Drug Development and Assessment in Man Pharmaceutical Medicine

1. Drug Development and Assessment in ManPharmaceutical Medicine Thursday 11th October 2007 Dr John Stinson

2. An expert is somebody who is more than 50 miles from home, has no responsibility for implementing the advice he gives, and shows slides. Edwin Meese

3. What do Doctors Do? • Diagnose and treat • Cost of diagnosing • What do we cure? • What do we alleviate? • How do we achieve these effects? • Who makes medicines? • Future threats?

4. 1937 Sulphonamides 1944 Penicillin 1947 Cephalosporins 1947 Chloramphenicol 1947 Aminoglycosides 1952 Macrolides 1953 Tetracyclines 1956 Glycopeptides 1960 Flucloxacillin 1961 Rifampicin 1962 Fusidic Acid 1970 Trimethoprim 1975 Carbipenems 1982 Fluoroquinolones A new class of antibiotic every 3 years 18 year gap to 2000 Antibiotic Resistance

5. Introduction • 1935 Few effective Medicines • <1950 No antihypertensive agents • 1950s Diuretics • 1960s B2 Receptor antagonists • 1970s Calcium Channel antagonists • 1980s ACE Inhibitors • 1990s Angiotensin II receptor antagonist • BNF 2004 > 100 antihypertensives

6. Before 1960 Random screening and empirical drug design i.e. LUCK! • 1960s Medicinal Chemistry Better organic Biochemistry Mass spectroscopy NMR developments

7. 1970s Receptor Science Agonists/Antagonists • 1980s Protein Chemistry Enzyme Chemistry Inhibitors of Enzymes • 1990s Molecular Biology Gene Therapy Biopharmacuticals

8. Receptor Science Discovered Medicines Receptor Agonist/Antagonist Disease Benzodiazepine Diazepam Epilepsy, Anxiety Sedation Opiate Morphine Analgesia B2 Salbutamol Asthma B1 & B2 Propanolol Hypertension H2 Cimetidine Peptic Ulceration Dopamine Levodopa Parkinsonism 5HT Ondansetron Emesis AII Losartan Hypertension

9. Non Peptide Enzyme Inhibitors Enzyme Inhibitor Therapy ACE Captopril Hypertension HMG CoA Simvastatin Hi Cholesterol DHFR Trimethoprim Antibacterial b-lactamase Clavulinic acid Antibiotic Adjunc 14 a lactamase Ketoconazole Antifungal

11. Molecules Registered in Libraries • Screened in biological systems • >100,000 molecules screened • Automated systems • Intelligent screening using 3-D structures • Molecule Receptor Binding • Appropriate shaped molecule tried

12. Potential Drug Candidate • More intensely assessed for activity • As it passes more hurdles • Proceed into toxicology testing • Now considered a New Chemical Entity • NCE

13. New Chemical Entity • What route of administration? Parenteral Oral Transcutaneous Subcutaneous Inhalation Rectal Eye Buccal

14. NCE Formulation • Tablet • Suspension • Solution • Capsule • Enteric coated • Cream • Ointment • Pro-drug?

15. Route of Synthesis? • Economics (platinum) • Which Salt? Hydrocortisone = mild steroid Hydrocortisone butyrate = potent • Solubility • Physicochemical properties • Stability • Compatibility with excipients

16. Clinical Pharmacology • The Scientific basis of drug therapy, includes: Pharmacokinetics Pharmacodynamics Pharmaceutical development Pharmacovigilance Pharmacoeconomics Pharmacoepidemiology

17. Pharmaceutical Process • Is the drug getting into the patient? Route? Formulation? Dissolution? Absorption?

18. Pharmacokinetic Process • Is the drug getting to its site of action? Absorption? Distribution? Metabolism? Excretion?

19. Pharmacodynamic & Therapeutic Process Is the drug producing the required pharmacological effect? Is the pharmacological effect being translated into a therapeutic effect?

20. Phase 1 Trials • Initial studies in man to determine tolerance and the safe dosage range and to give indication of metabolic handling. These studies are usually undertaken with healthy volunteers but may be extended to include patients. Pharmacokinetic (ADME) and pharmacodynamic activities are measured if possible. • N= 30-80

21. Phase II Trials • Early controlled trials in a limited number of patients (with the disease) under closely monitored conditions to show efficacy and short term safety. • Humans exposed 250-500

22. Phase III Trials • Extended large-scale trials to obtain additional evidence of efficacy and safety, and definition of most common adverse effects. Longer term trials possible • Humans exposed 300 - 10,000+

23. Phase IV Trials • These are performed after the medicine has been licensed and marketed. Post-marketing surveillance occurs after the clinical trials programme is complete. It is used to collect adverse event data from a large patient population. • Humans exposed 10,000+

24. When Phase I to III Complete • Apply for Product Licence or authorisation • From FDA • From EMEA • From National authority (IMB etc) • Decision based on Safety Data Efficacy Data Pharmaceutical Quality

25. Pharmacovigilance • Sulfanilamide one of first antibiotics • Effective against streptococcal infections • Not under patent protection (1908) • Many manufacturers marketed it • A small company decided to produce a liquid formulation • Found that diethylene glycol was a suitable solvent

26. Pharmacovigilance • Raspberry tasting elixir of sulfanilamide • 72% diethylene glycol, 16% water, 10% sulfanilamide • “Control laboratory” found it suitable with regards to appearance, flavour and flagrance. • There was no toxicity testing of the ingredients

27. Pharmacovigilance • 105 patients died (out of 353 treated) • A mass poisoning • The only rule broken by the manufacturer, the Massengill Company, was that it called the product an elixir although it did not contain ethanol! • The FDA changed the law: • Manufacturers had to prove safety before marketing a medicine.

28. Toxicology Testing • Thalidomide 1956 Germany Antiemetic in pregnancy • 1961 Reports of Phocomelia no cases in 1949-1959 477 cases in 1961 alone 400-500 cases in UK 1959-61 • 1963 CSM in UK • 1968 Medicines Act UK Regulatory Control

29. Pharmacovigilance • Thalidomide was not approved in US • However studies were undertaken in US • 624 Pregnant women received thalidomide • 10 cases of Phocomelia occurred • FDA tightened rules to all stages of drug development • This required extensive testing in animals first

30. Before NCE tested in Man • Safety Pharmacology in Animals Dog&Rat CNS Activity CVS Activity Respiratory Activity • Pharmacokinetics Dog & Rat usually Absorption Distribution Metabolism Excretion

31. Before NCE tested in Man • Acute Toxicity single dose 2 Species of animlas by 2 routes Usually IV and Oral (or proposed route) Maximum well tolerated dose • Repeat dose toxicity Rodent and non-rodent Using route proposed for man Duration depends on proposed duration in man

32. Before NCE tested in Man • Genotoxicity Ames Test- bacteria gene mutation S.Typhi, E.Coli Mouse Lymphoma Cell line – mammalian gene mutation Chinese Hamster Ovary – chromosomal damage Micronucleus Test mammalian in vitro chromosome damage Assay of DNA synthesis in rat liver • Reproductive toxicity only if women of child bearing potential

33. Adverse Drug Reaction Reporting

34. Pharmacovigilance • When a new medicine gets a licence • On average about 4,000 humans have received it in trials • Many have only received it for a short time • If an adverse event only occurs in 1: 5,000 • No chance to detect it • Especially if it occurs rarely in background • Pharmacovigilance only starts with licence

36. VIOXX –Rofecoxib • MSD – COX 2 inhibitor • In theory less risk of GI bleeds • Approved by FDA in 1999 • $ 2,500,000,000 per year • VIGOR study RR 5 x of AMI compared to naproxen • FDA estimate 27,000 excess AMI/deaths between 1999-2003

37. VIOXX • APPROVe study • Study in preventing colonic polyps • Showed increased CV deaths • September 30th 2004 product withdrawn • Cost will probably be $9 billion in sales & $5 billion in law suits

38. Bayer statin • Statin withdrawn due to rhabdomyolisis • Dose response curve not properly explored • Could have been avoided? • Pharmacovigilance does not stop at licensing, indeed it really only starts then

39. Pharmacovigilance Methods • Spontaneous Reporting • Cohort Studies Defined size group of patients Followed for defined period of time 10,000 pts recruited from 2500 GPs Non-promotional, only if going to be Rx Doctor reports and ADEs Can come up with new ADEs “Hypotheses generating”

40. Pharmacovigilance Methods • Case Control studies Hypothesis testing, not generating Select cohort with suspected disease/ADE Select larger cohort without ADE Look for differences in exposure to drug

41. Pharmacovigilance Methods • Computerised databases Prescriptions/Patients Linked To medical adverse events/disease Getting better as I.T. improves Depends on quality of data entered

42. The interface between the medical profession and the pharmaceutical industry • Research State funded = €30 million/year • Research Funded by Pharma = €50 million • Approx 160 doctors, nurses and scientists are funded by pharma industry • Used to be area of growth --now ? • Fraud rare but does occur

44. Medicine Promotion • Advertisements Strict Guidelines safe, best, most etc. reminder vs full advertisement Code of practice Complaints procedure

45. Medicine Promotion • Representatives Educational Informative Promotional Not paid by commission Rising standards Must have data sheet Must report ADEs Must not mislead

46. Medicine Promotion • S safety • T tolerability • E efficacy • P price

47. Medicine Promotion • Samples • must be in response to signed dated request • No more than 6 samples per year • Smallest pack available • Marked “not for resale/free medical sample”

48. Medicine Promotion • Sponsorship IPHA code of practice (new 6th edition) Doctors should not ask for a fee for apt Sponsorship should be appropriate & not out of proportion Sponsored meetings must have major educational component No sponsorship for non-medical people