CMS spends big on unproven drugs ...
... after Big Pharma companies fail to complete confirmatory trials for meds given accelerated approval
Thirty years ago, Congress gave the Food and Drug Administration the authority to approve new drugs based on clinical trials showing they were “reasonably likely” to be effective. The goal of the so-called accelerated approval program was to give patients faster access to innovative and potentially life-saving drugs.
A simple example. Short-term trials for a new cancer chemotherapy drug shows it shrinks tumors. Tumor shrinkage under the accelerated approval regulatory scheme is considered a surrogate marker, a measurable result that is reasonably likely to predict the desired outcome, which is longer life.
There was a catch, of course. The pharmaceutical companies using the accelerated approval pathway had to conduct a follow-up trial, which often takes two years or more, to prove the drug actually produced better outcomes.
Several studies in recent years have shown drug companies using the accelerated approval pathway routinely fail to conduct the follow-up trials. A disheartening high number of the trials that are completed used the same or different surrogate markers and not the required outcomes endpoint.
For instance, a review in JAMA Internal Medicine of 93 cancer drugs approved under accelerated approval between 1992 and 2017 revealed only 20% of their manufacturers completed the required follow-up trials confirming the drug actually benefited patients. When those trials were done, the benefits often amounted to just two or three months of additional life.
Moreover, in a direct violation of the spirit of the program, over 40% of the follow-up trials submitted to the FDA used either the same or different surrogate markers. And, worst of all, one out of every four drugs given accelerated approval failed to complete the required post-approval trials.
For a large majority of drugs given accelerated approval, therefore, physicians are still in the dark as to what their patients could expect from taking the drugs. “Until the requirements to transition from accelerated approval to regular approval are met, the clinical community will have less information about the risks and benefits of drugs approved by the accelerated approval program,” the authors concluded.
That didn’t stop the FDA from declaring the program a big success. The regulatory agency, then under Trump-appointee Dr. Scott Gottlieb, pointed to the fact only five drugs had either been withdrawn or had their accelerated approvals revoked under the program. Most were converted to standard approvals based on the limited evidence provided in the follow-up trials, which more often than not involved another surrogate marker.
Accelerated approval has been used most often in oncology, where patients are desperate for anything that might allow them to live longer. Several of the top-selling cancer drugs that have been heavily advertised in recent years have had their initial approvals come under the program.
Now, a new study in JAMA Health Forum shows how costly that has been for taxpayers, who foot a disproportionate share of the bill for cancer chemotherapy. The researchers found the Centers for Medicare and Medicaid Services spent $68 billion on 38 drugs given accelerated approval between 2012 and 2017, with the government spending over $40 billion or 59% of the total on drugs whose manufacturers never completed confirmatory outcomes trials.
Hail Mary prescribing
The two most costly drugs without confirmatory trials for many of their indications were Bristol Myers Squibb’s Opdivo (nivolumab) and Merck’s Keytruda (pembrolizumab). Each company tapped CMS’ coffers for more than $2 billion. These targeted immunotherapy drugs, greeted with great fanfare a decade ago, cause severe side effects (they mobilize the body’s immune system to attack not just the cancer but normal bodily functions) and are wildly overpriced given the limited life extension benefits for the few indications where outcomes follow-up trials were completed.
Keytruda “has been seen as a Hail Mary for all these other indications with so much hope tied to it. So many patients of mine have been on it,” said study co-author Dr. Reshma Ramachandran, a primary care physician and a post-doctoral fellow at the Yale School of Medicine. “It’s always striking that when I’m counseling patients about this drug, and you look at the body of evidence the FDA has and what’s publicly available, there’s still uncertainty about the benefits.
“It’s very difficult to tell my patients that,” she said. “The striking thing for me is the FDA isn’t demanding manufacturers do the studies that document the actual benefit.”
The study’s lead author, Dr. Joshua Skydel of Dartmouth-Hitchcock Medical Center in Lebanon, N.H., said a follow-up clinical trial for Opdivo that matched the FDA’s request wasn’t even listed in ClinicalTrials.gov, the government’s database. “We don’t know if the trial is delayed, or is still enrolling patients,” he said. “We couldn’t find one for it.”
There’s a small chance that could change if Congress moves to address the high cost of drugs in a slimmed down Build Back Better bill, which Sen. Joe Manchin of West Virginia said this week was back on the table. The Senate HELP Committee (Health, Education, Labor and Pensions) is considering adding FDA reforms to the bill.
Dr. Ramachandran, who chairs the Doctors for America FDA Task Force, last week sent a letter from 14 organizations and 19 physician and public health researchers asking the HELP committee to include revamping the accelerated approval program in the legislation. They want the FDA to require clinical trials confirming clinical benefit already be underway when granting accelerated approval. They say the FDA should automatically withdraw approval if those trials are not completed within five years of approval.
They also want the FDA to impose penalties on drug manufacturers that fail to enroll diverse populations in all their clinical trials, including the confirmatory trials conducted after accelerated approval.
Here’s hoping the Democrats in the Senate can get their act together. Congress before open enrollment begins this fall also needs to renew the expanded subsidies that enabled an additional 2 million people to sign up for individual health insurance plans under Obamacare. Failure to get at least that much done will deal a major health and economic blow to an already demoralized Democratic Party base.