Drug Regulators, EMA (EMEA), Publish Draft Guidance on the Evaluation of Medicinal Products Indicated for Treatment of Bacterial Infections.

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Following adoption of the Note for Guidance on evaluation of medicinal products indicated for the treatment of bacterial infections (CPMP/EWP/558/95 rev 1) it became apparent that some areas of the guideline would benefit from further explanation of the requirements for approval of new antibacterial agents and for significant variations to the marketing authorisation. Additional matters requiring guidance arose during provision of scientific advice to sponsors and the assessment of application dossiers.
The microbiological evaluation of antibacterial agents should include efforts to identify the precise mechanism of action. Activity against pathogens that are resistant to other antibacterial agents, including agents of the same class if this is applicable, should be explored. Organisms inhibited only at unusually high concentrations of the test antibacterial agent should be investigated for possible mechanisms of resistance and cross-resistance to other agents. During clinical studies the use of central laboratories is recommended for confirmation of identification and susceptibility test results, for serological studies and for typing of isolates to distinguish relapses from new infections.
Pharmacokinetic/pharmacodynamic (PK/PD) analyses may be used to select dose regimens for clinical studies and as one of the tools for setting the breakpoints for susceptibility testing. If the PK/PD relationship is well-established and the analyses are convincing it may be possible to omit formal dose-finding studies and proceed directly to the evaluation of one or very few regimens during indication-specific studies of efficacy.
Each study of clinical efficacy should aim to select patients with infections strictly relevant to the indication sought that require antibacterial therapy by the route of administration specified. Enrolment criteria intended to differentiate complicated from uncomplicated infections do not necessarily distinguish infections according to degree of severity and may not be sufficient to identify infections that can be treated by oral, parenteral or topical routes of administration. Therefore additional steps should be taken to ensure that the patient population is optimal to support the indication claimed and the dosing recommendations.
It is preferred that each clinical indication for use is supported by at least two randomised and controlled studies. The provision of a single pivotal study may be acceptable if this has been conducted in accordance with applicable CHMP guidance. Comparative studies should be double-blind unless this is really not feasible. Most confirmatory studies of efficacy will aim to demonstrate non-inferiority between the test antibacterial regimen (which may consist of a single agent, a fixed drug combination, a hybrid molecule or combined treatment with a beta-lactam and a beta-lactamase inhibitor) versus an appropriate comparative regimen, which should be one of the best available treatments. The choice of non-inferiority margin requires particular attention in accordance with the available CHMP guidance.
In some indications a non-inferiority study cannot reliably support a conclusion that the test antibacterial agent would be superior to placebo if the comparison were actually to be made. These will primarily be indications where the magnitude of effect of the active comparator relative to placebo is not consistently reproducible or is not well quantified. In these cases, a demonstration of superiority versus placebo or versus an active comparative regimen is required based on at least one clinically important endpoint.
Data on efficacy in relatively rare types of infection or infections caused by relatively rare pathogens, including those that demonstrate multidrug resistance and/or an unusual pattern of resistance to specific agents, may be collected during the course of indication-specific studies. Alternatively, and if feasible, sponsors may conduct separate studies with the specific aim of generating data on efficacy against the pathogen of interest. In both these possible approaches to collecting efficacy data the number of cases treated is likely to be small but it is still preferred that the clinical experience is gained in randomised study designs whenever possible, even if these are underpowered. The number of treated cases required to support a specific claim in the SPC must be judged on a case by case basis.
Very occasionally the only way to accumulate clinical experience with specific antibacterial agents in the treatment of specific pathogens, which may or may not express multidrug resistance, could be in studies that enrol patients with well-documented infections regardless of which body site(s) is/are affected. In these exceptional cases a pathogen-specific indication for use may be possible (i.e. referring to treatment of named organisms regardless of the documented site of infection).
In many instances the nature and course of bacterial infections is sufficiently similar between age groups that efficacy data obtained in adults may be used to support use of an antibacterial agent in the same indication in children of various ages provided that there are sufficient safety and pharmacokinetic data available to support age-specific dose recommendations. Bacterial infections that occur mainly in children or for which the pathogens or clinical course may differ by age group require specific data to be obtained on efficacy in children.
The evaluation of safety of antibacterial agents should include an assessment of the data generated within each indication and against each comparative regimen since pooling across all studies may be misleading. The last visit in each study should be conducted at a sufficient interval after the last dose to detect possible late drug-related adverse reactions, such as severe skin reactions and antibiotic-associated diarrhoeal disease.
Some sections of the SmPCs for antibacterial agents require special consideration due to issues such as multiple indications for use, some of which may be age-specific, the possibility of indication-specific dose regimens and the need to describe the microbiological data, including the efficacy observed by pathogen in clinical studies. Recommendations for the content of relevant sections of SmPCs are provided in the last section of this guideline and should be followed as far as is appropriate for individual agents.
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