Team:Sydney Australia/Applied Design

The Issue

The price of insulin is too high for many across the globe. For type I diabetics, who must take insulin every day to survive, and roughly 30% of type II diabetics, this issue constrains their quality of life. Worse still, diagnosis of diabetes is on the rise.
Currently 92% of the insulin market is produced by 3 pharmaceutical companies. In economics, this kind of market share is called an oligopoly. In these kinds of markets, generic or biosimilar insulins have a hard time breaking through, simply due to the enormity of market share that the other three own.
To make things just a little more difficult, clinical trial expenses and regulatory licensing means that very few small to medium sized manufacturing plants can enter the market. Because of these constraints, the insulin market has spiraled out, and as such, insulin is largely unaffordable and inaccessible across the board.

Barriers

Click on the Segments in the Pie Chart to learn about the barriers to enter the insulin market.

Technical Barriers to Entry

In the current manufacturing world, recombinant methods are seen as difficult and time intensive. As a result of this, many avoid using recombinant technologies for therapeutic production regimes.

Legal Barriers to Entry

It took our iGEM team a full couple of months before we were comfortable to say that we had a new insulin to add to the market. We were also able to utilize expertise to navigate through the legal sphere, which greatly aided our process. In general though, due to the number of analogue insulins under patent, its very difficult to ‘create’ a new insulin.

Market Barriers to Entry

Every 5 years, the Australian governments Pharmaceutical Benefits Scheme undergoes negotiation with the respective manufacturing plants and suppliers to discuss price points for that period.
This system ultimately favours highly established, elite market players with the market scale to supply an entire region.

Cost Barriers to Entry

When people say ‘nothing comes cheap,’ they’re really talking about drug development. To say its expensive really undermines the meaning of expensive. Clinical trials generally cost around US$1 Billion to start with. Production plants for insulin manufacturing can fall anywhere between US$100-$500M, and then a license can cost up to another US$100M. Understandably, these costs limit majority of the wishful market entrants.

Potential Solutions

1. PUBLIC TRADING SCHEME

2. OPEN-SOURCE INSULIN PUMP

3. STANDARD BUSINESS MODEL

4. PRIVATE INVESTMENT

5. BATHTUB INSULIN

6. PUBLIC INVESTMENT

7. GENE THERAPY

8. GUT BACTERIA INSULIN

9. ANIMAL
INSULIN

10.BLACK MARKET
INSULIN

Find out More Info About these Solutions By Clicking on Their Box!

1. Public Trading Scheme

BACKGROUND

Rather than a single entity attempting to build a factory, allow individuals and businesses to invest in the manufacturing of open-source medication. This could be done through a few other options, like designing a public stock exchange for investment into manufacturing plants. The scheme could provide a return on investment following drug approval, investors receive their money from dividends

ISSUES

• Return on investment must scale the with relative risk of the medicine’s chance of making it to market.
• Return on investment must be less than the current return on IP earned by pharmaceutical entities (else the price of drugs will increase)
• These two points together suggests that the biosimilar market would be ideal for testing this business model, as no novel applications are involved.

2. Open-Source Insulin Pump / Cloud Monitoring

BACKGROUND

Insulin pumps have been designed already to remove the need of needle injections following meals by diabtetics. These pumps however have been designed to service just a single companies insulin, which means that your insulin determines the pump you are on. Recently, there has been a calling for an open source insulin pump which is universal to all insulins. Furthermore, continuous glucose monitoring systems, which has recently become an open source system, could be integrated in with the insulin pump to remove all day to day stresses of blood glucose levels.

ISSUES

• The technology could be modified to serve the whims of a totalitarian regime…however this is the case with all science these days.
• Doesn’t really impact any issues of inaccessibility to insulin felt by a large portion of diabetic globally on its own.
• Insulin pumps are specialized for a single insulin, which also means that a specific insulin would need to be designed for it. Unless of course the pump could be designed to universal, but we are unsure as to how this would work.
• These insulin pumps are extremely complex medical device, may have to be reverse engineered with long term patents still covering a significant portion of these technologies.

3. Standart Business Model

BACKGROUND

Following a standard business model, a patented insulin could be taken to market following relevant clinical trials completed. Upscale procedures would also need to be completed to ensure efficiency and meet cost-effective price points. The business could either license a current up and running manufacturing plant to produce the insulin, OR could set up a manufacturing plant themselves to produce any produces. If the later option were chosen, manufacturing plant Good Manufacturing Practice licenses would be needed.

ISSUES

• Likely need about US$200m for a medium-scale facility.
• Initial investment will leave manufacturer vulnerable to a price war if price drops suddenly.
• Good Manufacturing Practice licenses would cost around US$100M

4. Private Investment

BACKGROUND

We could rethinking the road to market for open-source medicine. Rather than a single entity attempting to get approval for a patent, allow individuals and businesses to invest in the clinical trials of open-source medication. Public stock exchange for investment in the approval of open-source medication. Once the drug is approved, investors receive their money + dividend from manufacturers.

ISSUES

• Return on investment must scale the with relative risk of the medicine’s chance of making it to market.
• Return on investment must be less than the current return on IP earned by pharmaceutical entities (else the price of drugs will increase).
• These two points together suggests that the biosimilar market would be ideal for testing this business model, as no novel applications are involved.

5. Bathtub Insulin

BACKGROUND

Bathtub insulin would provide small-scale insulin manufacturing and purification equipment to local doctors in developing nations. The idea is, that using bathtubs, insulin could be purified through a grass-roots approach from local doctors. This system would provide suitable training to other skilled medical professionals in order to create a grassroots pharmaceutical industry in developing nations.

ISSUES

• Regulatory and Safety Nightmare. Puts way too many people at unnecessary risk.
• Considering economies of scale, it may be worth skipping this entirely and focusing on large-scale manufacturing projects in newly industrialised nations.
• The profits will not benefit developing nations, but the industry efficiency would hopefully mean that they gain access to more affordable insulin.

6. Public Investment

BACKGROUND

Convincing public entities such as the Chinese, Indian or US government to invest in insulin manufacturing and purification facilities. This could fall under the normal grant scheme, or through a newly designed investment scheme. This could be further enhanced by creating investment initiative programs, such as ‘matching’ any investment in Active Pharmaceutical Ingredient manufacturing plant makes.

ISSUES

• Capitalist governments are often reticent to invest in public infrastructure due to current economic theory.
• However, John Maynard Keynes1 would argue that this is an excellent way to create economic growth.
• Socialist governments (e.g. CCP) would also require significant lobbying in order to convince the right people that investment is important.

7. Gene Therapy

BACKGROUND

Generally, when we think of pharmaceutical solutions, its generally to elevate symptoms. Very rarely do we come up with an effective cure. In the case of diabetes, we could be able to edit the genome to hopefully cure it once and for all. Recently, there have been developments in the field towards this end(2)

ISSUES

• The true solution to Diabetes is a cure, rather than endless treatment.
• Extremely costly.
• Long and tiresome research to continue on from what progress has already been made.
• Clinical trial expenses will also be required to trial a potential gene therapy.

8. Gut Bacteria Insulin Secretion

BACKGROUND

Utilising a naturally occurring human gut bacteria to secrete insulin in the gut, to be exported to the blood stream for distribution following meals. This system would hope to remove the need of daily injections and glucose blood sugar monitoring all together.

ISSUES

• Difficult to match rate of secretion to the requirements of the body.
• Difficult to engineer two-way signaling from gut to blood and back to gut again.
• Risk that bacteria may become pathogenic through mutation rates.
• Releasing GMOs into the environment may cause unforeseen adverse reactions.
• Risk of transferring to non-diabetic individuals. This could result in a number of reactions when insulin levels are normal in the blood that would need to be carefully examined prior to release into the community.

9. Animal Insulin

BACKGROUND

Returning to older animal insulins to supply developing nations with cheap insulin. This would involve running an animals blood through a form of dialysis to purify the insulin out for human use.

ISSUES

• Higher rate of allergy to animal insulins than regular human insulin.
• Human insulin manufacturing with economies of scale should be cheaper to manufacture. Animal insulins only seem like a viable alternative due to the artificially high prices.

10. Black Market Insulin

BACKGROUND

We could potentially go rogue from the normal entry to market options and start producing insulin on the black market. This option would not require any approval processes for processes used to make insulin, and could be sold online through trading sites such as Ali Baba. Regulatory oversight wouldn't’t be used either.

ISSUES

• Will put patients at serious risk if Good Manufacturing Practice is not met.
• Legal risk for manufacturer if anyone is harmed through use of the insulin produced.

Our Solution

In light of all of these potential solutions, we have had to formulate our own decisions as to how we should

1. Approach the issue as a whole, and
2. How to bring our solution to fruition.

To see the full thought process to come to the conclusion that we have, please visit our Integrated Human Practices Page. Various stakeholders invested great time to help guide us towards our solution:

Open Source Insulin Producing Bacteria which has a purification method that is simple to do!

An overall theme from above is simple upfront costs. The best way for us to help in reducing these costs is not so much approaching it through an avenue that tries to remove those costs all together, but in a way where we provide a cheaper alternative once certain costs are made. For example, rather than going through the litigation process of reducing the costs of Good Manufacturing Practice approval processes, or by investing into creating a new trading platform for public investment, we are providing a simple to produce insulin for up and running manufacturing plants to take on, or for manufacturing plants to be developed to produce these insulins.
We have specifically designed our expression systems such that there are three locations where the insulin will be accumulated. In E coli, we have insulin being accumulated in the cytoplasm and periplasm. In Bacillus, we hope to be able to purify straight from the media from secretory accumulation of Insulin. Through these methods we should be able to compare easily which worked, and which didn’t, and then the associated purification methods which simplified the process.
Furthermore, we have designed our own single chain insulin to help remove a lot of the post-purification methods associated with getting insulin into its active form. A series of di-sulphide bonds make it quite difficult to fold properly within bacterial cells. On top of that, for Proinsulin to become Insulin, the C-chain must be removed. So, we’ve designed a single chain insulin with a small C chain linker which doesn’t need to be removed, and should also position the A and B chains more favorably to form the di-sulphides correctly. Our solution is by no means in isolation of other options also. Further down the track, following scaling up our production schemes, considerable efforts will be put into developing an open source pump to go alongside the insulins we have developed. Further efforts will then be put on to manufacturing contracts with medium-large scale plants to start pumping insulin out globally. On the side, efforts will also be put towards developing a gene therapy to ultimately cure diabetes in the mean time.

References

1. Kushibiki, T., Okawa, S., Hirasawa, T. & Ishihara, M. Optogenetic control of insulin secretion by pancreatic [beta]-cells in vitro and in vivo. Gene therapy 22, 553-559, doi:10.1038/gt.2015.23 (2015).