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An introduction-to-drug-development
- 1. An Introduction toDrug Development Sourabh kosey
- 2. What is drugdevelopment? Molecular pharmacology Cell physiology Cell pharmacology Tissue physiology Clinical effect Organ Physiology Agonist at β2 adrenoceptor, activates adenylate cyclase Increase in cyclic AMP Relaxation of smooth muscle Bronchodilatation Improved lung dynamics Breathing better
- 3. Tra d ition a l p h a s e s o f d ru g d e v e lo p m e n t T h is is in te n d ed as a g en e ra l g u id e o n ly . T h e n atu re o f th e sta ges can v a ry g re atly acco rd in g to th e d ru g u n d er d ev elo p m en t. S ub m is sio n fo r appro val D rug dis cov ery P re -clin ic al te stin g C o m p o u n d p ate n t fo r 1 7 y ears 20 00-10 00 patie nt volu nte ers P h arm aco lo gic al evalu atio n and to xicolo gy P hase I E valu atio n of sa fe ty and p harm aco - kin etic s in hu m ans 20-80 health y volu nte ers P hase II E valu atio n of sa fe ty and p harm aco - kin etic s in targ et p op ula tio n. M ay in clu d e som e evalu atio n o f th era peutic d ru g actio n. 100-300 patie nt volu nte ers P hase III E valu ate effe ctiv eness in se le cted p op ula tio n. E valu ate sa fe ty in lo n ger-te rm use. 10 00-30 00 patie nt volu nte ers P hase IV P o st-m ark etin g stu die s N ew in d ic atio n s N ew fo rm ula tio n s 4 y e ars 1 y e ar 1 y e ar 1 2 ye ars in d ev elo p m en t 2 y e ars 4 y e ars 5 years ex clu siv e m ark etin g 5 00 0 co m p ou n d s 5 en te r tria ls 1 appro ved E valu atio n of sa fe ty and e ff ic a c y b y re g u la to r y auth ority E valu atio n of q uality o f m an u fa ctu re d pro duct P erm issio n to p ro ceed fro m re gu la to ry auth o rity There is a process but it’s much more than that..........
- 4. Where to start-vision for your medicine • What are the potential indications and what is the optimal sequence to investigate them? – How does the science link to clinical benefit? • Which patient segment will receive the most benefit and how will this develop? – Which group has the optimal risk /benefit profile? • In each target segment, which treatment option(s) will be displaced? – Is this really offering something that is of value? • What is the medicine's differentiating Scientific Advantage? – Is there clear differentiation that everyone can understand and agree with? • What differentiates this medicine for the prescriber, payer and patient? – Why should I presribe/pay/take for this? • What is the “Value Proposition” to the payer/policy maker?
- 5. Where do drugscome from? • Natural Products • Mimicry of endogenous substrates • Serendipity • Systems biology – Rational drug design
- 6. Devising an earlyclinical plan • What you know before you start • Chemical information about the drug and its formulation • Pharmacology in vitro and in vivo • Toxicology (28 days) in 2 species • Information on ADME in animal species • What you want to know by the end of the early phase • Is the drug sufficiently safe and tolerable that you can give enough of it for long enough to have a chance of showing a beneficial clinical effect? • Does the drug engage its target at sufficient concentration for long enough to have the potential clinical benefit?
- 7. Start with theend in mind 1- the disease • What is the nature of the disease I am trying to treat? – Acute vs Chronic – Natural history • What is the profile of the patient population I wish to treat? – Young vs elderly – Single disease or many co-morbidities – Drug interactions Proof of concept study
- 8. Start with theend in mind 2- the drug • Pharmacokinetics – How can it be given? – How long does it last? – How is it eliminated? • Pharmacodynamics – What dose? – How long to treat? • Safety – What are the likely adverse effects? – Are there any critical interactions? • Drug/Disease
- 9. A traditional approachto early drug development First into Man Repeat dose study PD study with dose ranging in patients ADME study Formulation study Food effect study Safety and tolerability in target patient population Proof of concept study Drug interaction studies Safety study in patients
- 10. The traditional approach •Delivers a comprehensive package of information at POC • Ability to explore a wide dose range • Suitable for precedented mechanisms (high probability of success) • Potentially slow to POC • Expensive • Not very suitable for novel mechanisms
- 11. The targets arechanging Molecular biology has delivered new types of Target eg pluripotent modulators of second messenger systems p38 MAP kinase Rheumatoid arthritis Migraine Cystic fibrosis COPD Depression Post PTCA Severe asthma Crohns Neuropathic pain Huge potential but which disease represents the best target to show PoC?
- 12. Drug development prioritiesfor new targets • Does the drug hit the target? • Does the target contribute significantly to the pathophysiology of the disease?
- 13. How early drugdevelopment is changing First into Man With PD marker Repeat dose safety and tolerability in target patient population (with PD marker) Proof of concept study
- 14. The new approach •Quickly establishes whether have a developable drug • Good for novel mechanisms- clinical role may not be known • Complex (expensive) studies • Scarce resource • Relies on PD markers (how useful are they?) • Carry safety risks later into development
- 15. Why do drugsfail? Nature Reviews Drug Discovery 10, 328- 329Phase Only 20% of drugs are successful in phase II
- 16. Full development- traditionalapproach Dose Ranging Phase IIB study Replicate placebo- controlled phase III studies Learning Confirming e.g. H2 antagonist •4-6 week endoscopic studies •80-90% healed on drug •30-40% healed on placebo e.g. H2 antagonist •Similar design, similar endpoint
- 17. Full development- new targets,new challenges Phase IIb Phase III Learning Still learning? •Plaque volume •Plaque stability •Presence of thrombus •Glycaemic control •MI/Stroke/mortality •MI/Stroke/mortality •Pulmonary embolus •Microvascular complications Globalization Different standards of care Risk management plans
- 18. Full development- changingparadigm Inlicensed following positive POC study Phase IIIPhase IIb Clinical Pharmacology package
- 19. The evolving regulatoryframework Clinical Development Package FDA EMA early review and level of approval Marketing Additional indications New formulations Focussed development package FDA EMA review and approval Limited Marketing More comprehensive safety data Longer term efficacy data Broader label Wider reimbursement
- 20. GCP and clinicaldevelopment
- 21. Purpose of GCP •Toprovide a unified standard for the European Union, Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. • May also be applied to other clinical investigation that may have an impact on the safety and well-being of human subjects.
- 22. ICH (International Conference onHarmonization) A joint initiative involving both regulators and industry as equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines. • European Commission - European Union (EU) • European Federation of Pharmaceutical Industries and Associations (EFPIA) • Ministry of Health, Labor and Welfare, Japan (MHLW) • Japan Pharmaceutical Manufacturers Association (JPMA) • US Food and Drug Administration (FDA) • Pharmaceutical Research and Manufacturers of America (PhRMA)
- 23. ICH Guidelines • "Quality"Topics, i.e., those relating to chemical and pharmaceutical Quality Assurance. – Examples: Q1 Stability Testing, Q3 Impurity Testing • "Safety" Topics, i.e., those relating to in vitro and in vivo pre- clinical studies. – Examples: S1 Carcinogenicity Testing, S2 Genotoxicity Testing • "Efficacy" Topics, i.e., those relating to clinical studies in human subject. – Examples: E4 Dose Response Studies, Carcinogenicity Testing, E6 Good Clinical Practice. • Multidisciplinary Topics, i.e., cross-cutting Topics which do not fit uniquely into one of the above categories. – M1: Medical Terminology (MedDRA)
- 24. Is it aclinical trial?
- 25. Summary • Drug developmentshould aim to answer critical questions about how what a medicine offers and how it should be used – Its not just a set of programmed procedural steps • Line of sight is critical to successful drug development – Make sure you know what constitutes success and what does not • The regulatory framework is evolving • ICH GCP describes the responsibilities and expectations of all participants in the conduct of clinical trials