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Despite GxP and data-management challenges, pharma is moving toward new models for clinical trial logistics.
Clinical trials pose major manufacturing and distribution challenges, which have been magnified by the trend to outsource more operations. The success of any clinical trial demands strong adherence to GxPs--required good current practices in manufacturing, clinical, distribution, and documentation. The end goal, says Matthew Caponi, senior director of North American depot and production services at PAREXEL, is providing assurance that the rights, safety, and wellbeing of patients are protected, and that the results of the trial will be unbiased and credible.
A number of factors, including increasing complexity of drug forms and increased reliance on outsourcing, has made it more difficult to optimize manufacturing, packaging, and distribution for clinical trials.
In addition, a growing number of manufacturers are moving from traditional to direct-to-patient clinical trial designs, a shift that will change basic communication, logistics, and the way that manufacturing, patient compliance, and logistics data are exchanged. This article examines some current trends and changes that can be expected in clinical trial logistics in the near future.
On the manufacturing side, failure to maintain GMP standards at the clinical stage is resulting in an increased number of new drug approval delays. In 2016, for example, FDA issued a record number of complete response letters (CRLs) for new drugs under development. CRLs detail problems found at pre-approval facility inspections for new drug applications (NDAs) and require that manufacturers or contract partners fix these issues before the NDA approval process can continue.
According to John Jenkins, retired director of the Office of New Drugs in FDA’s Center for Drug Evaluation and Research (CDER), the agency issued 14 CRLs for new drugs (1) in 2016, and five involved cGMP issues at contract development and manufacturing organization (CDMO) or contract manufacturing organization (CMO) partner facilities (2).
Some of these cGMP deficiencies are due to tight timelines and the fact that formulations are becoming more complex, especially as drug development shifts from an emphasis on small molecules to one on biologics, says Sanjay Vyas, corporate vice-president, global head of clinical trial supplies and logistics at PAREXEL.“Clinicians want a simple dose to administer the most robust and efficient drug formulation, but some dosage forms must be administered intravenously instead of orally.” In addition, he says, a number of new APIs require a difficult synthesis, and the resulting drug products can require special storage and cold-chain handling.
Not all that long ago, many oral, solid-dose products were shipped in corrugate, and temperature monitoring was not even needed, says Vyas. “Today, a biologic must be moved in shippers using phase-change material of far more robust and technical design, with temperature monitoring devices to ensure and demonstrate environmental control,” he says. “All of these specific requirements must be supported by a supply logistics chain that can ensure that the material is maintained exactly as required as it moves along the supply chain--the chain of custody must be unbroken and documented as such,” he adds.
Packaging for clinical trials must not only support the required storage conditions but also enhance patient compliance and ease of use, as well as efficient logistics, says Vyas. “A blister card that clearly shows the morning and evening dose as part of its design will work better than a series of bottles presented to the patient, each with different dosing instructions,” he says, adding that smaller, less complicated packs will help support logistics efforts.
Beyond basic manufacturing, the most challenging part of any clinical trial is maintaining the practice of double blinding, which helps to ensure unbiased trial results by preventing patients, healthcare providers, and those who collect and analyze trial data from knowing whether each individual subject in the trial has received the actual drug being studied or a placebo. The challenges posed by blinding requirements run from manufacturing to dosage-form selection, packaging, and distribution. “The range of potential unblinding or at least complicating factors is enormous, and as varied as the products themselves,” says Caponi.
Even numbering the kits to be used by each individual patient in a clinical trial requires strategy. If the randomization and trial supply management (RTSM) or interactive response technology (IRT) system being used is not configured with blinding in mind, it will be possible for sites to see trends in the dispensation of kit numbers and identify kits that are different from another, explains Tony Street, PAREXEL’s head of global portfolio leadership for clinical trial supplies and logistics. “The use of scrambled rather than sequential numbers eliminates this risk, but this approach can present operational challenges at the warehouse if the selection of kits is completely random,” he says.
Street suggests using a hidden sequence number that will not be visible on the kit, which will allow depot and warehouse staff to know the order in which kits will be requested, so that packing can be done most efficiently. “When selecting your RTSM/IRT vendor, it is essential that you work with a team that fully understands the process at study sites and the GMP/GCP implications of system set up. Something as small as the sequential numbers utilized on a patient kit can jeopardize the credibility of an entire clinical trial program,” says Street.
In trials where two compounds are being compared, a double dummy approach may be required, in which each of the drugs and its placebo are given distinctive forms, for example, different colors for oral solid-dosage forms and their placebos.
However, careful and early planning can eliminate the need for this approach, says Caponi. “An early decision on dosage form may prevent the need to resort to double dummy designs, in turn, reducing the total number of dosage forms manufactured, as well as the labels produced, packaging components used, and simplifying overall packaging design strategy. “The end result is a dosing regimen that is easier for the patient to maintain and less expensive to produce,” he says.
For oral solid-dosage forms, the best solution for blinding may be as simple as over encapsulating the product comparator with the same size capsule, Caponi says. “Injectables present another whole spectrum of issues--questions to ask include: Does your syringe look the same or can it be somehow blinded to the comparator? Is the actual product visually the same color?” he says.
It’s especially important to be aware of issues that can result when blinded drugs for clinical trials are manufactured on existing commercial lines, a practice that is becoming more common, and will become to be widespread in the future.
Caponi recalls a case in which transdermal pouches were produced at various clinical strengths on a single commercial production line. Each of the pouches was marked so that it could be traced back to the production line, a useful practice for commercial operations. However, when the material was received by the clinical supplies packager, something had to be done to blind these marks, because each mark indicated a difference in strength for each pouch manufactured on that line.
The move from traditional to direct-to-patient clinical trials (in which patients take the medication independently in their own homes) is gaining ground, and is likely to result in fundamental changes in the way products are packaged and distributed and how product data are transferred. “Distribution and medical adherence will now be more closely intertwined with the design of the clinical trial itself and the locations of the distribution of the drugs,” says James Streeter, global vice-president of life-sciences product strategy at Oracle.
In formulation and drug delivery, ease of use and safety will become even more important, because patients themselves, rather than healthcare providers, will be administering dosing, says Vyas. As a result, products such as infusions or those that need to be reconstituted at the point of use will need to be reformulated, he says, while packaging design will have to become even more streamlined. Biologics manufacturers will also be under greater pressure to develop products that remain stable under a wider range of temperatures and conditions, he adds.
Instead of sending large shipments to investigator sites, manufacturers will now be sending multiple, smaller shipments to patients, Vyas says, and logistics planning and patient monitoring data will need to be linked. Planning the last mile of drug delivery to the patient’s home from either the manufacturing plant or the storage depot will become more challenging, he says, because each country has its own different product stability requirements as well as different geographies and climates.
“For the clinical supply provider, orchestrating an integrated technology and data sharing capability becomes highly important to ensure that not only the right drugs reach the right patient safely and on time, but also that patient information remains blinded from the sponsor to support regulatory requirements,” says Vyas. Proactive supply chain planning, agility, and integrated technology will be key to success.
In the direct-to-patient world, shipping controls and tracking will be handled through new methods that will involve direct contact with patients. Third-party vendors will interact with patients who will get supplies either directly at home or at their local pharmacies, says Oracle’s Streeter.
Tracking and controlling who gets these drugs will shift from one central operation to individual operations, and regulators will require that patient adherence data be aligned with distribution control, Streeter predicts. In fact, he says, distribution, patient adherence, and overall clinical trial data will no longer be managed separately, but together, because operations teams running the clinical trials will need all three types of data to optimize trial control. In addition, although investigators will still be responsible for patient safety, their operations will also need to be monitored.
Blinding and packing the pharmaceuticals used in clinical trials will no longer be controlled at the package level, but at the level of the individual dose, says Streeter, who adds that social media will make blinding more challenging, because patients may inadvertently share information with each other about drugs and their packaging. The need to ensure that dosage form and packaging appear identical will be crucial. Individual dosage forms and their packaging will require unique identifiers, and each will need to be monitored closely, he says.
Sponsors will have to have the technology required for tracking and monitoring as part of each clinical trial design and as part of their overall data-management toolkit, Streeter says. “We won’t be tracking data at the individual patient’s kit level, but at the level of the individual pill, and data will become part of overall operations data, so a much more coordinated approach to data management will be needed,” he says.
Data lineage and even blockchain methodologies will be required so that manufacturers will be able to trace each drug, its packaging, and shipments precisely, Oracle’s Streeter says. As a result, he says, data requirements will explode, requiring large amounts of storage space, analytics and machine learning software to manage and mine.
“Evidence-based medicine has become the norm in the medical field today, and, as the need grows for real-world evidence in clinical trials, so will the need to break down the silos that still separate manufacturing, patient compliance, and logistics data. Together, these forms of data will provide better overall control, and promise to reduce the overall costs of clinical trials in the future,” he says.
1. J. Jenkins, “A Review of CDER’s Novel Drug Approvals for 2016,” FDAVoice, January 4, 2017.
2. A. Thayer, “The Complete Response Letter: The Mail No One Wants to Receive,” cen.acs.org, May 15, 2017.
Volume 30, Number 11
When referring to this article, please cite it as A. Shanley, “Moving Toward Direct-to-Patient Models," BioPharm International 30 (11) 2017.