The Coronavirus and the IVDR

Tuesday, February 11, 2020

The coronavirus broke out in China at the end of 2019 and has dominated the headlines ever since. The question now is how people with the virus can be diagnosed and treated quickly.

Does our overflowing medical device law even allow us to react quickly enough to epidemics like this?

What do manufacturers of in vitro diagnostic medical devices need to know in order to place the devices required on the market quickly if an epidemic breaks out?

Learn how regulations affect the speed at which in vitro diagnostic medical devices (IVDs) can be made available and how IVD manufacturers can react to them.

1. Coronavirus: How serious is the situation?

a) Reports and assessments from experts

Since January 22, 2020, Tagesschau.de alone has reported on the coronavirus over 300 times. Nevertheless, we can’t draw conclusions on the seriousness of the situation based simply on the number of daily news reports.

The frequency of these reports is also a result of hyper emotionalism and our communicative behavior, as Sascha Lobo has explained.

The WHO assessed the situation as follows on January 23, 2020:

“Make no mistake, this is an emergency in China,” Tedros Adhanom Ghebreyesus, the WHO’s director general, states, “but it has not yet become a global health emergency.”

Source

As the first patient to die from the coronavirus outside of China died a few days later, arguments started as to whether this was an epidemic or whether it was already a pandemic.

b) Definitions

The terms epidemic and pandemic are defined as follows:

Definition: Epidemic, pandemic

An epidemic refers to a very frequent, localized and temporally limited occurrence of a disease, especially of an infectious disease.

A pandemic on the other hand refers to a transnational, globally distributed disease and is, therefore, not the same as a localized epidemic.

Source

c) In the gray area between an epidemic and pandemic

According to these definitions, the spread of the novel coronavirus is in the gray area between an epidemic and a pandemic.

If the virus spreads to other regions, then it would no longer be an epidemic according to this definition.

However, if such a spread can be prevented, then we would still be looking at an epidemic. Individual cases outside China that can be controlled by hygiene and quarantine measures would not change this.

 

2. The need for a quick and reliable coronavirus diagnostic test

a) Consequences of false negative and false positive results

In order to be able to effectively contain the spread of the disease, a quick and reliable diagnostic test is required.

False negatives aid the further spread of the coronavirus.

In contrast, false positives lead to unnecessary and drastic measures, such as the isolation of the supposed patients. In addition, these actions take up resources urgently needed for people who are actually ill.

b) Factors determining the speed of the diagnostic test

The term “quick diagnostic test” can be understood in a variety of ways:

  1. Development: The specific reagents for established, e.g., PCR-based, methods must be developed quickly.
  2. Authorization: Only then can manufacturers develop the in vitro diagnostic medical device (IVD) and, if necessary, have it authorized worldwide.
  3. Production, supply: The IVDs should be made available to medical case workers quickly. This requires fast production and delivery to all relevant markets.
  4. Measurement: The IVDs must deliver the results quickly so that the treatment required can be initiated in good time.

The next sections will look at these factors in more detail.

3. Influencing factor: device development

a) To the genome in three days

The Pasteur Institute in France recently demonstrated how quickly reliable detection methods can be developed: researchers sequenced the whole genome of the novel strain of the virus from two cases in France in just three days.

The Chinese authorities had already published the genome as sequenced from samples from patients affected in Wuhan on January 11, 2020.

Fig. 1: Coronavirus. Color transmission electron microscope image. Photo: Dr. Fred Murphy & Sylvia Whitfield/CDC

The center of this international cooperation is the WHO’s Global Influenza Surveillance and Response System (GISRS) and GISAID – Global Initiative on Sharing All Influenza Data.

b) From genome to test

As a result, the path is clear for the development of molecular genetic tests, for example based on real-time reverse transcription PCR (real-time RT-PCR), which enables the qualification and quantification of the virus per volume unit.

As soon as the specific biomarkers have been derived from the genome sequence and the sampling and laboratory processes established based on published protocols, a medical laboratory or IVD manufacturer can start targeted development very quickly.

The WHO has even already published a protocol that makes reference to the genome sequence that can be obtained from GISAID. It expects validated PCR tests to be available soon and, in the meantime, recommends working with reference laboratories that are already able to detect and sequence coronaviruses.

In addition, the WHO already provides guidelines for sampling and sample storage, as well as on safety measures to prevent infection.

However, the regulations governing medical devices apply from this point.

4. Influencing factor: regulatory requirements

Both medical laboratories and IVD manufacturers are bound by regulatory requirements. However, these requirements differ. And furthermore, these requirements have been changed by the introduction of the In Vitro Diagnostic Regulation (IVDR).

a) Current situation for manufacturers (IVDD)

Relevant regulations

As a general rule, manufacturers want to place their reagent products on the market and, therefore, have to comply with the German Medical Devices Act (MPG) and thus the IVD Directive (98/79/EC). These regulations require manufacturers to perform a conformity assessment procedure before their devices can have CE marking.

Classification of the coronavirus according to 98/79/EC

The lists of pathogens (list A and list B) in Annex II of EU Directive 98/79/EC do not contain coronaviruses or the associated diseases. This means that all tests, whether screening assays, confirmatory assays or supplemental assays for 2019-nCoV fall under “other IVDs”.

As long as manufacturers do not declare the tests to be self-tests and the tests are intended for professional use, manufacturers may perform the “self-declaration” as per Annex III of the IVDD without the involvement of a notified body.

This means that it is still relatively easy for a manufacturers based in the EU according to the IVD Directive (98/79/EC) to place a test for 2019-nCoV on the market.

Impact of regulations on the duration of development

Because manufacturers can act independently of a notified body, it is above all the efficiency of its own QM systems that affect how long it takes to receive “authorization”.

Of course, the QM system must be suitable for actually demonstrating conformity with the requirements of Annex I, as well as for documenting this proof and presenting it to the authorities on request.

b) Current situation for medical laboratories

Medical laboratories can offer their own developments as a service in their own laboratory. The IVD Directive does not apply to in-house developments, as these are excluded by Article 1 (5). However, medical laboratories in Germany are subject to the German Medical Devices Act, which in §12 requires compliance with the essential requirements of the IVD Directive. In addition, the Medical Device Operator Ordinance  requires compliance with the requirements of Part A of the Directive of the German Medical Association on Quality Assurance of medical laboratory examinations.

Further information

Read more on lab developed tests here.

 

a) Future situation for manufacturers (IVDR)

Relevant regulations

From May 26, 2022, the IVDR will replace the IVDD. The IVDR obliges manufacturers to establish an intended purpose based on the selected biomarkers and to classify the devices accordingly.

The involvement of a notified body in the conformity assessment procedure according to Annex VIII is required for all devices with the exception of those in the lowest class, Class A. A “self-declaration” can be carried out for the CE marking.

Classification of the 2019-nCoV under the IVDR (2017/746)

The IVDR (EU 2017/746) no longer classifies products based on concrete lists. Instead it uses a rule-based classification system (Annex VIII).

The following specifications are particularly relevant for the coronavirus:

1.1. Application of the classification rules shall be governed by the intended purpose of the devices.

[…]

1.9. If several classification rules apply to the same device, the rule resulting in the higher classification shall apply.

1.10. Each of the classification rules shall apply to first line assays, confirmatory assays and supplemental assays.

IVDR, Annex VIII

Thus, in order to classify a device, it must have an intended purpose. This could be:

“In vitro diagnostic reagent kit for confirmation and exclusion of 2019-nCoV in the presence of pneumonia from human blood or lung tissue.”

As this test is intended for a high-risk population who already have a known lung disease, not for screening a healthy population, it is a confirmatory assay. This brings with it different inherent risks compared to those involved in a screening assay. However, devices for both assay types have to go through all the regulations, as established by implementing rule 1.10.

An assay that only distinguishes subtypes (e.g., a mutant variant) would be classified as a supplemental assay, but the same specifications would apply to it.

Rule 1.2 already applies to the above intended purpose for the confirmatory assay:  

Devices intended to be used for the following purposes are classified as class D:
[…]
“— detection of the presence of, or exposure to, a transmissible agent that causes a life-threatening disease with a high or suspected high risk of propagation;”
[…]

IVDR, Annex VIII

2019-nCoV is clearly a pathogen with a “high or suspected high risk of propagation”. In addition, the number of deaths shows clearly that the pathogen can be characterized as causing a life-threatening lung disease.

Therefore, both conditions of this rule (life-threatening and high risk of propagation) are fulfilled.

Therefore, the test for coronaviruses falls into the highest risk class: class D!

The other rules would normally also have to be taken into account. However, this is not necessary in this case because there is no higher class and implementing rule 1.9 applies.

Impact of regulations on the duration of development

For the 2019-nCoV confirmatory assay, the manufacturers would have to

  1. Go through a conformity assessment procedure that includes assessment by the notified body of both the technical documentation and the QM system and
  2. Obtain batch release from a reference laboratory.

The test for coronavirus is a novel test. Therefore, it is likely that the scrutiny procedure will also be required. This means that a performance evaluation based on performance data must be performed by the competent EU expert committee.

All of this could make the approval of such a test a very lengthy and expensive process. Not many manufacturers have this kind of staying power.

d) Future situation for medical laboratories

The article on lab developed tests (LDTs) describes the situation for medical laboratories.

5. Approaches to solving the problem

a) Cooperation with medical laboratories

In order to make quick develop possible even under the IVDR, manufacturers can develop their reagents in collaboration together with medical laboratories. This would enable them to swiftly develop a compliant IVD as a laboratory developed test based on an in-house design and process the clinical data obtained in the laboratory work so that it will stand up to the notified body review.

b) Research-only approach

Some manufacturers are considering selling their devices for “research use only” without a partnership with a medical laboratory. Medical laboratories could then use these reagents to offer a lab developed test.

However, this approach should be viewed with skepticism, as the “research only use” statement could be seen as a self-serving claim that does not reflect the actual intended purpose: the product is for diagnostic purposes.

c) Splitting up the device

Manufacturers should consider splitting their IVDs into generic and specific components or devices to accelerate development and authorization.

For example, they could declare enzymes (e.g., TAQ polymerase), buffers, etc. to be general laboratory reagents that actually belong to class A according to the IVDR.

They would then only have to classify the specific IVD reagents (primers and probes) in the higher classes and only have to go through the lengthy and costly conformity assessment procedure for these reagents.

In this case, the final diagnostic device would be a system made up of differently classified IVDs.

This separation greatly reduces the time and cost involved in the creation of the technical documentation that is later checked by the notified body.

6. Conclusion and summary

a) Regulations cancel out benefits from technological progress

Global networking leads to more travel. These journeys help the spread of disease.

Technological progress increases the speed at which diseases can be diagnosed, which is necessary for their effective treatment.

But regulations, especially the IVDR, cancel out this speed advantage.

This is because the new classification rules assign the devices to higher classes, which go hand-in-hand with more complex “authorization procedures”.

b) Unsuitable classification

This is particularly regrettable because the IVDR (like the MDR) does not base classifications on risk but on the severity of potential damage.

In contrast to the IMDRF, it does not also take into account the chronology of any damage. Since most infections do not cause permanent damage, the high classification is unnecessary and counterproductive.

c) Consequences

The consequences of these “design errors” are potentially far-reaching:

  1. The “authorization procedure” takes too long. IVDs will not be available quickly enough to detect and combat pandemics adequately, safely and comprehensively.
  2. Manufacturers shy away from investing the time and money required and do not get involved in the development, production and distribution of the medical devices required. These devices are then not available on the market.
  3. Other manufacturers bypass the regulatory system, place devices on the market for “research use only” and thus avoid necessary quality assurance measures.

Each these consequences is the opposite of what the regulations actually intended.

The attempt to increase patient safety through safe devices leads to a lack of devices being placed on the market as quickly as is needed and means that the benefits associated with these devices are lost.

The regulations should be focused on the preservation of public health, not just on ensuring that devices are safe, as the definition of the term “clinical benefit” shows us. The MDR and IVDR are not obviously pursuing this objective.

In terms of risk management, it is essential to consider not just the risks but also the benefits and to weigh up the two.

Maybe the authors of the IVDR and MDR should read the IVDR and MDR.

Sebastian Groemminger

Author:

Dr. Sebastian Grömminger

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