Drug Development and Assessment in Man

Pharmaceutical Medicine

Thursday 22nd March 2007

Dr John Stinson

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

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?

Antibiotic ResistanceAntibiotic Resistance

• 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

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

• Before 1960Random screening and empirical

drug design i.e. LUCK!

• 1960s

Medicinal ChemistryBetter organic BiochemistryMass spectroscopyNMR developments

• 1970s Receptor ScienceAgonists/Antagonists

• 1980s Protein ChemistryEnzyme ChemistryInhibitors of Enzymes

• 1990s Molecular Biology

Gene TherapyBiopharmacuticals

Receptor Science Discovered MedicinesReceptor Agonist/Antagonist DiseaseBenzodiazepine 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

Non Peptide Enzyme Inhibitors

Enzyme Inhibitor TherapyACE Captopril

Hypertension

HMG CoA Simvastatin Hi Cholesterol

DHFR Trimethoprim Antibacterial

-lactamase Clavulinic acid Antibiotic Adjunc

14 lactamase Ketoconazole Antifungal

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

Potential Drug Candidate

• More intensely assessed for activity

• As it passes more hurdles

• Proceed into toxicology testing

• Now considered a New Chemical Entity

• NCE

New Chemical Entity

• What route of administration?Parenteral

OralTranscutaneousSubcutaneousInhalationRectalEyeBuccal

NCE Formulation

• Tablet• Suspension• Solution• Capsule• Enteric coated• Cream• Ointment• Pro-drug?

Route of Synthesis?

• Economics (platinum)

• Which Salt?Hydrocortisone = mild steroidHydrocortisone butyrate = potent

• Solubility

• Physicochemical properties

• Stability

• Compatibility with excipients

Clinical Pharmacology

• The Scientific basis of drug therapy, includes:PharmacokineticsPharmacodynamicsPharmaceutical developmentPharmacovigilancePharmacoeconomicsPharmacoepidemiology

Pharmaceutical Process

• Is the drug getting into the patient?

Route?Formulation?Dissolution?Absorption?

Pharmacokinetic Process

• Is the drug getting to its site of action?

Absorption?Distribution?Metabolism?Excretion?

Pharmacodynamic & Therapeutic Process

Is the drug producing the required pharmacological effect?

Is the pharmacological effect being translated into a therapeutic effect?

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

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

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+

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+

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 DataPharmaceutical Quality

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

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

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.

Toxicology Testing

• Thalidomide 1956 Germany Antiemetic in pregnancy

• 1961 Reports of Phocomeliano cases in 1949-1959477 cases in 1961 alone400-500 cases in UK 1959-61

• 1963 CSM in UK• 1968 Medicines Act UK

Regulatory Control

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

Before NCE tested in Man

• Safety Pharmacology in Animals Dog&RatCNS ActivityCVS ActivityRespiratory Activity

• Pharmacokinetics Dog & Rat usually Absorption

DistributionMetabolismExcretion

Before NCE tested in Man

• Acute Toxicity single dose2 Species of animlas by 2 routesUsually IV and Oral (or proposed

route) Maximum well tolerated dose• Repeat dose toxicity

Rodent and non-rodentUsing route proposed for manDuration depends on proposed

duration in man

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 damageMicronucleus Test mammalian in vitro chromosome damageAssay of DNA synthesis in rat liver

• Reproductive toxicityonly if women of child bearing potential

Adverse Drug Reaction ReportingAdverse Drug Reaction Reporting

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

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

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

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

Pharmacovigilance Methods

• Spontaneous Reporting• Cohort Studies

Defined size group of patientsFollowed for defined period of time10,000 pts recruited from 2500 GPsNon-promotional, only if going to be RxDoctor reports and ADEsCan come up with new ADEs“Hypotheses generating”

Pharmacovigilance Methods

• Case Control studies

Hypothesis testing, not generatingSelect cohort with suspected

disease/ADESelect larger cohort without ADELook for differences in exposure to drug

Pharmacovigilance Methods

• Computerised databases

Prescriptions/Patients LinkedTo medical adverse events/diseaseGetting better as I.T. improvesDepends on quality of data entered

The interface between the medical profession and the pharmaceutical

industry

• Research State funded = €25 million/year

• Research Funded by Pharma = €40 million

• Approx 160 doctors, nurses and scientists are funded by pharma industry

• Used to be area of growth --now ?

• Fraud rare but does occur

Medicine Promotion

• AdvertisementsStrict Guidelines

safe, best, most etc.

reminder vs full advertisement

Code of practiceComplaints procedure

Medicine Promotion

• RepresentativesEducationalInformativePromotionalNot paid by commissionRising standardsMust have data sheetMust report ADEsMust not mislead

Medicine Promotion

• S safety

• T tolerability

• E efficacy

• P price

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”

Medicine Promotion

• SponsorshipIPHA code of practice (new 6th edition)Doctors should not ask for a fee for aptSponsorship should be appropriate & not out of proportionSponsored meetings must have

educational componentNo sponsorship for non-medical people