Draft AML guidance takes targeted therapies into account

Regulatory NewsRegulatory News | 17 August 2020 |  By 

The US Food and Drug Administration(FDA)  has issued a new draft guidance for developers of drugs and biologics to treat acute myeloid leukemia (AML).
The new draft guidance takes into account a shift in the treatment landscape for AML as new targeted treatments are being developed for this and other cancers. "In some cases, these newer approaches may extend survival without the prospect for cure, but extending survival may be a meaningful benefit for patients who would live for only weeks if left untreated," says the guidance.
The draft guidance, said the agency, represents an updated approach to clinical trial design and regulatory submissions.  Among the shifts 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.
Regulatory considerations for study design
In terms of regulatory considerations, the draft guidance offers several points regarding trial design. 
“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,” according to the guidance. Also, such innovative trial designs as master protocols are encouraged 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 many cases where targeted therapies are being developed, “a companion diagnostic may be essential for patient selection in IND protocols,” said the agency. In this case, sponsors can request a study risk determination either directly from the Center for Devices and Radiologic Health, or through the IND process. 
Special populations
Specific portions of the guidance address the inclusion of special populations. open Chrome FDA encourages sponsors to address the Pediatric population early in their clinical development program for drugs for the treatment of AML," according to the guidance. The disease can affect individuals of any age, from neonates to the elderly.
AML is relatively common in pregnant women, so sponsors should also include a plan to address that population. Although there may be certain circumstances where pregnant women with AML could be considered for inclusion in clinical trials, sponsors should also look to relevant non-clinical studies to support safety before enrolling pregnant women in clinical trials. The draft 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 guidance, and the average AML patient is nearing 70 years of age. When older adult patients are enrolled in clinical trials for AML drugs and biologic therapies, however, dose reductions may be required. In general, patients older than 75 years of age are not 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, said the FDA. 
The draft guidance also gives specific criteria to define which patients with organ impairment should be included in trials in order to support marketing approval of the therapy.

Adverse events
Since both AML and cytotoxic therapies may provoke serious adverse events for patients in clinical trials, the draft guidance notes that adverse event reporting may be both “burdensome  and not useful” when a high rate of adverse events is anticipated. Sponsors should discuss with the agency alternative reporting arrangements or the possibility of a specific waiver, according to the guidance. 
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, proximate cause and root cause of death as well as the study day of death, clarified the guidance. 
The guidance outlines detailed definitions of a variety of efficacy endpoints, such as overall survival, that are common in trials of AML therapies. The agency also provides a discussion of statistical considerations for analyzing time-to-event endpoints. Binary endpoints, such as complete remission and transfusion independence, are also discussed in detail in the draft guidance, which also lays out statistical considerations for these endpoints.
Those sponsors wanting to use alternative biomarkers or efficacy measures, or real-world data to support their marketing application should obtain early advice from FDA to ensure that the outcome measures will adequately support the application.
Specific considerations for exploratory trials, including first-in-human trials, are also provided by the guidance. The document’s discussion of confirmatory trial design for trials with curative, non-curative and palliative intent includes which endpoints are acceptable in each case.


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Tags: clinical, FDA, trials, US

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