Over the past 20 years, ethical concerns have been raised about the use of placebos when effective treatments are available. Having an active control arm means that people are offered either experimental medicine or standard of care, potentially making it easier for the trial to recruit and retain participants.
Demonstrating superiority of a drug to an existing product on the market is also desirable. If findings are positive, this can support discussions with regulatory agencies and payers, helping the experimental drug to gain approval and secure reimbursement. There are also potential advantages of using comparators, such as safety, convenience and cost-effectiveness.
As a result of these factors, pharma companies have increasingly employed comparators in clinical trials, particularly in late-phase development. However, this shift has also raised a number of complex issues.
When starting a comparator-sourcing project, it is essential that pharma companies know their supply needs and how they might be impacted by external regulatory issues, quality standards, commercial factors, as well as the local procedures and contingencies related to the movement of products. This demands an understanding of the volumes that manufacturers are able to supply, how that might change as a trial progresses, the quality and customs documentation required and a host of other issues outside the core competencies of drug developers. These must be tackled while facing resourcing pressures.
$50 million
Average clinical supply budget across 11 large pharma companies surveyed – half of which was used for comparator sourcing.
Tufts Center for the Study of Drug Development
A 2018 survey conducted by Informa found that cost was cited as being particularly challenging, with around two thirds of respondents citing this as their biggest issue. There is a lack of data on the costs of comparator sourcing, but based information available suggests that the costs are high. A 2012 study by the Tufts Center for the Study of Drug Development reported that a large pharma company estimated spending $120 million per year on comparators. The average clinical supply budget across the 11 large pharma companies surveyed by Tufts was $50 million, half of that was used for comparator sourcing.
Plan ahead
The supply chain strategy requires thorough planning in advance. It should be completed when the protocol design is drafted. As comparator drugs come from a wide variety of sources across a number of countries, particular attention should be paid to regional variations and differing trade regulations of governance.
The globalisation of clinical trials provides the ability to source comparators from different markets, including more cost-efficient ones. In general, comparators are less expensive in emerging regions, such as Asia and Latin America, than in places like North America. However, this approach requires a high level of knowledge about the differing regulations specific to countries and also the ability to meet those regulations. It is also important to note that emerging markets tend to have higher transport costs and are therefore not always financially advantageous.
The risks of comparator sourcing are increased without a well-planned and executed strategy. If procurement teams are required to source comparators at short notice, wholesalers or suppliers must be quickly identified and appraised, which can lead to hasty decisions being made that do not always pay off in the long run.
Wholesalers may be unable to provide large single-lot batches of drugs with long expiration dates. Pharma companies may have to buy the comparator in multiple lots, resulting in clinical inconsistencies. This can create substantial operational challenges as well as more paperwork to complete audits or recalls.
Specialist partnership
Compliance to sourcing regulations and logistics is another potential issue when dealing with wholesalers. It is essential that suppliers know the import and export requirements for each country, in addition to the specific handling criteria needed for each type of delivery.
Short lead times prevent pharma companies from being able to source directly from the manufacturer Comparators
Clinical Trials Insight / www.worldpharmaceuticals.net 19 through a sourcing specialist. Establishing robust relationships with suppliers can, therefore, be hugely helpful in streamlining the process.
If it is possible to work with a sourcing specialist, there are a number of advantages to this partnership. For example, they can leverage relationships with manufacturers to make bulk purchases to reduce costs. Savings can also be made indirectly by lowering the risk of time-consuming delays. Specialist comparator sourcing partners understand production manufacturing schedules, have insights into market shortages and know in advance about upcoming formulation challenges. This enables them to be attentive to potential risks, ensuring that pharma companies can make informed decisions to secure a sustainable supply of comparators for the duration of a trial.
Being able to prevent delays to the trial and subsequently the time to market is hugely important. A clinical trial can even come to a halt if the comparator drug is not available throughout the study, affecting timelines and incurring substantial costs for the sponsor. A 2018 report by McKinsey found that if a competitor gets to market first, the laggard company will experience a 6% market share disadvantage a decade later.
Working with sourcing specialists is also beneficial in a local context. They can liaise directly with the manufacturer at the local level to schedule production runs to meet short or long-term comparator requests. This helps achieve flexibility of supply if a study is extended. Sourcing from a manufacturer also provides access to large, single lots of the comparator with maximum shelflife and specific batch numbers.
Obtaining the proper documentation from the manufacturer is essential, as this provides information about the full chain of custody from the source to the designated point of delivery. Availability of these documents is not guaranteed when sourcing from wholesalers, which can risk non-compliance with regulatory requirements.
Look to the future
The ultimate goal of comparator sourcing is, of course, to get the right drug, in the right quantities, at the right time. However, in light of the ongoing growth in clinical research in regions such as Russia, Asia, South America and the Middle East, future geographical challenges are inevitable and it is essential to be prepared. The increased burden on supply and clinical operation teams will require a compliant and efficient supply chain to be established.
It is important to carefully consider the pros and cons of different sourcing strategies. While sourcing comparators from a single geographical area can ease the demands on internal supply and logistics departments, reliance on one source for a comparator is risky and will need the supplier to be carefully verified. Although a sourcing specialist can help to identify and mitigate potential barriers, adopting a decentralised strategy by using different suppliers may be a more favourable option.
Regardless of the strategy used, it is imperative that the need for speed does not compromise decision-making. A transactional approach to sourcing – where the focus is on finding a comparator as quickly as possible – increases the likelihood of supply issues occurring during the course of a study. A ‘last-minute’ approach is hugely precarious.
Comparator sourcing should be considered an important strategic element in the early stages of planning and preparations for a clinical trial. The procurement team should clarify needs for the comparator and the time allowed, in order to fully evaluate all of the options.
Close communication between the supply chain and clinical teams facilitates better planning and will ensure that comparator sourcing does not impede the progress of a smooth-running trial, both now and in the future.
6%
The market share disadvantage experienced by a laggard company a decade later if a competitor gets to market first.
McKinsey
Success and risk factors of clinical trials
This failure rate (or success rate) of drugs in clinical trials depends on a multitude of factors – many that are highly stochastic and uncontrollable for companies. Clinical approval rates differ by therapeutic areas, which is partially explained by the differing scientific objectives and underlying science knowledge base for a given drug class. Success rates across all therapeutic areas and phases of six studies ranged 5.1–26.1%. Additionally, depending on the location of the clinical studies, companies may have limited expertise in handling regulatory requirements in different countries. This may lead to multiple layers of review and increased regulatory scrutiny. Furthermore, the advantages of being the first product to the market for a particular indication creates competition between companies. On average, first entrants achieve a minimum of 7% more market share over their competitors. As a result, the loss of potential market share from not being first-to-market may drive a company to abandon research efforts.
From a quality management perspective, ensuring product quality throughout the clinical supply chain can be particularly challenging. In such a disruptive environment, it is often quite difficult to ensure timelines are satisfied, especially when resources are constrained. Because of this, companies may rely on contract research organisations or contract development and manufacturing organisations to scale up research efforts and manage the clinical supply chain. If communication, project management and risk mitigation efforts between the company and these entities fall short, product quality may suffer, which may lead to poor trial outcomes.
Additionally, the clinical trial enrolment and study design are particularly important to the success of clinical trials. For instance, enrolment in clinical trials for oncology patients is relatively low, with approximately 2–3% of all oncology patients enrolling in clinical trials. Under these circumstances, when the clinical study design includes a treatment arm that may be perceived to be more aggressive or favourable than the alternative, this may further reduce enrolment and potentially put the study at risk of failure.
With companies spending an average of approximately $33.4 million throughout the clinical trial process, developing an understanding of the key factors associated with clinical trial success is of elevated importance to supply chain organisations. More specifically, the uncertainty associated with clinical trial outcomes, which may create cascading disruptions throughout a clinical supply chain, is of particular importance to the purchasing and supply functions.
The inability to meet quantity demand, discontinuity of supply and geographic concentrations of suppliers, among other supply risks, are particularly relevant in supply chain networks with similar characteristics. The ability to readily identify key risk factors in a clinical supply chain allows for a better understanding of network performance and potential areas of vulnerability. Understanding the relationships between these influencing factors enables individual companies to develop targeted strategies to improve performance, minimise cost and risk, and reap the benefits of being the first to market.
Source: Journal of Pharmaceutical Innovation
