Drug development; synthesis

phase, preclinical and clinical

phase.
Dr Sokiprim Akoko
 Drug Evaluation

• This is the confirmation of a drugs identity,

determination of its purity and quality and
detection of nature of adulteration

•Reasons for evaluation include

• Substitution or adulteration may be due to
carelessness or by intention
• Biochemical variation in the crude drug
• Deterioration due to treatment or storage of crude
drugs
 Drug Evaluation
• Methods used in standardization or evaluation of crude drugs include
• Organoleptics (Morphological) Evaluation
• evaluation by means of our organs of sense and includes other sensory organs like
odour, colour, taste and texture.
• It includes the study of morphology and other sensory characters.
• Microscopic or anatomic Evaluation
• This method allows a more detailed examination of a drug and it can be used to identify
organised drugs by their known histological characters.
• This can be done by powdering, cutting thin sections of the drug or preparing a
macerate.
• Physical Evaluation
• Physical contents such as 1. elasticity in fibres, 2. viscosity of drugs. 3. congealing point
of volatile and fixed oils, 4. Melting point 5. boiling points 6. water contents are some
important parameters used in the evaluation of drugs. Ultraviolet light is also used for
determing the fluorescence of extracts of some drugs
 Drug Evaluation-1
• Chemical Evaluation
• Determination of the active constituent in a drug by
chemical tests
• Biological
• It is employed when the drug cannot be evaluated
satisfactorily by chemical and physical methods.
• In this method, the response produced by the test drug
on a living system is compared with that of the stranded
preparation.
• Such an activity is represented in units as International
Units (I.U).
 Drug Development
• In drug research and development the patient is the main focus. The
mission for the pharmacologist is to help the patient overcome a
disease and improve their quality of life.
• The drug development process is designed to ensure that innovative
new medicines are effective safe and available for patients in the
shortest possible time.
• The first step in drug development is to discover the best targets for
treating or preventing a disease.
• Targets are usually proteins in the patient's body which are
associated with a disease or proteins in microorganisms causing a
disease
 Drug Development-2
• The challenge is to identify which proteins are
relevant and more importantly confirm their role in a
disease
• It is important to understand cellular networks of
proteins or pathways. A single protein may transmit
messages to several other proteins sometimes in
multiple pathways affecting their function.
Example is Chlorphenamine (Piriton)
 Drug Development-3
• knowing how these pathways work and interact helps to
identify the most appropriate target for a drug.
• The pathway approach allows us to better understand the
mechanisms of a disease. This knowledge together with the
desire to address unmet medical needs determines the
priorities in target discovery in drug discovery.
• Several methods like high throughput screening and
computer-based design are used to find chemical
compounds or biologics that bind to the identified target.
 Drug Development-4
• If a compound modulates the target in a way that is
expected to alter the disease, this so-called hit will
be refined to improve its safety and effectiveness
eventually becoming a drug candidate.
• Discovering and bringing one new drug to the market
typically takes an average of 14 years of research
and clinical development efforts and costs; of 10
000 or more hits tested in early drug discovery only
one may eventually lead to a drug that reaches the
market.
 Drug Development-5
• In the late pre-clinical stage further experiments are conducted on the
drug candidate to ensure it is safe for patients and has the required
pharmacokinetic properties like appropriate absorption and
metabolism by the human body.
• These experiments are executed with extraordinary diligence to
minimize any risks to human test subjects.
• Animals play a critical role in the drug discovery process as well
although much research and development can be done using various
experiments or using computers complex disease mechanisms can
often only be understood through the use of animal studies.
• WHY Rats?
Non-Clinical Perspectives
Non-clinical studies are conducted to
support clinical trials and, ultimately,
approval for new drugs
 Drug Development-5
• Governments and regulatory authorities require that medicines be tested in
animals before they are tested in humans
• Scientist keeps this research as limited as possible and always ensures
that animal research is scientifically acceptable according to current
standards and regulations for these reasons we continue to use animals in
its quest to find innovative safe and life-saving medicines for patients at
the same time
• Scientists are committed to refining reducing and replacing the use of
animals in research and upholding the highest standards in animal welfare
clinical trial programs consist of several phases, each of which is focused
on evaluating drug safety and effectiveness or efficacy.
Dose Response Relationship
• Dose:
• Only Dose makes the poison
• Any chemical is capable of evoking an effect
• Amount of material needed tp produce an adverse effect
• Response:
• An adverse effect as induced by a chemical
• Response is comparison between treated and non treated(control)
Dose Response Relationship-2
• The dose response relationship is a fundamental and essential
concept in toxicology. It correlates exposures and spectrum of
induced effects
• The dose response relationship is based on observed data from
experimental animal, human clinical or cell studies.
 PRECLINCAL PHASE
• Therapeutic Index (TI)

• TI = LD50/ED50
• or TI = TD50/ED50
• TI is the ratio of the doses of the toxic and the desired responses.
• TI is used as an index of comparative toxicity of two different materials;
approximate statement of the relative safety of a drug.
• The larger the ratio, the greater the relative safety.
Some chemicals have both therapeutic
and toxic effects: Vitamin A

Too low:
Too high: Anorexia,
Blindness,
anemia, nose bleeds,
Adverse response

dry skin,
muscle and joint pain
increased
infections
Threshold

Dose
 Dose-Response Curves for Beneficial Substances
death

threshold for

toxicity
adverse response

region of
homeostasis

response
deficiency toxicity

dose

•For substances required for normal physiological function and

survival, the dose-response curves will be U- or J-shaped.
•At very low doses, there is an adverse effect (deficiency), which
decreases with increasing dose (homeostasis). At very high
doses, an adverse response appears from toxicity.
•For example, vitamin A can cause liver toxicity and birth defects
at high doses and vitamin A deficiency is lethal.
Limitations of LD50

• The LD50 gives a measure of the immediate or acute toxicity

• Results may vary greatly
• LD50 is not tested on humans
• All relation to humans are only a guess
• The LD50 test is neither reliable nor useful Because the human
lethal dose is difficult to be predicted from animal studies
IARC Overall Evaluation of
Carcinogenicity to Humans
1 Carcinogenic to Humans
2A ProbablyCarcinogenic
2B Possibly Carcinogenic
3 Not Classifiable
4 Probably Not Carcinogenic

Weight of Evidence
How do Non-Clinical and
Clinical Development Influence
Each Other?
• How do you get from non-clinical studies into the
clinic?
• What types of non-clinical studies are needed to
continue clinical development?
• What role do non-clinical studies play in clinical trial
design?
Types and Timing
of Non-Clinical
Studies
 Non-Clinical Studies M3(R2)

• Safety pharmacology GLP

• Pharmacokinetics
• ADME (absorption, distribution, metabolism, elimination)
• General toxicology
• Local Tolerance
• Genotoxicity
• Carcinogenicity
• Reproductive toxicology
• Special studies
Exceptions
• ICH M3’s recommendations for types and timing of studies most directly
applicable to systemically- administered small molecules intended to treat non-
life-threatening conditions

• Exceptions
– Life-threatening conditions
– Topically-applied products (skin and eyes)
– Certain medical imaging agents
– Biologics (ICH S6)
Types and Timing of
Non-Clinical Studies
 Types and Timing of
Non-clinical Studies
(Relative to Small
Study Type Biologic
Clinical Trials) Molecule

Safety pharmacology
Prior to Phase 1 Yes Product
• Cardiovascular specific
• Respiratory
• CNS

Prior to Phase 1, 2 Yes Yes

General toxicology
and 3 (2 species) (1 species
acceptable)
Types and Timing of
Non-clinical Studies
Timing
Small
(Relative to
Study Type Clinical Trials) Molecule Biologic

Genotoxicity
• Prior to Phase 1
• Bacterial mutation
• Prior to Phase 1 Yes Generally no
• In vitro chromosomal
aberrations • Prior to Phase 2
• In vivo chromosomal
aberrations
• In vivo micro
nucleus
Types and Timing of
Non-clinical Studies
Timing
Small
(Relative to Clinical
Study Type Trials) Molecule Biologic
Reproductive Toxicology
• Prior to Phase 3
• Embryo-fetal Generally Product
• Prior to Phase 3 specific
development Yes
• Prior to Phase 3
• Male fertility
• Marketing approval
• Female fertility
• Pre-/post-natal
development

Yes Product
Carcinogenicity Marketing approval
(chronic specific
drugs)
Nonclinical Programs for
Small Molecules
Study Type Oral Dermal Ocular
General toxicology Rat and dog Mini-pig (dermal) Rabbit, pig, dog,
Rat (systemic) monkey (ocular)
Rat/non-rodent
(systemic)
Genotoxicity Yes Yes Yes
Safety Yes Generally yes, but Not routinely expected
Pharmacology consider systemic
exposure and body
surface area
Melanin Binding Not routinely Not routinely Generally yes
Photosafety As needed As needed As needed
Hypersensitivity Not routinely Yes Not routinely
Reproductive Yes Yes Might be able to waive
toxicology some studies
Carcinogenicity Yes Yes Might be able to waive
 What is the Role of
Non-Clinical Studies?
• Data from non-clinical studies are used to support the
safety of clinical trials and drug approval
– Identify adverse effects of a drug
– Select starting dose for Phase 1 clinical trials
– Support safety of ongoing clinical
 Questions that Non-Clinical Studies Answer
• What are the toxic doses in animals?
• What are the target organs?
• How do the toxic doses compare to the
effective/clinical dose(s)?
• Can the toxicities be monitored in patients in
the clinical trials?
• Are the toxicities reversible?
 Non-Clinical Reasons for
Clinical Hold
• Appropriate studies were not conducted
• Study designs were flawed
– Insufficient number of animals
– Inappropriate endpoints
– Study duration not appropriate
• The toxicities presented unacceptable risk
• NOAEL was not identified
Overview of Clinical
Trials
 Drug Development 101
PRE-CLINICAL RESEARCH CLINICAL STUDIES NDA REVIEW
E PHASE 1

E PHASE 2
SYNTHESIS
AND PURIFICATION
PHASE 3

ACCELERATED DEVELOPMENT REVIEW

ANIMAL
TESTING
SHORT-TERM E TREATMENT IND

LONG-TERM
INSTITUTIONAL REVIEW BOARDS

FDA TIME IND SUBMITTED NDA SUBMITTED

INDUSTRY TIME EARLY ACCESS:
SPONSOR
SPONSORED/FDA MEETING ENCOURAGED E SUBPART E REVIEW ANSWERS ANY
ADVISORY COMMITTEES DECISION QUESTIONS FROM
REVIEW
Phase 1, 2, and 3 Trials

Phase 1: Phase 2:
 Safety and pharmacokinetics  Efficacy and safety
 Generally 20 to ~80 subjects
 Usually no more than
 Closely controlled
several hundred subjects
 Closely controlled

Phase 3:
 Efficacy and safety
 Several hundred to several
thousand subjects
 Clinical Trials
• Phases of clinical investigation defined in 21
CFR 312.21
• IND (Investigational New Drug) may be
submitted for one or more phases of an
investigation
• Clinical investigation of a new drug is
generally divided into 3 phases
– Phases 1, 2 and 3
 What are Phase 1a, 1b, 2a
and 2b?
• No regulatory definition or description
• Way to classify/subdivide clinical trials
• Example
– Phase 1a – Single dose
– Phase 1b – Repeat dose
What is Phase 0?
Exploratory IND (eIND) approach
– Limited human exposure
– No therapeutic intent
– Not intended to examine tolerability
• Non-clinical approach more limited than for traditional IND
– Different options possible
• Most applicable to imaging agents
What is Phase 0?

eIND guidance documents

– FDA, Exploratory IND Studies (2006)

– ICH M3(R2), Guidance on Nonclinical Safety Studies

for the Conduct of Human Clinical Trials and Marketing
Authorization for Pharmaceuticals (2010)
Types of Action
• Approval
• Complete Response (CR)
– Results of studies (non-clinical and/or clinical)
show that drug is unsafe for use under the
proposed conditions
– Lack of evidence of efficacy
– Chemistry and manufacturing issue
Drug Development and Testing
CLINICAL TRIALS
Phase 1:
• It focuses on safety, and pharmacokinetics
concerns on healthy subjects within the
therapeutic dose.
• Includes initial introduction of a new drug into
humans
– Closely monitored
– Safety and pharmacokinetics, drug metabolism
and mechanism of action
– Healthy volunteers or patients
– Generally 20 to 80 subjects
Drug Development and Testing-2
Phase 2:
• Here the question to answer is- Does it work?
• It’s usually done on patients and used with a control. It could be a
single blind or double blinded study protocol. The sample population is
usually very small- 100-250 patients with the disease to evaluate its
efficacy and to determine optimal dose.
• The safety and side effects are also evaluation as this may be different
in patients compared to the healthy patients in Phase 1.
• The idea of Prove of Concept trials are a mix of Phase 1 and 2
studies. A group of select well defined individuals will be treated
with the drug to provide information such as -does the drug work on
the target in the intended way? Does it have a beneficial impact on
the disease?
Drug Development and Testing-2
Phase 2:
• Evaluate effectiveness of a new drug for a particular indication in
patients with the disease
– Define doses for Phase 3
– Determine short-term risks and side effects
– Closely monitored
– No more than several hundred subject
Drug Development and Testing-3
Phase 3:
• Is concerned with How well does it work (effectiveness) and what are
the common side effects? It uses larger study populations 0f 1,000-
3,000 or even more with the investigation drug.
• It also compares the investigation drug to established treatment and
gathers additional information that allows the drug to be used safely.
• For a new drug to enter the market, it must be registered by NAFDAC or
any countries FDA. To do this data from the preclinical and clinical
trials are collected to review its efficacy and safety information to
support the final intended use of the drug.
• Once approvals are done several activities continue like post
monitoring like drugs safety monitoring which is mandatory, post
authorization safety updates, annual reports and any additional
information required by NAFDAC must be provided at intervals as long
as the drugs remains on the market.
Drug Development and Testing-3
Phase 3:
– Performed after preliminary evidence of
efficacy has been demonstrated
– Intended to gather additional information on
safety and efficacy
– Evaluate risk vs. benefit
– Several hundred to several thousand subjects
Drug Development and Testing-4
Phase 4:
• Often, this phase is initiated to collect additional data not
collected in the phase 3. Post marketing surveillance and
untoward effects, also known as Pharmacovigilance.
• Efficacy, safety, additional benefits and risk information as well as
pharmacoeconomics data are part of what phase 4 entails. It’s
important to note that Drugs are likely to be withdrawn in Phase 4
if these information are not available.
Regulatory Agencies
What is meant Regulatory Toxicology?
• Regulatory Toxicology encompasses the collection, processing
and evaluation of epidemiological as well as experimental
toxicology data to permit toxicologically based decisions directed
towards the protection of health against harmful effects of
chemical substances.
Regulatory Agencies in Nigeria
• National Drug Law Enforcement Agency (NDLEA)
• National Agency for Food and Drug Administration and Control
(NAFDAC)
• The Nigeria Police Force (NPF)
• Nigeria Customs Service (NCS)
•That’s All
Thank you for staying awake