Product Development
Our Approach
We, iGEM Stockholm 2017, believe that lung probiotics are the future, and we want to be at the forefront of this field together with PROlung.
To prepare PROlung to become a possible start-up in the future, we have conducted different parts of a theoretical product development strategy with the help of the book BIODESIGN The Process of Innovating Medical Technologies.
Pharmaceutical and biotechnological development are usually characterized by the development of a product looking for an uncertain market. In our opinion, the final customer should be always in the center of the development process and, because of this, we have used the product development strategy of the MedTech industry as our baseline, as we search for a way to provide a high-value solution for the patients.
In order to develop our product, having the final customer always in the center, we have included a section concerning this in the analysis of the disease state fundamentals, the existing solutions, the stakeholders involved in this area and the landscape of market for a treatment to respiratory diseases related to high mucus production. But most importantly, we have found the need behind our product, by listening to the opinions of different stakeholders.
Through the background analysis we performed and studies of customers’ needs, we were able to successfully develop the product design. For the product we had designed we made a theoretical study of the regulations it would be subjected to, the ethical concerns it may raise and the intellectual property protection we could apply for, and the product could interfere with. At the end of the process, we were also able to determine how the product could be reimbursed in healthcare and a possible business model for it. We believe that conducting all this would give PROlung a head start in becoming a company.
Since we know the target audience for this document has a very varied background, we have included, in the beginning of each segment, a short description of its purpose. We hope that this description of and business concepts and the word list of complex medical terms we have also included can inspire future teams to think about the product development of their projects.
We have divided our product development in two different parts: the journey to finding a need and the journey to putting a product in the market. We have taken this decision for a matter of simplicity and thought this is the key point to do so as the product design step of the product development is a turning point for the innovator in which there is a change from a more social, value based mindset to a more utilitary and practical one.
Disease state fundamentals
What is this?
Disease state fundamentals is establishing a detailed knowledge of the relevant disease state, with a particular focus on its mechanism of action. A disease state fundamentals is key to validating any need and understanding how it can best be addressed.
Word list
Physiology:The way in which bodily part functions
Epidemiology:The study and analysis of the patterns, causes, and effects of health and disease conditions in defined populations
Pneumothorax: There is a tear in the lung and air escapes into the chest cavity
Dyspnea: Shortness of breath
Recurrent sinusitis: The small, air-filled cavities behind your cheekbones and forehead get inflamed
Mucociliary clearance: Self-clearing mechanism of the bronchi
Anatomy of the lungs
The human lungs are a pair of large, spongy organs optimized for gas exchange between our blood and the air, as our bodies require oxygen in order to survive.
The air that you breathe goes down your windpipe into tubes in your lungs called bronchial tubes, that branch many times into smaller, thinner tubes called bronchioles. These tubes end in bunches of tiny round air sacs called alveoli. Small blood vessels called capillaries run along the walls of the air sacks.1.
Physiology of the lungs
When air reaches the air sacs, oxygen passes through the air sac walls into the capillary blood At the same time, a waste product, carbon dioxide (CO2), is removed from the blood, into the air sacs. This gas exchange process brings in oxygen for the body to use for vital functions and removes the CO2.
The airways and air sacs are elastic, each air sack fills up with air like a balloon, and deflates when breathing out.
The air sacs are covered in a viscous substance called mucus which traps foreign molecules and consequently, prevents them from entering the body. Tiny hairs called cilia constantly move the mucus with the entrapped pathogens upwards and out of the lungs. Thus, the mucus functions as a protection against the outside world, continuously keeping the airways clear of foreign particles.2
Existing solutions
What is this?
Analysing the existing solutions is to explain the current and emerging solutions, how they work, when they are used, how effective they are, their cost and the overall value they deliver. The aim is to clarify the gap in existing solutions, where new opportunities become apparent.
Word list
Bullectomy: Surgical removal of a bulla, which is a dilated airspace in the lung parenchyma
Osteoporosis: Bones becoming less dense due to the loss of bone material
Exacerbation: Increase in the severity of a disease
Hoarseness: Abnormal voice changes
Summary
The most common medications for cystic fibrosis, COPD and asthma are the inhalation devices like bronchodilators, mucus thinners, and steroids. A famous new drug on the market is Orkambi. Thick mucus also contributes to bad bacteria in the lungs were often antibiotics are necessary. These medications are always taken together with airway clearance techniques and in severe cases, a lung transplant may be needed.
Cystic Fibrosis
Current commercially available approved drug class are:
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators (ivacaftor (Kalydeco®) and lumacaftor/ivacaftor (Orkambi®).) The Lumacaftor moves the defective CFTR protein to the correct place on the cell surface, and ivacaftor increases the protein's activity once it is in place. Orkambi is today one of the most attractive medications for CF but the therapeutic effect only targets a subpopulation people with specific CF mutations3.
Bronchodilators is an inhalation device that helps widen the airways, and can also be used for asthma and COPD patients. There are two different types, short-acting and long-acting and can be used before other treatments and before exercise.
Mucus thinners, such as Mucolytic drugs is a type of inhalation medicine that alters the chemical characteristics of mucus to decrease its viscosity and facilitate its removal. There are two types hypertonic saline works by increasing the amount of sodium in the airways and Dornase alfa (a DNA functions by cutting DNA strands released by white blood cells, which makes the mucus thinner.
Potential disadvantages of inhalation medication in CF patients compared to other drug administrations are:
Uncertainty about drug dose at the target site, severely affected lung areas may not be reached, drug delivery depends on inhalation technique and device performance, local side effects (e.g., cough, airway narrowing, hoarseness), variable systemic drug absorption, time-consuming drug administration, need for education and training, limited information on drug interactions in the lung, specific drugs may need specific delivery devices, poor adherence, potential pollution of the environment, potential device contamination and patient infection, need for hygiene control and maintenance of the equipment and limits social functioning4.
Anti-infective drugs include antibiotics and antibacterials, antifungals, antivirals, and antiprotozoals. These work by either killing the infectious agent or by inhibiting it from spreading.
Antiinflammatory drugs have two main purposes, to act as painkillers or to reduce inflammation5.
Pancreatic enzyme supplements are taken by mouth with the purpose to digest carbohydrates, proteins, and fats, absorb essential nutrients such as vitamins and minerals and help the patient gain and maintain a healthy weight6.
Lung Transplantation can extend and improve patient’s quality of life, but it involves an extensive evaluation process and a commitment to living the lifestyle required to keep your new lungs healthy.
COPD
Bronchodilators (mentioned above).
Inhaled steroids such as inhaled corticosteroid medications can reduce airway inflammation and help prevent exacerbations. Side effects may include bruising, oral infections and hoarseness.
Oral steroids work for patients who have a moderate or severe acute exacerbation. Short courses (for example, five days) of oral corticosteroids can prevent further worsening of COPD, however, long-term use of these medications can have serious side effects, such as weight gain, diabetes, osteoporosis, cataracts and an increased risk of infection.
Phosphodiesterase-4 inhibitors is a new type of medication approved for patients with severe COPD and symptoms of chronic bronchitis. One example is roflumilast (Daliresp), a phosphodiesterase-4 inhibitor. This drug decreases airway inflammation and relaxes the airways. Common side effects include diarrhea and weight loss.
Theophylline is a medication, which might help improve breathing and prevent exacerbations. Side effects may include nausea, headache, fast heartbeat and tremor. Side effects are dose-related, and low doses are recommended.
Antibiotics can act against respiratory infections, such as acute bronchitis and pneumonia.
Surgery is an option for some people with some forms of severe emphysema who aren't helped sufficiently by medications alone. Surgical options include:
- Lung volume reduction surgery
- Lung transplant
- Bullectomy7
Asthma
Asthma medications are divided into two main parts, long term, and short term medication, where the first acts to reduce airway inflammation, which helps prevent symptoms from starting and the second one acts to give rapid, short-term symptom relief during an asthma attack. Asthma has very similar medications as COPD such as the inhaled steroids, bronchodilators and Theophylline.
Other long-term control medicines include:
- Cromolyn
- Omalizumab
- Inhaled long-acting beta2-agonists
- Leukotriene modifiers
Short terms include:
- Ipratropium (Atrovent)
- Prednisone
- Methylprednisolone
- Inhaled short-acting beta2-agonists8
Airway clearance techniques
In addition to medication, techniques can be taught by a physiotherapist to help restore clear airways in all of our targeted diseases. Such exercises includes: active cycle of breathing techniques (ACBT), a technique that involves a sequence of relaxed breathing, followed by deep breathing exercises and then huffing, autogenic drainage, a series of gentle breathing techniques that clear mucus from the lungs, modified postural drainage, a technique that involves changing your position to make it easier to remove mucus from your lungs and airway clearance devices, a handheld devices that use vibration and air pressure to help remove mucus from your airways9.
Stakeholders
What is this?
Stakeholders are the parties that are directly and indirectly involved in financing and delivering care for the patient. In this analysis, you uncover who the user, payer, decision maker and influencer is.
There are many different stakeholders with a potential interest in new medical technology. Those include patients, patient’s families, patient advocacy groups, physicians, professional societies, nurses, family administrators, public payers, governments and non-governmental organizations.
Some examples of different societies and and non-governmental organizations in Sweden are Riksförbundet Cystisk Fibros, Astma- och Allergiförbundet and Riksförbundet HjärtLung. The majority of the countries with people suffering from these diseases have similar associations for these diseases10.
n Sweden, the responsibility for medical care and health is shared by the central government, county councils, and municipalities, and therefore they are the decision makers. They are also the payers as the major population in Sweden possesses public insurance. The county council is responsible for ensuring that the needs of tomorrow are met by today, in healthcare.
The doctors and government officials influence the upcoming treatments on the market, and the user is, of course, the patient.11
Need
What is this?
Needs correspond to opportunities for innovation. They are characterized by describing an outcome that is currently unmet for a problem, in a particular population, which helps direct the opportunity. By clearly and concisely articulating the needs they have observed, innovators will be in a much better position to then determine which ones represent the most compelling opportunities.
Summary
To identify the need, we targeted our most valuable stakeholders: the patients and healthcare professionals. We conducted a survey to reach as many patients as possible and could observe 3 outcomes: an unmet need for mucus-targeting medication, patients are willing to try a GMO as a drug and the preferred administration device would be a nebulizer. We arranged interviews with doctors, physiotherapists, nurses and family members, similar outcome as from the patient survey. There is a need for PROlung and nebulizer would be the most effective device. They all would be happy to prescribe PROlung to their patients as long as it’s safe.
We discovered the need for a new medication by approaching our most valuable stakeholder: the patient. In order to gather as many opinions as possible, we conducted a survey available in both English and Swedish and managed to collect almost 300 answers. We reached out to the Facebook group “Cystic Fibrosis” with almost 30 000 members, disease organizations such as “Riksförbundet Cystisk Fibros”, ”Astma & Allergiförbundet” as well as “ Riksförbundet HjärtLung” who posted the survey in their newsletters and social media pages. The whole team also attended the biggest event for cystic fibrosis awareness in Sweden, where we presented our project and talked to patients about the need for a new medication.
There main outcome from the patient survey was that there is an unmet need for mucus-targeting medication. In total, 228 asthma patients, 41 CF patients, and 10 COPD patients answered our survey. The reason that a majority of the answers came from asthma patients may be that asthma is a much more common disease than the CF and COPD. We took this in consideration when analyzing our results as the diseases have slightly different needs.
The questions asked to patients:
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How long have you been diagnosed with this disease?
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Approximately, how many times do you visit the doctor every year?
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How many hours a week do you perform any type of physical activity?
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Have you been trained on exercises that can improve the capacity of your lungs and help in the progress of the disease?
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What is your current treatment? If you are not sure of the name, please describe your medication or state unknown.
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How many times have you changed treatment?
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Are you satisfied with your current treatment?
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Do you have problems with excessive mucus?
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On a scale of 1-5, how much has your current treatment improved your excessive mucus? (1 being not improved, 5 being highly improved).
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If a new treatment was to be released, outstanding in the performance of the current ones, would you take it if it involved the use of GMOs (Genetically Modified Organisms) in the body?
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If this treatment was to be released, which type of device would be more suitable for its administration?
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Up to 50% have changed their treatments more than 5 times, which stated that the current medications do not work sufficiently enough for longer time use. 20% are very satisfied with their current treatments, 45% are satisfied and 35% are not satisfied.
About 50% answered they have issues with excessive mucus. In this answer, we also have to take into account that 228 asthma patients answered, who do not suffer from mucus in the same amount as COPD and CF does. The majority that answered the survey does not think that their current treatment is good enough against the mucus. This is probably our most interesting answer as this clearly states that there is a need for a new effective medicine targeting mucus. Although we have to take into account that over 60 % are satisfied with their treatments. After going through the answers individually, we concluded that the patients suffering the worst from excessive mucus are not satisfied with their current treatment as it does not target mucus, whereas patients with milder mucus production are more satisfied with their treatment. About 40% said yes to a medication being a GMO, and the rest stated maybe. 50% said the most suitable device would be any type of inhaler. The rest of the solutions, such as an orally dissolving tablet (ODT), injection and a surgically implanted device had a similar small percentage.
From the results we obtained from our surveys, we decided to create personas. Personas are fictional characters, which you create based upon your research in order to represent the different user types that might use your service, product, site, or brand in a similar way. By writing about personas we are able to emphasize the need and to put our reader in the skin of the person suffering the disease.
David
David is 12 years old and was diagnosed with Cystic Fibrosis when he was just a baby. David loves being outdoors and doing sports, but unfortunately, he has to spend many hours inside taking his medicines and doing his breathing exercises. Last week he missed three classes in school due to his doctor's appointments, and now he has to change medicine again, as the current one is not as optimal as before. David hopes that he will grow older than his grandparents and that in the future there will be a cure for cystic fibrosis.
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Anna
Anna is 56 years old and suffers from COPD. Anna loves spending time with her grandchildren but feels ashamed to be out in public with them as her coughing draws too much attention. Anna doesn’t know how many more years she has to live and all she wants is to be able to see her grandchildren grow up. Her lung function is very low and she hopes for a lung transplant, although many people stand in line before her. At this point, Anna is open for any type of treatment.
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Additionally, we decided to target the second largest stakeholder, the doctors, physiotherapists, and nurses. We knew we couldn't target an equally big group as with the patients, and therefore decided to conduct interviews with six professionals in healthcare.
We interviewed Michael Runold, a pulmonary physician, treating all kinds of pulmonary diseases but mainly COPD; Niclas Johansson, a physician in infectious diseases, treating mostly respiratory infections like tropical fever and COPD; Annika Hollsing, a physician in pulmonology and infectious diseases, treating mostly CF and asthma; Robert Dickson, a pulmonary disease and internal medicine doctor working with pulmonary diseases, specifically COPD and asthma; Pernilla Sönnerfors, a pulmonary physiotherapist for mostly asthma and COPD; and Ulrica Sterky, a children’s nurse and also the mother to a son with cystic fibrosis.
Questions asked to healthcare professionals:
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What is your background?
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What are the symptoms you check for when you have an appointment with a patient?
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What type of medications do you prescribe/prefer to the different diseases/what exercises do you teach them?
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Is there a gap in medication for cystic fibrosis, asthma, and COPD?
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How do you treat patients who have problems with mucus?
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Would there be a need for a medication targeting mucus?
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Would you be open to prescribing a drug involving the use of a GMO?
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If this GMO treatment was to be released, which type of device would be the most suitable?
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The symptoms were very similar for all answers, such as cough, shortness of breath, tightness of the chest, breathing problems and mucus. The same goes for the prescribed medications, including for an example steroids, bronchodilators or antibiotics. The mucus targeting medications that were mentioned were DNAse, acetylcysteine, bromhexine, sodium chloride, mucolytics and extensive training on how to eliminate the produced mucus, but they all agreed that there is a gap in medications targeting COPD, asthma, and CF and they insisted strongly that there is a need for a medication specifically targeting mucus, especially as the ones today do not work for all patients. This was also encouraged by Pernilla, the physiotherapist that said:
"There is absolutely a need, it would be a great win for those that have a hard time moving the thick mucus upwards. If there was a good enough mucus targeting solution today, the patients would not have to visit me, there is definitely a need."
Pernilla Sönnerfors, a pulmonary physiotherapist
We asked Ulrica, children's nurse and mother to a son with cystic fibrosis “What do you think it is like living with cystic fibrosis?”
Her answer:
“In the big picture, when your child gets the diagnosis, it's a very hard time for patient and families. You have to keep track of the infections, make sure they eat enough with their enzymes, practice the breathing exercises and make sure they do them correctly and always in the back of your head, you know it's for life. You just have to learn to live with it, knowing that many do not survive over middle age years.”
Ulrica Sterky, a children’s nurse and also the mother to a son with cystic fibrosis.
All the participants addressed GMOs as a medication very positively. They said as long as it’s safe and approved, and of course works, why not?
Additionally, when we asked what device would be the most suitable, the questions were quite similar but with some differences. To summarize, the patients are quite tired of using inhalers and the ones today are quite complicated. If the medication could be given as a pill, that would be the easiest. Although considering side effects and the fact that the pill might not deliver the medication as specific as wished, all of them agreed that an inhaler like a nebulizer would be the best. More specifically, it would be the easiest for the patients if the inhaler was small enough to fit into a pocket.
Amanda and Sonia together with Michael Runold, a pulmonary physician.
Sonia at Karolinska university hospital together with Niclas Johansson, a physician in infectious diseases.
In regards to the possible market of our potential solution, about 40% of the surveyed patients said yes to a medication being a GMO, and the rest stated that maybe would maybe buy it, giving our product a very interesting number of potential customers.
On the physician side, all the participants addressed GMOs as a medication very positively, said that as long as the product is safe and effective, they would not have any problem prescribing it.
Overall, we have been able to understand what the priorities the health care professionals and patients have for the use of PROlung. Additionally, from the surveys and interviews, we were able to identify the different customers, who have stated interest in this solution and would be willing to buy it.
Market
What is this?
Market analysis aims to give a broad understanding of the need in terms of its total size, range of existing solutions and competitors, and gaps that may exist and indicate opportunities for innovation. It also focuses on a detailed evaluation of different segments within the overall market to determine which one(s) the innovators should potentially target.
Summary
We aimed to map the how well customer needs are met, key players and stakeholders and market size, is it expanding or contracting? As discussed, the need is not fully met as current mucus treatments aren't efficient enough. Key players are companies as Vertex, AstraZeneca, GlaxoSmithKline, F. Hoffmann-La Roche, Novartis, Merck and more. Key stakeholders are doctors and patients. The market for cystic fibrosis is growing due to increasing prevalence with a size of $ 3.56 billion. For COPD and asthma, the market is expanding, with asthma having the largest market size of $ 20.7 billion and COPD, $ 11.3 billion. North America is the largest market for all three diseases but Asia Pacific is expected to become the fastest regional market in the future.
Word list
Prevalence: The amount of a population who have/had a specific characteristic in a given time period
R&D: Research & Development
Reimbursement: To pay back money to someone who has spent it for you or lost it because of you
Value: A measure of the benefit provided by a good or service to an economic agent
Revenue share: The distribution of profits and losses between stakeholders
Market capitalization: The total market value of all of a company's outstanding shares
Doing the market analysis, we took help from the book Biodesign, The Process of Innovating Medical Technologies by addressing following questions (in italic) to analyze the market of our target diseases.
We were able to clarify these questions by addressing the market with a quantitative and qualitative research, by both looking at existing data and also doing surveys and interviews with current stakeholders.
How well are customer needs generally addressed by existing solutions and how closely aligned are available solutions with the need the innovators are seeking to address?
There are no solutions today that target the specific area of breaking down the mucus directly. As read under existing solutions for cystic fibrosis, there are so-called mucus thinners, but they do not degrade the mucus directly and serve more to make it thinner by adding salt or using DNase.
Especially in cystic fibrosis and COPD, mucus is a major problem, which current treatments do not satisfy completely. For asthma, on the other hand, mucus is more of an indirect issue, and tightness of airways is the major problem, breaking down mucus could act as a complement to airway dilators.
What is the approximate size of the total market for all existing solutions? Is the market expanding or contracting?
Cystic Fibrosis:
The increasing prevalence of cystic fibrosis (CF) (In the U.S., the number of patients in 2010 rose from 26,366 to a total of 28,983 patients in 2015)) together with rising treatment rate is one of the key reasons for the market growth. In upcoming years, an increase in R&D funding by both private and public organizations, a rising number of initiatives undertaken by nonprofit organizations, and presence of favorable reimbursement policies are expected to drive the market.
| The Global Market Size |
$3.56 billion |
COPD:
The global market size of COPD is expanding. Much of this growth is a result of a high number of new, more efficacious and convenient products entering the market and commanding greater value compared to the therapies already in the market.
| The Global Market Size |
$11.3 billion |
Asthma:
Although asthma has the biggest market size, it is anticipated to show a slow growth rate of 2.2% over the forecast period from 2016 to 2024. And increasing incidence of respiratory diseases together with the demand for cost-effective treatment options is expected to push the asthma therapeutics market growth during the forecast period. According to the estimates published by the Global Initiative for Asthma (GINA), in the year 2013, around 300 million patients globally were reported to be afflicted with this disease and the number is expected to grow in the coming years11.
| The Global Market Size |
$20.7 billion |
What is the size of the market opportunity in each market segment and the potential for growth and expansion?
Cystic fibrosis:
The market for cystic fibrosis is segmented into pancreatic enzyme supplements, mucolytics, bronchodilators, and CFTR modulators.
In 2016, CFTR modulators accounted for the largest revenue with a share of approximately 47.3% owing to the launch of new drug Orkambi. This drug is responsible for correcting the function of a defective protein caused by the CF gene.
The market is also segmented into oral route and inhaled drugs. Oral route drugs account for the largest share of nearly 63.7%.
According to the U.S. patient registry 2015, hypertonic saline was prescribed to 21.5% of children in the age group of 0 to 3 years and 41.9% children in the age group of 3 to 5 years. Increasing prevalence of CF among newborn babies is one of the key factors responsible for growing demand for oral drug formulation.
Country wise, the market is segmented into North America, Europe, Asia Pacific, Latin America, and Middle East and Africa. North America accounted for the largest revenue of $ 2,396.4 million in 2016. CF is most prevalent in North America.
Asia Pacific is expected to be the fastest growing segment with the lucrative growth rate of 18.8%.
Currently according to the Cystic Fibrosis (CF) Therapeutics Market Analysis By Drug Class, the availability of CF-specific drugs is low, however, growing approvals and product launches in this market are anticipated to impel growth.
COPD and Asthma:
Key drugs employed for control and diagnosis of asthma and COPD may be classified on the basis of their types which include bronchodilators, leukotriene antagonists, and immunosuppressants.
For asthma, the combination therapy segment including inhaled corticosteroids with long-acting beta-agonists dominated the overall therapeutic class market in 2015. This segment captured over 48.0% of the global market share and this drug class boasts of the following benefits: enhanced therapeutic effect, extensive availability, and enhanced patient medication adherence.
The inhaler segment for asthma includes dry powder, metered dose, and soft mist inhalers. The metered dose inhalers (MDIs) segment dominated the overall market in 2015 in terms of revenue share at over 45.0%. This is majorly attributed to, among others, reliability, versatility, self-containment, easy availability, portability, and cost-efficient medical aerosol delivery option. Increasing requirement for emergency treatment options aimed against sudden asthma attacks and portable devices constitute the crucial determinants contributing towards the largest market share possessed by the dry powder inhalers (DPIs) product segment.
Nebulizers demonstrate significant benefits in the home healthcare section which is expected to provide this segment with future growth opportunities. Nebulizers are small, portable, and able to dispense medication directly into the respiratory tract. These associated benefits are expected to boost its usage rates in the future13.
The growing aging population coupled with increasing automotive and industrial exhaust gases have remained the key drivers for the global asthma and COPD market, especially in the low-income population in the emerging economies of China, India, Brazil, and Russia.
Increasing disposable income levels in emerging economies as well as developing countries of Latin America, Middle East, and Africa has led to the increased usage of asthma pumps and sprays in these regions. However, the unknown etiology of asthma and COPD in medical industry may restrict the market growth in the next six years. Upcoming treatment methodologies such as once-a-day combination products and monoclonal antibodies have created new opportunities for market growth.
New bio-based medications in combination with biotechnology promise immense growth opportunities along with sustainable development for asthma and COPD market over the next decade.
Currently, North America leads the global market for asthma and COPD drugs and devices, followed by Europe in terms of market capitalization. However, because of the expiration of several patents, these regional markets will lose out some of the market shares to other emerging regional markets. Asia Pacific is expected to become the fastest regional market for asthma and COPD14.
Who are the key players of the market?
For cystic fibrosis, the key companies are AbbVie, Inc.; F. Hoffmann-La Roche Ltd.; Gilead; Novartis AG; Vertex Pharmaceuticals Inc.; AIT (Advanced Inhalation Therapies); Alaxia; Teva Pharmaceutical Industries Ltd.; Merck & Co., Inc.; Alcresta Therapeutics, Inc.; Allergan; and AstraZeneca15.
For asthma and COPD, the key companies are AstraZeneca, GlaxoSmithKline, F. Hoffmann-La Roche, Novartis, and Merck. Other significant companies operating in the global asthma and COPD market include Abbott, Amgen, Actavis, AptarGroup, Aurobindo, Boehringer Ingelheim, Cipla, Dr. Reddy’s Laboratories, Glenmark, Mylan, Pfizer, Ranbaxy, Sunovion, and Vectura.
Which stakeholder could recognize the greatest value created by a new solution?
The patient is the most valuable stakeholder for all three diseases. Their life quality is affected by their sickness, and they are the ones carrying the daily difficulties to get rid of the mucus, Finding a new medication that works affects them the most and, they are also the ones ready to take a “risk” developing GMOs, for a better life.
Product Design
What is it?
Based only on information about the need, innovators are able to develop promising solution concepts, trying to create something technically feasible, viable, efficient… The final concept will continue to be refined, tested, iterated, and improved during development and implementation.
Summary
The solution iGEM Stockholm has developed for the need “a treatment for diseases with excessive mucus production” is a smart genetically modified bacteria that secretes mucus degrading enzymes. The solution we have developed combines a nebulizer for the administration of the genetically modified bacteria, the genetically modified bacteria and the enzyme that will degrade the mucus in the lungs.
Word list
Microaspiration: Used when patients have an asymptomatic aspiration of small volumes of oropharyngeal secretions or gastric fluid into their lungs.
Vector: DNA molecule used as a vehicle to artificially carry foreign genetic material into another cell.
Microbiota: Microbes colonizing the human body, includes bacteria, archaea, protists, fungi and viruses
Glycosidic linkages: Covalent chemical bond joining a carbohydrate molecule to the group to which it is attached (which may be in another sugar, as in polysaccharides, or in non-sugar molecules)
The nebulizer
A nebulizer is a device that converts a liquid into aerosol droplets suitable for patient inhalation using pressurized air. A nebulizer is comprised of, a compressor, a container holding the medication to be administered, a tube connecting both parts and a mouthpiece or mask for the administration of the medication.
Particle size is of great importance at the site of deposition in the respiratory tract of humans and animals. A Collison nebulizer has been previously used to generate small-particle aerosols with a mass median aerodynamic diameter (MMAD) of 1 to 3 μm for animal exposure studies, this correlates with the small particles around the size of a bacterium (1 to 5 μm) that would deposit in the alveoli.16
The advantage of using a nebulizer instead of a pocket inhaler is due to its normal breathing medicine intake rate. By this, we mean that for the inhalation of medicine through a pocket inhaler the patient needs to take deeps breaths for the medicine to reach the lungs, however, for patients with a respiratory disease, this may not be a possibility due to the narrowing of the airways in these diseases. Additionally, nebulizers can deliver short-acting or long-acting medication therapies.
For the bacteria to survive, the administered medication placed in the nebulizer will need to contain the GMO plus a medium which is required for the viability of the bacteria. The most probable scenario would be that bacteria will be in vial protected and preserved and upon administration, when it will be inserted into the nebulizer and inhaled. It should be noted that it is wise to avoid keep GMO in the nebulizer container while there is no use in order to decrease the risk of release into the environment.
- Connect the compressor to an outlet.
- Place the medication in the container.
- Connect the tube to the compressor and the liquid container.
- Attach the mouthpiece or mask.
- Put the mouthpiece around the mouth and secure it over nose and mouth, leaving no gaps.
- Slowly breath in and out until the medicine is gone. This may take up to 15 minutes.17
The advantage of using a nebulizer instead of a pocket inhaler is its normal breathing medicine intake rate. By this, we mean that for the inhalation of medicine through a pocket inhaler the patient needs to take deeps breaths for the medicine to reach the lungs, however, for patients with a respiratory disease, this may not be a possibility due to the narrowing of the airways during these diseases. Additionally, nebulizers can deliver short-acting or long-acting medication therapies.18
There could be other alternatives for the administration of the genetically modified bacteria, like microaspiration and dispersion of oral bacteria into the lungs. However, diseased lungs have the tendency to create niches for pathogens and neutral distribution does not affect the deposition of bacteria. Also, it would be even more difficult to assess the amount of bacteria practically reaching the lungs. So far, no models have been successful describing this neutral distribution. At last, it would be optimal if the administration minimizes the risk of any release into the environment which does not seem optimal upon oral or nasal application.
Once the bacteria reach the lungs, it would be necessary to control the dynamic process where selective pressure exists while mucociliary clearance and immune system strive to eliminate any foreign particle, for the bacteria to be able to stay long enough to release the enzyme.
The genetically modified bacteria
Our proof of concept has been generated in E.coli, since it is a well-characterized bacteria suitable for engineering. It became clear to us that the next step would be to transfer this genetic construct to a strain more suitable for a lung probiotic.
In order to achieve this goal we considered two main approaches. On one hand to extrapolate our system from E.coli to a new bacteria we proposed the use of shuttle vectors, plasmids compatible with two different species which allow us to move cellular machinery from one bacterial chassis to another.
Our basic selection criteria was therefore based on two premises: the selected bacteria should have a shuttle vector compatible with E.coli and it should be one of the species that are part of the lung microbiota.
After reviewing the available shuttle vectors on the iGEM Registry of Standard Biological Parts we came down to two strong candidates: Pseudomonas aeruginosa and Staphylococcus aureus.
Although both organisms are well defined within the lung microbiota and have available shuttle vectors, the higher compatibility of P. aeruginosa for genetic manipulation would make it a better choice. Nonetheless there is one major drawback for the use of either of these organisms: its pathogenicity. Our initial strategy to cope with this limitation would be to begin with a lung-adapted isolate of P. aeruginosa that doesn’t produce virulence factors.
Another option within this approach could be the use of the part BBa_J153000. This shuttle vector was originally designed to work on cianobacteria that holds the potential to work with a broad range of gram negative . This would allow us to attempt to use non-pathogenic gram negative strains from predominant genus such as Fusobacteria or Veillonella.20
On the other hand taking into account the constant advancements in genetic engineering we could consider another approach with a lesser focus on shuttle availability. A great example of this would be the use of S.carnosus, a non-pathogenic strain for which a shuttle vector is currently under development and has successfully expressed hyaluronate lyase from E.coli.21
Our hypothesis is that our lung probiotic will reside naturally in the lungs of the patients (bronchi, bronchioles); on the mucus layer. As the osmotic pressure of the mucus is higher in the previously mentioned diseases we took advantage of this, by introducing an osmotic promoter in our bacteria and place the gene of interest, in our case, an enzyme called sialidase, under its regulation. Thus, when an abnormal osmotic pressure is detected by the bacteria, the gene expression of the mucus degrading enzyme would subsequently be triggered.
Once the enzyme is expressed and secreted, sialidase will cut the sialic acid in the branches of the thick mucus. Altering the mucus composition would make the mucus thinner and restore the mucociliary clearance.
The mucus degrading enzyme
We have mainly focused on two enzymes. Firstly sialidase, an enzyme that hydrolyzes glycosidic linkages of terminal sialic acid residues in glycoproteins. These sialic acids have been suggested to inhibit mucin degradation. Using a genetically engineered bacteria to remove these protective terminal groups will improve interaction and degradation of the mucins. Secondly, endo-β-galactosidase, is an enzyme that hydrolyzes the bonds next to galactose saccharides in the polysaccharide chains of mucins. It has been proven to release saccharide chains from glycans expressed in the gastric mucous cell-type mucin.22
In the mucin constructs, saccharides interact with water and form a mucosal layer. The large mucin constructs give the mucosal layer its visco-elastic properties. By using the aforementioned enzymes, these polysaccharides will be removed from the protein backbone, resulting in the mucus losing some of its gelatinous attributes.
There are two main differences between using an enzymatic approach instead of using mucolytics. The first one is the specificity. Enzymes are highly specific in comparison to other chemicals and will only interact with the mucin as well as often have a reaction time that is several times faster.The second difference is that the bacterial approach provides an autonomous system. This system will regulate the expression and secretion of the drug/enzyme accordingly to the disease state. More specifically, it is not until the bacteria can sense the elevated osmotic pressure that it will subsequently initiate the expression of the enzyme(s). The conventional therapy of mucolytic simply attempts to provide a one-time bolus to restore the mucus state, limiting its effects to being temporary.23
The way our system is constructed, the amount of enzyme expressed and secreted in the lungs will be associated and proportionate towards the osmotic pressure, making our treatment a personalized medicine. In contrast, a patient using mucolytic will have to try to decide on his/her own what dosage is needed for that particular time.24
When the mucus has been degraded, and thus its visco-elastic properties have been restored, the cilia are once again able to move the mucus, and hence restore the mucociliary clearance. The superfluous mucus can subsequently be coughed up or swallowed.
Product design was one of the most complex parts of our product development, and one of the one where we required more help. For the successful completion of this part, we had support from Andreas Lundquist. Andreas holds two masters, one Technical Design and one in Mechatronics. He was a Clinical Innovation Fellow for the Center for Technology in Medicine and Health, and is currently the course leader for the master level course Product Development in the Biomedical Industry at the Karolinska Institutet.
Andreas Lundquist, Clinical Innovation Fellow and course leader for Product Development in the Biomedical Industry at the Karolinska Institutet.
Intellectual Property
What is this?
Intellectual property (IP) refers to inventions such as literary and artistic works, designs and symbols, names and images used in the industry and is protected by law with patents, trademarks, and copyrights to gain financial benefit or recognition from what you’ve created or invented. Source.
Word list
Patent: Exclusive right to sell, license or use an invention, a product or a process of the human intellect
Provisional patent: Allows the inventor to file for the priority date of an invention without a formal patent claim, oath or declaration, it has a one year validity, after which a patent application should be filed or dropped.
Summary
We have developed a patent strategy for our product while fulfilling the biobrick sharing agreement. In order to do so, we have divided our patent search into three parts, lung therapeutics, E. coli GMO and drug enzyme. After executing a patent search, we have analyzed all the patents that are related to our project and we were not able to find any patents combining the three parts of our search. The next strategic step, if we wanted to continue with the development of our product and create a company out of it, would be to file a provisional patent application before we present our results in the Jamboree.
One of iGEMs values is sharing, an example of this is the biobrick agreement, where you share your biobricks and therefore get access to other biobricks. A problem arises for those that wish to continue with their iGEM project as a start-up, as everything that is shared can not be patented. Many of the iGEM teams that want to start a business, could do so by patenting program codes instead of sequences or similar25 26.
Still, one of iGEM’s greatest achievements is the number of startups it has generated. So, is there a way to keep sharing, but still be able to run a start up after iGEM?
We in iGEM Stockholm have - with the help of IP experts - completed a strategy to turn an iGEM project into a startup, while still respecting and acknowledging iGEM values. This will be exemplified with our project, PROlung.
In terms of IP strategy, our project can be divided into three parts:
- Part A: Lung therapeutics
- Part B: E. coli GMO
- Part C: Drug enzyme
In an initial patent search, we would firstly, have to look for patents inside the field of A, B or C, and see if any of those are relevant for our research. Secondly, we would need to study the combinations of A and B, B and C and A and C, in order to obtain a deeper understanding of the current situation in this field. Thirdly, we would have to see if there is any patent as a combination of A, B and C, that could have similar, or the same claims of our intended patent. All of this in addition to all scientific papers published before the filing date of the patent counts as prior art to our invention and could invalidate its patentability. If our invention is able to have a characteristic feature that does not infringe any of the explained options and combinations, it would be patentable.
Result
With the help from Rosa Lönneborg, a lecturer in patent search and critical information literacy inside the life sciences at the KTH Royal Institute of Technology, we were able to develop our patent strategy and to identify patents related to our product.
Sonia and Amanda working on patents together with Rosa Lönneborg
Using the strategy previously mentioned, we were able to perform a patent search describes how current and expired patents relate to the product we had developed:
Patents covering Part A:
- US20150017150A1- METHODS, COMPOUNDS AND COMPOSITIONS FOR TREATMENT AND PROPHYLAXIS IN THE RESPIRATORY TRACT27
- WO2015184526A1 SOLUBLE BACTERIAL AND FUNGAL PROTEINS AND METHODS AND USES THEREOF IN INHIBITING AND DISPERSING BIOFILM28
- WO2008001045 A1 MEMBERS OF THE GLYCOSIDE HYDROLASE FAMILY 31 FAMILY OF PROTEINS29
- WO03010298A1 PROBIOTIC LACTOBACILLUS SALIVARIUS STRAINS30
- WO2003010299A1 PROBIOTIC LACTOBACILLUS CASEI STRAINS31
Patents covering Part B:
- WO2003010297A1- PROBIOTIC BIFIDOBACTERIUM STRAINS32
Patents covering Part C:
- WUS20150017150A1- METHODS, COMPOUNDS AND COMPOSITIONS FOR TREATMENT AND PROPHYLAXIS IN THE RESPIRATORY TRACT33
- WO2007114881A1- SIALIDASE FORMULATION FOR TREATMENT FOR OF EX PULMONARY DISEASE34
- US2008166760A1- COMPOSITIONS AND METHODS FOR ENZYMATIC DETACHMENT OF BACTERIAL AND FUNGAL BIOFILMS35
- WO2004066945A2 ENZYMES AND THE NUCLEIC ACIDS ENCODING THEM AND METHODS FOR MAKING AND USING THEM36
- US20050112751A1 a novel class of therapeutic protein-based molecules where the use of sialidase is to preventing a pathogen infection37
- WO2000010388A1 SIALIDASES AS MUCOSAL ADJUVANTS38
As seen from this analysis, we could not find any patents combining ABC only A, B, C alone or two of them combined. This results in an opportunity to patent ABC together as a system.
A strategic solution after doing the patent research would be to file a provisional patent application during the iGEM competition. This way, you can share all of your work with fellow iGEMers, but still start your own business afterwards.
Regulation
What is it?
Without the approval or clearance by the regulatory agencies, even the most innovative and important breakthrough medical technologies will never reach a patient. Because of the critically important role that the regulatory issues play in the success of a technology, understanding the regulatory landscape is essential, as well as keeping a close relation with the regulatory agencies.
Summary
The next step in the product development process would be to analyze the regulation our product is subjected to. Our product is a so-called “combinational product”, which is a product comprised of any combination of a drug and a device, a biological product and a device, a drug and a biological product, or a drug, device, and a biological product. The last example would be our product. Because of this, our product would be subjected to three different regulations, the nebulizer would be accounted as a medical device (Europe Class IIa and US Class II), the genetically engineered bacteria as a recombinant Live Biotherapeutic Product (LBP) (evaluation of Human Safety, Environmental Safety, and Risk Assessment, visit our policy to know more) and the substance produced by the bacteria would be accounted for as a drug (proven safety and efficacy through clinical trials). In this case, our strategy to obtain regulatory approval would be to focus on the use of the drug for the treatment of one specific disease, cystic fibrosis.
Word list
Medical device: An instrument, apparatus, machine or other article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.
Device class: A classification for a device determines the strength of the regulatory standards the device will have to go through and depends on the level of risk that is associated with the device.
Standard: General controls and procedural regulations that medical devices are subjected to.
The nebulizer part of the device would be classified as a Class IIa medical device by the Medical Products Agency (MPA). This Class IIa consideration is due to the device being invasive with respect to a body orifice, the mouth. However, there would need to be more research done on the importance of the mode of action on the efficacy and safety of the administered bacteria, in which case, the nebulizer would be included in the class IIb.
As a medical device, the product would have to fulfill the requirements under the European Medical Device Regulation. A medical device needs to be safe and suitable for its intended use, in order to be able to receive a certification of conformity. This certification indicates that the product fulfills the requirements established by the MPA and allows the manufacturer to include the CE marking (European Conformity) symbol in the product. The intended use of the product is to release bacteria that will produce a drug that will degrade mucus for patients with excessive mucus production 39
For a class IIa device, a European Notified Body would need to do a quality assessment of the product, and there would not be a need for a clinical evaluation of the product. The organization manufacturing the product would, on the other hand, need to prove that it has effective quality management systems (QMS) (International Organization for Standardization (ISO) 13485), pass a EC verification exam, assure maximum quality of the product and production process and have a EC declaration of conformity. A successful QMS needs a Risk Management System (RMS) (ISO 14971). A good RMS comprises an analysis of the intended use and potential misuse, a failure mode and effect analysis, a risk management report, a risk management plan, and a risk acceptance (risk/benefit ratio) analysis 40.
For a further description of this process read the Guideline in the Pharmaceutical Quality of inhalation and nasal products of the committee for medicinal products for human use inside the MPA umbrella.
In the US, the product would be classified as a Class II medical device by the Food and Drug Administration (FDA), and would get market authorization through a 510(k) exemption, meaning it would be approved by its similarity to other products that have received approval previously 41.
The used applicable standards are ISO and International Electrotechnical Commission (IEC) standards, and even though they are not mandatory, they facilitate getting a CE-mark. In addition, they are useful to identify risks that could be related to the use of our locator system.
Firstly, ISO 13485 will be used, which is a standard for working with quality management system.
Secondly, there are some standards of product level that will be used: ISO 14971 is a standard used for application and risk management and IEC 62366-1:2015 specifies a process for the manufacturer 42.
The intended use of our device is according to the data, supplied by the manufacturer on the labeling in the instructions. The intended use of our device is to administer a GMO based treatment for diseases with high mucus production.
For the intended use of this device, we have used a failure mode and effects analysis (FMEA) to identify the risks and their consequences, as well as an action plan that can be used in case a risk occur. For the development of this FMEA, we have used the guidelines provided by the European Medicines Agency 43.
For the genetically engineered bacteria, the product would need to follow special regulation for a recombinant Live Biotherapeutic Product (LBP). The current regulations for recombinant LBP leave different grey zones that are key for the successful introduction of a product with these characteristics into the market. Because of this, we have developed a policy that we hope can start the discussion over this subject.
If you want to read our policy please go here!
For our product, the specific steps to follow would be to assess Human Safety, Environmental Safety and risk assessment for the recombinant LBP of our choice.
In terms of human safety, for a LBP the policy recommends:
- identification of the genus and species of the probiotic strain by using a combination of phenotypic and genotypic tests as clinical evidence suggesting that the health benefits of probiotics may be strain specific
- in vitro and in vivo testing to delineate the mechanism of the probiotic effect, the safety and the efficacy
- substantiation of the clinical health benefit of probiotic agents with human trials
- patterns of antimicrobial drug resistance
- metabolic activities
- adverse effects noted in humans during clinical trials and after marketing
- toxin production and hemolytic potential if the probiotic strain is known to possess those properties
- lack of infectivity in model organisms 44
Additionally, in order to certify human safety, as a recombinant LBP, different extra measurements are regarded:
- Conduct a proper risk-benefit ratio where the benefit of using a specific solution should be large enough to exceed the risk of not taking any action.
- Conduct Laboratory toxicology studies including 28-day repeated-dose toxicology studies in two species, in vitro and in vivo genotoxicity tests, safety pharmacology, and reproductive toxicity assessment.
- Develop and validate a sophisticated bio-containment strategy limiting the growth of LBP to defined environments. A three-layered strategy has previously been described which holds promise but still needs to further be improved.
This sophisticated biocontainment strategy should be properly designed ensuring human and environmental safety.
In terms of risk assessment, different characteristics should be analyzed:
- Dose and frequency of use
- Short-term and especially long-term effects
- Interactions with other substances (including alcohol and medicaments)
- Individual characteristics
- Characteristics of the social environment45
A Failure Mode Effects Analysis (FMEA) is recommended in order to analyze all the factors considered before 46.
Once in vivo studies in different model organisms have been performed, clinical research would be the final step to execute before final assessment of the recombinant LBP. Clinical trials must be extremely well structured and regulated and the profiles of the individuals taking part in the trials should be well assessed and documented.
The drug part of the product would need to follow the International Conference on Harmonisation (ICH) standards of quality, safety, efficacy and multidisciplinary through preclinical studies and clinical trials. Inside the preclinical studies, the drug would have to go through preclinical Drug Metabolism and Pharmacokinetics, safety, pharmacological and toxicological studies. With all these results from preclinical trials, information about the drug substance and product, purity, risk/benefit ratio in other species, there would be enough information for us to prove safety in animals and initiate a Clinical Trial Application (CTA, EU) or Investigational New Drug (IND, US) before starting clinical trials.
During the different phases of the clinical trials, the efficacy, dosage and commercial claims of the drug will be tested. After clinical trials, all the data from preclinical and clinical, would comprise a common technical document for a market access application (MAA, EU) or a New Drug Application (NDA, US). After the market access has been granted, the drug would need to go through Post Market Surveillance, proving safety and effectiveness in a larger scale 47 48
Throughout the process, Good Manufacturing Practices and Good Laboratory Practices should be assured, for further description visit the ethics part of this wiki.
Our strategy to obtain regulatory approval would be to focus on the use of the drug for the treatment of one specific disease, cystic fibrosis. Cystic fibrosis is considered an orphan disease, as it affects less than 0,075% of the population in the US and 0,05% in the rest of the world, a requirement for a disease to be considered as an orphan one. To gain orphan drug designation, a drug needs to have a significant benefit for an orphan disease without a satisfactory current treatment. The designation as an orphan drug would help in the expenses before market approval of the product 49. For European regulation, there would not be a need to pay protocolar assistance fee, nor the application fee for market authorization application, and our product would gain 10 years of market exclusivity, that could be extended for two more years of market exclusivity if it is approved for pediatric use. After that, we would go for market approval for the rest of the targeted diseases.
For more information visit the guidances for drug development of the FDA and EMA.
When developing our regulatory strategy we counted with the invaluable support from Katarina Mercer, a Senior Advisor for Clinical Development & Regulatory Affairs at Scandinavian Development Services. With her help, we were able to identify the possibility of achieving approval for the use of our product in an orphan disease, cystic fibrosis, before targeting any other diseases, as the requirements and investment needed for this approval for specific use would be much lower than for any other diseases. Katarina also helped us confirm that our product would be considered a combinational product between a device, a drug, and a Live Biotherapeutic Organism.
Ethics
What is it?
An ethical analysis tries to describe the most common questions and concerns a product may raise in the society and to search for a way to understand and implement them into the developed structure.
Summary
Like every other research project that may have a clinical application, our product may raise different ethical questions. Because of this, throughout the process of discovery and development, it must comply with different ethical principles. This includes Good Laboratory Practices (GLP), general research ethics, Good Manufacturing Practices (GMP), Good Clinical Practice (GCP) and the Basic Principles of Medical Ethics.
All these ethical principles make sure that the rights, safety, and well-being of the patient prevail in the development of the product. This entails that the quality of the product the patient is taking is optimal, that data generated in the testing parts of the development are true and valid and that throughout the development process, the principles of autonomy, justice, beneficence and nonmaleficence and the privacy and confidentiality of the subjects are always respected 50 51 52 53.
For a detailed description of what these practices entail and the measurements made during the development of a project from bench to market, please visit the ethics part of our Policy for the regulation of Live Biotherapeutic Organisms inside the human body.
Click here to access our policy.
In the past, the use of GMOs has raised different debates inside the population. Because of this, our product will not be except from an initial skepticism and criticism. A dialogue, where both parties commit to understanding both visions and public education in the subject would need to be executed when the technology is in development, and before any product like this is ready to reach a market.
We have particularly found really interesting an article published by Science in August 2017 that shows that people want to be involved in a public discussion about these topics, that two-thirds of Americans approve of editing human DNA to treat disease and that the opinions the public has vary a lot based on their religious beliefs and how much they know about these subjects54.
This article, and the survey performed to obtain its data proves our ideas of the need to educate the public, bring different opinions to the table and dialogue.
For the discussion of the different ethical concerns our project may raise and the creation of our Policy for the regulation of Live Biotherapeutic Products inside the human body (see our integrated human practices) we counted with the support from Erik Forsse. Erik has worked for more than 20 years with administration in higher education and research and within research policy. He has been the secretary of the European Forum of National Ethics Councils and also has experience as an expert by the Commission for ethics review of research proposals.
In this picture, we can see Amanda and Sonia discussing ethics and education with Erik.
For the development of the ethics strategy, we also counted with the support of Marko Ahteensuu, a Docent in Practical Philosophy, Doctor of Social Sciences from the Technical Research Centre of Finland, a Collegium Researcher at the Turku Institute for Advanced Studies (TIAS) and a Research Integrity Adviser at University of Turku.
Marko Ahteensuu, counselor for our ethics strategy.
Reimbursement and Health Economics
What is it?
A reimbursement and health economics analysis is used to determine whether or not the existing healthcare payment infrastructure will accommodate a new solution to the clinical need it solves.
Summary
The solution we have developed targets the alleviation of diseases with excessive mucus production and has a better outcome than the existing solutions. Currently, there is not a cure that fully targets this need, and therefore, there is a great necessity for a treatment to help the patients in having a normal life with the disease, which makes the possibility for a product like this to reimbursed high.
In order to estimate if the product would get reimbursed by public authorities, we would need to have determined its risk-benefit ratio and quality-adjusted life year (QALY) measure. If the benefits of using this technology are heavier than the potential risks it may raise, and the QALY measure is big enough, the product may be adopted for public healthcare reimbursement.
Word list
Alleviation: Making suffering, deficiency, or a problem less severe.
Quality-adjusted life year (QALY): A measure of disease burden, quantifying the health effect of a medical intervention or a prevention program that helps payers allocate healthcare resources.
In order to be able to target a relevant market early in the process, we established a solution that would be suitable for the alleviation of diseases with excessive mucus production and have a better outcome than the existing solutions. Currently, there is not a cure that fully targets this need, and therefore, there is a great necessity for a treatment to help the patients in having a normal life with the disease55.
As previously discussed, there are different disadvantages over the use of the current solutions. These include drugs that target only subpopulations of the disease, time-consuming drug administration, time-consuming breathing techniques exercises for the elimination of mucus, need for education and training or a need for very specialized trainers in the area, that are costly. On the other hand, the current solutions have different positive aspects as well. For example, their mode of action has been well researched and is well known, the doctors and other healthcare personnel is well trained to prescribe it and there is a big amount of information covering the use of combinations of these treatments in patients.
Our solution proposes a revolutionary change to the treatment of these diseases. The main advantages over the current solutions we can foresee are:
- An increase in the quality of life of the patient, that would need less hours to move the mucus out of the lungs, allowing them to have a more active role in society.
- A decrease in the economic burden these diseases put on the society. With the use of the product, the patients would be able to increase their productivity and have full-time jobs. The patients would not need to visit as many times the doctor’s office and their education in breathing techniques would be shorter and more effective, liberating pressures on the professionals working in the field.
- A lack of need from new training for physicians, nurses and physical therapists. Since the product uses the same technology as the widely spread nebulizers, support and opinion of the healthcare personnel is expected to be positive.
Nevertheless, the developed product brings different concerns, for example, there is no practice that can certainly predict if the product will be well adopted by patients and healthcare personnel, as the know-how is a very important variable in this industry. The product raises new questions with regards to measuring safety and effectiveness by regulatory authorities and about how the reimbursement codes should be assigned by different countries, having different reimbursement systems. Even if the product is able to successfully break down mucus, it may need from the use in combination with bronchodilators and from training in effective elimination from the lungs.
The product does not provide a cure for any of the diseases, or potentially increases the number of years a patient will live with the diseases, but makes the disease more bearable and increases the quality of the disease.
The successful introduction of the product in a market and its reimbursement by public authorities would be therefore determined by a study of the risk-benefit ratio and of the quality-adjusted life year (QALY) measure.
We have extensively spoken about the different benefits this technology can bring to healthcare and about some of the risks it may create. In order to overcome the weight of these risks and have a well-structured plan in case of failure, well built Risk Management Systems should be implemented.
For example, one of the risks the product may create is if the genetically modified bacteria got stuck before reaching the targeted area in the lungs. In this case, an opportunistic infection could be a possible adverse effect, which exists even in the current probiotics. The bacteria would need to be cleared by the cilia in the respiratory tract caused by an immune reaction. In order to prevent this, the developed product must have a kill switch (in our case chemical induced mechanism) which will ensure the death whereas does not have a negative impact on the lung.
The QALY is able to provide a currency that allows comparisons between different disease areas and the cost-effectiveness of any treatment by combining the effects of health interventions on mortality and morbidity into a single index. The calculation is simple, the number of QALYs gained is obtained by multiplying the change in utility value induced by the treatment is multiplied and the duration of the treatment effect .
If the benefits of using this technology are heavier than the potential risks it may raise, and the QALY measure is big enough, the product may be adopted for public healthcare reimbursement.
For the reimbursement and health economics part of our product development we had the guidance and support of Patrik Hidefjäll. Patrik holds a PhD in innovation management and is currently working for the Swedish National Board of Health and Welfare. With his help, we were able to understand the structure of the decision making in the Swedish healthcare systems and the requirements for adoption and reimbursement by public healthcare.
In this picture, we can see Patrik having a relaxed discussion with Amanda and Sonia.
Business model
What is it?
A business model broadly refers to how an offering is defined and the way it will generate revenue and deliver value to customers.
Summary
Word list
Customer interface: The place where an organization meets its customers
Value proposition: An innovation, service, or feature intended to make a company or product attractive to customers.
Key activities: The most important tasks a company must carry out in order to fulfill its business purpose
Key resources: The most important assets needed to make a business model work, such as physical, financial, intellectual, or human resources.
Customer segments: The practice of dividing a customer base into groups of individuals that are similar in specific ways relevant to marketing, such as age, gender, interests and spending habits.
Cost revenue: The total cost incurred to obtain a sale and the cost of the goods or services sold
Revenue streams: The amount of money that it receives from selling a particular product or service.
The most used way for a company to illustrate how its business is built is the business model. According to Chesbrough & Rosenbloom 59a business model is:
“a framework that takes technological characteristics and potentials of the company as inputs, and converts them through customers and markets into economic outputs.”
In 2009, the concept of the business model canvas was developed by Osterwalder and Pigneur. The business model canvas was created as a visual template for the strategic management of a company’s business model, that allows the sketch of new or existing business models 60.
The business model canvas is built around four pillars: customer interface, value proposition, financial pillar, infrastructure management and uses nine interdependent elements: key partners, key activities, key resources, value proposition, customer relations, channels, customer segments, cost revenue and revenue streams 61.
The pharmaceutical industry has been built around the blockbuster model, where the structure of pharmaceutical companies is fully integrated, with every step in the value creation process kept in-house. For the success of the development of our product and taking into account that iGEM Stockholm would be a small company with not enough core competences to fully develop a pharmaceutical product, we have decided to build our business model to be a disintegrated one, basing our business by focusing on becoming specialists on a specific part of the value creation process, for a specific disease and creating a networking and partnerships with companies specialised in other core competences, for developing joint business projects.
For this part of the product development process, we counted with the support from Gustav Notander, our finance advisor and Technology Transfer Manager at KTH Innovation. Gustav was involved from the beginning in the development of our project and we are very grateful for Gustav’s help with our product development structure and how to execute our work.
On this picture you can see Gustav together with Amanda and Sonia, working on PROlung’s Business Model Canvas.
Conclusion and future steps
We in iGEM Stockholm 2017 believe that our project PROlung and lung probiotics are the future, and we aim to be the pioneers in this field. To be able to do so, we spent over six months conducting a detailed product development research, in the spirit of entrepreneurship, including and analyzing all aspects in to ensure PROlung has a place and purpose on the market.
In this search we always kept the final customer of our product in our minds, taking into account their concerns and opinions at all times. In the end were able to characterize what makes our product have the competitive advantage over the rest and to draw the path that our product would need to go through if it was ever to be developed.
If we took the decision to develop this product further, the next steps to follow we would be to file a provisional patent application and start contacting regulatory authorities. These two movements would assure that our product would be able to take a leading position in the market if it had regulatory approval.
Once enough data about pharmacokinetics and toxicology was collected, trials in animals could start, and if animal safety was proven, the next step would be to apply for an Investigational New Drug Exemption in order to conduct clinical trials with our product.
Only if these trials are successful, reimbursement strategies and business models would need to be taken into consideration. In the end, once regulatory approval is taking its lasts trials before being granted, a specific marketing plan would need to be developed for this product. As any other therapeutic product, during this stage patient groups, doctors would need to be targeted in order to make market entry successful and start having a return on the investment made.
