DDLC

Slide 1 : Swetha Khokale - agCampus DDLC – Drug Development Life Cycle

Objectives and Expectations : 2 Objectives and Expectations Objective : To give an introduction to DDLC, explain its processes and understand how DDLC fits into our scope of work at Aris Global Expectations: At the end of this session, you will have a good understanding on : Pharmaceutical Industry and Drugs Drug Discovery Drug Development and its phases Role of Regulatory Authorities How our products fit in

Contents : 3 Contents Overview of the Pharmaceutical Industry An Introduction to DDLC Basics of Drugs Drug Discovery Basic Research Clinical Trials Registration and Launch Summary Important Individuals Patents How our products fit in Quiz !!

Overview of the Pharmaceutical Industry : 4 Overview of the Pharmaceutical Industry The global pharmaceutical industry is Competitive Highly regulated Very big It is a major employer, both directly and through suppliers, agents and CROs It is an important factor in national economies Trade balances (export and import) Taxes Healthcare costs The pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies can deal in generic and/or brand medications. They are subject to a variety of laws and regulations regarding the patenting, testing and marketing of drugs.

The World Market : 5 The World Market Traditional main markets include Europe North America (USA and Canada) Japan Expanding markets include Asia Pacific Latin America Africa Eastern Europe China

Drug Development process : 6 Drug Development process

Drug Discovery : 7 Drug Discovery What is a Drug? A drug is any chemical or biological substance, synthetic or non-synthetic, that when taken into the organism’s body, will in some way alter the functions of that organism. In the United States, the Federal Food, Drug, and Cosmetic Act defines a drug as: being an article "intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals“ an article "(other than food) intended to affect the structure or any function of the body of man or other animals

What are the sources of Drugs? : What are the sources of Drugs? Drugs are derived from the following four main sources: Plant sources: Obtained from plant parts or products. Seeds, stem, roots, leaves, resin, and other parts yield these drugs. Examples include digitalis and opium Animal sources: Glandular products from animals are used, such as insulin and thyroid Mineral sources: Some drugs are prepared from minerals, for example, potassium, chloride, and lithium carbonate (an antipsychotic) Synthetic sources: Laboratories duplicate natural processes. Frequently this can eliminate side effects and increase the potency of the drug. Examples include barbiturates, sulfonamides, and aspirin

How are drugs discovered? : 9 How are drugs discovered? Random screening Rational design (molecular models, biotechnology, etc.) Folk medicine Luck!

Compound Success Rates by Stages : Compound Success Rates by Stages 10 Preclinical Testing Laboratory and animal testing Phase II 100-300 patient volunteers used to look for efficacy and side effects Phase III 1,000-5,000 patient volunteers used to monitor adverse reactions to long-term use FDA Review/Approval Additional Post-Marketing Testing Phase I 20-80 healthy volunteers used to determine safety and dosage 14 0 3 7 10 Compound Success Rates by stages 5,000-10,000 screened 150 enter preclinical testing 5 Enter clinical testing 1 Approved by the FDA Discovery (2-10 years)

Stages of Basic Research : 11 Stages of Basic Research Disease targeting Target Identification Target Validations Lead Optimization Chemical Synthesis Scale-up Stability and Formulation Development

Step 1 – Disease Targeting : Step 1 – Disease Targeting Disease Targeting can happen in following ways: A drug company may decide to develop a new drug aimed at a specific disease or medical condition Sometimes, scientists choose to pursue an interesting or promising line of research In other cases, new findings from university, government, or other laboratories may point the way for drug companies to follow with their own research Once the disease area is selected: New drug research starts with an understanding of how the body functions, both normally and abnormally, at its most basic levels Investigate each component of a disease e.g. what are the symptoms, what is the cause, which is the target organ, what are Biochemical pathways? Together with the information obtained in previous researches and publications find out at which step we can stop the disease from progressing or developing thus selecting the TARGET

Target Identification : Target Identification 13 To find the right compound, scientists usually screen hundreds or thousands of compounds. In a series of test tube experiments called assays, compounds are added one at a time to enzymes, cell cultures, or cellular substances grown in a laboratory. The goal is to find which additions show some effect. This process may require testing hundreds of compounds since some may not work, but will indicate ways of changing the compound's chemical structure to improve its performance

Target Validation : 14 Target Validation Biological or chemical extraction/synthesis of active substances at laboratory scale Robust Assays High throughput screening Creation of pharmacological animal models Evaluation of potentially active compounds

Lead Optimization : Lead Optimization 15 Patent Evaluation Patent Application Basic enzyme/receptor potency and selectivity Basic pharmacological screening In vitro/in vivo metabolism and pharmacokinetic screening

Chemical Synthesis Scale-up : Chemical Synthesis Scale-up 16 Following activities as conducted during this phase: Isolate the compound Large-scale manufacturing / bulk and formulations Safety of environment and people involved in manufacturing Manufacturing Patent issues Financial consideration New investments in manufacturing facilities vs. profit projections

Stability & Formulation Development : Stability & Formulation Development 17 Is chemically stable on exposure to light, moisture, temperature etc. ? Can be formulated into small tablets and capsules? Is it dispersible ?

Overview of the CT phase : Pre-Clinical Phase The product is approved for sale/marketing On-going Pharmacovigilance Phase IV Studies (Post-Marketing) Clinical Phase Animal testing Long-Term Overview of the CT phase

Pre- Clinical Trials : Pre- Clinical Trials A drug may be associated with lot of side-effects which could just out-weigh the benefits it provides. Thus it is very important to establish the safety of the drug prior to the trial on the human beings. The objectives of animal testing is to: Measure how much of a drug is absorbed into the blood How it is broken down chemically in the body The toxicity of the drug and its breakdown products (metabolites) How quickly the drug and its metabolites are excreted from the body Generally, two or more species (one rodent, one non-rodent) are tested because a drug may affect one species differently from another Animal studies are categorized in 2 segments: Short-term testing in animals ranges in duration from 2 weeks to 3 months, depending on the proposed use of the substance Long-term testing in animals ranges in duration from a few weeks to several years. Some animal testing continues after human tests begin to learn whether long-term use of a drug may cause cancer or birth defects At the end of this phase, this information is submitted to FDA (IND Application) when a company requests to proceed with human clinical trials. The FDA reviews the preclinical research data and then makes a decision as to whether to allow the clinical trials to proceed 19

Submission to RA’s : Submission to RA’s Step 1 Submission of IND Step 2 FDA Review Step 3 Approval Entry into Clinical Trials

Regulations for Research in Humans : Regulations for Research in Humans 21 Good Clinical Practice (GCP) A standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of the trial subjects are protected

Phase 1 Studies : Phase 1 Studies Features: 1) To assess primary safety and dose range 2) 20-80 healthy volunteers 3) PD – Dose Response, Half-Life, Threshold Dose, Lethal Dose (LD50) 4) PK – ADME 5) Conducted under strict vigilance 6) Patient monitored every 5 mins or even lesser at times 7)Specialized units required

Phase II Studies : 23 Phase II Studies Features: 100-300 patients suffering from the indication - Tests the effectiveness of the drug, gives the most effective dose - well- controlled - Closely monitored - Go/No- go decision - Gives short term side effects and risks

Phase III Studies : 24 Phase III Studies Features: Conducted in 500 – 3000 patients - Global in nature -Overall safety and efficacy in a larger population - Conducted in major hospitals throughout the world - Gives information for labeling - Designed to provide information for submission to authorities seeking approval to release the drug into the market - Pivotal studies – III b - Controlled and monitored

Marketing : Marketing Authorisation MAA Submitted Phase IIIb Phase IV Phase II/III Secondary regulatory package(s) for Market extension(s) Primary regulatory package R&D Commercialisation Marketing Data to fill Information Gaps Agencies…. “Is product safe / effective in long term?” Prescribers…. “Does the product provide better quality of life for my patients?” Payers….”Is it a cost-effective therapy?” And to drive Product Success Differentiate from competitors Increase Market penetration

Steps 1,2 & 3 : Steps 1,2 & 3 Answer not necessarily ‘yes’ or ‘no’ Approval: Indications, Limitations, Phase IV studies, Chemical testing

Registration and Launch : Registration and Launch

Phase IV : 28 Phase IV Features Could be required by RA’s - Conducted by the sponsor for additional information - Conducted on a very large population > 3000 patients - Long term safety and efficacy - Long term side effects - Drug-Drug interaction - Can be as regulated as the other phases - Data very critical for long term success of the products

Important Individuals : 29 Important Individuals

: Summary

Patent Protection : Patent Protection Only 1 out of every 12 marketed drugs recoups the investment Prolong patents by developing new formulations and/or new indications Patent granted for 20 years from IND application 12 years to develop the drug 8 years to sell it exclusively Invest 500-800 Million US$ Recoup the investment

Aris Global - Core Systems : 32 Aris Global - Core Systems

Put the following events in chronological order from FIRST to LAST. : Put the following events in chronological order from FIRST to LAST. A Pivotal Study B NDA C New Chemical Entity D IND Speed Round

What is the purpose of conducting clinical studies? : What is the purpose of conducting clinical studies? To determine whether a prescription medicine should be recalled To demonstrate that a new medicine is safe an effective in humans To determine how well a new drug will sell after it is approved for marketing To demonstrate that a new medicine is safe and effective in lab animals 1

What is another name for a human volunteer or patient in a clinical trial? : What is another name for a human volunteer or patient in a clinical trial? Guinea Pig Subject Sponsor Victim 2

What is another name for “animal studies”? : What is another name for “animal studies”? Phase I Studies Preclinical Studies Pivotal Studies Post marketing Studies 3

Characterisation of a drug’s absorption, distribution, metabolism and excretion is usually referred to as? : Characterisation of a drug’s absorption, distribution, metabolism and excretion is usually referred to as? Efficacy Safety Pharmacokinetics Pharmacodynamics 4

Which phase of trial usually starts with the initiation of studies in which the primary objective is to explore therapeutic efficacy in patients? : Which phase of trial usually starts with the initiation of studies in which the primary objective is to explore therapeutic efficacy in patients? Phase I Phase II Phase III Phase IV 5

What is another name for a Post marketing trial? : What is another name for a Post marketing trial? Phase I Trial Phase II Trial Phase III Trial Phase IV Trial 6

What is a pivotal study? : What is a pivotal study? All Clinical Studies Preclinical Study Phase I Study Phase III Study 7

What is the name of the application in which the sponsor attempts to obtain the US regulatory authority permission to begin clinical testing of a new drug? : What is the name of the application in which the sponsor attempts to obtain the US regulatory authority permission to begin clinical testing of a new drug? A) NDA B) FDA C) IND D) CRO 8

Which of these is the regulatory authority governing medicinal products in the USA? : Which of these is the regulatory authority governing medicinal products in the USA? A) FDA B) NDA C) IND D) CRO 9

Which of these is the regulatory authority governing medicinal products in the EU? : Which of these is the regulatory authority governing medicinal products in the EU? A) MHRA B) CTA C) MCA D) EMEA 10

Thank you for attending! : Thank you for attending! 44