For example, the agency has established a Cooperative Research and Development Agreement (CRADA) with the IT firm Mortara
Instrument to operate a databank of electrocardiogram (ECG) data from pharma companies. In the past, sponsors provided FDA
summary analyses of ECG data. Now the need to evaluate specific drug-induced cardiac toxicity evidence, has prompted FDA to
seek more specific ECG waveform data. Norman Stockbridge, director of FDA's division of cardiovascular and renal products,
explained the technical logistics for submitting such data at a workshop held in September.
The real value of the data will come when FDA is able to share them with outside researchers. For example, the Duke Clinical
Research Institute seeks to establish a collaborative effort to gain access to the ECG warehouse to study drug effect on QT
prolongation and other issues. The aim is to address the growing debate over whether QT data really reflects risk for cardiac
adverse effects, such as torsades de pointes. This proposal has been the subject of intense discussion in recent months, as
pharma companies have expressed concerns about sharing ECG information with anyone outside FDA. FDA wants eventually to link
ECG data to patient outcomes and PG/PD data from QT trials.
A meeting sponsored by Duke in October revealed the difficulties with collaborative efforts that involve pharma companies
sharing data bases linked to specific drugs, particularly in the cardiovascular area. Companies appear reluctant to share
even data from placebo studies. FDA would like to know why different drugs have different effects and why a small percentage
of patients have problems in this area.
"Whoever owns the data has to have an opportunity to look at the project that's going to be done with the data and say, 'You're
appropriately respective of proprietary and patient confidentiality issues,'" explains Throckmorton. "We've done that in the
past. That's been a pretty standard thing."
In Search of Markers
One central Critical Path theme is to build a scientific framework for using more biomarkers in product development. Better
biomarkers can more precisely identify animal toxicities and early screens for human toxicities, but FDA recognizes that it
is necessary to develop new models for biomarker qualification.
Pharmaceutical companies regularly develop biomarkers for their own internal use in clinical evaluation, but they do not share
this knowledge with competitors. FDA sees broader use of biomarkers as key to streamlining clinical trials, but recognizes
that joint approaches are needed to avoid duplicative efforts and reduce the cost of validating biomarkers.
At a recent advisory committee meeting, Larry Lesko noted that a few validated biomarkers exist, namely those for anti-coagulants,
viral load and blood glucose. Biomarkers are key to model-based drug development, enhancing drug safety by avoiding adverse
drug events, managing drug risk, and making product labels more informative as to appropriate dose.
New biomarkers also may play a role in retrospective drug rescue scenarios. For example, by identifying the patient population
likely to benefit from a drug without suffering from safety problems, a manufacturer might be able to return a troubled product,
such as Vioxx (rofecoxib), to the market.
To clarify what needs to be done to validate new biomarkers, FDA seeks to identify endpoints already in use. FDA issued draft
guidance for cancer trials in April 2005 on what endpoints besides survival or irreversible morbidity can be used—tumor size/shrinkage,
symptom relief, quality of life—and how to measure them. The agency plans to follow this general guidance with a series of
guidances for specific cancer types.
To obtain a broader picture of what biomarkers are being used by the research community, FDA is surveying its medical officers
about biomarkers that have been filed in applications over the years and accepted as surrogate endpoints by reviewers. Remarkably,
there was no central repository of the information; indeed, when the survey began, the agency learned that there was not even
substantial agreement about the definition of "surrogate endpoint."
Another major Critical Path effort involves using models and new approaches to make the clinical research process more efficient
and less costly. A major symptom of current problems is a continued 50 percent failure rate of Phase III clinical trials.
A recent McKinsey & Co. analysis of almost 300 Phase III failures at major pharma companies revealed that half failed to show
efficacy compared to placebo. McKinsey analyst Rodney Zemmel says that only five percent should fail in Phase III for that
reason. The data suggest that something is seriously wrong with earlier stages of development.