The pharmaceutical industry is trapped in a deepening productivity crisis: The years 2003 and 2004 marked a 25-year low point in market launches for new active compounds. However, the number of investigational drug applications to the Food and Drug Administration (FDA) reached a new high in 2004, passing a record that had been held since 1998. Evidently, the discovery and preclinical development process is highly productive, but the fraction of candidates that make it through the subsequent clinical evaluation process is steadily decreasing.

Currently, approximately 30% of new molecular entities fail in phase 1 clinical testing, and although a 20% failure rate in phase 3 trials was common in the early 1990s, this figure is now closer to 50%. Of all compounds that begin human clinical testing, more than 80% fail because of efficacy or safety issues. For those candidates that made it to United States pharmacy shelves as prescription drugs, around 10% faced market withdrawal or severe use restrictions between 1975 and 2000.

Although the changing characteristics of early-stage compounds that emerge from the discovery process and marginally adequate animal models certainly represent one part of the problem, the way human trials are presently designed and conducted makes greater contributions to the delays, failures, and exploding costs that are current hallmarks of the clinical process. So far the industry has reacted to these problems essentially by only "streamlining" existing processes and introducing information technology in a cautious and evolutionary fashion.

No fundamental changes were attempted, in large part because the FDA and other regulatory authorities worldwide tended to rely on tried and tested study designs, clinical endpoints, and modes of documentation. However, the FDA's Critical Path Initiative of 2004 has shown that the agency is now not only willing to work toward a remedy with representatives from industry and academia, but to take the lead in this process.

I believe that a bidirectional approach is needed to accelerate the clinical process and make it more effective. These two avenues — revamping trial design and pervasive modeling and monitoring driven by information technology — are fundamentally different from each other but need to be implemented in a closely linked fashion. Although radical in effect, none of these changes would involve concepts or technologies that are unknown today.

On the design level, phase 1 would assume a new role as a brief confirmatory testing stage for the model of drug-human interactions that the sponsor has proposed. Phases 2 and 3 would merge into a single, advanced-stage human testing phase that involves fewer patients than today, relying on relatively small populations that are highly homogenous with respect to key criteria of pharmacologic response.

Likewise, systematic postmarketing studies and a significantly improved and extended postmarketing surveillance system that goes far beyond adverse event reporting would be integrated into a postmarketing monitoring phase that documents real-life use of the newly licensed drug.

Those new processes can be made possible through holistic mathematical models, such as the "virtual patient" (representing not the "average human" but variants of target patients of both sexes, different ethnicities, and various ages, with medical conditions that typically coexist in this target population), extensive biomarker monitoring, and "pervasive computing." The last-mentioned omnipresent information technology relies not so much on vastly improved software algorithms or hardware (although both will be needed), but more on the concept of seamless capture of every elementary act (driven by radiofrequency identity tags and distributed processors) and seamless worldwide data exchange, driven by global standards.

With full implementation of all changes by 2015, the stage would be set for a new world of drug development. The preapproval clinical trial phase might be shortened to about three years, and 40%–50% of all candidate compounds that enter this stage could complete it, with the majority of the failures occurring in the early human validation phase. Instead of being plagued by safety issues, as is the case today, the purpose of the advanced-stage human testing phase would be to determine whether efficacy is sufficiently superior over the established standard of therapy to warrant the cost of launch and the mandated postmarketing monitoring. Although that could allow developers to recoup development costs earlier and to enjoy a longer life cycle under patent protection, it would also require that more and closer attention be paid to real-life use of the newly licensed drug.

Although implementation of such a reinvented clinical process by 2015 is feasible from a conceptual, technical, and logistical point of view, it might face delays stemming from deficiencies in international cooperation between regulatory authorities. However, such political resistance would not be a permanent hurdle in an increasingly globalized economic environment because, in my view, no alternative option exists for reinvigorating pharmaceutical productivity.

This executive summary is reprinted with permission from A New Paradigm for Clinical Development: The Clinical Trial in 2015. The full report outlines an innovative strategy for reinventing clinical development and demonstrates why a complete overhaul of the clinical trials process is feasible from a conceptual, technical, and logistical point of view. This Advances Report was published in November 2005 by Cambridge Healthtech Associates of Waltham, MA. www.advancesreports.com

Hermann AM Mucke, PhD, is an independent pharmaceutical consultant in Vienna, Austria; fax 43-1-494-9989, h.mucke@hmpharmacon.com , www.hmpharmacon.com .

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