Multiple product indications withdrawn, FDA accelerated Approval How to reform?

When accelerated approval is no longer accelerated, and indications on the "shortcut" path are constantly withdrawn, AA path reform is imperative? !

Two more blockbuster indications have been withdrawn

Johnson & Johnson and partner AbbVie announced that it will voluntarily withdraw two indications for accelerated ibutinib approval: in patients with mantle cell lymphoma (MCL) who have received at least one previous regimen, and in patients with marginal area lymphoma (MZL) who have received one previous anti-CD20 regimen.

As the first marketed product of BTK, ibrutinib received accelerated approval from FDA in 2013 for the treatment of MCL indications. In 2017, ibrutinib received accelerated FDA approval for the treatment of MZL indications.

After Ibrutinib was launched, sales shot up. According to Johnson & Johnson's 2016 financial report, three years after its launch, Ibrutinib's annual sales increased from $200 million in 2014 to $1.251 billion, becoming a new growth point for Johnson & Johnson.

However, the confirmatory clinical data of ibrutinib did not meet expectations after it was marketed through accelerated review. The Phase III trial, called SHINE, evaluated ibrutinib in patients with MCL.

Although the primary endpoint of progression-free survival (PFS) was achieved, ibrutinib was associated with significant side effects compared to placebo. The results showed that at a median follow-up of 84.7 months, the median PFS was 80.6 months in the Ibrutinib group and 52.9 months in the placebo group. However, due to the greater side effects of ibrutinib, which affected OS, the 7-year OS of the Ibrutinib group was 55% lower than that of the placebo group (56.8%).

In SELENE, the Phase III trial evaluating an indication for MZL, ibrutinib did not meet the primary endpoint of PFS.

As the FDA tightened its oversight of the accelerated approval process, Ibritinib had to withdraw two indications that had been approved through the AA route.

Similarly, CovisPharma recently withdrew Makena, its drug for premature births, at the FDA's request. Makena initially received accelerated FDA approval based on a clinical trial called Meis. The study, which included 463 women with a history of spontaneous preterm birth, showed that hydroxyprogesterone caproate, the active ingredient in Makena, reduced the risk of recurrent preterm birth.

However, the neonatal outcome endpoint was included in the confirmatory post-marketing trial to PROLONG the clinical benefit of Makena in neonates. The results did not prove that Makena had an effect on the surrogate endpoint of preterm birth, neonatal outcome. In the end, all 15 experts voted against the Makena confirmatory trial on the benefits of neonatal morbidity and mortality from preterm complications.

In another core discussion, whether the available evidence suggests that Makena is effective in an approved indication to reduce the risk of preterm delivery in women with single pregnancies who have a history of spontaneous preterm delivery, 13 experts dissented, with the remaining two voting in favor or abstaining.

Makena received accelerated FDA approval in 2011, but CovisPharma did not submit confirmatory Phase III data to the FDA until eight years later. And the FDA didn't recommend revoking the accelerated approval until 2020 after the PROLONG results were announced, and didn't hold a hearing until late 2022.

In fact, in recent years, in addition to ibutinib and Makena, there are many drug indications required to be withdrawn by FDA. For example, in 2022, FDA successively withdrew three PARP inhibitors, Rucaparib, olaparib and nilaparib, in four indications of ovarian cancer...

This tortuous long process all exposed the AA approach of institutional shortcomings. To break this problem, the FDA has also reformed its expedited approval system.

AA path reform is imperative

In 1992, in response to the HIV-AIDS crisis, the FDA created the acceleratedapproval (AA) pathway, which is designed to speed much-needed drugs to market.

Based on this pathway, drugs to be approved can rely on alternative endpoints rather than necessarily clinically significant endpoints such as overall survival (OS), allowing for faster results than traditional clinical trial endpoints.

According to FDA regulations, AA-approved drugs must be shown to improve survival benefits in confirmatory clinical trials before they can be fully approved, or face the possibility of withdrawal.

Since the establishment of the AA pathway, it has played an important role in global drug development. However, in the later development process, the AA path also deviated from its original intention to some extent.

According to the British Medical Journal, up to 44 percent of the 253 drugs approved under the AA pathway have not yet been shown to be clinically effective. In a study published in JAMA Internal Medicine, only 19 of 93 cancer drug indications for accelerated FDA approval from 1992 to 2017 demonstrated improved patient OS in validation trials.

Based on the above data, the American industry has been constantly calling for AA reform. Especially in June 2021, when Aduhelm, a new drug for the treatment of Alzheimer's disease, was approved through AA pathway, the industry insiders' doubts on AA pathway reached a peak. Under heavy pressure, FDA began to reform the AA path.

In what areas will the reform take place?

FDA Commissioner RobertCaliff has said that he will require drug companies to provide the scientific evidence needed to expedite drug approvals, in response to the FDA's slowness in withdrawing drugs that have been shown to be ineffective.

At the same time, the director of the FDA's Center for Drug Review and Research said the agency needs more authority to quickly withdraw accelerated approvals. With regard to recommendations on how to improve fast-track approval, the industry had suggested that the FDA should make it a condition of expedited approval to finalize confirmatory trials, which would automatically trigger a decision to withdraw the drug from the market if the confirmatory trial failed.

Future changes to the FDA's accelerated approval process are likely to be largely modeled on similar processes used by regulators in the European Union, the United Kingdom, Switzerland and other countries.

One direction of reform may be to impose a deadline on the completion of confirmatory trials to ensure that companies complete them as soon as possible; Another direction could be the conditions under which drugs are allowed to enter the accelerated approval process, such as in the European Union, Switzerland, the United Kingdom, etc., where only new molecules are allowed to receive accelerated approval.

In March, the FDA also issued draft Clinical Design Guidelines for Accelerated Approval of Oncology Drugs, which emphasized that randomized controlled trials are the gold standard for accelerated approval, while single-arm trials will be used only in certain circumstances. The agency also requires companies to conduct confirmatory clinical trials while submitting drugs for accelerated approval.

For example, if two RCTS are designed to support accelerated approval, one can use an early endpoint (such as response rate) to support accelerated approval and the other a long-term endpoint (such as survival) to confirm clinical benefit, but the second confirmatory trial needs to be conducted at the time of submission of the accelerated approval, preferably with enrollment completed.

When single-arm clinical trials are used to support accelerated approval, higher requirements are put forward for the end points of single-arm clinical trials. If new alternative end points are used, strong mechanism should be supported, and the clinical end points should be consistent with the label after product approval.

For confirmatory trials after accelerated approval, it is strictly required to verify clinical benefits through confirmatory trials after expedited approval, which should be initiated prior to approval and fully communicated with FDA in advance.

summary

Since its inception in 1992, the accelerated approval path has helped advance the release of a number of innovative drugs, providing immediate relief to patients in dire need.

Among the new drugs approved by the Center for Drug Evaluation and Research (CDER) of the FDA from 2018 to 2020, 7 percent (2018), 19 percent (2019), and 23 percent (2020) received accelerated approval, respectively.

However, due to the slack of enterprises, the development of medical level, and the difficulty of patient recruitment, confirmatory clinical trials cannot be completed on time to verify the efficacy of drugs.

Ineffective drugs on the market are not only bad for patients, but also waste health insurance funds. So just as important to the FDA as speed to market is speed to delisting.

Reference:

1. "BTK Inhibitor Changes: Johnson & Johnson falls, Beigene is Full", Pharmaceutical Investment Tribe, 2023-04-08;

2.Failed cancer immunotherapies cost Medicare hundreds of millions. How should FDA revamp accelerated approvals?

3.https://www.regulations.gov/comment/FDA-2020-N-2029-0381

https://covispharma.com/index.php/covis-pharma-reports-on-fda-advisory-committee-hearing-for-makena/.

4.Modernising the US FDA's Accelerated Approval pathway. Lancet Oncology. 2023 Mar; 24(3): 203-205. doi: 10.1016/S1470-2045(23)00020-7.