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

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.

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)

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

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

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

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

Identification of drug targets

I. DISCOVERY Resource identification - Natural organisms, in particular plants - 52% of the drugs approved in the U.S. from 1981-2002 were natural products or derived from them - 26 plant based drugs were approved during 2000-2006, 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

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

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

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…)

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

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

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: http://www.ppdi.com/about_ppd/drug_development.htm#2

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: http://www.ceb.utk.edu/images/zebra4.jpg

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!)

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).

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

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

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

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

Preclinical Testing Assess primary safety, biological activity, and therapeutic ratio In vivo animal models In vitro physiological models 1 in 10,000 compounds pass 3.5- 4 years to develop compound

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)

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

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)

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

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

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 (100-300) – 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

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 (500-2000) – 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

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

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

Timeline for Discovery and Development A. Laboratory and animal studies 6 yrs B. File Investigational New Drug (IND) to FDA C. Phases I- III 7 years D. File New Drug Application (NDA) at FDA: 1.5 years E. Phase IV (post approval) 6 years

Allocation of time (in years)

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.

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

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

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

The End