DRUG DEVELPOMENT & DISCOVERY- CLINICAL TRIALS

1. DRUG DEVELPOMENT & DISCOVERY- CLINICAL TRIALS PRESENTED BY: SHUBHA SHARMA M.SC. PHARMACOLOGY RUHS-CMS , JAIPUR

2. CLINICAL TRIALS Clinical trials are scientific investigations that examine and evaluate safety and efficacy of new drug in human subjects. Essential to get marketing approval from regulatory authorities. May require upto 7 years.

3. MAJOR STAGES OF DRUG DEVELOPEMENT Preclinical testing IND Application Clinical testing – phase 0 ( Microdosing study) C linical testing – phase I (Human pharmacology and safety) Clinical testing – phase II (Therapeutic exploration & dose ranging) Clinical testing – phase III (Therapeutic confirmation) New Drug Application Clinical testing – phase IV ( Postmarketing surveillance)

4. INVESTIGATIONAL NEW DRUG APPLICATION When the new compound passes the preclinical pharmacological screening the manufacturer may file a ” Preclinical New D rug or Investigational New Drug” application (IND application) to the authorized drug control body of the country. A pplication to the CDSCO/ Drug Controller General of India (DCGI) to request permission to begin human testing in India. The IND application permits the use of an investigational new drug for the sole purpose of conducting clinical trials .

5. The IND must contain the following information : Information on the composition and source of the drug. Chemical and manufacturing information. All data from animal studies (pharmacokinetics, pharmacodynamics, toxicological studies with ED50 & LD50). Proposed plans for clinical trials. The names and qualifications of investigators who will conduct the clinical trials. A compilation of the key data relevant to study of the drug in humans that has been made available to investigators and their institutional review boards. An agreement from the sponsors to submit annual progress report. A certificate that ” informed consent” will be obtained from human volunteers and that ” ethics of research in human beings”.

6. Only when the approval is given by this body, the drug can be administered to the men for clinical trials. The testing in humans is begun only after sufficient acute and subacute animal toxicity studies have been completed.

7. PHASES OF CLINICAL TRIALS PHASE 0 Recent designation, also known as human micro-dosing studies . Developed to reduce cost and time of drug development process. Small sample size of 10 -15 subjects is required Designed to speed up the development of promising drugs. 1/100 TH of the estimated human dose, or a max. of 100ug total dose of candidate drug, are administered to healthy volunteers and pharmacokinetics is worked out.

8. Why conduct micro dose studies ?  To obtain information on human pharmacokinetics as early as possible.  Compare ADME parameters for several drug candidates where animal data may be conflicting  Helps in selecting the first dose for a Phase I study  Validate animal model for pharmacology and toxicology  Pharmacoeconomics – Cost benefit analysis

9. Goal of Phase 0 studies  To assess whether the mechanism of action defined in pre clinical studies is achieved or not  Define specific biomarkers or targets in human studies  Determine special methods to assess the pharmacokinetics of the drug  Develop novel models to evaluate the pharmacodynamics  Define human PK/PD data prior to phase I

10. ADVANTAGES Requires minute quantities of drug – not intended to produce any pharmacological effect; risk of adverse events less Decreases time of drug development decreases cost significantly Reduces animal testing Helps patients and industry with earlier availability of test drugs LIMITATIONS Insufficient information on body’s reaction to micro dose and pharmacological dose Micro dosing may not be predict kinetic parameters accurately for drugs showing non-linear kinetics Metabolism and stability of compounds Limited specificity

11. PHASE I Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness. 20-80 Healthy Volunteers. These trials are NON- BLIND /OPEN LABEL. Performed by clinical pharmacologists in a research centre , equipped for pharmacokinetic studies. Takes a year or less to complete.

12. These trials are designed to obtain the following information: Safety – Determine the most significant adverse events in human subjects. Tolerability – The safe dose range is determined by dose escalations and corresponding serial lab tests. Pharmacokinetics – How the drug molecule is absorbed in the body and its metabolites are distributed and eliminated from the body Pharmacodynamics – The effects of the drug on the body, i.e. how the effects of the drug vary with the plasma concentration.

13. Types of Phase1 trials : - Single Ascending dose studies - Multiple Ascending dose studies - Pharmacogenomics studies ( PGx ) - ADME studies

14. Types of Phase1 trials: -Single Ascending dose studies - Multiple Ascending dose studies - Pharmacogenomics studies ( PGx ) - ADME studies SINGLE ASCENDING DOSE STUDIES Small group of subjects given single dose of drug and observed for a period of time. If Pk data is in line with predicted safe values, the dose is increased in a new group of subjects Continued till maximum tolerated dose (MTD) is defined. MULTIPLE ASCENDING DOSE A group of subjects receives multiple low doses of the drug Samples (of blood and other body fluids) collected at various time points and analysed Gives better understanding of pharmacokinetics and pharmacodynamics of the drug

15. ADME studies Objectives:  To assess the absorption, distribution, routes and rates of excretion  To assess the metabolite profile and metabolite identification. Pharmacogenomics study  Broadly refers to the study of drug exposure and/or response as related to variations in DNA and RNA characteristics and ,  Contribute to a greater understanding of inter-individual differences in the efficacy and safety of investigational drugs.

16. PHASE II conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks. 100-500 Patients with target disease Carried out at 2-4 centres . Controlled blind studies (single as well as double) Often take 1-2 years to complete. • Concerned With: – Safety – therapeutic Efficacy – Drug Toxicity – Drug Interaction

17. These trials are divided into 2 phases: EARLY PHASE Small no. of patients (20-200) To observe potential therapeutic benefits and side effects. Usually SINGLE BLIND design. LATE PHASE Larger no. of patients(50-300) Determine optimal dose-response range. Controlled DOUBLE BLIND design.

18. PHASE III Involves giving the drug to a large number of patients (500-3000 ) Purpose is to.... Confirms earlier efficacy results Identify adverse events which when drug is given to a larger population over a longer period of time Designed to minimize errors in the information gathered in phase I &phase II trials. RANDOMIZED DOUBLE BLIND CROSS OVER design. Conducted by different clinicians at many centers. Takes an average of 3-5 years to complete.

19. Subsets of Phases : PHASE IIIa Trials conducted prior to the regulatory submission of a New Drug Application(NDA). Conducted in patients in whom the drug will be eventually intended. Generate additional data on both safety and efficacy. Information for package insert and labelling of medicine. PHASE IIIb Clinical trial after regulatory submission of an NDA but prior to approval and launch. Supplement earlier trials, complete earlier trials, directs towards new trials or phase IV evaluations. This is a period between submission and approval of a regulatory dossier for marketing authorization.

20. Clinical Trials Testing in Humans

21. NDA – New Drug Application If the results of all the previous testing is positive, then the pharmaceutical company files an NDA S ubmitted to the FDA/DRA, if Phase 1, 2 and 3 trials indicate the drug is safe and effective. NDA contains all of the information gathered during preclinical to phase III Usually contains thousands of pages. FDA required to make a decision within 180 days of the date the NDA is submitted Can take 2-3 years for FDA to review. Once approval is obtained to market the drug, phase IV of the trials begins.

22. PHASE IV Phase IV Clinical trial is also known as Post Marketing Surveillance Trial . It is the post licensing phase- field trials. Has no fixed duration. Phase IV trials involve the safety surveillance (Pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold New age groups, races, and other type of patients will be studied.

23. Monitor the ongoing safety of marketed drugs by reassessing drug risk based on … New data collected after the drug is marketed By recommending ways of trying to most appropriately manage that risk Includes adverse reaction reporting by the medical community of the pharmaceutical company that markets the drugs Periodic sampling and testing of the drug Periodic inspections of the manufacturing and distribution process

24. Clinical Trials In Special Population  Pregnant and Nursing Women  Children  Geriatric patients  Renal dysfunction  Hepatic dysfunction  Ethnic group/Vulnerable population

25. Pregnant Women:  Ideally excluded in all phases of trials.  Included if medicinal product is for use in Pregnancy.  Follow Up till term  Follow of foetus and child very important Nursing Women:  Included for study of excretion of drug/metabolite in human milk.  Babies should be monitored.

26. Paediatric trial  Paediatric regulation requires Paediatric Investigational Plan (PIPs) to be submitted. PIPs :  Includes a description & timing of study.  Measure for formulation acceptable in children.  Cover all age group from birth to adolescence.  modified at later stage as knowledge increases.  Studies deferred until after adult studies conducted, when safe and ethical.  Waiver for PIP: eg . Parkinson's disease. Paediatric trial Key considerations:  Ethical consideration always paramount.  Pk studies important to determine appropriate dose.  Age appropriate formulation.  Long term follow-up studies for effects on growth  Newborns most vulnerable, undeserved.

27. Geriatric Trial  Includes healthy young, healthy elderly male and female volunteers  Mostly Open-label, non randomised study, single dose.  Objective- PK and metabolism, safety tolerability Organ impairment studies/Trials  Hepatic impairment, Renal impairment.  Needed as drug is substantially metabolized, eliminated via a specific organ (>20% or if narrow therapeutic index)  Primarily to evaluate PK and metabolism.  Often difficult population to engage.  Small Number Patient.  Key influence on label. Pharmacoeconomy in trial  New dimension in Trial  Differentiates two treatments of equal efficacy & safety  Important: Health care spending is High.

28. PRINCIPLES OF GCP ( GOOD CLINICAL PRACTICE) Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s). Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

29. Clinical trials should be scientifically sound, and described in a clear, detailed protocol. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/ favourable opinion. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s ). Freely given informed consent should be obtained from every subject prior to clinical trial participation.

30. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. Systems with procedures that assure the quality of every aspect of the trial should be implemented.