Trials with Maya Z

Maya: Hello everyone! Welcome again to Trials with Maya Z. Today I have a very special guest with a very special topic. First, let me present Martin Krauss, the CEO of FGK Research and the president of the German Association of Clinical Research Organizations. Martin, thank you very much for joining me.

If you want to say a little bit more about yourself [00:01:00] first.

Martin: Yeah. Thank you very much, Maya. It is really a pleasure to be here. I'm more than 25 years in the clinical research already. By background from a long time ago, I'm a statistician. I founded my own company in 2002, and in 2017 I became also the President, as you said, of the chairman of the CRO Association.

So I'm very well connected also in the CRO industry and in clinical research overall and I like what I'm doing and it's really exciting and always with challenges. And today we are talking about a real challenge with CT R Cities. That will be fascinating, I guess. Yeah.

Maya: Yeah, absolutely. You're absolutely right. Today the topic is something that many people are expecting. Let me tell everyone the story behind why I invited you precisely. We work with a lot of clinical research organizations and pharmaceutical companies and biotech companies, and since the [00:02:00] new CTIS that was launched last year. We started getting all these questions - what do we do now,can you give us a little bit more insights, etc. And then one day one of my colleagues came to me and said, "Hey, Maya, I know you're doing this podcast and have the perfect guest for you."

And I was like, "Okay. Who?" And she said, "You should definitely speak with Martin Krauss because they are a key opinion leader regarding the CTIS. Check their white papers and all the things that they're writing out there. And that's when I actually saw on LinkedIn how much you actually speak about the CTIS for our guests, let's first explain what CTIS means.

Actually, the CTIS is the essence for the clinical trial information system. It's new system across all European countries, actually. Countries within the European Union mainly. It has a great goal to [00:03:00] unify the submission, all the processes around clinical trials, but because it's also very new, there are a lot of questions and challenges right now, and I'm so happy to see companies like yours who speak loud about.

Take these challenges and about the solutions that you've discovered one way or another. And I'm very happy that today you're going to give us more from the kitchen, so to say, your perspective on how can we handle the CTIS. And I have a few questions to start with, Martin.

Again, from your perspective, did the CTIS manage really to prove its concept of producing the submission timelines to increase the transparency and centralization because what the CTIS really tries to achieve is have one place, one submission place for all countries. So was this achieved?

Martin: Yeah, so there are several questions perhaps, I would like at least to start at [00:04:00] the channel idea of a creator of harmonization across Europe - it is definitely the right approach and CTR, the clinical trial regulation and, I would say technical software solution to handle that as the clinical trial information system is definitely a possibility to get it done.

But there are obstacles and then you're talking about reduce and submission timelines. I'm not sure whether this is really achieved and whether this is really the most important topic to achieve. We have with the recent report on CDIs performance, and there are so-called key performance indicators, a report from the EMA from the European Medicines Agency.

It's an average timeline of around 90 calendar days. This is not too far away from what we have seen before under the old legislation and this is not, does it look like a clear reduction of timelines? [00:05:00] And as I said, maybe this is not the most important part. You need to have a reasonable revenue.

You need time of it. We will talk later on perhaps as well, difficulties for sponsors and CROs to handle so-called request for information in a certain small timeframe. And then, on the other hand, it really depends on the type of the study. If you have a mono national study, many authorities have reduced timelines. So this is perhaps okay in how it has been resolved.

Maya: I just wanted to ask you - if we have to start first with the biggest strengths of this new system, which are these top strengths that the new system represents to all of us? Which are these pluses that the new system represents to all of us from the clinical research ecosystem. What are these [00:06:00] positive sides of the system?

Martin: The positive sides are definitely in a real international trial. You are getting one consistent study protocol over all countries and, in principle, with one submission, you can cover up to 30 countries. It's the European economic area that's covered. And, this is an important clinical research area and you can cover it with one submission.

Definitely an advantage you get through the system. Finally, then you can start the trial in every country you have submitted, or you have included in your submission immediately at the same time. And in a consistent protocol, this is good for a consistent clinical research informative.

We had different versions of study protocols over the different [00:07:00] countries and difficulties to analyze them, to handle them, to make that consistent. And so this is definitely a blast. And as I said from the very beginning, harmonization across Europe is an important topic and that's the right idea behind say this word.

Maya: So what are the weaknesses then? So what haven't we done right yet?

Martin: Right. Yeah. You mentioned in a question about that - transparency. So, in principle, transparency is a good thing and the patients are eager to know key information about the study. They are participating and perhaps also the society is interested. However, what has been done is that this transparency is going far beyond and making it much too complex.

So, in principle, it's a little bit. Some of the information needs to be made public only after seven years. And at that [00:08:00] time any real secret is still in the documents. But as a result, I think that every sponsor thinks that, "Oh yeah, transparency. I don't want it to get published already, even if it's only after seven years."

There is a certain bad gut feeling. And this is something which is bad because we don't want to decrease the number of clinical trials in Europe in this territory, but it doesn't make it more attractive with these transparency rules that make everything very complicated. Also, to save, say, data protection issues, to save personal data, you redact documents, you have to upload many documents in a double version, one not redacted for the authorities, and one redacted for the public.

And this is very cumbersome and this could have been done better, and I think we need to think [00:09:00] about it, how we can make it, again, more efficient.

Maya: Okay. And what about, I know my colleague was very eager to understand more about these first red signs so to say. We're speaking about the errors that you can get. So when you're submitting your documents that we need to, basically, the submission needs to be pulled back and then initiated from the very beginning.

And then there is also a limit on the number of substantial modifications that you can do. So these are some red flags reported January, 2023. So has this been already improved in one way or is it still the case?

Martin: At the very beginning, some applications were rejected because they were invalid. There had been former deficiencies and difficulties, and of course, still up to now one of the hurdles is that for the formal deficiencies, you have [00:10:00] only 10 calendar days time to resolve it as a sponsor and for content deficiencies - only 12 calendar days. And if you miss it, then you have to do it anew. You pull back, you initiate from the very beginning. And that's not the best approach, indeed. And the clinical trial information system is the only communication platform.

In former days, you pick up the phone because there were some deficiencies that you don't understand correctly or what's difficult, and then you ask "What do you expect?" And then you get an answer and then you could answer it in a correct way. Now, it's much more difficult. That's one of the, the obstacles about the limitation of substantial modifications.

That's only partly true. This is true for one EU member state. If this EU member state would not authorize the substantial modification directly, then, it's different. So, um,

Maya: Mm-hmm.

Martin: [00:11:00] There could be seven or even 12 substantial modifications per year. Perhaps it's too going too far into detail - 7 is for part one, 12 for part two, but this is not a big issue, I would say.

Maya: Hmm, I understand. So, Martin, you're the CEO of a clinical research organization with lots of experience. What does the CTIS mean for you as a CRO?

Martin: Yeah, on the one hand, it means much more work, much more interaction between the sponsor and the CRO at the very beginning. It starts with having the right user account access rights - who is doing what, responsibility list, who is authorized to do what with the user accounts within the CT system.

It's not that easy because all the sponsors are differently organized and also the CROs. And during the process you need to be [00:12:00] organized very efficiently. It's only calendar days, so working over the weekend or even working within a very tight timeline. We are not a global CRO, but I've heard from my colleagues in global CROs that they have set up teams all around the globe to work 24 hours to meet the timelines.

And this is really a difference compared to former days.

Maya: But would it result at the end of the day in a much faster submission, for example?

Martin: Yeah, I would say it should be at least, I mean, you can start once you have approval, you can start in all the European countries you have involved. At the same time, maybe you need a little bit more preparational time. Why is that? On the one hand, you need to collect all the information from all sides, from all countries in advance to separate it once, first and second.

Maybe you would like to prepare even [00:13:00] the study protocol and everything much better just not to get too many deficiency requests or requests for information. It's now called in a deficiency letter where you have only 10 or 12 days to respond, not to start from the very beginning. So if you take this overall, I think, yeah, it could be faster starting at once, but you need to invest something in advance to make that possible.

Maya: Okay, so basically, it's the same timelines more or less, but then you have to restructure your work, more preparation versus then doing more after work. In a way, honestly, I'm listening to this challenge and I'm thinking that probably it's the right thing to do, not just in Europe, but everywhere.

Because preparation can avoid a lot of mistakes down the road. It can avoid repetitive work. It should, actually, the promise should be to have much better communication with their regulatory bodies as well. So, [00:14:00] I know any change actually is a challenge because you're just changing your habits.

You're doing something differently. But the promise of just having one place to submit all your documentation, let's say, is pretty good. What you need to do though is pay the price, which is better preparation. So tell me about the sponsors. Are they now prepared to comply with these new requirements, let's say, what's the impact of the CTIS on the sponsors?

Martin: Yeah, they're definitely prepared. It started quite long ago when they announced CTR is not a new one. I think it was 2014 when it was published. And then over the years there was a lot of trainings, presentations, interactions, sponsors. Large sponsors have started to have their own working groups to be prepared for [00:15:00] the system.

But, I mean, once it started, in principle, then the technical issues are perhaps something you could not foresee. And this has perhaps the largest impact on one hand, the system to handle a user account. On the other hand, the clinical trial information system with all the complexity still box, and difficult workaround.

So, this is something you really could prepare for. And as you know, only if you are really using it, then you are recognizing the difficulties. And so I think for everyone it was a challenge.

Maya: Yeah. And how do you feel on behalf of the support that you're getting from the CTIS team? Were they prepared to support you and cover technical challenges quickly? Are they now improving in a way?

Martin: Yeah, that's a difficult question. We are still not satisfied with the system, so [00:16:00]

Maya: Hmm.

Martin: it still seems to be much too complex if you're looking at the whole development. It was difficult. The IT company that has set it up has been changed during the whole process. You know it, also with your company, if you are setting up, if you are developing software and you are changing even companies, not only teams, then it's very difficult to have a consistent product at the very end. What they have not done the right way is they wanted to do it at once, everything in high complexities instead of starting with core functionality and start from there and add on modules.

And that's really something we are still suffering until today. I would say just some clear words. EMA with [00:17:00] that system is really violating the existing law because in the clinical trial regulation, article 80 about this EU portal, that's the CTIS, it's definitely written. The EU portal shall be technically advanced and user-friendly so as to avoid unnecessary work.

And what they have done, even when they have started, they have already mentioned many bugs that are still in there. They have set up, say, cumbersome, time-consuming workarounds and workarounds are considered to be a resolved issue, and that's not fair because it puts a lot of burden onto sponsors and CROs to handle the whole system, the support.

I mean, principle EMA would like to support, but the personal, the stuff there are just overwhelmed by so many issues that this is [00:18:00] still not satisfying saying these words. It's not impossible. I mean, we need to be fair. It's not terrible, but it could be much better.

Maya: Yeah, and I can imagine, like with every new product, it just takes some time to go through the early versions of this product and recognize which are these inefficiencies that you didn't plan for, you didn't and you couldn't predict. But then you need to have ways to quickly adopt the client's feedback and trying to improve. In words, it sounds simple, but actually it's not that simple. There are whole methodologies around how you build products and how you release MVPs and so on and so forth. But I hope, I really hope that with the time that will get better and we'll get closer to this goal of transparency and simplicity and so on and so forth.

[00:19:00]

Maya: Martin. I also want to ask you another thing about the UK because now the UK is outside of the CTIS. Is that a plus or minus for the UK?

Martin: Yeah, it could be both. I think the brand equity of the United Kingdom as a venue for clinical trials based on the language and the eminence of the investigators, compared to studies in the European Union. Another beneficial feature is that most of the study documents will not be published, talking about transparency, but in real life, the overall approval process for status in the UK needs a lot of work, is complex, also confusing somehow, and [00:20:00] ever-changing. So, at least in the past, they have not achieved being a better place. However, their publication is much better. So, currently, they have a lot of staffing issues and problems in at the MHRA and it takes longer. They are announcing that they will be improving and the advantage is, of course, that they can operate outside the European Union.

So just their own country. But whether they're really getting into first-class environment of clinical trials, we will see. I hardly believe it, but they are promoting it already. And then it will be an interesting place. But, currently, also based on experience, they are not yet there.

So you see even alone.

Maya: Hmm.

Martin: It's not as easy as we have some issues and difficulties [00:21:00] within the European Union. I think that's currently a fair perspective on that. UK could have advantages making it better than the European Union. Whether they really achieve it, we will see.

It will be exciting to see the further development.

Maya: Um, and if we are to speak about, let's say, Europe versus the US, like FDA in general, are we behind or, actually, are we trying to achieve what they have achieved in the past or are we bringing something completely innovative in terms of way of working?

Martin: Yeah, it's always a little bit like everything. What happens in the US is coming sooner or later also to Europe. That's perhaps one of the biggest experiences overall, not only in clinical trials. The US also is a quite expensive place in running clinical trials that might be a disadvantage.

On the other hand, they try to be very innovative and bringing new [00:22:00] developments faster into the clinical research area and we need to keep up with that speed in Europe. That would be a good advice to become even better. But as you know, we have so many key opinion leaders in Europe. We have excellent hospitals, clinics, clinical research universities, much better than in the US.

In the US you have these excellent medical centers, but there are only a few of them and lots of medical centers are not as excellent as the majority in Europe. So it's a big discrepancy here in the US between the good ones and the bad ones. And in Europe it's more equally distributed. So there are good arguments for coming to Europe and that we will compete overall globally in the clinical research area.

Maya: Listening to you about the medical centers in the States, it just reminds me of the rationale behind the diversity and inclusion in clinical trials. I think, for example, that's a big trend right now across [00:23:00] the space. Everyone's thinking, "How can I diversify the patient population that participates in my clinical trial in Europe?" We're less concerned, but because I think, like you said, Martin, our system is quite different also.

An observation on my end is that in the space you have more professional research centers, where in Europe, most of the research centers are also hospitals with normal access to patients. All sorts of patients, right? So I guess everywhere there are pluses and minuses and I guess everywhere we are fighting different fights on how to make it bette. ,I hope we'll find a way to unify it across everywhere, because let's not forget that clinical trials are a global thing.

I call it a global animal.

Martin: It is, it is. And I think that, thinking about it, what others are doing better, what we can do better, that this competition also improves the whole clinical research [00:24:00] globally. And that's what we are doing in our companies as well. We are making clinical research better because we are in competition.

So this is also something to have in mind. Looking at the others, what can we do? What can we improve? And perhaps UK in this regard helps us as well, being a forerunner in some areas where we can also get into. So, let's have an optimistic view finally on the whole topic.

Maya: Um, Martin, any recommendations that you have? To other colleagues from the CRO space, and not just CROs, but also sponsors while working with the CTIS or anything that they should be expecting.

Martin: Yeah, I think very important is that, on the one hand the interaction between sponsors and CROs needs to be very close at the very beginning. So they should be talking to each other, making, right responsibilities, user accounts that I've [00:25:00] mentioned. On the other hand, it's very important to have a very open communication to say, "Look, there will be hiccups just to make it very clear. We will make it until the approval." So there's no doubt about it. The system is not a full disaster, but it's not working as it's expected. So if you are not telling your sponsor the truth that there will be some difficulties and it will be not the fault of the CRO.

It'll be just a matter of fact that it's difficult. Then it's easygoing. So if you do not have these high expectations at the very beginning, you will get through it and then the second one is this - open communications, also these short response timelines for the sponsor, even for small companies.

That's a huge challenge. If you imagine 10 calendar days, I mean, this is nothing. If there is a certain request and you need to think [00:26:00] about what can you, how can you answer it? And you need to approve. Do you have revenue cycles? That's the big challenge. So, this specific part needs to be communicated very clearly.

That's an advice. And then it's a team working effort and then you will get it done, finally.

Maya: Your recommendations now remind me of one of the episode that wes released a few weeks ago with one of the experts within the biotech space. And I asked him about his advice, how you should better work with clinical research organizations because he's usually on the sponsors' side, and he more or less gave the same advice, even though it wasn't related to the CTIS.

So I just want to summarize that because it's, again, super important. Not only because of the CTIS, but in general in life, if you want to have better results, if we want to be more productive together, sponsors and CROs, we need to have a [00:27:00] close interaction, open communication, transparency between each other.

What you said, raising realistic expectations - in this case, the CRO communicating because you come with experience -communicating that there may be some challenges with the CTIS, maybe challenges with other things. On top of my head is the recruitment rates, right? But being transparent and raising realistic expectations so that the sponsor knows what to expect.

And then the third one is finding processes and ways to work together so that you can rely on each other, not only short response time. You mentioned short response time because for the CTIS, this is very important, but across the board I have seen that relying on each other, having processes and tools in place that enable this interaction at the end of the day will make you more productive.

Martin: Absolutely. Maybe I can add when you mentioned that also the preparation of the submission, including the start board call is perhaps important part that [00:28:00] the sponsor also accepts that.CROs usually have a real big experience in doing so and hearing what they are saying regarding the regulatory approach the study design, some topics of that which is important not to fail, say, in the whole process. So good preparation of work. Also interaction with the investigators, perhaps not with all of them, that makes it complicated, but with the most important ones, just to make sure that you have a feasible start protocol that's acceptable to authorities and ethics committees.

I think that's an important preparation of work for both sponsors and CROs.

Maya: Yes. That's very important. Martin, thank you so much for mentioning that. And I hope that in half a year from now or okay, let's say a year from now, we'll have another conversation this time to discuss how much the CTIS got improved and how much positive impact it has on our work, because you are right, Europe [00:29:00] is the second probably region selected for conducting clinical trials after the US, for example. So having better system in place. It's good for the region, it's good for patients, it's good for everyone, for the world and the future of clinical research. Martin, thanks once again for sharing your experience and good luck with your next submissions.

Martin: I hope so too. Yeah. Thank you very much, Maya.