Biological Standardization
Preclinical Testing
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Course Time Schedule
Week
Subject
Teaching Staff
Introduction , Types of trials
Dr Mahmoud Khattab
CVS Preclinical Testing
Dr Lamiaa Ahmed
CVS Preclinical Testing
Dr Lamiaa Ahmed
CNS Preclinical Testing
Functional Operation Battery (FOB)
Dr Nada
Functional Operation Battery (FOB)
Cognitive Function Preclinical Testing
Renal Function Preclinical Testing
Respiratory Preclinical Testing
GIT Preclinical Testing
Bistatistics
Dr Yasmeen
Dr Doaa
Dr Aly Shokry
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Reasons for Dug Attrition
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British Journal of Pharmacology (2011) 163 675–693
Aim of Safety Pharmacology
 The aim of Safety Pharmacology/Preclinical Testing is to
characterize the mutual interactions among a drug pharmacodynamics/pharmacokinetics (PK/PD) and its adverse effects
using reliable methodology
 The final goal is to predict rare but lethal or serious events
 This part is applied at the preclinical phase 0 in order for a
potential molecule to receive the FDA approval for an
Investigational New Drug (IND)
 Finally, health care teams are responsible to predict and
monitor clinical safety after FDA approval into the market or
what is called post-marketing surveillance
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Safety Pharmacology
“Core Battery Studies”
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Discovery
Preclinical
Development
Investigational
New Drug IND
Proof of
Molecular
Target
Safety &
Efficacy
Dose Ranging
Drug Delivery
Clinical
Development
Phases I, II, III
Pivotal Proof
of Safety &
Efficacy
Human PK
Dose
Selection
Approval
Marketing
Postmarketing
Surveillance
Post-marketing
Surveillance for
Safety and
Efficacy
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Types of Clinical Research
 Case Reports
 Observational
 Case Control/Retrospective
 Cross Sectional
 Prospective  Risk Factor Associations
 Drug Development
(Phase 0, Phase I, Phase II, and Phase III)  Dose
/activity and clinical safety/efficacy
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Phases of Clinical Trials
 They can be broadly categorised into four types largely
depending on the main aim
 Phase 0, Preclinical Testing
 Phase I, “first in man’ studies”
 Phase II, “preliminary assessment of efficacy”
 Phase III, “randomised controlled trial (RCT)”
 Phase IV, “Post-marketing Surveillance”
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Phase I Trials
First time a new drug or regimen is tested on
humans
 Few participants usually <30
 Primary aims are
 find a dose with an acceptable level of safety
(maximum tolerated dose, MTD),
 examine the biological/pharmacological effects
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Phase I Trials
Designs
 Phase I studies aim to determine a sufficiently safe dose
 They involve giving a certain dose to a few subjects (usually
3), and if tolerable, the next group receive a higher dose
 This continues until the administered dose is associated
with an unacceptable level of side-effects (MTD) or
 dose where 1/3 of patients experience dose limiting
toxicity (DLT)
 This is not the same as trying to find the most effective
(optimal) dose, the objective of phase II and III trials
 Although a small number of subjects in each dose group is
used, the study should provide enough information on safety
and efficacy to determine whether a new drug should be
investigated further
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Phase I Trials
Type of subjects
 Healthy volunteers are often used, and if safe enough,
there could follow another phase I study in patients affected
with the disorder of interest
 An exception is cancer drug trials, where traditional anticancer drugs are first tested in cancer patients because the
expected toxic effects make them inappropriate to test in
healthy volunteers
 Furthermore, healthy people may be able to tolerate cancer
drugs at higher doses than a cancer patient
 Cancer patients included in phase I studies have usually had
several previous therapies, but did not respond, so they
tend to be less fit than the target group of patients, estimates
of treatment effectiveness need to be interpreted carefully
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Phase I Trials
Type of subjects
 Several phase I studies may be conducted, each looking at
different aspects of a new therapy
 For example, examining the pharmacological effects when
 the drug is taken with and without food,
 giving multiple doses,
 and renal impairment
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Phase I Trials
Outcomes
 The principle aim is to find the maximum tolerated dose
(MTD)
 Sometimes, it is the dose at which a pre-specified
number of individuals suffer a severe adverse event,
indicating that this dose may be too unsafe, so the next
lowest dose would be investigated further
 This definition can also be called the maximum
administered dose
 At other times, the MTD could be the dose that has an
acceptable number of side-effects and is therefore used
in further studies
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Phase II Trials
 The aim of a phase II study is to obtain a preliminary
assessment of efficacy
 Number of subjects usually less than 100
 A phase II study could have more than one treatment to
examine
 There could also be a control arm in which subjects are
given standard therapy
 If the results are positive, the data in each arm are used to
design a randomised phase III trial, for example estimating
sample size
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Phase II Trials
 When there is more than one intervention, it is best to
randomise subjects to the trial groups
 A randomised phase II study could also provide
information on the feasibility of a subsequent phase III
trial, such as how subjects are to be randomised
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Purpose of phase II studies
 The aim is to obtain preliminary evidence on whether a
new treatment might be effective (EFFICACY)
 Safety should still be monitored closely
 The results of a phase II study often help design a phase III
trial
 Phase II studies may also be pilot (or feasibility) studies,
used to assess whether a phase III trial is likely to be
successful
 The study is designed and conducted in a similar manner to
a phase III trial, but the protocol specifies that an early
assessment is made after a proportion of subjects have
been recruited first (e.g. 25%), or the trial has run for a fixed
length of time
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Phase III Trials
 A phase III trial is commonly referred to as a randomised
controlled trial (RCT)
 Subjects must be randomly allocated to the intervention
group(s), and there must be a control (comparison)
 The aim is to provide a definitive answer on whether a new
intervention is better than/similar to the control
 Sometimes, there are more than two new interventions
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Phase III Trials
 Phase III trials should be designed and conducted to a high
standard, with precise quantitative results on efficacy
and safety
 This can be particularly important for pharmaceutical
companies who wish to obtain a marketing licence from a
regulatory agency for a new drug or medical device
 Trials used in this way can be referred to as pivotal trials
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Phase III Trials
 Must be randomised and with a comparison
(control) group
 Relatively large (usually several hundred or
thousand people)
 Aim is to provide a definitive answer on
whether a new treatment is better than the
control group, or is similarly effective but there
are other advantages
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Objectives of Phase III trials
 The main objective of a phase III study is usually based on
efficacy and/or safety
 Commonly, it is desired to comparing two interventions, A
and B
 B could be the standard treatment, placebo or no
intervention
 Final conclusion fall into one of the following categories:
 Superiority: A is more effective than B
 Equivalence: A has a similar effect to B
 Non-inferiority: A is not less effective than B, i.e. it could
have a similar effect or be better
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Types of phase III trials
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Types of Phase III Trials
 Most trials have parallel groups: each group of subjects
receives only one intervention
 They are used when treatments have long-lasting effects,
such as life-threatening disorders, or for disease prevention or
cure
 For chronic disorders, where the desired outcome is relief
of symptoms rather than disease cure, it is possible to
allocate both the new and standard treatment to the same
subject in sequence in a crossover trial
 Crossover trial design is also used for bioequivalence trials
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Types of Phase III Trials
 There are also bioequivalence drug trials, in which two
forms of the same drug, for example a different
formulation, are compared, rather than two different drugs
 All that is required is to determine that a similar amount of
drug is taken into the body, i.e. similar bioavailability
 A completely new trial with one of the common true efficacy
endpoints such as mortality or disease cure is unnecessary
 If bioequivalence is demonstrated, it is assumed that there
would be the same effect on a true endpoint
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