Protected links – safeguarding the supply chain

When Didier Basseras thinks about the best way of managing the supply chain in a clinical trial, he imagines a recent relay race between French and US athletes. On paper, there should have only been one outcome: the American runners were quicker, stronger and far more successful than the other teams on the track. But as the athletes stormed down the home straight on the final leg, it was clear that people's expectations had been wrong.

"Before the race, if you looked at the total ability of the individual performers, the US were a lot better than the French," Basseras, vice-president of clinical supplies at Sanofi says. "But in the end, France won. Why did this happen? It wasn't because of the efficiency of each athlete in the race but because of how the baton was transmitted from one part to another; the key point is the baton transfer."

How does this relate to the clinical trial supply chain? For Basseras, it's simple: over the years, the field has become increasingly complex, meaning efficiency in the supply chain is now more important than ever before.

Rather than focusing on each stage in the journey as an individual area, however, pharmaceutical companies must, according to Basseras, look at the process as a whole, understanding how each part is connected to the other.

"Over the past three or four years, we have moved very quickly and are now facing a number of different challenges," he says. "One is a change in the future of the medicine itself. There will be a lot of bio-products coming out soon and, from an operational point of view, the challenge will be the cold chain. There's also increased complexity around new regulations, which are not always very relevant at the point where operations take place and decisions are made. To perform the processes better and remove complexity, within our company, we try to ensure a better sense of collaboration along the supply chain, to transfer the baton on the most efficient way.

"This starts right at the beginning, at the time when we are coming up with new formulas for new compounds, taking into account how the compounds are going to be dispensed to the patient, who is often a long way away from the lab at the time we are preparing the drug. At the end, you have a patient, and you have to consider how the patient can use the drug in the best way and how robust the cold chain is."

That last stage - at the patient's home or the caregiver's facility - is where things become particularly complicated, according to Basseras. The lives of active patients don't always fit in with the requirement that a drug remains refrigerated and a cold chain unbroken.

"When we are moving a drug across the last mile from the hospital to the patient's home, the cold chain and the refrigerated area are not always so well controlled," Basseras says. "Sometimes, the patient may have to move from their residence to somewhere outside, so we have to ask how do we consider the life of the patient and continue to have a secure dispensation of the drug? This isn't easy given the challenges involved when dealing with bio-compounds, which are increasingly dispensed via the cold chain."

On time and in line

Achieving efficiency across the supply chain and getting packaged drugs sent to investigational sites and, ultimately, to end users, is complicated at the best of times. Everything needs to be on time and in line with the regulatory requirements, often in multiple different territories. Doing this when several different therapeutics have to be accounted for - something Basseras has direct experience of - is even harder.

"There is a lot of complexity when you have multiple drugs within a clinical trial," he says. "First, and perhaps most obvious, is the number of cases where we have to combine our drugs with our competitors. When we're performing clinical trials, it's not easy to get drugs just launched from our competitors. At first, you may try to see whether you could have some kind of gentlemen's agreement with different organisations, but, at the end of the day, we are facing situations where the race between the big labs is very tough and, for business reasons, the collaboration remains a good intention. This situation isn't any better when you have to source placebos for double-blind trials."

So what impact does this lack of collaboration have on clinical trials involving different therapeutics?

"One example is that, in most cases, competitors are not providing their drugs with all the stability data," Basseras says. "This is difficult because it means that we have no cold chain break allowed. You have no time out of refrigeration to perform packaging operations. For technicians having to prepare these drugs for the trials using a cold area, this really isn't very easy, but can be worst at the point where for blinding purposes you may have to unlabel syringes or devices in a cold area."

This is made especially difficult by the fact that there are multiple sites being used in so many clinical trials. Without the stability data, the cold chain can't be broken, but with so many transfers between sites, that can be hard to achieve.

"If we are considering operations along the drug product cycle - from drug substance, bulk manufacturing to pack, label and distribution operation - we may have numbers of sites involved in the supply chains," Basseras says. "So, from one site to another, we have to accumulate and add the time out of refrigeration in order to be sure that, at the end, the total time out of refrigeration is accurate with the stability data, keeping when needed a pure cold chain without any time out of refrigeration."

This can be a problem across the supply chain but, according to Basseras, it's particularly acute within hospital and investigational settings, where the right equipment and the right training doesn't always exist to help secure the cold chain.

"We have a number of standard operating procedures and processes around securing the chain for all the sites," he says. "But a lot of issues get concentrated at the hospitals and the investigational sites because, around the world, these places are not so well prepared for a new era of care where a lot is going to be based on cold chain. The current practices and the training are also a major challenge for all the nurses and all the patients. We need to be in a position where we can help them to have the correct handling and dispensation of the drug."

Rules of the road

Regulation is another challenge when it comes to trials involving multiple different drugs. "On one hand you may get some regulations for very specific countries that require you to get an investigational drug from one manufacturing site only," Basseras says. "This dramatically reduces our flexibility. At the very beginning, when you are trying to organise the master production plan to meet the clinical demand, such constraints create a difficult barrier to jump over."

Then you have other standard regulatory problems that become even trickier when multiple drugs are at stake. According to Basseras, regulatory authorities are often out of touch with the reality of what is happening on the ground. One particular example he gives is the requirements around drug shelf life.

"Particular countries can request a minimum shelf life exceeding 'X' months, which is not always compatible with existing stability data at the time when we intend to launch a new trial," he says. "When you are putting into perspective the cycle of production and the shelf life, the challenge is being in a position to dispense the drug covering the treatment period before expiration. Operational excellence has to help to reduce the production cycle. But at the end of the day, the recruitment forecast in different countries and different investigational sites has to be robust enough to secure the way the drug is going to be used. It is quite clear that in a number of cases, there is uncertainty around this.

"At the time when we are discussing upstream the clinical protocol, this can influence the treatment duration covered by one kit, meaning a number of different kits for one patient to cover the full treatment. Higher complexity for IRT, higher number of visits - these can limit any loss of product during the opened window to use the drug."

Basseras continues: "The continuation of the treatment of all our patients is vital; you may have no drug ready
with a life long enough to continue the treatment. At the same time, when new regulations intend to request the expiry date be printed at the primary packaging level, GMP re-labelling operations at the site level seems questionable with a potential loss of product in case of a change of shelf life."

In the end, whether a trial involves one drug or multiple drugs, the regulatory and logistical challenges of operating in a globalised world are set to remain. And while it might mean industry experts like Basseras spend most of their time with severe headaches, they know all too well the benefits it brings. "Our children are so connected and, tomorrow, our medical devices should be extremely well connected to patients," he says.

"They will care and treat them and help them control their diseases. We cannot ignore so major a change and how the new era of a multi-connected world will influence our work."