With its Critical Path Initiative over the past several years, the FDA has attempted to accelerate the drug development process by making it less empirical and more science-based. While much of the focus has been on clinical trials, including validation of biomarkers and surrogate endpoints, many pre-clinical contributions have been made as well. I’d like to highlight the impact of some in vitro models on clinical trials, consistent with the spirit of the Critical Path Initiative.
In the early 1990s, ~40% of drug candidates failed in clinical trials due to poor ADME (Absorption, Distribution, Metabolism and Excretion) properties. Nearly twenty years later, that number is around 10%. Why? In vitro testing, some of which is now required by the FDA and implemented at an early stage by drug developers, identifies potential problems long before a compound reaches the clinic. Today, toxicity and poor efficacy result in most clinical trials failures because it remains difficult to predict these factors with preclinical models. This emphasizes the value of reliable, predictive in vitro model systems.
The development of in vitro ADME models, beginning with the “M”, metabolism, goes back to the late 1980s, when an alarming number of cases of sudden death were associated with the drug Seldane® (terfenadine). We now know that the cause was a harmful interaction with certain co-administered drugs, typically antibiotics or antifungals, which ultimately caused an often-fatal cardiac arrhythmia. The point is that an in vitro model was used to discover the exact mechanism of the drug-drug interaction. By 1997, when the FDA mandated the use of human in vitro models to test for potential drug interactions, the pharmaceutical industry was already on board. Subsequent FDA guidances specified the clinical consequences of in vitro drug interaction findings: a positive result required a follow-up clinical drug interaction trial, but a negative result in vitro was sufficiently definitive on its own.
Now, the “A” in ADME, absorption, can also be predicted in vitro. Caco-2 cells were first characterized as an in vitro model for predicting intestinal drug absorption by Hidalgo, Raub and Borchardt in a 1989 paper in the journal Gastroenterology and have since become the de facto standard for that purpose in the pharmaceutical industry. The correlation between apparent permeability across a Caco-2 monolayer in vitro and absorption of orally administered drugs in vivo is well established and responsible, in part, for the aforementioned decrease in the number of clinical drug failures attributable to poor ADME properties. Sponsors of NCEs can now select those drug candidates with desirable ADME properties based on in vitro testing.
In vitro models such as Caco-2 have had an equally dramatic impact on the development of generic drugs. The 2000 FDA guidance on the Biopharmaceutics Classification System, or BCS, established a mechanism by which a generic drug developer could obtain a biowaiver based on in vitro data. A biowaiver means that a clinical bioequivalence study is unnecessary – another example where appropriate in vitro data, obtained with a properly validated system, can substitute for an otherwise necessary clinical trial, thereby saving valuable time and money. The industry is gradually catching on to the significance of the BCS: Absorption Systems has seen a steady increase in the number of BCS studies per year since 2001. The new European Medicines Agency (EMA) Guideline on the Investigation of Bioequivalence, which goes into effect August 1st and includes a section on BCS-based biowaivers, will be a centerpiece of the IQPC Conference on Bioequivalence and Bioavailability in Munich, Germany October 26-27, 2010.
Most people on the development (as opposed to discovery) side of the pharmaceutical fence probably give little or no thought to in vitro studies. But they should – the FDA and EMA allow sponsors to avoid certain clinical trials based on appropriate in vitro data, so why wouldn’t you take advantage of that?
Chris Bode, Ph.D., is the Vice President, Corporate Development of Absorption Systems (http://www.absorption.com). He can be reached at 610-280-1451 or via email at cbode@absorption.com.