Characterization of Internal Validity Threats to Phase III Clinical Trials for Chemotherapy-Induced Peripheral Neuropathy Management: A Systematic Review

Abstract

Objective: The recent American Society of Clinical Oncology (ASCO) Clinical Guidelines for chemotherapy-induced peripheral neuropathy (CIPN) management (48 Phase III trials reviewed) only recommend duloxetine. However, before concluding that a CIPN intervention is ineffective, scientists and clinicians should consider the risk of Type II error in Phase III studies. The purpose of this systematic review was to characterize internal threats to validity in Phase III CIPN management trials. Methods: The PubMed, CINAHL, EMBASE ® , and Scopus databases were searched for Phase III clinical trials testing interventions for CIPN management between 1990 and 2018. The key search terms were neoplasms, cancer, neuropathy, and CIPN. Two independent researchers evaluated 24 studies, using a modified Joanna Briggs Institute Checklist for Randomized Control Trials developed by the authors specific for CIPN intervention trials. Results: Two studies exhibited minimal or no design flaws. 22/24 Phase III clinical trials for CIPN have two or greater design flaws due to sample heterogeneity, malapropos mechanism of action, malapropos intervention dose, malapropos timing of the outcome measurement, confounding variables, lack of a valid and reliable measurement, and suboptimal statistical validity. Conclusions: Numerous CIPN interventions have been declared ineffective based on the results of Phase III trials. However, internal validity threats to numerous studies may have resulted in Type II error and subsequent dismissal of a potentially effective intervention. Patients may benefit from rigorous retesting of several agents (e.g., alpha-lipoic acid, duloxetine, gabapentin, glutathione, goshajinkigan, lamotrigine, nortriptyline, venlafaxine, and Vitamin E) to expand and validate the evidence regarding ASCO's recommendations for CIPN management.

Effectiveness of Duloxetine on Oxaliplatin-induced Allodynia and Hyperalgesia in Rats

“…Both studies used the physician-graded Common Terminology Criteria for Adverse Events (CTCAE) to assess the primary outcome. A growing body of literature provides evidence of the CTCAE’s psychometric limitations (Alberti et al, 2014; Griffith et al, 2010; Park et al, 2019; Postma et al, 1998), and these limitations have compromised the internal validity of most CIPN intervention trials that have been conducted over the past 30 years (Gewandter et al, 2018; Hershman et al, 2014; Lee et al, 2019; Loprinzi et al, 2020).…”

Identifying participants’ preferences for modifiable chemotherapy-induced peripheral neuropathy prevention clinical trial factors: an adaptive choice-based conjoint analysis

“…In addition to the lack of evidence surrounding the underlying mechanisms of neuropathy, a limitation to determining new treatments for CIPN prevention is the overall poor study quality of previously conducted randomized clinical trials [7,8]. For example, Lee et al (2019) conducted a systematic review to characterize internal threats to validity of Phase III CIPN prevention or management trials between 1990 and 2018. The authors reported that 16/17 (94%) Phase III CIPN prevention clinical trials had two or more internal threats to validity (e.g., confounding variables, lack of reliable measurement or statistical validity) [9].…”

“…For example, Lee et al (2019) conducted a systematic review to characterize internal threats to validity of Phase III CIPN prevention or management trials between 1990 and 2018. The authors reported that 16/17 (94%) Phase III CIPN prevention clinical trials had two or more internal threats to validity (e.g., confounding variables, lack of reliable measurement or statistical validity) [9]. To improve CIPN clinical trial design, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks Consortium on Clinical Endpoints and Procedures for Peripheral Neuropathy Trials released several recommendations for CIPN clinical trial design [7,8].…”