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Agnes Shanley is senior editor of Pharmaceutical Technology.
Increasingly complex trial protocols have added to IMP manufacturing challenges.
In July 2018, The Tufts Center for Drug Development released a report (1), which found that more complex clinical trial protocols are driving up clinical trial costs. Examining 9737 protocols from 178 global pharmaceutical and biotechnology companies, Tufts researchers found that Phase III trials have seen the greatest increase in complexity over the past 10 years, while companies are collecting data on 86% more endpoints than they did last decade, necessitating new procedures.
In addition, Tufts found, between the four-year periods 2001–2005 and 2011–2015, pharmaceutical manufacturers doubled the number of countries involved in clinical trials, and increased the number of Phase III support sites by 63%.
For operating companies and their contract partners, whether contract development and manufacturing or contract research organizations (CDMOs or CROs), the increased complexity has posed some serious challenges. Impacts are being felt on the manufacturing and operations side, which, according to recent estimates, already accounts for 20% of all clinical trial costs, or some $30 billion per year (2).
Manufacturing is feeling the impact of increased protocol complexity in terms of risk mitigation (i.e., in the way that studies are being designed), as phases are combined or changed in midstream based on interim results.This approach requires far more focus on upfront planning than traditional study design did. “Maintaining the flexibility and agility needed to react to changing clinical protocols is a very real challenge,” says Mark Lewis, Alcami site director of Wilmington Drug Product Manufacturing Operations.
“Client requirements in early phase studies often evolve based on clinical results. This frequently means redevelopment or expansion of the dosage range covered by manufacturing,” says Lewis, “And our ability to respond to changes that benefit the patient is critical.” Any shortages of investigational medicinal products (IMPs), or other delays, can affect results of a trial and lead to financial losses of $1 million per day (2).
Driving much of this change is the move to personalized medicine, says Andrea Zobel, senior director of product management, clinical trial supplies and logistics, for PAREXEL. Replacing the “one-drug-fits-all” model are individual preparations and dosages, and patient-specific drugs in autologous therapies. Consequently, patient numbers per batch are decreasing, and manufacturing must be flexible for products with short shelf-lives.
In addition, Zobel says, clinical materials are being manufactured closer to the clinical site, and the timelines for GMP quality processes are being shortened and automated. “Manufacturing sites with partial automation to produce hundreds or thousands of packages are no longer required. Instead, manufacturing sites with many parallel workstations are needed to produce many small batches continuously,” she says.
She cites an example of a pharmaceutical firm whose focus has shifted from cardiovascular therapies to oncology drugs. “In oncology today, the majority of innovative drugs are biopharmaceuticals with short shelf-lives and requirements for cooled or frozen storage and distribution. Therefore, the decoupling point when a drug package is made to be trial-specific should be as late as possible.”
Currently, Zobel explains, the manufacturing site for clinical supply of all global studies is comparably small, with approximately 20 different labeling/packaging rooms. These rooms are continuously producing clinical trial medication for many parallel trials with various treatment arms.
The most advanced process is “manufacturing on-demand,” an approach in which the IMP kit is labeled just-in-time for when the shipment request for a site is generated by an IRT system.While the process itself can be supported by technical solutions such as label printing on demand, label work stations connected to IRT systems, and decentralized manufacturing sites with standardized equipment, GMP-compliant quality controls and releases remain a challenge. Again, technical solutions can help to give the quality managers the required oversight and documentation to enable even remote releases (e.g., in-process-controls using bar-coded components), which are tracked in an electronic release system and can replace the paper based and visual checks.
Additionally, the regulations must be adapted for some new therapies, especially cell and gene therapies, which are prepared individually for single or small groups of patients and cannot comply with the traditional quality and analytical process steps. Regulations such as the EU guidelines on GMP for Advanced Therapy Medicinal Products (ATMPs) address these new requirements, says Zobel.
Interactive response technology (IRT), including interactive voice response (IVR) software, first appeared on the scene about 20 years ago to help sponsors and contract partners better respond to clinical trial complexity. The software aims to help users manage increased randomization and complexity, and help ensure that drugs are distributed to trial sites and dispensed to patients correctly.
Cenduit, for instance, was launched in 2007 as a joint venture between Fisher Clinical Services (now Thermo Fisher Scientific) and Quintiles (now IQVIA) to help address these problems. Since that time, eClinical IT systems have been developed, and IRT programs are interfacing with electronic data capture (EDC) systems and distribution systems, and with lab systems or electronic clinical outcome assessment (eCOA) tools to improve clinical trial manufacturing and operations.
Still, it is up to sponsors to ensure that data are adequate and properly interpreted to optimize inventory levels and delivery times. “Complex study protocols with dose changes, re-randomization, and dynamic design updates are much harder to plan for with regards to how much drug is needed. Initial planning needs to be done based on numerous assumptions, and it’s important to continuously fine tune the forecast of drug needs during the study based on actual data. This approach increases planning certainty and accuracy and allows a reduction in expensive overages,” according to Stefan Dürr, senior director of client delivery and head of Cenduit’s Drug Supply Center of Excellence.
Anticipating the impacts of clinical trial protocol changes means that manufacturers face moving targets. Often, manufacturing and packaging must start even before study portfolios are finalized, says Dürr.
As a result, sponsors often gear manufacturing to worst-case scenarios to ensure adequate supplies, but the result is wastage, and, with costly biopharmaceuticals, in particular, the economic impact can be high. In reviews of more than 200 clinical trials, Cenduit has found that 65% of the clinical supplies packaged for those trials were not used at the end of the study.
Some manufacturers are using modeling tools to help improve initial project planning. Used with IRT, simulating for forecasting and management offers insights into study designs and supply strategies that allow avoidance of excess inventory and optimize overage, considering possible delays in shipping (e.g., customs), says Vince Santa Maria, vice-president of worldwide clinical trial material and depot operations at PAREXEL.
Simulation, with IRT, can also be done during a study, using actual study IRT data to help mitigate issues along the way as well as up front, says Santa Maria. “In such cases, overages are discussed with the sponsor early on during the setup phase of a study to establish an optimal approach later on. Risk mitigation strategies and suitable potential remediation can also be discussed at length during simulation to assure for proper planning upfront before issues occur, as well as over the lifetime of the study as patterns emerge,” he says.
Software such as Bioclinica’s Monte Carlo simulation software, Optimizer, can be used to develop different forecasting and supply scenarios, based on how the studies might be run. In addition, contract services providers are becoming creative in setting up and maintaining the IRT’s resupply module, says Melissa Peirsel, Manager of IRT Services at Sharp Clinical Services. “Resupply has never been a ‘set-it and forget it’ portion of a clinical study, where we could once set the resupply parameters for the entire study based on where the study was with recruitment, we are now finding that the system needs to have specific resupply settings for the demand at each site.” When it comes to global trials, she says, there is a growing requirement for ancillaries to be sourced locally.
“We have also been seeing a trend where there are more kit types, but less supply available to support the trial. This places a demand on the IRT system to have just the right amount of trial materials on site without causing insufficient inventory errors or overstocking a site that will never use the supply. Some sponsors are resorting to site-to-site transfers of materials and evaluating returned unused materials for redistribution to other study sites, Peirsel says.
Planning relies on sharing data more effectively, and more sponsors are partnering with contract partners to ensure that clinical supplies are delivered on time and in full. In addition to simulation tools, Santa Maria sees a move to greater use of just-in-time (JIT) labeling, in which medication is initially labeled without protocol or country- specific information, without a batch number or expiry date, and with the minimal information to ensure correct picking against a shipment request. Complete regulatory-compliant labeling is then performed as close in time to shipment to the site as possible. Final packaging, labeling, release, and shipment are performed within 48 hours of receipt of trial/country/patient specific shipment request.
IRT can also help prevent quality issues, says Dürr, by creating the kit list required for labeling and excluding expiry dates from the label if it is controlled by IRT. “This approach can reduce drug wastage and remove the requirement to relabel drugs at depots and sites if stability allows to extend the expiry date,” he says.
Through collection of additional data, the risk of patients taking a therapy after its expiration date could be reduced even further, Dürr notes. For example, sites could scan the kit number prior to dispensing and when the patient returns the drug, so that IRT can check that the drug was indeed returned prior to the expiry date, and send alerts in case there is a drug with the patient that is going to expire soon.
Within the past five years, returns management, or the need to return unused experimental treatments, has become more of an issue. Compliance requires closer connections between partners and sponsors, says Lewis, and companies are recording data and functionality into their IRT systems.
Even though returns and destruction of unused IMPs are required, and part of all good clinical practice (GCP) and GMP regulations, follow through is often an issue in clinical trials, says Zobel. “Processes are often not described in enough detail during study set-up; training is often not sufficient ;and responsibilities are often not assigned,” she says.
Zobel believes that the upcoming EU Regulation (EU) No 536/2 (3) will add additional complexity when the tracking and documentation is expanded to used and unused IMPs and auxiliary products. However, she notes, new requirements will also improve clarity because they will require description in the protocol of the specific arrangements for tracing, storing, destroying, and returning IMPs.
Although the clinical site is initially planned to be where the IMP is destroyed, many trials’ country regulations and site capabilities often require a reverse supply chain with return shipments to certified destruction facilities in the same or other countries. Sponsors must consider carefully whether a network of local depots or a central hub will be the best and cost- effective solution, Zobel says.
Recently, IRT systems are being used to handle reverse logistics (e.g., with reports of used or unused IMPs and automated return shipment requests), says Zobel. These systems also support clinical site accountability. “The new trend to apply barcodes on IMP packages, instead of reading and entering kit numbers, allows packages to be scanned and tracked automatically and reduces workloads for clinical staff while improving data quality,” she says.
Ensuring cold chain performance has become essential to ensuring patient safety, says Santa Maria. Close integration between IRT and distribution systems is essential to enable manufacturers to manage supply risks faster and ensure there are no site stock outs, says Dürr. Thorough testing is required to ensure that IMPs are kept at the right temperature, not just in transit but also during storage.
The move away from traditional trial models to direct-to-patient (DTP) approaches is also complicating clinical trial operations. This newer approach to clinical trials may make logistics more complex and costly, says Dürr. However, he notes, it will also reduce inventory requirements at clinical trial sites, make trials more patient-centered, and reduce overall IMP oversupply problems.
The new DTP models will also move manufacturing to the pharmacy level, says Zobel. At this point, CMOs are only licensed in a few countries to handle this type of manufacturing and have a licensed pharmacist available to dispense medication directly to patients. In addition, most pharmacies have no GMP licenses for IMP primary and secondary packaging, she says.
As the move to personalized therapies and DTP models continues, clinical trial complexity will remain a “given” for drug manufacturers. IRT will continue to play an important role in ensuring continuity of clinical trial supply to sites, while also minimizing drug overage and wastage, predicts Tim Gilbert, senior director of product management, randomization, and trial supply management at PAREXEL.
1. Tufts Center for the Study of Drug Development, csdd.tufts.edu,“Rising Protocol Complexity Is Hindering Performance while Driving Up Cost of Clinical Trials,” Press Release, July 17, 2018.
2. Cenduit, “Why is There So Much Wastage in Clinical Supplies?” May 31, 2018.
3. European Commission, EU No 536/2014, Clinical Trials Regulation EU No. 536/2014
Vol. 42, No. 9
When referring to this article, please cite it as A. Shanley, “Clinical Manufacturing: Clearing Higher Hurdles” Pharmaceutical Technology 42 (9) 2018.