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  3. Kings College London (KCL)
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  7. Drug Safety and Toxicology (6BBM310)

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Regulatory Toxicology: the role, content and evolution of toxicology and pathology in non-clinical studies

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Detailed description of regulatory toxicology, involving the types of toxicology studies under ICH M3 guidelines

Last document update: 4 year ago

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  • February 17, 2021
  • February 17, 2021
  • 34
  • 2019/2020
  • Lecture notes
  • Dr. nandi
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Regulatory Toxicology: the role, content and evolution of toxicology
and pathology in non-clinical studies

Regulatory studies involves looking at the guidelines required when
considering marketing of a product. It involves looking at how various
components of the non-clinical data such as pharmacokinetics, in
vitro, in silico and in vivo toxicity and clinical data are integrated
together in designing regulatory studies to evaluate the safety of a
new compound for use.

Human medicines are licensed on the basis of quality, safety and
efficacy. Establishing the quality, safety and efficacy of a medicine is a
lengthy stepwise process. It involves the evaluation of quality, non-
clinical and clinical safety information. A risk to benefit ratio
(evaluation of the beneficial effects of the medicine against the
possible harmful effects) is considered on a case-by-case basis for
each medicine.

Toxicology studies are done to understand the effects of substances
on human health in both voluntary and involuntary exposures.
Voluntary exposure in the form of pharmaceuticals and involuntary
exposure in the form of contaminations and food additives.
Toxicology studies are also carried out to ensure safety in workplace,
safety for workers, safety in transport of the substances, and the
environmental impact of the use and production of the substance in
question. This involves carrying out an environmental risk assessment
before any compound/substance is released onto the market.

The role of toxicology studies in non-clinical studies is fundamental.
Some work is also done in the clinical studies phase. Of particular
interest, phase 4, which is pharmacovigilance, is when toxicology
studies happen, to pick any toxic risks that manifest in the larger
population.
1

,In pharmacology and in drug discovery and development, risk vs
benefit is an important concept. There are exceptions to this rule
depending on the quality of the drug under development. For
example, oncological drugs have a high risk of toxicity, however due
to the demand and benefit, their approval is put under special and
careful consideration.
Hazard is the intrinsic capacity of a chemical to cause an adverse
effect on human health
Risk is the probability of that adverse health effect occurring
Safety is the converse of risk, and in common usage, refers to a
situation of minimal risk.
Efficacy is the beneficial effect to the patient.

Preclinical testing are done as a requirement to support clinical
development of a drug. preclinical testing involves in silico modelling,
and it requires evidence of efficacy and safety.
In-silico modelling is the easiest way, as the cell can be modelled
using software packages, thereby reducing the number of drugs that
are put down to testing. Evidence of efficacy is required for a drug to
move from preclinical studies to clinical studies. Finally, evidence of
safety is required from preclinical studies to adapt to the target
population. E.g. if a drug is shown to have toxic effects and unsafe
effects with women, then certain contraindications will be put in
place in the clinical trials.
Preclinical testing also provides information concerning risk to
patients, and this is safety testing is done in 2 animal species: rodent
and non-rodents. Advantages of using rodents such as mice and rats
is that they have a short pregnancy term of 21 days. non-rodent
species are dogs, non-human primates are also sometimes used such
as Zynomolagous monkey and marmazade.


2

,Furthermore, the role of preclinical studies is also to prevent the
development of unsafe drugs, by making sure that all aspects of the
safety pharmacology and supplementary studies are carried out.
Preclinical studies are majorly carried out in animals, even though
there are currently being developed other alternatives using the 3Rs
concept: Replacement, refinement, and reduction.
Preclinical tests are conducted prior to commencement of human
trials/human use (most commonly associated with pharmaceutical
development) to ensure that there is no genotoxicity and to ensure
safety and efficacy. Also, preclinical trials are used to define the
pharmacological and toxicological effects of the test compound, not
only prior to initiation of studies in humans but also throughout
clinical development.
More specifically, preclinical studies have a role in the Protection of
patients in initial and subsequent clinical trials. (human volunteers
are sometimes used). Also, Assessment of safety endpoints not
amenable to clinical evaluation. (phase II, III – still looking at some of
the toxicology in animal studies, - studies are done in parallel, it
keeps going throughout).

Preclinical non-clinical studies are then Extrapolation to the human.
The results of appropriate pharmacology, toxicology and
pharmacokinetic results are used to indicate possible risks to humans
in the clinical stage. It is important to integrate all available data in
analysing the actions of a medicinal product, and suggesting possible
mechanisms and exposures required to produce them. Preclinical
studies looking at the maximum tolerated dose is used to identify any
Adverse Reactions. Preclinical studies’ role is also to identify a NOAEL
(no observable adverse effect level), in order to achieve a safety
therapeutic level.

The Marketing Authorisation (MA) stage of the drug discovery
process requires the following non-clinical safety studies:
3

, Pharmacodynamics, Secondary pharmacodynamics, Safety
Pharmacology, Pharmacokinetic (ADME) studies and toxicokinetics.
Other studies include Single and repeated dose toxicity studies – one
off or a cyclic dosing and how ADME of a drug is affected when
interacting with other drugs. for example, the effect of possible co-
administration of two drugs, how the lipid absorption is affected,
how diet interacts with the drug’s pharmacodynamics.
Other examples of non-clinical preclinical studies are Reproduction
toxicity studies, Genotoxicity studies – looking at the carcinogenic
potential of a substance, Local tolerance studies, and other studies as
appropriate: photo toxicity – absorption of drug onto skin – does this
change when absorbed by light.
Overall, the preclinical studies conducted should be appropriate for
the type of compound and its intended clinical indication. Preclinical
studies are conducted also to give us an indication on how we are
going to have a mirrored effect of dosing.
OESD guidelines – protocols looking at acute, repeated dose tasting.
The number of animals, species, rat vs non-human primates.
Important but only guidelines – only to understand and determine
how to change it when taking it onto FIH.

Regarding the Clinical Phase, Clinical drug development consists of 4
temporal phases:
• Phase I: Exploratory (FIH) investigations in a small number (20-100)
of human volunteers and patients for safety and dose range finding.
• Phase II: Safety and efficacy in a larger number (100-300) volunteer
patients
• Phase III: Extensive investigations of safety and efficacy in a larger
number (1000-3000) of patients
• Phase IV: Further studies on newly authorised medicines to monitor
for rare and/or unanticipated adverse effects.


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