Clinical trials have become increasingly global in nature. In some cases, there is a need to demonstrate improved efficacy over existing products, which requires a large number of patients in different geographic locations. For drugs designed to treat chronic diseases, extended trial times across many locations are often required. With the percentage of orphan drugs in the pharmaceutical pipeline, there is a need to enroll patients from many more countries, often in remote locations with little medical support services. Personalized therapeutics such as cell and gene therapies, which account for a growing number of drug candidates in clinical trials today, require full visibility and tracking from patients to distant manufacturing locations and back again, within limited time periods.
Greater demand for direct-to-patient (DTP) services, in which patients receive treatment and have blood samples drawn and prepared for shipment at their homes, is one outcome of these trends. DTP clinical trials services are particularly beneficial for studies involving orphan drugs, which often require the enrollment of patients in remote locations, as well as drugs for the treatment of patients with limited capacities, and children. They also often result in improved patient retention and compliance with protocols.
Compared to commercial drug products, clinical trial materials (CTM) are produced in small quantities and according to specified manufacturing protocols. There is typically limited data available with respect to the stability of the formulated products. Expiration dates are therefore often very short. Many are biologics, which are also temperature sensitive and require shipment at controlled temperatures such as -20C, 2-8C or other ranges. Most are high-value products with costs per dose in the thousands of dollars. Given these issues, just-in-time shipment of clinical trial materials is often necessary, or frequent replacement of unused materials must be planned into the protocol in order to keep overage as low as possible.
Outbound distribution of clinical trial materials must, of course, also be in compliance with the import/export regulations of each country that the drugs will be entering and/or departing from on the way to the patient or investigator site. As trials become more global and complex, knowledge of differing country requirements is essential to effective logistics planning. Compliance with Good Distribution Practice (GDP) regulations around the world is required. Exact shipping routes must be mapped out, in advance, of any clinical trial material pickup from the pharmaceutical company or contract manufacturer, including specification of drivers, street routes, airports, air carriers, flights and flight numbers, etc. Contingency plans are critical in case the preferred route cannot be utilized for any reason.
Due to the increasing prevalence of clinical trial materials that require temperature-controlled shipment, packaging manufacturers have invested in the development of solutions that allow maintenance of a specific temperature throughout delivery of the drug product. The need to comply with GDP requirements has been an additional factor in the development of cold chain solutions. As a result, today there are many packaging options now available for most controlled-temperature shipments to match all levels of different temperature ranges needed.
There is, however, a need to be more sustainable while meeting shorter and shorter turnaround times. While these solutions have facilitated the choice of packaging materials for distribution of temperature-sensitive clinical trial materials, they have made the return of reusable packaging more complicated. Many of these solutions are based on specific phase-change materials. As a result, there are thousands of packages used to ship clinical trial materials at any given time that must be returned in an efficient manner back to their origin or the closest packaging condition hub for reconditioning and reuse.
Reconditioning is a detailed and documented process. Each container must be inspected to ensure that it has not been damaged. Testing should be conducted to confirm that pinhole leaks or moisture absorption have not affected the performance of the vacuum-insulated panels, and that the phase change material is not leaking. The container must be washed and sanitized. Any damaged materials and any materials that experience wear during shipment (such as corrugated cardboard) must be replaced. Refrigerators, freezers and monitoring systems must be checked to ensure they are operating correctly. Effective quality management systems are essential to ensure procedures and equipment are properly calibrated, maintained and linked to a monitoring system.
Effective management of outbound clinical drug distribution is important to the success of any clinical trial. If the supply chain is not operating at peak performance and a drug is not delivered and experiences a temperature excursion, potentially leading to damage of the product, the seamless flow of a trial can be severely impacted.
If a patient does not receive his or her drug in a timely manner, then he/she may have to drop out of the trial, which could require additional patients to be recruited, if even possible, or impact the overall results for the study. If an entire batch of clinical trial material is lost during transition, the trial could be negatively impacted, which could in turn impact large numbers of patients.
Given the combination of tremendous complexity and the potential for significant negative consequences of ineffective outbound clinical drug distribution, many pharmaceutical companies turn to third-party logistics service providers — supply chain logistics providers — to manage these activities. A company that focuses on clinical trial logistics is able to develop the depth and breadth of expertise and knowledge required to ensure the smooth passage of drug products from the manufacturer to the patient. They are experts in regulations in all of the countries around the world in which clinical trials take place, and they develop the most secure routes and methods for shipping clinical drug products.
For instance, because Marken is 100% dedicated to providing clinical logistics services and has served approximately 900 customers, each with their own specific requirements, we have amassed a substantial body of knowledge. We have a true understanding of the regulations in each country and are in a better position to take on the risks associated with establishing the logistics for clinical trial materials. As a leader in DTP services, we also facilitate direct-to-patient trials around the world. We apply our expertise and knowledge to each new customer scenario, establishing optimized and cost-effective clinical logistics solutions.
Supply chain logistics providers that can provide a number of different clinical logistics options are also better positioned to provide optimum solutions. A clinical trial for a drug to treat a rare disease may not have a large number of patients, but many of those enrolled may be in remote areas that require DTP services, whereas a trial for a drug candidate intended to treat a more common disorder may have large numbers of patients located in many different countries. Some protocols indicate that drugs must be distributed from the investigator site, or through a central pharmacy, while others may allow for delivery from a central depot directly to the patient.
A provider with experience supporting hundreds of different clinical trials has the expertise needed to determine which logistics approach will be most effective — for instance, delivery from the manufacturer first to a depot site and then the investigator site, or directly to the investigator site. Factors to be considered include the number of overall patients, the number of patients in different countries and in remote versus central areas, the stability of the drug itself, the value of the drug and import license requirements.
If a protocol only indicates that a drug should go to the investigator site, the decision must be made whether to ship to a depot first. This decision will depend on any potential issues that may arise along the shipment route, such as any potential inspections for Customs clearance. If import requirements are complex, the drug product is stable and there is sufficient clinical trial material available, shipping to a depot would be recommended. On the other hand, if only small quantities of the drug product are available, and if it is clear that the drug can be delivered in a timely fashion and cost calculations are acceptable, then shipping directly to the investigator site might be preferable.
For direct-to-patient trials, the same questions must be addressed — deliver to the investigator site for dispensation or to a depot, from which the drug is delivered to the patient. In either case, the investigator site or central pharmacy must be responsible for dispensing the drug to the patient’s home. Marken has experience with central pharmacies, which enables us to store clinical trial materials in a central GMP-compliant depot and dispatch the drugs to patients in their homes.
Most personalized treatments, such as autologous cell and gene therapies, pose many more challenges. These clinical trial materials may be bio-hazardous, and require special handling at all temperature-controlled ranges, typically at cryogenic storage conditions. An effective chain of identity must also be established. Highly sophisticated scheduling details ensure that the advanced therapy medicinal product (ATMP) is safely delivered back to the correct patient at the predefined time. The supply chain must be fully mapped from each investigator site and, if applicable, from each apheresis center to the manufacturing site. The patient-specific tracking of their unique samples, as well as their own ATMP returned back to the patient, is key to the success of these treatments. Recognizing the specificity of these treatments and the close collaboration needed with all involved partners, along with the proactive planning needed, creates the groundwork for a successful outcome. Choosing the best distribution model is dependent on the regulations, protocol and patient schedule, which should be discussed and outlined with the client prior to the start of the trial.
One other clear current mandate of the industry is to provide a complete end-to-end visibility for shipments. Marken offers cloud-based shipment tracking from booking to delivery through the use of state-of-the-art GPS technology. The Sentry and Sentinel GPS trackers, available exclusively to Marken, allow real-time GPS tracking of a package’s location (and each component within a shipment), monitoring of any temperature variations, vibration, light and shock, and provides for geofencing and complete end-to-end visibility. To be most effective, however, it is essential that suppliers like Marken are an integral part of clinical trial set-up to ensure that their experience, expertise and technical capabilities are appropriately utilized and leveraged so that the supply chain solution for each protocol is optimized.
Marken has an unparalleled network consisting of 46 global customer service and operational locations, including 10 GMP storage depots, allowing drug product manufactured in the US, Europe, Asia or elsewhere to be delivered as close as possible to preselected clinical trial investigator sites and patients. Local qualified service providers with intimate knowledge of evolving local regulations work in close cooperation with the Marken network to provide services in areas with fewer patients. We provide 24-hour control of our network.
Over the past several years, Marken has focused on building a team of experts with not only logistics expertise, but also with experience working for pharmaceutical companies, contract research laboratories, contract manufacturers and packaging firms. As a result, we have a strong grounding in the fundamentals of clinical trial protocols to develop the most appropriate supply chain solutions.
We continue to expand this comprehensive network with additional strategically located sites, adding new locations as needed to maintain or increase focus in areas of clinical trial growth.
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