Per the FDA, the new draft guidance represents an updated approach to clinical trial design and regulatory submissions.
The FDA has issued a new draft guidance for developing drugs and biological products for the treatment of acute myeloid leukemia (AML).
According to the agency, the new draft guidance represents an updated approach to clinical trial design and regulatory submissions. Specifically, the guidance considers the changes made to the treatment landscape for AML, as new targeted therapies are being developed in this disease space.
Some of the transformations in AML therapy that the guidance considers are an expansion of the reason for treatment, a broader patient population, and the emergence of new drug classes that are alternatives to traditional, highly cytotoxic drugs.
“The purpose of this guidance is to assist sponsors in the clinical development of drugs and biological products for the treatment of acute myeloid leukemia (AML),” the guidance says. “Specifically, this guidance addresses FDA’s current thinking regarding the overall development program and clinical trial designs for the development of drugs to support an indication of treatment of AML, including indications limited to an individual phase of treatment (e.g., maintenance, transplantation preparative regimen, etc.).”
With regard to trial design, the draft guidance considers several points, including that “in large randomized trials, an interim analysis for futility is strongly recommended to ensure that the benefit-risk ratio for enrolled patients continues to be favorable.” The FDA also encourages innovative designs such as master protocols in the interest of efficient drug developments, though frequent consultation with the agency is recommended throughout the pre-investigational new drug (IND) application process.
In addition, in cases where targeted therapies are being developed, “a companion diagnostic may be essential for patient selection in IND protocols,” according to the agency. In cases such as this, the FDA suggested sponsors can request a study risk determination either directly from the Center for Devices and Radiologic Health, or through the IND process.
Moreover, portions of the guidance discuss the inclusion of special populations. For example, the guidance says that “[the] FDA encourages sponsors to address the pediatric population early in their clinical development program for drugs for the treatment of AML.” Of note though, the disease can affect patients of any age, including neonates and elderly.
Given that AML is rather common in pregnant women, the FDA recommended that sponsors also include a plan to address that population. Though there may be certain circumstances where pregnant women with AML could be considered for inclusion in clinical trials, the agency indicated that sponsors should also look to relevant non-clinical studies to support safety before enrolling pregnant women in clinical trials. Overall though, the guidance recommends an early meeting with the agency to address the inclusion of pregnant patients.
"Sponsors should enroll a population that is representative of the age range of patients with the disease,” according to the FDA, and the average age of an AML patient is almost 70 years of age. Therefore, patients older than 75 years of age should not be included in trials of intensive chemotherapy; however, trials of some of the newer, less toxic therapies could be conducted with no upper age limit for enrollment. When older adult patients are enrolled in clinical trials for AML drugs and biologic therapies though, dose reductions may be required.
Further, since both AML and cytotoxic therapies may incite serious adverse events (AEs) for patients in clinical trials, the guidance indicated that AE reporting could be both “burdensome and not useful” when a high rate of adverse events is anticipated. Due to this, the FDA suggests sponsors discuss alternative reporting arrangements with the agency or the possibility of a specific waiver.
However, “to assist with the adjudication of causality of fatal adverse events, the submission should include a data file with complete information” regarding the date, approximate cause and root cause of death, as well as the study day of death, the guidance explained.
Additionally, the guidance outlined detailed definitions of a variety of efficacy endpoints, such as overall survival (OS), that are common in trials of AML therapies. The FDA also provided a discussion of statistical considerations for analyzing time-to-event endpoints.
Importantly, for sponsors wanting to use alternative biomarkers or efficacy measures, or real-world data to support their marketing application, the FDA indicated they should obtain early advice from the agency to ensure that the outcome measures will adequately support the application.
Specific considerations for exploratory trials were also provided by the guidance. Notably, the agency’s discussion of confirmatory trial design for trials with curative, non-curative, and palliative intent includes which endpoints are acceptable in each case.
FDA. Acute Myeloid Leukemia: Developing Drugs and Biological Products for Treatment. FDA website. Published August 2020. Accessed August 31, 2020. https://www.fda.gov/media/140821/download