EMPIR Research Potential Project - 16RPT03 - inTENSE:
Development research capabilities for traceable intraocular pressure measurements
This project aims to establish a competence centre for intraocular pressure (IOP) metrology at CMI. CMI will become a service provider to other Central European metrology institutes who, for lack of capacity or because of different priorities, can then refer their national customers to CMI. This focusing of competence at one site will strengthen research capacity of CMI in this area, allowing them to develop calibration services for current and future ophthalmologic instruments. The expansion of this centre to other European countries and to further medical devices is in progress.
Glaucoma - the leading cause of irreversible blindness and ocular hypertension, where the IOP is higher than normal, is the most relevant and the only treatable risk factor for this disease (untreatable risk factors include a genetic predisposition to the disease and the refractive index (geometry) of the eye). Non invasive IOP measurements, taken by tonometers, are used to screen for this condition and to monitor its progression. Several European countries have national regulations for tonometers to ensure in service performance. These are implemented through periodic metrological checks or (re-)verification by NMIs, DIs and/or by other authorised metrology bodies. Few NMIs/DIs, however, are prepared to provide traceable calibrations for tonometers and test devices. Medical device metrology, as a whole, is unevenly developed across Europe. The Medical Devices Directive of the EU was introduced when the Eastern European NMIs were in a transition period, hence, they were not able to catch up with current developments. This project aims to develop metrological research capabilities in the field of IOP and possibly other ophthalmologic measurands. It focuses on Central Europe at this stage, but the long term goal is to create a Europe wide research and metrological traceability network for medical devices in general.
With this in mind it is necessary to first establish the necessary measurement and research capabilities at CMI, enabling them to provide and maintain a competent IOP metrology service for other Central European NMIs/DIs. CMI will engage in extended proactive research in order to be able to follow the latest technological developments and to identify potential new measurands. Building on these expanded capabilities the technical, legal, and organisational conditions must be clarified to actually install such a competence centre for IOP metrology at CMI and to make its service available to other NMIs/DIs. Finally, the options, risks and possibilities for expanding this concept geographically and thematically will be explored.
The specific objectives of the project are:
1. To jointly develop traceable measurement and research capabilities at CMI for IOP measurements using common contact and non contact tonometer types in the physiological and pathophysiological range of 10 mmHg – 80 mmHg.
2. To jointly develop research capabilities enabling CMI to identify other related ophthalmological measurands or non standard measurement conditions, both existing and likely to be developed, and to evaluate them with respect to their suitability as targets for metrological checks.
3. To develop and implement a concept for smart specialisation in the field of traceable IOP measurements; for CMI to establish collaborations with the national and international medical research community and to develop a strategy for the perpetuation of the acquired research capability in IOP measurements and a strategy for offering calibration services from the established facilities to national or international customers including NMIs/DIs; for other NMIs/DIs from within the consortium or other EURAMET countries to utilise these services, thus ensuring that a coordinated and optimised approach to the development of traceability in this field is developed.
4. To develop a strategic plan to extend the smart specialisation concept to other medical devices with a measuring function and beyond the Central European region.
5. To closely engage with all major regional stakeholders, including the responsible ministries, state authorities, calibration services and other governmental or non governmental offices involved in ensuring that the legal metrological requirements in their countries are met, thus ascertaining that their needs are known and considered and that they know about the project and its results and accept and implement them for their future work.
Progress beyond the state of the art
PTB is the only NMI having the current state of the art in IOP metrology. This refers not only to the calibration capabilities that ensure traceability for today’s standard tonometers, but also to the research background that is needed to adapt to the demands of new technological developments. To reach the same level of competence, CMI completed a series of advanced training sessions and successfully passed an external technical review. CMI is currently preparing for an external quality management audit.
The state of the art in ophthalmologic metrology will be expanded as the new ophthalmologic measurands will be identified and assessed for their metrological relevance and potential. External scientific expertise from university partners (STU BA, UPOL) will be crucial to achieve this goal. For the first time, mathematical modelling of the measurement process including the eyeball itself will be introduced to this sector of metrology. Future decision making in the field of measurements of the additional ophthalmologic parameters can then be based on a rigorous scientific basis.
The existing (technical) state of the art in IOP metrology will be made accessible to a broader range of countries. This will be pursued by condensing the expertise and knowledge at one site, CMI, while simultaneously making it accessible to others. A centre of excellence for IOP metrology has been developed at CMI, which is not only designed for the needs of the Czech Republic but also for the needs of all European NMIs/DIs in this field who cannot or do not want to build and maintain this capacity for themselves.
This concept will be expanded by anchoring it to the relevant international and European metrological institutions, making it sustainable, known and accessible to the widest metrological community. The first exploration steps towards an expanded scope of this competence centre: geographically beyond Central Europe and thematically beyond ophthalmologic instruments were made, with a particular focus on blood pressure devices.
1. To jointly develop traceable measurement and research capabilities at CMI for IOP measurements using common contact and non-contact tonometer types in the physiological and pathophysiological range of 10 mmHg - 80 mmHg. - Meeting this objective will lead to CMI having state-of-art level calibration, verification and research capabilities in the field of traceability of contemporary eye tonometers. Moreover, CMI will be able to further develop these capabilities and to keep pace with technological progress in this field. This objective needs to be achieved in order to fulfil all of the other targets in this project. The plan and priorities for the training courses were agreed by the consortium (impression tonometers and applanation tonometers for the first training course, non-contact tonometers for the second and the third training courses, and contour tonometers, Mackay-Marg tonometers and re-bound tonometers for the fourth training course). All of the planned advanced training of CMI personnel was successfully accomplished. The efficacy of the training was assessed by two external experts in the period 5-6 November 2018. The staff of CMI met all of the requirements necessary to pass the technical assessment. The strategy for the establishment of a future CMI training centre was discussed with the partners and the stakeholders during the second project meeting and workshop in November 2018 in Bratislava. Also the most suitable transfer standard for eye-tonometry comparison was discussed and the consensus was to use a Goldmann applanation tonometer.
2. To jointly develop research capabilities enabling CMI to identify other related ophthalmological measurands or non-standard measurement conditions, both existing and likely to be developed, and to evaluate them with respect to their suitability as targets for metrological checks. - CMI will be able to introduce, and ensure, the necessary metrological checks for the emerging ophthalmological measurands (i.e. corneal thickness, corneal stiffness, etc.) which appear as additional functions in most modern eye tonometers, as well as for the instruments. This will also enable CMI to undertake IOP measurements under non-standard conditions (e.g. incumbent patients). A thorough literature survey and a series of consultations with medical experts were carried out and the factors that most influence IOP measurements were identified for the common situations and for the most widely used eye-tonometers (properties of eye tissues, physical activities, hypoxia, head position, hydration of the subjects, intake of beverages like coffee or energy drinks, pupil dilation, accommodation, diurnal rhythm etc.). The most significant influential factors were identified for the most commonly used tonometers such as the Goldmann applanation tonometer, non-contact tonometers and rebound tonometers. A final report concerning all of these findings was delivered. A virtual digital model of the eye cornea was created. A real mechanical model corresponding to the virtual model was constructed for mutual verifications which have already started. A wider cooperation with academia was established in the comparison of the data from non-contact and rebound tonometers with the known properties of the applanation tonometer and in the study of the factors influencing the IOP. The IOP data using rebound and non-contact tonometers from more than 40 subjects were measured. Another study also started which is focused on the influence of physical activity, head position and water on the IOP. Materials for publication of the effect of hypoxia on IOP were processed and published.
3. To develop and implement a concept for smart specialisation in the field of traceable IOP measurements; for CMI to establish collaborations with the national and international medical research community and to develop a strategy for the perpetuation of the acquired research capability in IOP measurements and a strategy for offering calibration services from the established facilities to national or international customers including NMIs/DIs; for other NMIs/DIs from within the consortium or other EURAMET countries to utilise these services, thus ensuring that a coordinated and optimised approach to the development of traceability in this field is developed. - The metrological and research capabilities developed for IOP metrology at CMI will initially be available for all of the NMIs/DIs in Central Europe and subsequently for all of the NMIs/DIs throughout Europe and for other customers, including academic and research. This will be achieved through a collaborative network developed on the basis of the smart specialisation concept. The consortium is investigating relevant national legislation. The participant NMIs are currently in contact with their management and legal departments in order to establish their role in the proposed smart specialisation concept. At the same time, cooperation agreements between the NMIs are under development and they intend to sign these before the end of the project. After a clear position has been decided, the national responsible authorities will be contacted (responsible ministries).
4. To develop a strategic plan to extend the smart specialisation concept to other medical devices with a measuring function and beyond the Central European region. - The first steps towards broadening the cooperation network established for the field of IOP metrology, within the smart specialisation concept, beyond the Central Europe region and to other medical measuring instruments were made by adding blood pressure instruments to the priority list of the competence centre. PTB successfully applied for a new OIML Recommendation “Ophthalmic instruments – non-contact tonometers” under TC 18 “Medical Measuring Instruments”. The project is currently at the stage of forming the group, with the intention for most NMIs in the consortium to become participating members and thus being able to directly influence the development of the new recommendation. The consortium evaluated the content of the MDR and discussed the changes introduced at national and EU level. The latest information regarding these changes were obtained from national authorities, from participation at relevant meetings and from official publications and further disseminated to stakeholders during our first workshop in Bratislava. CMI and PTB are in advance discussions concerning the establishment of a European Centre on Medical Device Metrology based in the Czech Republic. A legal contract between the two institutions is under development.
Impact on industrial and other user communities:
The consortium started the process of reorganisation of the metrology landscape for IOP measurements in Central Europe by undertaking the first steps in establishing the Centre of Excellence for IOP measurements at CMI. This will positively impact various communities. The manufacturers and distributors of IOP devices will deal with a homogenously developed market which is ready to absorb the newest trends. A well developed metrological infrastructure will provide them with clear guidance, and hence legal certainty, on how the requirements can be met. Ophthalmology professionals and their organisations will be able to rely on a clear compliance, a correct traceability chain, correct measurement results and validated methods. The patients will benefit from the most up to date metrological traceability in the eye tonometry field. They will receive access to the best care and will gain rapid access to new technological developments. In order to ensure a smooth and active interaction with stakeholders, the working group “Eye Tonometers” was established during the workshop in Bratislava. This working group will exist beyond the end of this project and it will be used as a forum to promote the uptake and use of the newest solutions.
Impact on the metrology and scientific communities:
This project will lift the level of intraocular pressure measurements in east central Europe to the state of the art found in the western part of this region. The regional authorities, from the Ministries of Health to the local calibration offices, whose responsibility it is to meet existing and future regulatory requirements in their countries will benefit from a re established traceability chain, the higher level of regional cooperation and the wider experience and information exchange enabling them to reflect and even to lead this research area. This group will have the opportunity to directly interact with the project researchers, e.g. via a collaboration network, to make their needs known and considered, and to simultaneously benefit from metrological advice. As this project will build a research capacity rather than just establishing a momentary state of the art, the primary stakeholder group can confidently rely on a sustainable metrological infrastructure which will be able to flexibly adapt to technological or regulatory changes in the future. The first steps in the direction of creating the training centre for IOP metrology were made. CMI completed all planned advanced training sessions and successfully passed the external technical assessment. The institute is currently preparing the first training for interested small NMIs from the consortium. The training centre for IOP metrology, established within the project, will continue providing services after the end of the project. These services will be continuously improved and upgraded according to the latest developments.
The links between the consortium and optometry researchers from different departments of UPOL were established and the cooperation was agreed. In the frame of this cooperation, the IOP data obtained under different conditions were collected and analysed. Recently, some original results were provided to the research community in the form of an open access publication in an impacted journal. SMU and STU BA have started a mutual cooperation between the medical experts from the Medical Faculty of the Comenius University in Bratislava. Part of this cooperation is in the transfer of knowledge between the medical and metrology fields in order to improve the cornea virtual model and the characterisation of the effects that influence IOP measurements in practice. Furthermore, initial contacts have been established with companies dealing with eye tonometry measurements. Another cooperation has also started between SMU and the Slovak Office of Standards, Metrology and Testing, which is focused on legislation in the field of eye pressure measurements within the Slovak Republic, but also in adjacent countries.
Impact on relevant standards:
Thus far, the key body involved in the standardisation of the metrological requirements of IOP metrology has been OIML TC18 “Medical measuring instruments”. The consortium is currently preparing a draft for a new Recommendation “Ophthalmic instruments – Non-contact tonometers”, which will complement the existing OIML R 145 recommendation on applanation and impression tonometers. To further support and promote this Recommendation, communication will be established with the CCM WGPV and IMEKO TC16 and their support will be sought. The chair of the CCM Working Group – Pressure and Vacuum was contacted regarding inclusion of IOP comparisons into the CIPM MRA scheme and a discussion on the topic is planned for the next meeting of this Working Group.
The German - Leitfaden für die messtechnische Kontrolle von Medizinprodukten mit Messfunktion (Guidelines for Metrological Checks of Medical Devices with a Measuring Function) is the unofficial, but de-facto, standard in Germany and Austria. The document is currently being translated into English and will soon be made available to everyone interested on the homepage of PTB.
Najmanová E, Pluháček F, Botek M, Krejčí J and Jarošová J (2019) Intraocular Pressure Response to Short-Term Extreme Normobaric Hypoxia Exposure. Frontiers in Endocrinology 9:785.