All things considered31 January 2020
Every clinical trial needs not just the investigational product but a host of ancillary supplies, ranging from laboratory equipment to the paper required for audit trails. Kim Thomas asks Kevin Crawford, head of clinical operations at Tenax Therapeutics, for some tips on procuring, stocking and distributing ancillary supplies to clinical sites.
We are all aware of the challenges in managing the supply of trial drugs to test sites, including the importance of maintaining the cold chain, dealing with regulatory complexity, and using packaging that allows for the randomisation and blinding process. But clinical trials also require a host of ancillary supplies that may be necessary as part of the treatment stipulated in the protocol but are not considered to be an investigational product.
Because studies often involve large groups of patients, and are carried out over multiple sites and even multiple countries, the management of ancillary supplies has become more complex: it is not just about making a list of items that the trial needs and procuring them. You need to think about issues such as how to manage a range of vendors, how to replace equipment and how to deal with the individual characteristics of different countries involved in the trial. It is easy to forget, for example, that power supplies and plug types for electrical equipment are not the same in the US as in Europe. Similarly, a medical device that meets regulatory requirements in Australia might not be CE-marked for countries in the EU.
Kevin Crawford is head of clinical operations at Tenax Therapeutics, a pharmaceutical company focused on providing products that address conditions with significant unmet clinical needs. He has long and deep experience of arranging the supply of ancillary materials for clinical trials. The range of items required for a study can be hugely varied, and include everything from centrifuges, refrigerators and computers to small wearable medical devices and electronic diaries for patients to complete.
So what are the main kinds of ancillary supplies he finds himself sourcing?
“Probably the number one thing is laboratory kits for different haematology, chemistry or pharmacokinetics studies – and a lot more companies are doing pharmacogenomics studies,” says Crawford.
As well as lab kit, he says, there may be “ancillary supplies that are related to the study drug itself”, such as syringes. “I did a study where it was an inhaled form of the drug, so we had to make sure that not only the drug was there, but also the device itself that patients put together and inhale.” Finally, he says, even today paper is still an important element of clinical trials. These can include reference manuals, trial procedures and case report forms.
“The regulatory agencies still like to see paper and have audit trails,” says Crawford. “I always send three ring binders that investigational sites can put paper in, usually branded with either the study or the sponsor logo.” He might also send copies of the protocol, he adds, and any other relevant documents.
Generally speaking, says Crawford, most ancillary supplies aren’t hard to source, although it is unlikely that you will be able to find a single vendor who can meet all your needs.
“There are specific vendors to do specific things, and you can’t just go to a large vendor to have certain pharmacogenomics done,” he notes.
That means it will be necessary to deal with a number of different suppliers for a single trial – and that can brings its own challenges. Currently Crawford is working on a “very small study” that requires him to deal with seven different vendors. You may need to think about how supplies sourced from different vendors will be shipped to the sites, and what your lead times are – some supplies may take weeks to be delivered.
Ask your vendors the right questions
It is crucial, therefore, to know exactly what your vendors can and can’t do, so you can allocate responsibilities right at the start of the process. It is a good idea to check, not just that the supplier has the equipment, but that they can also meet the requirements of the trial. That can range from providing the right number of items, through packaging or repackaging to enabling you to access your inventory – do they have an online portal, for example, so you can see for yourself?
You might need to think, too, about whether the vendor has a warehouse and, if so, whether it has enough storage space and is climate-controlled. When electronic devices are involved, there is the question of how data is collected.
As an example, Crawford cites the questions he needs to ask when sourcing one of the items required for his current study: an ePatch monitor, which is a wearable device similar to a Holter monitor.
“Who has that and at what price?” he asks. “How fast can they ship this to site? How fast can they read the data? If they can’t ship to a number of different countries, who are they outsourcing it to?”
Another key issue in working with vendors is “making sure that if I send 100 things out I get 100 things back”, says Crawford. It is essential to have a “good reconciliation process with your vendors and an agreement to make sure they are collecting on a regular basis and they are keeping you informed – and if they are not receiving samples or different supplies back that there is an escalation pathway to allow you to address the issue. Otherwise you are going to find out at the end.”
Obviously, planning is an important part of the process of procurement and delivery. Think, for example, about what problems might come up and how to identify, log and communicate them. Do you have a plan for finding a resolution to those problems? By putting in the effort at the planning stage you can avoid escalating costs or delayed timelines later.
Communication and harmonisation
So, how does Crawford manage to procure, and keep track of, supplies from multiple vendors?
One tip is to start communication as early as possible. He also uses mind-mapping software at the outset, “to create a chart of each of the pieces of study, and the data flow and the communication flow. It just gives me a good visual for what I need to do and to see if there are any pathways that aren’t connecting to each other.” After that, an Excel spreadsheet can be used to keep track of all the supplies – although vendors will tend to have their own proprietary software for tracking each item. Even if dealing directly with a vendor supplying the ancillary supplies, that data eventually needs to go to another large contract research organisation (CRO).
If you are using a CRO, Crawford says, then it’s a good idea to “allow them to be in charge of harmonising each of your vendors to create data transfer agreements between each of those vendors and themselves”. One of the major considerations is resupply. “If we have an investigational site and they enrol five patients and you send them six kits, they only have one left,” says Crawford. “You need to be thinking: are you automatically resupplying that based on the number of patients enrolled? Or do you have to manually order the kits?
“So you need to think about how you are going to resupply your study, and if it is a global trial, you can see that you have 50 or 60 places to send things to, and it becomes quite tough.”
It is a good idea, therefore, to put in place a requirement to automatically resupply stock once supplies are down to a certain level.
The international nature of most clinical trials poses a particular set of challenges. “If you are doing laboratory samples, for example, where are you testing those?” asks Crawford. “If you were to use a large central lab, you may still be testing the blood samples in Singapore, in London, in New York, or across the globe, but they are all standardised to the same system under the same vendor.
“If you didn’t have the ability to do that, how would you ensure that you were comparing apples to apples across the different samples? So there is the harmonisation of the process used for running the samples and coming up with the same data.”
Thinking about the whole process is key. “It is about understanding that, yes, you can send a kit out, but how are you going to get that kit back?” Crawford explains. “Once you have put blood into a tube, you have got a different element now, whereas you were just sending out something that was inert at the beginning.”
Collecting blood that may contain HIV creates another set of “hoops you have to jump through” in certain countries, he adds.
Expiration dates and partnerships
When procuring laboratory kit, you have to be mindful of expiry dates. “If you are supplying saline or sterile water to reconstitute your drug, there might be an expiration date on there,” says Crawford. “So keeping track of expiration dates, and keeping sites aware of when these expiration dates are happening, is important – otherwise you run into the issue of needing a kit and having only something that is expired.”
This is particularly important over a long trial. If a particular piece of equipment is likely to expire over the course of the trial, then buy the minimum necessary at the beginning of the trial and restock later. It is something that needs to be brought up with the vendor at the outset.
“If the vendor says, ‘Yes, we’ll send out 10,000 kits’, and you ask when they expire, and the answer is ‘next month’ – and you are not starting for six months – then you have planned poorly, but you are paying for them,” says Crawford.
Another consideration is the appearance and layout of the clinical trial sites. What if they are not big enough, for example, to house some of the larger pieces of equipment? If you don’t check first, you can end up losing valuable time. It can be worth going to visit a site, but if that is not possible, then it is still important to find out as much as possible about it.
If the site is unseen then it is necessary to check whether there is appropriate storage space for the supplies, or if there is a -20°C freezer, which might be required for certain samples. So what is the single best piece of advice for those managing the provision of ancillary supplies for clinical trials?
“It is about partnerships,” says Crawford. “I think it can often be forgotten or dismissed as ancillary – ‘It is over there, it is not the main thing that we are doing’ – but I think having a good partnership with a vendor that understands your needs and is proactive in their approach to your needs is invaluable.”