Check the forecast: supply challenges

March 2013 saw what was possibly the largest clinical trial ever conducted in India, its headline-grabbing scope designed to have as much impact as possible on an urgent matter of public policy. Published in The Lancet, the finished project involved two million pre-school children and was intended to test the effectiveness of two treatments: the impact of Vitamin A on mortality rates and the effect of intestinal de-worming on a child's nutrition, growth and cognitive development.

It served as a radical example of a pre-existing upwards trend: clinical trials are increasing in scope and complexity. This improves the reliability and effectiveness of a study, but it also brings to light new issues where logistics are concerned. Making sure everything runs smoothly at every stage of a massive international drug trial across several borders and involving thousands of patients is not easy.

Supply chain management comes with a range of tricky challenges. For one, demand is changeable, and trials are costly and unpredictable. And when the lives of large numbers of patients relying on the successful completion of a drug could be at stake, as well as potentially millions of dollars in investment, there's a lot of pressure to avoid delays and keep the process working well.

Companies have other concerns, too, and guaranteeing sufficient time for supply forecasting and the sourcing of comparator products - as well as making sure that compliance is all above board - is crucial. Even guaranteeing that every patient involved is adequately supplied with the drug they're meant to be testing is an unimaginably complex challenge.

At the forefront of new technology and developments in the industry are David Gilliland and his team at Daiichi Sankyo. He and his colleagues serve as the firm's main hub for clinical project management and deal with the majority of global studies.

Key responsibilities include making sure that the supply team is kept up-to-date on research, making critical decisions and changing plans, ensuring that proper standard operating procedures are in place, covering issues such as interactive voice response system (IVRS) or interactive web response systems (IWRS) capabilities, and labelling processes.

Cross-pollination and tracking software

The trend towards larger and more complex trials has meant a whole range of new managerial and structural challenges in day-to-day work. A major impact of the increase in the size and scope of studies, Gilliland argues, is that the strategy behind package designs and submissions becomes even more critical, requiring much more cross-functional input and the assembly very early on of a study team to identify where there might be interruptions to the supply chain.

He says that his work increasingly revolves around a more collaborative and multi-disciplinary group discussion as opposed to tasks being carried out in isolation from each other.

"You need to identify first of all the countries you're going into and the hurdles that each country has, because different countries have their own regulations," he says. "We know they're subject to change too."

This divergent regulatory environment, Gilliland says, increases the importance of the study design, and the impact of patient kit design and distribution strategy.

"Nowadays, it's become much more critical that the team works more collaboratively," he says. "The timeline still needs to be hit, so we're trying to do more complex studies but in a shorter timeframe. We were doing lesser studies in the past. So that's the challenge and it's one that I'm quite happy to take on."

This "cross-pollination", as Gilliland calls it, is a new way of working for many pharmaceutical companies and there isn't one perfect solution - different companies are at contrasting stages in the development of the most effective process to meet their circumstances.

"I don't think you can get the optimal process but you can strive towards it," he says. "You need a very well-structured project team at the start, one that is cross functional because I think this is going to pull all the different functions together more effectively.

"The team approach is going to become more critical downstream, and the technologies we're looking at need to work on a cross-functional basis - not just on one area."

Central to making sure companies can keep an eye on developments in a drug trial is the use of effective tracking and clinical trial management software, and as these operations become more complex and multifaceted, the right kit, Gilliland argues, is all the more important. Biologicals and oncology drugs, increasingly popular in the current climate, are products where GPS technology, for example, could be used to make sure they are being transported correctly.

"If you're dealing with something that's refrigerated or even frozen, and you've got it in shipping going out to a depot, it would make perfect sense to be able to track it, to make sure it's within the required storage temperatures," he says. "But I'm open to other discussions about using technology in another way; for instance, we could track the dispensing into the patient to make sure we've got the right kit at the right time.

"But what that should not do is take away the onus on the sponsor to make sure that the optimal packaging is in place to ensure it doesn't go out of specification," he adds.

There are, of course, a range of issues that can bring about change to the way a supply chain is being managed. Gilliland argues that a decision - such as the wish to have a particular visit schedule for patients, for example - made down the chain can have an impact on the design of the kit, or the IVRS, and that good management is crucial to making sure that this does not disrupt the process.

IVRS/IWRS is all-important as an essential way of managing the large amounts of information that a trial generates. Callers respond to questions about their study and their answers are logged into an easily accessible database, so professionals can quickly react to changes in clinical supply.

"The turnaround time for a booklet label can obviously take a while; you could be talking anywhere from three to six months, depending on the number of countries," he says. "So that is a significant timeline."

Dispensing and study drugs

From Gilliland's perspective, another critical supply chain issue is patient dispensing requirements. He doesn't believe it should take more than a month, which can be difficult to achieve when critically ill patients are involved. However, he argues that it's a target he strives for and consistently meets.

"When you're running global clinical trials, updating the expiry date can become a real challenge - because of the timeline issues you gain, you have to go through a whole process and this can impact the IVRS quite a bit," he says.

"It also impacts the cross dialogue we need to have with the other functions, particularly the regulatory departments."

It all ties into a key aspect of supply chain management, one that gets more difficult as trials get bigger: the need to consistently provide patients with the study drug. When he began work at Daiichi Sankyo, Gilliland committed to ensuring that patients would not be without them, and so far he has kept that promise within the studies he's been controlling.

"From a CSO perspective, I've taken a very clear approach on the forecast for the study, the resupply strategy for the study, the expiry dating needs to be taken into account, any blinding of comparators, and the process for that and associated stability needs to be taken into account," he says.

This is critical because of the importance of controlling the cost of materials in distribution, and if the study does meet the recruitment requirements it can adjust the forecast production demand in order to not waste drugs.

But it's also vital for the patients and the study they're involved with.

"I can react to a fast recruitment situation and ensure that they get their drug in time - and I'm not compromising the safety of the patients," he says. "It's a fine balance, but I think it's something we're extremely good at."

This is why demand forecasting is key and Gilliland argues that, within the regulations, there should be a supply strategy in place for any study to ensure - as much as possible - that patients will not go without study drugs.

"It's key to making sure that shipments going out to the site should compensate for the randomisation process," he says. "This means that if you have two patients walking in on the same day, you have to have the study drug to ensure that those patients are able to get it. The set-up is critically important."

"At Daiichi Sankyo, we do require that our clinical teams provide us with an updated forecast on a regular basis. I don't need that to be 100% accurate; I'm not expecting that. But what I do is build in enough strategy in the process as the study progresses, so I can still react to it."

Putting himself in the patient's shoes is fundamental, as is thinking about whether the packaging is convenient and practical, and rendering it as optimal a process as possible. When this is done properly, Gilliland argues, the study usually takes care of itself.

"If you've got patients that comply, and you've got sites that find it very easy to dispense the product and provide instructions for them, that's a key component of making sure that a study is going to be a compliant study, at the end of the day," he says.

"I think a lot of companies are so eager to get stuff out the door as quickly as possible, that I think it's often not with maybe the most compliant packaging - and that can ruin a study very easily."

Gilliland has witnessed a lot of changes since his early days working in the clinical trials business. In the early 1990s, he says, the biggest studies involved at most 1,000 patients in two countries, used single panel labels and worked without the use of IVRS/IWRS. The most recent innovation is use in those days, he says, was the laptop computer.

"As time has moved on the studies have gotten much larger," he says.

"We finished off a large study last year, for example, which involved 21,000 patients across about 54 countries. When you get into things like that it becomes a lot more complex."