Table 1.

Appraisal of the characteristics of PK studies that affect the comparability of results among factor concentrates. Presented are the domains of a study to be considered when assessing if a study reporting a PK analysis can be trusted, applied to a given clinical situation, or its results compared to those from another study. The same criteria apply when assessing comparative studies

Domain	Cueing question	Characteristic assessed	Notes
Population	Are the populations used to assess the PK characteristics of the concentrates similar to each other and to the population of interest?
	Did the study design and conduct control for baseline imbalance of participant characteristics?	Study design	Crossover design (each participant acts as its own control); randomized trial (the two arms are practically identical) .
	Did participants represent the full, or at least similar, spectrum of the population? Were the demographics and clinical characteristics of the population(s) at baseline described?	Population composition	The baseline characteristics of the participants are usually described in a table.The range of observed participant characteristics (eg, age, weight) is similar to the population of interest.
	Was a sufficiently large sample enrolled in the study?	Study size	The number of subjects is sufficient to capture the variability. For a conventional study, 12‐15 subjects are deemed sufficient; for a population PK study around 20‐30 subjects with dense data or 100 with sparse data are suggested.
	Is the precision of the findings appropriate?	Observed variability	The range of observed PK values around the average is typical for the population; smaller or larger variability may require careful consideration.
	Is (are) the population(s) in the studies representative of the one I plan to apply the results to?	External validity	Would the patient(s) I am planning to apply the results of the study to have been enrolled in the study(ies)?
Intervention	Did the administration of the concentrates under assessment happen in a similar way across the comparators and with respect to the intended use?
	Was the study performed under routine clinical conditions?	Study setting	Usually patients studied during regular prophylaxis, in non‐bleeding conditions, with exclusion of the surgical setting.
	Were participants subject to a wash‐out?	Study design	If no washout then comparisons should be in steady‐state conditions.
	Were the doses of the concentrates tested comparable?	Study design	PK of factor concentrates is supposed to be dose independent, but use of extreme doses may require specific considerations.
Measurements	Were the sampling strategies sound and similar across the comparison?
	Were samples drawn over comparable time periods across the comparison?	PK assessment method	PK estimates can change depending on how many samples are used in the analysis, and for how long they are collected.
	Were samples measured with the same laboratory test and reference standard?	Laboratory method	Using different laboratory tests and/or reference standard may imbalance the comparison.
	Were samples below the limit of quantitation (BLQ) recorded?	Laboratory method	Results for measurement below the level of detection must be reported as “BLQ” followed by the minimum detectable concentration.
Analysis	Were the analysis plans similar, sound, and clearly reported across the comparison?
	Was the PK and/or PopPK analytical approach described in sufficient detail to be reproduced?	PK analysis	Details of the modelling approach must be provided and discussed, particularly when different for different concentrates.
	Were the structural models (non‐compartmental, one or multiple compartment) assumptions similar across the comparison? If not, was the case for the difference explained?	PK analysis	Justification for the modelling approach must be provided and discussed, particularly when different for different concentrates.
	Were reasonable assumptions used for PopPK analysis?	PopPK analysis	Justification for the endogenous activity, choice of covariates, number of samples, and subjects, modelling approach must be provided and discussed.
	Were BLQs accounted for in the analysis?	PopPK analysis	BLQs must be modeled as other post‐infusion measures. The M3 method is often used, but others may be acceptable.
Results	What are the results? Are they similar, sound and clearly reported across the comparison(s)?
	Were all expected results reported with their variability?	PK/PopPK analysis	Are there any incomplete data reporting or any selective outcome reporting?
	Were results comparable with previous/contemporary analyses on the same concentrate?	PK/PopPK analysis	Differences in the results that cannot be explained by differences in the population, intervention or analysis should be carefully considered.
	Were results comparable with those obtained with other concentrates in the same class?	PK/PopPK analysis	Differences in the results that cannot be explained by differences in the population, intervention, or analysis should be carefully considered.
	Are clinical outcomes presented in addition to the PK?	Study Design	PK/PopPK studies are often performed as part of a larger efficacy/safety study. Reporting (or referencing) clinical outcomes might be of help in interpreting, comparing, and applying the PK results.

PK, pharmacokinetic; PopPK, population pharmacokinetic.