FDA issues draft guidance on pulmonary tuberculosis drugs

The US Food and Drug Administration (FDA) has released new draft guidance on developing drugs for pulmonary tuberculosis.
 
FDA’s latest draft guidance is intended to update the agency’s 2013 draft guidance with the same name, which was never finalized. “Since the 2013 final guidance was issued, there have been improvements in nonclinical models and further interest in streamlined clinical development programs as well as consideration for combination regimens with treatment-shortening regimens with improved safety and efficacy,” FDA wrote in a Federal Register notice.
 
In the new draft guidance, there is a new focus on nonclinical models, design considerations for early phase trials and a discussion on using superiority and non-inferiority as efficacy endpoints. There are also updates for including pediatric patients in trials as well as considerations for labeling, endpoints and safety in trials.
 
For early phase development, sponsors should consider the impact of each individual drug within drug combinations, either in phase 2 trials or nonclinical testing of early bactericidal activity (EBA). FDA noted that sponsors should contact the agency as early as possible to develop a plan for demonstrating the individual contribution of investigational drugs in drug combinations.
 
Sponsors can demonstrate superiority in trials with regimens of one or more investigational drug compared with a standard regimen, and in trials where the investigational drug plus an optimized background regimen is compared to placebo with the optimized background regimen. To demonstrate non-inferiority, the investigational drug regimen is compared to the standard regimen where the “investigational regimen performs within a prespecified margin of the performance of the standard regimen,” or an investigational drug is within an “acceptable” non-inferiority (NI) margin when replaced with a drug in a standard regimen. The non-inferiority margin is considered “highly dependent” based on the trial design and previously conducted trials, the agency said.
 
“For both superiority trials and NI trials that assess the activity of the investigational drug regimen as a whole, the sponsor will also need to address the added contribution of the components of the regimen,” FDA wrote. “This may be accomplished through nonclinical trials, EBA studies, phase 2 trials and/or as part of the pivotal efficacy trials.
 
In a change from the 2013 draft guidance, pediatric patients with pulmonary tuberculosis can now be included alongside the adult population if appropriate, rather than as a separate population for drug development to be discussed at the end of phase 2 trials.
 
“The FDA encourages sponsors to begin discussions about their pediatric clinical development plans as early as is feasible,” the agency wrote. “The additional safeguards of 21 CFR part 50, subpart D, for enrolling children in clinical investigations, affect the timing and design of trials that support pediatric drug development.”
 
Another change from the previous draft guidance is in how FDA instructs sponsors to label tuberculosis drugs in trials. Instead of simply describing that a drug is used to treat tuberculosis, the label should now detail how the investigational drug interacts with other drugs in combination to treat tuberculosis, and should also reflect the patient population.
 
In addition to defining clinical success as tuberculosis negativity without relapse or recurrence, FDA is also considering surrogate endpoint of sputum culture conversion over a period of time as well as secondary and exploratory endpoints of “well-defined and reliable evaluation of symptoms” and “[m]olecular or other biochemical evaluations” to identify whether a patient has relapsed or been reinfected.
 
Concerning safety, FDA has asked sponsors to examine their investigational drugs for risk of hepatotoxicity, QT prolongation, and arrhythmias. “Sponsors should discuss the size of the preapproval safety database with the FDA during drug development,” the agency wrote. For assessment of risks and benefits in subjects with an unmet medical need, a smaller safety database of approximately 300 subjects treated at (or greater/longer than) the proposed intended dose and duration may be sufficient. If safety signals are identified, a larger safety database may be needed.”
 
Draft guidance
 
Federal Register notice