Specific comments on text Line number(s) of the relevant text (e.g. Lines Comment and rationale; proposed changes (If changes to the wording are suggested, they should be highlighted using 'track changes') Recommendation (To be completed by the Agency) 6-8 and 17-18 The title refers only to antibacterial agents, but lines 130-131 indicate that the document could apply to antimycobacterial and antifungal agents as well. Amend title to refer either to all 3 classes of agents by name or to “antimicrobial agents” as an overall entity. 130 Most of the recommendations made in the guideline do not apply to non-absorbed and locally or topically acting agents. Add “… systemically administered” to sentence 187-188 It is suggested that this sentence may be better placed under “Scope” (Section 2) trial
344 – 350 We agree that an early read of the PK in patients is important so that the population PK model generated with healthy volunteer data can be updated with patient specific data and used to confirm the dose/exposure for larger clinical studies. We do not agree with specifying the sample design. The guidance should point to the need for a sample design that allows development of a robust model and accurate/precise PK parameter estimates to be obtained. Break these lines into 2 parts and change to: “PK data should be obtained from patients typical of the intended target population in terms of site of infection and severity of infection (but regardless of pathogen susceptibility) as early as possible in development and should be used to update the POPPK model based on healthy volunteer data. The updated model can support repeat PK-PD analyses and simulation to confirm or reject the likely sufficiency of the dose regimen before proceeding
354 – 360 If a drug is not highly protein and there is no in vitro evidence of concentration-dependent binding, further study is not needed. Non-linear binding may need to be addressed by measuring free concentration in a study or using a model-based approach [e.g., Singh et al. CP&T 2014; 95(suppl.1):S87]. Technical difficulties in measuring protein binding may be an issue. Change to: “The degree of binding of the test agent to human plasma proteins in the presence of clinically relevant concentrations should be assessed. Initially, this is typically done in vitro. For drugs with non-linear binding, if technically feasible, further assessment may be necessary during drug development.”
361 – 363 We agree with the importance of obtaining drug concentration data at bodily sites more relevant to the site of infection in both preclinical animal efficacy studies and in humans. But, we remain concerned about the limitations and use of data obtained at body sites outside of plasma and would offer two points for consideration. First, we would not specify “free” (line 361) as free drug is not always specifically assayed for (e.g., ELF). Second, and using ELF as an example, limitations of the data (BAL collection methodology, sampling limitations, drug/urea assay quality) and the influence of these limitations on measurement variability are Change to: “As relevant to the test agent and its intended clinical uses, test agent concentration-time data should be presented for specific body fluids and related to plasma/serum levels using compartmental PK modeling.”
be designed to address the potential for PPV to affect PK? How does one determine if PPV will affect the PK of a test agent based on its physicochemical properties? 407-408 While relevant for renally cleared drugs, no allowance made for drugs not impacted by renal function Revise to say “For renally cleared drugs, including a distribution for creatinine clearance that is usually found in the target population should be considered.”
407-408 Does this speak to renal insufficiency or to augmented renal clearance (ARC)? For ARC, how do we better understand and predict this phenomenon? The use of the Cockcroft- Gault equation may be a less precise estimate of creatinine clearance in certain circumstances such as when renal function is not stable. Methods of estimated creatinine clearance should be clear & justified. Sponsor should consider whether using existing methods for estimation of creatinine clearance is an appropriate approach vs. an independent population PK derived approach for predicting the drug’s clearance. The Agency is requested to speak to strengths/limitations of methods of estimating creatinine clearance for simulation purposes and insights on predicting individuals with ARC.
417-418 and Sponsor should consider incorporating these factors into the core justification of the PDT(s) used in simulations, instead of increasing the number of PTA analyses. The text implies potential for generating a large number of tables/figures. Modify text to suggest instead that the presentation should on the PTA for the relevant PDT for the given indication and population.
members of an existing drug class clinical and nonclinical data for existing approved antimicrobial agents as “benchmarks” for determining the PDTs of new agents. In these cases, the extent of bacterial killing and PDTs in nonclinical models with humanized exposures of an existing approved agent may provide a “benchmark” target for the new agent from the same class. The sponsor should provide justification of PDTs selected for use in analyses of PTA by considering clinical endpoints, disease severity, burden level of the pathogen, and drug
438-449 Appropriate that risk:benefit be considered. No mention of how to handle combinations (e.g. BL/BLIs) and if joint PTA preferred method versus other integrated approach through approaches such as a dynamic MIC or a pharmacometric-based mechanistic model. Suggest emphasizing value of PTA as tool for relative comparison with known members of the class, other internal controls, or between organs, indications, pathogens or PDTs, instead of focusing on a specific numerical PTA cut off (i.e., specific targets such as 90% PTA should be given as examples rather than hard targets).
473-474 We agree that there are well-delineated limitations for deriving E-R relationships in some settings. Although such analyses should be attempted by Sponsors, it may not be possible to derive clinical PDTs in all settings, supporting reliance on nonclinical targets. We agree with and support retention of the language noting the limitations of analyses and support reliance on nonclinical targets in this setting. 486-493 This section is unclear as it relates to E-R analyses. Please expand this section to clarify intentions or delete the section
510-512 We appreciate EMA consideration in that E-R supports predicted PTA, but it may NOT fully reflect successful response rates due to multitude of potential confounding factors. When E-R relationships are derived, they may have additional application to support difficult indications (e.g., nosocomial pneumonia) or those in which NI margins are not well defined (e.g., bloodstream infections, osteomyelitis, diabetic foot infections, etc…). Consider this additional language particularly for indications where knowledge base is less: “Sponsors are encouraged to consider E-R analyses, and other analyses, for estimation of treatment effect sizes and hence, as a support in selection of margins.”
520 For BL-BLI the concentration of BLI used in susceptibility testing often gets linked with the concentration(s) used to define the PK/PD relationship. A there is currently no mention of susceptibility testing in the document, we feel it would be helpful to add some clarity around the differences. Somewhere in a subsection of 4.6 (at the end of the paragraph beginning on line 529 would make sense), add this text: In addition, the fixed concentration of BLI used in in vitro susceptibility testing does not necessarily relate to target threshold concentrations from PK/PD experiments that describe the PDT.
549-551 There are a couple of sections which highlight that the PK/PD of the BLI needs to be defined for each BL. We suggest consolidating some of this recommendation into one place, and rather than using a specific drug example to make the point, describe the reasons. Amend text as show by underlines: A index that expresses the relationship between drug exposures and antibacterial effects in preclinical models should be established for each BLI. The PK-PD index should be established using bacterial strains that have been characterized for type of and other relevant resistance mechanisms to the beta-lactam and/or inhibitor (e.g., permeability-based) to understand the impact of varying organisms and
types on the PDT for the BLI. 552-554 The current recommendation is that in non-clinical infection models the BL/BLI should be administered to mimic the anticipated mode(s) of clinical use. We agree, but also note that there are studies used during development of the PK/PD understanding which may not mimic the mode of clinical use, but still have utility and should not be discouraged. Thus we propose a slight modification to the text. Amend text as show by underlines: In establishing the index, studies should be included in non-clinical infection models wherein the BL/BLI should be administered to mimic the anticipated mode(s) of clinical use……
data than can be obtained from clinical trials. 595-607 Recognizing all the limitations noted above about body site penetration, there are times when a clinician may need to consider use of a new agent for a patient with an infection at an as yet unstudied body site. In such cases, having even a sense of low, medium or high penetration relative to plasma can be invaluable. To the extent the data are available, provide a table of tissue penetration by body site in the SmPC. Sites without indications can be listed separately. The caveats on use of such data should be noted.