Safety Data Generation

Juny Sebastian
Lecturer, Dept. Pharmacy Practice
JSS College of Pharmacy,
JSSAHER, Mysuru
Pre Clinical Phase
 Development Phases
• Objective of Preclinical phase
• Discover and develop patentable drug candidates on
targets of relevance
• Generate data that gives reasonable estimate of clinical
efficacy and safety
• Provide enough evidence to obtain regulatory approval for
“first in human testing”
Non- Clinical Drug Development

Preclinical Phase

Reg.
Preclin
LG LO Approval
Develop
(IND)

Discovery

Development

Regulatory IND
 Lead Generation
Target identification
• Identification of new, clinically relevant, molecular targets is
of utmost importance to the discovery of innovative drugs
• Choose a disease
• Choose a target
• Current therapy is based upon less than 500 molecular
targets
• 45% of which are G-protein coupled receptors
• 28% are enzymes
• 11% are hormones and factors
• 5% ion channels
• 2% nuclear receptors
• Many more drug targets still exist! How to identify them?
• Besides classical methods of cellular and molecular biology,
new techniques are becoming increasingly important
• Genomics
• Bioinformatics
• Proteomics
• Target validation
• Involved in pathogenesis of disease
• Can generate experimental model of clinical disease (Proof of
concept)
• Possible to have compounds bind to active site
Lead Compound Identification
Compounds are identified which interact with the
target protein and modulate its activity
• Screening of natural products
• Fermentation (antibiotics)
• Plant extracts (anticancer agents)
• Chemical modification of natural products (semisynthesis)
• Screening synthetic compound ʹlibrariesʹ
• 75 % of drugs are synthetic chemicals
• Chemical modification of existing drugs
• Captopril à Enalapril, cilazapril
• Starting from the natural ligand or modulator compounds
• Salbutamol and isoprenaline are derived from adrenalin
New technologies used in Lead Identification
• High-throughput Screening
• Computer-aided drug design
• Combinatorial chemistry/Parallel Synthesis
• De-novo synthesis/Virtual screening
Lead Optimization
 Lead Optimization
• Molecules are chemically modified and subsequently
characterized in order to obtain compounds with
suitable properties to become a drug
• Leads are characterized with respect to
pharmacodynamic properties such as efficacy and
potency in vitro and in vivo, physiochemical properties,
pharmacokinetic properties, and toxicological aspects
• This process ideally requires the simultaneous
optimization of multiple parameters and is thus a time
consuming and costly step
• In parallel to compound characterization with respect to
potency and selectivity, in vitro assays for the prediction of
pharmacokinetic properties should be performed
• Compounds that do not fulfill the requirements for a
successful drug development candidate have to be
optimized through the synthesis of better suited
derivatives
• Once compounds with desirable in vitro profiles have
been identified, these are characterized using in vivo
models
• It is vital to conceive lead optimization as a simultaneous
multidimensional process rather than a sequential one
 Pre-Clinical Development
• Efficacy data – proof of concept (GLP)
• Animal models of disease
• Therapeutic dose calculations
• Animal PK
• Rodents
• Large animals
• Safety Pharmacology
• Toxicology/Toxicokinetics
 Efficacy Data
• Experimental proof-of-concept
• To be established before new drug can be given IND
• The animal model Should provide predictable
information that is relevant to clinical effects
• Disease specific animal models
• Transgenic / knock out/ knock in animals
Pharmacokinetic Information
• In vivo ADME
• Bioavailability
• Peak plasma concentration
• Duration of drug action
• Metabolic stability
 Safety Evaluation
• Safety pharmacology studies provide a dynamic
and flexible approach of the potential functional
disturbances induced by a new chemical entity
• Many studies regarding vital functions can be
carried out very early, prior to clinical study, at single
dose, with short-term design, sometimes using in
vitro methods and with small amount of product
 Safety Pharmacology
• CNS studies
• CNS Function Tests
• Motor activity
• Behavioral changes

• Cardiovascular studies
• ECG
• Hemodynamic parameters
• Respiratory function tests
• Gastrointestinal motility studies
• Hematological Evaluations
• Blood Coagulation
• Hepatic and Renal functional Status
 Toxicology Studies
• Preliminary (Range-Finding) Toxicity
• Maximum tolerated dose (MTD)
• Dose limiting toxicity's (DLT)
• Up/Down toxicity study
• Single/multiple dose range-finding
• Subacute, Subchronic Chronic toxicity
• Single or multiple dose
• Duration: 2, 4, 13, 26 weeks
 Toxicology Studies
• Reproductive & Development Toxicology
• Teratogenicity, Generation Studies
• Genotoxicity
• Ames Salmonella Test, Reverse
• Mutation assay
• In vivo micronucleus Test
• Chromosomal Aberrations
• In vitro Chromosomal Aberrations
• Gene Mutations
 IND Application
• Documentation  that  allows  investigational  clinical  testing  
of  a  new  medicine  
• The  main  purpose  is  to  provide  the  data  showing  that  it  is  
reasonable  to  begin  tests  of  a  new  drug  on  humans    
• Must  be  9iled  with  FDA  before  drug  administered  to  
humans  
• Studies  may  begin  within  30  days  of  application…..if  no  
response  from  the  FDA    
 Content and Format of IND Application

A. Cover Sheet (FDA Form-1571)

B. Table of Contents
C. Introductory Statement and General Investigational Plan
D. Investigator's Brochure
E. Protocols
F. Chemistry, Manufacturing, and Control Information
1.Chemistry and Manufacturing Information
2.Drug Substance
a. A description of the drug substance, including its physical, chemical,
or biological characteristics
b. The name and address of its manufacturer
c. The general method of preparation of the drug substance
d. The acceptable limits and analytical methods used to assure the
identity, strength, quality, and purity of the drug substance
e. Information to support the stability of the drug substance during the
toxicologic studies and the proposed clinical study(ies)
3.Drug Product
a. A list of all components, which may include reasonable
alternatives for inactive compounds, used in the
manufacture of the investigational drug product
b. Where applicable, the quantitative composition of the
investigational new drug product
c. The name and address of the drug product manufacturer
d. A brief, general description of the method of
manufacturing and packaging procedures as appropriate
for the product
e. The acceptable limits and analytical methods used to
assure the identity, strength, quality, and purity of the
drug product
f. Information to support the stability of the drug substance
 4.A brief general description of the composition, manufacture, and
control of any placebo to be used in the proposed clinical trial(s)
5.A copy of all labels and labeling to be provided to each investigator
6.A claim for categorical exclusion from or submission of an
environmental assessment
G. Pharmacology and Toxicology Information
1.Pharmacology and Drug Distribution
2.Toxicology: Integrated Summary
1. A brief description of the design of the trials and any deviations from the
design in the conduct of the trials
2. A systematic presentation of the findings from the animal toxicology and
toxicokinetic studies
 3. Identification and qualifications of the individual(s) who evaluated the
animal safety data and concluded that it is reasonably safe to begin
the proposed human study
4. A statement of where the animal studies were conducted and where the
records of the studies are available for inspection
5. Whether the GLP requirements were fulfilled during the animal experiments
– if any non-compliance during the process; how does it affect the findings
of the study – implications in clinical studies

3. Toxicology - Full Data Tabulation

4. Toxicology - GLP Certification
5. Monitoring of Effects of these Clarifications

G. Previous Human Experience with the Investigational Drug

Phases of Clinical Trials
Phases of Clinical Trials;

• An investigational medication must go through different

phases of clinical trials before Food and Drug
Administration approval.

• Clinical trials are conducted in a series of steps, called

phases.

• The phases are described as I, II, III and IV.

• If the drug successfully passes through Phases I, II,
and III, it will usually be approved by the national
regulatory authority for use in the general population.

• Phase IV are 'post-approval' studies.

• Before pharmaceutical companies start clinical trials

on a drug, they conduct extensive pre clinical studies
 32

Phase 0 trial ( Micro-dosing

studies)
05/04/19 33

• Phase 0 studies are not so common and not mandatory

as per regulations
• Recently (2006), FDA approved testing of small quantities
of the experimental drug in man to understand the path of
the drug in the body
• These studies do not provide any data on safety and
efficacy, use a dose too low to to produce any therapeutic
effect
05/04/19 Pharmacopoeias 34

• Drug development companies carryout these studies to

rand the drug candidate in order to decide which has the
best pharmacokinetic parameters in human
• To take go/no-go decision based on the relevant human
model instead of relying on on inconsistent animal data
Clinical Trials Timeline
 36

Phase 1 trial ( First in human

studies/ Human pharmacology
studies)
 Phase I Studies
Does the drug really work, is it safe, how does it behave in humans ?

Aim Ï to ascertain safety

Ï to identify range of doses tolerated
Ï to look at
Ø absorption
Ø distribution
Ø metabolism and
Ø excretion
Study population 10-20 normal, healthy
human volunteers
Scope 8-10 tests
10-20 M US$
Phase 1 trials – Is the treatment safe?

• After an experimental drug or treatment has been tested in the

lab and/or on animals, it enters a phase 1 trial.

• In phase 1 trials researchers test a new drug or treatment in a

small group of people for the first time to evaluate its safety,
determine a safe dosage range, and identify side effects.

• The goal of a phase I clinical trial is to prove that a new drug or

treatment which has proven to be safe for use in animals also
may be given safely to humans.
Phase 1 trial – what is the dose range?
• These trials also help determine the best way to give the drug,
whether oral or intravenously.

• In phase I clinical trials the dose of an investigational drug is

gradually increased to determine the optimal safe dose. This
process is called dose escalation.

• The first participants are given a small dose of the drug. If there
are no or few side effects, the next group is given higher
amounts of the drug until the doctors determine the optimal
dose with the fewest side effects.
• Phase I clinical trials generally last several months and involve
a very small number of people, usually no more than 10 to 20.

• Most phase 1 studies are initiated in fit male volunteers who

may be recruited through various teaching institutions or
medical schools.
Phase II Trial
( Therapeutic Exploratory
Studies)
Phase II studies
Is the drug really efficacious in patients ?

Aim to have a first look at efficacy

Design • Placebo controlled

• Randomised
• Double blind
At select medical research centers

Study population 200-300 patients suffering

from target illness

Scope Two years

Go / No Go decision 20-40 M US$
Phase 2 trials – Does the treatment
work?
• Once the initial safety of the study drug has been confirmed in
Phase I trials, it enters phase 2 trials.

• The experimental study drug or treatment is given to a larger

group of people (100-300) to see if it is effective and to further
evaluate its safety and to gather additional information
regarding safe dose range.

• Phase II studies are sometimes divided into Phase IIA and Phase
IIB.
• Phase IIA: designed to assess dosing requirements (how much
drug should be given)
• Phase IIB : designed to study efficacy (how well the drug works
at the prescribed dose(s)).

• Patients rather than healthy volunteers are used as subjects.

Phase III Trial
( Therapeutic
Confirmatory Studies)
Phase III studies
Aim To establish Safety and efficacy in a large
patient group

Design • Randomised
• Controlled (Placebo or control drug)
• Double blind
At several major hospitals,
pivotal studies are often multinational

Study population 2000-3000 patients

Scope May take up to 3 years

100-150 M US$
Phase 3 trials – Does the new treatment
work better than the standard treatment?
• In Phase III studies, the study drug or treatment is given to
large groups of people [1000-3000] to confirm its

üEffectiveness

üMonitor side effects

üCompare it to commonly used treatments

üCollect information that will allow the drug or treatment to

be used safely
• Phase III clinical trials are usually randomized,
meaning that patients are assigned treatment groups in
a non-ordered way.

• Although phase III trials focus on patients with a

specific disease, they typically include patients of
various ages, multiple ethnicities, and both genders so
that the results, once obtained, may be applicable to a
large number of people.
• The number of people enrolled in a phase III clinical
trial can range in the hundreds to thousands and take
many years to complete.

• Because of their size and comparatively long duration,

Phase III trials are the most expensive, time-
consuming and difficult trials to design and run,
especially in therapies for chronic medical conditions.
• Once a drug has proved satisfactory after Phase III trials,
the trial results are usually combined into a large document
containing a comprehensive description of the methods and
results of human and animal studies, manufacturing
procedures, formulation details, and shelf life.

• This collection of information makes up the "regulatory

submission" that is provided for review to the appropriate
regulatory authorities in different countries.

• If data from the clinical trials meet the FDA's standards,

the treatment will be approved for a specified use.
Phase IV Trial ( Post
Marketing Surveillance
Studies)
05/04/19 52

• For safety surveillance/ the drug or treatment can be used

for other situations
• Designed to detect any rare or long term adverse effects
of drug in larger population.
 Frequency Terminology

Very common* > 1/10 > 10%

Common
> 1/100 and < 1/10 > 1% and < 10%
(frequent)

Uncommon > 1/1,000 and <

> 0.1% and < 1 %
(infrequent) 1/100

> 1/10,000 and <

Rare > 0.01% and < 0.1%
1/1,000

Very rare* < 1/10,000 < 0.01%

Source: Council for International Organizations of Medical Sciences (CIOMS), 1995 * Optional categories
Pre-licensure Assessment of Vaccine Safety
Adverse Reactions
Sample size Common Rare

Animal trials +/− −

Clinical trials
Phase I 10-100 +/− −
Phase II 100-1,000 + −
Phase III 1,000-10,000 + −

– Does not detect adverse reactions which are:

• rare, delayed, unexpected
• occur in sub-populations
• with vaccine combinations