Adaptive Trial Design and IVRS

IVRS becomes a valuable tool

By Edward Montoya

A 2005 study by Christopher Adams and Van Brantner of the Federal Trade Commission detailed the cost of prescription drug development based on more than 3,000 new molecular entities (NMEs)1. The researchers discovered costs that ranged from $500 million to $2 billion, with an average cost $868 million. The preclinical component totaled $381 million while the clinical component averaged $487 million — or more than 56% of development costs. The globalization of studies, driven by the need to find suitable patient populations, may also contribute to longer timeframes and add complexity and associated costs to projects. Thus, researchers and developers must find ways to combat these trends so companies can remain competitive and profitable, and patients can find relief from their maladies sooner.

While not definitive, these factors are certainly indicative of one market reality: clinical trials represent the majority of development costs and should therefore be the focus of cost containment efforts.

Adaptive trial design — a process for creating a clinical trial protocol that identifies the safest and most efficacious dose of the compound being tested more quickly than a traditionally designed trial — has proven to be a powerful cost containment tool. When properly implemented, this process adds flexibility, potentially shortening the trial and reducing its cost.

Adaptive trial design is a multi-stage study format that uses accumulating data, gathered in real time using a form of electronic data capture (EDC). This information enables clinical analysts to decide how to modify aspects of the study without undermining the validity and integrity of the trial. When properly defined in the study protocol, adaptive trial design allows some trial modifications after it has enrolled its first patient in (FPI). This may mean adding or deleting treatment arms, adding or reducing patients, altering the randomization scheme or, for patient safety, discontinuing the trial altogether.

The basic challenge to implementing adaptive trial design is managing change. Doing so requires comprehensive support from involved groups, including clinical, bio-statistics and data management teams, distribution and logistics, regulatory and project managers. Adaptive trial design also requires appropriate planning. All of the possible changes and adaptive reactions must be clearly identified in the protocol for the trial to be validated by regulatory agencies.

IVRS/IWRS for Realtime Data Collection

Successfully implementing an Adaptive design trial relies entirely on real-time collection and ongoing analysis of actionable data via reports or data transfers. Doing so requires that data be “un-blinded” to a limited group of experts. The un-blinded observations must be clearly defined and “firewalled” from any parties outside the defined expert team who could potentially influence the results of the trial.

In my opinion, the solution for achieving real-time data collection is EDC, specifically Interactive Voice Response Systems (IVRS) and Interactive Web Response Systems (IWRS). IVRS/IWRS technologies give project managers the ability to immediately turn treatment arms on or off, revise patient stratification and randomization schemes, and manage inventory to suit these changes.

First used in clinical trials by the clinical industry in 1989, IVRS and its newer Web-based counterpart are guided by FDA regulation CFR part 11. These systems have been routinely used to handle patient enrollment, randomization and multiple patient drug assignments, and track screen failures and all patient discontinuation reasons and rates. On the back end, IVR provides data for CTM inventory management – a core necessity to successful adaptive design.

Additionally, IVRS/IWRS are used to enter and manage electronic Patient Reported Outcomes (ePROs), more commonly known as patient diaries. When applied correctly, these systems can yield patient compliance rates of over 90%, compared with about 30% compliance for traditional paper diaries.  ePROs will also return more accurate data than paper diaries because patients are prompted by the IVRS to respond in a timely manner, eliminating the “parking lot syndrome,” where patients attempt to retroactively complete their diary entries in the parking lot immediately prior to their next scheduled physician’s visit.

IVRS/IWRS in Efficient Inventory Management

Manufacturing clinical supplies based on the “worst-case scenario” option for inventory management is the least desirable technique, yet it is a commonly used strategy in traditional trial protocols. This option calls for manufacturing enough for all possible treatment arms — typically 150 to 200% of actual need. This is the most costly means of inventory management. IVR systems can eliminate the need for this option.

As the trial is designed to shut down losers, extend winners or otherwise adjust activity in accordance with data analysis, IVR systems give project managers the ability to effectively manage inventory. This may mean increasing or decreasing the distribution of particular doses, redirecting clinical supplies, recalling inventory, or increasing or decreasing stock at various supply chain levels such as warehouses, depots and sites. When tied to Just-In-Time (JIT) distribution, these tactics prevent shortages and over-investing in unwarranted CTM production.

With a daunting 50% failure rate of pharmaceutical compounds entering Phase III trials and less than 8% of commercialized drugs ever becoming profitable, cost control and efficiency are of paramount importance. As drug developers and researchers begin to use Adaptive trial design more commonly to control costs, an IVRS/IWRS can provide the additional critical benefits of realtime data collection and ongoing analysis of actionable data.

---

Reference

1. Christopher Adams, Van Brantner, Estimating the Costs of New Drug Development: Is it Really $802m? (December 2004)

Edward Montoya is director of IVRS/IWRS at Bilcare Global Clinical Supplies.