(Bloomberg Businessweek) -- The cancer drug Pepaxto got its blessing from US regulators in 2021 based on a single study. The trial had found the intravenous treatment shrank tumors in almost a quarter of 97 bone marrow cancer patients for whom nothing else worked. Despite the small sample, the US Food and Drug Administration gave Pepaxto the greenlight using an accelerated approval process meant for getting promising medicines to people with few or no other options.
Now, the FDA is testing the power of a new law to try to rescind the drug's approval. A follow-up study has since sowed doubt on Pepaxto's efficacy and even suggested it might be dangerous. Although a finding such as that might sound like the death knell for any drug, the agency has struggled to efficiently take fast-tracked, not fully proven treatments off the market.
Over the past three decades, drugmakers have used the shortcut pathway for about 300 different disease applications, mostly for cancer treatments. Most of those later go through the more rigorous study required to stay on the market. But in some cases, pharmaceutical companies drag their feet, and at least one drugmaker refused to take its product off the market. These drugs tend to be expensive and can reap many millions of dollars in sales. Until recently, regulators lacked a formal process to act quickly.
This is the FDA's initial attempt to use legislation passed late last year that, in theory, gives the agency more muscle to force drugmakers' hands. The outcome will show if regulators finally have what they need for proper oversight of drugs sped through the accelerated approval process or if drugmakers still have the advantage.
“This will be the first time the FDA is implementing their authority” under the new accelerated approval law, says Reshma Ramachandran, a physician at Yale University who studies accelerated approval. If the agency backs down from its threat to take the drug off the market, it will signal to other drug companies that they can successfully fight the process, too, she says. “They'll go to the FDA and say, ‘Hey, you let this drug stay on the market based on that. Why can't we?'”
An advisory panel to the FDA last year voted 14-2 against Pepaxto. Oncopeptides AB in Stockholm insists that regulators are interpreting the new data wrong and that its drug does help a subset of patients. “Withdrawal of Pepaxto is premature,” it wrote in a 31-page appeal alleging that the FDA made “legal errors” in its attempt to revoke the drug's approval. This week, a closed-door hearing seals the treatment's fate. A spokesperson for the FDA wrote in an email to that the decision is “high priority” and it will announce a verdict as soon as practical after the Oct. 2 hearing.
The stakes are high for Oncopeptides. The biotech's stock soared to a multiyear high immediately after Pepaxto was approved, but it's since collapsed, losing 95% of its value, after doubts emerged about the drug. The $19,000-a-month medicine for multiple myeloma, a cancer of the bone marrow, is the company's only approved treatment in the US, and it's suspended US sales while its appeal plays out.
“There is no doubt that our drug benefits a large and growing group of elderly patients in later lines of treatment of multiple myeloma … that have few treatment options left,” Oncopeptides Chief Science Officer Jakob Lindberg said in an email.
Accelerated approval was pioneered in the 1990s for promising HIV therapies. It's meant to get drugs to patients with incurable diseases if early lab or test results show they're “reasonably likely” to work. The process was never meant to end there. The FDA requires follow-up studies to collect more definitive data, and if regulators aren't satisfied, they can take action. In practice, however, the program historically “had fly-by-the-seat-of-the-pants standards,” says Ravi Parikh, an oncologist at the University of Pennsylvania. “There wasn't really that much enforcement.”
Critics say regulators haven't done enough to pressure drugmakers to conduct timely follow-up studies or to rapidly rescind approval for drugs not meeting their standards.
Delays for confirmatory trials aren't uncommon. A Bloomberg News investigation found 19 drugs with accelerated approvals whose follow-up studies were still listed as delayed as of April.
A study published in found that from 2016 to 2022, more than a quarter of patients with certain types of advanced stomach, breast, lung, liver and bladder cancer used accelerated-approval drugs that were later shown to be ineffective for those specific uses. Some patients may have been exposed to side effects for no benefit. The study included popular immunotherapy drugs from Bristol-Myers Squibb, Merck & Co. and Roche Holding, which are still on the market for uses that received conventional approvals.
Sometimes unproven medicines have retained their FDA approval for years, even decades. A burn treatment called Sulfamylon powder was available for 25 years, even though its manufacturer, Mylan, now part of Viatris Inc., never completed the required trials to prove the drug worked. It was only pulled from the market after the drugmaker agreed to do so in 2021, telling the FDA further study was no longer feasible.
In fact, most withdrawals are voluntary, often after prodding from the FDA. Of the 11 drugs with accelerated approvals that have been rescinded in the past two years, drugmakers willingly pulled all but one. It's when the companies push back that regulators run into issues. Makena, a medication for preventing preterm labor, got its accelerated approval in 2011. Eight years later, a big study done by the drugmaker indicated it didn't work. By 2020 the drug had a new owner, and its maker at the time, Covis Pharma Group, fought to keep it available. The FDA finally recalled the product and its generics in April of this year.
The new law gives regulators a road map for expedited removals, though it doesn't specify a timeline: The FDA must provide an explanation to the company for why it's pulling the drug and allow the public to comment. If the agency hasn't already done so, drugmakers can request the matter be heard by a public advisory panel, and drugmakers can appeal the decision to the FDA commissioner, as Oncopeptides is doing now. Separately, the law also gives regulators the power to require that follow-up trials are underway at the time of a drug's approval.
To its credit, Oncopeptides did complete a larger trial only five months after Pepaxto's US approval. The study found patients taking the drug died a median of five months sooner than those in a control group, leading the FDA to warn of “an increased risk of death.” Although worrisome, that finding was not statistically significant.
After agreeing in October 2021 to formally withdraw the drug, Oncopeptides changed its mind in early 2022 after further review of the trial data suggested it safely worked for a subset of patients. This analysis apparently swayed European regulators, who approved the treatment for those people in August 2022, making it authorized for use in the European Union. Back in the US, though, a panel of FDA advisers in September 2022 decided the benefits didn't outweigh the risks. In July, following passage of the new law, the agency formally asked the company to withdraw its drug in the US.
Oncopeptides blames the negative vote last year on a “skewed voting question,” the wording of which, it says, suggested the drug was unsafe. Arguing that the process was undermined appears to be the drugmaker's last chance to keep its offering on the market. The FDA's decision after the hearing this week will be final.
Among multiple myeloma doctors, opinions are split. Some who prescribed the drug to patients say it should be given a second chance. “We need all the options to serve the various populations affected,” says Paul Richardson of the Dana-Farber Cancer Institute. He's consulted for Oncopeptides and says the FDA should find a way to allow the company to resume trials to prove the drug works.
But Aaron Goodman, a hematologist at the University of California at San Diego, argues that the drug has never proven to be any better than cheap decades-old chemotherapy. “It needs to go,” he says.
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