Evidence review

Clinical and technical evidence

Regulatory bodies

A search of the Medicines and Healthcare Products Regulatory Agency website revealed no manufacturer Field Safety Notices or Medical Device Alerts for this device. No reports of adverse events were identified from a search of the US Food and Drug Administration (FDA) database: Manufacturer and User Device Facility Experience (MAUDE).

Clinical evidence

A literature search revealed 38 relevant journal articles. Studies have been included in this briefing if they compared the effectiveness of TearLab against other tests or self‑reported symptoms in either diagnosing DED or measuring response to treatment. To avoid confounding results, studies have only been included if the study populations had symptoms of DED, but no other presenting factors (such as allergies, eye deformities or infections). Retrospective studies and studies with fewer than 30 patients were excluded. As a result, 6 studies have been included in this briefing.

The aim of the study reported by Caffery et al. (2014) was to assess the correlation between tear osmolarity readings (measured using TearLab) and symptoms of DED, and to determine how well these correlate with the self‑assessment of DED. People (n=249) were recruited from attendees at the American Academy of Optometry conference and did not have clinically diagnosed DED. People who had worn contact lenses in the past 2 weeks were excluded from the study. Patients completed the Dry Eye Questionnaire 5 (DEQ‑5) and a Gestalt self‑assessment. The DEQ‑5 is a validated 5‑item self‑assessment questionnaire, used to help diagnose DED and quantify its severity. The DEQ‑5 questions are related to eye discomfort, eye dryness and watery eyes. The Gestalt self‑assessment asks the person whether or not they think they have DED. People then had osmolarity testing using TearLab done by experienced clinicians. There was no statistically significant correlation between the DEQ‑5 scores and tear osmolarity. No significant differences were seen between the 'yes' and 'no' (Gestalt self‑assessment) self‑reported dry eye groups and average osmolarity (p=0.23). The authors concluded that there was no statistically significant correlation between tear osmolarity and self‑reported ocular symptoms (as measured by the DEQ‑5) or the Gestalt self‑assessment.

The aim of the Jacobi et al. (2011) study was to evaluate the diagnostic accuracy of the TearLab osmolarity system to assess the osmolarity of tear samples from people with moderate to severe DED (DEWS Dry Eye severity level 3; n=133) compared with healthy people as controls (n=95). The severity of DED was assessed using Schirmer's test, TBUT and results of the Ocular Surface Disease Index (OSDI) questionnaire. Inclusion criteria were a TBUT of less than 5 seconds, a Schirmer's test result of less than 5 mm per 5 minutes and positive symptoms according to the OSDI. People were placed in the healthy control group if they were asymptomatic and had normal TBUT and Schirmer's test results. Findings from the study revealed a statistically significantly higher osmolarity in people with moderate to severe DED than in healthy people in the control group (p≤0.05). The sensitivity of the TearLab test was 87%, and the specificity was 81%. The authors concluded that TearLab can be an effective objective diagnostic tool in the diagnosis of DED.

The aim of the Messmer et al. (2010) study was to evaluate the ability of the TearLab osmolarity system to differentiate between people with DED (n=129) and healthy people acting as controls (n=71). A diagnosis of DED was made if more than 3 out of 6 clinical criteria were met. These included results from the OSDI questionnaire, corneal staining, TBUT and slit‑lamp examination indicating DED. The results of the comparison showed that there was no correlation between TearLab osmolarity and the 6 DED criteria. The authors concluded that the TearLab test was not sensitive enough to discriminate between people with DED and healthy people.

The aim of the Lemp et al. study (2011) was to assess the diagnostic performance of tear osmolarity compared with that of other tests. People (n=299) were recruited from the general population and had 6 commonly used tests to diagnose DED, including tear osmolarity measurement using the TearLab osmolarity system. Of the 6 tests, tear osmolarity had superior diagnostic performance. The most sensitive threshold between normal and mild or moderate DED was 308 mOsm/litre, whereas the most specific was 315 mOsm/litre. At a cut‑off of 312 mOsm/litre, tear osmolarity showed 73% sensitivity and 92% specificity. In contrast, the other tests showed either poor sensitivity (corneal staining 54%; conjunctival staining 60%; meibomian gland grading 61%) or poor specificity (TBUT 45%; Schirmer's test 51%). The authors concluded that tear osmolarity is the best single metric for diagnosing and classifying DED.

The aim of the Sullivan et al. (2012) study was to compare the variability of 6 commonly used biomarkers for DED diagnosis (tear osmolarity, TBUT, Schirmer's test, staining, meibomian grading and OSDI) over a 3‑month period. Two measurements were reported: the range and standard deviation of each test. Patients (n=52) had all been diagnosed with DED within the 2 years before the study. The results showed that tear osmolarity (TearLab) values had a statistically significantly lower range and less variability than corneal staining (range p=0.029; variability, p=0.040), conjunctival staining (range p=0.0035; variability p=0.002), and meibomian gland dysfunction score (range p=0.0001; variability p=0.0001). The average variability of tear osmolarity was also lower than that of TBUT, Schirmer's test and OSDI, but these differences were not statistically significant. At the end of the 3‑month observation period, a subset of 10 people with severe DED entered an additional 3‑month interventional study to determine the reproducibility of the tests when measuring treatment outcome. Tear osmolarity was the only test to show a statistically significant response to treatment with ciclosporin (p<0.0001) with average osmolarity and variability decreasing from 341±18 mOsm/litre to 307±8 mOsm/litre. The authors concluded that tear osmolarity was the only objective test sensitive enough to detect a response to ciclosporin over a 3‑month period.

The aim of the Tomlinson et al. (2010) study was to compare osmolarity results from the TearLab osmolarity system with those from the Clifton osmometer (Clifton Technical Physics), and to evaluate the diagnostic accuracy of each instrument. Thirty six people were recruited for this study and were assigned to DED and non‑DED groups using inclusion criteria based on the results of several standard DED tests (non‑invasive TBUT, Schirmer's test, McMonnies questionnaire). Both the DED (n=15) and non‑DED groups (n=21) had osmolarity testing (randomised to instrument). A statistically significant correlation was found between the TearLab and Clifton osmometer measurements (r=0.904; p=0.006). The values measured by the 2 osmometers showed a high level of agreement with only a minimal number of points falling outside the 95% confidence limits. Cut‑off values taken from the distribution of osmolarity values were used to diagnose DED with 73% sensitivity, 90% specificity, and 85% positive predictive value for TearLab and 73% sensitivity, 71% specificity, and 65% positive predictive value for the Clifton osmometer. The authors concluded that TearLab has the potential to provide clinicians with a readily available test that could become the gold standard for DED diagnosis.

Recent and ongoing studies

Two ongoing or in‑development trials on the TearLab system for tear film osmolarity measurement were identified in the preparation of this briefing.

TearLab core validation study to establish referent values for dry eye disease (CVS) trial NCT00848198. This is an observational, prospective, case control, multicentre (10 sites in the US, Europe and Japan) study comparing osmolarity measured with TearLab in tear samples from people with DED with age‑ and gender‑matched healthy people as controls. The study began in February 2009 and was expected to complete by July 2010. This study is currently recruiting patients (by invitation only).

Tear osmolarity clinical utility in dry eye disease trial NCT02417116. This is a non‑randomised, open label, efficacy study that will investigate the efficacy of 2 non‑pharmaceutical eye drops (0.3% hypermellose and hylo‑forte 0.2% sodium hyaluronate) combined with an omega 3 nutritional supplement and warm compresses compared with placebo (saline) for people with DED, by measuring tear osmolarity changes over a 3‑month period using the TearLab system. This UK‑based (Aston University) study began in June 2015 and is expected to complete in December 2015. Estimated enrolment is 120 patients and the study is currently recruiting.

Costs and resource consequences

If the TearLab osmolarity system was adopted in the NHS, it would be used in addition to existing tests and clinical evaluation for diagnosing patients with DED. Dry eye symptoms are common, and in people aged 65 years and older the reported prevalence rates are 15–33%. The NICE clinical knowledge summary on dry eye syndrome notes that the prevalence of DED increases with age and it is more common in women than in men. Because the current care pathway for DED is not clearly defined, the likely NHS usage for the TearLab osmolarity system is difficult to estimate.

There will be no need to change the way in which current services are organised or delivered. No other additional facilities or technologies are needed alongside the technology.

No published evidence on resource consequences of using the TearLab osmolarity system was identified in the systematic review of evidence.

Strengths and limitations of the evidence

The evidence considered in this briefing ranged from small single‑centre to multicentre prospective cohort studies. Study patients were adults who were either healthy people acting as controls or people with DED. No randomised controlled trials were identified. Studies were carried out in various regions, including Europe, the USA and Japan. All studies aimed to examine the relationship between tear film osmolarity and severity of DED and to evaluate the potential of tear osmolarity (measured by the TearLab osmolarity system) as an objective measure in the diagnosis of DED.

A potential source of bias is the composition of the participating population. The cohort used in Caffery et al. (2014) was conference attendees who were self‑assessed and had not had a DED diagnosis. It is possible that this population may have had milder forms of DED than those studied in clinical research settings, which could account for the relatively low osmolarity findings. The person's occupation (eye care practitioners, optometry students, optometric staff) may have influenced their answers on the DEQ‑5 questionnaire. Finally, by excluding people who wear contact lenses, the study may have missed a significant population with DED.

DED is considered to be a multifactorial condition and there is no gold standard to diagnose it. It is generally recommended (DEWS 2007) that a diagnosis is based on a clinical history, and subjective (DEQ‑5, Gestalt questionnaire) and objective tests (including Schirmer's test, TBUT and corneal staining). But the lack of an established combination of tests and cut‑off values complicates DED diagnosis, and studies use different combinations to stratify DED severity. Caffery et al. (2014) introduced further uncertainty into their study by using global self‑assessment, a single subjective measure, as a surrogate for DED diagnosis.

The results of the Caffery et al. (2014) and Messmer et al. (2010) studies are dependent on the validity of the correlation between subjective symptoms and the objective presence of DED. In a retrospective study on the relationship between signs and symptoms of DED in a clinic‑based population, Sullivan et al. (2014) found no consistent relationship between common signs and symptoms of DED and noted that 'each type of measurement provides distinct information about the condition of the ocular surface'. The authors stated that 'symptoms alone are insufficient for the diagnosis and management of DED', and that 'measurements of osmolarity may more closely reflect the central pathogenesis of DED than other commonly used signs and symptoms'. They concluded that a consensus of clinical signs may better reflect all aspects of the disease. Foulks et al. (2015) state that although DED is usually symptomatic, 40% of people with clear objective evidence of dry eye disease are asymptomatic, so correlations between signs and symptoms of DED are questionable as an assessment of the validity of tear osmolarity testing for diagnosing DED.

The Tomlinson et al. (2010) study found a positive correlation between the TearLab system and the Clifton osmometer for measuring tear osmolarity in 15 people with mild to moderate DED and 25 healthy people as controls. The authors noted that the sensitivity, specificity and positive predictive value did not reach the level of diagnostic effectiveness expressed in other reports. The sample size in this study was relatively low compared with other studies presented in this briefing. Smaller sample sizes can lower the power of a study. The study outcomes are not representative of people with severe DED.

Another potential source of bias is the level of training of the clinicians in using TearLab. Caffery et al. (2014) note that the study examiners were clinicians who were experienced in using TearLab in their own clinical settings, and that technical support was available from the manufacturer. In contrast, none of the other studies reported whether the investigators had training with the TearLab osmolarity system, nor did they report the investigators' level of experience.

Messmer et al. (2010) was the only study to report in detail the technical problems that happened while using the TearLab osmolarity system. First, the authors note that the scientific principle of TearLab was not publically available at the time of the study so the investigators did not know whether it measured osmolarity directly or indirectly (for example, by determining salinity). Second, they discuss how TearLab may be inefficient in detecting the small osmolarity changes in tear meniscus between people with and without DED. Third, the authors were uncertain whether, by using the TearLab osmolarity system, they collected the correct type of tear. Pathological changes can only be measured in basal tears (not in reflex tears) making their collection critical for measuring meaningful osmolarities. Although the TearLab pen is designed to collect minimal tear volumes directly from the tear meniscus without inducing reflex tear secretion, the reduced osmolarity values seen are similar to those expected from reflex tears, provoked by contact with conjunctiva and lids. Messmer et al. (2010) measured osmolarity in either the subjectively worse eye or the left eye (if both eyes were equally affected), rather than in both eyes as recommended in the product labelling. The manufacturer recommends using the higher of these 2 measurements for clinical assessment.

Lastly, the studies by Sullivan et al. (2012), Lemp et al. (2011) and Tomlinson et al. (2010) were funded by the manufacturer and this introduces the potential for bias in the reporting of outcomes.