Safety Pharmacology

Dr. Tina Saldanha

Safety Pharmacology: Definition & History
 Safety Pharmacology is the discipline that seeks to predict whether a
drug if administered to human (or animal) populations, is likely to be
found unsafe, and its professional mandate is to prevent such an
occurrence

 Prior to 1990, pharmaceutical companies conducted only

toxicological testing of lead compounds as part of preclinical drug
discovery

 However, it became increasingly clear over several decades that

drugs may progress as far as phase 3 clinical trials before rare and
potentially lethal adverse effects become apparent

 The vigilant post-marketing surveillance (PMS) efforts by regulatory

authorities is necessary to confirm the existence of a rare adverse
event which may occur after approval for human use
Terfenadine is withdrawn from the market
 In the mid 1990s the antihistamine, terfenadine was withdrawn

 Terfenadine could evoke the potentially life threatening cardiac

syndrome, torsades de pointes (TdP), in otherwise healthy
patients

 Prior to this, the general perception was that only

cardiac/cardiovascular compounds were considered to possess
such a tendency (liability)

 The problem here was that terfenadine, a non-cardiovascular

drug, had low efficacy to evoke TdP

 It was so rare an event that it required several million prescriptions

before its liability became suspected
Terfenadine is withdrawn from the market

 The other important

consideration here is that the
indication for which
terfenadine was used is Benefit: Cure a
hayfever (totally non-life runny nose
threatening)
Risk: death
 Therefore, risk (death)
clearly outweighs benefit
Realization of need for Safety Pharmacology
 The Terfenadine episode was of great importance to what we now
call Safety Pharmacology

 Predicting terfenadine’s TdP risk was not possible by the

conventional preclinical toxicity testing methods conducted at the
time

 Preclinical toxicology testing, involved determining the high-dose

adverse event profile of a compound given at chronic, toxic doses

 However it would not have detected a rare lethal event liability at

therapeutic dosage

 Even though it was known that repolarization delay in the ventricles

of the heart was associated with TdP occurrence, it was not until
1996 that Brown’s group identified the likely mechanism of
terfenadine’s ‘cardiotoxic’ actions
 Agenda of Safety Pharmacology
 Regulatory authorities* give approval for drug use in humans.

 Therefore, convincing the regulators that a drug is safe and

efficacious is a key part of the drug discovery/development process

 Thus, it is important to consider who the regulators are and what they
want to know

 The structure of a Safety Pharmacology ‘core battery’ programme is

to determine the potential undesirable pharmacodynamic effects of a
drug on the
Central nervous system
Cardiovascular system and
Respiratory systems

 Besides the core battery tests, supplementary tests to evaluate other

organ systems
* the FDA (US), Health Canada (Canada), European Medicines Agency (EMEA) and Japanese
Pharmaceutical Manufacturers Association (JPMA), DCGI (India), MHRA (UK)
Safety Pharmacology: Core battery mentioned in ICH
Guidelines S7A and S7B

ICH S7A and S7B: the regulatory guidance document that provides general principles and
recommendations for safety pharmacology studies
Safety Pharmacology: Follow up studies and risk/benefit
assessment

 Follow-up studies may be triggered if there is a need to characterize

specific adverse effects found in initial Safety Pharmacology studies

 One of the key roles of Safety Pharmacology is to help inform the

decision to begin testing in humans

 Pharmacology alone does not define the fate of a new drug

 It is important to determine the point at which it is ethical to proceed

with clinical trials

 Once human testing has begun, risk/benefit assessment continues,

this time in the patient population

 This means taking into account the seriousness of the disease as

well as the seriousness of any adverse effects
Safety Pharmacology: Follow up studies and risk/benefit
assessment
 This is primarily relevant to pharmaceutical company choice making
about investment (spending)

 Thus, a very promising cure for a rapidly progressing disease with a

poor prognosis, such as pancreatic cancer, will likely be allowed to
enter phase 1 clinical trials in pancreatic cancer patients with minimal
preclinical Safety Pharmacology testing

 In this case, the extent of Safety Pharmacology investment will be

minimized

 Thus, the oncology division at the FDA may not fully enforce ICH
S7A depending on the seriousness of the disease and current
therapy (or the absence of current therapy) in this population
 Safety Pharmacology: Follow up studies and risk/benefit
assessment
 An IND is a request to regulator (eg FDA) to allow initiation of clinical
trials

 A successful IND may be filled with an abbreviated version of the

core battery investigation if the regulator deems it is worth providing
this drug to patients quickly

 Eg. for a drug indicated for a life-threatening disease, a single study

(dogs, n=4) with below parameters may be sufficient to fulfill the core
battery requirement:
Integrated telemetry (recording of cardiovascular parameters)
CNS neurological examination
Respiratory profile using a pneumotachometer
 Safety Pharmacology: Follow up studies and risk/benefit
assessment
 In contrast, if the condition to be treated is not life-threatening it may
be necessary to
Implement the full functional observational battery (FOB)
Respiratory function in a second study and
Haemodynamic telemetry in dogs

 Drugs for diseases for which treatments are already available (even
life-threatening diseases such as Hodgkin’s lymphoma) will usually
require a complete Safety Pharmacology investigation programme
and a relatively favourable safety profile

 Thus, there exists a risk/benefit continuum; many currently available

anticancer drugs are not in any way ‘safe’ for healthy humans but
they are considered ‘safe’ for cancer patients given their debilitating
condition
FOB is a formalized systematic evaluation of nervous system function in the rat, comprising more than 30
parameters across autonomic, neuromuscular, sensorimotor and behavioural domains in rats
Safety Pharmacology: Follow up studies and risk/benefit
assessment

 The nature of the drug is also an important factor that will modulate
the requirements for Safety Pharmacology testing

 Eg. a monoclonal antibody (biologic) will be allowed to progress to

first in human (FIH) studies with minimal investigation of, for
example, TdP liability

 In contrast, a small molecule first in a new drug class will require a

complete Safety Pharmacology assessment before it can progress to
phase 1 assessment in healthy volunteers

 This is due to the probability that a a monoclonal antibody will have

better target selectivity
 Non-clinical methods recommended for use in the safety
pharmacology core battery (ICH Guidelines S7A and S7B)
Safety pharmacology core battery Measured variables

Central nervous system (Modified) Irwin’s Coordination, body temperature,

test functional observation battery (FOB) in behavior, neuromuscular,
rats sensorimotor, convulsions
Respiratory system Plethysmography in rats Respiratory rate, tidal volume, airway
resistance/compliance, pH, pCO2, pO

Cardiovascular system Blood Pressure, Heart Rate, ECG,

QT Interval (telemetry) in dogs Cardiac Output, Left-Ventricular
hERG (in vitro) Pressure, Contractility, TRIaD, hERG
Isolated Purkinje fibers (Langendorff IC50
Isolated Hearts) (Proarrhythmia Models)
Supplemental systems Intestinal transit time, Gastric
Gastrointestinal emptying and secretion, urine volume,
Renal/genitourinary total protein, Cl rate (GFR, Na+,K+, Cl-)
Blood Electrolytes, BUN, platelet
Inflammation aggregation, bleeding time
Immunological
Non-clinical methods recommended for use in the safety
pharmacology core battery (ICH Guidelines S7A and S7B)

 The Safety Pharmacology core battery is typically conducted with a

single administration of drug using the same administration route in
conventional toxicology studies/future clinical studies

 Evaluations usually up to 24h

 Cardiovascular safety is assessed in a conscious telemetry study (for

example, n=4) usually in a Latin square or dose-escalation design
with sufficient drug ‘wash out’ times between dosing

 These studies usually use the same species as in the large animal
toxicology studies
Latin square experimental design for dog telemetry
Non-clinical methods recommended for use in the safety
pharmacology core battery (ICH Guidelines S7A and S7B)

 Respiratory Safety Pharmacology is typically evaluated in conscious

rats (for example, n=8 given the greater variability of respiratory
parameters)

 Large animals such as dogs and monkeys may also be used when
rodents are not suitable

 Eg. if drug target is absent in rodents or absorption distribution

metabolism elimination (ADME) profile is not adequate

 Neurological safety is usually evaluated using a modified Irwin test in

rats where qualitative evaluations are conducted by an evaluator
blinded to study treatments (n=10 per group)
Plethysmography in rats
The challenge of validation of safety pharmacology
approaches (possible pitfalls)
 The key question about the core battery tests (as far as the
regulators are concerned) is: are they validated?

 In other words, does the chosen model accurately identify the safety
liability of the drug candidate?

 Validation of Safety Pharmacology test systems for GLP compliance

is achieved at each test site using positive control drugs with
currently accepted models

 This remains a vexing issue in Safety Pharmacology

 It is important to emphasize that models and biomarkers are ‘valid’

only when they detect all and only those drugs that have the same
effectiveness and safety in the human

 There is a major paradox inherent in this requirement, one that is not

well recognized and one that is a fundamental problem for the
newest most potentially revolutionary drugs.
The challenge of validation of safety pharmacology
approaches (possible pitfalls)

 In Safety Pharmacology, no model is validated until a range of

positive and negative controls have been shown to produce the
same outcome in the model as occurs in humans

 This sounds simple; however, it is a huge problem for certain types

of adverse effects

 Thus to validate a model that is to be used for detecting a liability for

a drug to evoke a very rare (but potentially) lethal event (RLE)
requires precise and accurate human data on the liability of a range
of drugs to evoke the RLE (the ‘gold standard’)

 Because new drugs are new by definition the disease for which the
drug is intended may have no presently available treatment to
compare with