Clinical research continues to accelerate at an extraordinary pace with the emergence of new therapeutic Indications, adaptive trial designs, decentralized studies, and global recruitment for clinical trials. However, amidst all the technological advances and unprecedented speed, there continues to exist one essential building block of success: obtaining the right comparator compound in the right location at the right time.

Because of these changing conditions, the importance of acquiring comparator compounds has changed from being an operational task to a necessary component of strategic planning and can frequently mean the difference between success and failure for many clinical trials. Delayed comparator compound supplies, misalignment with regulatory authorities, and mistakes in the acquisition of comparators can lead to lengthy delays, increased costs, and compromised integrity of the resulting data.

The article will discuss the current realities of comparator drug sourcing in clinical research today. The discussion will extend beyond the traditional topics and will highlight different approaches to managing risks associated with the acquisition and use of comparator compounds, various ethical issues, global logistics for comparator drug sourcing, drug lifecycle planning of comparative studies, and strategic planning to be ready for the future. If you are involved in the operations of clinical research, procurement of clinical trial materials, or the strategy for providing materials to support your comparator sourcing for clinical trials, this article will help you to evaluate how you can better integrate the sourcing of comparator drug supplies into your overall development plans.

Understanding Comparator Drugs in Today’s Clinical Trial Environment

Comparator drugs serve as reference treatments when evaluating the safety and efficacy of an investigational product. A comparator drug can be one of several options: a branded innovator product, a generic version of a branded product, or a standard of care based on study design and regulatory requirements.

The definition of comparator drugs has not changed in recent years; however, sourcing them has become increasingly complex.

In today’s environment of clinical trials:

• They are often conducted in multiple countries at the same time.
• They are subject to greater regulatory scrutiny.
• They are being developed with adaptive or hybrid protocols.
• They tend to be more patient-centric.

These factors create extra demands on sourcing comparator drugs.

Many comparator drugs are commercially available products; as a result, the comparator drugs sourcing is inherently different from sourcing investigational medicinal products (IMPs) because comparator drugs typically are not manufactured for trial purposes. Sourcing issues arise for comparator drugs with respect to availability, pricing volatility, labelling compliance, shelf life, and continuity of supply throughout the duration of the clinical trial.

Why Comparator Drug Sourcing Is a Strategic Priority, Not a Procurement Task

Typically, in the past, the function of comparator drug sourcing has been viewed and performed as a purchasing operation, including identifying an appropriate supplier, negotiating pricing, and arranging shipment of supplies to a depot. That approach no longer suffices.

The requirements for effective comparator drug sourcing today include:

• Early involvement in protocol development.
• Collaborative interaction between clinical, regulatory, and supply chain functions.
• Predictive estimates of potential risk.
• The acquisition of market information for a variety of geographic areas.

When organizations consider comparator drug supply strategically, they benefit from:

• Greater predictability for the conduct of clinical trials.
• A decreased risk of having to amend an existing clinical trial protocol.
• Increased assurance from Regulatory Authorities.
• Improved long-term financial management of clinical trials.

To achieve a successful outcome from comparator drug sourcing for a given clinical trial, the sourcing process must provide for consistency in achieving the trial’s scientific aims, fulfil the ethical responsibility for conducting a fair and impartial trial, and meet all practical constraints associated with the operation of the clinical trial.

The Hidden Risks Lurking in Comparator Drug Supply Chains

The vulnerabilities of comparator drug supply chains are frequently underestimated in comparison to the other significant problems in the manufacturing of Investigational Medicinal Products (IMPs) that the sponsor has direct control over with respect to how the comparator drugs are manufactured, shipped and/or discontinued.

1. Market Withdraws & Product Shortages: Commercially available products can be withdrawn, reformulated or deprioritized by the manufacturer with little to no warning. The comparator selected during protocol development may no longer be available at the midpoint of the clinical trial.
2. Country-Specific Differences: The formulation, strength and excipients of the same drug can vary from region to region. These differences may create concerns about the comparability of the two products and/or the equivalence of the data between regions.
3. Regulatory Restrictions: Many regulatory authorities expect comparators to be locally sourced and/or comply with local standards of practice. Failure to comply with these local requirements will result in delays in obtaining regulatory approval.
4. Price Instability: Unlike the prices paid for comparator medicines for use in clinical research (which are influenced by clinical trial budgets), the price of comparator medicines is influenced by market conditions. The lengthy clinical trial period exposes clinical trial sponsors to the risk of increased pricing for comparators.

Identifying and appropriately sourcing comparator medicines before the need arises will ultimately lead to more efficient and effective sourcing of the comparators than reactively sourcing the comparators after the need arises.

Ethical Considerations in Comparator Drug Sourcing

While the cost and logistical aspects of comparator drug sourcing are often the primary focuses, there is a level of ethical responsibility associated with ethical sourcing to ensure that clinical trials provide patients with appropriate standard-of-care treatment, no matter where they live in the world.

Some ethical considerations in sourcing comparators include:

• Using comparators that are reflective of local treatment guidelines.
• Ensuring that the comparator drugs are not substandard or out of date.
• Ensuring a consistent level of quality from region to region.
• Avoiding disparities in trial populations.

The selection and sourcing of the comparator drug can also impact the level of trust that the patient has in the clinical trial, the ability to recruit patients into the trial successfully, and the overall trustworthiness of the clinical trial.

This is why Ethics Committees or Institutional Review Boards (IRBs) have begun paying more attention to how a trustworthy comparator drug supply is selected and sourced. Ultimately, sponsors who use ethical reasoning when selecting and sourcing comparators will be in a better position to gain approval for their trials and have the confidence of all stakeholders involved in the trial process.

Final Thoughts

Comparators are not hidden costs in a clinical trial anymore; they are an extremely valuable resource that allows for successful trials.

Through a future-oriented and ethically/conscientiously fueled view of comparative studies, and through proper use of technology and lifecycle planning, sponsors and CROs can lower risks, manage costs, and increase speed to market. 

Sourcing comparators is not only seen as a necessary part of every clinical trial; it has become one of the most critical parts of every successful trial.