Clinical Trial Supply Case Study: Ricardo Lima - Bial
Ahead of the Clinical Trial Supply Europe Conference on 21-23 January in Frankfurt Germany, we interviewed Ricardo Lima, Head of Pharmaceutical Development at Bial Research & Development. He spoke to us about the challenges Bial face in regard to compliance, emerging markets and forecasting.
Gerald Clarke: Ricardo, in the smaller biotech company, what are the specific challenges in clinical trial supply?
Ricardo Lima: Well, Gerald, as you probably know, Bial is not specifically a biotech company; we work, basically, with small molecules. However, I consider ourselves as being a small molecule development company and the challenges that we currently face in our clinical trial supply are mainly driven by the clinical trials themselves. So, when you move from phase to phase, of course, you find a great amount of logistics issue in your clinical supply area and those clinical supply logistics issues, I think, are more or less aligned with others that companies such as biotech may have.
Of course, if you think, for instance, in the clinical trials, nowadays, being completely international, multinational, you also start thinking on different countries with different policies, which, of course, tends to make things a bit difficult. Sometimes lengthier, for instance, if you think, in Latin America. Sometimes it’s complex, for instance, if you think, in Asia, or in even emerging markets. So, I think for clinical trial supply today, the great difficulties or, at least, challenges that we are facing are really related to how can you get your truck inside specific countries with quality.
Clarke: Would you say or do you think that Bial’s approach differs with regard to clinical trial supply, when contrasted with larger companies?
Lima: I think, we do because we must. We are small and being a small company brings a lot of additional challenges, but as well, advantages. If you think, in a small company we’ve limited teams that outsources a lot of work. You need to have more control and oversight as you don’t have a very large team looking at every specific different topics. You have a small team that needs to control the whole process and by the whole process, I’m referring to getting the drug manufactured, getting the drug packed, getting the drug labelled, and, of course, then taking care of the logistics.
Also, when you think about the determination of the needs for the clinical trial itself, it’s also a bit more challenging, because small companies may be limited also on budget and, that triggers another issue; you want to run your clinical trial with a higher level of quality, but you still need to very tightly control your budget. Of course, it’s easy for everyone to understand that the house budget for R&D, despite being considerable, as we all know, for clinical trial development and for clinical trial supplies, budgets are always critical and considerable. But if you compare these with a Novartis or Pfizer budget for a clinical trial, of course, things may be different because we are talking about different dimensions.
So, we need to go with the same approach and with the same level of quality but taking a bit more control over everything that is being done and cost control is one of our main concerns. Again, let me take the example of the clinical trials phase 3, for instance, that go multinational; it is not difficult if you don’t have a very tight control since the beginning. It is not difficult for things to get a bit out of control because here and there you will need more patience. Here and there, you will need more medication. Here and there, you will have issues getting the medication inside certain countries and, of course, if you’re dealing with CMOs, that always represents an increase of cost and that’s exactly why you need to have a credit control and oversight. You should be able to foresee exactly where you are going because you may find yourself in a situation where you have to stop just because you don’t have the best background or you did not create the best background to proceed.
Clarke: What is Bial’s approach, with regard to comparators and comparator sourcing in clinical trial supply?
Lima: We started working with comparators in clinical trials some time ago. And, of course, this is mainly driven by the type of clinical trials that you are running. If you are running a head-to-head comparison or you are having a non-inferiority study, of course, you will need a comparator there. In the past we used different approaches formulating the comparators. For instance, we started by using double whammy studies. We all know that a double whammy approach is not the best one, especially for the patients, but also for the logistics of the clinical trial supply itself because it adds work. It also adds new formulations and new developments to the project. But, at the end of the day, for the sake of the patients, you wouldn’t want the patient to take more medication than what is really needed and, of course, the double whammy approach forces the patient to do it.
So, currently, our approach, regarding the comparator use is to follow standardised processes to get blinding guaranteed. Because we’re working with different CROs and CMOs, regarding phase 3 and between brackets, let me just add that we mainly work with comparators in phase 3 clinical trials. We rely on our CMOs and CROs to source these comparators and from time to time, we have issues sourcing these comparators. So, you also need to have backup times here and again, let me just go back your previous question and here is again, where your oversight is really necessary and you need to have control over everything. If you have a campaign that is planned for a two or three-month timeframe and you face yourself with the shortage of your comparator and the provider cannot guarantee that they will provide the comparator on time, then you may have an issue. So, it’s always important to have the backup times in place and ready to go, even if that represents going to the direct market—forget the wholesalers, forget the manufacturers—go directly to the market and try to source as best as you can, the comparator you will need.
Currently, with the CMOs and CROs that we work with, regarding the comparator sourcing, I must say that we did not have a great number of issues sorting these comparators. Mostly, these CMOs and CROs have direct contacts and contracts with big wholesalers that, according to plans and forecasts, can easily provide those comparators to us and to them. But in some cases, also, a good relationship and, eventually, contract with the primary manufacturer may also be very important; and let me just give two examples that basically result in the same outcome: we had two situations where we moved from buying the comparator from the wholesaler directly to the primary manufacturer and we start buying bulk and that represented two things.
The first one was a saving in the cost of the global products and the second one, was a saving in the tax that the CMO was running for us. Why? Because when you buy a comparator and the comparator comes packed, then you two extra steps because at the CMO or the TRO, they need to unpack the product, they need to de-blister or de-bottle the product so that they can start working on blinding and final packaging for your clinical trial. If you have your product as bulk, then you have a two-way saving and that’s something that we are always looking for.
Clarke: So, how important is forecasting in clinical trial supply for your company?
Lima: As I mentioned, very important, and I gave you two examples already, so the forecasting for our product, our drug, but also the forecasting for other drugs that you may need to use. So, when we think and for us, working in clinical trial supply, this is a reality. This cannot be seen as a one-man show, because it’s not. Forecasting for clinical trials cannot be seen as a responsibility for the clinical supply team. Some people continue playing that game but, to be honest, this is something that must result from a deep and intense discussion between, at least, the clinical trial supply team and, of course, clinical ops; they know the clinical study. It’s our reality here in Bial: we participate actively in the design of the clinical study. We participate actively in the revision of core documents, such as the clinical trial protocol, so we have a good insight on what’s going to happen in the clinical study.
Of course, there are some variances, not only in the beginning, but also during the course of the clinical study, that only clinical ops can control and operate and, of course, this information is critical; so relevant for us to forecast properly. We need to have a great understanding of the clinical study that we are running, but more than that, we need to have a great understanding on how it is going to run. And what changes will we need to include in the clinical study during its course? So here, the discussions between the two teams are really, really relevant and that’s exactly what we do, for some time now, here internally at Bial: We sit together. We discuss how is this running and how will this run?
So, forecasts are forecasts – we all know that. But forecasts in the beginning of the study must be based on also an enrolment forecast. Not only an enrolment forecast, but also on a global amount for a certain period of time in a clinical trial that you think you need to be covered for, otherwise, the study will not run or will not start as quick as you could expect and, don’t get me wrong, we also had issues in the past where you go theoretically, you base your forecasts on your pure theoretical assumptions and a couple of months after, you are looking to what you really have in your sights, in your depots and the first thinking that you have is shortage: that’s the worst thing that can happen in a clinical trial environment. When it may not be a reality, but, at least, you think that you may face a shortage on medication.
So, forecasting is extremely important, not only in the beginning of the study, but also throughout the study. We all know studies change. Studies are so volatile. We need to have a flexibility that sometimes goes beyond what we are used to. Again, taking the example I gave you before, because more patients need to go, because the drop-out rate is extreme and patients are still using the medication that you gave them because of the complexity, because of the amounts; and another point that is very, very important when you think about clinical trial supplies is that we are always looking forward. So, basically, we are looking to the patient, to the patient needs, but we need to take a look back as well and think API. For you to manufacture a drug, you need your API. So, you need to have your right amounts in-house.
Availability of slots: for you to get your drug manufactured, the ones who are manufacturing your drug need to have the right slot available so that you can have your drug ready to go to the CRO, to the CMO, to the packager on time. Availability of slots when the CMO and CRO need to pack and label and we all know that these companies, these outsource companies do not work with one, two or three clients; they work with several. So, from time to time, to get real flexibility is difficult and we also need to find against this and, of course, properly forecasting is extremely important.
To close down this topic, let me just tell you one thing: again, forecasting is forecasting. So, I’m not saying that even if you forecast properly and you have a clear, clear understanding of your needs, things may not change and you may not face yourself in a situation where you need to quickly, with a lot of flexibility, revise everything that you have done. And, of course, again, here this is the teamwork. The worst thing that we can think is forecasting as a one-man show task, because it’s not.
Clarke: So, you were mentioning earlier about the difficulties of operating multinationally. Are Bial running any trials in emerging markets? And what are the specific challenges of operating in these countries?
Lima: Yes. Bial is, in fact, running clinical trials in emerging markets. Several of our clinical trials have sites in emerging markets and, I think that, currently, it is the approach that most of the companies with R&D and clinical development are following, when it comes to reducing cost and getting more patients back in your clinical development programme; of course, emerging markets are always the good choice and a good opportunity for you to move fast and with less costs. Of course, and you certainly made that clear, of course, that we have some issues, some challenges with those countries. The first one is really the regulations; different and sometimes tight regulations that those countries have and that for us in Europe, but also for the companies in the US, in Asia; we are used to our own regulations, so when it comes to complying with local regulations that sometimes are very difficult to understand or to interpret, that may cause an issue, not only for the clinical trial supply, but also for the approval of the clinical trial itself. I could give you dozens of examples where the situation got really difficult trying to get approval in certain countries. Even in Eastern Europe, we have some countries that are not very easy to deal with; for instance, Russia or the Ukraine are definitely not very easy to deal with. But those countries, once they are approved and start working, for instance, for patient inclusion in the study, those countries move really, really fast.
Another point that is really important to focus on is recording the assessment of compliance because when it comes to getting the data into a file to submit to reg authorities in Europe and the US, we need to make sure that levels of compliance—and we spoke already about quality, not only quality on the drug that are providing, not only quality in our supply chain, but also quality in terms of the clinical data—of course, these assessments of compliance, not only for GMP but also for GCP, must be guaranteed by the sponsor and that’s an extra workload that we have on our side, on the clinical trial supply with audits and making sure that everything on a logistic point of view and sometimes in the manufacturing point of view is fully compliant with European GMP regulations.
But also on the GCP side, with audits to sites and, to be honest, we know that, well, each case is a case, of course, but we know that in these countries, some sites may not be working properly. Of course, the level of control that we need is very tight and that is, of course, very demanding, especially for small companies. When it comes to getting the product inside those countries, from time to time, we also have challenges. And it starts with the importation. Some countries have very tough regulations regarding import and afterwards export and, of course, you need to overcome that. The easiest way that we’ve found at Bial to try to overcome this is to try to get specialised and local people helping us, going through those processes. For instance, Bial is not directly submitting import licenses in some of the countries. We have others doing that for us and, to be honest, the results that we obtain, they are pretty favourable.
So, basically, we spend less time, then our direct interactions are local interactions and, of course, the results are usually very positive. I’m not saying they are quick. Well, some countries may be quick, but most of them are not and, for instance, if you think unlink them, Brazil—the time to get the import licence approved is huge, then the time to get the drug imported is huge and then the time to get the drug released at customs is huge. So, basically, we are summing up time after time after time after time. But still, it’s good that we made the decision to start moving forward with local interactions because that helps a lot in the whole process.
What we saw, especially, in clinical trials over the year is that from time to time we have issues with the transportation because the transportation is so lengthy and then we have these stopovers for customs clearance; we see that in the emerging markets— and this is our example; of course, may not be for other companies—but we see that in most of our shipments to these emerging markets, we face temperature excursions and, of course, we have already a team that has elements from Pharmdev, Clinical Supply, Stability Group, QC. We have these teams ready to reply to those excursions, basing their decisions on the existing data that we have. So, of course, that is always a concern when you have these situations, because you may be in the edge to lose medication and that’s exactly what you don’t want to happen, especially when you’re talking about these countries and the time the process takes overall.
I think that the only point that I would call the attention as a potential challenge: it’s not really a challenge. It’s something that it’s more likely curiosity, if I’m allowed to… because when we started working with these countries, it’s not only these countries that require the existence of local reports; other countries require that as well, but in some of these emerging markets where the local reports are mandatory, by the local regulations, we thought in the beginning that that would be a great advantage because if you think linearly, what’s going to happen? You will have a bulk drug shipment shipped to a local depot. You will have a control over the shipments that you are doing to your local sites and, of course, you have a better control over the medication that you are shipping. Not the depot because that’s a box shipment, but then from the depot to the site. That would mean, basically, that the level of control that you have will allow you to, basically, not save medication, but better control the waste and that was a very, very positive point that we got from the use of local depots.
Unfortunately, the reality is not as linear as we may have thought and when you put together the use of local depots with, for instance, a centralised randomisation where you need to have everything everywhere, then things may not be that easy. On top of this, you may also add the fact that in some countries, and against everything you may think, the shipments may take long and now you ask me, is this because of internal policies? Is this because of the way the depot works? Well, that’s exactly what you, as a sponsor need to control and that’s why we also audit these local depots and try to understand their difficulties, the challenges that they also face, locally. But to be honest, the final conclusion about the use of the depots is that the expectable decrease in drug waste is not as visible as we would expect and desire, of course. I think that the bottom line, Gerald: these are, in fact, the direct challenges that we faced, while working in the emerging market. Not the only ones, of course. We need to bear in mind that the emerging market topic would keep us talking for hours but I would say that the ones that came immediately to my mind are these.
If you would like to find out more about this topic and the Clinical Trial Supply Europe Conference in Frankfurt this January 21st-23rdvisit us at www.clinicalsupplyeurope.com
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