In 2021 cancer researchers celebrated the 50th anniversary of the National Cancer Act, which opened the door to decades of progress and advances in cancer research. Today, we’re two years shy of the 75th anniversary of the approval of the first chemotherapy drug. As we mark these milestones, it’s important to reflect on more recent progress in the evolution of oncology treatments.
The last several years of innovation have been driven by biopharma’s increased energy and focus on bringing new drug and expanded indication launches to market. The 2017 opening of the Food and Drug Administration’s (FDA’s) Oncology Center for Excellence (OCE), which was part of the Cancer Moonshot Initiative, helped coordinate development activities and hasten drug approvals. Even the challenges of the pandemic have not thwarted momentum in driving more oncology drug approvals forward. In 2021 there were 80 approvals alone, including a mix of new molecular entities, 505b2 pathway approvals and supplemental approvals into expanded indications for existing entities.
The accelerated approval process has helped drive this innovation. Nearly 85% of accelerated approvals in the last 10 years were for oncology products, and they were largely reliant on the promise of interim readouts on surrogate endpoints. Accelerated approvals are typically based on earlier endpoints or surrogate endpoints, such as duration of remission (DOR) or progression-free survival (PFS). However, we believe the market may soon experience increased or additional barriers to accelerated approvals, judging from recent announcements of rescinded approvals and the withdrawal of products from the market due to insufficient evidence in confirmatory trials. Further, this could also suggest that a product’s success in gaining accelerated approval will not be sufficient in predicting its value and success in the market.
In the PD-1/PD-L1 space, the volume of accelerated approvals has prompted the OCE to take a closer look at them. While the trials in the PD-1/PD-L1 space did not verify a confirmed clinical benefit, marketing authorization was allowed to continue in a phenomenon known as “dangling” accelerated approvals. According to the FDA, the term dangling accelerated approval describes approvals for which confirmatory trials did not verify clinical benefit, but for which marketing authorization is ongoing.
We anticipate dangling approvals to meet greater scrutiny given the specific aim of the OCE’s Project Confirm, which was launched to address the issue of dangling approvals and create transparency of outcomes in accelerated approvals. Prior to 2020, only six accelerated approvals in oncology were withdrawn. However, since 2020 and the launch of Project Confirm, 13 additional approvals have been withdrawn with eight of those 13 being checkpoint inhibitors.
More recently, three anti-PD-L1 checkpoint inhibitors for six indications were scrutinized over accelerated approval for not showing benefit in confirmatory studies (Keytruda, Opdivo and Tecentriq). Ultimately four remained on the market, while two were revoked, including Keytruda for third-line stomach cancer and Opdivo in hepatocellular carcinoma. We can expect this to become the new normal as the FDA continues to review more dangling approvals and as the bar for demonstrating benefit becomes higher.
The oncology drug innovation boom has made manufacturers more competitive and eager to tell a differentiation story that providers will find compelling. In some cases that means looking beyond clinical benefits to persuasive pricing and dosing strategies, or product enhancements like subcutaneous administration. Yet another challenge manufacturers face is launching in more competitive spaces. This is particularly challenging when they have sought accelerated approvals to demonstrate incremental benefit beyond existing options or standard of care to warrant longer term marketing.
In the past, a “more is better” approach was the norm for assessing dosing for cancer products in clinical trials. This typically manifested in the form of dosing studies to identify the maximum tolerable dose and focused on healthier patients who fit the profile of patients enrolled in phase III clinical trials. But experts agree that this practice is hardly the best approach because it can result in the overtreatment of patients who will be on these drugs for months, or even years.
In 2021 the FDA launched Project Optimus, a multi-stakeholder initiative to create formal guidelines for oncology drug development and dosing requirements. Formal guidance for the project hasn’t been released yet, but we have begun to see the impact of this program in early FDA conversations around trial design, especially for trials actively in development. We’ve heard from clients that have been required to add dosing studies, which significantly delays progress on current trials.
While the expected effect on phase III studies in the future isn’t likely to change, pharmaceutical companies can expect to see guidance on post-marketing dosing studies for in-market products and indications. There are already examples of products where post-marketing studies led to updated dosing guidance, with Niraparib being most notable.
Until more recently, the FDA has supported the use of data from single-arm trial data to support accelerated approval. However, Julia A. Beaver, MD, and Richard Pazdur, MD, of the OCE warned drug sponsors the FDA would no longer look favorably on immune checkpoint inhibitor (ICI) approval applications based on data from single-arm clinical trials in patients with refractory disease. Roughly 45%of the indications for PD-1/PD-L1 ICIs have been approved through the accelerated approval pathway based on data from single-arm trials. Many of these trials used overall response rate (ORR) to predict clinical benefit. But, according to Beaver and Pazdur, clinical trials have shown that initial ORRs for this class of ICIs do not consistently predict long-term outcomes.
Additionally, on April 21, 2022, the FDA’s oncologic drug advisory committee (ODAC) published a briefing document challenging the paradigm of basing accelerated approvals of phosphatidylinositol-3-kinase (PI3K) inhibitors on single-arm trials. In the brief, ODAC concluded, “The experience with the PI3K inhibitors in hematologic malignancies illustrates challenges with the current paradigm of using ORR in single-arm trials to support initial approval.”
Without a control arm, attributing adverse events (AEs) to either the drug or underlying disease becomes difficult. Randomized trials are the most effective method to allow for assessment of AE attribution, PFS and overall survival.
For the time being, it seems that the FDA will still accept single-arm studies, but the burden for showing safety and efficacy is increasing. At the American Society of Clinical Oncology 2022 conference, Padzur recommended that drug sponsors have a confirmatory trial when applying for accelerated approval. Additionally, they should have randomized trials in earlier phases of clinical development.
In the first half of 2022, the FDA gave biopharma companies greater clarity on the need for more robust bridging data when conducting single-country studies. The FDA recently sent a complete response letter (CRL) to Hutchmed stating that their current new drug application, based on two positive phase III trials in China and one bridging study in the U.S., does not support an approval in the U.S. at this time. The CRL indicated that a multi-regional clinical trial will be required for U.S. approval despite Hutchmed’s bridging study with 16 patients in each disease subset. That study showed relatively similar responses as their phase III trial in China.
On March 24, 2022, Eli Lilly and Innovent Biologics announced that the FDA issued a CRL for their biologics license applications for Sintilimab. The FDA took issue with the data provided and asked for an additional multi-regional clinical trial.
According to a Reuters report, the FDA said there were at least 25 applications from China in drug development phases, planned for submission or already under review by the FDA that were predominantly or solely based on trial data from China. Pazdur told the panel that single-country submission is a step backward in achieving the racial diversity needed in the U.S., according to Reuters.
Coherus BioSciences and Chinese partner Shanghai Junshi Biosciences announced on May 2, 2022, that the FDA issued a CRL that indicated flexibility with respect to the sufficiency of single-country clinical data on its drug because there are no approved treatment options currently in the U.S. For both the Hutchmed and Shanghai Junshi treatments, the FDA said COVID-19 travel restrictions impeded inspections of the companies’ facilities.
When it comes to designing clinical trials, it seems that the importance of multiregional clinical trials is vital if the target indications already have treatment options. However, indications with unmet need may still have leeway in using single-country trials.
Given these events over the past couple years, we expect greater barriers for biopharma companies pursuing accelerated approvals. They will likely have to come to market with a comprehensive integrated evidence plan to meet these growing expectations, unless their treatment serves an unmet need with little to no treatment options.
Biopharma companies may not currently be worried about the accelerated approval process, but we believe that they may need to rethink their pipeline planning. To be a step ahead of this trend, we recommend that biopharma companies develop integrated evidence plans to encompass stronger evidence of safety and clinical benefit at earlier stages of clinical development. In addition, they should: target the best-fit patient segments to maximize likelihood of approval and reimbursement; re-evaluate clinical development costs and funding strategies and prepare for more uncertainty in FDA expectations through scenario planning.