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Revision as of 09:17, 17 October 2014
Policy & Practice
>
Future Perspectives
Application scenario
We are now in the year 2028, the world population has increased to over 8 billion people, putting an ever increasing pressure on healthcare to maintain a good livelihood for all. After facing major problems regarding antibiotic resistance in the early ten’s, a different kind of product was developed and marketed that could regulate the use of antibiotics and prevented the development of any resistant strains. Due to a well-defined implementation strategy of this technology in society, and by creating specific safeguards in the product, the rise of resistant strains has been brought to a halt. This story outlines the history of LactoAid, explaining how this product came to be and why it is such a success in modern healthcare.
It all started with the development of the concept by a group of students: to have a bandage that only produces antimicrobial compounds when needed, contrary to applying loads of antimicrobial compounds in advance (thus increasing the risk of developing resistant strains). A bandage that gradually releases antibiotics was one of the first ideas. Although this might prolong the use of a single bandage, thereby reducing the risk of infection, it still applied antibiotics in a preventative way. Also, electronic systems were considered as a carrier for this concept, but these were quickly discarded due to their limited applicability on the relatively small burn wounds, and given the high manufacturing costs involved. After this, it was argued that a perfect host to hold such a system would be a single-celled organism; a bacterium. Bacteria are small, easy to produce, and can be engineered to fulfil specific functions. However, the field of synthetic biology was just starting to emerge. Not much was known about the implications of messing around with the DNA of living organisms, resulting in societal hesitance to accept this new technology. To reduce the scope of the project, it was decided to take burn wounds as a case-study for such a concept. At a later stage in the product development, the bandage was also developed to fit other types of wounds.
The initial arguments against the implementation of GMO bacteria in a healthcare environment were mainly related to ethical and societal issues. Questions like; do the bacteria go into the wound? What is the risk of the bacteria getting out of the bandage into the environment? Is there a safeguard in case the bacteria leak out of the bandage? What are the chances of the bacteria mutating into a harmful pathogen? And many more. After these issues were addressed in the design of the bandage, as well as in the genetic design of the organism itself, the further development of the product was initiated. First of all, investors and strategic partners needed to be found to allow the full-scale deployment of this bandage. These issues were particularly important with regard to the scale of this project and to acquire funding (see timeline). Partners and investors were found by contacting research institutes and global health organizations (WHO, Red Cross).
Figure 1:
Illustration of relationship between concept generation and full scale R&D and product launch.
The full programme – from the concept generation to the product launch – was organized as a joint venture. Many parties from different industries were involved, and these were led by the group of students that started the project. It must be noted that the large pharmaceutical companies (Bayer, GlaxoSmithKline, Astrazeneca) were hesitant in the initial stage of product development, but contributed at a later stage when the demand for novel antibiotic moderators became crystal clear. A list of all parties involved in the final stage of the product development:
All healthcare related organizations/companies
Hospitals
Burn wound centres
WHO
Red Cross
Insurance companies
Big pharma (at a later stage)
Consumer-organizations
First-aid kits including infection detection.
Bandages to be bought in pharmacies.
The final product development, as described in the timeline, started in 2015 by generating different designs and testing their techno-economic feasibility. By 2018 the primary research and development was finalized, and the functionality of the best 5 designs could be tested in the lab (e.g. animal experiments) in the preclinical stage. The clinical trials were held between 2020-2026, after which all documentation was submitted to the EMA and FDA for approval regarding safety, risk and quality of the bandage. In 2027, both the FDA and EMA granted their approval for the LactoAid.
It was a difficult road to the market, especially regarding regulatory and safety issues, but finally the worldwide demand of this type of bandage was sufficient to drive the final development and help it through trials. Nowadays, the bandage is used in hospitals all over the world to treat open wounds. A consortium of companies and research institutes has been tasked to oversee the production and regulate the use of this bandage. This consortium is led by the WHO. There is no problem anymore with multi-resistant strains, and wounds can easily be kept clean throughout a patient’s stay. There is even talk of a LactoAid 2.0 (now in trials) that is genetically tweaked to produce growth factors. These are substances that stimulate cell growth. The result will be a super bandage that has the ability to heal certain wounds even faster.
The application of LactoAid is best explained through an exemplary patient that enters a regular hospital:
1. A patient enters the hospital, is heavily burned all over his/her body with 2nd and 3rd degree burn wounds.
2. The wounds are cleaned and then left to rest for three days to assess the severity of the wounds.
3. During these three days, the wound is protected by LactoAid.
4. After three days the wounds are found to be severe, and a skin transplant is needed.
5. The wound is rinsed again, and the skin transplant takes place. This needs to be done in multiple sessions due to the heavy impact the operation has on the body. This leads to a lot of time in which the wounds need to be kept clean. Therefore, LactoAid is again applied to the wound in the time between the operations.
6. As a result; A) patients suffer less because there is no air flow over the wounds, B) the wound is protected by the bandage from environmental pathogens, C) pathogens already in the wound are killed by the bandage, reducing the frequency of redplacing the bandage, D) wounds are healed quicker, cutting costs.
7. After every use (3-4 days), the bandage is deactivated and all modified bacteria are killed. Two systems are used to ensure no modified bacteria survive: A) after 3-4 days all nutrients are gone, B) a kill switch is activated by releasing an inducing compound within the bandage.
Techno-moral vignette: Tom's trust issue
It is the year 2045. Tom is now around 30 years old and has been cured with LactoAid many times. Every time he had a burn wound, the bandage worked as a charm and kept the wound clean. He even used it a couple of times on other types of wounds, for example that one time when he fell of his bike in the middle of the night. There were nasty, dirty grazes on his arms and legs, but LactoAid did the job. At least, that is what he thought, because there was no infection.
Nowadays, Tom is fully confident that the bandage cures every type of wound and prevents infections. He recommends this product to all his friends and family because he completely trusts this bandage. “No need to go to the hospital, we’ve got LactoAid in the kitchen” he used to say.
However, there has been a hitch in the workings of LactoAid. Tom is of course not the only person who believes in the ‘super bandage’. Many other people are using it for different wounds, even when they are aware that it is only aimed at specific types of infections. One example is Hilda, a niece of Tom. Hilda lives in a distant village, and has also used LactoAid many times before. But the last time it went completely wrong: she had nasty, greasy wound and thought that there was no need to go to the hospital because she had LactoAid. However, after two days the whole wound appeared yellowish and Hilda became ill. Even LactoAid started to fall off.
After calling her doctor, she was advised to go to the nearest hospital. When she arrived she was immediately treated with a different type of drug. Afterwards, doctors discussed that it was lucky she chose to come to the hospital so quickly, but it would have been a lot better (and it would have left less scars) if she had came immediately after having her accident. All in all, it was a close call, and Hilda is now advising Tom and her friends not to put too much trust in LactoAid.
Visit to the Dutch Commission for Genetic Modification (COGEM)
Figure 1:
Thomas and Lianne visiting COGEM in Bilthoven on August 22, 2014.
What are the greatest hurdles on the way to approval for our design as a product, apart from the technological feasibility? We already knew that approval would be needed for use of a Genetically Modified Organism (GMO), but how does this fit into the picture when you use a GMO for medical purposes? In that case, you would have to go through a double approval process, a) drug development, and b) GMO approval. With this in mind, we organised an interview with Frank van der Wilk, secretary of the COGEM, to talk about what he thinks of our product and how he sees its future.
Before a drug is released on the market, the EU places strict regulations on the approval process. Several permits for working with GMO’s exist that each cover a part of the whole process. The first permit that needs to be given is the ‘ingeperkt gebruik’ (contained use) permission. This is usual for all labs working with GMOs. The second permit is given before field trials are held, as there is a chance of modified bacteria being released in the environment. All this needs to be approved by the commission for human research (Commissie Mensgebonden Onderzoek CCMO) as well. When the field trials have shown good results, the permit for market introduction in Europe needs to be acquired. This involves the European Medicine Agency (EMA). Normally, the EMA is not used to use of GMOs, as there are simply not many of these kind of devices on the market yet. However, it is likely that the approval system will be the same for LactoAid as for all new drugs. All in all, drug development can take up to 12 years and involves many steps and stakeholders.
When we asked about social hesitance with GMOs in healthcare, Mr. Van der Wilk replied that we are lucky to work in this sector and not in agriculture. The use of GMOs in agriculture has a bad name, which makes new agriculture products hard to get accepted by the general public. There are not many GMO-medical devices , which may resolve the social acceptance issue.
Although our project has some practical safeguards to prevent the modified bacteria being released into the environment, we also should think of the origin of the genes that are in the ‘machine’. When genes come from a known pathogen, chances are that the product is regarded with a higher risk. When we wanted to incorporate an entirely synthetic gene, it will be near to impossible to get approval for market entry of the product. We are not using synthetic genes, and it appears that most of our genes are from non-pathogens, which is thus a positive point with regards to the approval process of the EMA . It would also be helpful if we could figure out if L. lactis can survive on the skin, or in the bloodstream. If this is the case, it is one less step to go towards complete approval.
When looking at the impact on society, the Commission for Genetic Modification looks at the possible effect of a product and the chances of such an effect happening. Even if there is the slightest risk of a negative side effect, the product will not be approved.
All in all a useful visit!
