FDA Guide on Developing Drugs for Pulmonary Tuberculosis

FDA has issued updated guidance outlining how drugmakers should design clinical development programs for new tuberculosis (TB) treatments, emphasizing the need for shorter, safer and more effective regimens as global drug resistance and HIV coinfection continue to complicate care. The guidance provides recommendations on trial design, safety evaluation and efficacy endpoints for sponsors pursuing approval of new anti-TB drugs and combination regimens.

FDA said resistance to multiple drugs and coinfection with HIV remain major challenges in TB management, increasing the need for therapies with novel mechanisms of action, improved safety profiles and fewer drug-drug interactions. The agency also highlighted the importance of developing treatment-shortening regimens, noting that standard therapy for drug-susceptible TB still generally lasts six months.

Under the guidance, FDA recommends that sponsors begin development with nonclinical testing followed by early bactericidal activity, or EBA, studies and Phase 2 trials. EBA studies, which typically last seven to 14 days, measure quantitative reductions of viable Mycobacterium tuberculosis in sputum samples and are intended to provide preliminary evidence of antimycobacterial activity and each drug’s contribution within a combination regimen.

FDA stressed that because TB treatment requires multidrug therapy, sponsors developing combination regimens must demonstrate the contribution of each investigational agent to the overall treatment effect. The agency encouraged sponsors to consult regulators early in development when planning combination-drug studies.

The guidance also details FDA’s recommendations for Phase 2 development programs, including dose-ranging studies and exploratory endpoints such as sputum culture conversion, absence of acid-fast bacilli after eight weeks of therapy, symptom improvement and biomarker assessments. FDA said sponsors should incorporate long-term follow-up into Phase 2 trials in addition to early microbiological assessments.

For pivotal studies, FDA said a single adequate and well-controlled trial could support approval if accompanied by strong confirmatory evidence from nonclinical studies and earlier-stage clinical trials demonstrating antimycobacterial activity.

The agency outlined both superiority and noninferiority trial designs that may be used to support approval. In noninferiority studies, investigational regimens would be compared against the standard six-month treatment regimen known as 2HRZE/4HR, consisting of isoniazid, rifampin, pyrazinamide and ethambutol followed by isoniazid and rifampin.

Although FDA said it has not formally estimated the exact treatment effect of the standard regimen, the agency noted that historical cure rates exceeding 90% support use of a 10% noninferiority margin in many cases. FDA added that wider margins could be appropriate depending on the patient population, unmet medical need and safety profile of the investigational regimen.

The guidance also places significant emphasis on safety monitoring, particularly for hepatotoxicity and QT interval prolongation, both recognized adverse effects of antimycobacterial drugs. Sponsors are expected to evaluate potential interactions with antiretroviral therapies and other concomitant medications commonly used in patients with TB and HIV coinfection.

FDA said that for therapies addressing unmet medical needs in pulmonary TB, a preapproval safety database involving roughly 300 treated participants may be sufficient, though larger databases could be necessary if safety signals emerge.

The draft guidance encourages inclusion of diverse patient populations, including pediatric patients, pregnant women, older adults, patients with renal or hepatic impairment and individuals coinfected with HIV. FDA said adolescent patients may be included in phase 3 trials when appropriate, while pediatric development programs should begin once adult phase 2b data identify suitable dosing regimens.

FDA also outlined preferred clinical efficacy endpoints, including sustained sputum culture negativity, survival and relapse-free follow-up extending 12 to 18 months after randomization. The agency noted that sputum culture conversion during treatment may also serve as a surrogate endpoint reasonably likely to predict clinical benefit under accelerated approval pathways for multidrug-resistant TB therapies.