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- Posted by: Salman Pathan
Clinical trials play a crucial role in the development of new therapeutics and vaccines, allowing drug manufacturers to evaluate the safety and efficacy of new medicines in a controlled manner. As the complexity of clinical trials increases — owing to globalization, technological innovation, evolving decentralized models, patient-centric concerns, and the challenges posed by the COVID-19 pandemic — it is crucial that trials sponsors form strategic relationships to assure reliable supply of all needed clinical trials materials, including the sourcing of comparator drugs.
Clinical Trial Trends
The failure rate for drugs in clinical trials is one of the greatest challenges faced by the pharmaceutical industry. That rate is still high for candidates evaluated in expensive phase III trials — as high as 54% in one study. Nearly half of these projects failed for reasons not related to the efficacy of the drug, but rather operational deficiencies attributed in part to the need to shorten timelines, reduce costs, and overcome challenges associated with increasingly targeted patient recruitment and retention.1
Patient recruitment can account for nearly a third of trial costs, but incomplete patient enrollment still occurs at nearly half of trial sites.2 Inefficient data management and the lack of evidence of patient outcomes also contribute to longer trial times and failures.
Some important trends are contributing to these challenges. Study complexity is increasing across the board, with innovative trial designs becoming more common. 6 A growing number of drugs — particularly in oncology — are being approved based only on phase I trials with large numbers of patients, and sponsors are increasingly focused on adaptive study designs3 that allow them to move through development without the need to close and reopen clinical sites and stop and restart patient recruitment. Platform studies, umbrella trials, and basket trials are some examples of “master” protocols.4
The increased trial complexity makes it more difficult to launch trials, particularly with respect to choosing the right sites, as on average 11% of sites never enroll a patient.2 In this context, independent sites are becoming more important, because they are more successful at patient recruitment and often more efficient than academic medical centers. Trial complexity is also driving the growing adoption of quality by design, risk-based quality management, and centralized monitoring approaches.4
Further contributing to growing trial complexity is the globalization of clinical studies, which is occurring in part as a response to the need to reduce costs, but also to gain access to more diverse patient populations that are interested in participating in clinical trials.5 The shift in focus from blockbuster to niche, targeted therapies for rare diseases, and the use of biomarkers to enable personalized medicines are two additional factors adding to trial complexity and problems with patient recruitment and retention.
All of these trends are driving a move within the clinical trial sector to implement direct-to-patient (DTP) or virtual/ remote and hybrid trials, and the application of a host of digital technologies.6 It has also created an urgency for the adoption of a patient-centric approach to trial design and implementation.7 Sponsors, CROs, and independent investigators are increasingly seeking solutions that make it easier for patients to participate in trials and to have a voice.
Technology is making that possible. Electronic data capture with centralized data management increases efficiency, contributes to better data quality, and allows more rapid analysis and understanding, including adverse events and positive results, thus enabling more adaptive trial designs.3 Wearables and ingestible sensors provide additional avenues for monitoring patient outcomes.1
Artificial intelligence, machine learning, and big data analytics are used for everything from target identification and biomarker discovery to formulation development and evaluation of real-world data (RWD).1 They can support patient enrollment and medication, protocol adherence, and contribute to advances in electronic clinical outcome assessment technology, which can facilitate patient-centric trial design and administration.3 Indeed, the growing importance of RWD for evaluating the performance of marketed drugs and in the context of drug discovery and clinical trial design is an important driver of wider technology use and enables the sharing of information between CROs, trial investigators, sponsors, pharmacists, physicians, and more.7
Clinical Trials In The Context Of The Covid-19 Pandemic
The trends driving changes in clinical trial design and implementation at the beginning of 2020 have only been accelerated by the emergence of the COVID-19 pandemic. Similarly, the challenges associated with conducting clinical trials heightened during this crisis.
A recent study found that treating COVID- 19 patients is consuming resources away from sites attempting to continue clinical trials, with 35% of the 363 clinical trial sites in 42 countries surveyed awaiting trial activation reporting postponement of patient recruitment by sponsors, 48% of sites actively enrolling having difficulty getting patients to come in for a visit, and one-third of sites experiencing protocol deviations.8
Nearly 100 companies had reported some level of disruption to their clinical trials due to the coronavirus pandemic, with smaller firms and phase I studies hit the hardest by far.9 Some of these trials have been halted to allow for resources to be shifted to trials focused on new therapeutics or vaccines against SARS-CoV-2.
For trials evaluating medicines that provide immediate and clear benefits, continuing could ultimately help millions of people improve their quality of life and/or extend their lifetimes.10 Creative modification of protocols combined with leveraging advanced technologies can help keep expensive and essential trials on track.
With stay-at-home orders common around the world and non-COVID-related activities at hospitals dramatically reduced, the move to remote/decentralized trial approaches has made it possible for many trials to continue.11 Despite challenges faced by the 363 study sites in the survey mentioned above, 92% were attempting to keep trials on schedule, with one-third switching to virtual visits.8 The use of telemedicine, video/online meetings, and telephone monitoring, combined with DTP delivery and sample pickup, and the use of local laboratory facilities, has been effective and may lead to an increased reliance on these technologies in the future, given their cost advantages.11
Nearly 100 companies had reported some level of disruption to their clinical trials due to the coronavirus pandemic, with smaller firms and phase I studies hit the hardest by far.
Comparator Sourcing For Clinical Trials Before And During The Covid-19 Pandemic
Comparator drugs are existing drugs, either investigational or marketed, used as a reference for comparison of the performance (efficacy, safety) of a drug candidate in a clinical trial. Placebos or inactive controls are also considered comparators.
Comparator sourcing involves the procurement of comparators for use in clinical trials. While this seems like a simple enough idea, it is not an easy exercise. Manufacturers of existing drug products do not have any incentive to supply their medicine for a clinical trial that is evaluating a potential, higher-performing competitor. For products already on the market and available through various channels, the challenge is not as great. For investigational drugs and biosimilars, which must be obtained from the manufacturer, relationships are crucial.
According to the Tufts Center for the Study of Drug Development (CSDD), the top 10 pharmaceutical companies together spend more than $20 million annually on comparator sourcing services provided by clinical trial supplies vendors, specialist comparator sourcing vendors, and networks/ consortia.12 Comparator sourcing is on the rise due to the growth of clinical trials in general, the increasing complexity of clinical trials, expanding interest in combination therapies, and increasing pressure to prove substantially better performance over existing treatments.17 There is also an ethical driver: rather than offering placebos, sponsors are preferring to give trial participants actual treatments, regardless of which arm of a study they participate in.
There are, however, significant challenges to accessing comparator drugs for use in clinical trials. Garnering approval for drugs that are available through traditional sources of supply and have support of the manufacturer for use as comparators is often quite lengthy. In addition, for most clinical trials, comparator materials must be sourced from a single manufacturing lot, which can be challenging, particularly if a large quantity is required.
Many pharmaceutical manufacturers place restrictions on the sourcing of their products for use as comparators, including limitations on quantity, long approval timelines, and requirements for additional disclosures. Medicines that are unavailable through the typical supply chain, such as biologics and products that fall under risk evaluation and mitigation strategies (REMS), can be more difficult to access for use as comparators.
Comparator drugs are also often expensive, and in many cases more costly than clinical trial managers expect. The typical response is to seek the lowest- cost supplier, which often results in late or failed deliveries and adversely impacted project timelines. Many trial managers also tend to seek comparator sourcing assistance late in a project rather than at the initiation of study design development. Given the difficulties with comparator sourcing, shorter timelines can cause significant challenges as well. Globalization of clinical trials also creates a need for extensive understanding of global regulations around drug sourcing, including import/export requirements. It is essential to deliver the right comparator drug, to the right site, in the right country, at the right time.
The emergence of the COVID-19 pandemic has magnified all of these factors. Regional lockdowns have led to some import/export restrictions, reducing the flow of medicines into and out of some countries. In addition, increasing shortages of APIs and formulated drug products have occurred, in part due to plant shutdowns in China and India, where the vast majority of starting materials and intermediates for pharmaceutical manufacturing are produced. Demand for some existing drugs that may potentially serve as treatments for patients with SARS-CoV-2 has also led to supply shortages. One of the important lessons learned here is that clinical trial sites should not rely on a single country for all product and service requirements.
A strong comparator sourcing strategy is needed for all clinical trials at all times. Because comparator sourcing involves much more than simply procuring a material, a holistic approach must be adopted. Action should also be taken early, with planning for comparator sourcing initiated during protocol development and well before the trial starts. The plan should be based on all relevant information, from site locations and numbers of participants to specifics about the comparator drug and its intended dosage.
Equally important is the selection of a partner with the capability to overcome all of the challenges associated with comparator sourcing. An effective sourcing partner has long-standing relationships with large, multinational manufacturers and independent pharmaceutical companies worldwide, allowing for cost-effective sourcing for even challenging products. A global network of leading drug manufacturers, major wholesalers, and an experienced team of sourcing specialists can allow a supplier to provide cost-effective access to many products in large quantities, even for the most difficult-to-source items. Fast delivery is possible through access to a global warehousing and distribution network.
As importantly, a comparator sourcing partner must have excellent quality and compliance management systems in place and be well versed in risk mitigation. A commitment to the delivery of high-quality material on time and at the right locations is also critical. Indeed, the best comparator sourcing partners provide not just comparator drug products, but tailored solutions designed to meet the specifications of each customer. They help their clients optimize clinical trial supply with a combination of global reach and local presence.
During the COVID-19 pandemic, and in any crisis situation, comparator sourcing partners need to ensure continued supply while also protecting the health and safety of their employees and all others in the supply chain. Under such challenging conditions, established experience in risk mitigation and long-term and deeply rooted relationships with many different suppliers located around the world are both paramount. Those sourcing partners that are proactive in identifying potential comparator needs and reaching out to potential suppliers are best positioned to support customers with shortened timelines. In addition, sourcing partners that offer a tailored, customized approach will be better able to overcome the evolving challenges created during such crises.
Integrated Solutions Are Even More Valuable In Times Of Crisis
Globyz Biopharma Services is dedicated to sourcing and supplying commercial medicines/comparators for research and clinical trial studies across all therapeutic areas. We provide a one-source solution for comparator and reference drug sourcing, clinical trial materials, ancillary supplies, clinical packaging/labeling, storage and distribution of investigational medicinal products, placebos, pharmaceuticals, and more.
Our expertise in managing the regulatory, logistics, and supply chain challenges of sourcing, storing, and distributing comparators for global clinical trials makes Globyz Biopharma Services the ideal partner for small and medium-sized pharmaceutical and biotechnology sponsors, CROs, CMOs and CDMOs that don’t get the attention they deserve from larger providers. We offer comprehensive clinical trial logistics services, from supply consulting to packaging, labeling and kit preparation, storage, and distribution in validated thermal shipping containers through a worldwide network of GMPcompliant warehouses and depots with the capability to handle temperature-sensitive materials. With offices and state-of-the-art GMP depots strategically located in the United States, Canada, Germany, India, Singapore, and Brazil, we have a presence in major markets across the globe and can provide end-to-end temperature-controlled logistics solutions from any point of origin to any destination, in any size and within any temperature range.
Our sourcing specialists utilize a global network of leading manufacturers and major wholesalers to provide cost-effective access to virtually any product, in any quantity, for even the most difficultto- source items. Supported by our global warehousing and distribution network, Globyz can also ensure fast delivery practically anywhere in the world. Whether customers are seeking comparator sourcing alone or a comprehensive package that includes packaging and labeling, warehousing and distribution, or regulatory support, we customize sourcing programs tailored to their needs.
A strong quality management system supports this focus on integrated customized solutions and our consultative approach. With access to all of the needed services under one roof, our customers do not have to seek out and manage multiple vendors. Consolidation of services streamlines processes, increases speed, enhances reliability, flexibility, and compliance, and reduces costs because the product is not moving between different service providers.