Implementation

I. Who are your proposed end users?

The project was created to be used by people who do not eat any or few animal products, such as vegan and vegetarian people. Vitamin B12, or Cobalamin, being mostly found in these products, people who do not eat them are the most at risk of a lack of this vitamin.

II. How do you envision others using your project?

Users of the device

If developed fully, the project could be used by the end users to test their blood vitamin b12 levels. Our aim is for Cobatect to make their life easier, by allowing them to regularly check their vitamin B12 levels, easily and at home.

They would have to buy the whole product once (the electronic part and the biological part) to be able to do a first test. The biological part being disposable and only usable once, they would then need to buy this part again for every test. The biological part would have to be conserved in the refrigerator / freezer to keep the bacteria in the appropriate growth phase until the test is used.

After addition of a drop of blood in the device, the results would be obtained in a few hours and displayed either directly on the device, or sent to an application on the user’s phone.

Then, the biological part would need to be discarded in a small biohazard bin which could be supplied by the pharmacy when the device (or a cartridge to reuse the device) is bought. This biohazard bin would then need to be taken back to the pharmacy so that they can dispose safely of the waste.

Usage by other iGEM teams

Other than the end users of the system, the other iGEM teams could also benefit from our project. Infact, from a scientific point of view, the aim of the project is to develop a bio-electronic sensor, which would deliver an electrical signal as a sensor instead of the usual bioluminescence / fluorescence. This type of sensor would be more precise and faster than the later. It could also be adapted to sense other molecules than vitamin B12 by using different genetic constructions, with riboswitches or aptamers. Therefore, our project could be used as a new type of reporter system.

This concept, as well as examples of other projects which could use our system and a general genetic construction which could be used are more developed in the Human Practice part.

III. How would you implement your project in the real world?

To implement the project in the real world, a business model has been developed, to identify the key elements needed.

Our value proposition would associate a product with a service : the product would allow the customer to know whether or not they have a deficiency in vitamin B12, and an application would then help them with the steps to follow depending on the results.

The key partners of the project would be the vegetarian associations, the ONAV (National Observatory of Vegetal Alimentation (France)), but also the pharmacists and nutritionists.

The key activity concerned by our product would be the wellness world, because our device concerns the detection of a deficiency.

IV. What are the safety aspects you would need to consider?

There are different safety assets we need to consider. In this section, we are going to present the problem, and the solution that we found to resolve the issue.

Problem: Leakage of the device would possibly lead to spreading GMO in the environment, which needs to be avoided at all cost.

Solution: We thought of modifying our bacterial strain so that it becomes auxotrophe, and therefore dies if it goes out of the medium containing the metabolite essential to its survival.

Problem: People hurting themselves with the tool used to draw blood for the test.

Solution: We cannot totally avoid this risk, but we can minimize it by using a tool already on the market and used by diabetic patients, where the needle withdraws itself into the tool once used.

Problem: Risk of surtension of the system.

Solution: Clearly displaying the maximum voltage of the charger to use to recharge the device, and clearly indicating to the patients that there is a risk if this recommendation is not followed.

Problem: Discarding biological wastes of GMO. As stated before, the patient would need to discard in a special bin the cartridge containing the GMO once used.

Solution: Provide a small biological bin with the purchase of the system (or a cartridge), which could contain the used cartridge and be brought back to the pharmacy where the test was bought for them to dispose of it accordingly.

V. What other challenges would you need to consider?

We need to consider that our device works with electricity, and therefore would need a battery to work properly. We have to think about the integration of this battery in our prototype, as well as recharging the battery / branching the device to an outlet if needed.

Another challenge we need to consider is the possibility of having false positives or false negative results. We would need to do more tests to be able to find the probability of having such results, but also maybe integrate a positive or negative control within the device, to be able to detect these problems.

There are different forms of vitamin B12, but only one which is interesting in our case : Cobalamin. Therefore, being sure that our test only detects this form and none of the other is also a challenge we need to consider.

Make our device more precise to have the accuracy of the Holo TC test, which only detects Holo TransCobalamin, which is the active form of Cobalamin in the body. Being able to reach this level of precision would mean that we could detect lack of vitamin B12 induced by the diet, but also problems of absorption and usage of vitamin B12 by the body, which are not linked to the diet.

The legal regulation surrounding our project is also an important challenge that we need to consider.

Regulation in the domain of medical devices

Medical devices and In Vitro Diagnostic medical devices (IVDs) have a fundamental role in saving lives by providing innovative healthcare solutions for the diagnosis, prevention, monitoring, prediction, prognosis, treatment, or alleviation of disease. The vitamin B12 blood level self-test kit of the iGEM IONIS team 2021 would enter under the category of in vitro diagnostic test. In the European Union (EU), where we aim to launch our medical device, In vitro diagnostic tests are under the Directive 98/79/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 27 October 1998 on in vitro diagnostic medical devices.

What the “In vitro diagnostic medical device” is?

What does it mean “medical device”? We would like to clarify it here to avoid any misunderstanding.

According to the directive [1] mentioned above, ‘In vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:

Concerning a physiological or pathological state
Concerning a congenital abnormality
To determine the safety and compatibility with potential recipients
To monitor therapeutic measures

As medical devices are in direct contact with its user, it should comply to many requirements strictly, this is why we think it is important to speak about them at least in brief in the implementation part, as soon as it will directly impact our device in future.

Quality control

First of all, according to the directive [1] the device’s producer should monitor regularly it’s security and quality, which means we will have to develop our quality control system and fill in required documentation. By doing so we will ensure safety of the users of our device as well as ease it’s entering the European market.

Essential requirements for safety

To be able to launch our product on the European market we should, without any doubt, put safety of the user in the core of our device design on the very first stages of the development. This way, when our self-test kit will be used for its intendent purpose, it will not compromise, directly or indirectly, the clinical condition or the safety of the patients, the safety or health of users or, where applicable, other persons, or the safety of property.

Of course, the risks will always exist, but we should make them acceptable and weigh them against benefits to the user and still ensure hight level of protection of health and safety.

Main regulatory documents on in vitro diagnostic medical devices

European Union

Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices

Below you can find key notions and abstracts from one of the main directives in Europe concerning in vitro diagnostic medical devices which allows to understand all the regulative aspects and requirements in that field. We will cite articles of the directive separately, highlighting key aspects which are essential for vitamin testing self-kit.

Article 2 - Placing on the market and putting into service

Member States shall take all necessary steps to ensure that devices may be placed on the market and/or put into service only if they comply with the requirements laid down in this Directive when duly supplied and properly installed, maintained and used in accordance with their intended purpose. This involves the obligation of Member States to monitor the security and quality of these devices. This Article applies also to devices made available for performance evaluation.

Article 3 - Essential requirements

Devices must meet the essential requirements set out in Annex I which apply to them, taking account of the intended purpose of the devices concerned. Here we list several essential requirements in order to give a general idea on what device should comply with. The requirements concern general design, chemical and physical properties, infection and microbial contamination, manufacturing and environmental properties and information supplied by a manufacturer.

The devices must be designed and manufactured in such a way that, when used under the conditions and for the purposes intended, they will not compromise, directly or indirectly, the clinical condition or the safety of the patients, the safety or health of users or, where applicable, other persons, or the safety of property. Any risks which may be associated with their use must be acceptable when weighed against the benefits to the patient and be compatible with a high level of protection of health and safety.

The solutions adopted by the manufacturer for the design and construction of the devices must conform to safety principles, taking account of the generally acknowledged state of the art.

Devices for self-testing must be designed and manufactured in such a way that they perform appropriately for their intended purpose taking into account the skills and the means available to users and the influence resulting from variation that can reasonably be anticipated in users' technique and environment. The information and instructions provided by the manufacturer should be easily understood and applied by the user.

Article 4 - Free movement.

Describes rules of putting medical devices into service on different territories.

Article 5 - Reference to standards.

Dedicated to the compliance with requirements stated in article 3 and national standards as well as to the importance of publishing reference numbers.

Article 6,7

Dedicated to the Committee on Standards and Technical Regulations.

Article 8,9

Considers safeguard close and conformity assessment procedures.

Regulation (EU)2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing

Directive 98/79/EC and Commission Decision 2010/227/EU

This Regulation lays down rules concerning the placing the market, making available on the market or putting into service of in vitro diagnostic medical devices for human use and accessories for such devices in the Union. This Regulation also applies to performance studies concerning such in vitro diagnostic medical devices and accessories conducted in the Union. For more details we invite you to read the full text of the regulation [2].

United States of America

In order to penetrate American market as well as European one, Cobatect should also comply with FDA requirements, which are detailed in the following documents (please find the full list on the website of FDA concerning in vitro diagnostic medical devices [7]:

Device registration: 21CFR807 [4]

Quality system regulation: 21CFR820 [5]

Reporting: 21CFR803 [6]

United Kingdom

Situation on the UK market has been difficult during recent years due to Brexit, therefore we provide here some guidance for current regulation Medical Devices Regulations 2002 [8] concerning in vitro diagnostic medical devices. This document outlines the current controls on the sale and supply of in vitro diagnostic (IVD) medical devices and explains the main features of Part IV of the Medical Devices Regulations 2002 (SI 2002 No 618, as amended) (UK MDR 2002). It covers the scope of the UK MDR 2002, the assessment process and in-house manufacture.

Sources

[1] DIRECTIVE 98/79/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 27 October 1998 on in vitro diagnostic medical devices

[2] REGULATION (EU) 2017/746 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU

[3] Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation)

[4] Code of Federal Regulations. Title 21, Volume 8, Part 807

[5] Code of Federal Regulations. Title 21, Volume 8, Part 820

[6] Code of Federal Regulations. Title 21, Volume 8, Part 803

[7] https://www.fda.gov/medical-devices/ivd-regulatory-assistance/overview-ivd-regulation

[8] Guidance on the regulation of In Vitro Diagnostic medical devices in Great Britain (January 2021)

Team:Ionis Paris/Implementation