Category: general

Last Mile in clinical trials

The last mile in clinical trials

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The last mile – this is what logistic service providers are afraid of: nightmare, black box, problem are just some of the words with which it is described. At the same time, the last mile is of immense importance. If medication gets ineffective on this last transport, all effort before is in vain.

In large refrigerated containers, the medication is sent to the depots close to the clinical trial site. There, the shipping is broken down into many small-volume units. These are being packaged for dispatch to the clinic, the pharmacy, for shipping directly to the patient or to a home trial support service.

Excursus: Direct to patient delivery in clinical trials takes place only in a few federal states in Germany. Many local health authorities regard the blinding as being in danger. In other countries, such as the US, Spain or France, however, direct to patient deliveries are already in place. Thus, one hopes to attract more subjects for clinical trials, which do not drop out of the study prematurely. Treatment at home without frequent doctor’s visits could be an incentive.

Data logging & last mile

To the depot the path of the medication, the temperature curve, humidity, etc. is well documented. New technical developments make tracking possible even during flights. Due to loggers placed at several points of the pallet, in the different packing layers, temperature deviations and deviations of humidity during transport do not go unnoticed. The last mile, however, is relatively poorly documented:

  • No geolocation tracking: Trackers would be too expensive in regard of the numerous individual packages.
  • Cost-intensive temperature loggers, which record the temperature curve, are rarely used. More common are loggers, which solely provide information whether the temperature has been exceeded.

The use of cost-intensive tracking technology is not worthwhile also because the transport boxes are often not returned by their recipients to the logistic service providers. The passive transport boxes are partly disposed of after single use, whether they are made of reusable material or actual disposable boxes. This also is due to the mostly poor visual appearance of passive transport boxes. If the logistics service provider does not become active and prompts the addressees to return the boxes or pick them up again, the fate of many boxes is sealed. An unnecessary burden on the environment.

In the future: even more last mile

It is apparent that transports on the last mile will increase. This is due to the trend towards direct to patient deliveries. Currently, at least in Germany, this is usually still within the range of treatment with so-called orphan drugs – medicines for rare diseases. In other countries, this trend has already developed further. So it is only a matter of time, when more medicine is being distributed directly to the patient here.

Logistics service providers will have an even larger number of transport boxes in circulation in the future. These must be small, flexible, safe, reliable and cost-effective in their use.

With Nelumbox pro we develop the solution for this.

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Passive coolers, Nachteile passive Kühlboxen

Passive coolers for temperature-sensitive medication

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On their last stage to the study site, temperature-sensitive clinical trial material is mostly transported in passive coolers. Passive coolers are equipped with cold packs or cooling pads to keep the cargo cool during transportation. Before that, they were transported from one country to another in large, actively cooled containers, passed several national borders and crossed various climatic zones. In the logistics hubs they are then prepared in small volumes for transport on the last mile.

Passive coolers: disposable and reusable

For the transport on the last mile, passive cooling boxes are currently most frequently used. Depending on the quality, they are one-way or reusable coolers. The latter means that they last for a maximum of 5-7 transportation cycles before they have to be disposed of. They are usually tampered with by the transports, so that they no longer a presentable to a customer. The difficulty of the reusable boxes is furthermore that, due to the appearance of the boxes, the addressees are not always aware of the fact that they it is a reusable cooler. This is why many people throw it away, even though they could still be used.

Both disposable and reusable passive coolers must be prepared in advance in order to ensure refrigeration for transport. The recharge time for the cold packs is 12 to 72 hours depending on the cooling requirements. An adhoc transport is thus not possible.

The passive coolers are done … what now?

In the case of disposable coolers, one and a half tonnes of garbage are thrown away for 1 liter of transported goods. In the case of cartons, which are equipped with cold packs, the former are relatively easy to dispose of. However, if transport boxes are made of polystyrene or similar material, disposal is costly. Polystyrene is made of petroleum with a high energy consumption and can be disposed of only with difficulty in the landfills, since high combustion temperatures are necessary for this material. In terms of environmental compatibility, the material is critical, since toxic gases are produced during combustion.

The costs

There are many manufacturers of such boxes and the list prices for these vary greatly. From 300 € for a disposable cooler up to almost 2000 € for a reusable one everything is represented. This is why the limited lifetime of these passive cooling solutions comes as a high cost factor. The cost of the necessary equipment ads to the purchase or rental costs of the coolers. In clinical trials monitoring temperature, humidity and location plays an increasingly important role (see Temperature logger). Sponsors and logistics service providers have a great interest in closely monitoring the transport of temperature-sensitive and high-priced freight. Disposable temperature loggers cost an additional € 40 – only for temperature measurement. If more data is to be tracked, this price increases quickly by several hundred euros.

As a conclusion, passive coolers are useful for cost reasons where the freight is of little value or the return of the boxes is difficult. This is not the case for logistics in clinical trials.

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Temperaturlogger, temperature logger

Real time temperature logger in clinical trial logistics

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We live in times, data logging has become so commonplace that we hardly think about it. Our smartphone tracks where we are, how long we are at that place, it detects motion and thus gives way to what we are doing. These are just some of the data that are being logged – and partly by our own doing. Never before have our lives been so well documented.

Temperature logger yesterday and today

Against this background, it comes as a surprise that data logging in the supply change of temperature-sensitive clinical trial material worth thousands of Euro seems almost antediluvian: A temperature logger is attached to the shipping, which measures at regular intervals. When the shipping reaches its destination, the temperature curve is sent as a PDF document to the sponsor and the Clinical Research Organization. At best, because there are even more complicated ways to do so. By USB stick for instance. On the stick, the temperature data is stored and must be transferred manually to the computer. A temperature logger version “traffic light” is also quite common: It shows only by means of a light, whether the shipment is fine – green light. It lights up red when the shipment has exceeded or fallen below the required temperature range during transportation.

The big disadvantage of these options is that it can only be determined upon arrival of the shipment if the clinical trial material is applicable. If that is not the case, replacement needs to be ordered, which leads to delays in the trial process. USB loggers are cumbersome because clinical trial sites require high safety standards for any foreign hardware. To plug in a USB stick to a computer, is not as easy as it might seem.

Tomorrow: Real Time Temperature Logger

Live tracking of temperature provides the advantage to know in real time whether the clinical trial material can be used upon arrival or not. This info alone helps little, because what can one do if the clinical trial material is just on its way across the Atlantic? But what if the temperature logger communicates in real time with an IRT platform[1] that automatically reorders material as the study material leaves a certain temperature range for a certain time span? From manufacturer to clinical trial site on to the subjects, the temperature could be fully documented this way.

Apart from the temperature and other data such as humidity, shock and motion, GPS[2] coordinates, the remaining battery level of the logger and the light (to detect when the box is opened) could be transferred live to the IRT platform. The latter could then set the appropriate process in motion: Reorder clinical trial material, coordinate the shipments, coordinate clinical trial sites etc. This is not a farfetched future scenario. Already data can be transmitted live. Where it still falls short, is the communication with the IRT platform.

Seamless tracking of sensitive clinical trial material is relevant also because clinical trials are becoming increasingly complex. Many parties are involved and so the medicine passes through many hands before reaching the subjects. These many interfaces represent a high risk to the integrity of the study medicine. To guarantee this, the GDP-directive provides for the complete recording of temperature data from beginning to end of the supply chain to be indispensable. It is just a matter of time before this directive, which is more of a guideline today, becomes binding. At least then real time tracking will be used extensively in the conduct of clinical trials.

[1] Interactive Response Technology

[2]Good Distribution Practice

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aktive Kühlbox, active cooler

Active Cooler: How does it work?

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One question that pops up from time to time when we present the Nelumbox is: You are developing a cooling solution for medicine and samples? Is not there something to do that already? Our answer to that: Yes and no.

Passive Cooler: problems

Currently, mostly passive cooling systems are used where we see the Nelumbox in use: in the transportation of small volumes, on the so-called last mile. These passive coolers operate in most cases with cool packs. Cool packs need min. 70 hours to be prepared in advance, meaning to be cooled down, in order to maintain the temperature of 2-8 ° C over a certain period of time. In addition, passive cooling systems have a very limited lifespan. Even so-called reusable boxes last for a maximum of 7 uses and must then be disposed. This is problematic since thus large amounts of waste are being produced. The impact on the environment is severe and costs are high for proper disposal. Logistic service providers are aware of the problem and are searching for potential solutions.

Active cooler

We want to face the above mentioned problems with an active solution. Active means that the cooler requires power for cooling – at least for a while. Then the integrated battery has enough power to operate for 48 hours autonomy without electricity. Electricity or the battery within Nelumbox drive a Peltier element. The Peltier element transports, spoken somewhat simplified, the heat from inside the cooling chamber, which contains the medicine or medical sample, outside. Since the Peltier element cannot keep running all the time – battery life without electricity would be considerably reduced – the cooling phases occur in intervals.

If the Peltier element is not in operation, the heat would flow back into the cooling chamber. This is prevented by using the patent-pending Smart Isolation Technology. A temperature sensor inside the cooling chamber, activates the Peltier element as soon as a certain temperature threshold is exceeded. With this technology, Nelumbox can be used more often than conventional passive coolers, since the battery lasts for many charge cycles. This saves money and benefits the environment. Nelumbox also cools immediately and does not have to be prepared in advance: plug it into the socket and the box runs. Thus, it is very flexible in its application.

So yes, for the transport of medicines and medical samples, there are already coolers, but they leave much to be desired. An active cooler, which can prevent heat return current through the Peltier element is therefore a novelty indeed.

 

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Logistics in Clinical Studies: Challenges

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The logistics behind providing clinical trial material is an enormous challenge in some respects. The top 2 challenges are the highly sensitive goods themselves and the complex supply chain.

  1. Highly sensitive, expensive drugs

 In the early stages I and II of clinical trials a drug or vaccine is only tested on few subjects. In addition, the drug/vaccine is not yet produced in large quantities. This is why the integrity of the clinical trial material and the integrity of blood or tissue samples is of uttermost importance. Only that allows a reliable statement on the mode of action and compatibility of a drug or a vaccine. Only given the integrity is confirmed a clinical trial can enter into phase III.

That alone sets high quality and safety standards on logistics. In addition, however, more and more temperature sensitive active agents enter clinical trials worldwide. So-called biopharmaceuticals provide a large future market, as we have already reported elsewhere: In Germany alone in 2015 30 % of newly approved drugs were biopharmaceuticals compared to only 18 % in 2012. The rise in clinical development candidates from 256 in 2005 to 626 by the end of 2015, suggests that the companies continue to invest heavily in these innovative products. Especially in the field of immunology, oncology and metabolic diseases research is driven forward. For the logistics of clinical trials, this means that the cooling must be guaranteed without any gaps from the manufacturer to the subjects. Given the already complex supply chain, across multiple national borders, the cooling provides an additional major challenge.

  1. Complex, global logistics

By the time the clinical trial material reaches the subject, it has already come a long way and has passed through numerous hands: from the manufacturer, it is taken to depots by large scale logistic services. These interim storage facilities are located in different places all over the world. The ongoing internationalization of clinical trials makes interim storage facilities on various continents indispensable. The logistics company Marken has 10 depots worldwide, World Courier 14. Besides the sites in the US and Europe, locations in the Middle East, Africa and Asia are highly important.

Densitiy of Clinical Trials Worldwide, Quelle: Brizzey
Densitiy of Clinical Trials Worldwide, Quelle: Brizzey

From this interim storage, clinical trial material is then shipped in smaller quantities by logistic services to the hospital that performs the clinical trial. This is predominantly done by passive cooling boxes. These provide long cooling, but demand lots of repackaging in order to tackle the problem of humidity. Thus passive cooling systems produce an lot of waste which is a severe environmental issue. Active cooling boxes can solve that problem. Once the clinical trial material reaches the clinic, the investigator in charge gives the test drug or the vaccine to the subject.

Excursus: „Direct to Patient“

According to a spokesman of Marken, a future trend is the direct delivery of the medicine or vaccine to the subject, evading the clinic. The direct delivery to the subject is a means to counter the dwindling number of participants and the high dropout rates. A direct supply reduces annoying hospital visits and increases the subject´s comfort. In many countries, as in the US, France, Spain or Italy this is already common practice.

In Germany, the direct supply of subjects is only allowed in some federal states, while in others, the health authorities are still sceptical. It is clear that the boundary between the supply of patients in clinical studies and the direct delivery of patients with drugs in general is getting more and more blurry. This gets particularly obvious in the course of the direct patient supply with so-called orphan drugs. Drugs against rare diseases. In medium term, the supply chain may continue well up to the patient.

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Big Data in der Medizin

Big Data in clinical trials = Big Health?

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It was just a little side notice: The pharmaceutical company Sanofi and Verily Life Sciences, belonging to the Big Data giant Google, form a joint venture called Onduo. Together they will support patients with type 2 diabetes in taking the medication timely, adequately and they will raise the patients´ awareness for healthy behavior. How exactly they want to achieve that, the published press release does not tell.

Google and Big Data

This joint venture is not the first undertaking of Verily Life Sciences. 2014, the company was working on a contact lens that would measure blood sugar levels via the eye fluid. In 2015 that very company developed a medical identification bracelet to measure heart rate, skin temperature and sunlight. It is clear that it is about data, about Big Data, where Google is involved. And Google is getting ready to become a major player in the health sector too.

The data sea

Big Data in the medical field is a current, but not a new phenomenon. While Germany is in a slumber concerning this issue, the move towards Big „Health“ Data in other countries is well underway. It has been recognized that in the medical field, a large amount of data is obtained: Personal patient data, disease history, family medical history, medical reports, medical expenses, data that may be incurred by technical equipment in the course of a treatment, such as by MRI, blood tests, X-ray, but also self-imposed health data e.g by means of health apps.

Fishing in the sea of data

The analysis of these heterogeneous data sets can reveal previously unknown relationships. What factors favor the emergence of a disease? Who is predominantly affected? What prevention measures are effective? Which therapy is promising for which group of people? At the same time costs can be reduced in the health sector: health insurance can compare courses of treatment for the same symptoms and prevent possible misdiagnosis. Likewise, doctors can decide on therapies based on similar illnesses, hospitals could improve their bed planning. Costly clinical trials could be superfluous.

Dr. Altman and Dr. Tatonetti from Stanford University found out – solely on the basis of data analysis -that the antidepressant Paxil and the cholesterol-lowering drug Pravastatin taken in parallel lead to an increase in blood sugar levels.

For information on risks and side-effects ask …?

These are the advantages of Big „Health“ Data. According to data protectionists however there are significant risks too. Medical data is highly sensitive information, which is not intended for foreign eyes. A 100 percent protection of this data cannot be guaranteed since systems can be hacked and sensitive information could get into the wrong hands. Then the question arises, for which aim all the data collected will be used. The fact escapes in many cases, contrary to German data protection law, the knowledge of the data donor. Lastly one must always be aware of the fact that Big Data is only about correlations, not about causal relation. Big Data cannot substitute scientific evidence.

A glance in the future

In Germany, merging medical data will remain difficult for the time being. The federal structure of health services and the low cross-linking of health actors such as doctors, health insurances, hospitals, corporate health services etc. make practical implementation hard. However, there are first initiatives to make data accessible for largescale analysis. So it is a question of time before the Big ( Health ) Data wave spills over to Germany.

Perhaps we could use the remaining time to prepare concrete measures on how to benefit from the advantages of Big ( Health ) Data without throwing privacy overboard. Here a look at our Swiss neighbors might be interesting. There, the project MIDATA was launched some time ago. It is a nonprofit organization that allows citizens, on a voluntary basis to store their data and to decide for themselves whom they give access to their data and for what purposes. The aim is to end the digital feudalism and to promote a self-determined data handling.

 

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Biosimilars

Biosimilars – same, but different

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In the US today the biosimilar Erelzi was approved by the Food and Drug Administration. That comes as a little surprise, because Erelzi is only the second biosimilar, which makes it to the US pharmaceutical market. In autumn 2015, the first biotech drug was approved in the US. In Europe, biosimilars have already been in use since 2006.

Enbrel gets competition

Erelzi by the pharmaceutical company Novartis is a generic product, a so-called biosimilar, of Enbrel produced by Amgen. Enbrel is based on the active agent etanercept which is used in the treatment of rheumatic diseases and psoriasis. The active agent is a genetically engineered protein, a so-called biological. It is produced in genetically modified cells of the Chinese dwarf hamster in vitrio.

Biologicals – highly effective mimosa

Biologicals have clear advantages over conventional pharmaceuticals: They are very similar to the body’s own proteins and are therefore decomposed more easily. In addition, there are no adverse drug interactions and biologicals can target diseases very purposefully, since highly specific antibodies can be produced by genetic engineering. However, they are highly sensitive to temperature changes. They must be stored and transported at 2-8 °C so that the biological is not damaged and thus ineffective. For pharmaceutical logistics this is a major challenge.

Biosimilars – generics of the future?

The production process of biologicals is complex and time-consuming because mammalian cells are expensive, difficult to cultivate and grow very slowly. In addition, the yield of produced proteins is very low. This is why the drugs go over the counter for enormous sums. A set of Enbrel pre-filled pen injections costs about 5.200 €.

Therefore it is not surprising that the market of high-priced Biologicals is interesting for generics. But: It is impossible to copy biologicals. Generics in the traditional sense will not exist for biologicals. They are too complex in respect of their active agent. The conventional pharmaceutical aspirin consists of only 21 atoms. Its structure is thus easy to copy. With 20,000 atoms of a complex biologicals it will be difficult.

Future market: biosimilars

Before biosimilars are to hit the market, they must undergo a trial program that confirms the comparability to the reference product. The European Medicines Agency has approved about 20 biosimilars since 2006 and many more are currently undergoing various test phases. In the long term biosimilars could ensure a healthy competition on the biopharma market. A market with enormous growth potential: In 2014 biotech products account for around 44 percent of global sales of the top 100 pharmaceutical drugs. 2020, the proportion will be more than twice as high.

 

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Diabetes Insulin

On vacation with Diabetes – a challenge

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In Germany, approximately 400,000 people suffer from type 1 diabetes (diabetes mellitus). Several times a day they have to inject the vital hormone insulin that their body can no longer produce. Insulin has the task of transporting the sugar captured through food from the blood into the body cells. These need the sugar in order to produce energy. If the body does not produce insulin, the sugar accumulates in the blood. This can damage organs, nerves and blood vessels.

Life with diabetes type 1

Johanna, 24 years old from Munich, has diabetes type 1 for 17 years. She was 7 when the autoimmune disease was diagnosed. Since then she has lived in the circle of measuring blood glucose and injecting insulin. A large incision into life and even more so during adolescence. While others try out things and start giving their lives their own rules, for Johanna it was about meticulously noting down every bit of food and drink, regularly measuring blood glucose and injecting insulin.

What was it like when you were diagnosed with diabetes?

I had to grow up at once, always keep an eye on my body. Everything was linked to clear rules and I had to learn a lot. What makes insulin in my body? Why do I need it on a regular basis? How should I inject it? When should I inject? How should I deal with the insulin? For example, I initially had Levemir as long-acting insulin and Liprolog as a short -acting insulin. Both were to be kept not above 25 ° C. Therefore, I have always kept in the refrigerator. But you have to watch out where you exactly put it there. It may, for example, never be put to the rear of the refrigerator because it can freeze and hence get ineffective.

And how did you keep it on the road?

I always had a small bag in which I kept my meter and my syringes. That was not really a problem. It was difficult, however, during long trips, for example to Tuscany. 10 hours without air conditioning in a car! My mom kept a close eye that the insulin was always cool. We always had a cooler with ice packs. But back then the insulin was also much more sensitive. It was still obtained from the pancreas of cattle and pigs. Today, insulin is produced chemically and is therefore more robust.

Was there some critical situation?

Once on holiday, we spent a day at the beach and when I wanted to give me my insulin injection, the syringe was totally hot. It may well be that the insulin was ineffective, but I can only guess. After that, my blood sugar was very high, but I can indeed have miscalculated with the food. You do not know when the insulin is ineffective, you cannot see it.

When do you go on holidays and what do you do with your insulin?

I probably go to Vienna next week. Some weeks ago I switched to an insulin pump. The insulin in there must not fall below body temperature. So that should not be a problem. But if I want to go on a beach holiday, I must ensure that I only stay in the sun not longer than 2 hours. Still you can get a bit of a tan.

Then have nice holidays and thanks for your time!

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Impfstoff, Zika, vaccine

Vaccine Zika – first human tests

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Nearly the Olympics had been canceled due to the rampant Zika virus in Central and South America – now vaccine undergoes first testings on humans.

In June this year the Summer Olympics in Rio de Janeiro stood for a short time on the brink. The Zika virus rapidly spread in Brazil, among other countries in South and Central America. An expert council consisting of 150 international scientists and physicians strongly recommended that the Olympic Games should be postponed due to the Zika epidemic. Meanwhile, scientists were feverishly searching for a vaccine.

Zika virus: symptoms

The Zika virus is transmitted primarily by mosquitoes of the Aedes aegypti type to humans. In rare cases, one can also be infected by the virus via unprotected sexual intercourse with infected people. With individuals that have a normal physical constitution, the virus can lead to symptoms such as rash, joint pain or fever. After one week, the symptoms gradually start to cease. The virus is particularly risky for pregnant women. It is proven that the virus leads to cranial malformations in newborns. In El Salvador women are therefore recommended to refrain from a pregnancy until 2018.

Zika virus: vaccine

In February this year, the World Health Organization (WHO) declared a global health emergency due to the Zika epidemic. Two laboratories were subsequently charged with the development of a vaccine against the Zika virus. The two laboratories, one at the University of Texas the other at the Institute Evandro Chagas in the northern Brazilian state of Pará, since then have done extensive research. Basis of the research were existing vaccines against related virus species, such as the dengue or West Nile fever. 3 different vaccinations were researched:

  • a DNA-based vaccination
  • a vaccination based on genetically modified viruses
  • live attenuated vaccination

The vaccines are currently tested with 80 volunteers in the US. For a vaccine this is an impressive speed. Yet, it is not clear when exactly the vaccine will enter the market.

Live vaccine

Live vaccines are used against yellow fever, rubella, measles, mumps, typhoid or cholera. Their mechanism is based on attenuated viruses, which are introduced into the human body multiply there and are active for a long time. As a result, a long-lasting immune response is being triggered. Once vaccinated with a live vaccine, one has a long-lasting effect. Live vaccines must always be transported and stored at a temperature between 2-8 ° C, otherwise the proteins the virus consists of, denature and cause no longer cause no immune response. For this reason, they must be transported via cold chain. Especially in the hot, partly tropical climate of Central and South America this is a huge challenge.

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Thorsten Schäfer-Gümbel bei Nelumbox

Thorsten Schäfer-Gümbel at Nelumbox

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The famous summer slump is the time, politicians like to go on summer tour in order to fill the former with positive messages about themselves. Thorsten Schäfer-Gümbel, deputy SPD party chairman and faction and regional chairman of the Hessian SPD, uses his tour to get to know the startup scene more closely. He makes a stop-over in our Darmstadt office.

Stop-over: Nelumbox

It is 12:00. The whole twelve-man entourage of television crews and journalists who accompany Thorsten Schäfer-Gümbel on his current tour of the Hessian startup scene, arrive in our 4-person office at the Technology Innovation Centre, Darmstadt. For Thorsten Schäfer-Gümbel we are already his 3rd date on this day.

For one hour he takes his time to get to know our project. One hour to get to know why we are enthusiastic to found a startup and to learn what challenges we face.

Founder mentality in Germany

As the chat touches on the differences between founding mentalities in Germany and the famous Silicon Valley, Thorsten Schäfer-Gümbel pulls out his notebook. He dislikes the much-quoted phrase “culture of failure “, Germany is supposedly missing according to many. Rather, he took from his previous visits, that there is no failure, but only valuable mistakes from which one can learn. If only this perspective would prevail in Germany, the start-up scene here would be very grateful indeed.

Nelumbox on TV

After a few pictures and interviews, our office is getting empty as rapidly as it filled before. Everything a little unreal.
If you missed it yesterday, you found our seven “seconds of fame” on SAT.1 Hessen Live and RTL Hessen.

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