Challenges and Trials: Conducting Clinical Trials with Adaptive Design on an International Stage

Mukesh Kumar, President of the Global Alliances of Indian Biomedical Professionals, joins Pharma IQ to discuss important insights on conducting adaptive trials in global settings.

Pharma IQ: Adaptive clinical trials are becoming increasingly common. However, conducting a trial with adaptive design poses unique challenges when conducted in an international setting. There are complex regulatory, logistical, financial and project management issues that exist from multinational trials. Can you give us, first, an overview of the potential risks and benefits of including sites in emerging regions in adaptive clinical trials?

Mukesh Kumar: Well, you know, emerging regions are very promising with regards to recruitment. People can finish trials relatively faster because they can recruit patients very fast, but adaptive trials, because they need adjustments while the trial is ongoing, leads to regulatory and practical issues when you are including multinational sites, not just emerging regions, but any regions.

The reason is regulatory approvals in emerging regions particularly, and I mean India, China, South America, Eastern Europe, most of these approvals are based on how many patients you are going to recruit, and how many sites you are going to initiate, and if you are not sure at the beginning of your trial how many patients or how many sites you might have, the regulators might come back with queries and might find it hard to approve a trial with a fluid number of patients and sites.

So that’s the first regulatory hurdle. Then of course, when you do trials, there are several logistical issues that you have to plan for, things like how much drugs do we share, how many people do we hire to manage your trial, how many times you need to do investigative meetings and so on, and all those get affected when you don't really know how much of the drug you need. For example, if you are shipping a drug to India, you have to know the correct amount of drug that you are going to ship into India, and every time you do, it takes several months to get the process in play. So, it becomes logistically hard to do.

So, the benefit is that you can obviously do trials faster, but the risks are that there are some regulatory and logistical issues that you have to plan for. It just needs more planning. It is doable and people have been doing it, it just needs more planning.

Pharma IQ: Okay, so the timing is the key. Can you give us a brief overview and comparison of the differences in planning and executing adaptive clinical trials say in India, China or countries in Eastern Europe?

Mukesh Kumar: Yes, I think the critical point of including these countries in your trial is number one, you have to, I mean adaptive trials need to be prospectively planned in the first place. So, you do have a good idea about what are the logistical issues that you have to address. Like how many sites do you need to be activated, to be initiated, how much drug you need to ship, and in general, any supplies.

You know, many times, almost all the time, trials would have lab suppliers that they have to send most of the time, for multinational trials the lab could be located in one of those countries. So, let’s say the lab is in the US and it has to send supplies to India and China – it takes a long time, not just for the drug to get there. I mean, of course it takes some time, but more importantly there are logistical issues such as clearance from customs, getting them to sites, individual sites, and managing those supplies. Those are the kinds of things that you need to plan much better.

So logistics I think, in short, logistics is a bigger issue when including emerging countries. Once the logistics are taken care of, it becomes relatively easy to execute. So planning would mostly include, you can’t have too many variables. So either you plan for the number of patients and an out and out amount of drug for the number of sites, but if you do too many variables, it becomes more and more logistically hard to manage those trials.

So, always my tip or advice to companies is that they should try to plan in such a way that they can predict much better how much of each of the logistical issues they would need to address when including any of these countries. Once those are addressed, everything else becomes easier.

Pharma IQ: I see, and are there any issues with regard to acceptance of adaptive trial design by regulators in the emerging regions?

Mukesh Kumar: Emerging regions, I mean India, China and Eastern Europe and most of these, and South America for that matter, do not have any regulations per se for adaptive trials. They do not have any guidance documents. They do not have anything anywhere in any of the communiqué that came out of the regulators, risk of, in favour or against adaptive trials.

Most of these regions, the regulatory affairs are very new. The clinical trial industry is very new in most of these countries, so they are not very experienced in conducting specialised clinical trials, like adaptive trials. Most of these places, the regulators look at US and Europe for guidance, and if the US FDA and EMA have approved a trial, they would be very comfortable allowing that trial in their country.

If the trial is done only in those countries and it is not supervised by the FDA or EMA, then it becomes very hard to get approvals because they don’t understand the designs and they don’t like those designs because they haven't done many of those. So, if you have approvals, and actually, when I do trials, adaptive trials in emerging regions, I always like to do them under an IND with the FDA or an IMPD with the EMA, and that makes my life a lot easier to get it approved in those countries.

Pharma IQ: What are some regulator strategies involved in ensuring acceptance of adaptive trials?

Mukesh Kumar: As I said, I mean having it approved by well recognised regulators, the US FDA is very well respected in most of these, in pretty much all these countries, and actually, US FDA is very involved in training and collaborating with almost all these regulators. So, if it is approved by US FDA, it certainly, you know, helps you. Similarly EMA, EMA of course, you know, it is not as well organised as the FDA, I would say, simply because there are several trials that don’t need to go to EMA, and sometimes many of the trials are done under regional authorities.

So, from a regulatory strategy perspective, I would suggest getting an FDA IND in place and then going for approval. Do it in a consequential manner. An approval from FDA would be the best strategy you can have, to get an approval from these local regions.

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Intreview conducted by Amber Scorah.