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Feasibility study: Cloud-based diagnostic software for infectious diseases

Periodic Reporting for period 1 - BACRES (Feasibility study: Cloud-based diagnostic software for infectious diseases)

Reporting period: 2015-12-01 to 2016-05-31

The problem of antibiotic resistance is considered one of the largest threats to human health by the World Health Organization (WHO). In EU and the US, antibiotic resistance infections have been estimated to cause > 48 000 deaths from 2,5 million resistant infections and confer an economic cost of over € 60 billion yearly. (Antibiotic resistance threats in the United States 2013, Centers of disease control and prevention (CDC) and
Todays diagnostic methods of antibiotic resistance are slow, resource-consuming and/or non comprehensive. It takes between 48h to a week to get a full resistance determination, resulting in a overreliance on empiric antibiotic treatment, resulting in higher morbidity and mortality, increased transmission of infectious agents in between patients and longer hospitalization. In the EU, 5-12 % of the hospitalised patients will aquire an nosocomial infection during their stay.

1928 Diagnostics (1928D) is developing a diagnostic software solution that takes advantage of the recent developments in modern DNA sequencing technology called next generation sequencing (NGS) to reduce the diagnostic procedures of antibiotic resistance determination to < 12 hours. NGS technology is already frequently used in hospital settings, but mainly for research purposes. The focus on research applications with the NGS technology is primarly due to the lack of automated analysis tools for the challenging data analysis required to handle the clinical routine samples at the hospital laboratories. 1928D addresses this lack of automated diagnostic analysis tools for NGS data by developing a NGS software-as-a-service that will automatically generate resistance profiles and bacterial species identification (typing) in less than 15 minutes. This is achieved by combining cloud computing and automated bioinformatics into a cloud-based software that handles the large data set generated from the NGS machine. The only thing that will be required at the hospital laboratory for the analysis is an internet connection in order to upload NGS raw data files and to download the software generated resistance and typing profiles that will be used as a decision support for the doctor in the choice of correct antibiotic treatment.

The usage of NGS based diagnostics will result in shortened time from patient sampling to treatment, resulting in reduced mortality due to earlier treatment (12 hour compared to > 48 hours with present methods); less transmission of resistant bacteria due to shorter time a patient carries the bacteria; and diminished costs for the health care system and society due to shorter hospitalisation, better recovery, shorter time away from work etc.

The overall aim of the innovation project is to deliver novel state-of-the-art, automated bioinformatics for analysis of NGS to the hospital laboratories resulting in faster and more efficient diagnosis of bacterial infections. The overall objectives of the innovation project are:

I. To generate a fully developed software-as-a-service for direct customer use, preparing for launch in markets selected in the currently proposed feasibility study
II. Preparation of regulatory documentation for CE mark application
III. Preparation for clinical studies to validate the software and to benchmark against competitors.

Our company has the following specific objectives:

1) Identification of key markets for conducting clinical pilot studies.
2) Define the country specific regulatory demands for setting up clinical pilot studies.
3) Understanding the country specific reimbursement policies for sales of diagnostic tests.
4) Establish contact with key opinion leaders within infectious disease and heads of clinical laboratories in selected markets.
5) Establish agreements with clinical laboratories where the pilot study can be done.
6) Generate a business plan that includes a complete roll-out plan for the innovation project, including funding requirments, cash-flow porjections, benchmarking against competing solutions, IP strategy, market analysis and partnering options.
The feasibility study has focused on understanding the customers and market demands on the first version of the product in order to reach the market in the most efficient way. The investigations has primarily been done by approaching and discussing these demands with clinical bacteriologists, clinical doctors and public health authorities. In addition, literature studies has been performed. The investigation was limited to the top five EU markets (Germany, Spain, UK, Italy and France).

1) Market analysis

The focus of the market analysis was to identify the most suitable markets for product introduction depending on i) the availability of NGS technique in the diagnostic laboratories, ii) country specific reimbursement factors and iii) regulatory demands for registration in EU countries. These issues were investigated by directed market studies (desktop research) in combination with interviews of key opinion leaders and clinical bacteriologists and doctors.

Availability of NGS technique
NGS equipment was frequently available at the large hospitals in all investigated markets. Although not always present in the bacteriology lab the possibility to use NGS from neighboring facilities was common. These machines were either placed at a research group or at the clinical diagnostic laboratory to use to diagnose cancer or to identify hereditary diseases. The NGS machines were not used to its maximum capacity why there were slots available for running bacterial samples. Also, many bacteriology labs were planning to buy NGS equipments to use for infection diagnostics or surveillance. The limiting factor today is the data analysis, which requires expert resources in bioinformatics not available today, why the service 1928 diagnostics will offer is often a prerequisite for high level usage of NGS.

Country specific reimbursement factors
Reimbursement in the European health care sector is very complex and differ between different EU countries although there are some similarities as well. There is a high level of public health care in Europe with public actors complementing the scene. In many cases there are certain product codes that needs to be used for procurement and reimbursement. The procurement and reimbursement processes are generally lengthy and time consuming and offering a challenge to small companies with innovative products. In many countries special processes has been implemented for introduction of products that have the potential to be highly value creating and have a strong innovative component. A CE mark is always required and also some type of Health technology Assessment at different levels. It is important to show the clinical and economic value to get reimbursement for the product. This project has provided us with a clearer view on the order we will approach different markets.

Regulatory demands for registration in EU countries
The CE marking is a key indicator of a product’s compliance with European Union (EU) health, safety and environmental protection directives and regulations. It is needed to launch products with intended clinical use in all EU countries. The regulations are harmonised so that the same documentation is valid in all EU countries. Enforcement of CE legislation is performed by national market surveillance authorities, in accordance with the national laws and procedures of the Member States of the EU. These national market surveillance authorities share information about products that show non-compliance and lack of safety.
This project has provided a strategy on how to get a CE mark (classification, procedures, timelines, regulatory support etc.)

2) Clinical studies

Laboratories in the Nordic countries and the top 5 EU markets were evaluated to become test laboratories for pilot clinical studies for the purpose of introducing analysis of S.aureus in clinical routine diagnostics. The aim of the clinical test lab period is to evaluate different workflows, customer satisfaction, customer willingness to increase sample volumes and product fitness. The following criteria were considered for selection of laboratories: i) availability of NGS-equipment ii) IT system access iii) S. aureus sample throughput. The pilot studies will be conducted in two phases, Phase 1 and Phase 2. In addition, a clinical comparative study will be performed to support regulatory documentation.

Contacts have been made with Head of departments and senior clinicians in Sweden, Norway, Finland, Denmark, Germany, UK, Spain, Italy, France and the Netherlands. These interactions resulted in:
1) A specific plan for rolling out the product in two test lab phases.
2) Established agreements with 2 clinical laboratories for the test lab phase 1.
3) Established agreement with one public health authority for delivery of genomes for clinical isolates for a clinical comparative study.
4) An established network of clinical bacteriologists with great knowledge and impact.

3) Business plan

A business plan was generated for the introduction of the first version of the product to the clinical diagnostic market including further expansion of product functionality and company growth.


The activities conducted during this projected generated the following results:
i. An increased network of contacts in the clinical microbiology field.
ii. Two clinical laboratories have signed agreements to be test laboratories.
iii. Collaborator for clinical comparative study selected and contracted.
iv. A refined regulatory strategy. The relevant ISO standards to follow have been identified and the classification has been set.
v. Improved understanding of how diagnostic tests are reimbursed in the top 5 EU markets.
vi. Increased knowledge about how the product will be used at the microbiology laboratories.
vii. A business plan will full commercialication plan have been generated.

The results from this project will generate the following effect for the innovation project:
i. A better product market fit.
ii. More efficient market entry.
The overall aim of the innovation project is to deliver novel state-of-the-art, automated bioinformatics for analysis of NGS to the hospital laboratories resulting in faster and more efficient diagnosis of bacterial infections.

Antibiotic resistance is a major global challenge that is considered to be one of the three largest threats to human health according to WHO that can affect everybody. We are now facing a situation were a large number of bacterial infections are untreatable or can only be treated with a limited selection of antibiotics. Antibiotic resistance is an escalating burden for EU and the rest of the world in the form of loss of human lives as well as costs for the healthcare system and society. Faster and more precise diagnostics has been pointed out as one of the key successors in the fight against antibiotic resistance. The innovation project addresses this challenge by utilizing novel technology (NGS) and bring it to the market of clinical diagnostics. Since all the technical components (infrastructure) are already in place at many hospitals, the innovation has the potential to be implemented very quickly and provide high value to the EU community.

Our diagnostic service is tailored to address the needs identified by clinical diagnostic laboratories in order to achieve a reduced morbidity and mortality from bacterial infections. The primary identified need, is a reduction in the bacterial sample handling time required for identifying the correct antibiotic treatment of a specific bacterial infection. We are addressing this need by enabling the use of NGS into the diagnostic workflow in order to deliver a correct treatment to the patient in 12 hours, instead of after at least 48 hours required for traditional diagnostic methods. The second need that has been idenitifed is the epidemiological traceability of bacterial infections within and between hospitals. With current methods this procedure takes 3-7 days. The 1928D software analysis in performed in minutes.

We see the alarming growth of GDP losses due to antimicrobial resistance as the equally growing value of an industry, dedicated to battle the problem. 1928 Diagnostics already today provides a key enabler to mitigate a large part of losses related to antibiotic resistance. The paradigm shift in diagnostics that we present will be able to catch a large part of this growing market. The 1928D solution combines fast and accurate epidemiological traceability and antibiotic resistance profiling and will save lives due to faster onset of correct treatment. It will also have a direct effect on reducing the hospitals running cost. The savings are made by both lowering the diagnostic cost per sample and by reducing the number of hospital nights due to morbidity for patients caused by wrong or delayed administration of the correct antibiotic treatment.