Simply does it

Sanofi first developed processes for direct-topatient (DTP) logistics for use in emergencies. “But,” admits Marc Sotty, head of the company’s studies and distribution unit for clinical supplies, “those were small emergencies.”

When reports of infections caused by a novel coronavirus in the Chinese city of Wuhan first reached Sotty, they didn’t necessarily point to anything different. Like many others, he expected a minor disruption more akin to South Korea’s 2015 and 2018 outbreaks of Middle Eastern Respiratory Syndrome (MERS) than the global trauma we’re all now living through.

As quaint as MERS might seem in 2020, South Korea’s experience in dealing with coronaviruses meant it was better prepared to deal with Covid-19 than almost any other country. Similarly, the fact Sanofi’s protocols and standard operating procedures (SOPs) for delivering investigational medicinal products (IMPs) directly to patients were primarily devised to deal with more challenging trial situations, meant Sotty’s pandemic response was more about optimisation than invention.

“We worked with our local team in China to implement a process during the Chinese New Year, which is not an easy time,” he explains. “It took two weeks to get an efficient process that was in agreement with data privacy regulation and the clinical quality department, while still being very simple. You hear a lot of people saying that we’re in a war against the virus. If you want to win a war, both Napoleon Bonaparte and Winston Churchill said that whatever strategy you use, you need to have something simple as a logistic – without that, you won’t succeed.”

Success is one word for it. Sanofi’s DTP shipments for March to June 2020 were 2,040% higher than they were over the same period in 2019, and on-time performance increased by 4.5%, too.

So, what made that staggering increase possible? Vitally, Sanofi-sponsored trials launched in the past two to three years already included DTP provisions in the core protocol and the informed consent process. As such, says Sotty, “the patient is in agreement that Sanofi’s qualified couriers may have their address and some other data that will not be used for anything except bringing the drug to the patient”. In most cases, that option was reserved for emergencies, but there are also more specific processes to limit the number of site visits, for example, as part of certain trials in paediatric medicine and for debilitating rare diseases, or when patients live a long way from sites, or if a number of triallists require home nursing.

“As an example, in paediatrics, parents have to take their kids to the site, and that might mean two days out of school,” Sotty explains. “Here, we decided that there would be calls between the investigator and the parents to check how the kids are, and monitor if there are any adverse effects and so on, and to decide between the courier and the patient when they can get it directly. They can fix a date and time, and the driver calls when he’s half an hour from the house to warn the parents that he’s coming.” As part of Sanofi’s agreement with its qualified couriers, drivers can neither discuss the trial with IMP recipients, nor enter into their home.

For patients who already had their IMP kits delivered, the most obvious change brought about by Covid-19 is that receipt is now acknowledged with photos rather than signatures. Behind the scenes, however, Sotty and his colleague Emmanuelle Quéré have waged a ruthless campaign of simplification.

If and when patients and site investigators agree on the need for DTP shipping, the investigators email a request to their clinical research associate (CRA) with the patient number, the agreed date of delivery and site contact information. The CRA then fills out a short Covid-19-specific Project Responsibility Agreement with the relevant product and delivery information, which is passed on to Sanofi’s local investigational product manager for validation. From there, it goes to Sanofi’s couriers, who work with the site to provide relevant shipping equipment, and to arrange IMP pick-up and delivery according to relevant privacy and data protection regulations (which prevent Sanofi from having any access to personal patient information).

On the day the IMP kit is collected, investigators at the clinical site act almost as they would for a typical visit, performing an interactive response technology call to allocate a treatment number, and speaking to the patient to check if there has been any change in their health status or concomitant medication. The IMP kit is then packed into a shipping box with a patient contact card, sealed by the courier, and taken out for delivery.

Some like it chilled

Perhaps the most telling example of Sanofi’s commitment to keeping things manageable concerns temperature excursions. “When we analyse temperature excursions at a global level for all shipments according to our normal process,” explains Sotty, “we don’t have so many. Only 0.8% of shipments have temperature excursions due to transfer from depots to clinical sites – so we decided to be very simple. In case of temperature excursions – meaning a monitor with a red light – we bring the kit directly back to the site and ship a new one. We needn’t take the time to analyse it. That’s what we do normally, but here we have to act in line with something simple, quick and easily understandable for everyone.”

That’s also why Sotty worked with Sanofi’s financial department to reduce the burden of monitoring all the extra expense that is incurred when introducing DTP protocol by protocol. “We looked at the data from the first two weeks in China and decided to ease the process. Now, we don’t put the price or cost of DTP on each trial; instead, we opened the centralised cost centre ‘Pandemic’, so everything linked with the pandemic goes directly on my budget. That could be something coming from Chile, Russia, New Zealand or wherever. The courier sends the invoice, and I have a tracker with data on all the shipments performed each week.”

As Sotty freely admits, that cost and excursion strategy is only appropriate in exceptional circumstances, but it clearly shows the importance Sanofi places on ensuring sites don’t get overwhelmed with the difficulties of managing trials remotely. Though it may seem like fewer physical site visits should equate to less work for site investigators, the number of handovers and points of communication required for a site-to-participant delivery model can create considerable friction.

The intent behind Sotty’s simplifications is to keep investigators focused on the patient file, rather than having them worry about the lingering complexities of regulatory interpretation or any logistics. In one case, Sanofi and its couriers, helped a site in the US ship IMPs to a study participant unable to get a flight home from Brazil. Similarly, a perfusion prepared by pharmacists in Barcelona was driven 800km to a patient in Córdoba, Spain, where it was administered by a local nurse.

“It’s costly, but it’s very important for the patient,” says Sotty. “There are plenty of specific cases where the patient cannot come to the site. Here, each time, we found a way to get the drug to the patient. It was something very simple, using an efficient communication network between the clinical sites and our local and global teams. We just said to the investigators that if you want to have that, you need to record and document the agreement with the patient and, eventually, the acknowledgement of receipt in the patient file – which was very easy for them. As a company, we’re just here to help, and to do our best to please the patient and the investigators by delivering what the patient needs.”

Charles Gentile, Sanofi’s US site head, uses these examples to highlight what DTP trial supply can do for patient retention. “Think about all the patients in China and the US that would have been off their meds during their trials, or not part of a trial because they’re not able to go out,” he stresses. “Really, one of the main reasons for it is higher – much higher – retention and fewer dropouts. And that’s with Covid and without.”

Indeed, Sotty draws a head-spinning parallel between the 2019 DTP benefit of allowing trial participants from northern US cities to spend the winter in Miami, and the 2020 necessity of providing products to patients stranded thousands of miles from home.

Global extension

Sotty doesn’t lack for examples of how much the world has changed, but Sanofi’s approach to DTP has succeeded largely by remaining the same. The process for implementing more DTP in China was put together to deal with what, at the time, Sotty expected would be almost entirely a Chinese issue, but, somewhat like a virus, it has since been “copied and pasted” into every region affected by Covid-19.

“In some ways, we have a single process,” he explains. “It’s not an SOP per country, so as it [the virus] moved through Asia, we used exactly the same logistics. Then it moved to Europe, and we took the same instructions to Europe. Then it moved to North America, and then Latin America, and we did exactly the same. As it spread, we knew our process worked, and everything that was still too complex we simplified. I didn’t want different approaches in different countries, so we copied and pasted and improved.”

Of course, there have been region-specific challenges – from the total quarantine of Wuhan to the Taiwanese law that means only nurses or doctors can give IMPs to patients – but, for the most part, Sotty feels that regulators and health authorities have done their best to accommodate the shift to DTP logistics.

“People think quicker than regulation changes,” he says, “but it has adapted. For instance, if I take France, normally you would go through the health authorities for each trial, but they decided to let us do what was necessary and review it later. The EMA and the FDA and others have said, ‘Do it, but take care of privacy and, at the end, go back to your normal way of working’ – but we already had it set up in our protocols almost everywhere.”

Looking beyond Covid-19, Sotty believes more sponsors and authorities will look to establish processes and best practices for DTP trial supply. Hungary, which has traditionally been wary of the data protection challenge of implementing DTP, has already invited him to speak to its Clinical Trials Management Society about how the supply model fits into the philosophy of patient-centricity.

More technically, there’s also a move within Sanofi towards using Bluetooth data loggers that give live information on IMP kit temperature, which can be monitored by sites, sponsors and vendors to give a better account of a product’s remaining stability budget and help reduce waste. They could also be tied into a more advanced process for no-touch acknowledgement of receipt.

“I feel that the crisis that we have today will change the way of performing clinical trials,” Sotty adds. “It won’t quite be the site coming to the patient – but almost. You will give them some connected tools, you will deliver the drug, and you will collect the data every day.” That doesn’t fully account for the trial participants who enjoy the community and connection of site visits, and it’s unlikely many patients will want too many reminders of Covid-19, but, big or small, emergency or no, there aren’t many people that would deny that trials can be simpler. And DTP’s role in fighting the pandemic may well change what the world expects from clinical research.

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