compound forward into clinical testing, approval of the national or international
regulatory agency is sought for by submitting the application for a new investigational drug. Provided that the mandatory studies have been executed according to the
relevant guidelines and that the outcomes of the toxicological evaluations allow to
discard potential concerns about the risk of the drug substance on health of the
human subjects, the third phase can be initiated.
The clinical development stage (Fig. 1) comprises three sequential phases and
commonly stretches over a period of 6–8 years. The major objectives of Phase I trial
are to recruit a small number of healthy volunteers (usually adult males of young
age) for assessing safety, tolerability, and pharmacokinetics of the new drug. By
gradually increasing the dose from sub-therapeutic levels, potential adverse effects
are recorded, and a maximum tolerated dose can be identified. Despite all the
encouraging findings collected during discovery and preclinical development, statistically speaking, about half of all Phase I trials conclude with the premature
termination of the project, be it for lack of safety and tolerability and due to
suboptimal pharmacokinetics properties. Compounds surviving the scrutiny of the
first clinical assays enter Phase II trials which is the first time that a patient
population with the target indication is treated with the new drug at therapeutic
doses. At this point, it all comes down to obtaining the proof of concept in studies of
limited duration and a relatively small population size (several tens to a few
hundreds): is the drug efficacious at the given dose with an acceptable safety profile?
This question is of particular importance for novel mechanisms of action, which
have not yet been validated in the clinics. In case of satisfactory findings, the drug
enters Phase III trials to evaluate efficacy and safety in a large number of patients
(several hundreds to several thousands) over an extended treatment period.
Despite all the understanding of the underlying mechanism of a disease and the
arsenal of “(bio)chemical weapons” to modulate them, and despite sufficiently high
safety margins estimated from a large number of toxicological studies in animal
species, the discouraging reality in the twenty-first century is that, on average, a mere
10% of all drugs entering into clinical trials are eventually granted marketing
authorization by the regulatory agencies as the ultimate authority for evaluating
the risk-benefit ratio of new drugs [3, 4].
Notwithstanding this rather modest success rate, numerous are the cases where
breakthroughs in treatment options of chronic diseases have led to outstanding
commercial triumphs. Two examples shall serve here to illustrate the economic
impact of very successful drugs: the monoclonal antibody adalimumab (AbbVie’s
Humira), which is prescribed for the treatment of several autoimmune diseases, was
in 2018 the best-selling drug worldwide generating revenues of 20.4 billion USD.
Another record is hold by the cholesterol-lowering atorvastatin (Pfizer’s Lipitor) that
generated sales figures on the amount of 150 billion USD from the time of approval
in 1997 until patent expiration, and therefore loss of market exclusivity, in 2011.
The Journey of Human Drugs from Their Design at the Bench to Their Fate in Crops
7
regulatory agency is sought for by submitting the application for a new investigational drug. Provided that the mandatory studies have been executed according to the
relevant guidelines and that the outcomes of the toxicological evaluations allow to
discard potential concerns about the risk of the drug substance on health of the
human subjects, the third phase can be initiated.
The clinical development stage (Fig. 1) comprises three sequential phases and
commonly stretches over a period of 6–8 years. The major objectives of Phase I trial
are to recruit a small number of healthy volunteers (usually adult males of young
age) for assessing safety, tolerability, and pharmacokinetics of the new drug. By
gradually increasing the dose from sub-therapeutic levels, potential adverse effects
are recorded, and a maximum tolerated dose can be identified. Despite all the
encouraging findings collected during discovery and preclinical development, statistically speaking, about half of all Phase I trials conclude with the premature
termination of the project, be it for lack of safety and tolerability and due to
suboptimal pharmacokinetics properties. Compounds surviving the scrutiny of the
first clinical assays enter Phase II trials which is the first time that a patient
population with the target indication is treated with the new drug at therapeutic
doses. At this point, it all comes down to obtaining the proof of concept in studies of
limited duration and a relatively small population size (several tens to a few
hundreds): is the drug efficacious at the given dose with an acceptable safety profile?
This question is of particular importance for novel mechanisms of action, which
have not yet been validated in the clinics. In case of satisfactory findings, the drug
enters Phase III trials to evaluate efficacy and safety in a large number of patients
(several hundreds to several thousands) over an extended treatment period.
Despite all the understanding of the underlying mechanism of a disease and the
arsenal of “(bio)chemical weapons” to modulate them, and despite sufficiently high
safety margins estimated from a large number of toxicological studies in animal
species, the discouraging reality in the twenty-first century is that, on average, a mere
10% of all drugs entering into clinical trials are eventually granted marketing
authorization by the regulatory agencies as the ultimate authority for evaluating
the risk-benefit ratio of new drugs [3, 4].
Notwithstanding this rather modest success rate, numerous are the cases where
breakthroughs in treatment options of chronic diseases have led to outstanding
commercial triumphs. Two examples shall serve here to illustrate the economic
impact of very successful drugs: the monoclonal antibody adalimumab (AbbVie’s
Humira), which is prescribed for the treatment of several autoimmune diseases, was
in 2018 the best-selling drug worldwide generating revenues of 20.4 billion USD.
Another record is hold by the cholesterol-lowering atorvastatin (Pfizer’s Lipitor) that
generated sales figures on the amount of 150 billion USD from the time of approval
in 1997 until patent expiration, and therefore loss of market exclusivity, in 2011.
The Journey of Human Drugs from Their Design at the Bench to Their Fate in Crops
7