\n\tArthur Allen<\/span><\/p>\n

Dr. Steven-Huy Han, a UCLA liver specialist, has prescribed Ocaliva to a handful of patients, although he\u2019s not sure it helps.<\/p>\n

As advertised, the drug is lowering levels of an enzyme called alkaline phosphatase in their blood, and that should be a sign of healing for their autoimmune disease, called primary biliary cholangitis. But \u201cno one knows for sure,\u201d Han said, whether less enzyme means they won\u2019t get liver cancer or cirrhosis in the long run.<\/p>\n

\u201cI have no idea if the drug will make them better,\u201d he said. \u201cIt could take 10, 20, or 30 years to know.\u201d<\/p>\n

Ocaliva came to market through an FDA review process created 30 years ago called accelerated approval, which allows pharmaceutical companies to license promising treatments without proving they are effective. It has become a common path to market \u2014 accounting for 14 of the 50 approvals of novel drugs<\/a> in 2021 compared with four among 59 in 2018, for example.<\/p>\n

The FDA\u2019s accelerated approval is usually based on a \u201csurrogate marker\u201d of effectiveness \u2014 evidence of lower viral loads for HIV, for example, or shrinking tumors for cancer. Debate rages over the validity of some of these stand-ins, and some of the drugs.<\/p>\n

\u201cIf you\u2019ve got a game-changing drug that truly is going to make a difference, you don\u2019t need surrogate markers to prove that. If it\u2019s effective, patients will survive longer,\u201d said Dr. Aaron Mitchell, an oncologist at Memorial Sloan Kettering Cancer Center. The shortened approval process, he said, is one reason \u201cwe are getting a lot of marginally effective, not clinically meaningful, more expensive drugs on the market.\u201d<\/p>\n

Many of the estimated 100,000 U.S. patients with primary biliary cholangitis \u2014 most are women \u2014 had few other treatment options. And their testimony, at FDA meetings and in online forums, helped boost Ocaliva to FDA approval in 2016. Its list price is about $100,000 a year.<\/p>\n

After Deborah Sobel\u2019s sister Sarah Jane Kiley died of liver complications in 2006 at age 47, Sobel met with members of Congress and bankers to urge support for the drug and its maker, Intercept Pharmaceuticals. Although the trial required for accelerated approval was too short to show long-term improvement, the drug lowered alkaline phosphatase levels in many patients who could tolerate taking it. For some, the side effects proved too much.<\/p>\n

Sobel, who also has the disease, began taking Ocaliva six years ago. Her last liver scan \u201clooked like I had rolled back some of the damage,\u201d said Sobel, 67, of Naperville, Illinois. \u201cI can\u2019t attribute that to the drug, but I\u2019m religious about taking it.\u201d<\/p>\n

Ocaliva\u2019s profile is typical for the FDA\u2019s accelerated program. In 2019 the drug ranked seventh<\/a> in Medicare spending \u2014 about $54 million \u2014 among products approved through the program, which launched in 1992. That same year, Congress passed the Prescription Drug User Fee Act, or PDUFA, a law committing the drug industry to pay so-called user fees to help fund the FDA\u2019s drug approval process.<\/p>\n

The fees have steadily swollen in importance, accounting for $2.9 billion of the agency\u2019s $6.5 billion 2022 budget<\/a>, including two-thirds of the drug regulation budget, and the work of at least 40% of the FDA\u2019s 18,000 employees. Companies in recent years have paid between $2.5 million and $3 million<\/a> to have each drug application reviewed.<\/p>\n

In most cases, companies that win accelerated approval must submit additional data, after the drug goes to market, that proves it cures or successfully treats the disease.<\/p>\n

It turns out that some surrogate markers are better than others. Critics lashed out<\/a> at the agency in 2021 after it approved Aduhelm for Alzheimer\u2019s disease based on the drug\u2019s capacity to dissolve clumps of amyloid plaques in the brain. Despite that evidence, most patients, who were in the earliest stages of Alzheimer\u2019s, didn\u2019t get better, and over a third suffered brain swelling<\/a>, a frightening and painful side effect.<\/p>\n

When it approved Ocaliva, the FDA required Intercept to conduct another trial to produce evidence of its benefit. But the company in 2021 stopped the trial<\/a>, saying it was unable to enroll enough patients. To that point, the trial had shown no clinical benefit for patients on the drug. Now, Intercept is asking the FDA to accept a combination of evidence, including studies that it says show patients taking the drug fared better than \u201cexternal controls\u201d \u2014 patients whose health records indicate they would have qualified for Ocaliva<\/a> but did not receive it.<\/p>\n

The FDA already uses such \u201creal-world evidence\u201d for post-market reviews of the safety of drugs, vaccines, and medical devices. But when it comes to drug approvals, records collected for routine health care are often erroneous and usually can\u2019t replace<\/a> the rigorous evidence of randomized controlled trials.<\/p>\n

Policy Born of Impatience<\/strong><\/p>\n