This is a blog written by Elemed expert guest blogger Dr Gabriel Adusei. Want to be a guest blogger? Email mathilde@elemed.eu for more info!
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- the dangers of the relaxation of the regulatory stringency in times of crisis,
- appropriate tests adopted with their sensitivity and accuracy,
- the consideration of the expedited process to bring medical technology to the marketplace in the current global crisis,
- the balance of the rigorous regulatory scrutiny, humanitarian considerations and the benefit-risk presented,
- the economic and health impacts on alleviation of the crisis,
Epidemiology
On 31 December 2019, the World Health Organization (WHO) was informed of a cluster of cases of pneumonia of unknown cause detected in Wuhan City, Hubei Province, China.
On 12 January 2020, it was announced that a novel coronavirus had been identified in samples obtained from cases and that initial analysis of virus genetic sequences suggested that this was the cause of the outbreak. This virus is referred to as SARS-CoV-2, and the associated disease as COVID-19.
To give a perspective of the number of infections, deaths and the recovery, as of 31 July 2020 (10:00 GMT), there were over 17.2 million cases have been diagnosed globally with more than 673,000 fatalities. In the 14 days to 31 July, more than 3.5 million cases were reported (European Centre for Disease Prevention and Control, situation update worldwide). The global cases as updated on 27 Nov at 17:05 GMT with confirmed infection cases recorded as 61,153,901, deaths recorded as 1,435,284 and those who have recovered is recorded as 39,193,425.
The WHO coronavirus dashboard has country by country information. WHO also publishes a daily international situation report. The total number of confirmed cases in many countries is published by the relevant departments working in the areas of Health and Social Care.
The other aspects of the ongoing research cover virology and aetiology of the disease, transmission and clinical features.
The current Covid-19 tests available and their strengths and limitations.
Diagnostic testing is one of the most powerful public health tools for fighting the spread of the coronavirus.
Among others emerging, there are currently two types of diagnostic tests available:
- The molecular real-time polymerase chain reaction (RT-PCR) test detects the virus’s genetic material.
- The antigen test detects specific proteins on the surface of the virus.
The RT-PCR nasopharyngeal tests are more widely used and more familiar. Most involve sticking a 6-inch swab deep into your nose to collect virus samples to test. However, some more recently approved RT-PCR tests seek to avoid the discomfort associated with the nasopharyngeal swab tests by allowing samples to be collected via a shallow swab of the nose or by testing saliva for the presence of the virus. If performed correctly, RT-PCR swab tests “would be pretty close to 100 percent accurate,”
To get the most accurate results, RT-PCR tests should be conducted 8 days after suspected exposure or infection, to ensure that enough viral material is present to detect, however it is the suspected infected and people who are swabbing samples for testing may not be passing that information along.”
Antibody testing might help determine whether people have had COVID-19, but its effectiveness depends on when the test occurs, according to an analysis by the Cochrane Database of Systematic Reviews.
Antibody tests have emerged as a potentially useful public health tool to identify individuals with previous COVID-19, according to the Cochrane database.
The challenges that come with determining the accuracy of Covid-19 tests.
Since the pandemic started spreading, regulatory agencies have received a significant increase in the request for emergency use authorisation. Many of these tests were developed at a breakneck pace in an effort to get tests out to the people.
False-positive results, while rare, can occur e.g. with PCR tests, because the coronavirus’ genetic material may linger in the body long after recovery from an infection and a test can’t tell if the person [had an infection] 3 days ago or 5 months ago.
Swabs are used to collect samples for antigen testing. These tests have the advantage of yielding faster results (hours rather than several days) but it has be reported that they less accurate than RT-PRC tests, mostly because they require test samples to contain large amounts of virus proteins to yield a positive result.
False-negative results from antigen tests may range as high as 20 to 30 percent.
The reason why authorised tests with high sensitivity and specificity still be harmful to large populations.
The test must also be administered properly, which means inserting the swab 3 inches or so to reach the cavity where the nasal passages meet the pharynx.
One clinical professional once said: “If you’ve had this test and it wasn’t uncomfortable, it wasn’t done correctly.”
“In time, we will learn whether having previously had COVID-19 provides individuals with immunity to future infection,” they said.
The dangers of unreliable tests reaching the public.
The false negatives are mainly due to specimen acquisition, not the testing per se. Scientists say that collection methods may be ripe for error. In many cases sampling is conducted blindly with the hope that swab gets to the right spot. Then as the disease progresses, the virus might migrate down into lungs. Once it’s in the lungs, that nasopharyngeal swab may not pick up any virus if it’s already been cleared from the throat. This means that the timing has to be right and one has to be at the right place at the right time.
But besides issues with how and when test samples are collected, questions are also being raised about the quality of the diagnostic tests themselves.
The impact of increased flexibility and fast tracked tests to the public by regulatory agencies
The provisions given the regulatory agencies with increased flexibility and fast-tracked tests to the public has had significant impact on the development of new technologies as well as facilitating the speedy response to manufacture and supply the right Personal Protective Equipment and the required medical devices to where they are needed. E.g. regulations governing the movement of goods for the diagnosis, treatment and management of COVID-19 may have been relaxed. However, the regulatory aspects in relation to quality, efficacy and safety of products are stringently maintained as their relaxation would ultimately lead to higher number of deaths by COVID-19.
The relaxation of the regulation - shall we be concerned?
If there is such a time for relaxation of relaxation of regulation, this era might not be it since there are so many uncertainties around the aetiology, expression and transmission of the disease, offering very patchy information to establish a strong epidemiologic principles and approaches in dealing with the pandemic, including statistical analysis, public health surveillance, field investigations, surveys and sampling, and discussions of the epidemiologic aspects of current major public health problems in global health. However; provisions are to be made for speedy critical regulatory review to expedite the transition of new technologies from research and development for regulatory approval for progression to manufacture and making it clinically available for diagnostic, treatment and management of COVID-19.
The dangers of unreliable tests reaching the public.
The dangers of unreliable tests reaching the public or clinical setting can be unimaginably enormous. To put it bluntly, the deleterious effects of unreliable tests reaching the public or clinical setting can catastrophically deadly and economically devastating and create social disintegration among others. For example the hospital admittance can be inundated with people who have been wrongly diagnosed as having COVID-19 (false positive) and subjected to unnecessary medical treatments and conversely, people who have the disease but have been diagnosed as not having COVID-19 (false negative) could be left in the communities to infect other unknowingly.
There is also an accreditation scheme for point of care testing against ISO 22870 (Point of Care Testing: particular requirements for quality and competence), applied in conjunction with ISO 15189 (Medical Laboratories: particular requirements for quality and competence). This accreditation is an important element in establishing and maintaining confidence in a point of care testing service.
WHO also has resources available to assist with the development of health laboratory policies and practices, as well as strategies for strengthening capacity. WHO documents are available offering guidance on laboratory set up as well as testing methods for a wide range of diseases. An example is the Technical Guidance Series (TGS) for WHO Prequalification – Diagnostic Assessment Guidance on Test Method Validation of in vitro diagnostic medical devices TGS–4.
How to balance the urgency of developing tests to diagnose Covid-19 with rigorous evaluation to ensure accuracy.
To balance the urgency of developing tests to diagnose Covid-19 with rigorous evaluation to ensure the highest degree of accuracy, a multidisciplinary approach is adopted whilst employing the principles of regulatory science; thus, focusing on science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all regulated products. Advancing Regulatory Science is to build on the achievements of existing regulatory programmes, with the efforts to transform the way medical products are developed, evaluated, and manufacture.
What further steps should be taken to ensure the accuracy of Covid-19 tests - do we need more regulation and a global standard for diagnostic test development?
It is encouraging to know that the regulatory agencies and other related authorities working indefatigably in providing support for the medtech industry to enhance the progression of new technologies to the point of use. Credit should be given to the regulatory agencies and other related health authorities working diligently and taking the necessary measures to manage the pandemic and ultimately reduce incidence and cases of Covid-19.
With further research information, it is likely that widely approved standardised diagnostic tests guidance and ISO Standards will be developed and made available to the industry and clinical environments.
References
WHO Clinical management of COVID-19, published 27 May 2020. (Updated regularly)
COVID-19: epidemiology, virology and clinical features: https://www.gov.uk/
About the author
Dr Gabriel Adusei
MedTech Consultant and Founding Member of the International Association of Consultants (IAC)
Gabriel Adusei, MSc, PhD Dr Gabriel Adusei has over 30 years of experience in the medical device industry interspersed with academic studies and professional career positions. Gabriel is a Principal Consultant at Triune Technologies Ltd, having worked on many high-profile projects in the medical device technology industry in many different capacities. His areas of expertise include Quality Management Systems and Regulatory Affairs covering Product Research, Design and Development, Risk Management, Usability and Human Factor Engineering, Biological Evaluation and Biocompatibility, Clinical Evaluation, SaMD, Connected Health Devices, Information Security Management System and Data Protection among many others.
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