1. Advanced Pharmacology-I (PHR5001) Lecture 2: Drug Development
Dr. M G Azam
Asstt. Professor
Dept. of Pharmacy, NSU

2. Drug Development Process
Discovery and formulation: Synthesis of a potential new drug molecule and an understanding of its interaction (mechanism) with the appropriate biologic targets. Repeated application of this approach leads to compounds with increased potency and selectivity
Preclinical evaluation: Relevant biologic effects, drug metabolism, and pharmacokinetic profiles and particularly an assessment of the relative safety of the drug must be characterized in animals before human drug trials can be started.
Clinical evaluation -Phases I-IV: With regulatory approval, human testing can then go forward in three phases before the drug can be considered for approval for general use.
The processes of new drug discovery and development are long, complicated and dependent upon the expertise of a wide variety of scientific, technical and managerial groups.

3. Basic Disciplines of Drug Development
Chemistry, Manufacturing, and Controls
– Discovery (serendipity, folk medicine, random screening, rational drug design)
– Chemistry (synthesis, purification, scale-up)
– Analytical (chemical structure and activity, excipients, purity and stability)
– Pharmaceutical (dosage form, route of administration, packaging and labeling)
– Good Manufacturing Practice (GMP):
• Guidelines related to manufacturing practices and specifications
• Focus on impurities
• Necessary to ensure quality of drug product (finished dosage form) and drug substance (bulk ingredients)

4. Basic Disciplines of Drug Development
• Nonclinical
– Testing in laboratory (in vitro) and in animal models (in vivo) to assess safety and efficacy
– Objectives:
• To develop the pharmacological profile
• To determine the acute toxicity in at least 2 animal species
• To assess toxicity with studies ranging from 2 weeks to several months
– Good Laboratory Practice (GLP):
• Guidelines related to studies in animal models
• To ensure the quality and integrity of data by establishing basic
standards for the conduct and reporting of nonclinical safety studies

5. Basic Disciplines of Drug Development
Clinical Investigation
– Submission of the Investigative New Drug (IND, a request for permission from FDA to begin testing)
– Conduct of Clinical Studies of the product in humans
(in healthy volunteers or in patients)
• Phase 1
• Phase 2
• Phase 3
• Phase 4 (post-marketing studies)
IND Submission – Compilation of the following:
• Data obtained during nonclinical investigation stage and from previous
human experience
• Chemistry, manufacturing, and control data (information on the composition and source of the drug)
• Protocol
• Detailed description of proposed studies
– 30-day review period at FDA
Takes an average of 6 years to complete the first three stages

7. Drug Development Process
A view on the process from the idea to the registered pharmaceutical
I. DISCOVERY
Drug discovery is the process by which new candidate medications are discovered.
Identification of target and resource

8. I. DISCOVERY Target identification
- Area of interest in terms of drug indication ?
- Relevant cellular or molecular targets ?
- Appropriate assays – established or to be developed ?
Available relevant literature ?
Patent situation in the target area ?
Resource identification
Potential resources for novel drugs:
- Natural organisms (plants, fungi, bacteria, animals) - Combinatorial chemistry
- Structure-based drug design
Methods for drug discovery:
- High throughput screening (HTS) of random samples : large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel GPCR, compounds will be screened for their ability to inhibit or stimulate that receptor .
- Ethnobiological approach:
Traditional use of natural organisms for medicines
HTS exampe: if the target is a protein kinase, the chemicals will be tested for their ability to inhibit that kinase

9. Identification of drug targets

10. I. DISCOVERY
Resource identification - Natural organisms, in particular plants -
52% of the drugs approved in the U.S. from were natural products or derived from them
- 26 plant based drugs were approved during ,
including novel-molecular based drugs
- In the future multicomponent botanical therapeutics will experience an increasing interest in biomedicine
Medicinal plants continue to play a significant role as a resource for the discovery of novel drugs.
Method of drug discovery - Ethnobotanical approach
Systematic screening of:
- Published literature on traditional medicinal plant use (e.g. documented traditional healers‘ experience)
Advantages: - Preselection of potentially active resources
- Promising safety profile (age-long experience)
- Cost-efficient and comparatively fast

13. II. HIT GENERATION: RESEARCH AND DEVELOPMENT
Process development – in phytopharmacy
Herbal raw material
Extraction solvent
Extraction
Miscella (Liquid raw extract)
Encapsulatable mass
Dry extract
Liquid extract, tincture
Soft capsules
Liquids, drops, ointments
Tablets,
hard capsules
Development of the test substance
Define: - Active substance (in phytopharmacy: native extract)
- Dosage form
Establish: - Physico-chemical profile (pKa, and solubility; permeability)
of active compounds
Investigate: - Pharmacology, - Mode of action

14. II. HIT GENERATION: RESEARCH AND DEVELOPMENT
Preclinical development
In vitro profiling:
Biochemical assays (e.g. enzyme activity assays)
Cell culture assays (e.g. cancer cell lines)
Isolated tissue assays (e.g. mucosa model)
In vitro toxicology:
Investigate potential toxic effects
in bacteria- or cell cultures

15. What is a Preclinical Trial/Testing?
Preclinical trial - a laboratory test of a new drug or a new medical device, usually done on animal subjects, to see if the hoped-for treatment really works and if it is safe to test on humans.
Many preclinical tests include pharmacokinetics - the study of how drugs move through living organisms.
Four processes are examined in pharmacokinetic studies: absorption, distribution, metabolism, & excretion
Other tests include chemistry tests on purity, stability, and shelf life of product, as well as development studies on dosing, packaging, & administration (tablet, injection, etc…)

16. III. LEAD GENERATION: RESEARCH AND DEVELOPMENT
Preclinical development
In vivo testing Animal model (mouse or rat)
Drug action: - Behaviour and reaction
- Physiology
- Histopathology
Toxicology: - Acute toxicity
- Subchronic toxicity
- Tissue specific toxicity
- Tolerability
Consider ethical aspects (e.g. number and kind of animals used)
long-term carcinogenic effects or toxic effects on mammalian reproduction
Heart, lungs, brain, kidney, liver and digestive system
Objectives:
To develop the pharmacological profile
• To determine the acute toxicity in at least 2 animal species
• To assess toxicity with studies ranging from 2 weeks to several months

20. III. LEAD GENERATION: RESEARCH AND DEVELOPMENT
Preclinical development (continued)
Pharmacokinetic studies What does the body to the drug ?
Investigate: - Liberation
- Absorption
- Distribution
- Metabolism
- Excretion
Pharmacodynamic studies What does the drug to the body ?
Investigate: - Physiological effects
- Drug action
- Relationship between drug concentration & effect
The main goals of pre-clinical studies are to determine a product's ultimate safety profile

21. Steps in Doing a Pre-Clinical Trial
Step One: Get an idea for a drug target.
Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease.
Scientists use a variety of techniques to identify and isolate individual targets to learn more about their functions and how they influence disease.
Compounds are then identified that have various interactions with the drug targets that might be helpful in treatment of a specific disease.
This information is from the website:

22. Steps in Doing a Pre-Clinical Trial
Step Two: Develop a Bioassay A Bioassay is a “live” system that can be used to measure drug effect.
It may be a culture of cells or organs or a whole animal.
For example:
Zebra-fish embryos - you can see effects of drugs on bone density, blood vessel growth and many other systems of the zebra-fish.
Picture from:

23. Steps in Doing a Pre-Clinical Trial
Step Three: Screen the drug in the Bioassay.
This is the actual test of the drug on the chosen bioassay.
This will determine if the drug is SAFE and if it is EFFECTIVE in the bioassay (BEFORE it is ever tested on humans!)

24. IND must show how the drug:
Step Four: Establish what dosage amount of the drug is safe and what dosage amount of the drug is toxic.
Most drugs have a toxic level or an amount at which the drug will become harmful instead of helpful.
Step Five: Application is made to the Food and Drug Administration (FDA) as an Investigational New Drug (IND).
IND must show how the drug:
Is manufactured.
Appears (color, solubility, melting point, particle size, moisture content).
Formulated (pills, liquid, etc. + inactive ingredients).
Will be analyzed for purity, concentration, stability.
Will be tested for safety (this will be the basis for allowing first use in humans).

25. Pharmacological activity Pharmacokinetics and drug metabolism
Preclinical Information Required Before A Selected Drug Candidate Can Be Administered To Humans
Pharmacological activity
Pharmacokinetics and drug metabolism
Toxicology
Pharmaceutics
Decision to proceed to man only after thorough characterisation of dose/concentration response relationships of candidate compound in vitro and in vivo

26. PHARMACOKINETICS AND DRUG METABOLISM
PK of drug in rodents, dogs and primates as predictor of the human situation
PK in animals is an essential part of drug selection to define the desired kinetic profile for a drug eg. half-life and bioavailability

27. Pharmacokinetics in Preclinical Species
Single dose administration, IV & P.O. in safety species and pharmacology model (usually rat, dog, monkey)
Purpose
Ensure good bioavailability and exposure in safety assessment species to enable further evaluation in safety assessment studies (adequate exposure margins for human studies)
Utilize data for prediction of human PK
Understand the relationship between PK and efficacy in animals
Data Obtained
Area under the Curve (AUC, µM·hr): Area under the plasma concentration-time curve – reflects exposure
Bioavailability (F, %): fraction of drug entering systemic circulation
Clearance (CLp, mL/min): vol of plasma cleared of drug per unit time
Volume of Distribution (Vd, L/Kg): measure of drug distribution in body
Half life (t1/2, hr): time taken for the drug concentration in plasma to be reduced by half.
Cmax, Tmax: maximum plasma concentration; time to reach maximum plasma concentration
PK studies – study PK after a single oral or intravenous dose.
Purpose – as written
Data obtained – as written

28. Challenges and opportunities in Early Clinical Drug Development
Understand the drug in context of;
the disease
How to measure
The chemistry/pharmacology
What causes the disease
How does the disease evolve
the patient
What different phenotypes exists
Are there different Genetic profiles
This is Translational Medicine
The "translation" of basic research into real therapies for real patients

29. Preclinical Testing
Assess primary safety, biological activity, and therapeutic ratio
In vivo animal models
In vitro physiological models
1 in 10,000 compounds pass
years to develop compound

30. Review: Steps to New Drug Discovery Pre-Clinical Trials
Get idea for drug target
Develop a bioassay
Screen chemical compounds in assay
Establish effective and toxic amounts
File for approval as an Investigational New Drug (IND) (leads to clinical trials)

31. Drug Safety Assessment
Lecture 3:
Clinical Trials
&
Drug Safety Assessment

32. Clinical Trials Purpose Is drug SAFE AND EFFECTIVE???
Clinical trials are a process of testing products prior to approval of a drug or treatment plan for widespread use in humans.
Purpose
Is drug SAFE AND EFFECTIVE???
Predict Toxic Effects
Determine Safe Dosage
Determine efficacy (effectiveness)
If the IND is approved, development moves to the clinical phase.
All participants go through informed consent process (given facts about risks & benefits)

33. Phase I Clinical Trials
Determine primary safety and the maximum-tolerated dose in humans
Usually involve a single administration of the product or a placebo
Normal, healthy volunteers (20-100)
identify side effects
Usually last 6 months to 1 year (30% of drugs fail Phase 1 testing)
evaluate its safety; common side effects: Fatigue, nausea, hair loss, vomiting
How drug is: Absorbed, Metabolized, Excreted, Duration of action
Determine ADME and pharmacological action of drug in humans

34. FINDINGS LIKELY TO LEAD TO PROJECT TERMINATION
FACTORS TO BE CONSIDERED IN DECIDING THE STARTING DOSE
Maximum no effect dose/exposure in toxicity studies using most sensitive species
Nature & severity of toxicity seen in animals
Slope of dose-response curve
FINDINGS LIKELY TO LEAD TO PROJECT TERMINATION
Poor tolerability at therapeutic concentrations
Unsatisfactory kinetics/metabolism
Low potency
Absence of efficacy
PK REASONS
Saturable clearance mechanisms
Multiple metabolites not covered by toxicity studies
PK REASONS FOR STOPPING DRUG DEVELOPMENT
Half-life (t ½) too short or too long
Poor bioavailability
Inconsistent bioavailability with low therapeutic index

35. Phase II Clinical Trials
Evaluate effectiveness, examine adverse effects, and select optimal dose
Involve patients who have the indicated disease or condition
– Small patient population ( )
– Usually last 2 years (37% of drugs fail Phase 2 testing)
Objective: – Final objective of Phase 2 Studies is to have rigorously defined the
dose regimen of the drug that elicits the desired
Study design: - Dosage comparison

36. Phase III Clinical Trials
Large-scale studies aimed at verifying efficacy establishing long-term safety & establish optimal dose and establishing the optimum dosage
monitor side effects
compare it to commonly used treatments
Interactions (with other meds)
– Involve a larger number of patients ( )
– Usually last 3 years (6% fail Phase 3 testing)
- Apply for a New Drug Application (NDA): 80% of an NDA is clinical data. About 80% of drugs that make it to Phase III studies get approved
Objective: – To provide the data sufficient to convince the FDA of the favorable benefit/risk ratio of the drug under investigation. Data must support that drug is more effective than placebo (a substance with no pharmacological effect) or drug offers alternative to existing medication
NDA Includes • Results of animal and clinical studies
• Any foreign clinical and marketing data
• Detailed chemistry, manufacturing, and control data
Study design: Comparison to placebo or to standard therapy
Overall aim of Phase III: Risk-benefit evaluation

37. Phase IV Clinical Trials
Post-marketing surveillance
Long-term safety and efficacy in large patient
populations
New indications for use
Special disease-state and populations
Drug interaction studies
Pharmacoeconomic studies
Conducted after approval to market has been granted by FDA.
Good Clinical Practice (GCP)
– Minimum standards for conducting clinical research
– Regulations hat seek to accomplish the following:
• Ensure the quality and integrity of the data and ensure that the FDA’s decisions
based on these data re informed and responsible
• Protect the rights and safety of subjects
– ICH E6 – GCP: Consolidated Guideline

38. Phase IV after the drug or treatment has been marketed
collect information about their effect in various populations
side effects associated with long-term use.
New indications: important for company to extend its patent protection.
Eg. Prozac – antianxiety, approved recently for PMDD (premenstrual dysorphic disorder)
Pharmacovigilance is the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medicines, biological products, herbals and traditional medicines with a view to:
Identifying information about potential new hazards
Preventing harm to patients.
Phase IV: Systematic and comprehensive monitoring of the patterns of use and beneficial or harmful effects of drug as used in medical practice and by the consumer

39. Timeline for Discovery and Development
A. Laboratory and animal studies 6 yrs
B. File Investigational New Drug (IND)
to FDA
C. Phases I- III years
D. File New Drug Application (NDA)
at FDA: years
E. Phase IV (post approval) 6 years

40. Allocation of time (in years)

41. The development and testing process required to bring a drug to market
Pre-clinical drug development is a complex, regulatory-driven process designed primarily to assess the safety and viability of new molecular entities.

44. Drug Safety Assessment
Drug safety assessment is an important goal in the drug development and Post Marketing Surveillance (PMS)
It contributes to the balance of benefits and risks of the product
It consists generally in anticipating, assessing and minimizing the cases of adverse drug reactions.
At each step of the drug development
Pre clinical
Phase 1, 2-3
PMS (Post Marketing Surveillance)
Mainly based on Spontaneous Reporting Systems

45. Drug Safety Assessment
Pre clinical studies
Objective : to assess toxicity in animal
Acute toxicity (LD50, …)
Subchronic toxicity (13 / 26 weeks)
Chronic toxicity and cancerogenesis
Reproductive testing
Phase 1 clinical studies
Objective
Assess safety or toxicity (depending on compound)
Define therapeutic window / Maximum Tolerated Dose
Available data
Few volunteers (or patients) / dose escalating process
Thorough clinical assessment
Statistical analysis
Limits

46. Drug Safety Assessment Phase 2-3
Objective : to assess safety of study drug in larger studies in patients vs. placebo or reference drug
General safety parameters
Adverse events (AE) / serious adverse events (SAE)
Biology / Biochemistry / ECG / Vital signs, …
Disease / class specific safety parameters
e.g. CV safety in diabetes
Statistical analysis (adverse events)
Descriptive tables (counts, crude incidence, incidence rate, …)
Number of AE (NAE) in a given primary system organ class
Number of patients (n) with at least one AE in a given preferred term or a given primary system organ class
Number Needed To Harm (NNTH)
Disease / class specific safety parameters e.gECG in QT prolonging drugs
Limits
Repeated statistical testing or confidence intervals
Trial size, event incidence, trial population

47. The End