Drugs for non-TB pulmonary disease see new FDA guidance

Regulatory NewsRegulatory News | 28 September 2021 |  By 

A new draft guidance from the US Food and Drug Administration (FDA) lays out considerations for sponsors who are developing drugs to treat certain lung infections caused by a mycobacterium related to the organism that causes tuberculosis.
The draft, posted to the FDA website on Tuesday, guides developers of drugs to treat nontuberculous mycobacterial pulmonary disease caused by Mycobacterium avium complex (MAC). It follows an April 2019 public workshop held by FDA that addressed the need for therapies for nontuberculous mycobacterial pulmonary disease (NTM-PD).
The progressive pulmonary disease caused by MAC is especially common in patients with some immunodeficiencies and with cystic fibrosis; it can also occur in the general population. Currently, “treatment for NTM-PD involves multidrug regimens with durations lasting months to years that often cause drug-drug interactions and adverse reactions such as hepatotoxicity, nephrotoxicity, ocular toxicity, and skin reactions,” noted FDA in the draft guidance.
One paramount consideration for trial design and conduct is the selection of clinically meaningful endpoints. Developers who are contemplating using a surrogate endpoint such as microbiologic outcome, even if it is “reasonably likely to predict clinical benefit,” should still consult with FDA before proceeding.
Some patients, given enough monitoring, may be able to participate in a brief placebo-controlled trial of a single agent that would serve as proof of concept, according to FDA.
However, sponsors should plan to conduct two Phase 3 trials that are both randomized and double-blinded, although one trial that shows “robust evidence of efficacy with confirmatory evidence” may suffice. Any new agents are likely be used in combination with other antibacterials, so the trial design should be designed to measure how a new drug would contribute to existing therapies.
The guidance gives three possible Phase 3 trial designs, while acknowledging that other designs could also be acceptable to FDA.
One possible design would be a superiority trial that evaluates standard-of-care (SOC) plus the new drug, compared with SOC plus placebo. Another superiority trial design could compare a new combination regiment to SOC. In certain populations such as treatment-naïve patients, FDA suggests that comparing a new combination regiment to placebo could be acceptable, “provided that there are appropriate criteria for instituting rescue therapy.”
MAC can cause two forms of NTM-PD, and sponsors should plan their Phase 1 and 2 trials to study new therapies in patients who have both the nodular bronchiectatic and the fibrocavitary forms of disease, so the appropriate populations can be included in Phase 3 trials.
However, patients with the two different NTM-PD forms may have different disease characteristics and responses to treatment, and different study endpoints may be required to capture clinically meaningful data. Similarly, in selecting trial endpoints, developers should consider appropriate endpoints for both treatment-naïve and treatment-refractory disease. Indications for a new drug or regimen “will reflect the patient population studied and may not cover all forms of NTM-PD,” according to the guidance.
Participants should be respiratory culture-positive for MAC at screening, and also have had a positive culture within the 6 months preceding screening. Trials should be planned so a racially and ethnically diverse study population can be enrolled.
To its point that a microbiological endpoint such as negative sputum cultures may not suffice as an efficacy endpoint, FDA advises sponsors in the guidance that only limited data are available to link sputum cultures with clinical outcomes. Pathogen clearance, said FDA, could potentially be considered as a secondary outcome measure.
Patient-reported outcomes (PROs) or other “appropriate clinical outcomes” should be selected as the primary outcome measure. However, FDA acknowledged a sticking point: “Currently, FDA is not aware of any specific PRO instruments that have been demonstrated to be fit-for-purpose to assess symptoms of NTM-PD to support regulatory decision-making and medical product labeling.”
In recognition of this, FDA is looking for sponsors to consider common NTM-PD symptoms in developing or selecting a PRO instrument. Since patients experience heterogeneous symptoms with the disease, FDA also suggests an approach where patients select their own most-bothersome symptom; the PRO would track the change from baseline in that symptom (or symptoms) “as the primary efficacy endpoint or at least as part of the endpoint.”
FDA suggests that sponsors pilot any proposed PRO instrument during Phase 2 trials.
The agency is requesting that comments on the draft guidance be submitted by 29 November 2021.


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