Many studies have shown that dry eye signs poorly correlate well with symptoms, although late day symptoms show moderate correlations with some signs  and composite scores including both signs and symptoms may improve diagnosis of the condition . This suggests a need for more emphasis on PRO in dry eye in order to fully assess the condition and effect of treatments [3, 50]. Existing PRO instruments focus on the ability to identify and diagnose dry eye, assess the prevalence of the condition, and assess the severity and frequency of symptoms. With novel treatments under development, the need evolved for an instrument to assess the impact of change in the dry eye condition. From a clinician's perspective, this will help in setting realistic expectations and in measuring the degree of improvement in individual patients and the remaining issues. From a regulatory perspective, such an instrument will allow a standardised method to assess treatment effectiveness in primarily symptom-based conditions such as dry eye so that claims can be supported with evidence in the form of PRO.
Despite being developed prior to the FDA PRO guidance, the IDEEL instrument was developed in accordance with standards outlined , which requires demonstration of content validity and saturation. The IDEEL was developed based on patient input and is the first dry eye PRO questionnaire to formally demonstrate saturation of relevant concepts, therefore supporting its content validity. The SS patients were quicker to express the detrimental impacts dry eye had on every aspect of their lives when compared to non-SS KCS patients during the focus group discussions, however saturation was achieved on the overall population. To further support content validity, when decisions were made to delete items, psychometrics and the clinicians' and patients' own opinions were considered. Multi-Trait and PCA analyses confirmed the hypothesised structure of the IDEEL as 3 distinct modules. The final IDEEL comprises 57 items organised into 3 modules, Dry Eye Symptom-Bother, Dry Eye Impact on Daily Life, and Dry Eye Treatment Satisfaction, that allow a comprehensive evaluation of the burden of the dry eye condition on patients. The assumption about the pre-defined structure of the IDEEL as 3 distinct modules and the lack of data from PCA and Multi-trait analyses on the questionnaire as a whole could be raised as limitations, as the purpose of these analyses is to allow the definition of the structure and organisation of the instrument. However, satisfaction, which is defined as an emotive evaluation which enables the assessment of the appropriateness of the perceived quality of treatment with expectations , is conceptually different from HRQL, that covers physical, psychological, social functioning, and somatic sensations . Similarly, it is now acknowledged that symptoms are a PRO distinct from HRQL . In light of these definitions, our assumption appears to be legitimate.
Psychometrically, the IDEEL final dimensions are reliable and valid. In particular, when comparing results to the SF-36 and EQ-5D, the IDEEL consistently outperformed these generic measures in distinguishing between patients' reported severity, clinician-rated severity and patient-rated severity groups, as one would expect with a condition-specific scale (data not shown) . The generic measures appear capable of distinguishing between more severe categories of patients (i.e., moderate versus severe), but not capable of distinguishing between mild and moderate levels. In contrast, the IDEEL dimensions are able to distinguish between the majority of severity levels, with the exception of the Treatment-related Satisfaction module; however treatment satisfaction might not be expected to differ by severity of condition alone. One might be surprised with the low correlation level between some of the IDEEL dimensions and the SF-36 (such as "impact on work" of IDEEL and "role physical" of SF-36; "emotional impact" of IDEEL and the mental component (or some of the related scales) SF-36). The SF-36 role-physical items focus on impact due to their 'physical health. We believe that when people respond, they interpret 'physical health' to mean a disease or bodily impairments (e.g. torso, limbs) and probably do not think of dry eye as a 'disease' nor think of the eye as being 'bodily'. Further cognitive debriefing of SF-36 would be required to confirmed or not this hypothesis.
In our testing across known diagnostic groups, results were fairly consistent across methods of defining severity (self-assessment, clinician assessment, or recruited diagnosis). Given the relative lack of clarity in the field on how to define dry eye severity precisely, we used these methods to define severity. We would recommend using this type of approach in any tests of known groups or clinical validity, since the use of insensitive or non-specific clinical criteria that do not relate to symptoms could result in concluding that a questionnaire is not discriminative or responsive, when in reality it is the clinical criterion used to define severity that is not discriminative or responsive. This issue is particularly important in dry eye because no single clinical measure is widely accepted as the 'gold standard' in predicting dry eye symptoms and the impact of dry eye on patients' quality of life,  although recent evidence by Sullivan, Lemp and coworkers suggests that tear film hyperosmolarity may correlate better than other clinical tests for the condition [18, 54]. Because clinical judgments remain central in the assessment of dry eye severity, the same team has proposed the use of composite severity index associating osmolarity testing with traditional tests of the traditional clinical tests in order to classify dry eye severity as accurately as possible . The likelihood that dry eye symptoms stem from a number of aetiologies also confounds the effort to start the diagnostic process from the signs rather than the symptoms. Determining that the patient is experiencing sufficient symptoms to warrant further diagnosis and treatment is a more effective clinical starting point for such a complex condition. Hence the importance of using a PRO instrument such as the IDEEL in conjunction with the clinical tests to properly assess the improvement of patients' dry eye condition.
Further development work is ongoing to allow the use of the IDEEL as an estimate of the overall health impact of dry eye and improvement by treatment. A recent study established the minimal clinically important difference of the IDEEL dry eye Symptoms-Bother dimension in mild, moderate and severe dry eye . A 12-point shift in the IDEEL Dry Eye Symptom-Bother dimension score was determined to be the clinical important difference relating to a global change in dry eye condition after implementing tear replacement drops . Research in assessing the overall dry eye health burden on the patients is ongoing, including its comparison to other diseases, and highlights the impact of dry eye condition in patients in terms of utilities outcomes .
The focus groups in the development and in the validation of the IDEEL included US and Canadian patients. At the same time in Europe, a PRO instrument, the Ocular Surface Disease (OSD), was being developed based on French dry eye patients' outcomes. Similar concepts and sub-concepts were identified from this study, supporting the validity of the concepts that had emerged from the focus groups, as well as the appropriateness of the items to European patients [56, 57]. It is likely that in other parts of the world, no different issues associated with dry eye will emerge, but this should be verified before being implemented in a study. The use of the IDEEL in Europe is made possible given the availability of linguistically validated translations in the different European languages. So far, currently validated or in development languages include German, Spain, French for France, English for UK, Polish, Italian Portuguese (Brazil), Simplified Chinese (Singapore), and Spanish for US.
The use of the IDEEL in other different studies will continue to provide further data to obtain further information on the importance of specific items for specific dry eye patients with different aetiologies. It may also allow the further reduction of items, while ensuring all the important concepts to patients are evaluated, in case of developing a briefer instrument for use in clinical practice. The items of the IDEEL are likely to be appropriate for specific sub-groups of dry eye patients; due to the similarity of the symptom-bother and daily life impact reported by patients with meibomian gland dysfunction (data not shown) . However, to ensure all issues of relevance in this condition are covered, future studies and saturation assessment would be required.
In conclusion, the IDEEL is a reliable and valid questionnaire relevant to the issues that are specific to dry eye patients and it meets the FDA PRO guidelines. The IDEEL is the only comprehensive instrument that was designed to assess the entire gamut of the impact of dry eye on patient outcomes: domains of patients' everyday life, treatment satisfaction, and amount of bother by symptoms. IDEEL will aid in the assessment of DE symptom severity and impact, and will complement information gathered through traditional clinical exams and measures. The continued use of the IDEEL instrument, either as a whole or as specific modules, will provide assessment of the impact of dry eye on patient dry eye-related quality of life that may aid treatment selection and dry eye management in clinical practices.