Pointing Us in the Right Direction

It's hard to argue with the basic premise of the FDA's Critical Path Initiative—to help the flow of medical products through the development pipeline. However, with its emphasis more on the integration of high science into the process, the Initiative may be downplaying an important point. Today's clinical trial operational model needs a major overhaul if we are to be effective and efficient in bringing medical innovation to patients.

Lawrence A. Meinert, MD

The escalation of drug development costs is well documented and sources such as CenterWatch report over 75% of trials being significantly behind schedule. Additionally, the trend toward more complex and costly clinical trials, driven by the new class of highly selective drugs, requires larger, more diverse patient populations.

The industry has applied aggressive containment tactics to costs such as investigator payments, and those for monitoring visits and case report form review. However, these tactics may not only drive up time and cost, but actually detract from the robustness of compound characterization derived from the clinical study.

Covance has supported over 12,000 clinical trials for sponsors worldwide. Our analysis of 80 completed studies indicates only a small percentage (~3%) of a study's overall budget is devoted to project planning and risk prevention. At the same time, "find and fix" remediation activities, currently the major activity in monitoring and data management, actually consume about 27% of the typical budget—more than the funds allocated to investigators.

This budget analysis shows us where the core problem lies. More time is spent on data and process issues than foreseeing and avoiding them. Are we perpetuating a downward spiral analogous to the automobile industry in the 1970s, where poor manufacturing quality lead to substantial cost-to-fix in the dealer channel and rampant customer dissatisfaction? Car manufacturers addressed this problem successfully by investing in up-front quality programs. Is there a case for a similar realignment of clinical trial processes? Unlike automobile recalls, retrospective "cleaning" of clinical trial data may be inherently biased and result in the destruction of up to two-thirds of the information content. How can we "build quality" into the initial selection, initiation, training and ongoing support of investigator sites?

Covance's analysis of project budgets from the past decade shows a progressive shift of funds away from investigators and prevention, towards data remediation. It also shows that performance variation across study centers—activation timelines, screening, accrual, drop-outs, and data quality—appears to be the most important prognostic indicator of overall study performance.

The Critical Path Initiative paints an impressive vision of next generation science, tools and technology, but pays limited attention to the practical design and conduct of clinical trials. Perhaps our industry would realize more immediate benefit by focusing on a realignment of our clinical trial processes and budgets toward primary investigational site performance, rather than high science.

With leading-edge client sponsors, Covance is building confidence in a new paradigm for conducting clinical trials. Experience indicates that an approach favoring risk prevention, rather than repair, holds great promise for improved productivity, lower operational risk, and improved scientific robustness. This new paradigm—which we call the Predictive, Proactive, Preventive (P3) clinical trial model — features:

• Predictive feasibility and modeling—analyzing and leveraging similar study experiences to optimize study design and site selection to best meet the requirements of a specific study

• Proactive project planning—anticipating sources of poor performance and shifting study budget allocations away from error detection and repair activities towards study center performance prediction and risk mitigation

• Prevention of errors—emphasizing new approaches to investigator grants that encourage improved pre-activation preparation efforts, and promoting and rewarding primary data quality

Today, the industry seeks to substantially improve R&D productivity and is increasingly willing to reconsider the drug development process. A shift to a P3 paradigm promises a means to simultaneously optimize quality and efficiency, enabling sponsors to shift development and resource investment from remediation of investigator errors, to higher value activities.

The industry's pursuit of the science and technologies envisioned by the Critical Path Initiative is important. But as valuable as advances such as biomarkers and imaging techniques may be, our most rewarding direction may be simple process re-engineering. The Predictive, Proactive, Preventive model promises faster time-to-market, less error remediation, and reduced operational risk.

The bottom line is that we can all agree on a common goal of bringing medical advances to patients sooner, but our success depends on taking the right forks in the road.