investment. The multi-faceted challenges encountered in drug development are
closely associated with the fact that the entire path toward marketing authorization
is highly regulated by the respective agencies (the FDA in the United States, the
European Medicines Agency at the level of the European Union, and the Pharmaceuticals and Medical Devices Agency in Japan). It is the task of these regulatory
bodies to evaluate the efficacy and safety of novel drug and may ultimately grant
marketing authorization for drug applications.
Taking into consideration that it takes tens of thousands of compounds to be
screened for affinity toward the pharmacological target, about 10 years from the first
hint of disease-relevant activity in an animal model to the solid proof of clinical
safety and efficacy in a large patient population, and an estimated 1,000,000,000
USD until submission of the dossier to the regulatory agency, it is clear that such an
undertaking requires an exceptional combination of financial resources, scientific
expertise, and, once the drug product has been approved, a well-implemented
commercial network that reaches out to patients and prescribers. This explains
why nowadays – after 25 years of major mergers and acquisitions in the sector – a
few global players among the pharmaceutical companies dominate the market, the
largest one being the United States with a value of 340 billion USD.
2 Drug Discovery and Development
The drug discovery and development process can be roughly divided into three
phases: the discovery phase (Fig. 1) usually starts with the hypothesis that alteration
of a physiologic pathway may lead to changes in a pathologic condition. For
example, inhibition of the enzyme cyclooxygenase (COX) was identified to reduce
the conversion of polyunsaturated fatty acids into prostaglandins, which are key
factors in the development of inflammation (this discovery eventually resulted in the
family of widely used non-steroidal anti-inflammatory drugs). Following the decision to pursue a target, chemical libraries with thousands of compounds are screened
for their affinity toward the receptor (e.g., COX). Modification of the resulting hits
by conventional organic synthesis then aims at improving the binding properties. It
is the medicinal chemists who attempt to understand the impact of specific structural
changes on the potency of the compounds. This reiterative process leads to the
discovery of highly potent, and ideally selective, substances. In parallel to the
improvements in potency, the chemical design addresses the aspects of target
exposure in order ensure efficient delivery of the drug to the site of action at
concentrations sufficiently high to trigger the desired biological response (see
Sect. 4 on pharmacokinetic principles). Next, the in vivo efficacy is tested in animal
models mimicking the human disease, for example, carrageenan-induced edema of
the rat paw. All these efforts made in a research program make up about 3 to 4 years
of the overall process and ultimately aim at identifying a candidate for preclinical
development. Apart from demonstrated in vitro potency, target exposure, and in vivo
efficiency, additional criteria for selecting appropriate compounds are high
The Journey of Human Drugs from Their Design at the Bench to Their Fate in Crops
5
closely associated with the fact that the entire path toward marketing authorization
is highly regulated by the respective agencies (the FDA in the United States, the
European Medicines Agency at the level of the European Union, and the Pharmaceuticals and Medical Devices Agency in Japan). It is the task of these regulatory
bodies to evaluate the efficacy and safety of novel drug and may ultimately grant
marketing authorization for drug applications.
Taking into consideration that it takes tens of thousands of compounds to be
screened for affinity toward the pharmacological target, about 10 years from the first
hint of disease-relevant activity in an animal model to the solid proof of clinical
safety and efficacy in a large patient population, and an estimated 1,000,000,000
USD until submission of the dossier to the regulatory agency, it is clear that such an
undertaking requires an exceptional combination of financial resources, scientific
expertise, and, once the drug product has been approved, a well-implemented
commercial network that reaches out to patients and prescribers. This explains
why nowadays – after 25 years of major mergers and acquisitions in the sector – a
few global players among the pharmaceutical companies dominate the market, the
largest one being the United States with a value of 340 billion USD.
2 Drug Discovery and Development
The drug discovery and development process can be roughly divided into three
phases: the discovery phase (Fig. 1) usually starts with the hypothesis that alteration
of a physiologic pathway may lead to changes in a pathologic condition. For
example, inhibition of the enzyme cyclooxygenase (COX) was identified to reduce
the conversion of polyunsaturated fatty acids into prostaglandins, which are key
factors in the development of inflammation (this discovery eventually resulted in the
family of widely used non-steroidal anti-inflammatory drugs). Following the decision to pursue a target, chemical libraries with thousands of compounds are screened
for their affinity toward the receptor (e.g., COX). Modification of the resulting hits
by conventional organic synthesis then aims at improving the binding properties. It
is the medicinal chemists who attempt to understand the impact of specific structural
changes on the potency of the compounds. This reiterative process leads to the
discovery of highly potent, and ideally selective, substances. In parallel to the
improvements in potency, the chemical design addresses the aspects of target
exposure in order ensure efficient delivery of the drug to the site of action at
concentrations sufficiently high to trigger the desired biological response (see
Sect. 4 on pharmacokinetic principles). Next, the in vivo efficacy is tested in animal
models mimicking the human disease, for example, carrageenan-induced edema of
the rat paw. All these efforts made in a research program make up about 3 to 4 years
of the overall process and ultimately aim at identifying a candidate for preclinical
development. Apart from demonstrated in vitro potency, target exposure, and in vivo
efficiency, additional criteria for selecting appropriate compounds are high
The Journey of Human Drugs from Their Design at the Bench to Their Fate in Crops
5