Unit and in the development of medicines.1 The



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toxicity and efficacy of a treatment can vary significantly in response to a
medication in an individual.1 This heterogeneity of a drug response today is
a major concern in clinical practice and in the development of medicines.1
The causative agents of such heterogeneity or variability in response to
medications occurs due to; the patient characteristics (age, body weight,
gender, etc.), the disease characteristics (hepatic and renal diseases), the
drug specificity (drug delivery, drug regimen), the environmental factors
(smoking, alcohol, concomitant food intake, weight, UV exposure) etc.2,3,4

physiologist Garrod was the first who proposed, that the genetic variant that
might regulate the variability after drug response. He suggested that enzymatic
defect results in, the gathering of endogenous i.e., inborn errors of
metabolism as well as exogenous substrates such as; drugs, foodstuffs, and
toxins, with clinical complications.5 It is estimated that the genetic makeup contributes 20% to 95%
of the heterogeneity or variability in response to drugs.6,7

The history of variation in genes has been
known early back as 510 B.C. when Pythagoras detected a fatal reaction
(due to the reluctance of haemolytic anaemia and jaundice) in some individuals
after consumption of fava beans.8 This noteworthy observation not only
provides the information about the variation in response to drugs but also gave
an evidence about drug toxicity and its adverse drug reactions.

Aforesaid interpretations gave birth to the
field of “pharmacogenetics”. The term pharmacogenetics was coined by
Friedrich Vogel in the year 1959.9 It is defined as
the study of variation in genes (due to inheritance) that causes the
variability in patients in response to a drug.10 According to ICH
topic E15 Definitions in Pharmacogenetics/Pharmacogenomics, it
is described as “The study of variations in DNA sequence as related to drug

accumulation of knowledge on genome-disease and genome-drug interactions,
resulting in the convergence of pharmacogenetics to pharmacogenomics.12

the meantime, the establishment of methods for identification of; variations,
new genes (associated with specific diseases) and cause for drug response in
relations to its efficacy and toxicity leading to the evolution of
pharmacogenomics.7,13,14 Though, we can say that pharmacogenetics comes under
the umbrella of pharmacogenomics.11


terms of the difference between these two terms “pharmacogenetics and
pharmacogenomics” the only difference is in the level of its applications.
Pharmacogenetics offers to assess the genetic cause of unanticipated drug
response while pharmacogenomics offers to assess a specific response to a
therapeutic drug before observing heterogeneity or genetic variations within
the population.15 So, it is not hard to believe that pharmacogenomics is the
future of drug development process especially in the field of precision
(personalised) medicine.


to ICH harmonised tripartite guideline E15, Pharmacogenomics is defined as “The
study of variations of DNA and RNA characteristics as related to drug response”.11

was predicted, that each year 1.5 million patients were affected due to ADRs
consequently, resulting in escalation of the number of patients
hospitalisations, number of deaths and higher health care costs. As the
metabolic pathway of each and every individual varies, this variation leads to
significant impact on the fate of efficacy and toxicity of the drug product.
The number of ADRs may get reduce as the knowledge or understanding of genetic
variation increases. It surely exhibits the noteworthy impact on patient
improvement and drug effect.16 It was found that genetically determined
variations in enzyme activity are the causatives of ADRs. For instance, the use
of acetylate isoniazid the patients suffered peripheral neuropathy due to inherited
changes. Subsequently, the outcome of incapacitating orthostatic hypotension
was also observed after debrisoquine (antihypertensive agent) use, resulting in
detection of the genetic polymorphism of the drug-metabolising enzyme
cytochrome P450 2D6 (CYP2D6). Therefore, from the above-mentioned information,
we can determine that the incidental observations of ADRs by standard doses of
drugs led to the insight of genetic polymorphisms. Moreover, the number of ADRs
gets reduced as per the information received from causative indicators from

Drug Safety Evaluation in Special Population

special group of population includes, children (paediatrics), elderly
(geriatrics), pregnant and the lactating woman (obstetrics). These special
populations should be taken into considerations and must be examined in
corresponds to the study design and the regulations during the drug development.17
In this chapter we have covered the evaluation of safety in special populations;
Paediatric, Geriatric and Pregnancy/Lactating woman.


paediatrics has the right of having safety, efficacy and quality of medicines.
The medicines used for paediatric population are mostly studied in adults. It
is a situation which urges continue the off?label and off-licence use of the drugs
in paediatrics, which is an area of major concern. The off?label use of
medicines in children leads to a greater risk of the occurrence of adverse drug
reactions that might be more severe due to unsuitable formulations, patient’s
age and inter-individual variabilities.

to WHO catalogue, “Promoting Safety of
Medicines for Children” the administration of the wrong dosage in children
gives rise to the treatment failure or the short-term toxicity. The perfect
example of this, the use of phenobarbital in a new-born with seizures. In which
a regular dosage of the drug phenobarbital (15 mg/kg daily) is more than
sufficient for a new?born. Moreover, a loading dose (an initial higher dose of
a drug) of phenobarbital (more than 20 mg/kg) is also required, which is then followed
by a maintenance dose (5 mg/kg). The other issue is the inaccessibility of paediatric
formulations without any data on the bio?availability, efficacy and toxicity.18

children and pregnant women have not been likely to endorse by the stakeholders
because of numerous complexities (ethical reasons, informed consent,
inter-individual variability), results in the paucity of the data.19, 20, 21

children’s comes under a group of susceptible population and are incompetent of
protecting themselves, therefore they have the right of having safety, efficacy
and quality of medicines. To minimise the risk in research it is the
responsibility of all who involved in paediatric research. However, the need of
clinical trials with children is recommended by the European legislation. To
develop reliable information, knowledge and effects on paediatrics, it is a necessity
today to study the drug in this population. The European Medicines Agency (EMA)
has introduced numerous ways for the evaluation of paediatric drugs such as; enforcement
of the Pediatric Investigation Plan (PIP), by introducing the incentives for
the stakeholders and by formation of the Pediatric Committee (PDCO).

PIP Plan

paediatric regulations (Reg 1901/2006/EU and Reg 1902/2006/EU) came
into effect on 26 January 2007. The aim of this regulation is to improve
health of children’s by enhancing the development and accessibility of
medicines. This regulation enforces the stakeholders to possess a compliant PIP
for any marketing authorisation application. This compliance must be for new
indications, pharmaceutical form, or routes of administration for currently
authorised drugs.

to the regulations, a PIP should include:

Ø  A
description of the measures to be carried out in children with the medicine;

Ø  Describe
the measures to adapt the medicine’s formulation to make its use more
acceptable in children;

Ø  It
should cover the needs of all age groups of children, from birth to adolescence:

Pre-term new born infants (born before 37
weeks gestation)

Term new born infants (0 to 27 days)

Infants and toddlers (28 days to 23

Children (2 to 11 years)

Adolescents (12 to 16/18 years, depending
on region)22

Pediatric Committee (PDCO)

to EMA “The PDCO was established in line with the Paediatric Regulation, which
came into effect in 2007, to improve the health of children in Europe by facilitating
the development and availability of medicines for children aged 0 to 17 years.”23

PDCO governs or directs the stake holders for the studies that must be carried
out in children’s. The committee also appraises the authorisation applications
for a full or partial waiver and for deferrals. In a nut shell the PDCO gives
allowance to the stake holders for those medicines that are not needed for
paediatrics or not appropriate, especially for diseases that only affect adult

development of medicines for paediatrics, the PDCO works in collaboration with Committee
for Medicinal Products for Human Use (CHMP), the Pharmacovigilance Risk
Assessment Committee (PRAC) and the Committee for Orphan Medicinal Products
(COMP). Moreover, the agency offers free scientific advice assistance on
questions relating to the development of medicines for children’s.24

Incentives for the stake holders

EMA has introduced numerous rewards and incentives for the development of
paediatric medicines:

Ø  The
EMA provides a Supplementary Protection Certificate (SPC) for a period of six
months for those medicines that are authorised with the results (even when the
results are negative) of studies as agreed in the PIP. For orphan medicines the
agency grant additional two years of market exclusivity.

Ø  A
product will be granted Paediatric-Use Marketing Authorisation (PUMA) “a type
of application” when the stake holder develops medicines precisely for
paediatric population, that allows the product to get the benefit for 10 years
of market protection as an incentive.

Ø  Moreover,
the agency offers free scientific advice, assistance with questions relating to
the development of medicines for children’s.25

Geriatric Population

to EMA, it is expected that by 2050 approximately 141 million people will be aged
65 years. This represents around 30% increase in the elderly population, which
was around 84 million in 2008. This increases the need for the development and the
approval of medicines, especially for the elderly population. In the context of
treatment and its effectiveness, the older people differ in numerous ways when
compare with the younger ones such as;

Ø  The
body of the older people responds differently while taking and on elimination
of the medicines, which influence the treatment.

Ø  These
population are vulnerable to number of diseases such as; Alzheimer’s disease,
bone diseases, heart disease and mental illnesses.

Ø  Often
these population suffer from multiple diseases, results in treatment complications.

Ø  The
older people are weaker and are susceptible to disease which possesses the risk
due to medical treatment.

the safety and monitoring of the medicines for older people, EMA plays an
important role by taking responsibilities for the evaluation of new medicines
in the EU. The agency covers medicines for various neurodegenerative and
nervous system disorders in older people. Besides these, the agency also assesses
the medicines even for cancer as well as for prolonged disease like diabetes. Moreover,
after approval of the medicines into the market the agency monitors the safety
of medicines “pharmacovigilance” for older people as these population is more
prone to side effects.

2011, EMA prepares its “geriatric
medicines strategy” which ensures the need for “development and evaluation of new medicines” for the elderly
population. On behalf of the “geriatric
medicines strategy” the agency in June 2013 prepared a concept paper for
the baseline frailty status of patients. This concept paper focused on the
enrolment of geriatric population in the clinical trials. The group included
physical mental frailty or comorbidity status of patients so that the agency
assesses and identifies doubts and able to make decision on post-authorisation

agency makes sure that the development of medicines should be tested on the
elderly population and must be of high quality before and after the
authorisation. In reference to the concept paper, EMA remarked on the Guidelines,
Concept papers and Reflection Papers which then followed the review and
comments by Geriatric Expert Group (GEG).The agency also continuously focuses
on the convalescence and gathering of information for those medicines that are
used on the elderly population. The EMA then developed scientific guidelines to
guide the stakeholders for the incorporation of the elderly population in the
clinical trials. This will help in evaluating the results of the effects of
medicines. These assessments led to the formation of the structure for the
participants (elderly population) in the clinical trial and development of safe
and quality medicines. Recently in August 2017, EMA released its consultation in
the form of reflection paper for the “better
address the needs of older people” which explains all the
details for instance “appropriate
routes of administration and dosage forms, dosing frequency, excipients,
container closure systems, devices and technologies, and user instructions in
the product information”.26

Pregnancy and Lactation

pregnant women hardly included in the development of any medicines unless the
medicine is specifically developed for women population or during the use of
pregnancy. When the childbearing women are included in the clinical trial, a proper
contraception process must be applied. The pregnant women have been at a high
risk of newly developing medicines because of its harmful effects especially
when it crosses the placenta or before the development of the foetus. It is
known that pregnancy in a women comprises of different stages and may possess
different effects at each stage by the developing drug. It may be understood
more clearly as for instance, the expression of major malformation, growth
retardation or death during the second or third trimester of pregnancy as a
result of exposure to a teratogenic agent. This teratogenicity may lead to the
pursuance of renal insufficiency, neurological disorders, stillbirth, etc.
Moreover, if the pregnancy is in third and fourth gestational week it may
result in significant risk to the embryo or its demise. To minimize the risk,
the exposure of the drug to pregnant population should be omitted. However, in
case of emergency or any serious illness these populations requires special
treatment unless, have the chance of serious risk to the foetus or to the

determine or to acquire more knowledge about the drugs or its latency
associated with teratogenicity, embryonic toxicity, etc. it is very important
to gather more and more information about all the drugs taken by pregnant
women. The appropriate information should also be collected from pregnant ones,
who have had medicine for underlying disease. These population should be communicated
about the benefits and risks before administration of the drug. Proper
information must be collected from such individuals especially pharmacokinetic
information, comparison of blood levels during pregnancy trimesters and
non-pregnant women’s with same dosage for the evaluation.

addition to pregnant population the breastfeeding women’s in the EU are also
considered on a priority basis about their health, protection and support
against medicines. Information should be provided to these populations,
especially during pregnancy and lactation for their exposure during clinical
trials. The safety evaluation in lactating women with medicinal product should
be evaluated by:

The analysis of plasma concentrations of
the breastfed infants;

Evaluation of the concentration of
medicinal product in milk;

By assessing the adverse effect case
reports and their follow-up;

Information should be collected by
retrieving the data regarding different levels of risks during lactation,
conclusion of pharmacokinetic studies and non-clinical studies.27

safety evaluation of medicinal products in these population is also evaluated
by the use of pharmacogenomics in the pharmacovigilance process. The “Guideline
on key aspects for the use of pharmacogenomics in the pharmacovigilance of
medicinal products” in the EU was established on 01 April 2016. The EMA till
date has published numerous considerations and guidance on technical and
therapeutic specific during the drug life cycle of a drug. The overview of
these guidelines on pharmacogenomics is elaborated below in Figure 1,
which helps the stake holders to
prepare marketing authorisation applications for human medicines: 28, 29

EMA = European Medicines Agency, FDA = Food and Drug Administration, PG =