Team:ETH Zurich/Practices/Experts
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Practices - Parts
- About Us
Talking to Experts from various fields
Overview
For the human practices part of our MicroBeacon project, we consulted experts from various fields ranging from ethics, patent/law, and medical doctors to newspapers and the general public. Our aim is to improve the design of our device by determining the societal impact of our circulating tumour cell (CTC) detection device. Our device is able to detect CTCs of various cancer types from blood samples, which we foresee as being an integral part of cancer diagnosis in the future worth investing in.
In this section you will find a brief report of the interviews with:
- Dr.Ralph Schiess, CEO of ProteoMedix, about the business perspective of a detection device.
- Dr. MD Heinz Läubli,from Universitätsspital Basel, about the medical part of our device
- Christina Dittrich, from ETH Transfer, about the patentability of our device.
- Raffael Iturrizaga, from the ETH Ethics Commission, about the ethics of our device
Talk with Dr. Ralph Schiess from ProteoMediX
Learning from experts
For the human practices part of our MicroBeacon project, we consulted experts from various fields ranging from ethics, patent/law, and medical doctors to newspapers and the general public. Our aim is to improve the design of our device by determining the societal impact of our circulating tumour cell (CTC) detection device. Our device is able to detect CTCs of various cancer types from blood samples, which we foresee as being an integral part of cancer diagnosis in the future worth investing in.
To get his views on this issue and to determine if our test can be scaled up to allow it to be deployed at hospitals, we interviewed Dr. Ralph Schiess, whose answers were greatly beneficial in helping us improve the design of MicroBeacon and setting our outlook and business plan. Ralph is the co-founder of ProteoMediX, a company developing a tool for detection of prostate cancer. We also asked him about his company's history and the procedure he went through to found it.
Founding a company
The first phase in commercializing a product is research, demonstrating a proof of principle and the concept, which takes about 3 years. Then, you specify your product precisely and test it extensively, which can take about 5 years and is expensive. Ralph roughly estimated the amount of money we would possibly need to bring our test to the market to be 15 to 25 million Swiss francs, equivalent to $16 to $26 million.
A proof of concept device does not necessarily have to be simple or elegant, it only has to work. Once the validation phase is reached, the product has to be developed to the point that it can be demonstrated on a much larger sample of patients. In the last phase of development, the product takes its final form and applications for a CE certificate and FDA approval are submitted.
FDA and CE
From here, we discussed the procedure for getting approval from the FDA, Swissmedic, and other authorities. Ralph explained that two differing procedures exist, one for Europe and one for the USA.
To commercialize a product in Switzerland you need a CE mark, which is easy to obtain for low risk tests such as ours. A test is defined as being “low risk” if a false negative result carries a low risk for the patient/user. Cancer diagnosis is still low risk, whereas tests for HIV and other infectious diseases pose a high risk. The requirements and workflow to get CE approval are roughly as follows: you have to first present a reliable, reproducible test, then go to a notified body and fill out several forms. When CE approval has been granted, you are allowed to market your product. For the test to be marketable, however, it must undergo clinical testing in addition to the tests required to get CE approval.
In contrast to the CE, the FDA has tighter regulations for diagnostics and showing clinical validation is required. Once FDA approval is granted, however, the test is marketable. In order to get FDA approval and market a test in the USA, in most cases, it is beneficial to incorporate a daughter company in the USA before starting the process. The procedure is also more costly than getting a CE. However, having FDA approval greatly expands your market, so it pays off eventually. Different labels exist for a given diagnostic test according to the stage of development, which includes RUO (research use only), IUO (investigational use only, that means it can only be uses for clinical studies), and IVD (in vitro diagnostic test).
Scale up and industrial production
Ralph also explained to us how it would work if we would like to scale up our project and have it produced industrially. “When you want to get access to the market you could either do it by partnering with one of the big companies to get on their machines. Or you go directly with your own tests.” The procedures for the two paths are slightly different.
Find a clear medical question to answer
Talking about how to sell a test well, Ralph also said that we should think about a clear medical question to answer with our test. For example, the test from ProteoMediX gives a clear answer for prostate cancer and has a defined goal: avoiding unnecessary biopsies. At the moment, with our test, we just check if the patient has CTCs. However, “the doctors will ask, what type of cancer?” For medical doctors, a test is useful only if it has medical consequences (actionable results) such as a more personalized treatment, a better survival rate for the patient, etc. For cancer treatment, “there are now markers needed to differentiate which [type of] chemotherapy, [what] kind of treatment, which drug [to use].”
We then went on to discuss some specific applications of our MicroBeacon product. With MicroBeacon, we will distinguish cancer cells from normal cells from a blood sample. Our system can then be used for two potential applications. The first one would be early diagnosis of cancer. For instance, it was demonstrated that lung cancer is discovered often really late. However, patients often produce CTCs before the cancer can be diagnosed by current methods. Unfortunately, our system in its current state cannot determine if a CTC is from blood, lung, prostate, or any other kind of cancer. Further characterization would require some additional sequencing steps. The second potential application would be for patients in the remission state of a previous cancer. Our system can be included in the routine of periodic cancer screening tests that patients have to undergo. If CTCs are found one or two years before the emergence of metastasis, it would improve the survival rates of those patients. Furthermore, we will already have an idea of where the cancer originally came from and treatment can be better targeted towards the patient.
Answer questions with a test – do not produce more questions
In general, a diagnostic test that leads to further questions should be avoided. “A medical doctor will use a test only if it can answer a very clear question and have an actionable result. If you think about a business idea in diagnostics, your test needs to have a clear, actionable result.” So as a business idea, our MicroBeacon test could be applied in the following way: someone has a localized cancer, the localized cancer gets removed, and while waiting to see if the tumor comes back, our test can be used for monitoring/testing for reccurrence to help initiate early testing and improve the patient's chance of survival.
Many circulating tumour cells vanish when the tumour they originate from is removed. However, some tumour cells can survive up to several years in the blood stream, waiting for a good opportunity to settle and initiate a metastatic tumour. That’s why many people come back to the clinic every year or even more often to do a test. So routine tests are done anyway, but our test would be cheaper than conventional tests.
Sensitivity and Specificity
Ralph later asked us about our test's sensitivity and specificity. Conventional tests are highly sensitive, but not as specific, so you get a higher false positive rate to avoid false negatives. With our approach, ideally, we want very high sensitivity to allow our test to diagnose early. If our test does get deployed at hospitals, it would be developed to sort the target cells, capture the cancerous ones, and then sequence them to determine which mutations they carry. In this context, false positive are acceptable, “because then you find out [if detected positives are true positives] at a later stage”. However, Ralph Schiess suggested that we should try to limit the number of false positives in our design, which is why we decided to include two sequential filtering steps to increase our specificity.
Never lose the business view – elevator pitch
When trying to develop a business plan, when explaining an idea to someone, it is important to never lose the business view of a project; it helps a lot to explain things in an easy understandable way, focus on the really important matters, and shape an idea. “For marketing it is important they can associate a clear idea with your business case, so they remember you. Its good for marketing, but it also helps you to shape your idea. You can get easily lost in writing all the technical aspects.”
Ralph also explained to us the concept of the “elevator pitch”: “you should be able to explain an idea in 90 seconds in an elevator...so you take out really the essentials. It can be like shells: you can always further explain it. The title and first two sentences should be really good!”
Faster, always faster
Answering our question about what he would do differently if he were to found another company, he said: “Nothing. But I would try to make it faster, always faster. If you do it the first time, you try to avoid stuff, to think twice. In the very beginning, it is hard to take the full risk, because you still think about opportunities/your academic career, it all takes time. One could do things quicker. Nevertheless, we avoided a lot of mistakes by doing things properly.”
Talk with Dr. MD Heinz Läubli from Universitätsspital Basel
How useful would it be to have an early detection of metastasis or cancer?
It depends on where the cancer comes from, especially if there is metastasis. The device would be useful if it leads to a better treatment. In patients with a localized tumor we would be able to use systemic therapy, like chemotherapy. Chemotherapy is used when the tumor cells are already disseminated.
Currently there is a device called Cell Search for detecting cancer. Are you using it?
No, we are not using it. In the last 10 years there has been many publications about secreted tumour cells, but it is still not completely standardized and it is not clear whether it is meaningful. You would need to talk with a pathologist about that. In Switzerland it is not used clinically and probably nowhere in the world.
Do you think it will be useful to treat residual illness (such as CTCs) after a treatment in a patient if they are not showing any metastasis?
The treatment would be useful in a biological sense, as it shows presence of residual disease, but to know if it is in a medical sense we need a clinical trial. Some studies have shown that healthy people also present CTCs, and no trial has shown whether it is useful to treat only if CTCs are present. However, if this is proved, it would be very useful to treat the disease while it is still possible.
How do you usually detect cancer? Which stages is it usually found in?
Patients are usually diagnosed during emergency situations: they either come with a pneumonia or another derived problem, or their family doctor sent them. When the patient arrives to oncology department, they have already done a biopsy. This is the best for the patient, as it is less disturbing than being referred immediately to oncology. The stage of detection depends on the screening method and the symptoms. By screening we can detect cancer in early stage. In many cantons the screenings are not covered by the insurance but they are highly recommended. However, this is not possible for all cancers. For instance, for lung cancer there is no screening and many patients come later to the doctor because of their lifestyle (eg. smokers). In these cases we unfortunately cannot help the patient. It depends on the organ and if there symptoms. For example, if there is disturbance of the sight, it is easily detected because the patient will consult immediately the doctor, but for symptoms concerning the intestines, it is harder to diagnose. We have some screening methods for colon cancer and at certain age colonoscopy is recommended.
Do you test the predisposition of the patients to have cancer with DNA tests?
It depends. If we have a woman of 28-30 years old with breast cancer we will certainly do a genetic test for BRCA1 and BRCA2. For a woman with 55-60 years old with no big family history of cancer, no. Currently much is decided with scores of how many relatives with cancer a patient has, and then we decide whether to make the test according to that. Genetic testing has advanced quite quickly, and with next generation sequencing we can do this tests quickly in pathology, so we can see if there is any punctual mutation that we can target in about 40 genes. Now we can detect a 2% of mutated cells from a tumor sample, which is not bad. In the future many more than this 40 genes will be analysed and we have to learn what to do with this information.
What do you think is worse: to have a false positive or a false negative?
Well... (laughs) A false positive can have a big impact on the psychological level and it’s very stressful for the patient, so it depends on the consequence of a positive test. If you can improve the treatment then it’s ok and you can accept the psychological impact. It’s the same with tumor markers, like CA23-29 for breast cancer. There are no trials that show that it’s useful to measure them and they might be stressful for many patients. It is also not nice to say your patient: “look, you have CTC but we don’t know what it means”. We need to do some trials first and also some counseling for the patients with this type of tests.
How many tests do you usually perform before you confirm that a patient has cancer?
Usually with a biopsy and an histology it is sufficient, especially if the pathologist says that there is invasive growth. Then, histochemistry will show the type of cancer. We can do a DNA test to find punctual mutations.
Our device requires of a period of incubation of the blood sample, before introducing it into the chip (4-5h). Do you think it would be possible to implement it in the clinics? Would it require trained staff?
Probably trained staff will be required in the lab. You can go to the hematology department of the hospital where you want to implement the test, as they are the most experienced with blood sample preparation.
Talk with Dr. Christina Dittrich from ETH transfer
Learning from experts
Our device for detecting CTCs in blood samples could, at some point, be very interesting for companies investing in cancer diagnostics. To find out more about whether it is possible to obtain patents for our project, we talked to Dr. Christina Dittrich. We wanted to know about the basics of patent law and the steps required to file a patent.
What is a patent?
The prerequisites for obtaining patent protection are that the invention is useful (industrially applicable), inventive and novel. Therefore, a publication of the results before the patent application date is novelty-destroying. This is the case for our device, since specifics about the device have been published on our project website. Publishing is defined very broadly. Clearly, having data available in a scientific journal or on the internet constitutes publication. However, also if ideas are published in a format that may be highly inaccessible to others, such as a master thesis available only as a hard-copy in a university library, still constitutes a novelty-destroying publication. Christina Dittrich also recommended not publishing anything on social media and to show the invention only to people who are bound to confidentiality (e.g. via a Non-disclosure agreement). In the USA, however, it is still possible to get a patent if an application is filed within one year after disclosure of the invention by the inventors (the so-called grace period). But having the possibility to obtain protection in the US alone because of prior publication, might be detrimental to the commercial success of a product. Especially the development of pharma products needs substantive investment which can only be returned if the product enjoys protection in many countries.
A patent contains various claims describing the invention. During the course of a patent infringement lawsuit, these claims are examined by the judge to determine whether an infringement has taken place.
The cost of a patent application is another important issue. Christina Dittrich noted that the cost of an application depends on whether a patent is desired in Switzerland, the EU, the USA, or worldwide. The drafting and filing of an application would already cost several thousand francs. In the case of something invented by ETH employees, ETH transfer (the technology transfer office of ETH) will evaluate the invention disclosure and jointly with the inventors decide whether a patent application makes sense in this specific case. If the decision is in favor of an application, the costs of the application will be covered by ETH.
How to get a patent?
The timeline for applying for a patent starts with handing in an application to a patent office. Upon filing, the application receives a priority date. The patent office then usually determines if the requirements of patentability are satisfied, meaning that the invention is patentable subject matter, that it is novel, non-obvious for an expert in the area and useful. Within one year after the priority date, it can be decided if patents in other countries should be applied for. When applying within one year after the first patent application, other countries acknowledge the priority date of the first application. However, applying for patents in many different countries is really costly. That is why a special system has been set up: the PCT (Patent Cooperation Treaty) system, which provides a unified procedure for filing patent applications. At present, the PCT has 148 contracting states. Once the initial search is done and the PCT phase is over, the application has to enter a national phase and can only be granted by a national patent office. Having to translate the application at that point and to engage local attorneys for the proceedings in front of the national patent offices increases the costs exponentially. The patent will be published 18 months after the priority date.
Finally, two, five or maybe even ten years later, the patent may be granted or the application rejected. If it is granted, it is valid for 20 years starting from the filing date.
What if somebody copies the idea while it is waiting for a patent?
Christina Dittrich explained that if one finds somebody who is commercially using the invention that is subject of a pending patent, the inventor can send a warning letter to the alleged infringer. If the patent is then granted later on, the inventor can ask for damages from the company through legal action retroactively.
Would MicroBeacon have been patentable?
When we asked which part of our project would have had the most potential for receiving a patent, she suggested patenting the whole device. For our MicroBeacon coli test, we could have claimed a patent on the whole genetic circuit or the method of cancer cell detection by the engineered bacterium. It would have been advisable to provide a step-by-step description of the method which is specific enough to be patentable, but general enough to not allow for slight variations on the idea to lead to circumvention solutions. In general, our whole project or parts of it would most probably have been patentable.
We also wondered if it was possible to patent microorganisms, as there has been quite a lot of polemics on this topic. According to Dr. Dittrich, for engineered microorganisms as the ones in our project it has not been difficult to obtain protection so far, as long as they fulfill the criteria of novelty, inventiveness and usefulness.
Who gets ownership of the patent?
iGEM is a team project, and as such, this idea belongs to the whole team and not to a single individual. When several people develop an idea together and want to patent it at ETH Zurich, an invention disclosure is filed. All the people who contributed towards the invention are listed as inventors in the patent. Any income from licensing will initially be used to cover the costs of patenting and marketing, any remaining income will be distributed as follows: one third goes to the ETH, one third to the professor's lab, and the remaining third is divided amongst the inventors. ETH Zurich owns the inventions made in the scope of an employment at ETH. However, students’ inventions belong to the students themselves because they do not have an employment contract. In the case of an employed co-inventor (e.g. a supervisor), both parties are joint owners. However, the students may transfer their rights to ETH Zurich and will then be supported and participate in any income on the same basis as ETH employees.
When the ETH owns a patent and a company wants to commercialize the technology, then the company must negotiate a license from ETH. So if somebody starts an ETH spin-off and wants to use a patent owned by the ETH, they also have to negotiate a license contract with ETH.