Cardiac Safety Speaks to the Heart of the Critical Path Initiative


Applied Clinical Trials

Applied Clinical TrialsApplied Clinical Trials-08-01-2005
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Ambitious in scale and scope, the Critical Path Initiative provides a rational construct for framing the central paradox of today's new drug and new device development industry.

It has been almost a year and a half since the FDA Critical Path Initiative was defined in the agency report entitled "Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products." Ambitious in scale and scope, the Critical Path Initiative provides a rational construct for framing the central paradox of today's new drug and new device development industry: Technological advances in discovery are outpacing the ability of technology to accelerate development; "the gap between bench discovery and bedside application appears to be expanding."1

Scott Grisanti

The Critical Path can be envisioned as a set of supply chain processes that begin with preclinical development and continue through marketing approval. Like any supply chain, performance is bounded by the ability to identify and optimize constraints. In the case of the overall supply chain required to "produce" new medical products, the constraints exist throughout the three tightly interrelated areas of safety, medical utility, and industrialization.

While all three dimensions are of cardinal importance, safety is perhaps the most hotly debated and publicly visible. Just as with medical utility and industrialization, safety is a complex area encompassing many important topics. It is only by focusing on these substrata individually and with a common goal that the Critical Path Initiative can hope to leverage a meaningful number of the "opportunities" identified in the report.

Cardiac safety data collection and analysis is an excellent example of such an opportunity. Cardiac effect of new drugs is currently the leading reason for delay in or denial of approval for marketing and for withdrawal of already approved products. The magnitude of this issue is suggested by reports that clinical failures due to liver toxicity alone have cost one leading drug developer more than $2 billion in the last decade.2 With costs to bring a new drug to market estimated at between $800 million and $1.7 billion,3 robust cardiac safety profiling runs at about 1% of total drug development program costs—a modest investment that can yield significant return in the form of risk mitigation and development program acceleration.

Recently, international regulatory authorities have collaborated in an unprecedented manner to develop consensus-based guidance to drive cardiac safety data collection and analysis in new drug development. The guidance focuses on the stages of preclinical and clinical development that correspond precisely to the scope of Critical Path Research. It is contained in two International Conference on Harmonisation documents—ICH E14, The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, and ICH S7B, The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. Guidance at this level of detail, especially as illustrated by ICH E14, is required to bring life to the Critical Path framework.

As E14 moved through the ICH process during the most recent two years, it gained momentum with evidence of broad-based support across the key conference regions of the United States, Europe, and Japan. While E14 is just now moving into Step 5 of the ICH process—formal implementation—the guidance has already had a profound effect on the Critical Path of new drug development.

A new type of study has arisen from the guidance—the Thorough QT (T-QT) Trial—with the key goal of using a standards-based design tuned for compound specific characteristics to determine the cardiac effect of a new drug on healthy subjects. Uniform standards for data collection and analysis allow drug developers and regulators to assess compounds efficiently and facilitate comparisons between drugs in the same therapeutic class for relative risk/benefit. Another important T-QT goal is to drive the cardiac safety collection profile for Phase III, allowing routine ECG collection when the T-QT study results are negative (no effect of concern). It is recommended that the T-QT study be conducted early in Phase II. This ensures that the definitive cardiac safety profile of a new drug candidate will be determined prior to exposing a large patient population with co-morbidities in late-phase studies. In addition, this sequence offers a financial benefit to sponsors, who reach an important milestone on the road to market approval with a single discrete trial prior to what is often a later phase program investment running well into the tens of millions of dollars.

The FDA has developed new cardiac safety data submission, review, and warehousing requirements that include support of an HL7 XML annotated ECG waveform standard. The FDA has entered into a Cooperative Research and Development Agreement (CRADA) with Mortara Instrument to develop the FDA digital ECG warehouse, which will provide tools for FDA reviewers to manage, review, and analyze digitally submitted cardiac safety data and waveforms more efficiently.4 The waveform is designed around a standard that resulted from significant cooperation across multiple industry segments. In fact, key scientists at AMPS, eResearchTechnology (eRT), and Mortara Instrument were recognized with FDA Commissioner's Special Citation Awards for contributions to annotated digital ECG waveform standards development. Waveform standards are building blocks for further advancements, such as the digital ECG warehouse. These efforts are illustrative of the level of collaboration required to make the Critical Path Initiative a reality.

The Critical Path Initiative acknowledges that safety issues should be detected as early as possible, distinguishing actual issues from potential issues, yet recognizes that current tools are often cumbersome or imprecise. Digital collection and central analysis by a proficient ECG core laboratory eliminates these barriers to navigating the Critical Path. An ECG core laboratory serves as a trusted third party that can provide the science, process, and technology to ensure consistency and quality in cardiac safety data collection and analysis.

The focus of ECG core laboratories, such as eRT, is consistent with the charge of the Critical Path Initiative. eRT is committed to continuing to provide the capacity and compliance required to support sponsors in the mastery of cardiac safety profiling for today's sophisticated compounds. We strive to enhance the value derived from the drug development industry's investment in cardiac safety data collection through advanced technology solutions that support sponsors' interactive analysis of cardiac safety data at the program, trial, center, and patient levels, with the ability to link direct from ECG analysis data to an associated annotated waveform. Also, eRT underwrites and produces complimentary industry educational curricula that are designed to provide a collaborative environment for regulators, sponsors, and industry experts to share knowledge that can propel the Critical Path Initiative toward its goal of facilitating creation of new, publicly available scientific and technical tools to accelerate the safe development of new medical products.


1. FDA, Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, (March 2004).

2. D. Rotman, "Can Pfizer Deliver?" Technology Review (February 2004).

3. Tufts Center for the Study of Drug Development, Backgrounder: How New Drugs Move Through the Development and Approval Process, November 2001; and J. Gilbert, P. Henske, A. Singh, "Rebuilding Big Pharma's Business Model," InVivo, The Business & Medicine Report, Windover Information, 21 (10) (November 2003).

4. "Mortara Instrument Announces Collaboration with US Food and Drug Administration (FDA),", June 8, 2004.

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