Safety Pharmacology

Safety Pharmacology-02.
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Safer Medicines Report
Safety Pharmacology working group report
November 2005
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Safety Pharmacology-02.qxd 11/4/05 20:38 Page 2
Contents
Page
Summary of key findings and recommendation 3
Chapter one: Introduction 5
Chapter two: General/secondary pharmacology studies 8
Chapter three: Cardiovascular and renal safety pharmacology 10
Chapter four: Respiratory safety pharmacology 12
Chapter five: Central nervous system pharmacology 14
Chapter six: Hepatic function 16
Chapter seven: Gastrointestinal safety pharmacology 18
Chapter eight Sensory safety pharmacology 20
Chapter nine: Immuno-safety pharmacology 22
Chapter ten: Paediatric indications 24
Chapter eleven: Biotechnology compounds 26
Chapter twelve: Compounds selective for human targets 28
Chapter thirteen: Education and training 29
References 32
2
Summary of key findings and recommendation

A review of human safety information concluded the
first administration to man of NCEs is very safe. CNS pharmacology
This suggests that the current paradigm for safety Neuropsychiatric adverse events (such as somnolence,
testing for untoward effects related to the major life dizziness and asthenia) have been shown to be dose-
sustaining physiological systems (respiratory, limiting in a number of Phase I/II clinical trials as well
cardiovascular and major CNS effects) successfully as accounting for 12% of drug withdrawals from the
prevents compounds being administered to man at market. In addition to these effects there is increasing
concentrations that may cause these effects. The concern related to the potential for CNS active drugs
establishment of dose response in these models clearly to cause adverse affective disorders (anxiogenic effects
fits with the successful identification of hazard and and suicidal tendencies). Animal models are used to
careful risk assessment prior to early clinical detect drugs with the potential to have anxiolytic and
evaluation. antidepressant activity, although the value of these
models to detect untoward affective effects is
Ninety-five medicines withdrawn from the US market unknown. This should be an area of further research to
between 1960 and 1999 were reviewed to try to develop animal models that can be used to test for
understand the main causes for ADR-related drug anxiogenic/depressant activity.
withdrawals. The principal interesting clusters of
reasons were: arrhythmias – 12%; neuropsychiatric
effects / abuse liability / dependency – 12%; Sensory function
hepatotoxicity – 9%; bone marrow toxicity- 7%;
allergy- 6%. The incidence of adverse drug reactions on vision and
hearing is relatively low compared with the incidence
of headache, nausea & vomiting, diarrhoea and
dizziness, although the consequence to volunteers and
Understanding proarrhythmia: patients may be greater. However, it is probable that
symptoms (changes in vision and tinnitus) would be
Considerable emphasis has been placed on studying
detected prior to the risk of long-term damage.
drug effects on the QT interval. However, the real risk
Nevertheless, investments should be made to increase
to human safety is the risk of causing Torsade de
the understanding between drug effects on visual
Pointes (TdeP), for which QT prolongation is a
function in animals and man to further refine non-
biomarker. The relationship between QT
clinical testing paradigms. Furthermore, studies
prolongation and TdeP is poorly defined and should
should be undertaken to develop predictive in vitro
be the subject of further non-clinical and clinical
tests of ototoxicity.
research. Such studies may support the safe
development of novel therapies that may otherwise be
discarded during non-clinical testing.
Immune mediated adverse events of low
frequency
Abuse potential There is confidence that currently available non-

clinical models are able to detect immunosuppression
The potential for centrally active drugs to have abuse and impaired host resistance despite the validation of
potential and drug withdrawal reactions is an area of these methods being incomplete. Methods to identify
increasing regulatory interest. Although non-human allergenicity have been widely used and for contact
primates are frequently used for these studies, literature sensitization several approaches are validated. There
data suggest that the rat has similar predictive value to remains a need to gain full acceptance for the methods
man. A systematic comparison between the rat and available to detect respiratory and gastrointestinal
non-human primate is required to identify the sensitisers. Approaches for the identification of
preferred species to predict this liability in man. autoimmune responses or idiosyncratic immune
3
response have proven to be elusive and there is a need identification of more efficacious medicines. The
for more intensive study. This should include current requirements for non-clinical studies prior to
consideration of genetic susceptibility factors and first dose in man needs to be re-evaluated with the
environmental factors (diet, overall health status, life objective of permitting limited, highly controlled
style etc). Furthermore, it is pertinent to ensure that all human studies to be conducted safely. Experience
information relevant to a consideration of immune with Safety Pharmacology studies together with
function from conventional toxicity studies, and an conventional toxicology studies has given reassurance
appreciation of cytokine expression patterns are that highly toxic compounds are readily detected.
included in an overall evaluation of impacts on Furthermore, safety pharmacology studies have great
immune status. potential to support first in human studies using ‘novel’
non-clinical safety paradigms.
Training and education for safety

pharmacology and clinical pharmacology Improving non-clinical testing paradigms
through data sharing
Formal training in life sciences within the UK has been
steadily declining over the past 10 years and in Developing better non-clinical testing paradigms is in
particular under graduate and post graduate training the interest of the patients, doctors, regulatory
involving the use of animals, in particular in vivo, in authorities and the pharmaceutical industry.
research has seem a marked decline. A clear need to Experience with groups such as ILSI/HESI has
invest in formal training within the UK exists. The shown that considerable advancements in our
number of pharmacology departments providing knowledge of the predictivity of non-clinical tests can
undergraduate training must not be allowed to reduce be made through the sharing of anonymous data. Such
further. Post-graduate training needs to be supported activities can effectively review current test paradigms,
more consistently with funds available to be targeted make recommendations for change and then assess
specifically at pharmacology and toxicology thus the value of these changes stimulating a cycle of
allowing development of safety pharmacologists with positive change.
the appropriate experience. Initiatives within industry
together with the BPS and BTS are welcomed but are In order to achieve the above proposals we
insufficient to meet the future needs for industry, recommend the creation of a UK centre,
academia and often overlooked the regulatory bodies perhaps virtual, for development of Drug
who will face dossier submissions containing data with Safety Sciences. Such a centre would
increased complexity. Continual professional facilitate the sharing of data without
development and a formal accreditation system to compromise to commercial interest and
support the development and maintenance of enable structured assessment of the
individuals involved in the non-clinical risk concordance between safety pharmacology
assessment of new medicines should be considered. studies in animal models against clinical
outcome to be prospectively assessed and
improved. Such a centre would also provide
First in human paradigms the academic focus to support the training of
non-clinical and clinical pharmacologists
Early and more efficient evaluation of new molecules and toxicologists.
together with more rapid validation of novel targets in
humans will lead to a major advance in the
4
Chapter one - Introduction

1.1 Studies conducted to investigate the defining the concentration/dose-response
pharmacology of new chemical entities (NCEs) relationship for effects in non-clinical models
are frequently classified as: that are used to predict the likely
pharmacologically mediated adverse effects
● primary pharmacodynamics (studies to associated with either the pharmacology of the
investigate the designed mode of action primary therapeutic target or with a secondary
expected to provide the desired clinical target that happens to be a property of the drug.
benefit); Information from safety pharmacology studies
● secondary pharmacodynamics (studies is used to guide the starting dose and set likely
designed to explore the broader stopping criteria in initial clinical studies and
pharmacology of a compound e.g. actions not also provides guidance on potential adverse
expected from its primary mode of action that events for which monitoring in further clinical
may arise from additional actions of the trials is appropriate. Safety Pharmacology also
compound); plays a role in understanding drug toxicities
identified in humans during clinical evaluation.
● safety pharmacology (studies designed to
investigate the potential undesirable
1.4 The design and conduct of non-clinical safety
pharmacodynamic effects of a substance on
pharmacology studies has been defined in ICH
physiological functions in relation to exposures
S7A (ICH S7A Safety Pharmacology Studies for
within the therapeutic range and above).
Human Pharmaceuticals, CPMP/ICH/539/00)
1.2 Adverse events are defined as any untoward that was introduced in 2001. Thus, prior to the
medical occurrence in a patient or clinical first administration to humans, core battery
investigation subject administered a (cardiovascular, central nervous and respiratory
pharmaceutical product and which does not system assessment) studies will be completed to
necessarily have a causal relationship with this investigate the safety pharmacology of the NCE.
treatment. Adverse Drug reactions are a subset A further non-clinical guidance document on
of Adverse Events that are thought to be causally the conduct of Safety Pharmacology Studies for
related to the use of a medicine. Adverse Events Assessing the Potential for Delayed Ventricular
and Adverse Drug Reactions can further be Repolarisation (QT Interval Prolongation) by
defined as seriousness criteria or by severity Human Pharmaceuticals (ICHS7B) has also
ratings (such as severe, moderate or mild). recently been finalised. Understanding the
Serious Adverse Events are those that s result in safety pharmacology associated with a new
death, require hospitalisation or extension of disease target has significant potential to reduce
hospital stay, are life-threatening, result in failure in development. Furthermore the design
persistent or significant disability or are a cause of Safety Pharmacology packages should be
of congenital abnormality. In general, severe influenced by an understanding of the target, its
adverse events prevent regular activities and are distribution and function and not simply
not relieved with symptomatic treatment. through fulfillment of ICH S7A. Mechanistic
Moderate ADR’s are bothersome, interfere with understanding will lead to better understanding
activities and are only partially relieved with of risk/benefit in man.
symptomatic treatment with mild ADR’s being
slightly bothersome and are relieved with 1.5 A literature review (Sibille et al., 1998) and an
symptomatic treatment. analysis of Phase I clinical trials from 4 major
pharmaceutical companies (the working group
1.3 Non-clinical Safety Pharmacology testing (in was blinded to the therapeutic class under
combination with other non-clinical sciences) is evaluation) has demonstrated that the FIH trials
directed towards prevention of serious ADR’s in are very safe with few, if any, serious ADRs being
early clinical testing. This is approached by reported. This suggests that safety testing for
5
untoward effects related to the major life reasons (Centre for Medicines Research 2003).
sustaining physiological systems (respiration, Non-serious ADR’s are often mechanism, drug
cardiovascular and major CNS effects e.g. class or disease related and may limit the utility
convulsions) are successfully preventing of the medicine but usually do not pose a
compounds being administered to humans at significant safety issue. Serious ADR’s in Phase
doses that may cause these effects. It should also 2b or Phase 3 tend to occur at low frequency
be noted that these initial clinical studies are and may be related to the pharmacology or to
conducted extremely diligently with intensive the chemical properties of the drug. The former
monitoring for the emergence of potential should be predictable from safety
ADR’s. Such careful entry into man has pharmacology assessment whereas the latter
prevented serious ADR’s occurring frequently may induce toxicity via direct chemical toxicity
even in drug classes commonly associated with or via hypersensitivity or immunological
high toxicity e.g. cytotoxic anticancer agents. mechanisms. The impact of such toxicity is
Adverse events do occur in these early studies always very high requiring warnings,
but are generally more frequently related to the precautions and contraindications or even
procedure rather than the drug under study. withdrawal from development or if detected
post approval drug withdrawal from marketing.
1.6 The above analysis from 4 pharmaceutical
companies revealed with remarkable 1.8 The actual incidence of serious ADR’s
consistency that common ADRs (10–30% of produced by marketed medicines is difficult to
volunteers) were: headache, nausea & estimate accurately. ADR’s are thought to be
vomiting, diarrhoea and dizziness. A large responsible for 4–6% of hospital admissions
number of other lower frequency ADRs was (Stephens 2004) with up to 106,000 deaths per
reported – these tended to be specific to the year in the USA attributed to ADR’s (Lazaraou
molecule under investigation and often related et al 1998). The latter figure may be an over
to the mode of action. A review of the dose- estimate but there is no doubt that ADR’s cause
limiting toxicities for 25 randomly selected significant patient harm and are a significant
molecules tested in single and multiple doses in burden to health care. Although the frequency
healthy volunteers revealed that seven may be very low the establishment of the
molecules had no dose-limiting ADRs. connection between pharmacological
Interestingly, nausea and vomiting, diarrhoea mechanism and the event may yield
and neuropsychiatric effects were dose-limiting opportunities to reduce risk. For example the
in four cases but these ADR’s were not relationship between hERG potassium channel
readily identified from the non-clinical blockade, prolongation of the QT interval and
safety pharmacology data. Conversely, safety induction of Torsade de Pointes (TdeP) has led
pharmacology testing clearly predicted effects to the rapid development of non-clinical
upon the QT interval of the electrocardiogram, screening tests that will help identify molecules
blood pressure effects, respiratory effects and with a reduced risk for this ADR.
diuresis. These findings are in agreement with
the published literature that single dose non- 1.9 Ninety-five medicines withdrawn from the US
clinical safety studies both under and over market were reviewed to try to understand the
predict the effects seen in man (Olson et al main causes for ADR-related drug withdrawals.
2000; Greaves et al 2004). Effects that The principal interesting clusters of reasons
frequently emerge during Phase 1 clinical were: arrhythmias – 12%; neuropsychiatric
evaluation and appear to be poorly predicted effects / abuse liability / dependency – 12%;
or extrapolated from the animal studies and hepatotoxicity – 9%; bone marrow toxicity- 7
warrant further development of predictive tests %; allergy- 6% (Stephens 2004). An earlier
appear to be in the areas of GI disturbance and review of 121 medicines withdrawn from the
neuropsychiatric effects. worldwide market between 1960 and 1999
showed a similar spectrum with hepatic toxicity
1.7 Approximately one in six drugs in clinical 26%, haematological 10%, cardiovascular 9%,
development is discontinued for clinical safety skin effects 6% and carcinogenicity issues 6%.
6
1.10 With the above background it is clear that pharmacology. Is the compound bioavailable
non–clinical safety assessment and safety and tolerated by the species under
pharmacology in particular is providing consideration? This may influence the choice of
information that is preventing harmful route of administration and therefore, the use of
candidate drugs entering clinical development, either conscious or anaesthetised animals.
is identifying some key and important adverse
events but is clearly failing to predict all adverse 1.12 Advances in technology and in particular the
events. In considering areas for future research miniaturisation of telemetric devices will give
it is clear that much is effort has been devoted to opportunities to improve the non-clinical
understanding drug induced QT interval models and potentially positively influence 3R
prolongation. There clearly remains a need to initiatives. There is a need to agree international
understand drug induced pro-arrhythmia and acceptance criteria for the validation of new or
its true relationship to altered repolarisation. improved non-clinical models. In addition, with
Hepatotoxicity, bone marrow toxicity and the continuous recording of physiological
immune mediated toxicity and GI toxicity are parameters and concomitant measurements of
areas warranting further development. It is drug plasma levels, these new technologies
striking that neuropsychiatric effects account for have great potential to be used to develop
a large group of drug withdrawals and they are a better understanding of the pharmacokinetic:
also prominent as dose limiting toxicities in pharmacodynamic relationship in safety
early volunteer patient studies that are not well pharmacology studies. Such an approach
predicted from the non-clinical models. may better inform clinical colleagues of
the likely adverse effect concentration in
1.11 The study design and choice of species to be man and potentially improve our confidence in
used in safety pharmacology studies needs to the safety margins defined in non-clinical
take into account a number of factors. Firstly, studies.
the known pharmacology of the compound, is
the target under investigation expressed in the 1.13 The changing demographics of the population
non-clinical species and/or does the compound with increasing numbers of elderly people
interact with the animal target? This is of requiring multiple-drug therapy is increasing
particular importance when studying the the concerns around polypharmacy. There is a
potential safety implications of the primary need to develop better testing paradigms.
7
Chapter two - General/secondary pharmacology studies

2.1 Actions of a potential drug at molecular targets animals and facilitates the screening of larger
(receptors, ion channel and enzymes) other than numbers of compounds during candidate drug
the desired therapeutic target may translate into selection.
deleterious, beneficial or no functional
effects. Increased knowledge of the ‘secondary’
target interactions can be expected to lead Challenges
to a better understanding of potential adverse
pharmacology. 2.5 The in vivo approach may not be sensitive to
subtle effects and inter species variation needs to
be considered when extrapolating from animal
models to man. Should the animal target have
Current situation
higher affinity for the drug false positives will
occur, potentially resulting in loss of valuable
2.2 Secondary pharmacodynamic studies have been
candidate drugs. These studies require the use of
defined as those that investigate the mode of
animals and so prompt ethical considerations;
action and/or effects of a substance not related to
its therapeutic target (ICH S7A, 2000).
2.6 The in vitro approach permits generation of
large databases with defined ‘hits’ at specific
2.3 Secondary pharmacology has traditionally been targets. For many targets the correlation
assessed in vivo and effects observed followed up between binding affinity and functional
using a range of tissue preparations in vitro. consequence remains unclear. Often the target
Effects are quantified and a mechanism of is a recombinant human target and an
action elucidated by application of in vitro assumption is made that the affinity is identical
studies which may be radio ligand binding to the native human target. A major question is
assays, enzyme assays or cell/tissue based whether in vitro radioligand binding assay data
functional assays to determine which molecular is predictive of secondary pharmacology effects
target the drug has affinity for. The in vivo in man. There is a clear need to establish
studies are performed where possible in confidence in such predictions;
conscious animals and involve investigation of
the effects of the drug on physiological systems.
This in vivo approach reveals unexpected effects Recommendations
in an integrated system, determines the
therapeutic margin and so aids risk assessment 2.7 Establishment of databases that bridge the non-
when entering clinical development. clinical data with observations from clinical
studies will clearly aid the predictivity of the
2.4 More recently the above approach has been non-clinical data. Access to data that summarise
reversed since it has become possible to screen the non-clinical secondary pharmacological
for binding against a wide range of molecular targets for marketed drugs would be the first step
targets (receptors, ion channels, transporters towards enhancement. Commercially available
and enzymes), often derived from human tissue databases are being developed (DrugMatix™,
or human cell lines. The methods employed are BioPrint™ and Receptor selectivity mapping
predominantly radioligand binding or enzyme database are examples) but to fully exploit this
activity assays. For activity that occurs within knowledge access to data from compounds in
the therapeutic concentration range additional development (including those that fail) as well as
studies to determine functional consequence of marketed drugs will greatly facilitate this
the secondary pharmacological activity is understanding. Such a database could be
warranted. The methods used are cell/tissue established within a confidential framework
assays together with specifically designed in vivo should a centre for the safety assessment of drugs
studies. This approach minimizes the use of be set up.
8
2.8 The emergence of large databases and their developing infrastructure to produce highly
considerable potential in this area highlight skilled in-vivo pharmacologists is essential.
the need for bio-informatic expertise. There
is clearly a need to focus training and 2.9 The development of databases that facilitate a
development of this key skill. Furthermore, better understanding of the functional
the availability of skills to integrate the consequence of secondary targets will aid
molecular information with in vivo development of structure activity tools leading
pharmacology has diminished. Focus on to better drug design.
9
Chapter three - Cardiovascular and renal safety pharmacology

3.1 The evaluation of drug effects on the primates) and in humans is good. This is
cardiovascular system can be effectively consistent with the low incidence of
conducted using a range of techniques and non- cardiovascular ADRs in FIH trials and the use
clinical species. of similar animal models in Drug Discovery to
detect novel cardiovascular products as new
therapeutics.
Current situation
3.5 Of great scientific, medical and regulatory
3.2 The development of telemetry techniques in
interest is in better understanding adverse drug
conscious animals has had a major impact on
effects on cardiac repolarisation (QT interval of
the conduct of cardiovascular safety
the ECG) and its associated risk of causing the
pharmacology studies. These techniques
life threatening arrhythmia, TdeP. Several
support the continuous collection of a range of
studies have established that a vast majority of
physiological data, including heart rate, blood
compounds that prolong the QT interval in
pressure, left ventricular pressure, ECG and
man do so via inhibition of the potassium
body temperature over 24 hours. Thus, drug
current, IKr. Conversely, not all IKr blockers
effects can be studied under ‘normal’
prolong the QT interval in vivo. During the last
physiological conditions often using the clinical
2–5 years, significant advances have been made
route of administration (e.g. oral or intravenous).
in our ability to test for drug effects on the IKr
The use of these technologies also support
current and a range of other cardiac ion
using a cross-over study design (each animal
channels. These in vitro assays, in conjunction
receives active treatment and vehicle) that
with the above in vivo cardiovascular/cardiac
provides a high statistical power to detect drug
studies, are able to detect a vast majority of
effects which, in turn, reduces the number of
compounds known to prolong the QT interval
animals used in each study. In addition, using
in man. The validity of these assays has been
telemetered techniques drug effects can be
established through ILSI/HESI and also JPMA
studied at plasma Cmax and Cmin levels with
initiatives. Both of these groups studied a range
the potential to define the pharmacokinetic:
of compounds with known torsadogenic risks in
pharmacodynamic relationships. Furthermore,
man in comparison with non-torsadogenic
effects of metabolites may be investigated.
compounds and were able to differentiate
Echocardiography applied to animal studies is
between these two classes of compounds.
a valuable technique that is probably under
utilised. It is also important to consider the 3.6 Thus, the risk of drug-induced changes in
need to measure regional blood flow on a case- cardiac repolarisation in man has been greatly
by-case basis. reduced. Despite these advances a major area of
3.3 Anaesthetised animals can be used when, for challenge in the cardiac/cardiovascular field
example, the compound is poorly tolerated in remains the understanding of the relationship
the chosen species (for example due to emesis) between drug effects on cardiac repolarisation
or relatively little is known about the compound and the risk of causing cardiac arrhythmias. This
at the time of evaluation. This raises the is an area that this working group recommends
complication of the unknown effect of further investment in both non-clinical and
anesthesia on responses to the compound under clinical research (see section 1).
study, although it is the view of this working
group that, at least the anaesthetised dog 3.7 The effects of NCEs on renal function can be studied
responds to cardiovascular effects of drugs in a in conscious animals, frequently the rat, following oral
qualitatively similar extent as the conscious dog. dosing. The primary end points are urine volume and
electrolyte concentrations. Although the methods
3.4 The concordance between cardiovascular effects used have not changed greatly in the last decade or so,
of drugs in animals (in particular dogs and the low incidence of renal adverse effects would
10
suggest that they are effective at detecting risks for that this working group recommends further
human safety. investment in both non-clinical and clinical
research.
Challenges and opportunities 3.11 The challenges for the future include the
further development of telemetry methods to
3.8 Greater understanding of structure-activity support the recording of more physiological
relationships will enhance drug candidate end points in a single animal. Companies are
selection. However, there is no crystal structure developing methods to record pulmonary
of the hERG channel known at present due to its mechanics, so the ideal would be to study drug
membrane bound nature. Site directed mutation effects on cardiovascular, cardiac and
and homology models based on the template pulmonary function in a single non-rodent
bacterial KcsA channel have been used to infer animal model. This would provide an excellent
important amino acid residues likely to be evaluation of the main physiological systems of
involved in the drug/channel interaction. Such concern to the safety pharmacologist and
models may support in silico screening to reduce and refine the use of animals in non-
minimise drug interactions with the hERG clinical testing.
channel. Studies to investigate drug effects on
cardiac ion channels should of course include 3.12 Consideration should be given to understanding
other ion channels such as sodium and calcium. drug effects under conditions of ‘physiological
Furthermore, understanding pharmacogenetics challenge’, for example, to improve our ability
and the importance of ‘outliers’ is likely to give to detect drugs that may cause postural
significant benefit in assessing human risk of hypotension.
cardiovascular drug toxicity.
3.13 Changes in cardiovascular function can lead to
3.9 The potential to expand in silico models such as, pathological consequences in toxicology testing.
“CardioprismTM”, using the IC50 profile for It is therefore important, and a current
different ion channels and a library of validated challenge, to integrate findings in cardiovascular
computer models to simulate the effects of safety pharmacology studies with those
compounds on in vitro preparations should be observed in regulatory toxicology studies.
explored further. The library contains in silico
models of the sinus node, Purkinje fibers, atrial
and ventricular myocytes including epicardial, Proposals and recommendations
midmyocardial and endocardial cells may have
future value to reduce adverse cardiac effects of 3.14 Considerable emphasis has been placed on
new potential drugs. Furthermore, these models studying drug effects on the QT interval.
are customized to reflect different species However, the real risk to human safety is the
common in non-clinical testing, namely rabbits, risk of causing TdeP, for which QT
dogs, and guinea pigs. prolongation is a biomarker. The relationship
between the magnitude of QT prolongation
3.10 The main area of challenge in the cardiovascular and TdeP is poorly defined and should be the
field is the improvement of the understanding subject of further non-clinical and clinical
of the relationship between drug effects on research. In vitro animal models are being
cardiac repolarisation (QT interval) and the investigated such as the rabbit Langendorff and
risk of causing TdeP arrhythmias, since the ventricular wedge preparation to identify
former is only a biomarker of the latter. The potential non-proarrhythmic QT prolonging
characteristics of subpopulations such as agents. Such studies may support the safe
diseased, young and old individuals as well as development of novel therapies that may
male/female differences have not sufficiently otherwise be discarded during non-clinical
been investigated. TdeP arrhythmia is an area testing.
11
Chapter four - Respiratory Safety Pharmacology

hexamethonium to the respiratory tract without
Current situation adequate non-clinical evaluation by this route of
administration. Adverse events in the respiratory
4.1 The ICH S7A guideline for safety pharmacology system that led to withdrawal from the market
clearly defines a need for evaluation of potential are rare, accounting for only 2 of 121 if
effects upon the respiratory system prior to entry anaphylaxis is excluded.
into man.
4.5 The incidence and extent of adverse reactions
4.2 The respiratory system has approximately 60 in the respiratory system are probably poorly
different cell types involved in its homeostasis understood, particularly the influence of disease,
and so it is particularly complex to study and pharmacogenetics and drug-drug interactions.
interpret drug-induced effects. It has been Complications from agents affecting respiratory
simpler to define effects upon the respiratory pattern during sleep is similarly poorly
system as mediated through the structures understood. The animal models available to
involved with movement of air or through gas assess respiratory function are complicated by
exchange. Broad classes of pharmacological clear species differences. For instance alveolar
responsiveness can be discriminated through surface area shows marked difference between
the functional changes induced. For instance humans and rats leading to very different
sensory irritants generally decrease respiratory concentrations present in lung fluid following
rate whereas pulmonary irritants increase rate. an equivalent inhaled dose. Experience with
insoluble particulate compounds has shown the
4.3 There are major challenges in extrapolating rodent is good at hazard identification but poor
between species. For example aspirin induced in defining risk because of the alveolar
asthma is common in humans with 21% of macrophage ‘overload’ phenomenon when this
adults and 5% of children affected yet there is no cell type is key for clearance.
predictive animal model. Evidence from cross
4.6 Technology to measure lung mechanics,
sensitivity between other non-steroidal anti-
particularly in unrestrained conscious animals,
inflammatory (93–100% of aspirin sensitive
is under-developed. The tests identified in ICH
patients responding to ibuprofen naproxen and
S7A regarding respiratory function monitoring
diclofenac) and paracetamol (2% cross
define (Murphy, 2002) a basic minimum
reactivity) suggest clear mechanistic differences
requirement but in some instances suggest
and possibly a genetic involvement. These
inappropriate insensitive measures such as
observations taken together with the availability
blood gas analysis.
of over 25 years of published clinical findings
with potentially fatal aspirin induced
bronchoconstriction suggest effects upon the Challenges and opportunities
respiratory system are under reported.
4.7 The ability of non-clinical studies to detect
4.4 The absence of frequent or profound adverse chronic pulmonary effects is poorly understood,
reaction in the respiratory system during initial together with our ability to interpret the clinical
clinical evaluation suggest non-clinical testing, as concordance of the data. The ability to detect
currently performed, appears to prevent major potential risks to human safety would be
respiratory reactions in early clinical enhanced following future enhancements in
development. In a study reported by Sibile et al respiratory technologies. Many features of the
(1998) there were no life threatening events in multi component respiratory system are best
1015 healthy volunteers during 54 Phase 1 studied in the integrated whole animal. In vitro
studies. However, the profound consequence of studies while useful to explain specific cellular
an adverse event (even if rare) is illustrated by the target toxicities are unlikely to be helpful in
death of a volunteer following administration of assessing functional respiratory function. The
12
focus should therefore be on development and effects) in man with changes in non-clinical
refinement of animal models of human parameters.
respiratory function. Murphy (2002) has
classified the respiratory system into two
compartments, the ventilatory pump and the Proposals and recommendations
gas exchanger. Respiratory depression is
accompanied by changes in ventilatory 4.9 The low incidence of known severe respiratory
parameters (rate, tidal volume, air flow and ADR’s suggests the current general approach
airway resistance together with lung compliance should not be minimized.
as a measure of ‘elasticity’) which although
technically demanding can be measured. 4.10 The present regulatory focus within ICH S7A of
Greater adoption of these methods in safety using blood gas analysis techniques (or pulse
pharmacology will facilitate identification of oximetry) solely as a means of non-clinical
drugs that adversely affect the respiratory respiratory safety assessment is inappropriate
system. It is clear that improved methods for due to the insensitivity of these approaches.
detecting airway obstruction are needed. Hence, the content of ICH S7A is suboptimal
and needs further modification to provide the
4.8 The development of micro – sensors and best non-clinical datasets for regulatory
transponders has led to opportunities in submissions.
developing telemetric methods for use in
unrestrained conscious animals. This will open 4.11 An increased willingness to share data for drugs
opportunities to broaden the species used in not taken into human clinical development and
respiratory function testing. Experience to date those with clinical experience to fully
has focused upon the rodent with expertise in understand the frequency and significance of
other species restricted to a few specialist changes in non-clinical models would greatly
centres. The validity of these new methods improve the understanding of their predictive
would benefit from a wider evaluation of drugs value. This could be facilitated by creation of a
known to affect the respiratory system in man centre dedicated to safety evaluation of
through comparison of the changes in FEV1 medicines. The routine inclusion of simple
(routinely carried out in clinical evaluation of respiratory function testing during early clinical
drugs known or suspected of adverse respiratory evaluation should be considered.
13
Chapter five - Central nervous system (CNS) safety

pharmacology
Current situation that affect drugs in all stages of development. It

is estimated that nausea and vomiting occur in
5.1 Effects upon the CNS are a significant cause of approximately 30% of initial drug trials and in
adverse drug reactions ranging from non- approximately 10% of phase 1 studies this effect
compliance with drug therapy as a consequence dose limiting. The non-clinical safety
of, for example, weight gain, nausea or anxiety pharmacology studies did not reliably predict
to severe reactions such as convulsions. Less the effect seen in man suggesting better models
readily recognizable effects are also important as are required.
a consequence of an aging population resulting
in a higher prevalence of neurodegenerative Food intake, weight gain and weight loss.
diseases. Effects mediated through an adverse
reaction in the CNS have been considered 5.5 Several classes of drugs have been associated
under the following headings: with disturbance of food intake and/or
bodyweight. The effects are generally of greater
Abuse Potential and Addiction Liability consequence in the very young, elderly or
severely ill patients. These parameters are
5.2 The potential of centrally active drugs to be routinely measured in conventional toxicology
associated with abuse potential/addiction studies. Furthermore, specific models to assess
liability is an area of increasing regulatory appetite are also available and appear to have
interest. Although studies to investigate these good predictive utility. There does not appear to
properties are not undertaken on a routine be a need for development of further more
basis in safety pharmacology studies they sophisticated tests other than to follow up
should be considered as part of the investigation specific drug related findings.
of the broader secondary pharmacology
properties of a NCE. Although the non-human Neuropsychiatric disorders
primate is studied extensively there is
considerable evidence to support the use of the 5.6 Non-clinical evaluation of drugs that do not
rat in self-administration studies to predict penetrate the blood brain barrier does not
abuse potential in man. routinely include any sophisticated assessment
for centrally mediated CNS effects such as
Drug induced Dizziness anxiety, depression, mood disturbance, learning
and memory or dependence. The current
5.3 The causality of dizziness is often ascribed to approach to assess specifically drug-induced
drug treatment, despite the subjectivity of the changes is prompted by evidence of brain
diagnosis and the fact that it rarely causes drug penetration or signals for the initial broad-
withdrawal. There does not appear to be a good spectrum assessments – Irwin or Functional
non-clinical model to predict this effect in Observational battery. In addition, animal
humans. It is unlikely, given the difficulty in models are widely used to detect primary
designing objective human measures, that a pharmacological effects that may have utility in
realistic animal model will be valuable and the treatment of anxiety and depression.
accepted since the mechanisms associated with However, the potential of these models to detect
dizziness are diverse. untoward drug effects (anxiogenic and
depression) is poorly defined. Nevertheless,
Nausea and Vomiting given the prevalence of neuropsychiatric
disorders in both clinical development and in
5.4 Nausea and vomiting are common adverse clinical use post marketing this approach should
effects of drugs often mediated through the CNS be re-considered.
14
USVs in many different social and emotional

Challenges and opportunities situations. Measurements of USV’s in e.g. the
open field assessment as part of the functional
5.7 Given the high incidence of nausea and vomiting observational battery (FOB) may lead to the
observed in clinical trials either greater emphasis identification of untoward drug effects.
on observations in non-clinical safety studies is
required or improved models to predict these
effects in man are required. The ferret, shrew and
marmoset show promise as useful species. This is Proposals and recommendations
an area where better prediction aiding design of
new drugs may yield considerable human benefit. 5.11 The potential for centrally active drugs to have
abuse potential is an area of increasing
5.8 The potential of animal models (currently used regulatory interest. Although non-human
to detect agents that may be of benefit in the primates are frequently used for these studies,
treatment of anxiety and depression) to identify literature data suggest that the rat has similar
potential anxiogenic and prodepressive effects predictive value to man. A systematic
is unknown and should be studied further, comparison between the rat and non-human
although it must be recognized that animal primate is required to identify the preferred
models used to detect, for example, species to predict this liability in man. In
antidepressant drugs are not animal models of addition to these effects there is increasing
depression. concern related to the potential for CNS active
drugs to cause adverse affective disorders
5.9 The value of the rat as a model to detect (anxiogenic effects and suicidal tendencies), as
potential abuse potential of CNS active drugs, well as abuse potential and drug withdrawal
in comparison to the non-human primate, reactions. Animal models are used to detect
should be thoroughly investigated. drugs with the potential to have axiolytic and
antidepressant activity, although the value of
5.10 The potential of new techniques to study CNS these animals to detect untoward affective
effects of NCEs should be considered. For effects is unknown. This should be an area of
example, the measurement of high-frequency further research to develop animal models that
ultrasonic vocalisations (USVs) in the rat. can be used to test for anxiogenic/depressant
Ethological studies have revealed that rats make activity.
15
Chapter six - Hepatic Function

injury is emerging. Hereditary defects in
Current situation individual bile salt transporters have been
associated with familial intrahepatic cholestasis
6.1 Mechanisms of drug induced liver dysfunction type 1 (FIC1 gene), type 2 (BSEP gene), type 3
are complex and remain relatively poorly defined (MDR3 gene) and Dubin Johnson Syndrome
and require better mechanistic understanding. (MRP2 gene). It is notable that several drugs
Liver toxicity and functional disturbance is that cause liver dysfunction have been shown
probably the most common serious adverse event to impair the transport activity of BSEP
seen in drug development and has account for 9% (Stieger et al 2000).
of drug withdrawals from the US market.
6.2 Drug induced liver dysfunction is detected 6.7 Diagnosis of liver toxicity is problematic. This is
frequently during both non-clinical and clinical linked, at least in part, to our incomplete
evaluation and is the cause of significant understanding of underlying mechanisms.
attrition and project delay. Some compounds cause pathological alterations
that do not result in overt toxicity as assessed by
6.3 Despite non-clinical models readily identifying evaluation of plasma levels of “liver enzymes”
hepatoxicity there are many examples where (e.g. biliary hyperplasia), while sporadic mild
non-clinical models have failed to adequately elevations of liver enzyme levels that are not
identify or characterise the risk to man. Many of accompanied by significant liver dysfunction
the drugs currently on the market are known to occur frequently in the human population. The
have the potential to cause adverse effects on “gold standard” criteria for assessing toxicity to
liver function in certain susceptible individuals the liver in animals plus man are liver histology
(Pritchard et al 2003, Olson et al 2000; plus elevated plasma liver enzyme levels.
Kaplowitz 2001; Boelsterli 2003; Lee 2003.). In Evaluation of liver histology has great value but
some cases the incidence and severity warrants can be difficult to assess in man because of
drug withdrawal (e.g. Troglitazone) in others ethical and safety issues. Also, evaluating small
dysfunction is mild and remains asymptomatic biopsy samples can be misleading – so
(eg Gentamycin). diagnostic liver biopsies in man are less
favoured now for diagnostic purposes than they
6.4 Relatively few case examples of liver toxicity were 20 years ago. ALT assesses hepatocellular
have been studied in depth and even where this damage but is not truly liver specific. Significant
has been undertaken our understanding elevations in ALT exceeding small multiples of
remains incomplete e.g. paracetamol. normal control range (with changes less than
1.5-fold generally considered not significant) are
6.5 Liver toxicity that occurs with a very low considered suggestive of liver damage. A
incidence (idiosyncratic) is poorly understood combination of a 3-fold elevation in ALT plus 2-
and in particular the individual susceptibility fold elevation of bilirubin is generally taken to
factors are sparsely known. There is a lack of indicate liver toxicity in man. Other plasma
appropriate experimental models. markers of liver toxicity that are widely used
include -GT, AST, ALP (indicative of
6.6 Greater understanding of the role of drug cholestatic damage) and bilirubin.
transporters in the function of the liver is
emerging and will potentially give better 6.8 Distinction between toxicity and adaptive
insight to mechanism and predictability of response by measurement of traditional clinical
hepatotoxicity. In particular the role of chemistry parameters is currently not
transporters in drug induced cholestatic injury achievable. Identification of better biomarkers,
and the abnormal expression of bile salt chemical or imaging for liver injury would
transporters in disease and drug-induced greatly improve diagnostic capabilities.
16
Appropriate use of the new approaches

Challenges and opportunities alongside conventional toxicity investigations,
to define key molecular events and
6.9 There is a clear need for improved biomarkers susceptibility factors offer the best opportunities
for liver dysfunction. The current methods are to understand mechanism. The role of biliary
widely used but old and in some circumstances efflux transporters in hepatobiliary toxicity is a
unspecific. Opportunities to use improved particularly promising avenue to explore, as is
imaging together with proteomic and the role played by reactive metabolites.
metabonomic methods should yeild new
markers for evaluation.
6.10 Development of improved in silico and in vitro Proposals and recommendations

approaches will aid design of drugs with
reduced hepatotoxicity potential. Structure- 6.14 More consistent and accurate detection/
toxicity databases need to be defined – but diagnosis of drug induced liver dysfunction
before this is feasible we need an improved during clinical trials (rather than post-
understanding of the role played by chemical marketing) using existing technologies with
structure as a determinant of drug-induced liver conventional liver function tests supported by
dysfunction. This should follow from a better more sophisticated causality assessments can be
understanding of mechanisms. The most expected to lead to better and earlier
promising avenues currently are prediction of identification of liver toxicity. This should be
formation of chemically reactive metabolites complemented by research focused on more
and transporter interactions. More complex in sophisticated application of existing approaches
vitro 3-D models (e.g. liver spheroids) and liver (most notably causality assessments), and on
slices, which have the advantage of more detection of novel biomarkers of liver
relevant cell architecture, are an attractive dysfunction.
option but require further development.
6.15 An improved ability to predict and avoid drug-
6.11 Searching for genetic and environmental induced liver dysfunction prior to introduction
susceptibility factors that can pre-dispose certain of drugs into man. Significant progress in this
patients to drug induced liver injury. Although area is likely to require a more sophisticated
some progress is now being made in identifying understanding of the key molecular and cellular
genetic factors, progress to date has been slow. mechanisms that result in drug-induced liver
dysfunction and that influence species
6.12 Improved in vivo models for assessing differences in toxic responses. Particular
compound-induced liver dysfunction and for attention should focus on the roles played by
circumventing species variability. These should drug disposition, chemically reactive
be linked to mechanistic considerations. metabolites, and transporters interactions. The
Transgenic technology could give us outcome from this work needs to be linked to
“humanised” experimental animals, which development and validation of structure-
improve the human relevance of non-clinical toxicity databases, and of in vitro experimental
safety testing in animals. Perhaps generating approaches, that can be used by medicinal
mice that express humanised bile canalicular chemists and bioscientists to design and select
transporters (BSEP, MDR1, MRP2 etc.) could safer compounds during drug discovery.
provide a relevant model system for improved
assessment of hepatobiliary toxicity. In this 6.16 Identification of susceptibility factors that
regard, an improved understanding of ADME determine why some individuals are markedly
properties in animals vs. man should also be of more susceptible to drug-induced liver
great value. dysfunction than the general population. These
susceptibility factors are likely to be
6.13 Improved ability to define mechanisms of liver multifactorial, and could well involve a complex
toxicity, once this is observed in man. interplay between genetics and environment.
17
Chapter seven - Gastrointestinal (GI) safety pharmacology

7.3 The challenge of defining the non-clinical GI
Current situation liability of a potential new medicine is not only
hampered by biological complexity of the
7.1 Adverse reactions in the gastrointestinal tract system under scrutiny, but also by fundamental
appear to occur at all stages of drug development differences in terms of GI function between the
and in subsequent clinical use. Drug-induced rat, the most commonly used species in
disturbances of GI function negatively impact research, and man. For example the rat does not
patient safety, compliance, quality of life and posses a gall bladder and does not vomit. This
clinical benefit. The impact of GI ADRs in terms raises important questions about the relevant
of drug withdrawals from the market has been species for conducting GI assessment. Based on
minimal, with only one example, pirprofen, in GI functional homology for man, especially
the period from 1960 to 1999, however, drugs motility, gastric emptying and pH, particularly
with labeling restrictions are commonplace, for in the fasted state which is analogous to the
example Lotronex (Fung et al., 2001). conditions prevailing in many Phase I trials, the
dog, is perhaps a more relevant species.
Moreover, the dog was a better predictor of
7.2 GI ADRs are some of the most frequently clinical GI ADRs than the monkey for 25
reported in all phases of clinical drug anticancer drugs. Although physiological
development and for marketed products, as similarity is an important requirement it is only
illustrated by the 700 drugs that are implicated one of many factors that must be considered
in causing diarrhoea. Furthermore, GI ADRs during species selection.
account for approximately 18% of all reported
clinical adverse drug reactions and 20 to 40% of
those in hospitalised patient. Given, however, 7.4 GI ADRs are some of those most frequently
that symptoms of disturbed GI function encountered in healthy volunteers and patients,
are encountered in everyday life, the actual yet assessment of potential new medicines on the
incidence of drug-related effects are most GI system is not a regulatory requirement before
likely extensively under-reported. The majority conducting Phase I trials, nor even for marketing
of reported ADRs are functional in nature approval. It is, however, recommended in the
(nausea, vomiting, dyspepsia, abdominal ICH S7A Guideline for Safety Pharmacology
cramps and diarrhoea or constipation) with a Studies (CPMP/ICH/539/00) that the GI
lesser number related to lesions (e.g., ulceration) system should be studied on a case-by-case basis.
or enhanced susceptibility to infection (e.g., The ICH guideline does not classify GI system as
pseudomembranous colitis). Of these, it is a “core” battery organ system, unlike the
estimated that approximately 80% are Type A respiratory, central nervous system and
predictable pharmacological reactions. Some of cardiovascular systems, of which assessment is
the most numerous and serious GI ADRs are mandated prior to Phase I trials. Moreover, the
attributed to chronic use of nonsteroidal anti- GI system is relegated to a group of supplemental
inflammatory drugs (NSAIDs). Widespread organ systems to be studied only where there is a
NSAID use and associated reports of gastric cause for concern.
complications, has given rise to the acceptance
that NSAID use carries a significant risk of 7.5 Further to the list of parameters in ICH S7A, a
developing peptic ulceration. In a recent recent publication has reviewed GI models and
prospective analysis of 18,820 patients in a UK techniques applicable for use in safety
hospital, 29.6% of all ADR cases were related pharmacology. One important element omitted
to NSAID. Furthermore, NSAID use in the from both ICHS7A and the review by Harrison
US alone is estimated to be responsible for et al., (2004) of particular relevance to
over 100,000 hospitalisations and 1,700 deaths anticancer drugs is nausea and vomiting.
per year. There is no doubt this omission reflects the
18
complexity of the symptom and that there are concentration rather than systemic
no non-clinical models able to relay nausea. concentration/response is needed.
There is, however, a growing understanding of
the causes nausea and vomiting and non-clinical 7.9 Two common major dose limiting effects,
dog and ferret models amenable for safety nausea and emesis, are poorly understood and
pharmacology testing. predicted. Better models are required.
7.6 The influence of GI intolerance on patient

compliance to medication is probably under Proposals and recommendations
reported.
7.10 Placing greater importance on GI-related
observations (e.g., emesis) in acute and repeated
Challenges and opportunities dose toxicology studies, including seemingly
isolated incidences may help trigger formal
7.7 A comprehensive review of non-clinical GI studies of GI function if not conducted
endpoints to determine the concordance routinely. The opportunities to use non-invasive
between non-clinical GI safety models and imaging techniques may enhance the predictive
man, to identify and promote appropriate capability of these tests and should be
models/species and relegate and exclude encouraged.
irrelevant misleading models/species is needed.
Current methods to assess GI function despite 7.11 There is a clear need to develop and validate
being well established have poorly understood non-clinical methods for detecting nausea and
predictive value. A clear need exists to develop emesis potential. Reducing these important side
a better understanding of the models available effects would be expected to facilitate drug
and their applicability to drug evaluation. development and also improve patient
compliance for marketed drugs.
7.8 Given its complexity the GI tract is a system
probably best studied in vivo. Despite this 7.12 Encourage and nurture links between GI
complexity there are clear advantages in specialists in academia and industry. In
understanding molecular targets associated with particular there is a need to understand better
GI dysfunction and this should be an area for the predictive value of the non-clinical models.
future research. There are opportunities to Establishment of a Safety Sciences centre within
combine key GI parameters (eg secretion and the UK that can act as a repository of data
motility) into single in vivo studies. To facilitate would greatly help understanding of the
understanding of GI risk in humans a better existing data available within individual
understanding of the importance of local companies.
19
Chapter eight - Sensory Safety Pharmacology

the relationship between drug effects on visual
Current situation function in man and in animals to established
the predictive value of existing test systems and
8.1 Adverse drug effects in man on the main to develop novel assays.
sensory organs, sight, hearing, taste and smell
are relatively poorly understood and occur with 8.4 Dizziness is a frequently reported adverse event
a relatively low frequency when compared with in man. This may arise through changes in
the incidence of headache, nausea & vomiting, blood pressure (postural hypotension), an effect
diarrhoea and dizziness. However, untoward on the central nervous system (CNS) or an
effects on the sensory organs, especially hearing effect in the inner ear. Non-clinical models are
and sight, could have a significant impact on available to investigate drug effects on balance
volunteers/patients well being. and motor coordination, such as the rota-rod
and activity box, although the sensitivity of
8.2 Behavioral pharmacology studies may detect these models to detect adverse drug effects on
untoward effects on balance and sight, although balance via an effect on the ear has not been
it is probably that significant deleterious effects systematically studied.
on these systems would be required before
changes in behavior would be detected. In 8.5 Ototoxicity is thought to be rare, but possibly
toxicology studies a detailed investigation of under reported (essentially confined to loop
drug effects on the eye are conducted as part of diuretics, aminoglycosides, anti-neoplastic
the clinical examination of animals is performed cytotoxics, aspirin and quinidine) although the
(corneal reflex (dog), anterior chamber and lens impact on the individual if affected is significant.
examination using a slit lamp and examination There is no safety pharmacology test used to
of the vitreous body and the retinal fundus using determine potential effects of NCEs on hearing
an indirect ophthalmoscope and a magnifying and there is no regulatory requirement to
lens). In addition, histological examination of evaluate ototoxicity unless there is a clear cause
potential effects on the structure of the retina for concern. However, early signs of ototoxicity
and optic tract are conducted. (tinnitus) can be detected in volunteers and
patients that would be a signal to stop therapy
8.3 Sophisticated non-clinical tests are available to prior to irreversible damage. This is an area that
investigate drug effects on the retina (the requires basic research to systematically
electroretinogram, ERG) and visual pathway investigate the predictive value of non-clinical
(visual evoked potential, VEP). Pharmacological assays using a diverse range of pharmacological
effects on the ERG have been reported with a agents. Until such tests are in place, non-clinical
range compounds with varying mechanisms of testing for effects on hearing cannot be
action. Such studies, when used in conjunction recommended.
with histopathology in toxicology, can be used
to establish a reversible pharmacological action 8.6 Electrocochleography measures signals at the
on the retina that would be less of a concern beginning of the vestibulocochlear nerve. An
with respect to human safety, or an irreversible immediate reduction in action potential has been
toxic effect on the retina that would be of great detected within minutes of an intravenous dose
concern for human safety. In the event of visual of aminoglycoside. Brain Stem Auditory Evoked
adverse events being reported in man, the ERG Response (BAER) is a technique for measuring
in both man and animals is a valuable hearing loss. These techniques can be used in
investigative tool to establish the site of action of both humans and animals. However, this is an
a compound and to provide a link between non- area that requires basic research to establish if
clinical and clinical data to build confidence in predictive non-clinical assays can be established.
the long-term safety of a drug. The challenges Until such tests are in place, non-clinical testing
for the future would be to further characterise for effects on hearing cannot be recommended.
20
drugs, routine testing of NCEs prior to FIH is not

Challenges and opportunities recommended in the absence of effects in
toxicology. However, the challenge for the future
8.7 As discussed above pharmacological effects on is to further characterise the relationship between
the ERG have been reported with a range drug effects on visual function in man and in
compounds with varying mechanisms of animals to establish the predictive value of
action. Results from non-clinical ERG studies existing test systems and to develop novel assays.
are best interpreted in conjunction with
histopathology. The challenges for the future is 8.10 Ototoxicity is a potentially important safety issue
to further characterise the relationship between for drugs, but is hard to detect. Although some
drug effects on visual function in man and in drugs are classically associated with ototoxicity,
animals to established the predictive value of the extent of the issue is probably
existing test systems and to develop novel underestimated since the symptoms may appear
assays. Furthermore, a more comprehensive gradually and are often indistinguishable from
understanding of the relationship between underlying disease processes. Any impact on
histological changes to the visual pathway and hearing is temporary and reversible upon
changes to the ERG and VEP is required. removal of the drug. Animal pharmacology
models are available, but their utility in screening
8.8 The ototoxicity potential of drugs is not is yet to be determined as few mechanisms of
routinely evaluated non-clinically which reflects ototoxicity have been determined and the
the low incidence of ototoxicity in man and the forward prediction of the available tests is not
fact that clinical signs of tinnitus can be detected established and can be insensitive.
in clinical trials. Furthermore, the predictive
value using a diverse range of pharmacological 8.11 Overall, the current model, where evidence of
agents of the existing animal models to man is hearing impairment in toxicology studies or in
unknown. The challenge, therefore, is to further clinical trials, is considered more appropriate.
our understanding of the concordance between Nevertheless more attention should be paid to
effects of ototoxic drugs in animals and in man this under-reported safety concern. In toxicology
and to identify appropriate non-clinical testing and pharmacology laboratories, animal handlers
strategies appropriate for the risk. and toxicologists should pay attention to
behavioral changes in animals that could suggest
an auditory dysfunction. Should these data, or
Proposals and recommendations emerging data in humans suggest further
investigation of auditory function is warranted,
8.9 Although safety pharmacology methods (ERG BAER or histopathology of cochlea could be
and VEP) are available to detect visual effects of used for investigational studies in animals.
21
Chapter nine - Immuno-safety pharmacology

9.4 Functional assays; SRBC/KLH assays or
Current situation immunophenotype analyses, particularly aimed
at defining the quality of the immune response
9.1 The available methods to assess the interaction and the selectivity of changes in type 1/type 2 T
of drugs with the immune system do not meet all lymphocytes, have been increasingly used to
the needs for safety evaluation. Approximately characterise adaptive immune function.
6% of drug withdrawals are ascribed to adverse
immune responses, with a further 7% associated
9.5 Methods for the identification and
with bone marrow toxicity for which an
characterisation of chemical allergens have
immune response may be contributory. The
been developed and are widely used in safety
difficulty with prediction of these responses is a
assessments. Validated methods for the
consequence of their low clinical incidence,
evaluation of contact (skin) sensitising potential
poorly understood mechanism of action, and
are available. In addition, as yet unvalidated
the inability of non-clinical models to reliably
approaches have been developed for
identify hypersensitivity reactions in man.
assessment of the potential of chemicals and
proteins to cause allergic sensitisation of the
9.2 Current methods for the non-clinical assessment
respiratory tract and (in the case of proteins)
of immunosuppression appear to identify the
gastrointestinal tract.
clinical risk adequately. For this purpose one or
more of the following approaches are used: (a)
9.6 Approaches to identify compounds that induce
examination of the histopathological appearance
autoimmunity, or to provoke idiosyncratic
and/or weight of key lymphoid organs (thymus,
reactions are not available. These types of
spleen and lymph nodes), together with
response will continue to be the most difficult to
considerations of haematological parameters
assess and predict. One general method that is
and of bone marrow cellularity, (b) tests
available (in several guises) is the popliteal lymph
designed to measure the functional integrity of
node assay (PLNA). This has been, and remains
the immune system in exposed animals. Of the
still, the subject of investigations but has not yet
methods available, tests for assessment of the
been established as a reliable indicator of hazard.
integrity of antibody production (to either sheep
An understanding of genetic and environmental
red blood cells [SRBC] or keyhole limpet
susceptibility factors will probably be the most
hemocyanin [KLH]), are commonly used, but
fruitful area of research.
other approaches (such as for instance
immunophenotypic analyses) are also employed.
9.3 Methods, albeit poorly characterized, to identify Challenges and opportunities

host resistance are available and have been
employed to assess defense against infectious 9.7 Although there are available methods that can
micro-organisms or transplantable tumour cells, be used for investigating the ability of
although the ability of these models to assess xenobiotics to interact with and/or perturb the
subtle effects is less confidently assured. The immune system, it is clear that they do not (at
advantage of host resistance assays is that, in least as currently deployed) meet all needs of
theory at least, they provide an holistic view of drug safety assessment. Thus, a common cause
changes in susceptibility that may reflect of attrition following launch of a new drug is the
compromised immune function. However, it appearance of idiosyncratic drug reactions,
must be appreciated that other forms of toxicity often manifest at only low incidence, that are
(such as, for instance, liver damage), and thought to have an immune/allergic
general ill health, may be reflected by changes pathogenesis. The ability of candidate drugs to
in host resistance in the absence of a primary provoke such reactions has proven extremely
lesion in the immune system. difficult to predict. There are a number of
22
factors that contribute to this difficulty, including: chemicals that have an intrinsic potential to
(a) the fact that such reactions normally occur interact with the adaptive immune system, or
only at low incidence, (b) there is frequently no which can be metabolically converted to such.
attempt to define the mechanisms through
which such reactions are provoked, and as a 9.11 Other approaches developed initially for the
result there is uncertainty regarding the relevant assessment of industrial chemicals include
immunobiological processes, and (c) it is likely methods designed to identify materials with the
that, as currently constituted, non-clinical potential to cause allergic sensitisation of the
toxicology and safety pharmacology studies are respiratory tract: the mouse IgE test and cytokine
not appropriate for identification of chemicals fingerprinting. These tests are designed to define
that have the potential to elicit hypersensitivity the quality of immune response that is provoked
reactions. by exposure to a chemical allergen, and
specifically whether selective type 1 or type 2 T
9.8 With respect to the last of these points, two lymphocyte responses are elicited. This
separate but related potential deficiencies can approach allows determination of whether a
be identified. The first of these is that chemical is likely to stimulate an IgE antibody
appropriate assessments are not conducted. The response – the major effect molecule in many
second is that at least some of the assessments forms of allergic disease.
that are conducted currently may yield
information of importance, but that the relevant 9.12 One potential innovation might be to consider
questions are not addressed, nor the correct the coordinated and structured application of
deductions made. the above methods, with or without
incorporation of one or other version of the
PLNA, to facilitate an holistic assessment of
Proposals and recommendations likely stimulation of an immune response. Used
in concert these methods could provide: (a) an
9.9 There is confidence that current non-clinical assessment of the inherent potential to provoke
models are able to detect immunosuppression an immune response, and of the level of
and impaired host resistance despite the immunogenicity, and (b) an indication of the
validation of these methods being incomplete. type (quality) of immune responses that will be
elicited preferentially.
9.10 Methods to identify allergenicity have been
widely used and for contact sensitization several 9.13 Approaches for the identification of
approaches are validated. There remains a need autoimmune responses or idiosyncratic
to gain full acceptance of the methods available response have proven to be elusive and demand
for detection of respiratory and gastrointestinal more intensive study and should include
sensitisers. The local lymph node assay (LLNA) consideration of genetic susceptibility factors,
is a fully validated, OECD guideline method for polymorphisms and environmental factors
the identification of chemicals that have the (diet, overall health status, life style etc).
potential to cause skin sensitisation. The test is Furthermore, it is pertinent to ensure that
predicated on the fact that skin sensitising information relevant for a consideration of
chemicals will provoke the stimulation of immune function from conventional toxicity
specific T lymphocyte responses in regional studies, and an appreciation of cytokine
lymph nodes draining the site of exposure. This expression patterns, are included in an overall
method therefore has the potential to identify assessment of impacts on immune status.
23
Chapter ten - Paediatric indications

for children and adult human safety data will
Current situation not be available as background to define risks.
10.1 In most regions of the world, the majority of 10.4 Potential differences between adults and children
drugs used in children have never been tested include pharmacokinetic (e.g. clearance pathway)
in this target population. Moreover, they were differences, and developmental differences in
approved only on the basis of data obtained in tissue structure and function, for example in
adults, either animals or man (although off- vision and other senses, thyroid function, CNS
label use is high). Nevertheless, in both the plasticity and the haematopoietic system (with a
United States and Europe, health authorities spleen and thymus focus, rather than bone
are encouraging paediatric studies by means of marrow in adults).
legislation such as the Best Pharmaceuticals for
Children Act (2002) and the Pediatric Research
Equity Act (2003) or the European draft 10.5 Clearly, non-clinical studies used to support an
legislation “Better Medicines for Children” (to investigational new drug, or even a marketed
be finalized, 2005). The aim of all of these drug for which paediatric use is desirable, may
considerations is to make valuable medicines not directly address the concerns or the
available to children as soon as possible, potential interactions of age, gender and the
addressing what is seen widely as an important relative development of the various organ
medical need. systems. Age- or gender-related kinetic and
metabolic differences in response are not
generally addressed. When performed, most
10.2 The need to extend the access of children into studies in juvenile animals use neonatal rats,
new therapies, and to develop paediatric dogs or swine, assuming equivalent postnatal
formulations of existing drugs reinforces the development to newborn infants.
urgency to implement strategies for early
prediction of specific safety aspects in this 10.6 In Europe, a guidance document addressing the
population. In this context, the use of juvenile use of juvenile animals on safety assessment of
animals may be helpful and is usually paediatric drugs is being prepared by the Safety
considered on a case-by-case basis. Working Party under request of the CHMP. A
concept paper including the several items under
discussion has been published in the EMEA
website. FDA/CDER is in the process of
Challenges and opportunities developing Guidance to Industry on Non-clinical
Safety Evaluation of Pediatric Drug Products.
10.3 Traditionally, drug development in children has This document provides guidance on the role
been performed once sufficient numbers of and timing of animal studies in the safety
adults have been studied to define risks. evaluation of therapeutics intended for paediatric
Therefore, drug approval has not required the use and when such studies might be needed. It is
same level of evidence for paediatrics as it has intended to serve as a general resource in testing
for adults, given the approvals already secured and provide specific recommendations based on
on the basis of adult safety data. Evidence from the available science and pragmatic
paediatric development programmes recently, considerations. There are no specific guidelines
however, has suggested that children are to address the use of juvenile animals for safety
dynamic and variable and reliance on adult data pharmacology studies of paediatric drugs,
may underestimate the risks of the drug to although there is a general statement in ICH S7A
children. Moreover, in the future, especially in Safety Pharmacology guideline that
the area of paediatric oncology, there will likely consideration should be given to selection of
be an emphasis on drugs designed specifically relevant animal models, including age of animals.
24
10.8 This group proposes that the adequacy and

Proposals and recommendations appropriateness of all supporting non-clinical
safety data (including safety pharmacology)
10.7 Given the issues described above, the utility of should be considered as part of a paediatric
safety assessment in juvenile animals is a subject investigation plan. Given the limited models
that continues to be debated. Due to interspecies available, the extent of non-clinical safety
differences regarding the development of several pharmacology testing to support paediatric
organs and systems, the value of studies in clinical development will inevitably be decided
juvenile animals to predict the drugs safety in on a case-by-case basis. Information from adult
children needs to be considered on a case-by- animal studies including reproductive
case basis, taking into consideration the toxicology should also be taken into account.
information from studies in adult animals
including reproductive toxicology studies.
25
Chapter eleven - Biotechnology compounds

claim success in this area. Ex vivo T-cell
Current situation activation assays and specialized animals
models including genetically engineered mice
11.1 Considerable experience in the development and MHC defined primates are promising
of biotechnology-derived compounds has been future directions.
gained over the past 20 years. Clinical
experience has revealed toxicity frequently not 11.6 Given the poor predictivity of the immune
predicted from the initial non-clinical studies. response the default has often been to use a
The traditional safety pharmacology studies primate model. It seems reasonable to challenge
need to be used with care with biotechnology- this premise and studies to establish its validity
derived compounds with the priority being and explore whether non-primate species can
assessment of functional indices of toxicity. The be more widely used should be encouraged.
following areas should be considered:
11.2 In vitro testing for tissue cross reactivity and

tissue distribution is essential in species Proposals and recommendations
selection and interpretation of pre clinical data.
11.7 Increase human sequence content: Several
11.3 Many humanized biotechnology derived approaches are pursued to minimize murine
molecules are immunogenic in animals. sequence content: chimeric antibodies
Animal species may produce neutralizing comprising mouse variable regions and human
antibodies, animal anti-human response constant regions; humanized antibodies in
(characterized by increased clearance and for which murine CDRs are grafted onto a human
loss efficacy), toxic antibodies which may framework and fully human antibodies
manifest responses disconnected from produced by phage display or in transgenic
pharmacokinetics and anti-idiotype antibodies animals. Nonetheless, antibody formation can
that result in high unexplained exposure not occur with all these modifications. Abbot’s
correlated with Humira®, the first FDA-approved fully human
pharmacodynamic/toxicodynamic actions. antibody, elicits an immune response in 12 % of
patients when administered without
immunosuppression. Fully human proteins can
Challenges and opportunities be immunogenic, as immune tolerance can be
broken under certain circumstances.
11.4 Since prediction of immunogenicity of
biotechnology-derived products in man is very 11.8 Improving solution properties: Protein
poor, improvement of immunogenicity aggregates are typically more immunogenic
reduction strategies is necessary. Continuing than dissolved proteins. Poor protein solubility
progress in prediction, detection and can be overcome by optimizing expression,
prevention of harmful immune responses purification, formulation and solution
brings the promise of safer and more conditions. An alternative method is to use
efficacious compounds in the future. rational solubility engineering.
11.5 Considering that factors other than protein 11.9 Removing antibody epitopes: Antibody
sequence are equally important for epitopes are often located at a small number of
immunogenicity, and that immune responses discrete sites on the surface of a protein.
are genetically determined and, therefore, Modification of residues can reduce
highly individual, sequence analysis may not immunogenicity and binding of existing
be sufficient to predict and avoid antibody antibodies. Modified variants of Factor VIII and
formation although a number of companies staphylokinase are examples.
26
11.10 PEGylation: The steric block of antibody 11.11 Identifying and removing class II MHC
binding by derivatizing the protein with agretopes: The production of IgG antibodies
polyethylene glycol (PEGylation) can decrease responsible for clinically relevant
immunogenicity. PEGylation also increases immunogenicity can be minimized by
solubility and often changes pharmacokinetic identifying and removing class II MHC
parameters which may permit less frequent agretopes from the therapeutic molecule. The
dosing. PEGylation has been used successfully binding site of antigen-derived peptides at the
to minimize immunogenicity of enzymes. class II MHC molecule and their binding
Protein design approaches may help to further specificities are well described. Following
optimize the balance between reduced computational or experimental identification
immunogenicity, improved pharmacokinetics, of MHC agretopes, a mutagenesis approach
and activity maintenance. can be used to produce variant sequences that
do not interact with MHC.
27
Chapter twelve - Compounds selective for human targets

compound developed to date are frequently
Current situation aimed at life threatening diseases whereas
human specific or highly selective targets are
12.1 The development of sophisticated technologies now being identified for disease that are not life
to screen large numbers of chemicals has led to threatening.
an increased use of human tissue derived
targets. Consequently there is an increased 12.4 In assessing the selectivity of a compound for a
likelihood that the drug candidates identified target two scenarios exist. The compound can
will be highly selective for human tissue/disease. have no cross reactivity with the animal target
While this may lead to more efficacious or cross reactivity can exist but the potency of
treatments it does give difficulty in species the compound at the animal target is
selection for non-clinical safety evaluation. substantially less than for human.
Pragmatically if the drop off is more than 20
12.2 There is increasing evidence that around 50% of fold it is unlikely that the dose levels can be
the toxicities seen with candidate drugs in achieved in an animal species that will enable
development can be ascribed to the sufficient assessment of pharmacologically
pharmacology (either primary or secondary) associated toxicity.
associated with the target receptor or protein. It
therefore follows that an increasing number of
projects will have compounds that do not cross Challenges and opportunities
react with the species commonly used for safety
assessment. While studies in conventional 12.5 Conventional evaluations will describe the
species will provide information on intrinsic safety pharmacology/toxicity associated with
toxicity related to the chemistry of the the chemistry of the molecule to be assessed
compound a gap exists in understanding the but the following may be considered to assess
evaluation of human selective or specific targets. pharmacologically related adverse effects:
12.3 The issue of non-clinical safety evaluation of 12.6 Profiling in established laboratory species to
human specific compounds has been confirm selectivity and selection of the most
previously considered with biotechnologically appropriate species.
derived pharmaceuticals. These have usually
been large molecules that have been 12.7 Demonstrate that human specific molecules
manufactured to replicate an endogenous possess high enough potency for animal target.
human protein or are an antibody to a human
specific target. Many of these biotechnology 12.8 Target distribution in normal and diseased
compounds were directed towards tissue. Where targets are expressed in normal
replacement therapy. The toxicity produced by tissue it is worth considering its function if
these molecules has been mediated through the known to assess the potential deleterious effects
specific target receptors and selection of of pharmacological modulation.
appropriate species has been imperative to
understanding human hazard. Toxicity with the 12.9 Sensitivity – in some instances the laboratory
biotechnology compounds has so far been species may be less sensitive to compounds with
underpinned by an extensive literature high potency to human targets whilst having a
supporting the understanding of the function of similar physiological role. In such cases use of
the specific target – examples being G-CSF, IL- conventional high dose toxicology may permit
1, IL-2, Erythropoietin and Insulin. For future establishment of satisfactory safety margins.
targets that are exploited using small molecule
chemistry it is likely that this prior knowledge 12.10 Transgenics – increasing access to transgenic
will not be abundant. Furthermore the biotech models will in the future give many more
28
options to evaluate the human specific targets. understanding physiological response would be
Approaches that may have utility will include assisted by use of disease models. Experience
knock-out/knock in models where the with recombinant erythropoietin where
endogenous animal gene is replaced by a hypertension was seen in patients and uremic
cloned human gene. Information from straight rats despite no change observed in normal rats
knock out models may also be useful if the support this view. Furthermore, in situations
function of the gene in the animal model is where the target is expressed only in the disease
assured to be similar in man. Where known, situation (frequently seen with targets thought to
information from human populations with be important in inflammation) the use of disease
either malfunctioning or absent genes is models may be helpful in establishing true
particularly useful. An important caveat when therapeutic indices.
considering knock out models is the potential to
overstate the toxicity of inhibiting the target or 12.13 Statistically or mechanistically it may not be
vice a versa. In these circumstances it may be possible to reproduce all human idiosyncratic
appropriate to consider use of a conditional reactions in non-clinical studies. It is important
knock out. It should also be established that the to understand the strengths and limitations of
transgenic model functions in a similar way such studies.
with the correct response elements operational
when drawing conclusions on the utility of a
transgenic model. Proposals and recommendations
12.11 Homologous systems i.e. animal specific 12.14 Evaluation of human specific targets can be
molecule to assess the pharmacology in a expected to increase in complexity over the
responsive animal species. Understanding the next 5 to 10 years. The understanding of
function of the target in both the animal species similarities and differences between the human
in comparison to man may also be important. disease, animal model and responsiveness of
With small molecules the option to use the normal laboratory animal will increase
monoclonal antibodies for cell surface targets is substantially. It is therefore unwise to regulate
also available and increasingly used. This this area until a much better understanding has
approach should also consider the effect on been achieved. Precedence from the
regulation of the target. If the target is not development of biotech large molecules should
a receptor approaches which target mRNA be used to guide each development programme
may yield useful information. Synthesis of an individually with the selection of species and
anti sense oligonucleuotide may provide such models justified rationally.
tools but consideration of the chemistry
associated with the oligonucleotide is also 12.15 Where small molecules are directed towards
worthwhile. human specific targets it will be necessary to
fully evaluate the intrinsic toxicity associated
12.12 Disease models – Toxicity and safety with the chemistry and assessment of the
pharmacology are traditionally assessed in pharmacologically related toxicity will need to
normal animals. It is conceivable that be supplementary and rationally developed.
29
Chapter thirteen - Education and training

new medicines will be generated at the non-
Current situation clinical level to permit the initial human dose.
However, the clinical pharmacologist receiving
13.1 Practitioners in the field of safety pharmacology the data must be able to relate to the science and
derive from a variety of core disciplines. The the scientist to discuss the interpretative
majority are trained as pharmacologists, elements of the data set. Training, therefore,
primarily non-clinical but some clinical whilst must be available to meet both types of need.
toxicologists, biochemists and biological The availability of such training is reducing in
scientists have all achieved success in the the UK and this was highlighted in the PICTIF
discipline. There is a strong integrative role of the report, in has been confirmed in various
safety pharmacologist in assessment of all the submissions from ABPI and Professional
available safety data as well as their own specialty Societies to government and by the
studies and also a need to relate to the expected practitioners themselves.
clinical utility of molecules under investigation. It
follows then that core skills need to be
supplemented with continuing development and
this, in the main, is provided in house by units Recommendations
providing safety pharmacology services.
13.5 The training provision for both non-clinical and
clinical pharmacologists needs core support
Challenges and opportunities from government to help address the current
limitations. Numbers of adequately trained
13.2 The current trend to reduce practical training at clinical and non-clinical pharmacologists are
undergraduate level is the initial fail point for falling which is a serious issue impacting on the
science-oriented students who may wish to performance of a major industry contributing to
develop a career in pharmacology. Lack of UK plc and to the underpinning academic base
opportunity to explore the range of science which supports it. New integrative Continuing
available in the field limits take up of further Professional Development (CPD) courses are
studies at Masters or Doctorate levels. needed to use both non-clinical and clinical
Furthermore, facilities for Masters courses in pharmacologists more effectively in the
this and cognate areas are minimal, largely development of new medicines.
driven by problems associated with animal
experimentation.
Value added and measures of success
13.3 Post graduate and postdoctoral training is also a
problem, which various Professional Societies 13.6 Compound attrition related to adverse effects
(notably the British Pharmacological and British detectable in safety pharmacology studies will
Toxicological Societies) are trying to address in be reduced e.g. nausea and vomiting, CNS
concert with industry. Whilst industry, notably effects and latter stage attrition related to
the pharmaceutical industry, can and does hepatotoxicity. In addition, increased
maintain state of the art facilities and provides tolerability may improve compliance increasing
ongoing training for its staff, the academic base drug efficacy.
of the discipline is essential for both the wider
good of the community but also to ‘educate the 13.7 Although Phase I studies are very safe, in these
educators’ of the future. study doses are escalated to identify the
maximum tolerated dose. It is possible that in
13.4 Training has two elements: technical and some circumstances tolerability issues prevent
interpretative and in the field of safety the achievement of exposures to predicted
pharmacology lies across two domains. Data on therapeutic levels that may be related to effects
30
detectable in safety pharmacology studies e.g. evaluation of human specific targets is an

dizziness, nausea and vomiting etc. Therefore, increased linkage between the target and the
improving safety pharmacology testing may disease leading to more efficacious compounds
reduce the Phase I attrition due to poor in humans.
toleration in volunteers.
13.10 Further refinement of safety pharmacology
13.8 Investments in understanding further the studies (e.g. simultaneous telemetered
relationship between prolongation of the QT recoding of cardiovascular and pulmonary
interval and proarrhythmia may support the parameters and the application of PK/PD
development of NCEs that prolong the QT modeling) will reduce the numbers of animals
interval that are not associated with causing used in non-clinical safety testing. This will
TdeP. This in turn will increase the ‘chemical contribute to the 3Rs.
space’ available for Discovery chemistry to
exploit against novel targets thus negating
the negative impact of hERG affinity. 13.11 Although compound attrition due to effects on
Furthermore, the incidence of late stage drug the sensory organs appears to be low, improving
withdrawals related to arrhythmias will be non-clinical testing strategies may reduce further
reduced/eliminated. the incidence of adverse events related to the
visual and hearing system. Furthermore such
13.9 Drugs selective for human targets are studies would raise confidence on the lack of
associated with specific challenges for the drug effects on the sensory organs and any
pharmaceutical industry. Improved testing potential long-term consequences.
strategies are vital in preventing the
discontinuation of compounds and potentially 13.12 Through data sharing and increasing our
loss of interest in targets based upon incorrect knowledge of the concordance between non-
and misleading adverse safety pharmacology clinical studies and human outcome would
or toxicity derived from inappropriate models. increase our confidence to make decisions on
The key value to gain from supporting drug development.
31
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Safety Pharmacology Studies for Human Pharmaceuticals Human subjects: Volunteer’s death prompts review Science,
(2000) Note for Guidance on Safety Pharmacology Studies 292, 2226–2227
for Human Pharmaceuticals
(CPMP/ICH/539/00). Murphy, D. L. (2002)
Assessment of Respiratory Function in Safety Pharmacology
ICH S7B Fundamental & Clinical Pharmacology, 16, 183–196
The Non-clinical Evaluation of the Potential for Delayed
Ventricular Repolarization (QT Interval Prolongation) by Ogilvie, R. I. (2001)
Human Pharmaceuticals (2004) Note for Guidance ICH The death of a volunteer research subject: lessons to be
Step 2 Revision learned
www.fda.gov/cber/ichqt.htm Canadian Medical Association Journal, 165,
1335–1336
Boelsteri, U. A. (2003)
Animal models of human disease in drug safety assessment Olson, H., Betton, G., Robinson, D., Thomas, K.
Journal of Toxicological Sciences, 28, 109–121. Monro, A. et al. (2000)
Concordance of the toxicity of pharmaceuticals in humans
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Markets – 1960 to 1999 Mortimer, E., Rolfe, B., and Cayen, M. N. (2003)
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development
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32

Safety Pharmacology

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Safety Pharmacology-02.

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Safer Medicines Report

Safety Pharmacology working group report

Summary of key findings and recommendation 3

Chapter one: Introduction 5

Chapter two: General/secondary pharmacology studies 8

Chapter three: Cardiovascular and renal safety pharmacology 10

Chapter four: Respiratory safety pharmacology 12

Chapter five: Central nervous system pharmacology 14

Chapter six: Hepatic function 16

Chapter seven: Gastrointestinal safety pharmacology 18

Chapter eight Sensory safety pharmacology 20

Chapter nine: Immuno-safety pharmacology 22

Chapter ten: Paediatric indications 24

Chapter eleven: Biotechnology compounds 26

Chapter twelve: Compounds selective for human targets 28

Chapter thirteen: Education and training 29

Summary of key findings and recommendation

Abuse potential There is confidence that currently available non-

Training and education for safety

Chapter one - Introduction

Chapter two - General/secondary pharmacology studies

Chapter three - Cardiovascular and renal safety pharmacology

Chapter four - Respiratory Safety Pharmacology

Chapter five - Central nervous system (CNS) safety

Current situation that affect drugs in all stages of development. It

USVs in many different social and emotional

Chapter six - Hepatic Function

Appropriate use of the new approaches

6.10 Development of improved in silico and in vitro Proposals and recommendations

Chapter seven - Gastrointestinal (GI) safety pharmacology

7.6 The influence of GI intolerance on patient

Chapter eight - Sensory Safety Pharmacology

drugs, routine testing of NCEs prior to FIH is not

Chapter nine - Immuno-safety pharmacology

9.3 Methods, albeit poorly characterized, to identify Challenges and opportunities

Chapter ten - Paediatric indications

10.8 This group proposes that the adequacy and

Chapter eleven - Biotechnology compounds

11.2 In vitro testing for tissue cross reactivity and

Chapter twelve - Compounds selective for human targets

Chapter thirteen - Education and training

detectable in safety pharmacology studies e.g. evaluation of human specific targets is an

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