Federal and state officials and advisers are putting more pressure on pharmaceutical companies to prove that medicines that are put on the market through accelerated approval do deliver meaningful benefits for patients.
One proposal is to reduce Medicaid payment for drugs that have received accelerated approval until they have been proven to be of clinical benefit, at which point payment would be increased.
A case in point is the drug for Alzheimer’s disease, amoxicillin cause herpes outbreak aducanumab (Aduhelm), the recent approval of which caused a furor over the summer months.
The US Food and Drug Administration (FDA) granted the drug an accelerated approval despite the recommendation against such a move by its own advisory committee, which was concerned because evidence of efficacy was very slim and there was real evidence of toxicity.
The uproar that followed has triggered federal and congressional investigations into the agency’s approval processes.
The Medicare program is taking the rare step of setting a national policy for aducanumab coverage.
The Centers for Medicare & Medicaid Services (CMS) is mulling over what coverage to offer for this particular drug. In comments submitted to CMS before an August 11 deadline, some people asked for access to the drug. But many physicians emphasized the persisting doubts about efficacy, and some have warned about the repercussions.
“Imagine the disgust and discredit that will flow to the medical profession and CMS if tens of billions of dollars are spent on a treatment that is not significantly effective,”
wrote James Mittelberger, MD, MPH, a geriatrician with 35 years’ experience treating patients with dementia.
“Yes, people want hope and new treatments, but we are not doing good by offering ineffective treatments for fatal conditions,” he added.
These comments echo many that have been made in recent years about cancer drugs that were granted accelerated approvals but that failed to improve overall survival of patients. These concerns were outlined, for example, in the recent Medscape commentary, FDA’s Accelerated Approval Pathway Is Broken.
A High-Stakes Bet
With accelerated approvals, the FDA essentially makes a high-stakes bet on early data.
These clearances allow more patients to take as-yet unproven medicines, usually to treat a fatal or serious condition, while companies continue to try to prove their benefits.
Sometimes it becomes clear pretty quickly that the gamble has paid off.
For example, it took only a year to show benefit with sacituzumab govitecan (Trodelvy).
The initial accelerated approval in April 2020 for use in metastatic triple-negative breast cancer was based on response data, but in April 2021, the FDA granted full approval on the basis of data from the ASCENT trial, which showed an overall survival benefit in comparison with treatment with single-agent chemotherapy. (More details of this are provided in a Medscape Oncology Decision Point.)
However, sometimes the FDA’s regulatory gambles fails.
It took about 3 years for the FDA to learn it made a bad bet on olaratumab (Lartruvo).
The drug was granted an accelerated approval for a certain type of sarcoma in 2016. At that time, the agency set a 2019 deadline for the completion of a confirmatory trial. However, this trial failed to show the expected benefit, and the company withdrew the product.
While it was on the market, olaratumab cost about $106,100 for 6 months of treatment. US patients had been the primary market for olaratumab, accounting for 63% of the product’s $304.7 million in revenue in 2018, its last full year on the market.
This was “a significant sum for a product that ultimately failed to benefit patients,” noted Steven Pearson, MD, president of the nonprofit Institute for Clinical and Economic Review (ICER), and co-authors in an April 2021 report.
In the case of olaratumab, the confirmatory trial was completed by the FDA’s deadline, so Lilly’s promptness prevented more patients from taking a drug that didn’t work.
But since the FDA began the accelerated approvals program in 1992, many companies have blown deadlines to deliver confirmatory results.
FDA Still Waiting for Confirmatory Data
Before the uproar this summer over aducanumab, the most controversial accelerated approval had been that of eteplirsen injection (Exondys 51) in 2016. This drug is used for a form of Duchenne muscular dystrophy (DMD). The drug can cost about $1 million per year for each patient.
The road to approval for eteplirsen was rocky, as Medscape Medical News reported at the time. As with aducanumab, the agency’s own advisory committee did not recommend approval. The committee concluded that the company had failed to provide persuasive evidence that the drug is effective in DMD.
In announcing the FDA’s 2016 clearance of Exondys, Janet Woodcock, MD, then director of the agency’s Center for Drug Evaluation and Research, said: “Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval.”
Woodcock, now the acting FDA commissioner, has still not received those data.
In its approval letter, the FDA gave the company a 2020 deadline to complete a confirmatory trial. The final report is due in 2021.
The required postmarketing study is currently scheduled for completion in 2026, a Sarepta spokesperson told Medscape Medical News. The spokesperson explained thatit took extra time for the company to determine the design and dose for the postmarketing study. The FDA and the company remain in discussion during the delay.
The FDA has taken no action against the company for these delays.
The FDA has granted accelerated approvals for two more Sarepta drugs for DMD, golodirsen injection (Vyondys 53), which was granted approval in 2019, and casimersen injection (“Amondys 45), approved in 2021.
These drugs are hugely expensive. Sarepta received $456 million in revenue last year while selling three products under accelerated approvals. All the drugs are for treatment of a rare muscle disorder.
This case should serve as “a cautionary tale,” comment Pearson and co-authors in their report, which takes an in-depth look at the FDA’s accelerated approval process.
In most cases, companies deliver evidence needed to upgrade these conditional clearances to full approval “within a reasonable timeframe,” often about 3 years, they found.
But there are serious concerns about cases in which these confirmatory trials have long been delayed. There are also several cases in which accelerated approvals remain in place after further studies fail to confirm a significant benefit for patients, they note.
“Ultimately, these concerns reflect a central risk: that patients will be harmed by having
their care diverted towards drugs that do not help them and that contribute to health care cost escalation that itself causes patient harm,” Pearson and co-authors warn.
Reduced Payments Until Clinical Efficacy Is Proven
The proposal for reduced payments for a drug with an accelerated approval comes from the Medicaid and the Children’s Health Insurance Program Payment and Access Commission (MACPAC).
In its June report to Congress, MACPAC recommended allowing a larger minimum rebate for drugs until an accelerated approval is converted to a full one after clinical efficacy has been proven, at which time the rebate would be increased.
Once the FDA grants the full approval for a medicine, the Medicaid rebate could be reduced to the usual level, providing more money for drugmakers.
MACPAC did not offer a specific amount by which the rebate should be increased. This would be decided by Congress. But the commission did include an estimate from the Congressional Budget Office that such a policy change could save the federal government $1 billion over 5 years.
Building off the MACPAC report, researchers with the Kaiser Family Foundation evaluated how increased rebates might apply to aducanumab, the recently approved drug for Alzheimer’s.
Biogen is planning to charge about $56,000 per patient for a year of treatment.
Under current law, the usual 23.1% Medicaid base rebate for brand drugs would reduce the annual net price for this product to about $43,000.
But if the Medicaid base rebate were to increase to 33.1%, the base rebate would be reduced to $37,000, the group estimated.
It’s unclear what Congress will do regarding MACPAC’s recommendation.
The pharmaceutical companies’ trade body had strongly objected.
“Advancing this misguided approach will have significant, negative effects on the ability to bring innovative, complex medicines to market and negatively impact patients,” Andrew Powaleny, spokesperson for Pharmaceutical Research and Manufacturers of America, told Medscape Medical News.
There was also some criticism of the rebate proposal from a MACPAC member.
MACPAC voted 16-1 in April in favor of this recommendation to Congress.
The dissenting vote was cast by Thomas Barker, JD, a MACPAC commissioner who is a partner at the law firm Foley Hoag.
“If there is a problem with the accelerated approval process with the FDA, then that’s a problem for the FDA to solve,” Barker said at an April meeting in which the proposal was discussed. He added that Congress could also get involved if lawmakers felt drugmakers were shirking on their responsibilities to complete confirmatory trials.
His fellow commissioners disagreed. They described the proposed rebate increase as a way to assist the FDA in getting drugmakers to complete confirmatory trials.
“I’m not sure what tools the FDA would be able to use short of not approving an accelerated approval drug or withdrawing approval for such a drug,” said MACPAC Commissioner William Scanlon, PhD.
He noted that the FDA’s accelerated approval pathway is intended to balance the risk of uncertainty about whether these drugs work against their perceived potential to aid patients.
“With that sort of balancing, a part of that responsibility is to move as quickly as possible to get the necessary information to make a final sort of determination” about a drug’s worth, Scanlon said.
Battles After Failed Trials
For many years, Congress’ message to the FDA has been to approve drugs faster, as is evident in laws such as the 21st Century Cures Act. There’s been less emphasis on the need for the FDA to make sure drugmakers deliver on their end of the bargain regarding accelerated approvals and the completion of confirmatory trials.
This is evident in how the FDA informs the public about its accelerated approvals.
The FDA’s biannual public reports on accelerated approvals include information as to the total time it takes for the agency to consider and complete this process.
But the agency does not provide information on the deadline for confirmatory trials, nor does it provide information about cases in which trials have been delayed or have failed. In the biannual report, a chart notes cases in which approval has been withdrawn, but the FDA does not inform the public about cases in which the agency has reason to doubt whether an accelerated approval should remain in place.
When a drug fails to produce the expected benefit, there can be a stalemate.
For example, the FDA is in the midst of a battle to withdraw the accelerated approval for the hydroxyprogesterone caproate (17P) injection (Makena), a drug intended to prevent preterm birth.
On the FDA’s chart, the status of this approval is listed as “not yet converted.”
This product was granted an accelerated approval in 2011.
The confirmatory PROLONG trial of Makena did not show improvement in the health of the babies born to mothers who were treated with the drug, the FDA said. This trial also failed to show a reduced risk for preterm birth with Makena, contradicting the findings of the original trial upon which the accelerated approval was based.
In 2019, an FDA advisory committee voted to recommend withdrawing this medicine.
In 2020, the FDA proposed the withdrawal of this drug from the market.
But Covis, which now owns the branded version of this drug, objected and requested a public hearing. The agency agreed to a hearing, but no date has been set.
The American College of Obstetricians and Gynecologists (ACOG) said it is watching the FDA’s proceedings on Makena closely.
After the FDA proposed withdrawing the product, ACOG issued a statement in which it emphasized that current guidelines recommend the use of progesterone supplementation by women with prior spontaneous preterm birth.
“Consideration for offering 17-OHPC to women at risk of recurrent preterm birth should continue to take into account the body of evidence for progesterone supplementation, the values and preferences of the pregnant woman and the resources available,” ACOG said in a statement.
Evolving Science in Oncology
Oncology has been a particularly active field for the FDA in terms of accelerated approvals. Advances in drug development, particularly in the field of immune checkpoint inhibitors, have led to numerous approvals for various cancer indications for this class of medicines, so much so that they skew the agency’s statistics.
The FDA’s tally says that since 1992, it has granted 269 accelerated approvals.
But more than 40 of the approvals listed on the chart are for various cancer indications for two immunotherapies, pembrolizumab (Keytruda) and nivolumab(Opdivo).
Many of these accelerated approvals for cancer indications are controversial, inasmuch as they are based on response rate data from early clinical trials. In subsequent trials, some of these drugs fail to show clinical benefit, such as an improvement in overall survival.
The FDA referred to these accelerated approvals as “dangling.” The agency convened a historic 3-day meeting in April to discuss the issue.
It may soon be easier to spot those cancer drugs that received accelerated approvals but for which confirmatory trials have been delayed or showed poor results.
The FDA Oncology Center of Excellence (OCE) and the Office of Oncologic Diseases are developing a web page that would provide a list of ongoing accelerated approvals for oncology drugs. The website would provide projected postmarketing commitment completion dates and clinical trial information, an OCE spokesperson told Medscape Medical News.
This scrutiny of accelerated approvals for cancer drugs is sorely needed, argues oncologist Bishal Gyawali, MD, and colleagues in a recent article in The BJM.
They cited 18 indications for 10 cancer drugs that received accelerated approval but that failed to improve the primary endpoint in post-approval trials.
Of these, six indications (33%) remain approved. Eleven were voluntarily withdrawn, and one indication, for bevacizumab (Avastin, for use in breast cancer), was revoked by the FDA.
Gyawali and colleagues found that in some cases, clinical practice guidelines continue to endorse certain uses of drugs after confirmatory trials yield negative results. They also noted that drugs that received accelerated approval drugs but that yielded negative results in confirmatory trials were given a second chance in another confirmatory trial while the accelerated approval indication remained in the drug’s labeling.
“The FDA should take actions to assure that risks and benefits are clearly communicated to patients and their physicians, including the fact that some of the approvals remain on the label despite the negative results from the confirmatory trials,” they concluded.
Kerry Dooley Young is a freelance journalist based in Washington, DC. She is the core topic leader on patient safety issues for the Association of Health Care Journalists. Young earlier covered health policy and the federal budget for Congressional Quarterly/CQ Roll Call and the pharmaceutical industry and the Food and Drug Administration for Bloomberg. Follow her on Twitter at @kdooleyyoung.
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