Table 1.

Summary of Evidence Workgroup Recommendations for Systematic Evaluation of DDI Evidence

Recommendation	Comments
Recommendations to be Adopted in the Short Term
Apply consistent terminology	Terminology defined by the Evidence Workgroup is provided in Appendix A.
Apply DIPS for evaluating DDI case reports [20]	DIPS guides users to conduct an explicit, transparent, complete, and balanced assessment of the attributes important to causality assessment of whether a DDI occurred and exists [30].
A new approach for evaluating a body of evidence	DRIVE was developed based upon important concepts from existing methods [31, 32] with modification to: (1) use simple evidence categories; (2) include causality assessment with DDI case reports (via DIPS); (3) apply reasonable extrapolation, including from in vitro studies; and (4) address evidence/statements provided in product labeling; and (5) describe study quality criteria and interpretation in the context of DDIs.
Evaluate statements/evidence in FDA documents and product labeling by same criteria as published evidence	DDI recommendations provided in labeling that are not supported by PK data or PD properties of the drugs are insufficient evidence. DDI listings/recommendations in CDS systems do not need to align with unsupported statements in product labeling.
Classify DDIs by therapeutic/pharmacologic class only when the evidence applies, or can be reasonably extrapolated, to the entire class of drugs	Class effects distinction commonly apply to PD DDIs, but rarely to PK DDIs.
Recommendations for Future Work
Evaluate DRIVE Instrument	Testing should include (1) usability; (2) inter-rater agreement, (3) concordance (where expected) with similar systems [31, 32]; and evaluation of DIPS for case reports [20].
Develop systematic DDI search criteria	See examples by Boyce et al. [33–35]. Search should include unpublished literature, including FDA preapproval reviews and post- marketing analyses [36, 37]. Search criteria are needed to identify evidence for: (1) the existence of a DDI; (2) clinical outcomes, including frequency and modifying factors; and (3) clinical management (e.g., monitoring, dosage adjustments, and therapeutic alternatives).
Identify or develop a system to evaluate and communicate the strength of DDI evidence with graded recommendations [49]	The GRADE approach is endorsed or used by numerous organizations (e.g., AHRQ, Cochrane Collaboration, WHO) [54–57]. A modified GRADE approach is used by the University of Liverpool for evidence of DDIs involving medications for HIV and hepatitis C [64, 65].

AHRQ = Agency for Healthcare Research and Quality; CDS = clinical decision support; DDI = drug-drug interaction; DIPS = Drug Interaction Probability Scale; DRIVE = DRug Interaction eVidence Evaluation (DRIVE); FDA = Food and Drug Administration; GRADE = Grading of Recommendations, Assessment, Development, and Evaluation; PD = pharmacodynamics; PK = pharmacokinetic; WHO = World Health Organization