All pharmaceutical development organizations, established firms and start-ups alike, share an urgent priority: The need to reduce time to market. The longer it takes to commercialize a drug, the longer patients go without treatment.
Among the key sources of delay in the development process is the length of the clinical trial process. Phase 1 trials to demonstrate safety and Phase 2 trials to establish efficacy can easily take years to complete, only to be followed by Phase 3 trials.
A further burden of conventional clinical testing is the formality of the regulatory oversight of trials. There has to be an approved test protocol in place before the trial begins. And in conventional trials, the protocol is fixed. Conventional trials require completion of testing according to the original trial design, even when it is apparent from the early-stage data that one or more of the dosages being investigated is ineffective or unduly risky. Continuing to test these dosages needlessly consumes the investigational drug, and exposes patients to ineffective dosages.
The investigators have two choices in these situations: Cut short the trial or go down what they already know is a blind alley.
In recent years, the Food and Drug Administration has allowed some pharmaceutical companies to mitigate these risks, and costs, by approving testing through what are called “Adaptive Clinical Trials.” In an adaptive trial, the investigators and their statisticians can take into account the early data from the first rounds of drug administration, and if investigational dosages are turning out to be ineffective or are producing side effects, the investigators can modify the protocols to eliminate those dosage levels.
By allowing investigators to try likelier safe/effective dosing, adaptive models often will allow quicker conclusion of trials, reducing the risk of failure and the cost of the trial. Large and small companies, including industry leaders like Bristol-Myers Squibb, have taken advantage of the adaptive or “flexible” trial model, or have at least studied it.
Supply Chain Issues
As attractive as the adaptive trial model is, it has its complexities, theoretical and practical. One pragmatic issue is that the supply chain for the investigational drug may not be flexible enough to take advantage of adaptive protocols.
That is, the investigators will not know in advance what dosage they will end up with, or when they will arrive at that decision. This introduces an economic issue: Investigators typically contract for a single large run of investigational drug in various test dosages in advance of the trial. But if some dosage levels are eliminated, the manufacturer (typically a contract manufacturing organization) will have sent drug to investigators who won’t be able to use it. This, obviously, is painful in trials of scarce and expensive compounds.
Usually, the investigators will send the unused drug back to the CMO with orders to destroy it – every item has to be accounted for, reconciled against the original shipment(s). The drug is expensive; people’s administrative time is expensive; clerical mistakes are expensive; and calling a contractor to dispose of the unused drug is expensive.
To respond to a desired change in the trial that would require additional formulation/fill/finish activities, (say for additional or new dose levels) may be difficult. Contracting with a CMO to package additional product requiring short runs on short notice is unlikely to be economically feasible for many CMO’s, which generally place priority on larger production runs. And this kind of flexibility is especially hard to accommodate for parenterals that need to be filled aseptically.
Automated, Short-Run Packaging Solution
Later this year, Singota will launch small volume aseptic filling services for parenterals, using robotic filling with pre-nested packaging components in a contained, aseptic fill environment. It is ideal for small lots of investigational drugs, and may represent an ideal solution for adaptive clinical trials.
The service incorporates the SA25 Aseptic Workcell (from Vanrx Pharmasystems). This system is efficient both in managing the flow of work and in reducing line losses for scarce and expensive drug product. Set-up is relatively quick and easy, and can be scheduled on short notice – the client will select standard-size containers and closures that Singota will keep in stock, with the available vials and syringes expected to suit most anticipated test requirements.
The system’s flexibility allows Singota to design a supply chain contract around the requirements of an adaptive trial, with checkpoints agreed to in advance. Real time course corrections in the trial can be conveyed to Singota through a dedicated client project manager.
Adaptive clinical trials are maturing from a study design perspective. There are still complexities, but solutions like the automated Workcell may reduce the time to market, allowing patients in need to receive treatment sooner.