The pharma-funded FDA gets drugs out quickly, but some work only ‘marginally’ and

Dr. Steven-Hui Han, a UCLA liver specialist, has prescribed Ocaliva for a handful of patients, though he’s not sure it will help.

As advertised, the drug is lowering the level of an enzyme called alkaline phosphatase in their blood, and this should be a sign of healing of their autoimmune disease, called primary biliary cholangitis. But “nobody knows for sure,” Hahn said, whether low enzymes mean they won’t get liver cancer or cirrhosis in the long run.

“I have no idea if medication will make them better,” he said. “It may take 10, 20 or 30 years to find out.”

Ocaliva came to market 30 years ago through an FDA review process known as accelerated approval, which allows pharmaceutical companies to license promising treatments without having to prove they work. This has become a common route to market – for example, accounting for 14 out of 50 approvals of novel drugs in 2021 compared to four out of 59 in 2018.

The FDA’s accelerated approval is usually based on a “surrogate marker” of efficacy — evidence of a low viral load for HIV, for example, or tumor shrinkage for cancer. Some of these are stand-ins and some debate the legality of the drug.

“If you’ve got a game-changing drug that’s really going to make a difference, you don’t need surrogate markers to prove it. If it works, patients will live longer,” said Dr. Aaron Mitchell, an oncologist at Memorial Sloan Kettering Cancer Center. The short approval process, he said, is one reason “we’re getting a lot of ineffective, clinically meaningful, more expensive drugs on the market.”

Many of the estimated 100,000 US patients with primary biliary cholangitis – mostly women – had few other treatment options. And their testimony, at FDA meetings and online forums, helped win FDA approval of Ocaliva in 2016. Its list price is about $100,000 a year.

After Deborah Sobel’s sister Sarah Jane Kiley died of liver complications in 2006 at age 47, Sobel met with members of Congress and bankers to advocate for the drug and its maker, Intercept Pharmaceuticals. Although the trial required for accelerated approval was too small to show long-term improvement, the drug lowered alkaline phosphatase levels in many patients who could take it. For some, the side effects proved excessive.

Sobel, who also has the disease, started taking Ocaliva six years ago. In his last liver scan “it looked like I had reversed some of the damage,” said Sobel, 67, of Naperville, Illinois. “I can’t blame it on the drug, but I’m religious about taking it.”

Ocaliva’s profile is typical of the FDA’s expedited program. The drug ranked seventh in Medicare spending in 2019 — about $54 million — among products approved through the program, which began in 1992. That same year, Congress passed the Prescription Drug User Fee Act, or PDUFA, a law that committed the drug industry to pay. So-called user fees help fund the FDA’s drug approval process.

The fee has grown significantly, accounting for $2.9 billion of the agency’s $6.5 billion 2022 budget, including two-thirds of the drug regulation budget and at least 40% of the FDA’s 18,000 employees. In recent years companies have paid $2.5 million to $3 million to review each drug application.

In most cases, companies that receive expedited approval must submit additional data, after the drug goes to market, that proves it cures or successfully treats the disease.

It appears that some surrogate markers are better than others. Critics drew criticism after the agency approved Aduhelm for Alzheimer’s disease in 2021 based on the drug’s ability to dissolve clumps of amyloid plaques in the brain. Despite that evidence, most patients, who were in the early stages of Alzheimer’s, did not improve, and more than a third developed brain swelling, a frightening and painful side effect.

When it approved Ocaliva, the FDA required Intercept to conduct another trial to establish evidence of benefit. But the company stopped the trial in 2021, saying it was unable to enroll enough patients. At that point, the trial showed no clinical benefit for the drug’s patients. Now, Intercept is asking the FDA to accept a combination of evidence, which shows that patients taking the drug fared better than “external controls” — patients whose health records indicated they would be eligible for Ocaliva but didn’t take it.

The FDA already uses such “real-world evidence” for post-market safety reviews of drugs, vaccines and medical devices. But when it comes to drug approval, records collected for routine health care are often inaccurate and generally cannot replace the rigorous evidence of randomized controlled trials.

Niti is born impatient

Impatience — among drug companies, investors, patients and politicians — has led to user-fee agreements and accelerated-approval, and that impatience, for profits and cures, fuels both programs.

In the late 1980s and early 1990s, the FDA was under tremendous pressure. As AIDS wreaks havoc in the gay community, workers staged a symbolic sit-in at FDA headquarters, demanding approval of the new drug. Meanwhile, conservative groups, frustrated that approval could take three years or more, debated changing the FDA’s charter to put the drug on the market after a damning review. Democrats were generally skeptical of industrial user fees — and many still are. During a debate in June, Sen. Bernie Sanders (I-Vt.) said drug companies may be “charging an outrageous price” because much of the FDA’s regulatory budget “doesn’t come from taxpayers who want more access to prescription drugs, but from the pharmaceutical industry.”

The user fee came after then-FDA Commissioner David Kessler and industry leader Gerald Mosinghoff agreed that the agency would pay the fixed amount to modernize practices, hire more staff and set deadlines for its review.

The effect was immediate. AIDS drugs were the first significant breakthrough in 1995, turning HIV from a death sentence into a chronic but manageable disease.

One way to rapidly review user fees is to expand communication between industry members and the FDA. Before that, “getting a meeting with the FDA was quite challenging,” said Dr. John Jenkins, a senior agency official for 25 years and now an industry consultant. As of 2019, the FDA hosts more than 3,000 pharmaceutical industry meetings each year. This has dramatically changed how companies operate, he said, providing more certainty about whether they are collecting the data needed for FDA review.

Although FDA-regulated products account for about a fifth of every dollar spent by U.S. consumers, Congress has never shown the appetite to dramatically increase its budget, so user fee renewals must be passed every five years. This is their year. User fee agreements — one for each brand-name, generic, and over-the-counter drug, as well as for veterinary drugs, biologics, and medical devices — include new programs, changes to old ones, regulatory deadlines, and other items negotiated by FDA and industry. Congress tackles its priorities on the authorization bill

Fee agreements are negotiated behind closed doors — industry and FDA officials have met more than 100 times to prepare the 2022 agreements. At least two of the industry negotiators were former FDA officials, and the lead FDA negotiator, Dr. Peter Stein, was a Merck and Janssen veteran before coming to the FDA in 2016. Want to include a single change.

The bill stalled over the summer due to disagreements over generic drugs, lab tests, dietary supplements — and riders affecting accelerated approval. The final bill, part of a stopgap spending measure, stripped language that would have made it harder for expedited products to stay on the market if manufacturers failed to prove lasting value in a timely manner. Stephen Ubil, president of the industry trade group Pharmaceutical Research and Manufacturers of America, or PhRMA, called the slimmed-down bill “a win for patients, biopharmaceutical innovation and regulatory predictability.”

‘I feel split’

Ocaliva patients and doctors are generally grateful for the drug, although some physicians interviewed for this article said they would not prescribe it. The drug can seriously harm patients who already have cirrhosis of the liver and produce side effects such as severe itching. But some patients cannot tolerate, or fail to benefit from, the less expensive drug ursodiol, the other main treatment for primary biliary cholangitis. And some doctors who have studied Ocaliva believe the drug may slow liver damage.

“I’m divided on this,” said Dr. Renumathi Dhansekaran, assistant professor of gastroenterology and hepatology at Stanford University School of Medicine. “As a scientist, the accelerated approval process worries me, but as a physician treating patients with a very challenging disease, translating some of these drugs quickly into the clinic is exciting.”

Pending final approval of Ocaliva for primary biliary cholangitis, Intercept is seeking a broad, lucrative market for the drug: the roughly 13 million Americans who have nonalcoholic steatohepatitis, or NASH, a form of fatty liver disease. The only current treatment is radical weight loss. The FDA is expected to rule on that application in 2023.

Ocaliva and Aduhelm are far from the only accelerated approval drugs whose long-term effects remain uncertain. According to a 2019 study co-authored by Dr. Vishal Gawali, associate professor of medical oncology and public health at Queen’s University, only a fifth of cancer drugs approved through the platform kept people alive longer than other treatments they were tested against. in canada

The FDA’s cancer branch has sought to remove ineffective accelerated approval drugs from the market and said it may begin requiring drugmakers to begin confirmatory testing before receiving accelerated approval for their products. But for now, many drugs with uncertain survival benefits remain on the market. Ibrance, an oral breast cancer drug that has brought Pfizer nearly $5 billion in annual revenue in recent years, falls into this category.

The FDA approved Ebrens for breast cancer in 2015 after a study showed it slowed tumor progression for a full year longer than aromatase inhibitors, then the standard of care. Although Pfizer won final approval through a definitive trial, the reduced tumor growth apparently did not translate to longer survival for Ebren’s patients, subsequent studies indicated.

Still, as new cancer drugs continue to hit the market, it makes sense for the FDA to approve promising new drugs even as their benefits grow, said Dr. Matthew Goetz, a breast cancer specialist at the Mayo Clinic.

“We were all excited when Ibrance came out,” he said. “It was an oral drug, very well tolerated and stopped before a patient needed chemotherapy.”

Giawali, another breast cancer specialist, said he has treated his patients with Ebrance. “Many oncologists would agree that this is a good tool to have in their toolbox.”

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