Lab to Clinic
What Next? Phases, Patents and the Future
For us, the Oxford iGEM team, it has been a long, hard and very rewarding summer. We wish we could continue our project further, but now, time is our greatest enemy. We hope that our research will pave the way for other groups, both within and without iGEM, to take the reins in the battle against catheter-associated UTIs, and the wider assault on antibiotic resistance.
We hope this page will be a useful guide to teams (in particular UK teams) with medically-orientated projects, who intend to progress from laboratory work into clinical trials. We have also written a brief guide to the process of patenting, and how this would apply to our project in the future.
Like most iGEM teams with projects in the Health and Medicine track, we have spent the summer developing our project in the preclinical stage. This is the 'laboratory' stage, where the different components of the project are constructed, tested, and optimised, without the use of human volunteers. The first goal is to discover if the team's invention is feasible; past that point, the preclinical goal is to improve the invention to point the point at which its efficacy and safety of use is maximised.
Progression to Clinical Trials
Extensive preclinical (lab) data is needed to support the use of the treatment on humans in clinical trials. As described above, the researchers must do their best to minimise the level of risk associated with the treatment, whilst maximising its efficacy, through lab models.
Any group wishing to trial their treatment on volunteers in the UK must abide by the Medicines for Human Use (Clinical Trials) Regulations of 2004. To abide by these terms, researchers must be granted a clinical trial authorisation (CTA) by the Medicines and Healthcare Products Regulatory Agency (MHRA). For a CTA application to be granted, the treatment must be reviewed and certified by a number of different review bodies, where each body scrutinises a different aspect of the project. We will use our project as an example here.
Most medically-orientated projects require approval from a Research Ethics Committee (REC). The committee makes sure that the volunteers have been well briefed (by the researchers) with regards to the trial, including; the possible benefits and risks of the treatment, the goals of the treatment, and who they should contact if they have any further questions. There are several RECs, found across the UK, who deal with clinical trial authorisations. There are several borough-based RECs in London - the iGEM team would most likely apply to one of these bodies.
As our treatment involves the use of a novel device (our 'custom catheter'), we need to apply to the MHRA, for a Notice of No Objection, to review the safety of the device. If granted, the notice would allow the device to be used in volunteers.
Potentially, we may attempt to model the effect our bacterial proteins have on human cells. To get hold of human tissue, we would need a license from the Human Tissue Authority (HTA). This includes extraction of tissue from a cadaver and a live participant.
In addition to the above approvals, we would need an organisation, such as a hospital or research institute, to host our trials. There are several funding bodies to which we could apply; however, it would be ideal to have funding from the NHS, as this is where we would most probably intend to host our trials - this is called Management Permission. Ideally, we would like our trials to be hosted by the NHS! At the time of our Management Permission application, we would most likely apply to the NHS for funding as well.
We would be very pleased if our project managed to get this far! However, there would still be a long way to go before our product could go on the market. The clinical trials are split into 3 phases, with each phase more rigorous than the last.
Phase I trials, also known as 'first-in-human' trials, present the first time a treatment is tested on human volunteers; as a result, there is an unavoidable element of risk involved. A typical phase I trial might involve 10 or fewer healthy student volunteers. However, due to the nature of our treatment, the likely candidates for our phase I trials would be people who already require the use of a catheter, but potentially not those who have a urinary tract infection (UTI).
This phase is primarily a risk assessment, so we would be looking for any signs of immune response to the introduction of our bacteria and their secreted proteins; in particular DNase and Dispersin B. In addition, we may be looking to see what range of protein dosages the volunteers might be able to tolerate before they experience significant side effects or discomfort.
If the volunteers from phase I show few side effects and the treatment is deemed safe enough, then the trials can proceed to phase II. These involve up to approximately 100 volunteers. This time, all these people selected should be ill, ie have a CAUTI, and the results of their treatment (reduction in the biofilm size) against the best current treatment; in our case this is antibiotic treatment.
If the results of the phase II trials suggest that the new treatment could be better than the current treatment, then the trials can proceed to phase III. As this is the last stage, the organisation hosting the trial must be sure, on a statistical level, that the new treatment is significantly better than the currently-administered treatment, for it to pass. Phase III trials therefore involve a very large group of ill volunteers, sometimes greater than 1000 people.
If solUTIon passed phase III, then we could officially license our treatment, and release it onto the market! Wouldn't that be swell?
Phase IV (optional)
This is an additional phase which is sometimes implemented, however it is not always required! Phase IV 'trials' are slightly different to the previous three, as they monitor the treatment success on real patients, ie after a marketing license has been granted. As the treatment has already been licensed by this point, phase IV simply involves analysis of data from patients receiving the treatment to check its safety and efficacy.
What is a patent?
A patent is a license, given to an inventor, which prevents any competitor from making, using or selling their invention in a certain territory for a specific time frame. The 'territory' of the patent may be a country, or even an entire continent, such as Europe. The patent 'time frame' is usually 20 years.
What is the point of a patent?
Patenting is essential to the healthy progression of scientific research; why would companies want to invest millions of dollars into an invention, only for it to be stolen by a competitor when completed? Therefore, patenting gives companies a chance to earn back the money they invest in their inventions. However, the patent holder may, during these 20 years, permit certain parties to make use of their product for a license fee.
What can be patented?
In synthetic biology, any organism (aside from a human) which has been genetically modified, and hence gives rise to "a new assembly of chemicals", can be patented. This includes novel bacterial strains, as well as transgenic plants and animals. Evidently, humans cannot be patented for ethical reasons.
However, there are additional factors that must be satisfied; for an invention to be applicable for patenting it must be both:
- Novel - the invention you present should not already be part of the 'state of the art' (basically anything published in a paper, presented at a conference, or anything freely accessible to the scientific community).
- AND Inventive - ie the invention should not be 'obvious' to those skilled in the field. It is often difficult to define if an invention is 'obvious'; however, several 'obvious' inventions can arise from, for example, the correlation of two previously-unlinked scientific papers.
Can Oxford iGEM apply for a patent?
There are a number of aspects to our project which are unpatentable. For example, the BioBricks we have constructed cannot be patented; they have been submitted to The Registry of Standard Biological Parts ('The Registry' for short) as part of our open source agreement. The Registry is iGEM's alternative to patenting; it allows for easy, open distribution of the many hundreds of BioBricks that now exist. In addition, EU law states that methods of therapy, treatment and diagnosis cannot be patented, to avoid conflict with doctors.
However, the device used within the method may be patented. Our method of tackling CAUTIs rests heavily upon the design of our custom-catheter, which is both novel and inventive; we therefore intend to apply for a patent on this device.