The FDA is willing to consider a range of clinical trial designs and various endpoints for new drugs or biologics intended to treat acute myeloid leukemia (AML), according to a new draft guidance.

Clinical studies of new treatments for the disease need to take into account potential interactions with currently available treatments. For example, the draft guidance says, because standard treatments for AML include drugs that are substrates, inducers or inhibitors of cytochrome P450 enzymes, sponsors should conduct in vitro metabolism studies to determine if their new treatment also works in such ways before starting the first-in-human trial.

It’s also known that currently available AML treatments can cause the cardiac side effect known as QT prolongation, so the FDA recommends sponsors assess early in clinical development whether their new product also has this side effect. Sponsors additionally need to consider that AML patients, especially the elderly, may have impaired kidney or liver function, so they “should identify elimination pathways of the parent [investigational] drug and its active metabolites,” which will help establish a “basis of dose modifications for patients with organ impairment in late-phase clinical studies,” according to the draft guidance.

The agency also encourages early pediatric studies, and there are special considerations for older adult patients and pregnant patients.

The draft guidance goes into considerable detail as to the efficacy endpoints it will consider in AML clinical studies. For example, the agency says, time-to-event endpoints commonly used include overall survival, event-free survival and relapse-free survival. Frequently used binary endpoints include complete remission, complete remission with partial hematological recovery and transfusion-independence.

Also possible in AML trials are minimal residual disease-based endpoints, such as remnants of the cancer in the bone marrow of less than 0.01 percent, which the agency has accepted in the past as supporting evidence of efficacy. However, the draft guidance cautions, such standards may change “as technologies improve and new clinical findings emerge.” Also discussed as possibilities are alternative biomarkers or measures of efficacy and well-defined and reliable patient-focused outcome measures.

Alongside such endpoint considerations, the draft guidance delves into patient enrollment criteria. For example, in dose-escalation trials to determine the maximum tolerated dose, “the eligible population is usually limited to patients who have failed all conventional drugs.” This could be broadened somewhat to include “patients with subtypes of AML that respond very poorly to conventional drugs, such as those with high-risk genetic abnormalities … even without prior treatment,” as long as the consent forms the patients sign are clear about the implications of forgoing conventional treatment.

In confirmatory trials, the agency recommends using blinded treatments where feasible to avoid bias. Sponsors should detail how they’re using specific genetic targets and other prognostic factors for eligibility or risk stratification. The draft guidance also cautions sponsors to seek advice from the FDA “rather than using outdated criteria solely to match a population used in support of a past approval.”

Public comments on the draft are due Oct. 13.

Read the draft guidance here: https://bit.ly/32fyapK.