Dry eye disease (DED) is a common condition with signs and symptoms that vary depending on a wide range of environmental factors to which people are exposed in their daily lives. Factors such as variable temperature, airflow velocity, relative humidity, seasonality, and pollutants can alter the rate of tear film evaporation, improving or exacerbating symptoms of DED. Results from currently available clinical tests do not always correlate well with patient-reported symptoms, and the continually changing environment and variability in DED symptoms present challenges for the design and conduct of clinical trials. Controlled adverse environment chambers allow standardization of temperature, humidity, and airflow and may minimize potential confounding factors in clinical investigations. Their use can promote accurate study of the pathophysiology of DED, discovery of disease biomarkers, and assessment of the effect of various therapeutic approaches on patients’ symptoms. Controlled adverse environment chambers have been used to simulate indoor surroundings such as airplane cabins and to test their effects on contact lens wearers. This review summarizes how these chambers may be useful for the development, approval, and differentiation of potential new treatments for DED.
This manuscript is a sub-analisys of this clinical trial Pinto-Fraga J, Lopez-Miguel A, Gonzalez-Garcia MJ, Fernandez I, Lopez-de-la-Rosa a, Enriquez-de-Salamanca A, Stern ME, Calonge M. Topical Fluorometholone Protects the Ocular Surface of Dry Eye Patients from Desiccating Stress: A Randomized Controlled Clinical Trial. Ophthalmology 2016;123:141-153.
Tear samples from both eyes were taken; those from one eye were shipped to University of Tamere (Finland), where proteomics was performed. More than 700 proteins were identified in just 1 microL of tears and some showed differential expression depending upon the severity of DED, the influence of the controlled adverse environment (CELab) and the treatment. Luminex analisys was done in samples from the other eye and this manuscript is being submitted for publication. Both manuscripts defined potental biomarkers of Dry Eye Disease severity, activity and therapy (fluorometholone in this case).
We have published in NATURE SCIENTIFIC REPORTS 23 January 2018 Comparison between direct contact and extract exposure methods for PFO cytotoxicity evaluation
A series of recent acute blindness cases following non–complicated retinal detachment surgery caused the release of several health alerts in Spain. The blindness was attributed to certain lots of perfuorooctane (PFO; a volatile and transient medical device). Similar cases have been reported in other countries. This has raised questions regarding the validity of cytotoxicity test methods currently used to certify the safety of PFO lots. The tests were performed according to the International Organization for Standardization (ISO) norms, using the extract dilution method or the indirect contact method as applied to L929 cells, a line derived from mouse fbroblasts. The limitations of those methods have been resolved in this study by proposing a new cytotoxicity test method for volatile substances. The new method requires direct contact of the tested substance with cells that are similar to those exposed to the substance in the clinical setting. This approach includes a few new technical steps that are crucial for detecting cytotoxicity. Our new method detected toxic PFO lots that corresponded to the lots producing clinical blindness, which previous methods failed to detect. The study suggests applying this new method to avoid occurrence of such cases of blindness
This certificate of GLP compliance confirms that Competent Authorities consider the studies carried out of :
2.1 In vitro toxicity
9.5 Safety Pharmacology
9.9 Biocompabtibility of medical devices
2.1 In vivo toxicity
2.1.1 Short term
2.1.2 Long term
2.4.2 Ocular tolerance
Comply with the Good Laboratory Practices (GLP) demanded by the Spanish legislation ( Royal Decree 822/1993, of the 28th of May, modified by Royal Decree 1369/2000 of the 19th of June) wich are in keeping with Directives 67/548/CEE, 87/18/CEE, modified by Directive 99/11/CEE and Directive 2004/10/CEE.
We expect this will be an added value for future studies performed at our facilities.
After the health alert that suspended the marketing authorization of Perfluoron® (product used in vitreo-retina surgery procedures), the new IOBA-CYTOTEST, patented methodology, developed in Valladolid, confirmed that the analyzed batches of this product were safe.
The European requirements (Directive 93/42/EEC Annex IX) recommended the International Organization for Standardization (ISO) 10993 and 16672 to assure safety of intraocular devices (Class IIb). Unfortunately, IOBA research has proven that some of the existing tests that comply with such regulations are unable to detect toxicity.
The new direct methodology (IOBA-CYTOTEST) has been developed in order to support the safety of some intraocular medical devices, by IOBA (Eye Institute of the University of Valladolid), which has commissioned Vision R&D to perform it.
European Authorities and main suppliers of intraocular medical devices are now in contact with IOBA and Vision R&D to propose a modification of the current ISO norms.
New Tools in Dry Eye Disease Research: A More Efficient Clinical Trial Design Using Controlled Environment and Molecular Biomarkers, and a New Clinical Questionnaire
On July 20, 2017, Dr. F. Jose Pinto-Fraga defended his Doctoral Thesis “New Tools in Dry Eye Disease Research: A More Efficient Clinical Trial Design Using Controlled Environment and Molecular Biomarkers, and a New Clinical Questionnaire”.
This thesis, received the designation of an International-awarded Doctorate Degree, was performed under the direction of Drs. M. Calonge, A. Enríquez de Salamanca and M.J. González-García. This is the latest work performed in the environment chamber (Vision R&D) in the CELab (Controlled Environment Laboratory) located at the IOBA building, University of Valladolid, Spain.
This research developed a novel two-step clinical trial design that, with only 20 patients in each arm, demonstrates how a therapy is not only effective against a patient’s Dry Eye Disease, but also protects their ocular surface against the worsening experienced through a 2-hr exposure to a controlled adverse environment. These adverse conditions are similar to those encountered in indoor offices, shopping centers, recreational facilities, cars, planes or even our own houses. This two-step design allows a potential therapy to also show a beneficial effect in normally encountered environmental situations.
Additionally, this kind of clinical trial allows examining patients thoroughly using the latest sophisticated tests so that the best primary clinical endpoints can be selected for future multicenter clinical trials.
Also important it is the fact that the collection of tears and cells from the ocular surface by minimally invasive means allows the detection of molecular biomarkers that help define the efficacy of the candidate drug.
In summary the two-step proof-of-concept or pilot clinical trial developed in CELab will provide the needed information for the go /no-go decision that pharmaceutical companies need in order to: 1) understand if their therapeutic candidate shows a therapeutic signal; 2) in which objectives that potential drug is showing a signal thus pointing at future primary/secondary endpoints; 3) to find out the best molecular signals that can define therapeutic efficacy for their drug.