Drug discovery & development

1. Drug discovery & development

2. New drug development: • Highly complex , tedious, competitive, costly, commercially risky process. • Average time to develop new drug is 10 -12 years, costs 500-1000 million USD. • On an average out of 10,000 – 30,000 potential substances only 1 could make it to the market.

3. Stages in Drug Development : Synthesis/isolation of the compound:(1-2 years) Preclinical studies: screening, evaluation, pharmacokinetic and short-term toxicity testing in animals: (2-4 years) Scrutiny and grant of permission (IND) for clinical trials: (3-6 months) Pharmaceutical formulation, standardization of chemical/biological/ immuno -assay of the compound: (0.5-1 year) Clinical studies: phase 0, phase I, phase II, phase III trials; long-term animal toxicity testing: (3-10 years) Review and grant of marketing permission (NDA): (0.5-2 years) Post marketing surveillance: (phase IV studies)

4. New Drug Development Process. Preclinical I N D A P P L I C A T I O N Clinical Development NDAReview Post-Marketing Adverse Reaction Reporting Phase I Initial Synthesis Phase IV Phase II Animal Testing Surveys/ Sampling Testing Phase III Treatment Use Inspections Range 3-10 Yrs. Avg : 5 Yrs. Range 1-4 Yrs. Avg:18 Mos. Range 2 Mon – 7 Yrs. Avg:24 Mos. FDA Time 30 Day Safety Review NDA Submitted NDA Approved Average of Approximately 100 Months From Initial Synthesis to Approval of NDA

5. Preclinical studies

6. Types of tests performed in preclinical studies • Screening tests: • e.g. analgesic or hypoglycaemic activity. • Tests on isolated organs, bacterial cultures, etc : • e.g. antihistaminic, antisecretory, vasodilator, antibacterial etc. • 3. Tests on animal models of human disease: • e.g. kindled seizures in rats, spontaneously hypertensive rats, experimental tuberculosis in mouse, alloxan induced diabetes in rat or dog etc.

7. General observational test • Tripling doses • Confirmatory tests and analogous activities • Mechanism of action : • e.g. antihypertensive is an α- blocker/β- blocker/calcium channel blocker/ACE inhibitor /centrally acting, etc. • 7. Systemic pharmacology: • e.g. nervous, cardiovascular, respiratory, renal, g.i.t .etc. • 8 . Quantitative tests: The dose-response relationship, maximal effect, comparison.

8. 9. Pharmacokinetics: ADME, Vd, half life • 10. Toxicity tests :mostly mouse/rat and dog (oral and parenteral) • Acute toxicity: single escalating doses • observed for overt effects & mortality for 1-3 days. • (LD 50 ) is calculated. • Organ toxicity is examined by histopathology on all animals. • Sub acute toxicity: • Repeated doses are given for 2-12 weeks • Doses selected on ED 50 and LD 50 . • examined for overt effects, food intake, body weight, haematology and organ toxicity.

9. Chronic toxicity: • The drug is given for 6-12 months & effects are studied as in subacute toxicity. • Generally undertaken concurrently with early clinical trials. • Special long-term toxicity: • These tests are performed only on drugs which cross phase I clinical trials. • Mutagenecity, carcinogenicity, teratogenecity. Etc. • GLP

10. Acute Toxicity Study Objectives • To determine the Median Lethal Dose (LD50) after a single dose administered through one or more routes, one of which is the intended route of administration in humans. • To determine Maximum Tolerated Dose (MTD) and No Observable Effect Level (NOEL). • To identify potential target organs for toxicity, determine reversibility of toxicity, and identify parameters for clinical monitoring. • To help select doses for repeated-dose toxicity tests. • DurationA few days to 2 weeks after a single dose • Test System/Animal System2 species required. Mice, rats, sometimes rabbits or dogs. • Dose Administration • Oral (by gavage or with food), Subcutaneous, Intraperitoneal, Intradermal, Inhalation • Intranasal, Topical (epicutaneous), Intravenous • Parameters • Mortality • Clinical pathology • Gross necropsy • Weight change • Signs of toxicity

11. Subacute Toxicity Study Objectives • To determine toxicity after repeated administration of the test material. • To help establish doses for subchronic studies. • Duration14 days • Test System/Animal System2 species required. Mice, rats,  rabbits, guinea pigs, dogs. • Dose Administration3 to 4 doses given by the same routes as previous toxicity tests. • Parameters • Mortality • Signs of toxicity • Pathology and histopathology • Weight change • Clinical pathology

12. Subchronic and Chronic Toxicity Study Objectives To establish a “no observable effect level” (NOEL) To characterize dose-response relationships following repeated doses To identify and characterize specific organs affected after repeated administration To predict a reasonable and appropriate dose for chronic exposure studies (maximum tolerated dose or MTD) DurationCommonly 90 days, but varies from 2 weeks to 6 months or up to 10% of species’ lifespan. Test System/Animal System2 species required. Rodents, dogs. Dose Administration  At least 3 doses given by the same routes as previous toxicity tests; the lowest producing no apparent toxicity and the highest producing toxicity but less than or equal to 10%  mortality. Parameters Mortality Weight change Signs of toxicity Clinical pathology Pathology and histopathology

13. Chronic Toxicity Study Objectives To evaluate the cumulative toxicity of chemicals. To assess carcinogenic potential. DurationRodents – 6 to 24 months; non-rodents – 12 months or longer or up to 10% of species’ lifespan. Length depends on intended period of human exposure. Test System/Animal System2 species required. Rodents, dogs. Dose AdministrationAs in subacute/ subchronic toxicity studies. Parameters Mortality Pathology and histopathology Weight change Clinical pathology of all animals (mortalities and survivors)

14. Regulatory requirements of toxicity studies

20. Clinical trials

21. Animal studies The Investigational New Drug Application (IND) The Investigational New Drug licence Suitable dosage form Clinical trial Less numbers Large numbers

22. GCP (good clinical practice) guidelines by ICH (International Conference on Harmonization)

23. Clinical Trials • “Trials to evaluate the effectiveness & safety of medications or devices by monitoring their effects on large groups of people”. • Currently, clinical trial programs follow ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use) guidelines.

24. Informed consent • “the process of learning the key facts about a clinical trial before deciding whether or not to participate”. • The facts include: • Why the research is being done. • What the researchers want to accomplish. • What will be done during the trial & for how long. • What risks are involved in the trial. • What other treatments are available. • What benefits can be expected from trial. • The fact that you have the right to leave the trial at any time.

25. Clinical Trials phases • Phase –I • Phase –II • Phase –III • Phase –IV In an attempt to both speed up the drug development process and to quickly identify safety issues, Phase 0 studies, also referred to as ‘human microdosing studies’ were introduced. 

26. Phase 0 • The official name of a Phase 0 study is an exploratory IND study, • the goal is to quickly establish whether an agent will work as desired in humans, based on in vivo safety pharmacology and toxicology preclinical studies. • In Phase 0 studies, a single subtherapeutic dose of the IND is administered to a small number of healthy subjects (10 to 15), over a short duration (7 days).  • Since the dose administered is too low to result in a therapeutic effect (ensuring the absence of toxic effects), preliminary pharmacokinetic (PK) and, where possible, pharmacodynamic (PD) data are collected for evaluation.

27. Phase –I Human pharmacology and safety • Clinical pharmacologists/ physicians • Vital functions monitored • Emergency facilities are available • Healthy human volunteers • Number of subjects : 20-40. • Lowest dose- effective dose. • To assess the safety, tolerability. • p’kinetic & p’dynamicsof drug. • No blind, open label. • It aim to find the best dose of a new drug with the fewest side effects • Doctors start by giving very low doses of the drug. Higher doses are given to other patients until side effects become too severe or the desired effect is seen. • If a drug is found to be safe enough, it can be tested in a phase II clinical trial.

28. Phase –II Therapeutic exploration and dose ranging • Physicians • Patients • Number of subjects : 100-400. • To assess the therapeutic efficacy, dose range, ceiling effect in controlled setting. • Blinded or open label. • 2-4 centres. • They’re usually given the same dose that was found to be safe in the previous phase. • Phase II trials further assess safety as well as if a drug works • Patients are closely watched to see if the drug works

29. Phase –III Therapeutic confirmation /comparison • Random, double blind, comparative trials • Number of subjects : 500-3000. • Many physicians in many centres. • Aim: establish the value of the drug in relation to existing therapy. • These trials assess the side effects of each drug and which drug works better. • Safety, tolerability, interactions- wider scale • P’kinetic data • There can be more than two treatment groups in phase III trials. The control group gets the standard-of-care treatment. The other groups get a new treatment. • The study will be stopped early if the side effects of the new drug are too severe or if one group has much better results. • expensive, time consuming. • Afterwards, NDA submitted.

30. Phase –IV Post marketing surveillance • Practicing physicians • Phase IV trials test new drugs approved by the FDA. • The drug is tested in several hundreds or thousands of patients. This allows for better research on short-lived and long-lasting side effects and safety. • To find out - • Efficacy, adverse effects, acceptability. • Idiosyncratic adverse effects, unsuspected drug interactions (may only be found in large groups of people.) • Special groups: children, elderly, pregnant/lactating women, renal/hepatic disease. • Further developments can be done after marketing..

32. Pharmacovigilance Pharmacovigilance(PV) DrugSafety It is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention of adverse reaction with Pharmaceutical products. "Pharmacovigilance” ( Pharmakon -drug +Vigilare-to keep watch)

33. AIMS OF PHARMACOVIGILANCE •  Early detection of unknown adverse reactions and interactions •  Detection of increases in frequency of (known) adverse reactions •  Identification of risk factors and possible mechanisms underlying adverse reactions •  Estimation of quantitative aspects of benefit/risk analysis and dissemination of information needed to improve drug prescribing and regulation.

34. The scope of pharmacovigilance • Improve patient care and safety in relation to the use of medicines, and all medical and paramedical interventions, • Improve public health and safety in relation to the use of medicines, • Contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use, and • Promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public

35. Why do we needpharmacovigilance? Humanitarianconcern ADR May cause sudden death Promoting rational use of medicines and adherence Ethics To know of something that is harmful to another person who does not know, and not telling, is unethical

37. Who reports the ADRs? Pharmacists Doctors dentists

38. Nurse Drug manufacturer Other health care professionals

39. Factors to be reported : • New drugs Report all suspected reactions including minor ones • For established or well known drugs All serious, unexpected, unusual ADRs Change in frequency of a given reaction • ADRs to generics not seen with innovator products • ADRs to traditional medicines

40. All suspected drug-drug, drug-food, drug-food supplement interactions Statement highlighting marine source of supplements such as glucosamine so that can be avoided by those with allergy to sea food • ADRs associated with drug withdrawals • ADRs due to medication errors • ADRs due to lack of efficacy or suspected pharmaceutical defects

41. Therapeutic index • “The gap between the therapeutic effect DRC & the adverse effect DRC”. • median lethal dose (LD50 ) • Therapeutic index = ------------------------------------ • median effective dose (ED50) • Bronchodilation, cardiac stimulation– isoprenaline, salbutamol.

42. LD0/MTD Maximum Tolerable Dose (MTD) is the highest amount of a chemical that, when introduced into the body does not kill test animals ED0 Dosage that relieves 0% of treated subjects