In Vitro to the Rescue

The intent of the FDA Critical Path Initiative has been to modernize and accelerate the drug development process by making it less empirical and more scientific and rational. While much of the focus of the initiative has been on clinical trials, including validation of biomarkers and surrogate endpoints, many of us in the pharmaceutical industry have been making contributions on the preclinical end as well. My intent here is to highlight the impact of some in vitro models on clinical trials, consistent with the spirit of the Critical Path Initiative.

Chris Bode, PhD

In the early 1990s, 40% of drug candidates failed in clinical trials due to poor ADME (Absorption, Distribution, Metabolism, and Excretion) properties. Fifteen years later, that number is around 10%. Why? In vitro testing, which identifies potential problems long before a compound reaches the clinic. Today, toxicity and poor efficacy result in most clinical trial 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, can be traced back to the late 80s, when clinicians began to realize that an alarming number of cases of sudden death could be attributed to the drug Seldane. The cause, as we now know, 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 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 1989 and eventually became the de facto standard for that purpose in the 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 for clinical development 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 need not be carried out—another example where appropriate in vitro data, obtained with a properly validated system, can substitute for an otherwise necessary clinical trial.

Most people on the development side of pharma probably give little or no thought to in vitro studies, but they should. FDA allows sponsors to avoid certain clinical trials based on appropriate in vitro data, so why wouldn't you take advantage of that?

Chris Bode, PhD ,Vice President Corporate Development, Absorption Systems