The pharmaceutical development world is in crisis. Budgets have been rising steadily, but ever fewer products have been reaching the market. What’s more, even products that  make it to market are facing increasing scrutiny over safety concerns.There are several reasons for the dearth of new products and rising cost of pharmaceutical development. One major challenge is the FDA’s requirement for so-called Thorough QT (TQT) studies to determine whether a drug may induce prolongation of the QT interval on ECGs in the healthy volunteers who comprise the Phase I study population.

As Alexandra (Sasha) Latypova and Anthony Fossa from iCardiac Technologies, Inc. –a company whose board I serve on– write in the current issue of Drug Discovery & Development:

The purpose of the TQT study, as stated by regulators, is to decide whether more extensive ECG monitoring is necessary in subsequent development… In reality, however, a positive TQT study or even QT prolongation detected in preclinical studies most often leads to termination of the drug development program, as both sponsors and regulators have become increasingly risk-averse in the wake of the recent, high-profile, market withdrawals of several blockbuster drugs.

Prolonged QT as a biomarker has been widely-criticized for its high rate of false-positives and false-negatives. Consider the case of cisapride (Propulsid), a drug for gastrointestinal motility disorder. When the drug was evaluated for cardiotoxicity in humans using FDA-required testing, cisapride exhibited a small prolongation of the QT interval and consequently was considered safe for marketing. Once on the market, cisapride was associated with numerous arrhythmic events, including 341 cases of life-threatening cardiac arrhythmias with 15 sudden-cardiac arrests over a period of six years.

[T]he litigation costs of false-negatives can be astronomical—class action suits and legal fees alone for cisapride exceeded $100 million. The conservative regulatory guidance has now dramatically reduced the probability of a false-negative QT study. However, false-positive QT studies produce an enormous “silent” burden on society. A false-positive QT study may cause an unnecessary termination or adverse labeling for an inherently safe drug and thus lead to lack of access to new medicines for patients that need them while at the same time contributing to the skyrocketing costs of new drugs. Some examples of false-positive QT drugs that did make it to market include moxifloxacin (an antibiotic), amiodarone (an anti-arrhythmic), tamoxifen (anti-neoplastic) and ziprasidone (an antipsychotic). All are associated with significant QT prolongation but do not have pronounced arrhythmogenic properties at therapeutic doses.

iCardiac is developing advanced cardiac safety biomarkers in order to overcome the limitations of TQT. Success will increase the chance that the next moxifloxacin, amiodarone, tamoxifen and ziprasidone make it to market, while protecting us from the next cisapride. I look forward to doing my part to help the company succeed.

I interviewed iCardiac’s CEO last year on the Health Business Blog.