Drug Development and Assessment in Man Pharmaceutical Medicine

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Drug Development and Assessment in
ManPharmaceutical Medicine

• Thursday 22nd March 2007
• Dr John Stinson

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

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Antibiotic 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

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Introduction

• 1935 Few effective Medicines
• lt1950 No antihypertensive agents
• 1950s Diuretics
• 1960s B2 Receptor antagonists
• 1970s Calcium Channel antagonists
• 1980s ACE Inhibitors
• 1990s Angiotensin II receptor antagonist
• BNF 2004 gt 100 antihypertensives

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

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

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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

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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

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Molecules Registered in Libraries

• Screened in biological systems
• gt100,000 molecules screened
• Automated systems
• Intelligent screening using 3-D structures
• Molecule Receptor Binding
• Appropriate shaped molecule tried

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Potential Drug Candidate

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

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New Chemical Entity

• What route of administration? Parenteral
• Oral
• Transcutaneous
• Subcutaneous
• Inhalation
• Rectal
• Eye
• Buccal

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NCE Formulation

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

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Route of Synthesis?

• Economics (platinum)
• Which Salt? Hydrocortisone mild
  steroid Hydrocortisone butyrate potent
• Solubility
• Physicochemical properties
• Stability
• Compatibility with excipients

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Clinical Pharmacology

• The Scientific basis of drug therapy,
  includes Pharmacokinetics Pharmacodynam
  ics Pharmaceutical development Pharmacovigil
  ance Pharmacoeconomics Pharmacoepidemiology

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Pharmaceutical Process

• Is the drug getting into the patient? Rout
  e? Formulation? Dissolution? Absor
  ption?

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Pharmacokinetic Process

• Is the drug getting to its site of
  action? Absorption? Distribution?
  Metabolism? Excretion?

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Pharmacodynamic Therapeutic Process

• Is the drug producing the required
  pharmacological effect?
• Is the pharmacological effect being translated
  into a therapeutic effect?

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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Before NCE tested in Man

• Safety Pharmacology in Animals DogRat CNS
  Activity CVS Activity Respiratory
  Activity
• Pharmacokinetics Dog Rat usually Absorption
  Distribution Metabolism Excretion

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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

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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 Micronucle
  us Test mammalian in vitro chromosome
  damage Assay of DNA synthesis in rat liver
• Reproductive toxicity only if women of child
  bearing potential

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Adverse Drug Reaction Reporting
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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

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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

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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

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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

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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

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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

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Pharmacovigilance Methods

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

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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

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Medicine Promotion

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

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Medicine Promotion

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

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Medicine Promotion

• S safety
• T tolerability
• E efficacy
• P price

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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

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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
  educational component No sponsorship
  for non-medical people

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