Fast-Track Drug Approval, Designed for Emergencies, Is Now Routine Three-quarters of new drugs get an expedited regulatory review, thrusting families and doctors into a new world of trade-offs
Peter Loftus
For decades, most drugs for critical illnesses passed through a standard battery of tests before regulators allowed them onto the market. A smaller portion were “fast tracked” to make them available to patients sooner.
Now that dynamic has flipped. Most drugs are released faster than ever through federal programs expediting their approval.
The new normal is transforming medical decision-making for the seriously ill, especially those who are out of other options. Families and doctors are thrust into a new world of trade-offs, raising complex questions about the medical and financial value of drugs with limited track records.
The U.S. Food and Drug Administration approved a record 43 new drugs last year through fast-track programs that skip or shorten major steps other drugs must pass, or 73% of total new drugs. That compares with 10 expedited drugs, or 38% of the total, approved 10 years ago.
The proportion of new drugs receiving expedited approvals has been at least 60% for each of the past five years. It was below 60% in the previous five.
These programs clear drugs for patients that the FDA considers to be in high need, often for deadly or debilitating diseases with few or no treatments. Regulators are typically responding to pressure from drugmakers, doctors, patients and policy makers to get drugs to market more quickly. The approvals often hinge on signs of promise in early research rather than on longer-term studies, or follow a shorter review period by FDA officials.
As regulators fast-track drugs, they are also shifting the level of proof needed for a drug’s effectiveness, relying more on surrogate indicators—other measures of a drug’s positive impact, such as tumor shrinkage— rather than evidence a drug improves a patient’s survival in deadly diseases. The hope is that comprehensive proof a drug truly works will be borne out after a drug hits the market.
The result is a rising proportion of new drugs for fatal diseases that lack extensive evidence they can prolong lives. Many continue to lack that proof years after entering the market.
It is an acceptable trade-off, says Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, because some patients get access sooner to drugs that later prove effective.
A Wall Street Journal review of FDA data shows how that trade-off is playing out in the biggest new-drug category: cancer.
The FDA is approving a rising proportion of expedited cancer drugs without ample evidence they extend patients’ lives beyond another drug or placebo in clinical trials, the Journal found, and many still lack evidence they improve survival rates for patients. The drugs are mostly made available to patients in the advanced stages of critical diseases, and the FDA requires a summary of the evidence of a new drug’s effectiveness and safety in the prescribing label dispensed with prescriptions.
“Drugs are coming to market with less and less evidence,” says Dr. Joseph Ross, a Yale School of Medicine associate professor who researches drug development. The upshot is government and private insurers pay for expensive treatments that aren’t effective, he says, sometimes exposing patients to unnecessary side effects and cost.
While insurance generally covers most patient costs for these drugs, Medicare enrollees, the underinsured and others may end up paying hefty out-of-pocket costs toward ineffective treatments.
In April, Eli Lilly & Co. said it would pull its fast-tracked cancer drug Lartruvo because a large new study showed it didn’t prolong lives of advanced-sarcoma patients. The FDA had expedited approval in 2016 based on a small study in which patients lived longer on average than those who didn’t take it.
About 5,000 U.S. patients have taken Lartruvo at an average of roughly $17,000 a month, Lilly says. Symantha Melemed, former Lartruvo product-team leader and now leader on another Lilly drug, says it was reasonable to seek approval based on the earlier study. “When you see a one-year survival advantage, you react.”
When Kenneth Snow started on Lartruvo in 2017 for sarcoma, he knew it was fast-tracked on early evidence. During treatment, his tumor sizes were stable or fluctuated, and “I just had the belief that it was working,” says the 59-year-old former highway-maintenance worker in Hanson, Mass. Mr. Snow said he experienced some cognitive side effects, but that the drug was relatively tolerable.
In January, after news of the failed follow-up trial, he quit Lartruvo and later started radiation treatment. He doesn’t regret taking Lartruvo, he says, because patients like him have no time to wait. “Disappointments are part of the process,” he says.
Mr. Snow said he was surprised by Lartruvo’s price, and he thinks companies shouldn’t financially benefit from drugs that prove ineffectual. Mr. Snow’s insurance covered most of the cost, and he paid for the rest himself.
The FDA granted “accelerated approval,” meaning Lilly could sell Lartruvo but would get full approval only if a follow-up study confirmed a clinical benefit. Patricia Keegan, a division director at FDA, says she and colleagues knew the early study had confounding factors, “but we didn’t know how to weight them” against the apparent benefit, she said. “We were aware it was imperfect.”
Dr. Keegan said at a cancer conference last month that fast-tracking “is something of an art to make that final decision. We don’t expect to be right all the time.”
In the 509-patient follow-up study, median overall survival for the Lartruvo-chemo combination was 20.4 months, versus 19.7 months on chemo alone, Lilly told doctors in January. The difference wasn’t sufficient to meet standards demonstrating Lartruvo’s overall-survival rate was significantly better, Lilly says.
Many health-care officials say drugs approved with little evidence should be discounted until proven effective or be subject to a mechanism that reimburses insurers and patients if ineffectual.
Dr. Michael Sherman, chief medical officer for insurer Harvard Pilgrim Health Care, has proposed that a third party set prices for expedited drugs and that companies get paid only if they work.
If a drug targets a devastating disease, “you might be willing to advance it to market even not having as large of a data set to look at all the potential safety questions,” says Dr. Scott Gottlieb, who was FDA commissioner until early April, and is now a venture capitalist.
Some fast-tracked drugs have been major successes, producing proven treatments for maladies such as HIV/AIDS, leukemia and hepatitis. The FDA expedited the approval of Novartis AG’s Gleevec to treat a type of leukemia in 2001 based on its effect on cancer cells; it has since shown a dramatic improvement in long-term survival. And drugs approved through the traditional path don’t offer guarantees to all patients, and carry risks of their own.
Even expedited drugs can take years to become available. According to a 2017 document by FDA officials, the traditional drug development process can take 9.5 to 14 years; expedited drugs can take 5.5. to 11 years.
To gauge the effectiveness of new cancer drugs, the Journal looked for drugs showing proof they met a key measure in medicine: whether they prolonged “overall survival.” That’s defined as the time from start of treatment until death from any cause beyond a comparator drug or placebo.
Some drugs showed other benefits, such as “progression-free survival”—the time from starting treatment until death or disease progression. Many doctors consider an increase in overall survival to be the ultimate goal for cancer drug efficacy.
The Journal found that of the 42 new fast-tracked cancer drugs the FDA approved from 2015 through 2018, just 19% had proof upon approval they significantly prolonged overall survival. That’s down from the 26% that had proof out of 34 new expedited cancer drugs from 2011 through 2014. The vast majority of new cancer drugs were fast-tracked in these years.
Surrogate markers are used because many experts consider them a predictor of a survival benefit. Oncologist Monica Bertagnolli at Boston’s Dana-Farber Cancer Institute says this approach generally strikes a balance between developing evidence and giving patients access. “There’s always going to be a little bit of a risk” without full evidence at approval, says Dr. Bertagnolli, past president of the American Society of Clinical Oncology.
But a cancer drug’s ability to shrink tumors or delay progression doesn’t always mean it prolongs life, says oncologist Vinay Prasad, associate professor at Oregon Health & Science University. A new drug may shrink a patient’s tumor by a certain amount, but the tumor could begin growing again at a rate that leads to death in the same amount of time as an older drug that didn’t shrink the tumor as much.
If the FDA used a higher bar, it would encourage companies to aim for better drugs, says Dr. Prasad. “I want drugs that improve survival.” Some of Dr. Prasad’s research is funded by billionaire John D. Arnold, a critic of high drug prices.
When the FDA expedites approvals on limited evidence, it generally requires larger “post market” studies. Of the fast-tracked cancer drugs approved from 2015 through 2018 without proof of overall-survival benefit, 88% still don’t have that proof in the tumor type for which the drug was initially approved, the Journal concluded. Among 2011-14 approvals, 44% still don’t have proof.
“Five years after approval, I believe the vast majority of cancer drugs should have demonstrated improved survival or quality of life,” says Dr. Prasad.
Some follow-up studies have shown better-than-initial benefits. The FDA in 2017 expedited approval of Novartis’s breast-cancer drug Kisqali, which Novartis said in June prolonged overall survival in a follow-up study.
In 2016, the FDA granted expedited approval to Roche Holding AG’s Tecentriq based on a small study showing it shrank tumors in some patients with advanced bladder cancer; the study didn’t compare it with another treatment or placebo. But in 2017, Roche said a larger, follow-up study showed the drug failed to prolong overall survival beyond chemotherapy in bladder-cancer patients.
In a third study, Tecentriq actually decreased survival among a subset of bladder-cancer patients versus chemotherapy. The FDA in 2018 tightened the drug’s prescribing label to warn against its use in that subset. It’s still approved for other bladder-cancer patients.
Roche says more than 11,000 U.S. bladder-cancer patients have taken Tecentriq, at an average of $12,900 to $13,500 a month. Sandra J. Horning, chief medical officer at Roche’s Genentech unit, says Tecentriq’s safety and tolerability were superior to chemotherapy in the approved bladder-cancer uses even though it didn’t improve bladder-cancer survival. Tecentriq has been shown to improve survival in lung-cancer patients.
“The regulatory flexibility that allows patients access to new therapies, while we collect further confirmatory evidence,” she says, “is in fact the right thing to do.”
Surrogate markers have value in rare diseases, says Richard Pazdur, the FDA’s oncology-division director, because it can take time to run a study proving an overall survival benefit.
When the FDA approved Lilly’s Lartruvo in 2016, it was the first new drug to treat newly diagnosed soft-tissue sarcoma since the 1970s. The FDA based its approval primarily on a 133-patient study, which showed adding Lartruvo to chemotherapy extended median overall survival to 26.5 months, compared with 14.7 months for those on chemo alone.
One doctor the FDA consulted while deciding whether to approve Lartruvo, Massachusetts oncologist James Liebmann, in a September 2016 conference call with the agency, said he felt it should delay approval until a follow-up study could confirm the benefit, according to an FDA memo, expressing concerns about whether the results “were real given the small sample size.”
That month, Dr. Hussein Tawbi of Houston’s MD Anderson Cancer Center told the FDA in a conference call “he wouldn’t want [Lartruvo] to become the standard of care without results from a confirmatory trial as there were too many variables…confounding the data,” an FDA memo says.
The doctors told the FDA they were concerned factors other than Lartruvo could have accounted for the benefit—for one, patients taking Lartruvo got greater cumulative doses of chemotherapy than those taking only chemotherapy. The FDA reviewers acknowledged the limitations but noted advanced sarcoma had few good treatments, an FDA review document shows. Dr. Tawbi declined to comment. Dr. Liebmann didn’t return calls seeking comment.
The same week Lilly said Lartruvo showed no benefit in the new study, David Sims learned his sarcoma was progressing again after having taken Lartruvo since he was diagnosed in the summer of 2018. Mr. Sims, 51, a grants administrator in Philadelphia, has switched treatments. He’s left with the uncertainty of knowing whether Lartruvo worked.
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