Report of the Subcommittee on Clinical Trial Design and Outcomes Members: Gary Foulks (Chair & SC Liason) Robin Chalmers Nancy Keir Isabelle Jalbert Craig Woods Trefford Simpson Richard Lippman William Gleason Debra Schaumberg Mark Willcox (Harmonization Subcommittee Member)

Clinical Trial Design and Outcomes Goals: Review previously published clinical trials Identify appropriate trial design parameters and outcome measures to guide future clinical research Identify features to reduce bias in conduct and analysis of future trials

Clinical Trial Design and Outcomes RESULTS OF PRIOR CLINICAL TRIALS PubMed search – “contact lens discomfort” Included interventional trials of CL wear w/ information about ocular comfort or discomfort – Need not have been primary aim or outcome of study Searched reference lists of included studies 29 trials published from 1999 – 2012 N ranged from 18 to 257 participants (most <100) Follow-up from 30 min – 2 years To date, investigations have focused on ocular surface sensation with little attention given to the possible visual disturbance aspect of CLD

Clinical Trial Design and Outcomes Study Characteristics Study Design Funding Source Interventions (e.g. regimen, composition) Primary/Secondary Outcomes Inclusion/Exclusion Criteria Disease Definitions/Criteria (AECC, etc.) Standardized Measures (VAS, SF-36, etc.) Sample Size Control Group Washout or Accrual Period Follow-up Period Number of Visits Conclusion

Clinical Trial Design and Outcomes Sample and patient characteristics Source of Sample – # sites – Geo location, etc. Patient Characteristics – Age – Sex – Ethnicity Disease Characteristics of Participants Material Replacement Schedule Contact Lens Care System Wearing Time (hours) Wearing Experience (years)

Clinical Trial Design and Outcomes Evidence Symptoms – CLDEQ – OSDI – Other Signs – Tear Breakup Time – Staining – Schirmer – Osmolarity – Lissamine Green – Fluorescein – Other Toxicity Adverse Events Other Quality Reproducible Methodology Adequate Randomization Concealed Allocation (if RCT) Sufficient Sample Size Comparable Groups Blinded (if RCT) Validated and Reliable Measures Adequate Follow-up Appropriate Analyses Accurate Results Potential COIs Comments (concerns e.g., data, definitions, etc.) Overall Quality Rating (strong, moderate, weak; low, intermediate, high risk of bias)

Clinical Trial Design and Outcomes Most studies primarily examined – Lens fitting characteristics – Lens type – Lubricating and therapeutic eye drops – Lens care regimens Common limitations – Not masked – Small N – Short duration – Lack of or inadequate randomization – Baseline imbalances – Poor control of other factors care regimen prior lens wear Timelines of reporting symptoms Extent of visual near tasks, computer/video terminal use concurrent medications seasonal allergy and climate But I only have 2 friends …

Clinical Trial Design and Outcomes OUTCOME MEASURES Patient reported outcomes Symptom of Dryness Frequently described in CLD & reduced tolerance for CL wear Higher intensity with increased wearing time CLDEQ / CLDEQ-8 Only validated CL-related dryness symptom measurement tool CLDEQ-8 copyrighted by Indiana University Cite copyright in any publications

Clinical Trial Design and Outcomes Further assessment of patient symptoms – Onset – Time course – CLD at beginning of day, improving with wear, may have a different etiology versus CLD with an onset at the end of the day – Duration of comfortable lens wear – Frequency and intensity of symptoms Methods – Daily diary – Visual analogue scale (VAS) – 0-10 scales

Clinical Trial Design and Outcomes Clinical measures PubMed literature review “comfort AND contact lenses” Additional search terms related to the outcome Broad categories Staining Hyperemia Tear film changes Vision Ocular sensitivity Contact lens surfaces

Clinical Trial Design and Outcomes Corneal Staining Most often measured in studies of CLD (12 studies) Various grading systems in use Some validated for precision and reliability Efron scale Cornea & Contact Lens Research Unit (CCLRU) scale May be related to CLD, literature mixed Location and type may be important Recommendation Report method and techniques used Adopt a common grading system Scales e.g. National Eye Institute/Industry may not be adequate to grade corneal staining in CL wear

Clinical Trial Design and Outcomes SignN studies Association w/ subjective CLD Staining, indentation, roughness of the bulbar conjunctiva 8Possible Lid parallel conjunctival folds (LIPCOF); Lid wiper epitheliopathy (LWE) 2Possible Conjunctival & limbal hyperemia3Unlikely Tear film stability6Possible Tear volume2Inconclusive Tear film lipid layer2Inconclusive Tear film osmolarity4Inconclusive Ocular sensitivity3Possible Contact lens wettability & deposits4Unlikely

Clinical Trial Design and Outcomes Conclusion regarding clinical outcome measures Standardization needed for CLD outcomes Ideal clinical outcome measures Objective Valid Precise Fundamental studies needed Delineate most relevant outcomes for CLD Clinically meaningful change Crucial for evaluation of on-eye performance of existing and emerging technologies is possible

Clinical Trial Design and Outcomes Considerations for clinical trial design Trial design (parallel groups, cross-over) Randomized when possible Methods for data collection Selection of outcome measures Clearly written protocol Inclusion of appropriate control arm Adequate length of trial Run-in and wash-out periods Adequate sample size Importance of masking Appropriate statistical analysis (e.g. ITT)

Clinical Trial Design and Outcomes Avoiding bias and ensuring quality Selection bias including spectrum bias Performance bias detection bias attrition bias reporting bias Psychometric bias habit bias Hawthorne effect self-limiting bias recall bias Statistical bias Simpson’s paradox (Yule/Simpson effect ) External validity

Clinical Trial Design and Outcomes Design & outcomes should be determined with respect to the specific questions, e.g. Duration of trial Short for CL adaptation Longer for chronic or persistent episodic CLD Probe parameters of discomfort unique to CLD, e.g. Features of timing, duration, severity and relationship to lens wear If a validated QQ not available for a particular trial then VAS, 1-10 scales, etc. can be developed and used

Clinical Trial Design and Outcomes SUMMARY Prior trials focused primarily on CL performance not on CLD or its characteristics or etiology Such trials provide guidance for future trials Patient discomfort ranges from awareness of CL, to sensation of dry eye, to pain Impairment of visual function includes blur, instability of vision, or fatigue in performing visual tasks

Accurate assessment of CLD outcomes requires Patient selection Randomization Adequate N Validated symptom QQ Standardized clinical assessments/scales Attention to contact lens material, lens design, lens care products, and wearing schedule Appropriate statistical analysis

Clinical Trial Design and Outcomes No specific clinical outcome instrument can be recommended CLDEQ-8 most validated More work needed on development of outcomes and trials for CLD Assistance w/ layout & images: Kian C. Dana