Clinical trials have become more complex than ever. Although there is still some debate around exactly how complex they have become (the April 28, 2016 Pharmaceutical Outsourcing Monitor has some good insights), trials today seem to have more endpoints, procedures, eligibility criteria, protocol amendments, and investigator sites than just 10 years ago. Add adaptive trials to the mix, and clinical supply executives have more to worry about than ever before.
But making sure your medicines get to patients participating in a trial, at the right time and in the right dosage, is something you shouldn’t have to worry about. Bernie Clark, global marketing director for Catalent Pharma Solutions, notes the life sciences industry has been operating under the traditional logistics model for more than a decade. Under that model, the primary and secondary packaging, as well as the labeling of the study drug(s), has been done in a single production run at a central location. This is in order to have a large stockpile of finished patient kits on hand before the study begins. Those patient kits are then bulk shipped to depots and sites around the world, often before the first patient is recruited.
Supplying sites in advance is necessary because of the length of time and documentation needed to distribute patient kits to the clinical sites can vary considerably from region to region or even country to country. But, this also leaves clinical sponsors with a surplus of finished patient kits, which can sometimes sit for months or even years.
“In the past, the traditional model has met the needs of the industry. But, as trials get more complex, sponsors are finding this model is just not very flexible,” says Clark. “Advance preparation of supplies via bulk packaging runs requires a certain amount of waste be factored into the production run, plus the lead time and cost involved can be significant. Since packaging is ideally being done very early on based on preliminary demand forecasts including anticipated patient volume at each site, oftentimes those forecasts turn out to be inaccurate. Sometimes significantly so.”
Those forecasts can contain many assumptions including estimates around the number of sites and patients that will be participating. Additional variables can include the various countries where the clinical supplies will be shipped, and the languages spoken there. It is common for forecasts to change as a study progresses and depending upon the degree of deviation from the original forecast. Adjustments in the supply plan or additional packaging runs may be needed, which can add both time and cost to a study.
In recent years, far more variables have entered the equation as studies have become more complex and have served to shine a light on limitations that exist within the traditional model and its lack of flexibility. Clark notes biologics are entering R&D pipelines in increasing numbers, and most require special handling and cold chain solutions. Adaptive trial designs, which allow for mid-study changes such as dosing requirements, are also throwing a wrench into the traditional logistics equation.
“Adaptive designs now require flexibility in the supply chain,” says Clark. “There may be changes in dosage, and investigator sites might have to be added on the fly. If you did all of the work up front and made some wrong critical assumptions, there is a high potential for waste in the form of surplus patient kits that are produced but never dispensed to patients. Overage amounts vary by study, but can be upwards of 200% or more which means that some patient kits may need to be returned, while others will simply expire and have to be destroyed. When you consider the cost of biologics and other high value drugs now entering clinical trials, the cost of that waste can be quite high. Most sponsors knowingly produce overages in an attempt to avoid supply shortfall situation with the assumption that some portion of those patient kits will go to waste.”
More Flexible Solutions Are Needed
Catalent still makes that traditional logistics model available to companies that choose to use it – and for many studies it is still the best option. But Clark notes his company has also been developing next-generation solutions, as well as ways to reinvent and reorganize its packaging and distribution services so as to provide more speed and flexibility to customers. The main goal is to alleviate some of the major drivers behind long lead times and high waste in the clinical supply chain.
One new service Catalent is now offering is its FastChain™ demand led supply model. Using the FastChain™ approach, Catalent is able to decouple the primary drug packaging from the secondary packaging of patient kits. Primary packaging (i.e. getting the drug into its primary container such as a bottle or blister pack) is still performed in a central facility. Catalent refers to those supplies as “bright stock,” because while they are uniquely bar-coded for inventory management purposes they have not been allocated to a specific protocol or patient. The bright stock is then distributed to regional GMP facilities around the world, where the secondary packaging and country-specific labeling is performed once a clinical site within that region indicates that a patient has been scheduled or they otherwise need stock.
“We are physically moving bright stock closer to sites and patients to enable clinical sites to receive the supplies they need, when they need them to meet actual patient demand rather than rely upon sending out bulk shipments in advance based upon estimated demand,” says Clark. “Secondary packaging is performed within the regional facilities once we know the number of kits that are needed and what countries and clinical sites they are going to. This allows us to use single panel labels rather than booklet labels which are costly, take time to produce and are not very patient centric. But most importantly, it means that the necessary patient kits arrive at the clinical site in a matter of days versus weeks or even months.”
With patient kits assembled, labeled and shipped on demand, the number of kits that expire or need to be returned is substantially lessened. According to Clark, feedback received from customers shows the amount of waste can be reduced to less than 20 percent, depending on the study. “Because the kit assembly and labeling is not performed in advance, sponsors can pool those supplies for use across multiple protocols,” adds Clark. “That is something that was simply not possible in the traditional model where each protocol would need to be fully packaged in advance.”
Right now, the inflexibility of the traditional model makes it a poor fit to meet the variable supply needs of adaptive trials, which might entail adding new countries and/or sites to a study, or changing the dosage amounts for patients. However, when the supply model is flexible, variability can be better managed. “This is a very interesting time for our industry,” adds Clark. “Sponsors are seeking innovative solutions and flexible supply models that help them achieve greater speed and efficiency. Their partners will have to push the boundaries of clinical supply to help them make drug discovery more efficient and get needed drugs to patients faster, which is a win for everyone involved.”