FDA Drug Initiative Vexes Startups

"For decades drugmakers have taken a more-is-more model when dosing cancer drugs in clinical trials. U.S. regulators want them to reconsider that approach.

Companies with cancer drugs in clinical trials must strike a balance between doses high enough to thwart tumors but low enough to avoid intolerable side effects.

For years, Food and Drug Administration officials have expressed concern that cancer drug doses are often too high, leading to unnecessary side effects. An FDA program launched in 2021, Project Optimus, requires companies to re-examine how they set doses of cancer treatments.

This typically involves larger clinical trials to test doses to find those that optimally balance safety and efficacy. Entrepreneurs support the aim, but some fear the initiative will add time and cost to drug development, putting startups at a further disadvantage to larger competitors.

"I don't think anybody disagrees with the idea that we're trying to find the best thing for the patient," said David Bearss, chief executive of biotechnology startup Halia Therapeutics. "I hope it doesn't have unintended consequences of actually suppressing innovation."

The FDA says it encourages drugmakers to discuss dosing plans with the agency and that new medications can still be brought to patients quickly.

"With adequate planning, drug companies can accomplish dosage optimization and also expedite development of new safe and effective cancer therapies," an FDA spokesperson said.

Craig Bleifer, a pharmaceutical lawyer and partner with law firm Akin Gump Strauss Hauer & Feld, said Project Optimus likely wouldn't change after the November election because it isn't as contentious as other issues, such as drug pricing.

Companies have long determined cancer drug doses by testing small amounts in initial clinical trials and increasing them until they reach the highest level patients can tolerate. Companies then test the maximum-tolerated dose in subsequent trials.

The approach goes back decades to the discovery of chemotherapy drugs that kill rapidly dividing cells -- cancerous and healthy. Toxic side effects were a surrogate for efficacy: if a chemotherapy wasn't harming healthy cells, it probably wasn't hurting tumor cells either.

Over the past two decades, drugmakers shifted to focus on treatments such as molecularly targeted medicines aimed at proteins overabundant in tumor cells, or molecules these cells overly depend on.

Because these medicines work differently, the maximum-tolerated dose can cause significant side effects without treating tumors more effectively, said Michael Fossler, executive consultant and vice president with Cytel, a contract-research organization serving pharmaceutical companies.

"If you give anything in a high enough dose you will get toxic off-target effects," Fossler added.

As these newer medicines proliferated, doctors, patients, researchers and others called for a rethinking of cancer drug dosing. A 2013 issue brief by the nonprofit Friends of Cancer Research, for example, noted the need to develop cancer treatments quickly often has taken precedence over finding optimal doses. It called for randomized dose-comparison studies.

A 2021 New England Journal of Medicine article, authored by FDA officials, also challenged the "more is better" model, citing cancer medicines whose doses or schedules were modified, after approval, to make them safer or more tolerable.

Project Optimus launched that same year, with a goal of pinpointing optimal doses before new cancer drugs reach the market. The FDA issued a draft guidance for industry on how to comply with the program in January 2023 and published a final guidance on Aug. 9.

Because Project Optimus is relatively new it will take a while for its full impact to be known. But it will likely add six to 12 months to the drug-development process, said Tara Raghavan, a pharmaceutical patent lawyer with Benesch Friedlander Coplan & Aronoff." [1]

1. FDA Drug Initiative Vexes Startups. Gormley, Brian.  Wall Street Journal, Eastern edition; New York, N.Y.. 30 Aug 2024: B.2.