saying that when you have a fridge of food, just ate breakfast, and merely lack a fruit-ice cream (radiation-drug) sundae, then people might say you are playing fast and loose with 'I am so hungry I would eat anything.'"

And though he agrees "that we should pursue radiation-drug combos," he also said, "'unmet need' is a dog whistle to drug companies that FDA will allow the use of accelerated and fast track pathways, and lower efficacy standards, for such approvals, and this would be unwise, irrational, and a bad decision, just like not having a fruit-ice cream sundae does not mean you are so hungry you would eat anything."

But radiation oncologists T. Jonathan Yang and Nancy Lee of Memorial Sloan Kettering Cancer Center disagree with Prasad's notion that "unmet need should be reserved for patients with dire cancers or with few treatment options," noting that "radiation therapy is overlooked in drug development. This has increasingly resulted in clinical conundrums and suboptimal care for our patients.

"To say there is no immediate need to examine the efficacy of radiation-drug combinations because there are ever more drugs is mistaken: it ignores that radiation-drug combinations may be better treatment options despite the
increasing number of drug-only options. We believe in the rigorous FDA approval process. If a radiation-drug combination demonstrates superior effectiveness over available therapy, or if the combination is able to decrease toxicity of the standard drug through drug-dose reduction, then consideration of fast track pathways would be appropriate," they said in an email to Focus.

They also noted that radiation, like drug therapy, "is continuously evolving. With the use of image-guided radiation treatment planning and delivery, radiation therapy can be extremely precise and specific. The notion that radiation is antiquated is belied by the literature, which is replete with strong evidence that supports our ability to deliver highly precise and conformal radiation treatments that result in improved efficacy in tumor control and reduced side effects. While older radiation treatment techniques ... can result in higher toxicities, the notion that radiation has not improved is simply not accurate."

International Journal of Radiation Oncology*Biology*Physics

Article updated 4/19 with comments from Yang and Lee.

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Categories: Biologics and biotechnology, Combination products, Drugs, Due Diligence, Regulatory strategy, Regulatory intelligence, News, US, FDA

Tags: hematology and oncology, radiation therapy, cancer drugs

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