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New drug development
The document outlines the stages of new drug development, beginning with the drug discovery phase that involves synthesis and isolation of chemical entities, followed by preclinical studies, and clinical trials through several phases, culminating in marketing approval and post-marketing surveillance. It discusses various approaches to drug discovery including random screening, serendipity, and rational drug design, while emphasizing the importance of toxicological and pharmacokinetic studies during preclinical testing. Additionally, regulatory guidelines for good clinical practice (GCP) are highlighted, along with the phases of clinical trials that assess drug safety and efficacy.
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New drug development
- 1. New Drug Development DrNaser Ashraf Tadvi Associate Professor
- 2. Stages in newdrug development • Drug discovery phase – Synthesis and isolation of compound – New chemical entity (NCE) – Takes 1-2 years • Preclinical studies – 2-4 years • Investigational New Drug Application (IND) – Submission & review by FDA – 3-6 months
- 3. IND Clinical Trials •Phase 1 •Phase2 •Phase 3 3 To 10 years Pre clinical studies continued Plus •Long term animal toxicity •Product formulation •Manufacturing & controls •Package & label designs New Drug Application (NDA) •Review & grant of marketing permission •0.5 to 2 years Post marketing surveillance (Phase -4) Stages in new drug development
- 5. Approaches to drugdiscovery • Random screening – Natural sources – Chemical Synthesis • Serendipity • Rational drug designing – Compound centered approach – Target centered approach • Designing a prodrug or active metabolite as a drug
- 6. Random screening • NaturalProducts – Morphine, digitalis, artemisinin, quinidine, atropine • Synthetic products – Randomly synthesized compounds tested for pharmacological activity • Barbiturates, chlorpromazine synthesized by this approach
- 7. SULPHONAMIDES CA inhibitors (Diuretics) Thiazide Diuretics Loop Diuretics Sulfonylureas (Oral Hypoglycaemic agents) Carbimazole, Methimazole (Anti-thyroid Drugs) Diazoxide (Anti-hypertensive) Dapsone(Anti-leprotic) Sulthiam (Anti-epileptic) Cotrimoxazole
- 8. 1st Antibacterial Drug ActiveMetabolite of Prontosil First Oral Hypoglycemic Drug First Carbonic Anhydrase Inhibitor Major Improvement in Diuretics Novel Hypotensive Drug First Loop Diuretics Other Sulfonamides Other Carbonic Anhydrase Inhibitors Other Thiazide Diuretics Other Loop Diuretics Other Sulfonylureas Prontosil (1932) Sulfanilamide (1935) Carbutamide (1955) Acetazolamide (1949) Chlorothiazide (1957) Diazoxide (1961) Furosemide(1962)
- 9. Drug Discovery bySerendipity • Happy observation by chance • New use of old drugs or its side effects find new therapeutic application – Penicillin – Methotrexate in psoriaris – Sildenafil now used in impotence – Lignocaine as antiarrhythmic
- 10. Rational drug designing •Compound centered approach – Beta blockers developed by modifying structure of Propranolol – Molecular modification/ manipulation • Receptor based approach ( target oriented) – Depends on sound knowledge & identification of specific target for drug action
- 11. Target oriented approach •Receptors – GPCR, Receptors with intrinsic ion channels, enzyme linked receptors • Ion channels – Na+, K+, Ca++ and Cl– • Transporters – Na+/K+ ATPase, H+/K+ ATPase, Na+-K+-2Cl– • Enzymes
- 12. Designing of prodrugor active metabolite as a drug • Paracetamol active metabolite of phenacetin • N acetyl procainamide active metabolite of procainamide • Bacampicillin prodrug of ampicillin • Levodopa prodrug of dopamine
- 13. Preclinical Studies Synthesis /Identification of Lead Compound(s) (Thousands) Few out of Thousands
- 14. Pre-clinical Studies • ScreeningTests • Tests on isolated organs • Tests on bacterial cultures • Tests on animal models of human diseases – Diabetic rats / dogs by diazoxide – Kindled animals for anti-epileptic drugs • General observational tests on intact animals
- 15. Preclinical Studies • Pharmacodynamicstudies • Toxicity studies – Acute toxicity studies – Subacute toxicity studies – Chronic toxicity studies – Special toxicity studies • Reproductive • Teratogenicity • Carcinogenicity • Mutagenicity • Local Toxicity • Pharmacokinetic studies
- 16. Toxicity Studies • AcuteToxicity Studies (1 – 3 days) – LD50 – Organ toxicity • Sub-acute Toxicity Studies (2 – 12 weeks) • Chronic Toxicity Studies (6 – 12 months) • Special Long-term Toxicity Studies – Reproduction ( including Teratogenicity) – Mutagenicity – Carcinogenicity
- 17. Good Laboratory Practice(GLP) • Embodies a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived.
- 18. Before Clinical Studies •Drug is formulated into a suitable dosage form • The clinical trials are done under the guideline of Good Clinical Practice (GCP) laid down by International Conference on Harmonization (ICH)
- 19. Investigational New Drug(IND) • IND license is obtained after successful completion of pre-clinical studies from regulatory authorities. • Regulatory Authority – India: Drug Control General of India (DCGI) – USA: FDA (Food and Drug Administration)
- 20. Good Clinical Practice(GCP) • GCP include – Protection of human rights as a subject in clinical trial. – Provides assurance of the safety and efficacy of the newly developed compounds. • Good Clinical Practice Guidelines include standards on – how clinical trials should be conducted, – define the roles and responsibilities of clinical trial sponsors, clinical research investigators, and monitors.
- 21. Phases of ClinicalTrials • Phase I Early Clinical Pharmacology & Safety • Phase II Therapeutic exploration and dose ranging • Phase III Therapeutic confirmation and comparison • Phase IV Post-marketing Surveillance / Studies
- 22. Phases of ClinicalTrials • In Each Phase – Exposure to greater numbers of human subjects – Collection of increasing amounts of data on safety and efficacy of the drug I II III IV
- 23. PHASE I (Early clinicalPharmacology and safety) • N = 20 – 80 healthy human volunteers (sometimes patients) • Carried out by qualified clinical pharmacologists or trained physicians • Carried out in emergency settings • No blinding, open label • Approx duration 1 year
- 24. PHASE I • Emphasis: Safety and Tolerability • Started with lowest estimated dose and stepwise increased to effective dose. • Data collection on – Pharmacokinetics – Systemic pharmacodynamics – General adverse effects • Acceptable dosing level is found
- 25. PHASE II (Therapeutic explorationand dose ranging) • Inclusion and exclusion criteria are fixed • N = 100 – 500 patients • Carried out by trained physicians • Duration: 2-3 years • Type: Open label / Blind • Venue: 2 – 4 centres • Establishment of therapeutic efficacy • Dose range for more definitive therapeutic trial identified
- 26. PHASE III (Therapeutic confirmation/comparison) • Aim is to compare new drug to existing therapy • Safety and tolerability assessed on higher scale • Indications are finalized and guidelines for therapeutic use formulated • Multicentric, Randomized, Placebo controlled, Comparative, Double-blind • Involves several physicians • N = 500 to 3000 patients
- 27. Registration • New DrugApplication (NDA) along with the Data (safety and efficacy) of Clinical Trials are submitted to relevant Regulatory Authority – India: DCGI (Drug Controller General of India) • Regulatory Authority, in convinced, gives a ‘marketing permission • Average time for approval: 2.5 yr
- 28. PHASE IV: Post-marketing Surveillance(PMS) • Practicing physicians are identified and data collected on a structured proforma regarding – Efficacy, tolerability and Adverse effects • n = 4000 – 5000 patients or more • Uncommon rare and long term adverse drug reactions and unsuspected drug interactions found out • Additional indications
- 29. PHASE IV: Post-marketing Surveillance(PMS) • Effect on special groups – Elderly & Neonates – Pregnancy & Lactation – Liver &Renal impairment • Exploration of possibilities – Modified release dosage form – Additional route of administration – Fixed dose combination • Even drugs / formulations are withdrawn from the market if found to be injurious to health
- 30. Examples of drugwithdrawal • Antihistamine: Terfenadine, Astemizole • Selective COX-II inhibitor: Rofecoxib and Celecoxib - cardiotoxicity • Nimesulide banned for all in Western countries & for pediatric group in India • Aspirin liquid formation: due to possibilities of producing Reye’s Syndrome in children
- 31. Phase 0 (Human Micro-dosing) •Offers a way of developing drugs in a faster, more cost effective and ethical way than ever before.