Oncology Endpoint Guidance: US FDA Reaffirms Support For EFS, MRD In Update

Update of 2007 guidance includes discussion on use of newer endpoints and clarifies that oncology endpoints can serve different purposes.

In an updated final guidance on endpoints for the approval of oncology drugs and biologics, the US FDA provided a written, formal reaffirmation of a series of outcome measures.

The new guidance, published Dec. 19, is an update to final guidance from May 2007, and specifically adds discussion on the use of event-free survival (EFS), minimal residual disease (MRD) and symptom improvement as endpoints.

EFS is defined as "time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence, or death due to any cause."

While EFS is similar to disease-free survival (DFS), the two are different in that for EFS, "randomization takes place before definitive surgery or radiotherapy in the adjuvant setting," the guidance states.

"DFS has been the primary basis of approval for adjuvant breast cancer hormonal therapy, adjuvant colon cancer, and adjuvant cytotoxic breast cancer therapy, whereas EFS is an appropriate endpoint for the evaluation of neoadjuvant breast cancer therapy given prior to definitive surgery," the guidance adds.

Sponsors have already begun using EFS in a variety of drug development programs.

EFS was notably used as the endpoint supporting the return of Pfizer Inc.'s acute myeloid leukemia (AML) drug Mylotarg (gemtuzumab ozogamicin) to the US market. (Also see "Mylotarg Returns: US FDA Approves Pfizer's Leukemia Drug With Bonus Pediatric Indication" - Pink Sheet, 4 Sep, 2017.) Although FDA has typically used overall survival (OS) to assess AML treatments, the Oncologic Drugs Advisory Committee gave an endorsement of EFS as an endpoint for Mylotarg. (Also see "Pfizer Hopes To Convince FDA With Event-Free Survival Data For Mylotarg" - Pink Sheet, 10 Jul, 2017.) and (Also see "Mylotarg, Event-Free Survival Endpoint Both Get FDA Panel Endorsement" - Pink Sheet, 11 Jul, 2017.)

Novartis AG's AVXS-101, a one-time survival motor neuron (SMN) gene replacement therapy for spinal muscular atrophy that is currently under review by FDA, also featured EFS as an endpoint in its clinical development program. (Also see "Keeping Track: Pfizer’s Talzenna Ensures Record Year For Novel US Approvals; Novartis Submits SMA Gene Therapy" - Pink Sheet, 21 Oct, 2018.)

On MRD, the guidance notes that it has been used has a surrogate for accelerated approval for an acute lymphoblastic leukemia (ALL) therapy. Indeed, for Amgen Inc. Blincyto (blinatumomab) picked up accelerated approval in March for the treatment adults and children with MRD-positive ALL based on the endpoint of a complete MRD response. (Also see "FDA Grants Blincyto Accelerated Approval Based On MRD Response Endpoint" - Pink Sheet, 30 Mar, 2018.) and (Also see "Amgen's Blincyto Has 'Potential Benefit' For MRD ALL, But Approval Chances Remain Unclear" - Pink Sheet, 7 Mar, 2018.)

The guidance describes MRD, along with metastasis-free survival – which was used as the endpoint in the approval of Johnson & Johnson's non-metastatic castration-resistant prostate cancer (nmCRPC) treatment Erleada (apalutamide) – as "emerging endpoints." (Also see "Metastasis-Free Survival Endpoint Spreads To Labeling With US FDA Approval Of J&J's Erleada " - Pink Sheet, 14 Feb, 2018.)

"If a sponsor is planning to use an emerging endpoint in its clinical development program, we recommend discussing such use with the applicable FDA Division or Office prior to initiating a trial," according to FDA.

The guidance also features a section on symptom improvement/palliation that was not in the initial 2007 guidance. FDA describes symptom palliation as a direct measure of clinical benefit rather than a surrogate.

"A decrease in the severity of cancer symptoms has been used to support traditional approval of anti-cancer agents where anti-tumor activity has also been demonstrated," the guidance states. "The use of a symptom palliation endpoint requires that the population be symptomatic at baseline, which can be problematic in many cancer trials where patients can often be asymptomatic at baseline."

Surrogates And Traditional Approval

What's more, the new guidance clarifies that various oncology endpoints can serve different purposes, such that a surrogate endpoint can be used to support traditional approval or an accelerated approval.

"The determination is based on the specific diseases and is highly dependent upon factors such as effect size, effect duration, depth of response (e.g., number of [complete responses]), available therapy, disease setting, location of disease, the clinical consequences of delaying or preventing disease progression or delaying administration of more toxic therapies, and the risk-benefit relationship," FDA says.

EFS, for instance, "can be a surrogate endpoint to support accelerated approval, a surrogate endpoint to support traditional approval, or it can represent direct clinical benefit based on the specific disease," according to the guidance.

The agency says the same for the endpoints of objective response rate (ORR), complete response (CR), and progression-free survival (PFS).

Improving Efficiency And Regulatory Predictability

Although many of the concepts in the guidance remain the same from the 2007 version, the update marks an incremental step in the agency's effort of making drug development more efficient and predictable.

The new guidance is just the latest in a string of oncology drug development guidances FDA has put out in 2018. Earlier this year, for example, the agency issued draft guidance documents aimed at expanding the ages of cancer patients eligible for clinical trials, giving sponsors more flexibility in designing studies, and clarifying when placebo controls should be used. (Also see "Guidance By Guidance, US FDA Is Reshaping The Look Of Cancer Drug Trials" - Pink Sheet, 30 Aug, 2018.)

FDA previously gave its endorsement of MRD as an endpoint when it put out draft guidance in October for sponsors developing drugs for the treatment of specific hematologic malignancies. The agency additionally published draft guidance in September on master protocols.

Commissioner Scott Gottlieb has frequently tied the issue of more efficient clinical development to lower drug prices. (Also see "US FDA's Gottlieb Touts 'Seamless' Clinical Trials, Worries About Second-To-Market Products " - Pink Sheet, 25 Jul, 2018.)

"Applying the most efficient clinical trial designs and using meaningful endpoints that measure benefits important to patients is key to our efforts to modernize clinical trial development programs," Gottlieb said in a Dec. 19 statement on the release of the guidance. "It helps make research and development more effective and can lower the cost of bringing safe and effective treatments to patients."