Kormanik Explains Difference Between Accelerated Vs Regular Approvals in Oncology

Natasha Kormanik, MSN, CRNP, FNP-BC, OCN

Randomized clinical trials allow regulatory agencies to better assess safety and efficacy with an investigative drug than a single-arm trial, according to Natasha Kormanik MSN, CRNP, FNP-BC, OCN, who is a senior regulatory health project manager at the FDA Office of Oncologic Disease in the Division of Hematologic Malignancies.¹

On April 21, 2022, an FDA Oncologic Drug Advisory Committee (ODAC) convened to discuss the safety of PI3K inhibitors and provide a consensus on a pathway for approvals with this class of drugs in hematology. Four PI3K inhibitors have received accelerated approval from the FDA for the treatment of patients with relapsed or refractory indolent non-Hodgkin lymphoma; however, all of these agents have had at least 1 of their indications voluntarily withdrawn by manufacturers following the publication of updated results.

During the 48th Annual Oncology Nursing Society (ONS) Congress, Kormanik and co-investigators presented on the oncology nurse implications with PI3K inhibitors and the accelerated approval process. Their poster presentation synthesized the history of the PI3K inhibitors approved to treat hematologic malignancies—including idelalisib (Zydelig), copanlisib (Aliqopa), duvelisib (Copiktra), and umbralisib (Ukoniq)—and concluded that the single-arm nature of trials supporting the accelerated approvals ultimately provided insufficient data on efficacy and safety, as toxicity concerns with these agents translated into a potential detriment in overall survival (OS) once these agents were assessed in randomized clinical trials.

Moving forward, the FDA has stated that future PI3K inhibitor approvals should be based on data from randomized clinical trials and not based on single-arm trial data. Further, there needs to be an ongoing confirmatory study in progress when the marketing application seeks accelerated approval.²

In an interview with Oncology Nursing News®, Kormanik provided a high-level overview of the difference approval pathways and what oncology nurses should understand about the accelerated approval regulatory framework. She also explained the findings of the PIK3 inhibitor review, underscoring why it is important that nurses understand the difference between these different approval pathways.¹

Oncology Nursing News: Please explain the difference between an accelerated approval and a regular approval.

Kormanik: Both regulatory pathways require [that] the product being submitted [is] safe and effective for intended use. Essentially, the evidence standard is the same for either pathway that [the agent is] submitted under.

The accelerated approval program was established during the HIV/AIDS [acquired immunodeficiency syndrome] epidemic, and it is a regulatory pathway that allows for earlier access to products to treat patients with serious or life-threatening diseases based on a surrogate or intermediate end point. The agency has used this program widely in oncology to provide access to safe and effective therapies for patients with cancer. With the accelerated approval specifically, it is important to recognize that confirmatory or postmarketing studies are required to verify clinical benefit of that particular product. Confirmatory trials must be well underway at the time of submission of the application to the FDA.

A regular approval means that the FDA has evidence on survival, [it requires] a direct measure of how the patients benefit. OS has been a longtime standard to ensure benefit for patients with cancer.

To talk about your poster from the ONS Congress, can you discuss the review that you conducted and what the findings were?

We evaluated the approved PI3K inhibitors for patients with hematologic malignancies. This review did not include [agents] approved for patients with solid tumors.

The FDA conducted a regulatory review for this drug class, and included the data supporting the initial approvals, which included a number of accelerated approvals. The review also included [data from] ongoing randomized trials, which were primarily evaluated in combination with patients with CLL [chronic lymphocytic leukemia] or indolent lymphoma. Across 6 randomized trials, we noted that there was a potential detriment to OS. Because of this, we wanted to have a better understanding of why that was happening. The review demonstrated that the potential detriment in OS was primarily because of a safety concern. The main safety issues were toxicity related.

With this class of drugs, can you talk about the unique mechanism of action and the associated toxicities that nurses should be aware of?

PI3K is an enzyme that plays a role in proliferation, cell growth and metastases. PI3K pathways are involved in a number of cancers, not just hematologic malignancies.

PI3K inhibitors are targeted immunomodulatory drugs that inhibit different isoforms. The distinct mechanism of action depends on the isoform directly being targeted. In the hematologic malignancy space, all PIK3 inhibitors inhibit the Δ isoform.

These products demonstrate several unique toxicities compared with other products, which may impact patient survival, [such as] grade 3 or higher adverse events [AEs]. With these products, this included infection, neutropenia—which most of us are familiar with—diarrhea, colitis, elevated alanine aminotransferase/aspartate aminotransferase, rash, and pneumonitis. Because we administer these products for a great length of time, some of those AEs may be delayed, so it is important to monitor these patients closely, not just at the beginning, but throughout their treatment.

Why does ODAC prefer randomized clinical trials over single-arm trials?

ODAC met in April of 2022 for a class-wide discussion. This really was the first time we have done this. Normally, we meet for individual products that we may have some concerns with or that we want to discuss. The purpose of this advisory committee [meeting] was to discuss class-wide safety findings observed with the PIK3 inhibitors in hematologic malignancies and determine the evidence needed to support the future approvals of drugs in this class.

The question to the committee was whether randomized trials should be required to support approval. The committee unanimously, with a 16-to-0 vote—[with] 1 voting member abstaining from voting— [agreed] that randomized trials are needed to inform the safety and efficacy of these products. As part of the advisory committee, there was a discussion on the limitations of the single-arm trials, specifically the challenges in assessing safety and certain efficacy end points such as PFS [progression-free survival], or OS. These are not interpretable in a single-arm trial, which is important to recognize. In contrast, there were also discussions about the benefit of randomized control trials, [which] allow for comparative assessment of safety and the ability to assess for PFS and OS.

What would you say is the key takeaway that you want your colleagues to understand about the approval process?

A takeaway for nurses, whether you are an APRN, or a nurse at the bedside, is that an accelerated approval is intended to provide access, but that confirmatory trials are still needed, and they need to be underway at the time of BLA [biologics license application] or NDA [new drug application] submission, per the new legislation.

[Although] I understand that regulatory talk may not be for everyone, I would love for nurses to understand—from a patient education standpoint—that there is a difference between accelerated approval and regular approval of a product. Being able to educate your patients on that [is important] because they may have some questions.

Regarding the PI3K inhibitors, there are important toxicities that should be monitored closely. Because of the chronic nature of the treatment, we may have some delayed onset of toxicities. It is important to continue to monitor [for] those.

Lastly, I would like to [note] that the FDA provides a lot of information and a label for safety and efficacy. There is a great wealth of information on toxicity and how effective the product works in the approved population that you are treating within the label. I encourage everyone to look at those. I have been there at the bedside, and I get that that you might [want] to just look at the snapshots, but when you are treating a patient with a drug that you’re unfamiliar with, or you don’t have as much experience with the US prescribing information, the label can be really informative.

References

1. Kormanik N, Wall L, Felluca D, Richardson N, Gormley N, Carioti T. FDA accelerated approval: oncology nurse implications with PI3K inhibitors. Presented at: 48th Annual Oncology Nursing Society Congress. San Antonio, TX. April 25-30. Accessed June 21, 2023. https://ons.confex.com/ons/2023/meetingapp.cgi/Paper/13231
2. FDA issues draft guidance aimed at improving oncology clinical trials for accelerated approval. FDA. News release. March 24, 2023. Accessed June 22, 2023. https://www.fda.gov/news-events/press-announcements/