TO SPECIFICALLY ADDRESS THE CLINICAL DEVELOPMENT OF NEW AGENTS TO
TREAT DISEASE DUE TO MYCOBACTERIUM TUBERCULOSIS

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This addendum to the Note for guidance on evaluation of medicinal products indicated for treatment of bacterial infections (CHMP/EWP 558/95 Rev 1) has been produced in response to recent advances in the development of agents intended for the treatment of disease due to Mycobacterium tuberculosis. Specific guidance was considered to be appropriate due to the differences in approaches to the treatment of tuberculosis compared with the treatment of other types of bacterial infections. In-vitro and in-vivo non-clinical studies can be used to assess the potential efficacy of test agents in various dose and combination regimens for the treatment of drug-susceptible and  drug-resistant M. tuberculosis. The data can provide some indication of the extent of exploratory clinical studies that may be needed before selecting one or a few test combination regimens to be evaluated in confirmatory studies of efficacy. If non-clinical studies indicate that an agent may be suitable for the treatment of drug-susceptible and drug-resistant M. tuberculosis clinical studies that investigate each mode of use may be conducted in parallel or in tandem. It is not considered possible to extrapolate a demonstration of efficacy against drug-susceptible M. tuberculosis to the treatment of drug-resistant organisms or vice versa. Each type of use must be evaluated separately in appropriate clinical studies. Patients should be enrolled into studies in the treatment of drug-susceptible or drug-resistant M. tuberculosis based on selection criteria intended to maximise the possibility that the results of susceptibility testing will confirm their eligibility. The population enrolled should be as representative as possible of the range of patients presenting with tuberculosis. Stratification according to important baseline factors is recommended (e.g. in terms of age, cavitation, extrapulmonary disease and HIV status).
In exploratory clinical investigations of efficacy the selection of regimens for further study may be based on biomarkers that are evaluated during or at the end of treatment. Nevertheless, none of these biomarkers has been shown to predict clinical outcomes at 24 months post-therapy. Confirmatory studies may assess the safety and efficacy of a test agent under conditions that include but are not limited to:
- Addition to or substitution for another agent within standard regimens to achieve shortened regimens, an improved safety profile, a lower potential for drug interactions or simplification of treatment for drug-susceptible M. tuberculosis

- Addition to optimised background treatment (OBT) regimens based on susceptibility test results to achieve superior efficacy to placebo + OBT in the treatment of drug-resistant M. tuberculosis.

The demonstration of a clinically important benefit for a test combination regimen in a primary analysis conducted at an appropriate time point may be considered sufficient to support an indication for use. Studies should plan to follow-up patients to 24 months post-therapy. An extrapolation of safety and efficacy in adults to some paediatric age groups may be justifiable, in which case it would be sufficient to establish appropriate age-specific dose regimens based on pharmacokinetic data obtained in children with tuberculosis. Nevertheless, children should also be followed for safety and efficacy using age-specific criteria for diagnosis and outcome assessments as appropriate.
The evaluation of the safety profile of a test agent for treating tuberculosis is confounded by the need to administer it as part of combination regimens in clinical studies. Identification of adverse reactions to the test agent should be possible when all other components of the regimens that are compared can be kept the same. However, this is not possible when the test agent has to be administered as part of a wide variety of combination regimens tailored to the susceptibility profiles of drug-resistant organisms
in individual patients. In all cases, a well-constructed and comprehensive Risk Management Plan is very important.

Damien Bové is THE Drug Development and Regulatory Consultant (pharmaceutical or biotechnology), I work with my clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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