Chapter 4: Clinical Drug Development – Part 1
Clinical research versus clinical trial?
A clinical research is scientifically sound an ethically acceptable research involving humans and
conducted by investigators in order to improve our knowledge of a disease or its treatment. The
definition of the WHO is (for the purposes of registration): A clinical trial is any research study that
prospectively assigns human participants or groups of humans to one or more health-related
interventions to evaluate the effects on health outcomes. The interventions include (but are not
restricted to): drugs, cells and other biological products, surgical procedures, radiological procedures,
medical devices, …. The evaluation concerns the efficacy and safety of the intervention(s) for a
specific disease. The first question you ask yourself is: “Is this intervention safe?”. If it isn’t safe, you
stop the trial! The ultimate aim being a decrease in disease related morbidity and/or mortality. We
want to improve the quality of life, so the aim is related to morbidity and/or mortality! So, as you
may see, the definition of a clinical trial is stricter than the definition of a clinical research. If we talk
about clinical trials, we mainly talk about prospective research, so research in the future. We want to
look prospectively on the effects of this intervention.
Phase I – From mice to man
The clinical part is divided into different
phases. The first step is going from
preclinical to clinical: a very important
step! We need to adhere to some
regulations before you can use the drug in
humans. The IB (investigation brochure) is
a file or dossier which summarizes all the
information which is currently available on this molecule. The authorities want some kind of proof
that this molecule is safe and useful to be further developed, so the clinical trial application (CTA) is
attached. To summarize: The IB is part of the CTA. Right now, it is safe in term of toxicology in
animals, and there need to be indications present in the IB that it is worth it to further develop, that
the molecule is useful at the end of the day – that the molecule has some kind of ‘need’ in society. In
the United States, they call the CTA an IND (investigational new drug application). The IND is
comparable to the IB. The IND is a separate kind of dossier. It needs to be submitted to the US FDA.
They need approval from this company before they can move into humans, this takes about 30 days.
So, in the United States, you need approval to go into clinical trials. In Europe, this is a one-step
procedure, because the application and the investigation brochure are combined in one dossier.
Non-clinical safety studies
What is the first dose we are giving to humans? We
can get this information from the animal studies. This
table shows us how long studies have to be performed
in animals (and in which kind of animals) before you
can use it in humans. If you want to do a clinical trial, how long can this trial last? When this trial can
last a maximum of 2 weeks, then you need an experiment in rodents (rats) and in non-rodents (dogs,
rabbits, monkeys, non-human primates, …) for a minimal of 2 weeks. So, you need to think about:
How useful is this toxicity study? Is the target what we aim for? Is this target useful? Is the target
specific for humans? Is it different in humans and animals? Is the target missing in the animal? In the
latter case, you cannot evaluate pharmacodynamics, but you can evaluate off-target effects and
toxicology! If the clinical trial is between 2 weeks and 6 months, you need toxicology studies in
animals that have the same duration as your clinical trial in humans. Remember: All these studies
need to be GLP compliance!
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Clinical research versus clinical trial?
A clinical research is scientifically sound an ethically acceptable research involving humans and
conducted by investigators in order to improve our knowledge of a disease or its treatment. The
definition of the WHO is (for the purposes of registration): A clinical trial is any research study that
prospectively assigns human participants or groups of humans to one or more health-related
interventions to evaluate the effects on health outcomes. The interventions include (but are not
restricted to): drugs, cells and other biological products, surgical procedures, radiological procedures,
medical devices, …. The evaluation concerns the efficacy and safety of the intervention(s) for a
specific disease. The first question you ask yourself is: “Is this intervention safe?”. If it isn’t safe, you
stop the trial! The ultimate aim being a decrease in disease related morbidity and/or mortality. We
want to improve the quality of life, so the aim is related to morbidity and/or mortality! So, as you
may see, the definition of a clinical trial is stricter than the definition of a clinical research. If we talk
about clinical trials, we mainly talk about prospective research, so research in the future. We want to
look prospectively on the effects of this intervention.
Phase I – From mice to man
The clinical part is divided into different
phases. The first step is going from
preclinical to clinical: a very important
step! We need to adhere to some
regulations before you can use the drug in
humans. The IB (investigation brochure) is
a file or dossier which summarizes all the
information which is currently available on this molecule. The authorities want some kind of proof
that this molecule is safe and useful to be further developed, so the clinical trial application (CTA) is
attached. To summarize: The IB is part of the CTA. Right now, it is safe in term of toxicology in
animals, and there need to be indications present in the IB that it is worth it to further develop, that
the molecule is useful at the end of the day – that the molecule has some kind of ‘need’ in society. In
the United States, they call the CTA an IND (investigational new drug application). The IND is
comparable to the IB. The IND is a separate kind of dossier. It needs to be submitted to the US FDA.
They need approval from this company before they can move into humans, this takes about 30 days.
So, in the United States, you need approval to go into clinical trials. In Europe, this is a one-step
procedure, because the application and the investigation brochure are combined in one dossier.
Non-clinical safety studies
What is the first dose we are giving to humans? We
can get this information from the animal studies. This
table shows us how long studies have to be performed
in animals (and in which kind of animals) before you
can use it in humans. If you want to do a clinical trial, how long can this trial last? When this trial can
last a maximum of 2 weeks, then you need an experiment in rodents (rats) and in non-rodents (dogs,
rabbits, monkeys, non-human primates, …) for a minimal of 2 weeks. So, you need to think about:
How useful is this toxicity study? Is the target what we aim for? Is this target useful? Is the target
specific for humans? Is it different in humans and animals? Is the target missing in the animal? In the
latter case, you cannot evaluate pharmacodynamics, but you can evaluate off-target effects and
toxicology! If the clinical trial is between 2 weeks and 6 months, you need toxicology studies in
animals that have the same duration as your clinical trial in humans. Remember: All these studies
need to be GLP compliance!
Pagina 1 van 20
