For Jazz Pharmaceuticals, Failure Is The New Winning

While the randomized controlled trial has been long accepted as the best way to determine whether a drug is effective and safe for the largest possible population, this method poses problems for small cell lung cancer studies.

A clinical trial’s Phase III — which can take as long as four years to assess a drug’s safety and efficacy against the current standard of care — would appear unwieldy if a disease is causing more than 90 percent of the afflicted individuals to die before five years have elapsed.

One technique developed by clinical researchers is using surrogate endpoints, or substitute evaluation criteria. Researchers believe these data points might correlate with two traditional clinical endpoints: extending life or improving its quality.

For example, the data that initially caught Dr. West’s eye in Phase II of lurbinectedin’s clinical trial was a surrogate endpoint called the overall response rate. (The FDA has at times called it an objective response rate.) This can involve measuring a tumor’s size over a period of weeks as someone takes a drug. (In lurbinectedin’s case, 35 percent of the study participants, or 37 individuals, had their tumors shrink 30 percent or more, with the effect lasting on average slightly less than five months.)

Another popular surrogate measurement for cancer trials is progression-free survival. This is calculated from the time after tumors stop growing (or disappear) until they grow again.

While progression-free survival and tumor shrinkage are certainly welcome developments, for people with small cell lung cancer they are often temporary events, given how common it is for tumors to grow back.

What’s more, a 2018 report in Clinical Cancer Research found that overall response rate and progression-free survival are poor predictors of a person’s overall survival.

A more detailed analysis of the tenuous links between response rate and increased patient life appeared in a Journal of the American Medical Association article in May 2019 by three doctors at Oregon Health & Science University: Emerson Chen, Vikram Raghunathan, and Vinay Prasad. They examined 85 indications for 59 oncology drugs that were granted FDA approval based on response rate and found that only six of them extended life span. (Some of these drugs were in the accelerated approval program; others were not.)

The FDA does not seem to have taken this research into account, however. In June 2018, FDA researchers published a triumphant review of the accelerated approval program’s first 25 years. From 1992 to 2018, the agency approved 93 indications for 64 products through the program, with only five indications subsequently withdrawn.

But to Harvard Medical School’s Dr. Aaron Kesselheim, the FDA is evaluating its accelerated approval program backward. In a May 2019 JAMA article that made a big splash, Dr. Kesselheim and two colleagues, Drs. Bishal Gyawali and Spencer Phillips Hey examined the 93 drug indications allowed through the FDA’s accelerated approval program. “We looked ‘underneath the hood’ at the FDA’s basis for approving those [93 indications of] drugs,” said Dr. Kesselheim during a Foundation for Financial Journalism interview. “Our question was simple: ‘Is there evidence that using [the FDA’s accelerated approval] pathway provides drugs that benefit patients?’”

Their answer: not really. Only 19 of the 93 indications investigated by Dr. Kesselheim and his colleagues, or slightly more than 20 percent, demonstrated any improvement in overall survival during Phase III of their clinical trials.

The real problem with the program, said Dr. Kesselheim, lies with the FDA’s use of “surrogate measures that are not clinically validated” for evaluating drugs. “There are valid uses for surrogate endpoints” in clinical trials, he noted: A drug’s effect can be measured faster by using a surrogate endpoint in lieu of a traditional clinical endpoint (which could require two years of study or more.)

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