Table 1.

Critical appraisal criteria for the assessment of internal validity in Phase III chemotherapy-induced peripheral neuropathy intervention studies

Internal validity threat	Appraisal criteria
Sample heterogeneity	Was the sample homogeneous (or stratified to control for heterogeneity)?
	Did all participants have similar exposure to chemotherapy before study initiation?
	E.g., Were all patients chemotherapy naive at baseline?**
	For trials evaluating chronic painful CIPN, did all participants have stable CIPN for at least 3 months following chemotherapy completion?†
Malapropos intervention mechanism of action and dose	Was the drug and dosage appropriate for the study aims?
	Was the tested drug’s mechanism of action consistent with the pathophysiology of the CIPN under investigation?
	Was the drug administration reasonable?
	Appropriate dose?
	Appropriate titration period?
	Right route of administration?
	No potential interaction with concomitant medications
Malapropos timing of outcome measurement	Were the time points of measurement appropriate?
	Were the outcomes time points appropriate based on the type of trial (e.g., prevention or management)?
	Was the drug administered for a long enough period of time to observe an effect of treatment?
	Were baseline CIPN severity scores high enough to be able to detect a difference in CIPN symptom severity between groups?**
	Was it possible that the effect of coasting or spontaneous CIPN improvement influenced CIPN symptom severity at the time point of measurement?†
	Were the outcome time points well defined and consistent across all participants?
Confounding variables	Was there adequate control for other CIPN influencing factors?
	Did the researchers stratify, exclude participants, or statistically control for covariates such as
	Chemotherapy regimen and dose received**
	Preexisting PN and prior receipt of chemotherapy**
	Conditions associated with PN: Cancer-related PN (e.g., paraneoplastic neuropathic, multiple myeloma-associated neuropathy), diabetes, symptomatic PAD, alcoholic disease, carpal tunnel syndrome, HIV/neurotoxic drugs, Vitamin B deficiencies
	Concomitant analgesic and psychotropic regimens
Lack of valid and reliable measurement	Were valid and reliable CIPN measures used?
	Were psychometrically strong CIPN PRO measures used?
	Were psychometrically strong objective (e.g., TNS) measures used?
	Were the selected CIPN measures aligned with the CIPN symptoms (e.g., sensory CIPN, motor
	CIPN, or painful CIPN) identified in the aims? E.g., if the study focused on treating painful CIPN, was pain measured separately from numbness and tingling?
Lack of statistical validity	JBI: Was appropriate statistical analysis used?
	Was the study adequately powered?
	Were the statistical procedures appropriate, given the aims, number of variables, and study groups?
	Was intent-to-treat analysis used?
	Were appropriate methods used for missing data (e.g., multiple imputation)?
Study design	Was CIPN defined as the primary outcome in the specific aims?
	Was the logical progression of trial research followed: At least two Phase II trials demonstrated efficacy before the Phase III trial?
	Were the design and methods consistent with previous trials’ designs? (e.g., drug/dosage)?

**Applies only to prevention trials, ^†Applies only to treatment trials. CIPN: Chemotherapy-induced peripheral neuropathy, JBI: Joanna Briggs Institute criteria, PAD: Peripheral arterial disease, PN: Peripheral neuropathy, PRO: Patient-reported outcome measure, TNS: Total neuropathy score