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Articles  |   October 2013
The TFOS International Workshop on Contact Lens Discomfort: Report of the Subcommittee on Clinical Trial Design and Outcomes
Author Affiliations & Notes
  • Gary Foulks
    Department of Ophthalmology and Vision Science, University of Louisville, Wilmington, North Carolina
  • Robin Chalmers
    Atlanta, Georgia
  • Nancy Keir
    CooperVision, Pleasanton, California
  • Craig A. Woods
    School of Medicine (Optometry), Deakin University, Geelong, Victoria, Australia
  • Trefford Simpson
    School of Optometry and Vision Science, University of Waterloo, Waterloo, Ontario, Canada
  • Richard Lippman
    R.P. Chiacchierini & Associates, Rockville, Maryland
  • William Gleason
    Foresight Regulatory Strategies, Inc., Wilmington, Massachusetts
  • Debra A. Schaumberg
    Moran Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, Utah
  • Mark D. P. Willcox
    School of Optometry and Vision Science, University of New South Wales, Sydney, New South Wales, Australia
  • Isabelle Jalbert
    School of Optometry and Vision Science, University of New South Wales, Sydney, New South Wales, Australia
  • Correspondence: Mark D. P. Willcox, School of Optometry and Vision Science, University of New South Wales, Sydney, NSW 2052, Australia; m.willcox@unsw.edu.au
Investigative Ophthalmology & Visual Science October 2013, Vol.54, TFOS157-TFOS182. doi:10.1167/iovs.13-13189
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      Gary Foulks, Robin Chalmers, Nancy Keir, Craig A. Woods, Trefford Simpson, Richard Lippman, William Gleason, Debra A. Schaumberg, Mark D. P. Willcox, Isabelle Jalbert; The TFOS International Workshop on Contact Lens Discomfort: Report of the Subcommittee on Clinical Trial Design and Outcomes. Invest. Ophthalmol. Vis. Sci. 2013;54(11):TFOS157-TFOS182. doi: 10.1167/iovs.13-13189.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Introduction
The goal of this report is to review previously published clinical trials addressing contact lens discomfort (CLD) to identify appropriate trial design and outcome parameters to guide future clinical research that will characterize and investigate possible causes of CLD. A further goal is to identify possible confounding features of clinical trial design and performance in order to reduce bias in conduct of future trials or analysis of data from those trials. 
Scope of Report
A contact lens is a foreign body placed on the eye, albeit of compatible material and design, applied to patients with variable biologic risk factors that influence the degree of experienced symptoms. The design of clinical trials and selection of appropriate outcomes that allow examination of CLD should be determined with respect to the specific questions being asked and answered by a specific trial. For example, the duration of a clinical trial to determine the time required for adaptation to a contact lens could be short, but such a time frame is inadequate for evaluation of chronic or persistent episodic discomfort. Similarly, evaluation of care system-related CLD would require control of not only the care system to be evaluated but also the contact lens (material, design, fit, and wearing pattern). Evaluation of symptoms of CLD should be done with questionnaire instruments that probe parameters of discomfort unique to CLD. For example, a symptom of “dryness” may be an appropriate outcome for CLD if qualified by features of timing, duration, severity, and relationship to lens wear. 13 If a validated questionnaire is not available for the particular trial design, then visual analogue scales or numerical rating scales of comfort (on 1–100 or 1–10 scales) can be used. Although most of the data gathered from the literature for this report is derived from trials involving soft contact lenses, the principles for clinical trial design also apply to rigid contact lenses. 
The proposed evaluation of CLD is for primary discomfort during lens wear. There are clinical conditions that can be produced by prolonged lens wear resulting in discomfort, but these conditions are secondary. For example, giant papillary conjunctivitis can occur in response to contact lens wear and produces symptoms of CLD (perhaps due to mechanical irritation from the edge of the lens or buildup of biological material on the lens), but this conjunctivitis would be considered a separate entity from CLD. 46  
Recognition of the fact that there is great variation in patient acceptance or tolerance of any noxious sensation requires that some qualification of the degree of discomfort be made. Thus a psychometric assessment of enrolled study participants may be required for some clinical trials. 7,8  
Results of Prior Clinical Trials
The CLD clinical trial subcommittee searched the PubMed database using the search term “contact lens discomfort” (last searched on January 25, 2013). We included interventional trials involving contact lens wear that collected information about ocular comfort or discomfort, even if this was not the primary aim or outcome of the study. We searched the reference lists of included studies for any additional studies not identified by the electronic search. Clinical trials of contact lens performance may be published in the non–peer-reviewed professional literature (e.g., Contact Lens Spectrum or The Optician). We did not search non–peer-reviewed literature or any conference proceedings. 
A review of published clinical trials assessing CLD is summarized in Table 1. 939 These were published between 1999 and 2013 and enrolled 18 to 362 participants. Trials typically were small; only four enrolled 100 or more participants. These participants were followed for 15 minutes to 3 months. It is clear that most prior clinical trials were designed to evaluate performance of certain contact lenses or lens care solutions rather than the specific nature and etiology of CLD. As a result, their ability to elucidate CLD is modest due to inherent weaknesses in the chosen study design. Nonetheless, certain features of CLD can be distilled from those clinical trials. To date, investigations into CLD have primarily focused on sensation, with little attention given to the possible visual disturbance aspect of CLD. 
Table 1. 
 
Assessment of Published Clinical Trials
Table 1. 
 
Assessment of Published Clinical Trials
Study Design (e.g., Placebo-Controlled RCT, Retrospective Cohort) and Reference Details of Intervention (e.g., Regimen, Composition) Comfort/Discomfort Outcomes Disease Definitions/ Criteria (OSDI) Sample Size, Overall and per Arm Follow-up Period, From Baseline Overall Quality Rating
Open label, single group, uncontrolled10 Preservative-free hypoosmolar (280 mOsm/L) copolymer, commercially available in Italy (Farmigea, Pisa, Italy); contains 0.2% hyaluronic acid and 0.2% tamarind seed polysaccharide, pH 7.4; 3 times daily on waking with no lens, early afternoon and before bed with lenses in CLD as measured by OSDI OSDI > 12; tear breakup time (TBUT) ≤ 10; Schirmer 1 > 10 mm 15 60 d Weak; high risk of bias (uncontrolled; placebo effect very likely)
Crossover, investigator masked11 Verbal and written instructions for using a no-rubbing, rinsing lens care regimen following the manufacturer's recommendations CLD as measured by OSDI Habitual soft contact lens daily wear for at least the past 6 mo, asymptomatic and satisfied with the vision and comfort of the habitual lenses 72 (65 completed) 10-wk study: 1-wk accrual (adaptation) followed by 2-wk trial × 3 conditions with 1-wk washout between conditions Weak; high risk of bias (nonvalidated secondary outcome measures, industry funded, bias due to inadequate randomization likely)
Open-label, parallel-group, randomized trial12 Azithromycin: 1 drop to each eye twice a day for the first 2 d, then 1 drop daily for days 3–29 applied in the morning before contact lens application
Visine for contacts: 1–2 drops 4 times a day for 29 d spaced by approximately 4 h on each dosing
Comfortable contact lens daily wear time (CFB) at week 4 (average of days 23–29) CLDEQ ≥ 2 50 (25 per arm) 4 wk (29 d) Moderate; intermediate risk of bias (open label), unbalanced, comfortable wear times at baseline may have favored treatment arm)
Open label, single group, uncontrolled, crossover13 Lotrafilcon A was worn, and fit was assessed by observer and by subjective comfort. 8.60 BC,* then 8.40 BC only if fit unsuccessful with 8.60 BC. Objective assessment of fit and subjective comfort rate (1–10 scale) after 1 and 15 min (lens settling) Habitual lens wearers 95 subjects (190 eyes), 49 eyes fitted with second lens 6-mo study but paper presents nondispensing fitting data only, 15 min Weak; high risk of bias (data from 2 eyes of 1 subject considered independent; uncontrolled, unbalanced, industry funded)
Randomized, double-masked, contralateral study14 Asymptomatic group: Focus Night & Day (CIBA Vision, Atlanta, GA) vs. Acuvue 2 (Johnson and Johnson Vision Care, Jacksonville, FL). Ocular comfort on 0–100 rating scale Habitual lens wearers 39 subjects; 20 asymptomatic lens wearers and 19 symptomatic lens wearers 7 h Moderate; moderate risk of bias (partly industry funded, no run-in prior to enrolment)
Symptomatic group: Focus Night & Day vs. Acuvue 2 (Johnson and Johnson Vision Care) and Focus Dailies (CIBA Vision) vs. Proclear Compatibles (CooperVision, Pleasanton, CA).
Randomized single masked, using deception as control15 Habitual daily wear hydrogel lens wearers were refitted with lotrafilcon A (Focus Night & Day; CIBA Vision) but told they were randomly assigned to wear either low-oxygen or high-oxygen permeability lenses and were “masked” to lens assignment. Subjective comfort and dryness VAS (0–100) Habitual lens daily wear with >4 y experience 87 (81 analyzed) 2 mo Moderate; high risk of bias (open label, habitual lens wear preintervention control likely to favor intervention; analysis not intention to treat; care regimen a potential confounder; industry funded)
Randomized, contralateral, crossover study, open label16 Hioxifilcon A lenses (extreme H2O, copolymer GMA-HEMA), diameter 14.2 mm, base curve 8.6-mm, center thickness at 3.00 diopter 0.07 mm, 59% water content, Group 2, high-water nonionic, cast-molded daily wear with fortnightly replacements. Omafilcon A (Proclear Compatibles; CooperVision), diameter 14.2 mm, BC 8.2 or 8.5 mm, center thickness at 3.00 D 0.065 mm, 59% water content, Group 2, high-water nonionic, cast-molded. OPTI-FREE Express (Alcon Laboratories) disinfection solution and Clerz Plus Lens Drops (Alcon Laboratories). Patient switched to hydrogen peroxide if solution problems suspected (number not specified) CLDEQ (frequency and severity of dryness, discomfort, and blurry vision) Previous diagnosis of mild to moderate dry eye or thinking one has dry eye or symptoms of dry eye AND either tear breakup time < 10 s, Schirmer 1 test ≤ 5 mm, staining ≥ 1, or bulbar redness 40 6 wk in each arm (crossover), 12 wk total Moderate; high risk of bias (open label, habitual lens wear preintervention control; use of baseline habitual lens wear control may have favored treatment arms; no washout)
Study 1: multicenter prevalence study
Study 2: uncontrolled, single-masked (subjects) intervention study17
Study 1: NA
Study 2: senofilcon A daily wear lens for 2 wk
Continuing with habitual lens care unless advised by investigator (unspecified)
Discomfort: 4-point scale (never, infrequent, frequent, constant) Problem contact lens patients: difference of >2 h between average and comfortable wear time OR frequent or constant discomfort or dryness symptoms on CLDEQ OR limbal or bulbar hyperemia ≥ 2 OR corneal staining ≥ 3 Study 1: 1092
Study 2: 257
Study 1: NA
Study 2: 2 wk
Moderate; high risk of bias (no washout; trial short; comparison to habitual lens wear control subject to bias; questionable external validity)
Randomized, controlled (no treatment), investigator-masked clinical study 18 Unpreserved 0.9% sodium chloride (Hydrabak; Laboratoires Thea, Clermont-Ferrand, France) in both eyes 4 times a day for 21 d. All subjects used the same contact lens care solution (type unspecified). Ocular comfort: 0–100 continuous VAS with anchors “excellent (lenses not felt)” at one end and “very uncomfortable (lenses cause irritation or discomfort)” at the other Experiencing ocular discomfort (irritation, stinging, burning , or sensation of intermittent blurred vision), TBUT ≥10 s, Schirmer 1 ≥ 5 mm in 5 min in both eyes 50; 30 randomized to intervention, 20 to control 21 d Weak; high risk of bias (no washout; trial short; comparison vs. baseline; lacking no-treatment control; confounders not measured)
Study 1: prospective cross-sectional (3 groups).
Study 2: randomized, contralateral, open label, no-treatment control 19
Study 1: etafilcon A 8.5-mm base curve (Acuvue 1-Day; Johnson and Johnson Vision Care)
Study 2: 20-μL ReNu MultiPlus (Bausch & Lomb, Rochester, NY) rewetting drop
Ocular comfort: 0–50 continuous VAS Study 2 Symptomatic: self-reporting of at least 1 symptom often or continually on Shippai Eye Study20 Dry Eye Questionnaire 60 (20 per arm) Study 1: 10 h
Study 2: 30 min
Strong; low risk of bias (no washout; primary outcome poorly described (anchors and descriptors not specified)
Single masked (subject), contralateral, no-treatment control21 2 drops of sterile, isotonic, buffered, solution of carboxymethylcellulose (CMC), sodium chloride, boric acid, potassium chloride, calcium chloride, magnesium chloride, purified water and preserved with PURITE (stabilized oxychlororcomplex) 0.005% (Refresh Contacts; Allergan, Inc., Irvine, CA) on back surface of contact lens prior to insertion vs. straight from packaging in contralateral eye Ocular comfort on 0–100 rating scale At least 1 mo of lens wear Symptomatic lens wearers based on answering “no” to “Are you able to wear your lenses for as long as you want?" 61 (59 analyzed): 12 symptomatic, 49 asymptomatic 8 h Weak; high risk of bias (2 authors employed by industry; investigator not masked; no washout; unequal arms; analysis not ITT; some data [e.g., comfort] not presented)
Crossover, single masked (investigator)22 OPTI-FREE Express Lasting Comfort No Rub Formula (Alcon Laboratories) vs. ReNu MultiPlus (Bausch & Lomb) Comfort (0–100 VAS) At least 1 y of lens wear, 8 h/d 8 4 wk Weak; high risk of bias (no washout; not randomized; sample size too low; confounders not controlled [e.g., lens type])
Multisite, uncontrolled, open label23 Nelfilcon A containing high molecular weight, nonfunctionalized polyvinyl alcohol (PVA) and packaging saline containing hydroxypropyl methylcellulose and polyethylene glycol (Triple Action Moisture DAILIES AquaComfort Plus; CIBA Vision) worn daily on daily disposable schedule Frequency and severity of 8 common subjective symptoms (tired eyes, irritated eyes, lens awareness, blurred vision, redness, discomfort, deposits, dryness) Contact lens wearer reporting at least 2 symptoms often or always 83 (81 completed) 4 wk Weak; high risk of bias (use of baseline habitual lens wear comparison may have favored treatment arm; no washout; industry sponsored, conducted, written)
Randomized, controlled, double-masked, single-center clinical trial24 3-mo absorbable glycolic acid and trimethylene carbonate punctual plug (EXTEND Absorbable Synthetic Implants; Odyssey Medical, Memphis, TN) vs. sham procedure CLDEQ Symptomatic dry eye contact lens wearers with CLDEQ score > 0.1325 32 enrolled, 22 eligible based on CLDEQ score, 19 completed 6 wk Strong; low risk of bias (sham procedure and blinding well described; regression toward the mean and placebo effect likely)
Randomized, investigator masked, placebo controlled26 Cyclosporine 0.05% ophthalmic emulsion (Restasis; Allergan, Inc.) twice per day vs. rewetting drops (carboxymethylcellulose 0.5%, Refresh Contacts; Allergan, Inc.), twice per day, to be used before and after lens wear Subjective evaluation of dryness severity (mild, moderate, severe), OSDI Self-reported history of contact lens dryness/intolerance 17 5 wk Medium; moderate risk of bias (patients unmasked; subjective bias likely); demographic data not provided
Randomized, double masked, placebo controlled39 Cyclosporine 0.05% ophthalmic emulsion vs. Refresh Preservative Free Artificial Tears (Allergan, Inc.) twice a day OSDI and National Eye Institute Refractive Error Quality of Life Instrument Chart review to identify contact lens wearers with complaints of dryness including irritation, burning, decreased wearing time 44 (22 per arm) 3 mo Strong; low risk of bias (continuing use of habitual lens and cleaning regimen potential confounder; no washout)
Randomized, double-blind, parallel-group 15- center study27 2% polyvinylpyrrolidone (PVP) vs. 0.9% NaCl 1–6 drops per day as required Overall contact lens comfort (VAS scale) Contact lens wearers complaining of discomfort and soreness, irritation, smarting, burning, blurred vision aggravated by environmental factors (air conditioning, heating, working conditions, e.g., prolonged use of visual display unit) 45 (25 PVP, 20 NaCl) 28 d Weak; high risk of bias (unbalanced; industry sponsored, conducted, written; variable dosage confounder)
Single-center, double-masked, randomized, crossover, pilot clinical trial28 Senofilcon A (Acuvue Oasys with Hydraclear Plus; Johnson and Johnson Vision Care) vs. habitual (control) during 75-min controlled adverse environment (CAE) exposure Ocular discomfort (0–4 scale) Soft contact lens wearers with histories of ocular discomfort during lens wear in windy or dry environments 11 75 min Weak; high risk of bias (use of habitual lens wear control a potential confounder; inadequate sample size; masking not described; industry funded)
Randomized, contralateral, crossover, open-label clinical trial29 Intervention 1: etafilcon A (1-DAY Acuvue; Johnson & Johnson Vision Care) vs. lotrafilcon A (NIGHT & DAY; CIBA Vision) Comfort (100-point scale) At least 12 mo of lens wear fitted 15 6 h on 4 separate days Moderate; moderate risk of bias (patients masked for lens type but unmasked for drop type except at insertion; investigators not masked)
Intervention 2: NaCl 90 mg/mL (AstraZeneca, North Ryde, NSW, Australia) vs. PVA 14 mg/mL, povidone 6 mg/mL, sodium chloride (Refresh; Allergan, Inc.) vs. carboxymethylcellulose (CMC) 5 mg/mL (Cellufresh; Allergan, Inc.) every 2 h for 6 h
Prospective, single-masked (subjects), randomized, crossover study30 Lotrafilcon A with hypoosmotic (280 mmol/kg) vs. hyperosmotic (380 mmol/kg) saline 15 μL 4 times a day Comfort (1–100 scale) Symptomatic lens wearers with maximum comfortable wearing time < 6 h 15 6 h Strong; low risk of bias (investigator not masked)
Randomized, controlled, double-masked, 19-site study31 OPTI-FREE RepleniSH (Alcon Laboratories) vs. ReNu MultiPlus No Rub Formula (Bausch & Lomb) Comfort and dryness scores (0–100 scale) Symptomatic wearers of group IV soft lenses answering disagree or strongly disagree to “My contacts are comfortable all day long” and agree or strongly agree to one or both of “During the day, I take my contacts out earlier than I like because they become uncomfortable” and “Late in the day, my contacts become uncomfortable but I continue wearing them” 362 (183 OPTI-FREE vs. 179 ReNu MultiPlus) 28 d Medium; moderate risk of bias (no washout; lens type solution interactions likely confounder)
Randomized, crossover study, open label32 Omafilcon A (Proclear; CooperVision) vs. new habitual lenses (control) Subjective symptoms VAS (10 cm) scale (comfort and dryness severity; dryness, eye irritation, itchiness, burning, soreness, scratchiness, grittiness, watering, light sensitivity frequency) Contact lens wearers with dry eyes (NEI definition: Schirmer without anesthesia ≤ 5 mm, rose bengal staining ≥ 3, fluorescein staining ≥ 3, meibomian gland dysfunction ≥ 2) 76 6-wk crossover Weak; high risk of bias (open label likely to favor new lens type; use of more than 1 lens type as control a confounder; industry funded)
Randomized, double-masked, cross-over study33 Lotrafilcon B with polyhexamethylene biguanide (PHMB) (Solocare Aqua; CIBA Vision) vs. PHMB with surfactant (Hidro Health, Disop, Spain) solutions 10-item symptoms questionnaire (0–10 scale): discomfort, blurry vision, lens-handling problems, dryness, redness, tearing, burning, itching, discharge, dissatisfaction + CLDEQ Daily wear of lotrafilcon B for >3 mo 54 1-mo crossover Strong; low risk of bias
Randomized, crossover, single masked (participant)34 5 silicone hydrogels: galyfilcon A (Acuvue Advance; Johnson & Johnson Vision Care); senofilcon A (Acuvue OASYS; Johnson & Johnson Vision Care); lotrafilcon B (O2Optix; CIBA Vision); lotrafilcon A (NIGHT & DAY; CIBA Vision); balafilcon A (PureVision; Bausch & Lomb) disinfected with ClearCare (AOSept Plus; CIBA Vision) for >6 h Comfort, burning, dryness, analogue scales (0–100) with verbal anchors at various times (insertion, settling, 8 h, 12 h on days 1, 4, 7, 10, and 14 using handheld wireless communication devices Adapted soft lens wearers 55 (45 completed and analyzed) 4-wk crossover with 1 d washout High; low risk of bias (base curve selection for 2 of 5 lens types a potential confounder; single masked only)
Retrospective multistudy, multicenter analysis, open label, uncontrolled9 Lotrafilcon A (NIGHT & DAY; CIBA Vision) or lotrafilcon B (O2Optix; CIBA Vision) daily wear or continuous Dryness during the day and end-of-day from CLDEQ Adapted soft lens wearers (nonsilicone hydrogel) 259 2 wk (lotrafilcon B) or 1 mo (lotrafilcon A) Weak; high risk of bias (open label; subject masked to study sponsor only, not to lens type; retrospective; uncontrolled; multiple wear schedule and lens type a confounder)
Contralateral, randomized, double masked35 Etafilcon A (Acuvue; Johnson and Johnson Vision Care) vs. Omafilcon A (Proclear Biocompatibles; CooperVision) Subjective comfort and dryness (100-mm VAS scale with anchors at 0 = very dry and 100 = no dryness) at 0, 1, 3, 5, and 7 h Symptomatic: Wearers with symptoms of dryness after 5 h of wear with consequently reduced wearing time and use of lubricating drops at least once daily 40 (20 symptomatic, 20 asymptomatic) 7 h Moderate; moderate risk of bias (no washout; contralateral eye effect potential confounder)
Asymptomatic: wearers without symptoms of dryness or discomfort who could wear lenses all day without use of lubricants
Randomized, investigator-masked, crossover study36 Hydroxypropyl methylcellulose (HPMC) (COMPLETE ComfortPLUS; Allergan, Inc.) vs. citrate (No Rub OPTI-FREE Express; Alcon Laboratories) solution with fresh habitual lenses Daytime and end-of-day comfort and dryness (50-point continuous scale with anchors 0 = impossible to wear and 50 = excellent) Experienced daily lens wearers 75 (64 completed) 1-mo crossover with 1-wk washout Moderate; moderate risk of bias (participants masked only to study sponsor; lens type confounder, industry funded)
Retrospective, 7-study open-label trial37 Senofilcon A (Johnson & Johnson Vision Care) daily wear with multipurpose solution (MPS) (one of Polyquad/EDTA, Alcon Laboratories; Polyquad/nonanoyl-EDTA, Alcon Laboratories; PHMB/borate, Bausch & Lomb; PHMB/phosphate, CIBA Vision) vs. hydrogen peroxide (H2O2) vs. daily disposable (DD) Comfort and dryness on a 1–10 scale with anchors 1 = poor and 10 = excellent Previous wear experience not specified 283 (160 MPS, 83 H2O2, 40 DD) 3 mo Weak; high risk of bias (open label; not randomized; retrospective; multiple MPS and replacement schedule confounders; unbalanced; same participants in more than 1 trial)
Randomized, investigator-masked, 2-site crossover study38 No Rub OPTI-FREE Express (Alcon Laboratories) vs. Complete (Allergan, Inc.) or ReNu MultiPlus (Bausch & Lomb) with Acuvue 2 (Johnson and Johnson Vision Care) or Softlens 66 (Bausch & Lomb) Subjective preference based on answer to “Did you notice a difference in comfort provided by the study solutions?” Daily wearers 89 (47 and 42 at each site); 71 completed 2-mo crossover with 72-h washout Weak; high risk of bias (participants not masked; unequal group sizes; randomization not stratified by site)
Interventional trials have included examining the effects of lens fitting characteristics, 13 lens type, 9,1417,23,28,29,32,34,35 lubricating 10,12,18,19,21,23,27,29,30 and therapeutic 12,26,39 eye drops, and lens care regimen. 11,22,31,33,3638 A common limitation of these studies is the poor control of confounding variables such as care regimen, prior lens wear, wear experience, and timelines of reporting symptoms. The extent of visual near tasks or computer/video terminal use should be quantified and characterized. Potential effects of concurrent medications, both topical and systemic, require evaluation, as well as effects of seasonal allergy and climate. 
Outcomes and Predictive Factors
Discomfort can be described by a study participant in a clinical trial in various ways. The relative activation by the stimulus of subpopulations of ocular surface sensory fibers evokes different qualities of irritation and pain sensations (see the report of the Neurobiology Subcommittee). 40,41 Most of this corneal sensory research has been conducted without contact lens wear, so the role of these various nociceptors in CLD is not well established. Dryness is a frequently described sensation of CLD in study participants with reduced tolerance for contact lens wear, 13 particularly of higher intensity later in the day of wear. 1,2,42  
Subjective Outcome Measurement
Clinical scientists rely on information in the form of data, some relatively direct (e.g., visual acuity) and other data less so (e.g., feelings of ocular surface dryness). These latter outcomes are often regarded as outcome measures and dealt with as though they are numbers, although whether all of these numbers can be regarded as distinct measurements is still unclear. 43 This concern is particularly salient when we do not have direct access to what is being measured and the dimensions or units as well as scaling of the metrics are unknown. This is by no means unique to the vision sciences and occurs frequently in psychometrics 4446 and psychophysics. 47,48  
Part of the problem with trying to develop and evaluate qualitative or descriptive measurements (so called latent variables) is that they may or may not represent the property being measured. Wearer experience of discomfort is influenced by multiple contextual factors, which adds to the complexity of measurement. When developing new instruments, it is important to consider content validity compared with an established reference, if possible. 49 If measurements are “the same” as a gold standard, this is an empirical demonstration that the novel metric is as good as the reference (this is not quite a calibration, but it demonstrates that the new and old measures map onto each other in some rational way). If such is not the case, the validity of the measurement needs to be demonstrated in a number of possibly less direct ways. 46 Distinct from the measurement of a one-dimensional sensation, a patient-reported outcome instrument attempts to capture the patient experience in a more aggregate form. These instruments often have many questions, but are validated to show that they relate to self-assessment of the severity of conditions and change in condition. Not many potential patient-reported outcomes instruments have been used to assess CLD in some quantitative way, and all but one have been tested in only subjects who were not wearing contact lenses. Table 2 summarizes this list. 1,25,5062 Only one of these instruments was directly designed to examine symptoms in contact lens wearers, 25 and it has recently been validated in a shorter iteration. 1  
Table 2. 
 
Candidate Outcomes for Clinical Trials
Table 2. 
 
Candidate Outcomes for Clinical Trials
Name, Reference Validation With a Contact Lens–Wearing Population
Developed for contact lens wear
 Contact Lens Dry Eye Questionnaire (CLDEQ)25 Yes; screening
 CLDEQ-81 Yes; screening and responsiveness
 Contact Lens Impact on Quality of Life (CLIQ)50 Yes; quality of life; keratoconus only
Developed for dry eye without contact lenses
 Dry-Eye Questionnaire (DEQ)51 No
 DEQ552 No
 Ocular Surface Diseases (OSD) questionnaire (in French)53 No
 Impact of Dry Eye on Everyday Life (IDEEL) questionnaire54 No
 McMonnies55 No
 Ocular Surface Disease Index (OSDI)56 No
 Symptom Assessment iN Dry Eye (SANDE)57 No
 Subjective Evaluation of Symptom of Dryness (SeSOD)58 No
 Short questionnaire for dry eye syndrome (DES) questionnaire59 No
 Unnamed questionnaire (in Spanish)60 No
 Standard Patient Evaluation of Eye Dryness (SPEED)61
 Texas Eye Research and Technology Center (TERTC)62 No
Generally the direct validation work for ocular surface symptoms has not been on lens wearers specifically and has been descriptive in nature; and there have been a few reports of use of a theory-based assessment of the measurements (all using Rasch Analysis). The only validated contact lens–related dryness symptom measurement tool at the present time is the CLDEQ or its short form, CLDEQ-8. 1 The CLDEQ was validated in 2002 as a measure predictive of a doctor's diagnosis of contact lens dry eye. 25 In its long form, it was shown to have a sensitivity of 83% and specificity of 67%. 25 Scoring of the CLDEQ-8 involves summation of the items. In the validation work, the ranges for CLDEQ-8 sum score at baseline according to the wearers' overall opinion of their habitual contact lenses was as follows: Fair 17.4 ± 8.7, Good 13.7 ± 6.4, Very Good 9.1 ± 4.7, and Excellent 6.4 ± 3.7. Thus, using the CLDEQ-8 assessment of the symptoms with habitual lenses may help determine wearers who would benefit from management of their CL-related discomfort, and scores of 13 or above should warrant clinical attention. This version's diagnostic accuracy has not been tested. (Note that the CLDEQ-8 is copyrighted by Indiana University for public use. The university requires only that the copyright be cited in any publication reporting results with the instrument.) 
Further assessment of patient symptoms can be done with respect to onset and time course to determine when CLD is occurring. Contact lens discomfort at the beginning of the day, but improving over time with wear, may have a different etiology than CLD with an onset at the end of the day. A further useful measure may be the duration of comfortable lens wear. Evaluation of the frequency and intensity of symptoms should be accomplished using a questionnaire designed to better understand the frequency and intensity of CLD. If a daily diary is used or it is necessary to assess symptoms at a particular point in time, a 0 to 100 visual analogue scale (VAS) or 0 to 10 scales may be more appropriate until alternative metrics can be developed and properly validated. 
Clinical Measures That May Describe CLD
In an attempt to assess a number of outcome measures that are not subjective but that may be predictive of CLD, a PubMed literature review was conducted using the search terms “comfort AND contact lenses” with the addition of search terms related to the outcome. The Subcommittee on Clinical Trial Design and Outcomes agreed in advance to investigate a number of outcome measures that fall under the broad categories of staining, hyperemia, tear film changes, vision, ocular sensitivity and contact lens surfaces. The resulting relevant manuscripts were reviewed and evaluated for standardization and agreement. There is a large volume of work reporting on contact lens outcomes, and so a representative list of studies investigating CLD is presented in Table 3. A few “other” assessments/responses to contact lens wear are also described in this section. 
Table 3. 
 
Clinical Measures of CLD
Table 3. 
 
Clinical Measures of CLD
Outcome Associated With CLD? Methods Key Findings
Corneal staining Yes Data obtained from 7 prospective trials, n = 283; 4 groups wore senofilcon A lens material on a daily-wear basis using multipurpose solutions (DW-MPS, n = 160), 2 groups using hydrogen peroxide (DW-H2O2, n = 83), and 1 group wearing the lens on a daily disposable basis (n = 40). Participants were followed for 3 mo using the same protocol. Comfort at insertion and end of day, and end-of-day dryness scores, were significantly lower for participants who experienced solution-induced corneal staining (SICS; 8.2 ± 1.6, 7.0 ± 1.9, and 7.0 ± 2.2) than for those who did not (8.8 ± 1.2, P = 0.004; 7.9 ± 1.7, P = 0.002; and 7.9 ± 1.8, P = 0.003, respectively).37
Yes Ninety-day, randomized, concurrently controlled, double-masked, multisite study involved 573 subjects at 30 investigational sites in the United States, using 1 of 2 multipurpose disinfecting solutions. Differences noted in the level of corneal staining (SICS) between the 2 disinfecting solutions, and the solution that gave most SICS was rated worse for subjective comfort (insertion, removal, overall).66
Yes Retrospective analysis of a series of open-label studies conducted with 24 groups of approximately 40 participants, each wearing 1 of 6 silicone hydrogel contact lenses with 1 of 4 lens care products bilaterally for 3 mo of daily wear. Participants with SICS had lower levels of comfort during the day (7.9 ± 1.7 vs. 8.5 ± 1.4, P = 0.03), comfort at the end of the day (6.6 ± 2.1 vs. 7.4 ± 1.9, P = 0.03), overall dryness (7.4 ± 1.9 vs. 8.0 ± 1.7, P = 0.04), dryness at the end of the day (6.7 ± 2.2 vs. 7.5 ± 2.1, P = 0.01), feelings of burning and stinging (8.5 ± 2.0 vs. 8.9 ± 1.8, P = 0.02), and overall vision (8.2 ± 1.6 vs. 8.7 ± 1.3, P < 0.001).64
Yes Two sites conducted a randomized, investigator-masked, 2-mo crossover study; n = 45 used regimen 1 and 2 for 1 mo each (study 1), and n = 44 used regimen 1 and 3 for 1 mo each (study 1). 1 of 2 soft lens types was randomly assigned, and the same lens type was worn throughout the study. Significantly more subjects preferred the comfort of an MPS that gave low levels of corneal staining (SICS) (61.8%) to that of regimen 3 (11.8%).38
Possibly One-week, daily-wear, subject-masked, bilateral, parallel-group study with subjects (n = 282) randomly assigned to 1 of 2 daily disposable soft contact lenses. There was a weak correlation between corneal staining and comfort for 1 lens (r = 0.27, P = 0.002, n = 136), but not the other (r = −0.11, P = 0.18, n = 140).70
Possibly Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses who were required to have consistently used a polyhexamethylene biguanide (PHMB)- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; corneal staining. No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, or burning or stinging. However, grittiness or scratchiness was higher with PHMB-containing system, and so were the level and extent of corneal staining (SICS).71
No Prospective, bilateral, single-masked (investigator), randomized crossover design with 4 phases (1 for each care system). Each study phase comprised 2 consecutive days of lens wear on which the lenses were inserted on day 1 directly from the blister-packs and worn for over 8 h, then inserted on day 2 after overnight disinfection with 1 of the study lens care systems. N = 25 adapted soft contact lens wearers who were able to wear their habitual lenses comfortably for more than 12 h were recruited. Even though 1 MPS was associated with high levels of corneal staining (SICS), there was no difference between the lens care systems and subjective comfort over a 2-d period.63
No Three-month prospective study; n = 120 participants were randomized into 1 of 3 lens types (etafilcon A, narafilcon A, and senofilcon A), all worn bilaterally on a daily disposable regimen; observations were at baseline, 2-wk, and 1- and 3-mo visits. No differences were found between lenses in the 1–100 rating scale (P > 0.05) even though some lenses had statistically worse corneal staining.64
No A series of pilot studies using a total of 27 subjects (some of whom were enrolled in 2 or more studies) was conducted over 11 mo using a double-masked, randomized, crossover design. Asymptomatic, adapted, daily-wear soft lens users were included; evaluations were at baseline and after 1 and 2 h of wear. Significantly increased extent of corneal staining (SICS) was observed at 2 h when subjects used silicone hydrogel lenses soaked an MPS, but significant levels of symptoms were not correlated with extent of staining.65
No Prospective, double-masked, single-investigator study; n = 20 participants were recruited for 2 visits with lenses worn bilaterally for 2 h. Comfort scores did not differ between eyes (P > 0.05) despite significantly less corneal staining (SICS) in 1 eye compared to the other.68
No Double-masked, randomized, 1-mo crossover study; n = 50 adapted soft lens wearers. Significantly different (P < 0.01) levels of relatively asymptomatic corneal staining (SICS) were observed with 1 lens care solution (37%) compared to the other (2%); symptoms were not correlated with the degree of staining.69
No Observational study; n = 50 (19 men, 31 women; mean age, 32.1 ± 11.4 y) adapted lens wearers. Comfort was evaluated using the Contact Lens Dry Eye Questionnaire. Corneal staining was assessed in the right eyes. Nonparametric analyses were used to study differences between groups and correlations between objective tests and symptoms. No difference in corneal staining observed between asymptomatic and symptomatic lens wearers.72
Conjunctival staining Yes The study was conducted on a cohort population of 27 established soft contact lens wearers, who wore each contact lens type, in a random order, for a period of 10 (±2) days. Circumlimbal staining was measured in a double-masked fashion through image analysis of digital photographs of lissamine green taken under controlled experimental conditions. An inverse association between circumlimbal staining and contact lens comfort was demonstrated. Lenses with a rounded edge design produced the lowest comfort (72 of 100) whereas lenses with a knife-edge design produced the highest (87 of 100).82
Yes Overall staining, as well as staining at 5 separate sites (limbal, nasal band, temporal band, superior, and inferior), was graded on an analogue scale in 48 contact lens–wearing subjects and 50 control non–lens wearers. The degree to which subjects experienced sensations of dryness, wateriness, itchiness, grittiness, and comfort was also assessed using analogue scales. In regression analysis, overall conjunctival staining was associated with the degree of dryness and the amount of itchiness.83
Yes Lissamine green and sodium fluorescein conjunctival staining were assessed in 102 soft contact lens wearers and 79 non–contact lens wearers. Lissamine green staining (≥grade 1) could discriminate symptomatic from asymptomatic lens wearers (P = 0.007).84
No/possibly Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses who were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; conjunctival staining. Nasal and temporal conjunctival staining was significantly higher for users of PHMB-containing systems (P < 0.05). No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, or burning or stinging; but grittiness or scratchiness was significantly higher with the PHMB-containing system.71
Conjunctival indentation Yes A new method to measure contact lens osmolality was validated by testing for repeatability and by evaluating independence of lens material, power, and osmolality value of the lens. This method was then used in a clinical study. 15 subjects wore each of 9 different lens types. Osmolality, tear film, and ocular surface parameters were tested for their association with comfort using linear mixed model. Comfort was associated with conjunctival indentation (P = 0.002, r = −0.37) (Stahl U, et al. IOVS 2009;50:ARVO E-Abstract 2611).
Palpebral conjunctival staining, including lid wiper staining and lid parallel conjunctival folds Yes Subjects were divided into 2 groups based on the presence or absence of dry eye symptoms. The lid wiper of asymptomatic (n = 75) and symptomatic (n = 30) soft contact lens wearers was examined following the instillation of fluorescein and rose bengal dyes. Lid wiper staining was graded zero to 3. Eighty percent of the symptomatic subjects displayed lid wiper staining compared to 13% of the asymptomatic subjects (P < 0.0001).92
Yes Observational study; n = 50 (19 men, 31 women; mean age, 32.1 ± 11.4 y) adapted lens wearers. Comfort was evaluated using the Contact Lens Dry Eye Questionnaire. Corneal staining, lid wiper epitheliopathy, and lid parallel conjunctival folds were assessed in the right eyes. Nonparametric analyses were used to study differences between groups and correlations between objective tests and symptoms. Lid wiper epitheliopathy and lid parallel conjunctival folds were significantly increased (P < 0.035) in the symptomatic lens wearers.72
Palpebral roughness No/possibly Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses who were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; palpebral roughness. No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, burning or stinging, but there was an increase in grittiness or scratchiness (P = 0.045) for the PHMB system and also an increased level of palpebral roughness (P = 0.014).71
Conjunctival hyperemia Yes Cross-sectional study on 415 contact lens wearers in which a number of tear film, contact lens, and patient-related factors were measured and examined in relation to dry eye status. Univariate and multivariate logistic regression models were used, and data from 360 of the 415 subjects were used in the analyses. Several factors were shown to be related to dry eye status in multivariate modeling, including limbal injection (P = 0.03).75
No Prospective, randomized, parallel-group, 3-mo study; n = 120 participants (40 in each group) wore 1 of 3 lens types (etafilcon A, narafilcon A, and senofilcon A), all worn bilaterally on a DD regimen. Participants were observed at baseline, 2-wk, and 1- and 3-mo visits in which ocular physiology and lens performance variables were collected on a 0–4 grading scale in 0.1 increments. Subjective comfort and vision ratings were collected on a 1–100 rating scale and in the form of symptom severity. Even though 1 lens type was associated with significantly more limbal redness (P < 0.01), there were no differences in comfort between lenses (P > 0.05).72
Limbal hyperemia No Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses who were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; limbal and bulbar hyperemia. No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, burning or stinging (except grittiness or scratchiness), or for limbal or bulbar hyperemia.71
Tear film stability Yes Thirty-eight subjects participated; 20 were successful contact lens wearers and 18 had discontinued contact lens wear because of discomfort. Baseline tear film (no lens wear) was analyzed with a range of clinical measurements and protein analyses (lactoferrin, sIgA, and lysozyme). Comfort was determined after 6 h of lens wear, and differences in tear film characteristics between subject groups were determined. Tests were performed in absence of contact lens wear. Tear stability (noninvasive tear breakup time) was significantly reduced in intolerant wearers (P < 0.05).107
Yes Cross-sectional study on 415 contact lens wearers in which a number of tear film, contact lens, and patient-related factors were measured and examined in relation to dry eye status. Univariate and multivariate logistic regression models were used, and data from 360 of the 415 subjects were used in the analyses. Several factors were shown to be related to dry eye status in multivariate modeling, including rapid pre-lens tear film thinning time (P = 0.008).75
Possibly Randomized, double-masked, contralateral, 7-h nondispensing study; n = 40 (20 symptomatic and 20 asymptomatic lens wearers). Lens water content was measured before and after 7 h of lens wear, and pre-lens noninvasive tear film breakup time (NITBUT) was measured immediately after insertion and after 5 h of lens wear. Subjective comfort and dryness were rated at 0, 1, 3, 5, and 7 h of lens wear. Symptomatic hydrogel contact lens wearers with decreased wearing time had measurably reduced NITBUT.35
Possibly Randomized, subject-masked bilateral crossover study of silicone hydrogel lenses in 24 adapted soft contact lens wearers. Tear film stability was superior for 1 lens over the other, and the authors concluded that this was associated with an overall better comfort for this lens.105
No Prospective, 8-h nondispensing study; n = 30 adapted soft contact lens wearers (16 symptomatic and 14 asymptomatic) were fitted with etafilcon A lenses. In vivo wettability, NITBUT, and subjective symptoms (vision, comfort, and dryness) were assessed at baseline and after 2, 4, 6, and 8 h. After 2-, 4-, 6-, and 8-h time points, lenses were collected, and total protein, total lysozyme, and active lysozyme deposition were assessed. There was no significant difference in the NITBUT values between the 2 groups at any time point (P > 0.05), but the 8-h time point was significantly lower than the baseline measurement in both the symptomatic and asymptomatic groups (P = 0.032).106
No Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; noninvasive and fluorescein breakup time. No significant difference between 2 preservative system groups was noted for overall or end-of-day comfort, discomfort, burning or stinging (except grittiness or scratchiness) or for tear breakup times.71
Tear film volume Yes Thirty-eight subjects participated; 20 were successful contact lens wearers and 18 had discontinued contact lens wear because of discomfort. Baseline tear film (no lens wear) was analyzed with a range of clinical measurements and protein analyses (lactoferrin, sIgA, and lysozyme). Comfort was determined after 6 h of lens wear, and differences in tear film characteristics between subject groups were determined. Tests were conducted in absence of contact lens wear. Tear volume (meniscus height and phenol red thread test) were significantly reduced in intolerant wearers (P < 0.05).107
No Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; tear meniscus height, Schirmer, and fluorescein clearance tests. No significant difference noted between the 2 preservative system groups for overall or end-of-day comfort, discomfort, burning or stinging (except grittiness or scratchiness), and tear meniscus height, Schirmer test, or fluorescein clearance.71
Tear lipid layer Possibly Randomized, subject-masked bilateral crossover study of silicone hydrogel lenses in 24 adapted soft contact lens wearers. Lipid layer thickness was superior for 1 lens over the other, and the authors stated that this may have been a reason for the better comfort for that lens over the other.105
No Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; preocular tear film lipids. No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, burning or stinging, except grittiness or scratchiness, and no difference in clinical assessment of tear film lipid layer.71
Tear film osmolarity Yes Cross-sectional study on 415 contact lens wearers in which a number of tear film, contact lens, and patient-related factors were measured and examined in relation to dry eye status. Univariate and multivariate logistic regression models were used, and data from 360 of the 415 subjects were used in the analyses. Several factors were shown to be related to dry eye status in multivariate modeling, including increased tear film osmolality (P = 0.05).75
No Prospective, 8-h nondispensing, crossover study; the right eyes of 15 neophytes were included. Tear osmolarity was measured before and after 4 and 8 h of each contact lens wear. Ocular comfort was assessed after 4 and 8 h of each contact lens wear. Tear osmolarity was not associated with ocular comfort.114
No Thirty-eight subjects participated; 20 were successful contact lens wearers and 18 had discontinued contact lens wear because of discomfort. Baseline tear film (no lens wear) was analyzed with a range of clinical measurements and protein analyses (lactoferrin, sIgA, and lysozyme). Comfort was determined after 6 h of lens wear, and differences in tear film characteristics between subject groups were determined. Tear osmolarity was not statistically significantly different between tolerant and intolerant contact lens wearers (osmolality [mOsmol/kg] 317.4 and 324.4, respectively, P = 0.069), even though intolerant wearers had a greater number of symptoms than tolerant wearers (P < 0.05).107
No A new method to measure contact lens osmolality was validated by testing for repeatability and by evaluating independence of lens material, power, and osmolality value of the lens. This method was then used in a clinical study. 15 subjects wore each of 9 different lens types. Osmolality, tear film, and ocular surface parameters were tested for their association with comfort using linear mixed model. Comfort after 6 h of lens wear was not associated with tear osmolality after lens wear (P = 0.993).85
Contact lens osmolality Yes A new method to measure contact lens osmolality was validated by testing for repeatability and by evaluating independence of lens material, power, and osmolality value of the lens. This method was then used in a clinical study. 15 subjects wore each of 9 different lens types. Osmolality, tear film, and ocular surface parameters were tested for their association with comfort using linear mixed model. Comfort after 6 h of lens wear was associated with the osmolality of the worn lens (P = 0.006, r = −0.41). Osmolality of worn lenses significantly correlated with tear film breakup time (P = 0.003, r = −0.22), lens water content (P < 0.001, r = −0.58), conjunctival indentation (P < 0.001, r = 0.45), and ocular sensitivity (P < 0.05) after 6-h lens wear.85
Optical quality No peer reviewed publications on this topic
Corneal sensitivity Yes N = 32 symptomatic and 29 asymptomatic contact lens wearers (aged 20–42 y, 6 males and 26 females; and 21–36 y, 9 males and 20 females, respectively). Mechanical stimulus thresholds of the cornea were determined using a Belmonte pneumatic esthesiometer and the ascending method of limits. Then 3 stimulus intensity groups (subthreshold, threshold, and suprathreshold) were applied to the eye in random order, each 20 times. Subjects rated the intensity of the stimuli using a scale of zero to 4. The rating data from the 2 groups were compared by Friedman nonparametric ANOVA. Adaptation was defined as the reduction in subsequent ratings compared with earlier ones. Adaptation was found to suprathreshold mechanical stimuli in the asymptomatic group but not in the symptomatic group121; in other words, the symptomatic group responded as much to the first suprathreshold stimulus as the last and never gained “tolerance” to the stimulus.121
No Non–contact lens wearers and subjects who had worn soft contact lenses for more than 1 y were recruited and were divided into 3 groups: (1) normal controls, (2) contact lens wearers without dry eye, (3) contact lens wearers with dry eye. Corneal sensitivity was measured with a Cochet-Bonnet esthesiometer. Nerve density and branching in the subepithelial plexus were measured using in vivo confocal microscopy. Tear nerve growth factor and tissue growth factor-beta1 levels were measured with an enzyme immunoassay. Both sets of contact lens wearers had reduced corneal sensitivity (P = 0.032) compared to the normal controls,122 but there was no difference in sensitivity between contact lens wearers with and without dry eye complaints.
Conjunctival sensitivity Yes Fifteen subjects, 9 lens types, lenses worn for 6 h; sensitivity measured with an air jet aesthesiometer at baseline and following lens removal. Comfort associated with a change in corneal and conjunctival sensitivity.159
In vivo contact lens wettability No Prospective, randomized, bilateral, crossover study; n = 15. Initial comfort and surface wettability were compared between 3 lens types (Novalens [Ocu-Tec, Bellshill, North Lanarkshire, UK], ENVISION [Bausch & Lomb], and D3X4 [Wesley-Jessen, Des Plaines, IL]). Initial comfort was significantly better with the D3X4 lens; no significant difference was found between the 2 rigid lens materials. No significant difference in lens surface wettability was found between the 3 materials.124
No Prospective, 8-h nondispensing study; n = 30 adapted soft contact lens wearers (16 symptomatic and 14 asymptomatic) were fitted with etafilcon A lenses. In vivo wettability, NITBUT, and subjective symptoms (vision, comfort, and dryness) were assessed at baseline and after 2, 4, 6, and 8 h. After 2-, 4-, 6-, and 8-h time points, lenses were collected, and total protein, total lysozyme, and active lysozyme deposition were assessed. In vivo wettability was reduced over the course of the day for both groups, but was not statistically significant (P > 0.05). There was also no significant difference in wettability between the 2 groups at any time point (P > 0.05).106
No Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness, and visual changes; noninvasive and fluorescein breakup time; preocular tear film lipids, tear meniscus height, Schirmer, and fluorescein clearance tests; limbal and bulbar hyperemia; palpebral roughness; corneal and conjunctival staining; lens front surface wetting; and lens film deposits. Front surface lens wettability was significantly better for group IV polyquaternium-1 users compared to PHMB users (P = 0.008), with 84% vs. 72%, respectively, with lenses graded by the investigator as having “good” or “excellent” wettability. No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, burning or stinging, grittiness or scratchiness.71
Ex vivo wettability Possibly Randomized, single-masked study, n = 6; test and control lenses were soaked for 12 h in either saline or 1% aqueous solution of poloxamine 1107. The advancing and receding contact angles were determined ex vivo after various periods of wear. Control saline-soaked lenses exhibited no change in wetting angles over time, indicating a lack of surface modification by components within the tear film. Poloxamine-soaked lenses exhibited a significantly reduced advancing angle (P < 0.001) and hysteresis angle (P < 0.001) when compared with control lenses. In addition, treated lenses were consistently rated as more comfortable than control lenses (P = 0.04).125
Staining of the Cornea.
Staining of the cornea is an established method of evaluating the ocular surface. 37,38,6372 For corneal staining, sodium fluorescein is generally used, and methods for instillation and observation have been reported. 73,74 Corneal staining is often measured in studies evaluating CLD; however, it has been reported to be a frequent outcome that is not well understood. 74,75 With respect to grading corneal staining, there are various systems in use; however, only some have been validated for precision and reliability, such as the Efron scale and the Cornea and Contact Lens Research Unit (CCLRU) scale. 76 Information related to corneal staining can include its severity, type, and location, which can be used to help identify the etiology for the staining and may be important to understand its impact on CLD. Diffuse staining, when people use daily wear of lenses with multipurpose disinfecting solutions, in a characteristic annular pattern across the entire cornea or concentrated in three or more peripheral quadrants, has been described as solution-induced corneal staining (SICS), 77 also known as preservative-associated transient corneal hyperfluorescence. 78 This is quantified mainly on the extent (or % corneal coverage) of corneal staining. 69,79,80  
Of the studies reviewed, investigations typically compare corneal staining at baseline to staining at follow-up visits, subsequent to an intervention with one or more contact lens types or lens care systems. Baseline visits often occur following a “washout” period of no lens wear or earlier in the day prior to lens insertion. Studies investigating SICS have performed measurements at baseline, then after 2 to 4 hours of lens wear, 65,79 and then again at the end of the day. 
As indicated in Table 3, corneal staining may be related to CLD; however, there have been mixed reports in the literature. The location and type of corneal staining may be important for different aspects of contact lens performance. 
It is recommended that studies report method and techniques used to assess staining and that a common grading system be adopted to aid in the interpretation of staining across studies. Grading methodology, such as the methodology proposed in the report of the National Eye Institute and Industry-Sponsored Dry Eye Workshop, 81 may not be adequate to grade corneal staining observed with contact lens wear. With respect to SICS, a better understanding of the uptake and release profiles of excipients in the disinfecting solutions with contact lenses may aid in study design, particularly with respect to determining the optimal times for clinical assessments to be conducted. In fundamental studies, where certain lens characteristics, lens care systems, or other variables are altered, controlling as many other factors as possible is warranted to better understand the relationship between corneal staining and CLD. 
Staining and Indentation of the Bulbar Conjunctiva.
Changes in the bulbar conjunctiva occur with CL wear. 71,8285 Either sodium fluorescein or lissamine green dyes are typically used for the assessment of conjunctival staining; however, lissamine green has been reported to be better at differentiating symptomatic from asymptomatic contact lens wearers. 84 A number of different grading scales have been used, such as the Efron scale 86 and the CCLRU scale. 87 Other scales developed for evaluation of dry eye include the National Eye Institute/Industry Workshop scale, 81 the TFOS Dry Eye Workshop scale, 88 and the Sicca scale 89 ; but these have not been validated for evaluation with contact lens wear. It is recommended that the type of conjunctival staining, such as lens edge–related conjunctival staining 8284,90,91 or diffuse conjunctival staining, be specified. As indicated in Table 3, conjunctival staining and indentation may be associated with CLD. 
Staining and Roughness of the Palpebral Conjunctiva.
Korb et al. 92 introduced the term “lid wiper” to refer to the area of the upper eyelid that spreads tears over the surface of the cornea (or contact lens) and the term “lid wiper epitheliopathy” (LWE), which refers to the disruption of epithelial cell integrity in this area. A similar area in the lower eyelid margin has also been identified. 93 The suspected etiology of this epitheliopathy is increased friction between the lid wiper area and the surface of the cornea or contact lens as a result of inadequate lubrication 94 ; however, this etiology still needs to be tested. 
There are studies suggesting that LWE is more frequent in individuals reporting CLD; however, there have been no studies showing that the amount of LWE is related to the level of symptoms. Confirmatory studies are necessary to determine whether LWE is a good outcome measure of CLD. Standardization of dye instillation and assessment are also warranted since various methodologies have been reported. 92,95 There is one study that showed a possible effect of palpebral roughness on the symptoms of grittiness and scratchiness during contact lens wear. 71  
Lid Parallel Conjunctival Folds.
Lid parallel conjunctival folds (LIPCOF) have been described by Hoh et al. 96 and are defined as subclinical folds parallel to the upper and/or lower eyelid margin in the temporal and nasal areas of the bulbar conjunctiva. Lid parallel conjunctival folds have been shown to be significantly increased in symptomatic contact lens wearers 9698 and to be positively correlated with LWE. 97 While LIPCOF may be predictive of CLD, prospective studies to investigate onset and recovery and whether the severity of LIPCOF is related to the severity of CLD are warranted. 
Conjunctival and Limbal Hyperemia.
Vascular dilatation can occur with CL wear. 67,75 Conjunctival hyperemia is often increased with contact lens wear compared to non–lens-wearing eyes. 99,100 However, since conjunctival hyperemia is affected by a number of factors, such as corneal hypoxia, 101 protein adsorption with lens overwear, 102 and lens fit, 103 it has generally not been a good outcome measure or predictor of CLD. 
Tear Film Stability.
Changes in tear film stability occur with CL wear. 35,71,75,104106 There have been mixed reports about the relationship between tear film stability and contact lens comfort. Reduced tear film stability has been reported in symptomatic and intolerant contact lens wearers, 75,107 while Fonn et al., 35 Guillon and Maissa, 36 and Guillon et al. 108 report no difference in tear stability between symptomatic and asymptomatic contact lens wearers in the absence of lens wear. Various techniques are used to assess tear film stability, and it has been noted that endpoint criterion used for measurements can also differ. 109,110 Standardization in methodology would be helpful to further evaluate the relationship between tear film stability and CLD. No optimal method for assessing tear film stability has yet been defined or validated, and this is needed. 
Tear Volume.
Tear volume can vary with CL wear. 71,104 Tear volume has been measured noninvasively by measuring tear meniscus height, which has been done with use of a slit lamp and grading system or with more sensitive measurement techniques, such as optical coherence tomography (OCT). Tear meniscus height as measured by OCT has been reported to contribute to ocular comfort in both symptomatic and asymptomatic wearers. 19 Glasson et al. 107 have shown that tear meniscus height (and area) is different between tolerant and intolerant lens wearers and that contact lens intolerance was best predicted by a combination of clinical variables, including tear film stability, tear volume, and the number of symptoms reported. 
Tear Film Lipid Layer.
The tear film lipid layer is affected by CL wear. 71,105 The lipid layer is generally graded on a scale that uses interference patterns to estimate the thickness of the layer. 108,111 The thickness of the lipid layer has been correlated with the evaporation rate of the tear film. 112 As contact lens wear increases the evaporation of the tear film, 113 it has been assumed that there may be a relation between lipid layer thickness and CLD. Nichols and Sinnott 75 showed in a sample of 360 lens wearers that reduced lipid layer thickness was predictive of contact lens dry eye, in addition to being correlated with an increase in pre-lens tear thinning (a surrogate for evaporation). However, that relationship, if one exists, has not been conclusively shown. 
Tear Film Osmolarity.
Osmolarity of the tear film is a sensitive marker of tear function. 75,104,107,114 (Stahl U, et al. IOVS 2009;50:ARVO E-Abstract 2611). Tear osmolarity has been shown to change with contact lens wear 115 ; however, there have been mixed results as to whether it can be used to predict CLD. It has been recommended that for bilateral measurements, the more severe measurement be analyzed due to the asymmetric effects of environmental stress. 115,116 With respect to methodology, it should be indicated whether measurements were completed with the lens on the eye or after it had been removed, since removal may result in reflex tearing and may result in lower values. 75  
While tear film osmolarity has been related to symptoms of dry eye in non–contact lens wearers, its effect on CLD is less clear. However, contact lens osmolarity (i.e., a property of the contact lens itself) has been associated with CLD 85 (Stahl U, et al. IOVS 2009;50:ARVO E-Abstract 2611), and additional studies would be helpful to better understand this potential outcome measure. 
Optical Quality.
Papas et al. (Papas E, et al. IOVS 2003;44:ARVO E-Abstract 3694) suggest that poor optical quality may have a psychological impact on perceived ocular comfort and it may be that lens awareness as a result of reduced optical quality is related to CLD. With contact lens wear, reduced optical quality can be related to a number of factors, including uncorrected refractive error, higher-order aberrations, 117,118 and poor front surface lens wettability. 119,120 Currently, there is insufficient information to make conclusions regarding the link between optical quality and CLD; therefore additional research is warranted. Challenges will likely include methods of testing, since subtle vision changes are not adequately measured using traditional visual acuity measures. The development of dynamic vision assessments, taking into account environmental factors and blink patterns, may be warranted. 
Ocular Sensitivity.
Ocular sensation may be altered by CL wear. 85,121,122 Trials measuring corneal sensitivity in contact lens wearers have used either the Belmonte pneumatic esthesiometer or the Cochet-Bonnet esthesiometer, and it would be expected that results could be impacted by the measurement technique. Overall, there have been few clinical trials investigating this outcome. Conjunctival hyperesthesia has been reported in dry eye subjects 123 but has not been explored in subjects with CLD. 
Contact Lens Surface.
The surface of the contact lens is a critical interface. 71,106,109,124,125 The relationship between contact lens wettability and CLD has been unclear, possibly related to the various techniques that are used to assess wettability in vitro and in vivo and their limitations in capturing the dynamic changes that occur with wear and between blinks (for more in-depth analysis see the report of the Contact Lens Materials, Design & Care Subcommittee). Validation of measurement and grading techniques and a better understanding of the variability of in vivo wettability may be beneficial in determining the role that wettability plays in CLD. 
Contact Lens Deposition.
A correlation has been reported between active lysozyme on worn lenses and subjective comfort (r = 0.6–0.7; P < 0.001). 106 Additionally, a study of mucin mobility on worn contact lenses has been conducted, and changes in MUC1 breakdown were significantly negatively correlated to the overall Ocular Surface Disease Index score (r = −0.891, P = 0.001). 72 However, the overall concentration of protein or cholesterol that can be extracted from contact lenses was weakly if at all correlated to comfort during lens wear (as measured on a VAS). 126 Additional studies investigating the role of contact lens deposition and CLD are necessary. 
A number of studies have measured CLD and clinical signs with contact lens wear but did not determine whether there was a relationship between signs and symptoms. 15,17,21,23,31,32,38,127133 This complicates the interpretation of outcomes related to CLD since the specific driver(s) of CLD cannot be determined. In addition, when correlations have been measured, often there is not a test for a direct causative effect. A number of studies have reported changes in clinical outcomes with contact lens wear; however, there has been little evidence or discussion as to whether these findings are clinically relevant. 
Studies With the Primary Objective of Predicting CLD.
There have been only a few studies with this primary objective. Berry et al. 72 evaluated signs and symptoms (using the CLDEQ) in 19 men and 31 women (mean age 32.1 ± 11.4 years) and reported that symptomatic contact lens wearers exhibit significantly more LWE and LIPCOF and decreased MUC5AC reactivity. Using a similar study design, Pult et al. 97 also reported that contact lens wearers with dryness symptoms exhibit significantly more LWE and LIPCOF, but not increased corneal staining, bulbar hyperemia, or decreased pre-lens tear breakup time. In a prospective, 2-month longitudinal study, Michel et al. 134 investigated new contact lens wearers and grouped them according to their response to the screening CLDEQ questions, resulting in 20 “symptomatic” and 13 “asymptomatic” subjects. They reported that the best combination to predict CLD using logistic regression was LIPCOF sum plus noninvasive tear breakup time (NITBUT) and OSDI scores (positive predictive value, 87%; accuracy, 91%). 134 Nichols and Sinnott 75 evaluated data from 360 contact lens wearers (33/360 were gas-permeable lens wearers) from a large cross-sectional study and reported several factors to be related to dry eye status in multivariate modeling, including female sex (P = 0.007), lenses with higher nominal water content (P = 0.002), rapid pre-lens tear film thinning time (P = 0.008), frequent usage of over-the-counter pain medication (P = 0.02), limbal injection (P = 0.03), and increased tear film osmolality (P = 0.05). In a prospective, observational multicenter study conducted by Young et al., 135 symptomatic soft contact lens wearers reported significant soft contact lens–related dryness using the CLDEQ preceding a protocol-driven dry eye examination. Of the 226 symptomatic wearers examined, 23% were without signs. The wearers classified as “No dry eye signs” had significantly longer prelens breakup time (9.8 vs. 6.6 seconds, P < 0.0001), better lens wetting (3.4 vs. 2.4 [0–4 scale], P < 0.0001), and lower levels of film deposits on lenses (0.45 vs. 0.92 [0–4 scale], P < 0.0001), and most slit-lamp signs. The wearers with no signs of dry eye were significantly more likely to be male (36% vs.19%, P = 0.013), were less likely to have deteriorating comfort during the day (81% vs. 97%, P = 0.001), reported longer average hours of comfortable wear (11 ± 3 vs. 9 ± 4 hours, P = 0.014), had older contact lenses (18 ± 14 vs. 13 ± 12 days, P = 0.029), and had greater intensity of photophobia early and late in the day (P = 0.043 and 0.021). 135 Glasson et al. 107 demonstrated that the type of drying of the tear film (spot versus streak during the interblink period), the number of ocular symptoms in absence of lens wear, and the tear meniscus area best differentiated tolerant from intolerant lens wearers. 
The combined results of these studies suggest that the clinical outcome variables of tear stability, tear meniscus height/area, LWE, and LIPCOF are most likely to be predictive of CLD, although predictive factors have yet to be evaluated prior to wear to be able to identify wearers likely to get CLD. However, LWE and LIPCOF may only allow classification of participants in trials into symptomatic and asymptomatic groups and may not be able to predict other aspects such as the increase in symptoms over the course of 1 day of contact lens wear. It would be beneficial if additional testing were completed to determine whether these are good outcome measures of CLD. An ideal outcome measure is one that is a good predictor of the level of CLD and one that is also modifiable in order to confirm the relationship with CLD and to evaluate treatments. Provocative testing may be a strategy to better understand the impact of contact lens wear on clinical measures and to control for confounding factors. 
As mentioned previously, many of the clinical trials investigating CLD have focused on the symptoms, but little attention has been given to the visual aspect of CLD. Yang et al. 11 investigated the effect of lens care systems on blink rate, ocular discomfort, and visual performance, but did not determine whether there was a relationship between these variables. 
Conclusions Regarding Outcome Measures
A goal of future studies should be to establish needed standardization and agreement for the outcome measures related to CLD. An ideal outcome measure would be objective, internally and externally valid, and measurable with minimal bias. To better understand the predictors of CLD, it is recommended that more fundamental, basic clinical trials be conducted in order to at least understand which outcome variables are related to CLD and what level of change is clinically meaningful. Once our understanding of these basic questions is improved, more advanced study designs can be employed to comprehensively evaluate in-eye performance of existing and emerging technologies. A few key considerations for future outcome measures related to CLD are understanding of onset and recovery; cause or effect relationship with symptoms; knowledge of clinically meaningful changes; identification of confounding factors; consideration of timing, so that outcome measures and symptoms are assessed at similar time points; validation of testing methodology; standardization of grading scales, as well as observation techniques. 
Considerations for Clinical Trial Design
Design and performance of clinical trials should follow the guidelines of good clinical practice, which are extensively reviewed in the 2007 Report of the International Dry Eye Workshop and are not repeated herein. 136 A simple checklist for conduct and reporting of a clinical trial is the CONSORT recommendation (in the public domain at www.consort-statement.org). 137 Understanding CLD requires careful thought and consideration when it comes to the design of a study. Many factors can have adverse impact upon the variables being measured and thus the results. 
The possible interrelationship between lens comfort and many other variables such as lens wearing time, lens care system used, lens material, lens design, form of vision correction (i.e., single vision, toric, or multifocal), current ocular disease, general health of the study participant, or use of medication requires that all these features be carefully controlled and considered. Many other factors about the study participant or the observer may inadvertently introduce bias and again must be considered with regard to the study design. 
Trial Design.
Consideration must be given to the correct clinical trial design. Prospective design with appropriate randomization of subjects is key. Clinical trials may employ single-eye, fellow (contralateral)-eye, 138 or crossover designs, 15,139 but there are advantages and limitations to each trial design depending upon the question being asked and the length and level of supervision of the trial. In any case, avoiding bias is an important consideration when designing a clinical trial, and studies comparing lens comfort performance by collecting data from right and left eyes should consider having participants wear the test lens and control in both eyes. When these methods are used, it is important to consider whether discomfort in one eye can influence assessment made in the other or whether the study participant has a preference toward one eye. When this preference is demonstrated to be strong, the lens wearer should be considered ineligible for the study. To avoid such bias, test and control lenses may have to be crossed over and worn bilaterally, and then comfort assessment would be the mean for each eye. 
Appropriate Data Collection.
Frequently lens comfort studies collect data that is subjective or opinion based. The tool used to collect these data must be carefully evaluated and crafted, whether the study is using a VAS, a numerical rating scale, a Likert scale, or a questionnaire. Visual analogue scale data may lack sensitivity, as most data points may be skewed toward one end of the scale or artificially enhance sensitivity by scale expansion. 140 The impact of ceiling and floor effects must also be evaluated. Some validated questionnaires thought to be useful in assessing lens comfort may also lack sensitivity due to the different populations that may have been used as part of their validation. 141 A specific questionnaire oriented toward lens comfort would be needed. Another consideration is that reported lens comfort changes both over the day of wear and over the life of the lens, 34,35 making the collection of these data time sensitive. Different methods have been trialed to ensure that data of this type are recorded by the study participant in a timely way. Stone et al. 142 used paper diaries that electronically recorded when data entries were made and found that 90% of the study participants hoarded time-sensitive data to one entry time point, encouraging the conclusion that paper-based diaries were not ideal. The incorporation of electronic devices to collect data directly has also been tried in various clinical trials with variable levels of compliance pertaining to recording time-sensitive data. 143,144 Relating to the field of contact lenses, Morgan et al. 145 reported high levels of compliance, with 93% of study participants responding within 30 minutes when requested via SMS messaging; Plowright et al. 146 reported between 76% and 82% responding, but the time delay for the response to their SMS messages was not reported. Woods et al. 147 developed an online Web-based system allowing entry via smartphones and reported a response rate of 97.5%, with 84.1% responding within the allotted time window for time-specific data. The use of smartphones with a data collection method for time-sensitive data would appear to be an obvious recommendation, particularly as their use is now considered to be ubiquitous. 148  
Clearly Written Protocols.
The process for conducting the study must be clear, and the protocol must describe each step of the study design as well as methods of data collection. It has been reported that CLD is time dependent, in relation to both length of lens wear and diurnal variation, and those features should be considered when one is measuring or differentiating lens comfort. 34  
Inclusion of Appropriate Controls.
Consideration must be given to ensuring that the correct control is used, in addition to the inclusion of an arm in which no change in products is made. Confounding influences must be considered. For a study that is investigating the impact of lens material on comfort, the lens care system being used must be carefully controlled. Studies have reported that different lens materials in combination with lens care systems can influence lens comfort. 11,139  
Adequate Length of Trial.
The length of time a contact lens has been worn (both during 1 day and over the recommended life of the lens in days) has been shown to affect lens comfort. 34,35 Therefore, comparisons to be made between studies to record end-of-day comfort must be associated with how long the lens has been worn in elapsed hours. The age of the lens also influences discomfort and should be recorded. 34  
Run-In and Washout Periods.
In order to compare the performance of a contact lens, all study participants should be exposed to the same conditions before the study starts as well as during periods between various phases of the study. During a run-in period at the start of a study, the participant's method of vision correction should be consistent, that is, a period of spectacle wear or all participants wearing the same lens type with a consistent lens care system. The same provision is advised for periods between study phases. 
Adequate Sample Size.
Sample size calculations should be considered before the study begins, except in the case of pilot studies that are intended to generate data from which sample sized can be calculated. For determination of sample size it is important to consider the variability of the primary variable being measured and a clinically meaningful difference in the variable. 
Prevention of Disclosure of Masking.
Frequently, lenses used in studies have engravings or markings on them rendering difficult, if not impossible, any attempt to mask the study participant with regard to the lens being used. 149 Having a research assistant insert and remove the lenses may avoid the study participant's identifying the lens but may not be practical for all study designs. The researcher observing and recording physiological changes should do so with the lens removed by another researcher to maintain the masking. The researcher who assesses lens fit should not collect other data in the study. 
Evaluation of Effectiveness of a Treatment/Modification.
This type of evaluation is used to assess whether a specific treatment or modification aimed at improving CLD has had an effect. In addition to a better score on the subjective rating scale used, increased wearing time, increased comfortable wearing time, reduction in the frequency or intensity of symptoms, preference ratings, and quality of life information may all be potential ways of assessing the effectiveness of such a treatment. 
Questionnaire Length.
When designing a questionnaire, it is important to consider participant fatigue. If the questionnaire is too long, this may encourage bias—habit bias or self-limiting bias (see below). Use of validated questionnaires is advisable. 
Collection of Data.
When designing a clinical study it is important to consider what the key variables are and not to try to collect every variable possible. This can make the study visits burdensome and induce fatigue, increasing variability. Some variables may affect others, that is, have an order effect. Use of fluorescein to assess corneal staining will affect a subsequent assessment of NITBUT. Repeated NITBUT assessments may affect a subsequent measure of vision. 
Appropriate Statistical Analysis.
Parametric statistical tests should not be used on data that are not normally distributed or continuous in nature. Careful consideration should be given to the appropriate statistical tests, and this should be described in the study protocol. 
Generalizations Outside of Study Results.
Reports or discussion in papers should expand only on the results from the study. It is important to remember that the study results relate only to the population tested and that the study population is not likely to be representative of all populations; avoid cohort bias. 
Discussion of Potential Bias.
Collecting subjective data can lead to various types of bias. Bias can be very difficult to control, so potential types of bias should be evaluated 149 (see later sections on bias). 
Evidence- versus opinion-based conclusions: Careful consideration needs to be given to the pyramid of evidence. Randomized clinical trials (RCTs) provide significantly stronger evidence than anecdotal opinions from experts or the authors. Care should be taken to ensure that reporting focuses on factual evidence. 
Excessive Reuse of Study Subjects.
Subjects who are regularly used by a research center as study participants can effectively become trained observers. If not taken into account, this could lead to bias and skew the study results. When conducting research it is important to monitor the frequency with which study participants are enrolled. Creating a pool of trained participants can be advantageous for a particular investigation. Consideration should be given to reporting the frequency with which study participants have been used in similar study designs. 
Ethics/Institutional Review Boards/ClinicalTrials.gov Registration.
The data collected from a study are of greater value when the study has been conducted as a RTC. The guidelines of good clinical practice (in the public domain at http://ichgcp.net) should be employed. Prior ethical review and approval are mandatory, and registration of the clinical trial is desirable and is becoming mandatory. 
Disclosure of Conflicts of Interest.
Researchers and authors need to pay careful attention to potential conflicts of interest, and these must be declared. 
Study designs that can be used to report on CLD at different phases of development are outlined in Table 4
Table 4. 
 
Candidate Designs for Clinical Trials
Table 4. 
 
Candidate Designs for Clinical Trials
Design Criteria Study Phase
Lens Design Phase 1 Biocompatibility Phase 2 Dispensing Phase 3 Postmarket Phase 4
Main purpose Emphasize short-term on-eye performance and comfort, for example, assessment of effects of lens edge, case curve, thickness, optic zone Emphasize the effect of material/tear film interactions on comfort and vision (variability). Examine the effects of changes to materials, surfaces, packaging solutions. Measure “normal use” performance over lens life. Emphasize material/tear film interactions on comfort and vision (variability). Measure adverse events during lens wear. Assess effects of changes to material, lens care, lens/surface aging. Measure use after lenses released for sale. Examine the wearer's experience. Assessment of adverse events during lens wear.
Features Short-term (minutes to hours)
Direct supervision
Many sequential comparisons  acceptable
Account for order effect
Contralateral design may be  acceptable, but not if this stimulates  excess tearing in one eye
Questionnaire design—enhance  differences
Short- to midterm (4–12 h)
Direct supervision
Not often sequential
Could assess effects of packaging  solution vs. being cycled in lens care
Contralateral design may be acceptable  but not if it stimulates excess tearing
Questionnaire design
–Diurnal changes
–Recall period
Mid- to long-term (days to months)
In-home use/dispensing
Lens care assigned if using reusable  contact lenses
Crossover preferred to contralateral  design
Need to define washout period
Questionnaire design
–Diurnal changes
–Recall period
Cross section
Prospective cohort
Registry
Essentials Double masking
Ensure adequate control/tests for potential false-positive results. That is, if changing from lens A to B and assessing comfort, also include masked change from lens A to lens A.
Double masking
Pre- and postexposure testing of ocular  surface staining
Observer masking more critical; wearer masking if possible
Pre- and postexposure testing of ocular  surface staining
Breadth
Variety of clinical settings
Population Can be asymptomatic wearers to determine whether change is detectable
Could select difficult-to-fit  subpopulation
Understand habitual symptom state
Possible participant groups include poor “wetters,” symptoms vs. no symptoms
Must be able to attend visits after lens  fitting
On premises best for new materials in  case of need for emergency lens  removal
Possible participant groups include poor “wetters,” symptoms or no symptoms
Account for adverse events between  scheduled visits
Fewer exclusion/inclusion criteria
Outcomes Decide on meaningful differences with scales Determine clinically meaningful and statistically significant differences Determine clinically meaningful and statistically significant differences Determine clinically meaningful and statistically significant differences
Setting Clinic Clinic Home use Home use
Remote access
Avoiding Bias and Ensuring Quality in Clinical Trial Design and Performance
There are many sources of potential bias in conducting a clinical trial. If not recognized, the bias can invalidate conclusions and, even if recognized before data analysis, may not be amenable to compensation in the final analysis. Therefore it is worthwhile to identify and avoid such bias. Bias can be introduced at several junctures in a clinical trial. Bias can be grouped into several categories. 150 These include selection bias, performance bias, detection bias, attrition bias, reporting bias, psychometric bias, and statistical bias. 
Selection Bias
This generally concerns a lack of comparability of baseline characteristics between intervention groups. This can be due to lack of random sequence generation to produce comparable groups or due to inadequate allocation concealment—concealment that is insufficient to mask study investigators to forthcoming treatment assignments and could thus result in nonrandom allocation of subjects. One of the most frequent sources of selection bias occurs with entry criteria that fail to segregate a study population into appropriate trial groups. As one example, if a diagnostic test is being validated against other tests and the first diagnostic test is included in the selection process for identifying subjects to be tested, there is a high probability that such a test will perform better than other tests due to the criterion of selection. This bias is occasionally encountered in evaluation of dry eye disease in which multiple contributory factors are responsible for the expression and severity of disease but are not appropriately compared. One way to attempt to avoid such bias is to use a composite (and possibly weighted) index to establish presence of disease. 
Another form of selection bias is spectrum bias, in which study subjects may be selected from only a portion of the entire spectrum of disease severity. This bias would weigh heavily against an evaluative test that had accuracy over the entire spectrum of disease but not with as great a differential performance as a second test that identified a more limited subset of disease. This bias can be avoided by ensuring that the entire spectrum of a disorder is included in the test population if results are to be generalized to a larger population. It is also necessary to include a large enough population that the entire spectrum of disease is captured. 
External validity can be questioned when the study population is not representative of the whole, which is more likely to occur with small sample sizes. One should not assume that the answers to a given survey match those for the whole population if the sample is small. Too many studies have small sample size as noted in the prior summary of published clinical trials. 
Performance Bias
This can occur due to inadequate masking of subjects or investigators. Knowledge of the allocated interventions on the part of participants and personnel during the trial may lead to differential provision of care to participants in one group as compared to the other. Inadequacy of masking does not need to be prior to allocation in order to bias results. If subjects or investigators are able to determine which treatment they are on at any point in the trial, this can cause bias (e.g., the patients' reporting of symptoms, as well as the investigators' interpretation of test findings, which in this case is also somewhat subjective—that is, the investigator “grades” some parameter). 
Detection Bias
This is due to inadequate masking of outcome assessment for the participants and investigators and subsequent systematic differences in the assessment of study outcomes between randomized intervention groups. 
Attrition Bias
This is due to systematic differences between groups in outcome data either in the amount, nature, or handling of incomplete data or to violations of study protocol. 
Reporting Bias
This can occur when reporting of outcomes is selective. A type of reporting bias occurs when there are systematic differences between reported and unreported findings (e.g., pulling out and preferentially reporting only statistically significant findings and not reporting those that were analyzed but found not to be statistically significant). This can be referred to as outcome bias or selective reporting bias. 
Psychometric Bias
This bias depends upon the responsiveness of the subject and thus is less easily detected and recognized but may be a particularly obstructive effect in the analysis of subjective tests. Habit bias occurs when responders stop thinking and answer “Yes,” as all previous answers have been “Yes.” This may be due to fatigue or may occur when the survey is too long or too complex. Habit bias can result in misclassification that will either reduce study power if nondifferential among randomized groups, or may bias study findings if differential among randomized groups. 
The Hawthorne effect occurs when respondents respond differently simply because they are being asked the question. This effect tends toward a positive bias: Subjects give the answer they think the investigator wants. This is similar to the bias that occurs simply due to testing a different lens on the eye. For example, subjects might rate a new lens type/design given to them as more comfortable than their previous lens simply because it is new. To minimize this bias, subjects should be randomized to receive a new lens type/design, masked if possible, and also a new lens that is simply a fresh lens of their previous type/design. In other words, in interventional clinical trials, placebo and nocebo effects must be considered. A placebo has been defined as “a substance or procedure . . . that is objectively without specific activity for the condition being treated,” and a “placebo effect” often occurs when the subject has a strong desire for the intervention in question to be successful. 151 The opposite effect is seen when a subject who disbelieves in a treatment experiences a worsening of symptoms. This is called a nocebo effect. 152  
Self-Limiting Bias
Self-limiting bias occurs when respondents try to make themselves appear in a positive light: Subjects give the answer they think makes them right. Recall bias, in which the participant may get things wrong, has several potential causes, such that the question being asked to collect factual data should not be too complex or rely on extensive memory recall. 153 The method of asking contact lens wearers what they are wearing (by asking them from memory, or showing a photograph of lens packaging or showing the actual packaging), particularly with respect to the name (brand) of lens and lens care system or manufacturer of products, can result in recall bias. 
Statistical Bias
This occurs in several forms. For a clinical trial, internal validity, the extent to which systematic error is minimized, requires control of selection bias (biased allocation to comparison groups), performance bias (unequal provision of care apart from treatment under evaluation), detection bias (biased assessment of outcome), and attrition bias (biased occurrence and handling of deviations from protocol and loss to follow-up). External validity (the extent to which results of trials provide a correct basis for generalization to other circumstances) requires control of patients' age, sex, severity of disease and risk factors, comorbidity, or the treatment regimen's dosage, timing and route of administration, type of treatment within a class of treatments (concomitant treatments), settings (level of care [primary to tertiary] and experience and specialization of care provider), and modalities of outcomes (type or definition of outcomes and duration of follow-up). 154  
A particularly problematic data analysis effect is Simpson's paradox (Yule-Simpson effect). 155,156 This occurs when a trend that appears in different subgroups of data is not seen when these groups are combined and indeed the reverse trend is demonstrated for the aggregate data. An example of this effect is the sex bias case at a major university alleging bias against women who had applied for admission to graduate schools there. The admission figures showed that men applying were more likely than women to be admitted, and the difference was so large that it was unlikely to be due to chance. 157,158 In the total cohort there were 8442 male applicants, 44% of whom were admitted to jobs, and 4321 female applicants, 35% of whom were admitted to jobs. But when examining the individual departments, it appeared that no department was significantly biased against women. In fact, most departments had a small but statistically significant bias in favor of women. 158 The research paper by Bickel et al. 157 concluded that women tended to apply to competitive departments with low rates of admission even among qualified applicants (such as the English department), whereas men tended to apply to less competitive departments with high rates of admission among the qualified applicants (such as engineering and chemistry). Alternative impersonal terms for Simpson's paradox are reversal paradox and amalgamation paradox. 
An additional feature of data analysis that can occur if a limited number of measurements of outcome values are obtained is regression to the mean. This is the phenomenon in which a variable is extreme on its first measurement but will tend to be closer to the average of its range on subsequent measurements. 158  
There are other possible sources of bias, many of which pertain only to particular study designs (e.g., carryover in crossover trials and recruitment bias in cluster randomized trials). At other times, less common types of bias may arise under specific circumstances in a trial (e.g., contamination of intervention groups, whereby the experimental and control interventions get mixed, for example, if participants switch their lens care systems or contact lenses). 
Recognizing that there are many potential bias effects in design and conduct of clinical trials is important to help avoid them or correct for them in data analysis. 
Recommendations
General recommendations for design of clinical trials that categorizes study by lens design and duration of trials have been summarized in Table 4. The best design is a prospective, randomized, double-masked clinical trial. The question whether these designs should incorporate parallel-group, contralateral-eye, or crossover design as the most appropriate depends upon the specific question being investigated in the trial. Contralateral and crossover trials help to control for variations in subject psychological pain tolerance, but suffer the disadvantage of having the potential of development of tolerance to any given stimulus in the same subject during the duration of the study. It is also possible that a sensation of pain or discomfort in one eye may have an impact on the reporting of pain or discomfort in the fellow eye. 
Regardless of the design, appropriate entry criteria and adequate sample size are critical. Also, appropriate masking of both subject and investigator is critical. In contact lens–related trials, masking can be complicated by the type of lens being evaluated, the cleaning and lubrication solutions employed, and the wearing schedule. Inherent lens characteristics (e.g., markings, tint, and shape) may prohibit true masking of investigators in some instances. Finally, based upon our review of the literature, no specific clinical outcome instrument can be recommended, but the CLDEQ-8 most approaches the best validated device. It is clear that there needs to be more work on developing specific and efficient questionnaires for contact lenses—that they should be specific, that is, for soft, gas-permeable, or scleral lenses—rather than assuming that one questionnaire will work for all. The use of technology that allows easy data entry and time tracking (e.g., smartphone, call-in, online ratings, or other time capture methods) is recommended. 
Modern experimental design is generally in two forms—one with fixed characteristics (primarily duration/sample size) and the other with adaptive characteristics (in which critical aspects [e.g., sample size and duration] are defined, a priori, as being modifiable). Under the current circumstances, the most appropriate design would be the former. 
What variables will be important to manipulate in order to demonstrate lens-related discomfort effects, inclusion of control/placebo groups, determination of the duration of the experiments and how frequently the intervals will be sampled, what hypotheses are being tested, and what statistical tests to perform are important considerations. Until these at least are tied down, there is no rational way to design experiments. It is also possible that many nontrial experiments need to be done. The lack of an evidence base for many outcomes and predictors might necessitate that pilot validation experiments be conducted before any trial is designed. Finally, the epidemiology of the outcome itself is poorly understood, so it is possible that basic prevalence data are required, as well as population-based long-term incidence studies, before any interventional experiments are designed. 
Summary Conclusions
Prior clinical trials measuring CLD have been focused primarily on lens performance rather than specific characteristics or etiology of the discomfort experienced by the subject. Lessons learned from these published clinical trials nonetheless provide some guidance with respect to future clinical trial designs and performance to investigate CLD. Patient discomfort ranges from awareness of the lens, through sensation of dry eye, to actual pain. Impairment of visual function includes impairment of clarity, instability of vision, or fatigue in performing visual tasks. 
Accurate assessment of the symptoms of CLD requires that clinical trial design include an appropriate and representative population of adequate size evaluated by questionnaires that specifically assess a particular clinical question symptom with well-controlled contact lens material, lens design, lens care products, and wearing schedule. Avoidance of bias is necessary in performance of the trial, including care in subject selection, implementation of random intervention group assignments, psychometric testing, and statistical analysis of the data. 
At this time no specific clinical outcome instrument can be recommended on the basis of an evidence-based review of the literature, but the CLDEQ-8 best approaches the most validated device. 
Acknowledgments
Disclosure: Each workshop participant's disclosure data can be found in the Appendix of the Introduction. 
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Footnotes
 See the tables in the Introduction for the members of the TFOS International Workshop on Contact Lens Discomfort.
Table 1. 
 
Assessment of Published Clinical Trials
Table 1. 
 
Assessment of Published Clinical Trials
Study Design (e.g., Placebo-Controlled RCT, Retrospective Cohort) and Reference Details of Intervention (e.g., Regimen, Composition) Comfort/Discomfort Outcomes Disease Definitions/ Criteria (OSDI) Sample Size, Overall and per Arm Follow-up Period, From Baseline Overall Quality Rating
Open label, single group, uncontrolled10 Preservative-free hypoosmolar (280 mOsm/L) copolymer, commercially available in Italy (Farmigea, Pisa, Italy); contains 0.2% hyaluronic acid and 0.2% tamarind seed polysaccharide, pH 7.4; 3 times daily on waking with no lens, early afternoon and before bed with lenses in CLD as measured by OSDI OSDI > 12; tear breakup time (TBUT) ≤ 10; Schirmer 1 > 10 mm 15 60 d Weak; high risk of bias (uncontrolled; placebo effect very likely)
Crossover, investigator masked11 Verbal and written instructions for using a no-rubbing, rinsing lens care regimen following the manufacturer's recommendations CLD as measured by OSDI Habitual soft contact lens daily wear for at least the past 6 mo, asymptomatic and satisfied with the vision and comfort of the habitual lenses 72 (65 completed) 10-wk study: 1-wk accrual (adaptation) followed by 2-wk trial × 3 conditions with 1-wk washout between conditions Weak; high risk of bias (nonvalidated secondary outcome measures, industry funded, bias due to inadequate randomization likely)
Open-label, parallel-group, randomized trial12 Azithromycin: 1 drop to each eye twice a day for the first 2 d, then 1 drop daily for days 3–29 applied in the morning before contact lens application
Visine for contacts: 1–2 drops 4 times a day for 29 d spaced by approximately 4 h on each dosing
Comfortable contact lens daily wear time (CFB) at week 4 (average of days 23–29) CLDEQ ≥ 2 50 (25 per arm) 4 wk (29 d) Moderate; intermediate risk of bias (open label), unbalanced, comfortable wear times at baseline may have favored treatment arm)
Open label, single group, uncontrolled, crossover13 Lotrafilcon A was worn, and fit was assessed by observer and by subjective comfort. 8.60 BC,* then 8.40 BC only if fit unsuccessful with 8.60 BC. Objective assessment of fit and subjective comfort rate (1–10 scale) after 1 and 15 min (lens settling) Habitual lens wearers 95 subjects (190 eyes), 49 eyes fitted with second lens 6-mo study but paper presents nondispensing fitting data only, 15 min Weak; high risk of bias (data from 2 eyes of 1 subject considered independent; uncontrolled, unbalanced, industry funded)
Randomized, double-masked, contralateral study14 Asymptomatic group: Focus Night & Day (CIBA Vision, Atlanta, GA) vs. Acuvue 2 (Johnson and Johnson Vision Care, Jacksonville, FL). Ocular comfort on 0–100 rating scale Habitual lens wearers 39 subjects; 20 asymptomatic lens wearers and 19 symptomatic lens wearers 7 h Moderate; moderate risk of bias (partly industry funded, no run-in prior to enrolment)
Symptomatic group: Focus Night & Day vs. Acuvue 2 (Johnson and Johnson Vision Care) and Focus Dailies (CIBA Vision) vs. Proclear Compatibles (CooperVision, Pleasanton, CA).
Randomized single masked, using deception as control15 Habitual daily wear hydrogel lens wearers were refitted with lotrafilcon A (Focus Night & Day; CIBA Vision) but told they were randomly assigned to wear either low-oxygen or high-oxygen permeability lenses and were “masked” to lens assignment. Subjective comfort and dryness VAS (0–100) Habitual lens daily wear with >4 y experience 87 (81 analyzed) 2 mo Moderate; high risk of bias (open label, habitual lens wear preintervention control likely to favor intervention; analysis not intention to treat; care regimen a potential confounder; industry funded)
Randomized, contralateral, crossover study, open label16 Hioxifilcon A lenses (extreme H2O, copolymer GMA-HEMA), diameter 14.2 mm, base curve 8.6-mm, center thickness at 3.00 diopter 0.07 mm, 59% water content, Group 2, high-water nonionic, cast-molded daily wear with fortnightly replacements. Omafilcon A (Proclear Compatibles; CooperVision), diameter 14.2 mm, BC 8.2 or 8.5 mm, center thickness at 3.00 D 0.065 mm, 59% water content, Group 2, high-water nonionic, cast-molded. OPTI-FREE Express (Alcon Laboratories) disinfection solution and Clerz Plus Lens Drops (Alcon Laboratories). Patient switched to hydrogen peroxide if solution problems suspected (number not specified) CLDEQ (frequency and severity of dryness, discomfort, and blurry vision) Previous diagnosis of mild to moderate dry eye or thinking one has dry eye or symptoms of dry eye AND either tear breakup time < 10 s, Schirmer 1 test ≤ 5 mm, staining ≥ 1, or bulbar redness 40 6 wk in each arm (crossover), 12 wk total Moderate; high risk of bias (open label, habitual lens wear preintervention control; use of baseline habitual lens wear control may have favored treatment arms; no washout)
Study 1: multicenter prevalence study
Study 2: uncontrolled, single-masked (subjects) intervention study17
Study 1: NA
Study 2: senofilcon A daily wear lens for 2 wk
Continuing with habitual lens care unless advised by investigator (unspecified)
Discomfort: 4-point scale (never, infrequent, frequent, constant) Problem contact lens patients: difference of >2 h between average and comfortable wear time OR frequent or constant discomfort or dryness symptoms on CLDEQ OR limbal or bulbar hyperemia ≥ 2 OR corneal staining ≥ 3 Study 1: 1092
Study 2: 257
Study 1: NA
Study 2: 2 wk
Moderate; high risk of bias (no washout; trial short; comparison to habitual lens wear control subject to bias; questionable external validity)
Randomized, controlled (no treatment), investigator-masked clinical study 18 Unpreserved 0.9% sodium chloride (Hydrabak; Laboratoires Thea, Clermont-Ferrand, France) in both eyes 4 times a day for 21 d. All subjects used the same contact lens care solution (type unspecified). Ocular comfort: 0–100 continuous VAS with anchors “excellent (lenses not felt)” at one end and “very uncomfortable (lenses cause irritation or discomfort)” at the other Experiencing ocular discomfort (irritation, stinging, burning , or sensation of intermittent blurred vision), TBUT ≥10 s, Schirmer 1 ≥ 5 mm in 5 min in both eyes 50; 30 randomized to intervention, 20 to control 21 d Weak; high risk of bias (no washout; trial short; comparison vs. baseline; lacking no-treatment control; confounders not measured)
Study 1: prospective cross-sectional (3 groups).
Study 2: randomized, contralateral, open label, no-treatment control 19
Study 1: etafilcon A 8.5-mm base curve (Acuvue 1-Day; Johnson and Johnson Vision Care)
Study 2: 20-μL ReNu MultiPlus (Bausch & Lomb, Rochester, NY) rewetting drop
Ocular comfort: 0–50 continuous VAS Study 2 Symptomatic: self-reporting of at least 1 symptom often or continually on Shippai Eye Study20 Dry Eye Questionnaire 60 (20 per arm) Study 1: 10 h
Study 2: 30 min
Strong; low risk of bias (no washout; primary outcome poorly described (anchors and descriptors not specified)
Single masked (subject), contralateral, no-treatment control21 2 drops of sterile, isotonic, buffered, solution of carboxymethylcellulose (CMC), sodium chloride, boric acid, potassium chloride, calcium chloride, magnesium chloride, purified water and preserved with PURITE (stabilized oxychlororcomplex) 0.005% (Refresh Contacts; Allergan, Inc., Irvine, CA) on back surface of contact lens prior to insertion vs. straight from packaging in contralateral eye Ocular comfort on 0–100 rating scale At least 1 mo of lens wear Symptomatic lens wearers based on answering “no” to “Are you able to wear your lenses for as long as you want?" 61 (59 analyzed): 12 symptomatic, 49 asymptomatic 8 h Weak; high risk of bias (2 authors employed by industry; investigator not masked; no washout; unequal arms; analysis not ITT; some data [e.g., comfort] not presented)
Crossover, single masked (investigator)22 OPTI-FREE Express Lasting Comfort No Rub Formula (Alcon Laboratories) vs. ReNu MultiPlus (Bausch & Lomb) Comfort (0–100 VAS) At least 1 y of lens wear, 8 h/d 8 4 wk Weak; high risk of bias (no washout; not randomized; sample size too low; confounders not controlled [e.g., lens type])
Multisite, uncontrolled, open label23 Nelfilcon A containing high molecular weight, nonfunctionalized polyvinyl alcohol (PVA) and packaging saline containing hydroxypropyl methylcellulose and polyethylene glycol (Triple Action Moisture DAILIES AquaComfort Plus; CIBA Vision) worn daily on daily disposable schedule Frequency and severity of 8 common subjective symptoms (tired eyes, irritated eyes, lens awareness, blurred vision, redness, discomfort, deposits, dryness) Contact lens wearer reporting at least 2 symptoms often or always 83 (81 completed) 4 wk Weak; high risk of bias (use of baseline habitual lens wear comparison may have favored treatment arm; no washout; industry sponsored, conducted, written)
Randomized, controlled, double-masked, single-center clinical trial24 3-mo absorbable glycolic acid and trimethylene carbonate punctual plug (EXTEND Absorbable Synthetic Implants; Odyssey Medical, Memphis, TN) vs. sham procedure CLDEQ Symptomatic dry eye contact lens wearers with CLDEQ score > 0.1325 32 enrolled, 22 eligible based on CLDEQ score, 19 completed 6 wk Strong; low risk of bias (sham procedure and blinding well described; regression toward the mean and placebo effect likely)
Randomized, investigator masked, placebo controlled26 Cyclosporine 0.05% ophthalmic emulsion (Restasis; Allergan, Inc.) twice per day vs. rewetting drops (carboxymethylcellulose 0.5%, Refresh Contacts; Allergan, Inc.), twice per day, to be used before and after lens wear Subjective evaluation of dryness severity (mild, moderate, severe), OSDI Self-reported history of contact lens dryness/intolerance 17 5 wk Medium; moderate risk of bias (patients unmasked; subjective bias likely); demographic data not provided
Randomized, double masked, placebo controlled39 Cyclosporine 0.05% ophthalmic emulsion vs. Refresh Preservative Free Artificial Tears (Allergan, Inc.) twice a day OSDI and National Eye Institute Refractive Error Quality of Life Instrument Chart review to identify contact lens wearers with complaints of dryness including irritation, burning, decreased wearing time 44 (22 per arm) 3 mo Strong; low risk of bias (continuing use of habitual lens and cleaning regimen potential confounder; no washout)
Randomized, double-blind, parallel-group 15- center study27 2% polyvinylpyrrolidone (PVP) vs. 0.9% NaCl 1–6 drops per day as required Overall contact lens comfort (VAS scale) Contact lens wearers complaining of discomfort and soreness, irritation, smarting, burning, blurred vision aggravated by environmental factors (air conditioning, heating, working conditions, e.g., prolonged use of visual display unit) 45 (25 PVP, 20 NaCl) 28 d Weak; high risk of bias (unbalanced; industry sponsored, conducted, written; variable dosage confounder)
Single-center, double-masked, randomized, crossover, pilot clinical trial28 Senofilcon A (Acuvue Oasys with Hydraclear Plus; Johnson and Johnson Vision Care) vs. habitual (control) during 75-min controlled adverse environment (CAE) exposure Ocular discomfort (0–4 scale) Soft contact lens wearers with histories of ocular discomfort during lens wear in windy or dry environments 11 75 min Weak; high risk of bias (use of habitual lens wear control a potential confounder; inadequate sample size; masking not described; industry funded)
Randomized, contralateral, crossover, open-label clinical trial29 Intervention 1: etafilcon A (1-DAY Acuvue; Johnson & Johnson Vision Care) vs. lotrafilcon A (NIGHT & DAY; CIBA Vision) Comfort (100-point scale) At least 12 mo of lens wear fitted 15 6 h on 4 separate days Moderate; moderate risk of bias (patients masked for lens type but unmasked for drop type except at insertion; investigators not masked)
Intervention 2: NaCl 90 mg/mL (AstraZeneca, North Ryde, NSW, Australia) vs. PVA 14 mg/mL, povidone 6 mg/mL, sodium chloride (Refresh; Allergan, Inc.) vs. carboxymethylcellulose (CMC) 5 mg/mL (Cellufresh; Allergan, Inc.) every 2 h for 6 h
Prospective, single-masked (subjects), randomized, crossover study30 Lotrafilcon A with hypoosmotic (280 mmol/kg) vs. hyperosmotic (380 mmol/kg) saline 15 μL 4 times a day Comfort (1–100 scale) Symptomatic lens wearers with maximum comfortable wearing time < 6 h 15 6 h Strong; low risk of bias (investigator not masked)
Randomized, controlled, double-masked, 19-site study31 OPTI-FREE RepleniSH (Alcon Laboratories) vs. ReNu MultiPlus No Rub Formula (Bausch & Lomb) Comfort and dryness scores (0–100 scale) Symptomatic wearers of group IV soft lenses answering disagree or strongly disagree to “My contacts are comfortable all day long” and agree or strongly agree to one or both of “During the day, I take my contacts out earlier than I like because they become uncomfortable” and “Late in the day, my contacts become uncomfortable but I continue wearing them” 362 (183 OPTI-FREE vs. 179 ReNu MultiPlus) 28 d Medium; moderate risk of bias (no washout; lens type solution interactions likely confounder)
Randomized, crossover study, open label32 Omafilcon A (Proclear; CooperVision) vs. new habitual lenses (control) Subjective symptoms VAS (10 cm) scale (comfort and dryness severity; dryness, eye irritation, itchiness, burning, soreness, scratchiness, grittiness, watering, light sensitivity frequency) Contact lens wearers with dry eyes (NEI definition: Schirmer without anesthesia ≤ 5 mm, rose bengal staining ≥ 3, fluorescein staining ≥ 3, meibomian gland dysfunction ≥ 2) 76 6-wk crossover Weak; high risk of bias (open label likely to favor new lens type; use of more than 1 lens type as control a confounder; industry funded)
Randomized, double-masked, cross-over study33 Lotrafilcon B with polyhexamethylene biguanide (PHMB) (Solocare Aqua; CIBA Vision) vs. PHMB with surfactant (Hidro Health, Disop, Spain) solutions 10-item symptoms questionnaire (0–10 scale): discomfort, blurry vision, lens-handling problems, dryness, redness, tearing, burning, itching, discharge, dissatisfaction + CLDEQ Daily wear of lotrafilcon B for >3 mo 54 1-mo crossover Strong; low risk of bias
Randomized, crossover, single masked (participant)34 5 silicone hydrogels: galyfilcon A (Acuvue Advance; Johnson & Johnson Vision Care); senofilcon A (Acuvue OASYS; Johnson & Johnson Vision Care); lotrafilcon B (O2Optix; CIBA Vision); lotrafilcon A (NIGHT & DAY; CIBA Vision); balafilcon A (PureVision; Bausch & Lomb) disinfected with ClearCare (AOSept Plus; CIBA Vision) for >6 h Comfort, burning, dryness, analogue scales (0–100) with verbal anchors at various times (insertion, settling, 8 h, 12 h on days 1, 4, 7, 10, and 14 using handheld wireless communication devices Adapted soft lens wearers 55 (45 completed and analyzed) 4-wk crossover with 1 d washout High; low risk of bias (base curve selection for 2 of 5 lens types a potential confounder; single masked only)
Retrospective multistudy, multicenter analysis, open label, uncontrolled9 Lotrafilcon A (NIGHT & DAY; CIBA Vision) or lotrafilcon B (O2Optix; CIBA Vision) daily wear or continuous Dryness during the day and end-of-day from CLDEQ Adapted soft lens wearers (nonsilicone hydrogel) 259 2 wk (lotrafilcon B) or 1 mo (lotrafilcon A) Weak; high risk of bias (open label; subject masked to study sponsor only, not to lens type; retrospective; uncontrolled; multiple wear schedule and lens type a confounder)
Contralateral, randomized, double masked35 Etafilcon A (Acuvue; Johnson and Johnson Vision Care) vs. Omafilcon A (Proclear Biocompatibles; CooperVision) Subjective comfort and dryness (100-mm VAS scale with anchors at 0 = very dry and 100 = no dryness) at 0, 1, 3, 5, and 7 h Symptomatic: Wearers with symptoms of dryness after 5 h of wear with consequently reduced wearing time and use of lubricating drops at least once daily 40 (20 symptomatic, 20 asymptomatic) 7 h Moderate; moderate risk of bias (no washout; contralateral eye effect potential confounder)
Asymptomatic: wearers without symptoms of dryness or discomfort who could wear lenses all day without use of lubricants
Randomized, investigator-masked, crossover study36 Hydroxypropyl methylcellulose (HPMC) (COMPLETE ComfortPLUS; Allergan, Inc.) vs. citrate (No Rub OPTI-FREE Express; Alcon Laboratories) solution with fresh habitual lenses Daytime and end-of-day comfort and dryness (50-point continuous scale with anchors 0 = impossible to wear and 50 = excellent) Experienced daily lens wearers 75 (64 completed) 1-mo crossover with 1-wk washout Moderate; moderate risk of bias (participants masked only to study sponsor; lens type confounder, industry funded)
Retrospective, 7-study open-label trial37 Senofilcon A (Johnson & Johnson Vision Care) daily wear with multipurpose solution (MPS) (one of Polyquad/EDTA, Alcon Laboratories; Polyquad/nonanoyl-EDTA, Alcon Laboratories; PHMB/borate, Bausch & Lomb; PHMB/phosphate, CIBA Vision) vs. hydrogen peroxide (H2O2) vs. daily disposable (DD) Comfort and dryness on a 1–10 scale with anchors 1 = poor and 10 = excellent Previous wear experience not specified 283 (160 MPS, 83 H2O2, 40 DD) 3 mo Weak; high risk of bias (open label; not randomized; retrospective; multiple MPS and replacement schedule confounders; unbalanced; same participants in more than 1 trial)
Randomized, investigator-masked, 2-site crossover study38 No Rub OPTI-FREE Express (Alcon Laboratories) vs. Complete (Allergan, Inc.) or ReNu MultiPlus (Bausch & Lomb) with Acuvue 2 (Johnson and Johnson Vision Care) or Softlens 66 (Bausch & Lomb) Subjective preference based on answer to “Did you notice a difference in comfort provided by the study solutions?” Daily wearers 89 (47 and 42 at each site); 71 completed 2-mo crossover with 72-h washout Weak; high risk of bias (participants not masked; unequal group sizes; randomization not stratified by site)
Table 2. 
 
Candidate Outcomes for Clinical Trials
Table 2. 
 
Candidate Outcomes for Clinical Trials
Name, Reference Validation With a Contact Lens–Wearing Population
Developed for contact lens wear
 Contact Lens Dry Eye Questionnaire (CLDEQ)25 Yes; screening
 CLDEQ-81 Yes; screening and responsiveness
 Contact Lens Impact on Quality of Life (CLIQ)50 Yes; quality of life; keratoconus only
Developed for dry eye without contact lenses
 Dry-Eye Questionnaire (DEQ)51 No
 DEQ552 No
 Ocular Surface Diseases (OSD) questionnaire (in French)53 No
 Impact of Dry Eye on Everyday Life (IDEEL) questionnaire54 No
 McMonnies55 No
 Ocular Surface Disease Index (OSDI)56 No
 Symptom Assessment iN Dry Eye (SANDE)57 No
 Subjective Evaluation of Symptom of Dryness (SeSOD)58 No
 Short questionnaire for dry eye syndrome (DES) questionnaire59 No
 Unnamed questionnaire (in Spanish)60 No
 Standard Patient Evaluation of Eye Dryness (SPEED)61
 Texas Eye Research and Technology Center (TERTC)62 No
Table 3. 
 
Clinical Measures of CLD
Table 3. 
 
Clinical Measures of CLD
Outcome Associated With CLD? Methods Key Findings
Corneal staining Yes Data obtained from 7 prospective trials, n = 283; 4 groups wore senofilcon A lens material on a daily-wear basis using multipurpose solutions (DW-MPS, n = 160), 2 groups using hydrogen peroxide (DW-H2O2, n = 83), and 1 group wearing the lens on a daily disposable basis (n = 40). Participants were followed for 3 mo using the same protocol. Comfort at insertion and end of day, and end-of-day dryness scores, were significantly lower for participants who experienced solution-induced corneal staining (SICS; 8.2 ± 1.6, 7.0 ± 1.9, and 7.0 ± 2.2) than for those who did not (8.8 ± 1.2, P = 0.004; 7.9 ± 1.7, P = 0.002; and 7.9 ± 1.8, P = 0.003, respectively).37
Yes Ninety-day, randomized, concurrently controlled, double-masked, multisite study involved 573 subjects at 30 investigational sites in the United States, using 1 of 2 multipurpose disinfecting solutions. Differences noted in the level of corneal staining (SICS) between the 2 disinfecting solutions, and the solution that gave most SICS was rated worse for subjective comfort (insertion, removal, overall).66
Yes Retrospective analysis of a series of open-label studies conducted with 24 groups of approximately 40 participants, each wearing 1 of 6 silicone hydrogel contact lenses with 1 of 4 lens care products bilaterally for 3 mo of daily wear. Participants with SICS had lower levels of comfort during the day (7.9 ± 1.7 vs. 8.5 ± 1.4, P = 0.03), comfort at the end of the day (6.6 ± 2.1 vs. 7.4 ± 1.9, P = 0.03), overall dryness (7.4 ± 1.9 vs. 8.0 ± 1.7, P = 0.04), dryness at the end of the day (6.7 ± 2.2 vs. 7.5 ± 2.1, P = 0.01), feelings of burning and stinging (8.5 ± 2.0 vs. 8.9 ± 1.8, P = 0.02), and overall vision (8.2 ± 1.6 vs. 8.7 ± 1.3, P < 0.001).64
Yes Two sites conducted a randomized, investigator-masked, 2-mo crossover study; n = 45 used regimen 1 and 2 for 1 mo each (study 1), and n = 44 used regimen 1 and 3 for 1 mo each (study 1). 1 of 2 soft lens types was randomly assigned, and the same lens type was worn throughout the study. Significantly more subjects preferred the comfort of an MPS that gave low levels of corneal staining (SICS) (61.8%) to that of regimen 3 (11.8%).38
Possibly One-week, daily-wear, subject-masked, bilateral, parallel-group study with subjects (n = 282) randomly assigned to 1 of 2 daily disposable soft contact lenses. There was a weak correlation between corneal staining and comfort for 1 lens (r = 0.27, P = 0.002, n = 136), but not the other (r = −0.11, P = 0.18, n = 140).70
Possibly Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses who were required to have consistently used a polyhexamethylene biguanide (PHMB)- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; corneal staining. No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, or burning or stinging. However, grittiness or scratchiness was higher with PHMB-containing system, and so were the level and extent of corneal staining (SICS).71
No Prospective, bilateral, single-masked (investigator), randomized crossover design with 4 phases (1 for each care system). Each study phase comprised 2 consecutive days of lens wear on which the lenses were inserted on day 1 directly from the blister-packs and worn for over 8 h, then inserted on day 2 after overnight disinfection with 1 of the study lens care systems. N = 25 adapted soft contact lens wearers who were able to wear their habitual lenses comfortably for more than 12 h were recruited. Even though 1 MPS was associated with high levels of corneal staining (SICS), there was no difference between the lens care systems and subjective comfort over a 2-d period.63
No Three-month prospective study; n = 120 participants were randomized into 1 of 3 lens types (etafilcon A, narafilcon A, and senofilcon A), all worn bilaterally on a daily disposable regimen; observations were at baseline, 2-wk, and 1- and 3-mo visits. No differences were found between lenses in the 1–100 rating scale (P > 0.05) even though some lenses had statistically worse corneal staining.64
No A series of pilot studies using a total of 27 subjects (some of whom were enrolled in 2 or more studies) was conducted over 11 mo using a double-masked, randomized, crossover design. Asymptomatic, adapted, daily-wear soft lens users were included; evaluations were at baseline and after 1 and 2 h of wear. Significantly increased extent of corneal staining (SICS) was observed at 2 h when subjects used silicone hydrogel lenses soaked an MPS, but significant levels of symptoms were not correlated with extent of staining.65
No Prospective, double-masked, single-investigator study; n = 20 participants were recruited for 2 visits with lenses worn bilaterally for 2 h. Comfort scores did not differ between eyes (P > 0.05) despite significantly less corneal staining (SICS) in 1 eye compared to the other.68
No Double-masked, randomized, 1-mo crossover study; n = 50 adapted soft lens wearers. Significantly different (P < 0.01) levels of relatively asymptomatic corneal staining (SICS) were observed with 1 lens care solution (37%) compared to the other (2%); symptoms were not correlated with the degree of staining.69
No Observational study; n = 50 (19 men, 31 women; mean age, 32.1 ± 11.4 y) adapted lens wearers. Comfort was evaluated using the Contact Lens Dry Eye Questionnaire. Corneal staining was assessed in the right eyes. Nonparametric analyses were used to study differences between groups and correlations between objective tests and symptoms. No difference in corneal staining observed between asymptomatic and symptomatic lens wearers.72
Conjunctival staining Yes The study was conducted on a cohort population of 27 established soft contact lens wearers, who wore each contact lens type, in a random order, for a period of 10 (±2) days. Circumlimbal staining was measured in a double-masked fashion through image analysis of digital photographs of lissamine green taken under controlled experimental conditions. An inverse association between circumlimbal staining and contact lens comfort was demonstrated. Lenses with a rounded edge design produced the lowest comfort (72 of 100) whereas lenses with a knife-edge design produced the highest (87 of 100).82
Yes Overall staining, as well as staining at 5 separate sites (limbal, nasal band, temporal band, superior, and inferior), was graded on an analogue scale in 48 contact lens–wearing subjects and 50 control non–lens wearers. The degree to which subjects experienced sensations of dryness, wateriness, itchiness, grittiness, and comfort was also assessed using analogue scales. In regression analysis, overall conjunctival staining was associated with the degree of dryness and the amount of itchiness.83
Yes Lissamine green and sodium fluorescein conjunctival staining were assessed in 102 soft contact lens wearers and 79 non–contact lens wearers. Lissamine green staining (≥grade 1) could discriminate symptomatic from asymptomatic lens wearers (P = 0.007).84
No/possibly Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses who were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; conjunctival staining. Nasal and temporal conjunctival staining was significantly higher for users of PHMB-containing systems (P < 0.05). No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, or burning or stinging; but grittiness or scratchiness was significantly higher with the PHMB-containing system.71
Conjunctival indentation Yes A new method to measure contact lens osmolality was validated by testing for repeatability and by evaluating independence of lens material, power, and osmolality value of the lens. This method was then used in a clinical study. 15 subjects wore each of 9 different lens types. Osmolality, tear film, and ocular surface parameters were tested for their association with comfort using linear mixed model. Comfort was associated with conjunctival indentation (P = 0.002, r = −0.37) (Stahl U, et al. IOVS 2009;50:ARVO E-Abstract 2611).
Palpebral conjunctival staining, including lid wiper staining and lid parallel conjunctival folds Yes Subjects were divided into 2 groups based on the presence or absence of dry eye symptoms. The lid wiper of asymptomatic (n = 75) and symptomatic (n = 30) soft contact lens wearers was examined following the instillation of fluorescein and rose bengal dyes. Lid wiper staining was graded zero to 3. Eighty percent of the symptomatic subjects displayed lid wiper staining compared to 13% of the asymptomatic subjects (P < 0.0001).92
Yes Observational study; n = 50 (19 men, 31 women; mean age, 32.1 ± 11.4 y) adapted lens wearers. Comfort was evaluated using the Contact Lens Dry Eye Questionnaire. Corneal staining, lid wiper epitheliopathy, and lid parallel conjunctival folds were assessed in the right eyes. Nonparametric analyses were used to study differences between groups and correlations between objective tests and symptoms. Lid wiper epitheliopathy and lid parallel conjunctival folds were significantly increased (P < 0.035) in the symptomatic lens wearers.72
Palpebral roughness No/possibly Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses who were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; palpebral roughness. No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, burning or stinging, but there was an increase in grittiness or scratchiness (P = 0.045) for the PHMB system and also an increased level of palpebral roughness (P = 0.014).71
Conjunctival hyperemia Yes Cross-sectional study on 415 contact lens wearers in which a number of tear film, contact lens, and patient-related factors were measured and examined in relation to dry eye status. Univariate and multivariate logistic regression models were used, and data from 360 of the 415 subjects were used in the analyses. Several factors were shown to be related to dry eye status in multivariate modeling, including limbal injection (P = 0.03).75
No Prospective, randomized, parallel-group, 3-mo study; n = 120 participants (40 in each group) wore 1 of 3 lens types (etafilcon A, narafilcon A, and senofilcon A), all worn bilaterally on a DD regimen. Participants were observed at baseline, 2-wk, and 1- and 3-mo visits in which ocular physiology and lens performance variables were collected on a 0–4 grading scale in 0.1 increments. Subjective comfort and vision ratings were collected on a 1–100 rating scale and in the form of symptom severity. Even though 1 lens type was associated with significantly more limbal redness (P < 0.01), there were no differences in comfort between lenses (P > 0.05).72
Limbal hyperemia No Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses who were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; limbal and bulbar hyperemia. No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, burning or stinging (except grittiness or scratchiness), or for limbal or bulbar hyperemia.71
Tear film stability Yes Thirty-eight subjects participated; 20 were successful contact lens wearers and 18 had discontinued contact lens wear because of discomfort. Baseline tear film (no lens wear) was analyzed with a range of clinical measurements and protein analyses (lactoferrin, sIgA, and lysozyme). Comfort was determined after 6 h of lens wear, and differences in tear film characteristics between subject groups were determined. Tests were performed in absence of contact lens wear. Tear stability (noninvasive tear breakup time) was significantly reduced in intolerant wearers (P < 0.05).107
Yes Cross-sectional study on 415 contact lens wearers in which a number of tear film, contact lens, and patient-related factors were measured and examined in relation to dry eye status. Univariate and multivariate logistic regression models were used, and data from 360 of the 415 subjects were used in the analyses. Several factors were shown to be related to dry eye status in multivariate modeling, including rapid pre-lens tear film thinning time (P = 0.008).75
Possibly Randomized, double-masked, contralateral, 7-h nondispensing study; n = 40 (20 symptomatic and 20 asymptomatic lens wearers). Lens water content was measured before and after 7 h of lens wear, and pre-lens noninvasive tear film breakup time (NITBUT) was measured immediately after insertion and after 5 h of lens wear. Subjective comfort and dryness were rated at 0, 1, 3, 5, and 7 h of lens wear. Symptomatic hydrogel contact lens wearers with decreased wearing time had measurably reduced NITBUT.35
Possibly Randomized, subject-masked bilateral crossover study of silicone hydrogel lenses in 24 adapted soft contact lens wearers. Tear film stability was superior for 1 lens over the other, and the authors concluded that this was associated with an overall better comfort for this lens.105
No Prospective, 8-h nondispensing study; n = 30 adapted soft contact lens wearers (16 symptomatic and 14 asymptomatic) were fitted with etafilcon A lenses. In vivo wettability, NITBUT, and subjective symptoms (vision, comfort, and dryness) were assessed at baseline and after 2, 4, 6, and 8 h. After 2-, 4-, 6-, and 8-h time points, lenses were collected, and total protein, total lysozyme, and active lysozyme deposition were assessed. There was no significant difference in the NITBUT values between the 2 groups at any time point (P > 0.05), but the 8-h time point was significantly lower than the baseline measurement in both the symptomatic and asymptomatic groups (P = 0.032).106
No Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; noninvasive and fluorescein breakup time. No significant difference between 2 preservative system groups was noted for overall or end-of-day comfort, discomfort, burning or stinging (except grittiness or scratchiness) or for tear breakup times.71
Tear film volume Yes Thirty-eight subjects participated; 20 were successful contact lens wearers and 18 had discontinued contact lens wear because of discomfort. Baseline tear film (no lens wear) was analyzed with a range of clinical measurements and protein analyses (lactoferrin, sIgA, and lysozyme). Comfort was determined after 6 h of lens wear, and differences in tear film characteristics between subject groups were determined. Tests were conducted in absence of contact lens wear. Tear volume (meniscus height and phenol red thread test) were significantly reduced in intolerant wearers (P < 0.05).107
No Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; tear meniscus height, Schirmer, and fluorescein clearance tests. No significant difference noted between the 2 preservative system groups for overall or end-of-day comfort, discomfort, burning or stinging (except grittiness or scratchiness), and tear meniscus height, Schirmer test, or fluorescein clearance.71
Tear lipid layer Possibly Randomized, subject-masked bilateral crossover study of silicone hydrogel lenses in 24 adapted soft contact lens wearers. Lipid layer thickness was superior for 1 lens over the other, and the authors stated that this may have been a reason for the better comfort for that lens over the other.105
No Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness; preocular tear film lipids. No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, burning or stinging, except grittiness or scratchiness, and no difference in clinical assessment of tear film lipid layer.71
Tear film osmolarity Yes Cross-sectional study on 415 contact lens wearers in which a number of tear film, contact lens, and patient-related factors were measured and examined in relation to dry eye status. Univariate and multivariate logistic regression models were used, and data from 360 of the 415 subjects were used in the analyses. Several factors were shown to be related to dry eye status in multivariate modeling, including increased tear film osmolality (P = 0.05).75
No Prospective, 8-h nondispensing, crossover study; the right eyes of 15 neophytes were included. Tear osmolarity was measured before and after 4 and 8 h of each contact lens wear. Ocular comfort was assessed after 4 and 8 h of each contact lens wear. Tear osmolarity was not associated with ocular comfort.114
No Thirty-eight subjects participated; 20 were successful contact lens wearers and 18 had discontinued contact lens wear because of discomfort. Baseline tear film (no lens wear) was analyzed with a range of clinical measurements and protein analyses (lactoferrin, sIgA, and lysozyme). Comfort was determined after 6 h of lens wear, and differences in tear film characteristics between subject groups were determined. Tear osmolarity was not statistically significantly different between tolerant and intolerant contact lens wearers (osmolality [mOsmol/kg] 317.4 and 324.4, respectively, P = 0.069), even though intolerant wearers had a greater number of symptoms than tolerant wearers (P < 0.05).107
No A new method to measure contact lens osmolality was validated by testing for repeatability and by evaluating independence of lens material, power, and osmolality value of the lens. This method was then used in a clinical study. 15 subjects wore each of 9 different lens types. Osmolality, tear film, and ocular surface parameters were tested for their association with comfort using linear mixed model. Comfort after 6 h of lens wear was not associated with tear osmolality after lens wear (P = 0.993).85
Contact lens osmolality Yes A new method to measure contact lens osmolality was validated by testing for repeatability and by evaluating independence of lens material, power, and osmolality value of the lens. This method was then used in a clinical study. 15 subjects wore each of 9 different lens types. Osmolality, tear film, and ocular surface parameters were tested for their association with comfort using linear mixed model. Comfort after 6 h of lens wear was associated with the osmolality of the worn lens (P = 0.006, r = −0.41). Osmolality of worn lenses significantly correlated with tear film breakup time (P = 0.003, r = −0.22), lens water content (P < 0.001, r = −0.58), conjunctival indentation (P < 0.001, r = 0.45), and ocular sensitivity (P < 0.05) after 6-h lens wear.85
Optical quality No peer reviewed publications on this topic
Corneal sensitivity Yes N = 32 symptomatic and 29 asymptomatic contact lens wearers (aged 20–42 y, 6 males and 26 females; and 21–36 y, 9 males and 20 females, respectively). Mechanical stimulus thresholds of the cornea were determined using a Belmonte pneumatic esthesiometer and the ascending method of limits. Then 3 stimulus intensity groups (subthreshold, threshold, and suprathreshold) were applied to the eye in random order, each 20 times. Subjects rated the intensity of the stimuli using a scale of zero to 4. The rating data from the 2 groups were compared by Friedman nonparametric ANOVA. Adaptation was defined as the reduction in subsequent ratings compared with earlier ones. Adaptation was found to suprathreshold mechanical stimuli in the asymptomatic group but not in the symptomatic group121; in other words, the symptomatic group responded as much to the first suprathreshold stimulus as the last and never gained “tolerance” to the stimulus.121
No Non–contact lens wearers and subjects who had worn soft contact lenses for more than 1 y were recruited and were divided into 3 groups: (1) normal controls, (2) contact lens wearers without dry eye, (3) contact lens wearers with dry eye. Corneal sensitivity was measured with a Cochet-Bonnet esthesiometer. Nerve density and branching in the subepithelial plexus were measured using in vivo confocal microscopy. Tear nerve growth factor and tissue growth factor-beta1 levels were measured with an enzyme immunoassay. Both sets of contact lens wearers had reduced corneal sensitivity (P = 0.032) compared to the normal controls,122 but there was no difference in sensitivity between contact lens wearers with and without dry eye complaints.
Conjunctival sensitivity Yes Fifteen subjects, 9 lens types, lenses worn for 6 h; sensitivity measured with an air jet aesthesiometer at baseline and following lens removal. Comfort associated with a change in corneal and conjunctival sensitivity.159
In vivo contact lens wettability No Prospective, randomized, bilateral, crossover study; n = 15. Initial comfort and surface wettability were compared between 3 lens types (Novalens [Ocu-Tec, Bellshill, North Lanarkshire, UK], ENVISION [Bausch & Lomb], and D3X4 [Wesley-Jessen, Des Plaines, IL]). Initial comfort was significantly better with the D3X4 lens; no significant difference was found between the 2 rigid lens materials. No significant difference in lens surface wettability was found between the 3 materials.124
No Prospective, 8-h nondispensing study; n = 30 adapted soft contact lens wearers (16 symptomatic and 14 asymptomatic) were fitted with etafilcon A lenses. In vivo wettability, NITBUT, and subjective symptoms (vision, comfort, and dryness) were assessed at baseline and after 2, 4, 6, and 8 h. After 2-, 4-, 6-, and 8-h time points, lenses were collected, and total protein, total lysozyme, and active lysozyme deposition were assessed. In vivo wettability was reduced over the course of the day for both groups, but was not statistically significant (P > 0.05). There was also no significant difference in wettability between the 2 groups at any time point (P > 0.05).106
No Observational, single-visit, investigator-masked study; n = 89 wearers of group IV hydrogel or silicone hydrogel lenses were required to have consistently used a PHMB- or polyquaternium-1-based solution for 2 y. Clinical assessments included average and comfortable wear time; overall and end-of-day comfort; signs of dryness, discomfort, burning or stinging, grittiness or scratchiness, and visual changes; noninvasive and fluorescein breakup time; preocular tear film lipids, tear meniscus height, Schirmer, and fluorescein clearance tests; limbal and bulbar hyperemia; palpebral roughness; corneal and conjunctival staining; lens front surface wetting; and lens film deposits. Front surface lens wettability was significantly better for group IV polyquaternium-1 users compared to PHMB users (P = 0.008), with 84% vs. 72%, respectively, with lenses graded by the investigator as having “good” or “excellent” wettability. No significant differences between the 2 preservative system groups were noted for overall or end-of-day comfort, discomfort, burning or stinging, grittiness or scratchiness.71
Ex vivo wettability Possibly Randomized, single-masked study, n = 6; test and control lenses were soaked for 12 h in either saline or 1% aqueous solution of poloxamine 1107. The advancing and receding contact angles were determined ex vivo after various periods of wear. Control saline-soaked lenses exhibited no change in wetting angles over time, indicating a lack of surface modification by components within the tear film. Poloxamine-soaked lenses exhibited a significantly reduced advancing angle (P < 0.001) and hysteresis angle (P < 0.001) when compared with control lenses. In addition, treated lenses were consistently rated as more comfortable than control lenses (P = 0.04).125
Table 4. 
 
Candidate Designs for Clinical Trials
Table 4. 
 
Candidate Designs for Clinical Trials
Design Criteria Study Phase
Lens Design Phase 1 Biocompatibility Phase 2 Dispensing Phase 3 Postmarket Phase 4
Main purpose Emphasize short-term on-eye performance and comfort, for example, assessment of effects of lens edge, case curve, thickness, optic zone Emphasize the effect of material/tear film interactions on comfort and vision (variability). Examine the effects of changes to materials, surfaces, packaging solutions. Measure “normal use” performance over lens life. Emphasize material/tear film interactions on comfort and vision (variability). Measure adverse events during lens wear. Assess effects of changes to material, lens care, lens/surface aging. Measure use after lenses released for sale. Examine the wearer's experience. Assessment of adverse events during lens wear.
Features Short-term (minutes to hours)
Direct supervision
Many sequential comparisons  acceptable
Account for order effect
Contralateral design may be  acceptable, but not if this stimulates  excess tearing in one eye
Questionnaire design—enhance  differences
Short- to midterm (4–12 h)
Direct supervision
Not often sequential
Could assess effects of packaging  solution vs. being cycled in lens care
Contralateral design may be acceptable  but not if it stimulates excess tearing
Questionnaire design
–Diurnal changes
–Recall period
Mid- to long-term (days to months)
In-home use/dispensing
Lens care assigned if using reusable  contact lenses
Crossover preferred to contralateral  design
Need to define washout period
Questionnaire design
–Diurnal changes
–Recall period
Cross section
Prospective cohort
Registry
Essentials Double masking
Ensure adequate control/tests for potential false-positive results. That is, if changing from lens A to B and assessing comfort, also include masked change from lens A to lens A.
Double masking
Pre- and postexposure testing of ocular  surface staining
Observer masking more critical; wearer masking if possible
Pre- and postexposure testing of ocular  surface staining
Breadth
Variety of clinical settings
Population Can be asymptomatic wearers to determine whether change is detectable
Could select difficult-to-fit  subpopulation
Understand habitual symptom state
Possible participant groups include poor “wetters,” symptoms vs. no symptoms
Must be able to attend visits after lens  fitting
On premises best for new materials in  case of need for emergency lens  removal
Possible participant groups include poor “wetters,” symptoms or no symptoms
Account for adverse events between  scheduled visits
Fewer exclusion/inclusion criteria
Outcomes Decide on meaningful differences with scales Determine clinically meaningful and statistically significant differences Determine clinically meaningful and statistically significant differences Determine clinically meaningful and statistically significant differences
Setting Clinic Clinic Home use Home use
Remote access
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