A growing focus on comparative effectiveness is translating into an increased expectation for drug developers to demonstrate the relative benefits of their drugs during the clinical trial process.

Comparative effectiveness studies for new drugs, however, are not yet commonplace, except when a manufacturer seeks to claim superiority versus a competitive drug or in cases where giving trial participants a placebo would not be ethical. In most cases, clinical trials compare investigational drugs to placebos rather than pitting a drug in development against an existing treatment.

As pressure mounts to conduct comparative effectiveness trials, trial sponsors must put in place robust strategies to first select a comparator drug and then source and supply that drug, in an uninterrupted manner, to all trial sites in a cost-effective manner.

Sourcing a comparator drug, which in all likelihood is manufactured by a competitor, can be a challenging task that exposes a company to operational, regulatory and financial risks. This article will examine a number of comparator sourcing and supply elements that, when included as part of a comparator sourcing strategy, can effectively reduce a trial sponsor’s exposure to risk.

A Strategic Approach

The process of sourcing and supplying comparator drugs for global clinical trials contains numerous pitfalls for the trial sponsor. The inability to obtain the necessary pedigree and product documentation for the comparator, lack of supply chain security with possible introduction of counterfeit comparators, and delays in re-supply throughout the course of the trial: these are just some of the problems that can lead to significant operational, regulatory, and financial setbacks for the trial sponsor. Drug developers must have a comprehensive view of what is involved in the process and formulate a customized, strategic approach to best support their trials.

In order to minimize the risk of delayed or interrupted clinical trials and the financial implications that can result, a comparator sourcing and supply strategy should include two key elements:

1. A thorough understanding of global regulation governing sourcing; and
2. Proactive demand planning that can rapidly accommodate changes in the quantity of comparator needed in light of fluctuating patient enrollment or unexpected changes to a trial.

Exposure to operational, regulatory, and financial risks can increase if comparator sourcing is approached as a series of transactional events—buying a comparator from a wholesaler as needed—rather than a process based on a well thought-out strategy. In situations where sourcing becomes an afterthought amidst all other trial requirements, a transactional approach can jeopardize the progress of a trial.

In a transactional situation where procurement teams are frequently faced with sourcing comparators at short notice, wholesale vendors must be quickly identified and vetted, a process that can be challenging in a compressed timeframe.

If the transactional approach is the only route available for short-notice supplies, one of the major risks it presents is that there can be great variability in supply throughout the course of a trial. Wholesalers may not be able to provide large single-lot batches with long expiration dates. The purchasing company may have to buy the comparator in multiple lots, reducing clinical consistency, and creating a significant challenge should there be a recall.

In addition, wholesalers may not be well-versed in the range of regulations governing use of comparators and the logistics necessary to deliver the comparator to global trial sites. Suppliers should know the requirements governing import and export, as well as the special handling criteria necessary for each type of delivery (i.e. cold chain requirements, controlled drugs laws, complex, small volume distribution).

Unfortunately, a short lead time may also preclude the ability to source directly from the manufacturer of the comparator through a sourcing specialist, a route that generally requires more time. That said, this direct route can mitigate supply risks through demand planning and development of long-term agreements for comparators.

Leveraging Connections

Probably one of the most effective ways in which the risk can be taken out of the sourcing process and comparator availability can be assured throughout the course of the trial is to source directly from the comparator’s manufacturer via a supply agreement. This direct route can be problematic, however, as most trial sponsors wish to maintain anonymity during the sourcing process. It should also be noted that a comparator’s manufacturer may have no interest in making a drug available to a trial sponsor seeking to prove superiority of over its compound.

Trial sponsors can leverage this direct sourcing route while preserving anonymity through partnership with a sourcing specialist that maintains extensive relationships with manufacturers and can negotiate on the sponsor’s behalf. Working with a specialist that has such connections to drug manufacturers also brings additional benefits beyond confidentiality.

A sourcing specialist can liaise directly with the manufacturer to schedule production runs to meet both short- and long-term comparator requirements. This demand planning helps ensure reliability of supply throughout a trial with the same quality of material and can help maintain flexibility of supply should comparator requirements change due to a study being extended or through fluctuations or delays in anticipated patient enrollment.

In addition to effective demand planning, sourcing directly from a manufacturer enables access to large, single lots of the comparator with maximum shelf life, and specific batch numbers when possible. Securing comparators with a lengthy shelf-life provides adequate time for characterization, demonstration of bioequivalence, relabeling and repackaging, if needed, while minimizing the frequency of costly re-supply.

Securing the proper paper trail for the comparator can reduce exposure to risk and this is much easier when dealing with the manufacturer. The manufacturer can routinely provide full pedigree documentation reflecting the chain of custody from the source to the designated point of delivery, along with full product documentation including certificates of analysis, certificates of conformity, package inserts, GMP compliance, equivalency data, material safety data sheets, and TSE/BSE documentation.

The availability of these documents is not guaranteed when sourcing comparators via wholesalers, putting a company at risk in terms of meeting regulatory requirements.While a wholesaler may be able to offer the lowest product cost, the lack of robust relationships with manufacturers and supply quota restrictions may result in an unreliable supply of comparator throughout the course of a trial, ultimately leading to a much higher total acquisition cost.

Figure 1 compares the process of sourcing comparators via a wholesaler with that of a sourcing and supply specialist. While the initial product cost may be lower from a wholesaler, a number of disadvantages can lead to significant costs during the course of the trial.Direct sourcing from a manufacturer via sourcing specialist can be expected to minimize the risk of unexpected costs.

Figure 1: Tactical vs. Strategic comparator sourcing Transactional via a Wholesaler Disadvantages Little understanding of trial requirements Cannot reliably deliver the required documentation No guarantee of supply throughout course of trial Transactional relationships only Supply quota restrictions Confidentiality not assured Some wholesalers may source from unknown suppliers Cannot always guarantee single batch Usually the highest total cost of acquisition Advantages Usually the lowest initial product cost Can mean access to a drug “below the radar” Strategic via a Sourcing Specialist Disadvantages Strategic input required to fully benefit from specialist Requires additional upfront planning May be more expensive up-front Advantages Understands comparator requirements Can work directly with manufacturer in demand planning Can secure single lots with maximum expiry Can secure full product documentation May offer regulatory resources, expertise Can offer global sourcing and logistics capabilities Can also facilitate transactional requirements when needed Should offer lowest total cost of acquisition over duration of trial

A Head Start

Probably one of the simplest ways to reduce risk during the comparator sourcing process is to start planning early, typically during the protocol design phase. A head start on planning is imperative, as comparator drugs are likely to be available from a wide variety of sources across a number of geographies. Each source, however, may exhibit regional variations and will be governed by different trade regulations, all of which must be considered prior to selecting the most appropriate source.

Advance planning allows time to:

• Put a comparator procurement strategy in place that allows assessment of options / availability / limitations for sourcing the desired comparator
• Evaluate regional variations of comparators, including dosage form, strength, API concentration, visual and packaging presentations
• Review sourcing options in terms of regulatory requirements, packaging, reformulation and re-labeling needs
• Establish required volume and delivery schedule
• Evaluate price and total cost of acquisition of comparator
• Confirm availability of required pedigree and product documentation

Right Time, Right Place

The ultimate goal of comparator sourcing is to get the right drug in necessary quantities to the study site at the right time. Indeed, the efficient management and movement of clinical trial supplies, including comparator drugs, is an important factor in the success of any trial.

Making this process more challenging is the growing number and increasingly global nature of clinical trials. Significant growth in the number of clinical trials conducted is expected in many regions; Africa, the Middle East, Eastern Europe and South America, in addition to Asia.

An expanding number of trials and their geographic diversity place an added burden on both regulatory and supply/logistics teams to establish and maintain a compliant, efficient and secure supply chain across many borders. Requirements established by local regulatory agencies regarding the source of comparators (i.e., whether a comparator sourced in the U.S. can be used in an EU-based trial) as well as general trade regulations governing import and export must be understood and followed. Further complicating supply and logistics are comparators that require special handling, such as cold chain requirements, controlled drugs, or complex, small volume distribution.

All of these factors are converging to put additional pressure on the supply chain and, if not managed effectively, can result in delayed delivery of the comparator to the site, which in turn, can lead to costly delays or interruptions in the trial.

An agile, global inventory and logistics management process, supported by extensive regulatory expertise, is more critical now than ever to ensure compliance, supply chain security, prompt delivery of comparators, and global batch traceability in the event of a recall.

Regulatory expertise specific to the countries to which the comparator is being shipped also helps ensure that proper documentation accompanies the drug. It is critical that trial sponsors remain updated on and attentive to the constantly evolving regulations affecting the geographies in which trials are running, and maintain close relationships with key regulatory bodies should sourcing-related questions arise.

Finding the Source

Once the desired comparator has been identified for a clinical trial, the task turns to locating a source for the drug. While the comparator may be available from a variety of sources, regional variations in the drug itself make it important to have as broad a view as possible of available sources across many geographies.

Detailed knowledge of the global comparator sourcing landscape enables assessment of a range of options, leading to selection of the most appropriate, reliable, and reputable source for a particular clinical trial.

Caution must be exercised, however, when evaluating sources for a comparator. Only those sources that are audited to ensure supply chain security and minimize the risk of counterfeit products should be considered.

Global sourcing capabilities also enable rapid identification of alternative sources for a comparator should there be an unexpected change in production or formulation of the original source material. Immediate access to information on alternative sources helps minimize the possibility of delays in delivering comparator drugs to trial sites.

Single Sourcing

Many trial sponsors are interested in the concept of single sourcing, that is, the supply of a comparator drug from a single geographic source to trial sites in multiple countries. When considering single sourcing in support of a trial, it is important to weigh the pros and cons associated with this strategy.

Single sourcing offers a number of benefits to the trial sponsor, including:

• Management of one comparator source
• Reduction in possible local supply problems
• Consistency in data collected across trial sites
• Greater flexibility (within regulatory guidelines) to shift comparator supply from one site to another depending on enrollment

Along with these benefits come a number of challenges. A trial sponsor should carefully evaluate single sourcing options from a regulatory standpoint and understand what is required in terms of supporting documentation. The FDA, for example, provides no formal guidance on single sourcing, so it is best to consult your comparator sourcing specialist, which will have the capabilities to advise you on a case-by-case basis and be in direct contact with agency officials on your behalf.

While single sourcing can ease the demands on internal supply and logistics departments, the dependency on one source for the comparator presents a different form of risk and requires stringent evaluation and verification of the supplier. A sourcing specialist can ensure that these risks are fully quantified and mitigated.

A clinical trial can come to an abrupt halt if the comparator drug is not available throughout the duration of the study, affecting trial timelines and having a significant financial impact on the sponsoring company. Delays in the start of a trial due to the inability to locate a reliable, secure source for the comparator or lack of the required product documentation are just as costly.

A transactional approach to sourcing where the focus is on finding a comparator as quickly and inexpensively as possible can increase the likelihood of these setbacks prior to and during the course of a clinical trial. Comparators that are sought via a “last minute” approach can open up a company to regulatory, operational, and financial risks.

Comparator sourcing should be considered as an important strategic element of the planning and preparation for clinical trials. The goal for the procurement team should be to have early visibility of comparator needs — timing, volume requirements, and geographic requirements — and the time needed to properly evaluate all sourcing options. Close communication between procurement and clinical teams enables advanced planning in all areas of clinical trial procurement and allows for identification of sourcing strategies that will minimize a company’s exposure to risk and possible significant, unexpected costs.