New guidance for developers of CINV prophylaxis shifts endpoints

Regulatory NewsRegulatory News | 19 May 2021 |  By 

New draft guidance from the US Food and Drug Administration (FDA) updates which endpoint assessments and evidence are needed to show efficacy for medicines that treat chemotherapy-induced nausea and vomiting (CINV).
The guidance shifts away from the previous approach, where sponsors would choose a primary efficacy endpoint of complete response, which was defined as no vomiting and no use of rescue antiemetic medication. Direct evaluation of nausea severity and frequency were typically “positioned as exploratory assessments,” explains FDA in the Federal Register announcement of the guidance.
“To promote consistency and interpretability in the assessment of nausea both within and across development programs,” FDA recommends in the new guidance that developers select a primary endpoint of complete response and a secondary endpoint of the absence of nausea.
Both the primary and secondary endpoints should be binary, with no vomiting and no use of rescue antiemetic medication being the primary endpoint, and no reported nausea and no use of rescue antiemetic medication being the secondary endpoint.  The endpoints should be assessed “by evaluating the difference in the proportions of responders across treatment arms to establish efficacy for the prevention of CINV,” according to FDA’s background information.
Patient characteristics, such as age, sex, prior history of morning sickness, alcohol use and other factors, should be used to guide subgroup analyses that will help sponsors “gain precision in evaluating overall treatment effects,” according to the draft guidance.
The statistical plan should also include an approach “to ensure tight control of type I error rate” when multiple endpoints are tested.
The draft guidance points developers to the American Society of Clinical Oncology (ASCO) for recommendations for treatment regimens to prevent CINV, as well as for a classification scheme that identifies which chemotherapy regimens are highly or moderately emetogenic. These regimens, without antiemetic prophylaxis, will induce nausea and vomiting 90% and 30-90% of the time, respectively.
These parameters are important for developers to consider when selecting clinical trial populations, notes FDA in the draft guidance. In order for a development program to support an indication for highly emetogenic chemotherapy (HEC), the patient population should receive ASCO-classified HEC.
Anthracycline-cyclophosphamide (AC) chemotherapy regimens are not sufficiently emetogenic to support a HEC claim as the sole chemotherapy studied, according to the guidance: “Programs including patients treated with AC chemotherapy should include multiplicity-controlled analyses of the primary and secondary endpoints limited to patients receiving non-AC HEC (per ASCO guidelines) to support a demonstration of efficacy for patients receiving HEC.”
However, FDA may consider granting an indication for CINV in moderately emetogenic chemotherapy (MEC) if the drug has been shown effective in HEC, and if there is “sufficient data to support the safe use of the drug in the MEC population.” If an independent MEC indication is sought, then the development program should include patients receiving ASCO-classified MEC.
Unless there is a “strong rationale for exclusion,” patients with brain metastases should be included early in the clinical trial process.
Background antiemetic therapy should be the standard of care according to ASCO guidelines; if sponsors are seeking to demonstrate superiority, trials should be randomized, double-blind, and placebo-controlled.
An active comparator trial is recommended if sponsors are seeking a noninferiority or superiority claim; these trials should include an active comparator arm with two to four ASCO-recommended drug classes as well as an investigational arm where the investigational product replaces the drug of the same class in the standard of care prophylactic regimen.
The timing of nausea and vomiting can also differ between regimens; some are considered acute and induce nausea and vomiting within 24 hours of administration, while others are associated with a delayed symptom course that begins more than 24 hours after chemotherapy administration, with symptoms lasting up to 120 hours post-administration.
Efficacy endpoints should prespecify whether they are evaluating efficacy against acute, delayed, or both acute and delayed CINV. A secondary endpoint can include assessment from 0 through 120 hours. “FDA does not recommend sponsors select the overall phase for primary efficacy assessments, as drugs are often found to be effective for either acute or delayed onset CINV, and this information is needed to inform optimal use,” according to the guidance.
FDA recommends that patients be studied through at least four cycles of chemotherapy. Sponsors should track clinical outcomes by a variety of measures including an instrument that captures qualitative patient data about their experiences with nausea. Instruments should have daily assessments and should be used at the same time each day; FDA recommends that sponsors consult the agency early in the development process to select instruments to measure clinical outcomes.
Comments to be considered in formulating the final guidance are due to FDA by 19 July.
Draft guidance


© 2023 Regulatory Affairs Professionals Society.

Discover more of what matters to you

No taxonomy