Guide: Best Practices for Point of Care Product Development

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In the fight against the Coronavirus pandemic, rapid detection of the disease is key.

Under normal conditions, a company must demonstrate the efficacy and safety of their new in vitro diagnostic (IVD) test before it can be approved by the Food and Drug Administration (FDA) in the U.S. However, during public health emergencies, when there are no adequate tests available, the FDA can fast track the process by issuing Emergency Use Authorizations (EUA).

All test approvals granted under EUA are valid while the emergency status is in place.

Just mere months into the COVID-19 pandemic, there are already several diagnostic tests available with varying degrees of sensitivity, specificity and time to result. However, considering the high infection rate of the novel virus, it is essential to minimize time to result, allowing rapid response to having control measures that stop the spread of the virus. Point of Care (POC) diagnostics can rise to the challenge by providing accelerated time to result at the point of need.

The race against time: A short history of COVID-19 diagnostic development

A vast amount of global research is underway to understand virus dynamics and host response to aid the development of treatment and vaccines. The World Health Organization (WHO) has created a database comprising all research findings on COVID-19, which is updated daily to ensure the latest findings are available to the global scientific community.

By mid-December 2019, within a few days of the first few cases, the SARS-CoV-2 genome was sequenced in China and it’s now known that the genome of the virus is relatively stable. This discovery led to the realization that molecular Nucleic Acid Amplification Technique (NAAT) tests could quickly be developed to support COVID-19 detection.

Rapid diagnosis of the condition would allow countries to track the virus, perform epidemiology studies and use this data to implement necessary measures such as social distancing to slow the spread of the disease.

In response to this need, WHO released an interim guide for laboratories for new molecular and serology tests in development. This included testing strategies in different scenarios such as guidelines for test subjects given the shortage of tests available.

To maximize the number of laboratories around the world performing molecular testing, WHO provided detailed step-by-step protocols from various sources including necessary primers and probes to perform Polymerase Chain Reaction (PCR) testing.

While each company and lab developed test (LDT) would likely target a slightly different part of the genome, knowing where to start promised to significantly decrease the primer and probe design phase.

Laboratory testing for COVID-19

The advantage of laboratory testing is greater sensitivity and specificity of results. This is crucial, as either false positive or false negative results have significant impacts on decisions made by governments and healthcare providers in treatment, hospitalization, tracking and steps necessary to flatten the curve of the virus’s spread.

However, the disadvantage of laboratory (centralized or hospital-based) testing is the long time to results. Once a sample is taken, it must be transported to the laboratory, received by staff, entered into the Laboratory Information System (LIS), performed by skilled scientists with final reports then being entered back into the LIS.

From the time a sample is collected, it can take 2-5 days to have the result available. Sample preparation and PCR at the lab would only take 1-3 hours, but due to the overwhelming number of samples, this timeframe increases significantly.

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Point of Care diagnostics – improving time to result

While centralized laboratory testing provides high-quality, high-throughput results, POC devices have the advantage of generating results at the point of need, significantly reducing the wait time.

Molecular Point of Care Systems

Molecular POC systems can significantly reduce time to result. Tests can be performed where the patient sample is taken (i.e., no lengthy transport necessary), skilled scientists are not required to perform tests, and the opportunity for patient mix-up is greatly reduced as only one patient is tested at a time.

While POC systems often perform qualitative rather than quantitative tests, with COVID-19, a rapid qualitative test is sufficient to drive action by the healthcare professionals. The FDA has already approved a number of cartridge-based sample-in-answer-out POC systems including GenMark’s ePlex, Cepheid’s GeneXpert and Abbott’s ID Now.

POC Systems capable of detecting COVID-19: GenMark’s ePlex, Cepheid’s GeneXpert and Abbott’s ID Now.

These POC diagnostics rise to the challenge of requiring accelerated time to result, providing an optimal solution for COVID-19 detection. However, some challenges exist with the availability of analyzers and cartridges at the point of need.

The prospect of ramping manufacturing of analyzers and their cartridges is not insignificant, nor is it an issue that is easily or quickly resolved. A great number of suppliers will need to increase their manufacturing capacity extensively in a very short timeframe.

One solution to this issue can be seen with diagnostics companies developing or augmenting their existing assay panels (molecular, immunology, or otherwise) to detect the COVID-19 virus. An example is MeMed Diagnostics, which is developing an assay for early detection of viruses (including Coronavirus) while having the ability to predict deterioration in a patient’s condition. VitaPCR (Credo Diagnostics Biomedical), BioFire (bioMérieux), QIAstat-Dx (QIAGEN) and SAMBA II (Diagnostics for the Real World) are other examples of systems and companies which have available (or under development) tests for the detection of the virus.

The advantage of developing a flexible molecular POC system is that the analyzers can serve as a platform allowing for quick expansion of a company’s test menu as the need arises. The initial analyzer that undergoes regulatory approval will have all the necessary infrastructure to allow test menu expansion in the near to mid-term future.

Once a new test panel is developed, achieving approval and time to market is greatly minimized. This lays the groundwork for rapid response and high confidence in diagnosis, in turn leading to a more responsive and effective healthcare system.

To date, molecular diagnostics has been at the forefront of COVID-19 diagnosis due to ease of development and accuracy; however, being mainly targeted at centralized laboratories, complex to perform and the long time to result has meant significant bottlenecks in testing.

Immunoassay Point of Care Systems

A second detection methodology that has become more available for COVID-19 diagnosis at the point of need is immunoassay. This type of Point of Care test (POCT) requires more time to develop and is less sensitive, but has the advantage of being easy to manufacture, easy to use, and offers a quick time to result. Lateral flow assay formats are the most common protocol, which is the same technology used in standard home pregnancy tests. Immunoassays also provide an indication of historic viral exposure.

Immunoassays work by using IgG/IgM antibodies to detect viral antigens in patient samples. Samples can be sourced from a finger-prick of blood. An alternative method is using cloned viral antigens to detect patient antibodies against the virus. These antibodies or antigens are immobilized on a nitrocellulose membrane at particular locations. If a patient is positive for COVID-19, the interaction between antigen and antibody leads to a visible colored line appearing on the test strip.

cellex workflow
Workflow and result of Cellex qSARS-CoV-2 IgG/IgM immunoassay test.

The most common recombinant SARS-CoV-2 proteins used are nucleocapsid protein (N-protein), spike protein (S-protein) and Angiotensin-converting enzyme 2 (ACE2).

  • N-protein is a structural protein that binds to the virus RNA genome, creating a shell around the enclosed nucleic acid.
  • S-protein is a surface protein on the virus which mediates the attachment between virus and the host cell surface receptors. It also facilitates viral entry into the host cell by helping in the fusion of viral and host cell membranes.
  • ACE2 is an endogenous membrane protein and its extracellular peptidase domain binds to receptor binding domain of S-protein.

As lateral flow tests become more available, our ability to test larger populations increases significantly. This is particularly important and impactful in remote locations and emerging nations where resources may be limited.

Rapid detection to stop the spread

Throughout human history, cholera, plague, smallpox, HIV and influenza have caused several pandemics leading to fatalities in the millions. COVID-19 is the most recent global pandemic, but due to advancements in detection, treatment and vaccinations, the death toll is going to be a lot smaller than it could have been. In addition, our modern understanding of modes of transmission means governments can put in place public health measures to limit the exposure.

While the development of pharmaceuticals and vaccines are still in progress, the detection of cases is the most critical priority. Robust detection and tracking are the only ways to provide governments with the data to make informed decisions about public health, which will enable us to return as quickly as possible to the common activities of our lives.

Guide: Best Practices for Point of Care Product Development

For strategies on how to accelerate timelines and decrease costs, download our Best Practices for POC Product Development Guide.

References

Business Insider. (2020, March 20). Point of Care at the Forefront of COVID-19 Testing in Quest to Break Transmission Chain [Press release]. Retrieved from Business Insider

Cellex. Cellex q Rapid Test [Product page]. Retrieved from Cellex

Centers for Disease Control and Prevention. (2020, April 19). Situation Summary [Webpage]. Retrieved from Centers for Disease Control and Prevention

Chen, Y. and Li, L. (2020, March 23). SARS-CoV-2: virus dynamics and host response [Article]. Retrieved from The Lancet

Eisenberg, J. (2020, March 20). How Scientists Quantify the Intensity of an Outbreak Like COVID-19 [Article]. Retrieved from University of Michigan

Food and Drug Administration. (2020, April 24). Emergency Use Authorization (EUA) information, and list of all current EUAs [Webpage]. Retrieved from Food and Drug Administration

Food and Drug Administration. (n.d). Cellex qSARS-CoV-2 IgG/IgM Rapid Test [Webpage]. Retrieved from Food and Drug Administration

National Center for Biotechnology Information (2020, April 24). SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) Sequences [Article]. Retrieved from National Center for Biotechnology Information

Ray Biotech. (n.d.). COVID-19 Proteins [Product page]. Retrieved from Ray Biotech

Sheridan, C. (2020, March 23). Fast, portable tests come online to curb coronavirus pandemic [News]. Retrieved from Nature Biotechnology

World Health Organization. (n.d.). Coronavirus disease (COVID-19) technical guidance: Laboratory testing for 2019-nCoV in humans [Webpage]. Retrieved from World Health Organization

World Health Organization. (n.d.). Summary table of available protocols in this document [PDF table]. Retrieved from World Health Organization