Impact Statements
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Specific dimensions of quality related to clinical pharmacokinetic research include study design, conduct, analysis, results validity, clinical relevance, and quality of reporting.
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Developing a critical appraisal tool to evaluate clinical pharmacokinetic studies will help end-users to apply evidence-based medicine to clinical practice and future research.
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The clinical pharmacokinetic critical appraisal tool (CACPK) developed in this study consisted of 21 items aimed at helping end-users to appropriately assess the quality of pharmacokinetic studies.
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The currently developed CACPK tool shall undergo periodic improvement in order to keep pace with changes in the literature and to maintain the practical benefits to the field of clinical pharmacokinetics.
Introduction
Aim
Ethics approval
Method
Use of pre-selected set of preliminary quality markers
Sampling and selection of Delphi experts
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academic experts with a designation that reflects their direct involvement in clinical pharmacokinetics as evidenced in their research and teaching portfolios.
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clinicians who had experience in the application of clinical pharmacokinetic principles or the provision of therapeutic drug monitoring in their clinical practice. These individuals should have experience in interpreting the findings of clinical pharmacokinetic studies and applying these to their patients.
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pharmaceutical industry researchers with years of experience in relevant positions involving clinical pharmacokinetic research.
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individuals in regulatory bodies who assess clinical pharmacokinetic studies when making decisions for their respective health authorities, e.g. FDA.
Modified Delphi survey
Modified Delphi process
Pilot testing
Results
Participants
Variables | Percentage (Actual number) |
---|---|
Filed of experience
| |
Clinicians | 56% (14/25) |
Academic sector | 20% (5/25) |
Industrial sector | 16% (4/25) |
Regulatory sector | 4% (1/25) |
Project director | 4% (1/25) |
Grographical distribution
| |
Canada | 52% (13/25) |
USA | 24% (6/25) |
Qatar | 24% (6/25) |
Consensus through modified Delphi rounds
Item | Consensus [N (%)]*
| Round of consensus**
| |
---|---|---|---|
Background | |||
1 | Was a clear description of the objectives of the study provided? | 21/21 (100) | 1 |
2 | Was a valid and comprehensive rationale provided to support the purpose of the study? | 13/15 (86.7) | 3 |
Design | |||
3 | Was the chosen study design appropriately selected and justified? | 20/21 (95.2) | 1 |
4 | Was the dosing (dose, route of administration, dosing interval) of the drug in the study justified for the intended study? | 19/21 (90.5) | 1 |
5 | Were the endpoints of the study appropriate to answer the objectives of the study? | 19/21 (90.5) | 1 |
6 | Were the exclusion criteria of participants included AND appropriate for the intended outcomes of the study? | 18/21 (85.7) | 1 |
7 | Where applicable, were the relevant baseline characteristics of the participants adequately described? | 14/15 (93.3) | 3 |
8 | Were plausible interacting covariates described a priori or in post hoc evaluation? | 18/19 (94.7) | 2 |
9 | Was the description of the used sample analysis methods or citations of prior validation studies provided in the publication or affiliated appendix? | 16/19 (84.2) | 2 |
Sampling | |||
10 | Was the method of data sampling appropriate for the study? | 19/21 (90.5) | 1 |
11 | Was a clear description of the sampling site and the sampling interval (the exact times at which samples are obtained) provided and justified? | 19/21 (90.5) | 1 |
12 | Was the number of half-lives elapsed within the sampling period appropriate for the analyzed drug? | 17/19 (89.5) | 2 |
13 | Were sample storage conditions appropriate and described in a manner that could be accurately replicated? | 20/21 (95.2) | 1 |
14 | If applicable, was there a clear description of the pharmacokinetic model, its development, validation and justification for use? | 20/21 (95.2) | 1 |
15 | Was the described population pharmacokinetic approach validation method appropriate for the analysis? | 15/15 (100) | 3 |
16 | Were the essential pharmacokinetic parameters required to make the results applicable in clinical settings addressed? | 16/19 (84.2) | 2 |
17 | Were the pharmacokinetic equations used to calculate patient pharmacokinetic parameters disclosed or cited within the article? | 16/19 (84.2) | 2 |
Applied Statistics | |||
18 | Were the chosen statistical tests and software to perform the statistical analysis appropriate to achieve the study objectives? | 19/21 (90.5) | 1 |
Results | |||
19 | Were all patients enrolled in the study accounted for? | 17/19 (89.5) | 2 |
20 | In the event of missing data or outliers, was the process for analysis justified and appropriate? | 19/21 (90.5) | 1 |
21 | Were appropriate summary statistics to describe centrality and variance used to document the pharmacokinetic results? | 19/21 (90.5) | 1 |
Critical Appraisal of Clinical Pharmacokinetic Studies (CACPK) Tool | |
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Appraising Background
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1. Was a clear description of the objectives of the study provided? • Authors should provide a clear statement of the objectives of the research to clarify the purpose and the scope of the study. | Yes No I Do Not Know Not Applicable Comments: _____________________________ |
2. Was a clear and comprehensive rationale provided to support the purpose of the study? | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
Appraising Study Design and Experimental Methods
| |
3. Was the chosen study design appropriately selected and justified? | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
4. Was the dosing (i.e. dose, route of administration, and dosing interval) of the drug in the study justified for the intended study?
Examples: • Authors should justify the use of single-dose versus steady-state analysis. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
5. Were the outcome measures endpoints of the study appropriate to address the objectives of the study? | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
6. Were the exclusion criteria of participants included AND appropriate for the intended outcomes of the study? • The exclusion criteria should be relevant to assist with decreasing significant confounders (e.g. co-administration of drugs, organ impairment, and special populations) that may impact outcomes. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
7. Where applicable, were the relevant baseline characteristics of the participants adequately described?
Examples: • Sex, race, age, weight, height, concomitant disease, administered medications, smoking status, pregnancy, severity of illness that may affect pharmacokinetic parameters, renal function, and hepatic function.
Note: Please refer to Appendix-1 Patient Demographics (Supplement 4) for further clarification. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
8. Were plausible interacting covariates described a priori or in post hoc evaluation?
Examples: • Demographic variables, laboratory values, concomitant medications, and relevant disease states to the drug being studied. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
9. Was the description of the used biological sample analytical methods sample analysis methods or citations of prior validation studies provided in the publication or affiliated appendix?
Examples: • Chromatography type. • Detection type. • Assay characteristics: mobile phase composition, gradient and flow rate, chromatographic column (packing material, dimensions). • Analytical runtime. • Operating temperature. • Detection parameters. • Validation method: specificity, recovery, linearity and sensitivity, the stability of the assay and its reproducibility. Refer also to EMA/FDA guidelines for bioanalytical method validation. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
10. Was the method of data sampling of analytics appropriate for the study?
Examples: • First vs. second order absorption, and lag time. • Evaluating for nonlinearity requires multiple dose levels and a complete profile is recommended. • Researchers obtain these data from previously conducted studies with completed concentration-time profile (e.g. phase I studies). • The method of data sampling should reference previously validated quantitative bioanalytical methods and if those are not available then the full description or defense of data sampling should be included. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
11. Was a clear description of the sampling site provided and justified?
Examples: • Sampling site should be consistent for all subjects in the study. • Arterial sampling is preferable during frequent sampling schedule. • Arterial sampling is more representative of the delivered concentration to the effect site in the case of peripheral elimination. • Arterial sampling is preferable when administering a drug that has a short duration of action or fast onset of action. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
12. Was the number of half-lives elapsed within the sampling period appropriate for the analyzed drug?
Examples: • Sampling interval should not exceed the expected half-life of the studied exponential phase (fast distribution, slow distribution and elimination). | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
13. Were sample storage conditions appropriate and described in a manner that could be accurately replicated?
Examples: • Sample storage, temperature, use and description of anticoagulants, stabilizers, centrifugation etc. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
14. If applicable, was there a clear description of the pharmacokinetic model, its development, validation and justification for use? It is recommended to provide the following details about the selected modeling process: • Description of studies from which dataset was driven • Model structure • Validated software for the pharmacokinetic analysis • Criteria for accepting valid model’s parameters • Fitting procedure defined prior to the initiation of the analysis. • A reasonable assumption based on which the scheme for weighting is considered to be appropriate and the transformation of data [e.g. logarithmic transformation to achieve the homoscedastic (constant) variance requirements] should be provided. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
15. Was the described population pharmacokinetic approach validation method appropriate for the analysis? 1- Basic internal method 2- Advanced internal method 3- External model evaluation
Note: Please refer to Appendix-2 Model Evaluation (Supplement 5) for further clarification. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
16. Were the essential pharmacokinetic parameters required to make the results applicable in clinical settings included?
Examples: • Total clearance (CL), Hepatic clearance, Renal clearance, Volume of distribution at steady state (Vss), Blood/plasma concentration ratio, Terminal half-life (t1/2 Z), Fraction of the unbound drug in plasma (fu), Absorption rate constant (Ka),Cmin, Cmax, tmax,, AUC, etc. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
17. Were the pharmacokinetic equations used to calculate the patient’s pharmacokinetic parameters presented or cited within the article?
Examples: • Equations used to calculate the following pharmacokinetic parameters: creatinine clearance, body weight calculations, Michaelis Menten, volume of distribution | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
Appraising Applied Statistics
| |
18. Were the chosen statistical tests and software to perform the statistical analysis appropriate to achieve the study objectives? | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
Appraising Results
| |
19. Were all patients enrolled in the study accounted for?
Examples: • Description of patient screening, enrollment, run-in or wash out phases, study period and follow-up periods are adequately described. Any loss to follow-up or withdrawals are described. | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
20. In the event of missing data or outliers, was the process for analysis justified and appropriate? | Yes No I Do Not Know Not Applicable Comments: ______________________________ |
21. Were appropriate summary statistics to describe centrality and variance used to present the pharmacokinetic results?
Examples: • Descriptive statistics such as confidence interval, standard deviation, mean, median, range, interquartile range, standard error and trimmed range | Yes No I Do Not Know Not Applicable Comments: ______________________________ |