Interpreting Evidence Interactions with the Pharmaceutical Industry

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Interpreting Evidence /Interactions with the
Pharmaceutical Industry

• __________________________________________________
  ___
• Dr Joseph Cheriyan
• Clinical Pharmacology Unit
• Department of Medicine

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NHS Annual Drug Expenditure
Drugs Total 5 billion
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Evidence Based Medicine

• The conscientious,explicit and judicious use of
  current best evidence in making decisions about
  the care of individual patients. The practice of
  EBM means integrating individual clinical
  expertise with the best available external
  clinical evidence from systematic research

Sackett DL, Rosenberg WM EBMwhat is it and what
it isnt. BMJ 312 (7023)71-2, 1996
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Wheres the Evidence?

• Primary Evidence
• Randomised controlled trials
• Observational studies
• Descriptive studies
• Case reports
• Secondary Evidence
• Meta analysis
• Systematic reviews
• Summary reviews
• Respected opinions
• Tertiary Evidence - Clinical Guidelines

Adapted from Richard Glickman-Simon, MD 2004
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Evidence portals

• MEDLINE
• PubMed
• Cochrane collaboration
• NICE reviews
• SIGN reviews (Scotland)

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Randomised Clinical Trials

• Blinding Open vs. single vs Double blind
• Randomisation Simple, blocked, central vs centre
  based,stratified, adaptive (covariate vs
  response)
• The most reliable assessment of treatment
  efficacy comes from randomised, double-blind,
  controlled clinical trials

(Friedman,,Furberg DeMets Fundamentals of
Clinical Trials 1982)
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Data from trials

• Quantitative eg weight, SBP
• Ordinal eg categories of mild, moderate,severe or
  unordered (eg death, AE, lost to F/up) or binary
  (eg success vs. failure)

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Measures of quantitative data

• Mean
• Median
• Mode
• Standard Deviation
• Range
• Standard error or Std error of the mean

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Measures of quantitative data

• Mean Sum of all values divided by n
• Median middle value of a sample after ranked in
  order
• Mode the most frequently occurring value
• SDaverage deviation from mean, about 95 of
  normally distributed data lie within 2 SDs of
  mean
• Range diff. between largest and smalest values
• SE (or SEM) Measure of the uncertainty of a
  single sample mean as an estimate of the general
  population mean

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Key Results in a Trial

• Relative risk
• Relative risk reduction
• Absolute risk reduction
• Number needed to treat

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Event Rates

• Event rate in experimental group
• Event rates
• n with event / total
• Control event rate (CER)
• Experimental event rate (EER)

Intervention Event No event Total Experiment
a b (ab) Control c d (cd) CER c
/ (cd) EER a / (ab)
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Relative Risk (reduction)

• Relative risk Experimental event rate
• Control event rate
• Relative risk reduction (RRR)
• RR-1
• Or control-experimental event rate
• control event
  rate

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Absolute Risk Reduction

• Difference in two event rates
• control-experimental event rate

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Numbers Needed to Treat

• NNT is the number of patients that need to be
  treated (for a specific time period) to prevent
  one event
• NNT 1 / ARR

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An ExampleCAPRIE Study Lancet 1996
3481329-1339
ARR 5.83-5.32 0.51 RR 0.89 RRR
0.51/5.83 0.087 or 8.7 NNT 1/0.0051 196
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Are Results Statistically Significant

• P-value
• beware the Type I error
• statistical false positive
• Confidence interval
• gives an idea of precision
• If not significant, what was the power of the
  study?

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Pharmaceutical Industry and Drug Development
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What is a Drug?

• Any chemical compound - sugar ???
• Anything which produces a change in the body -
  an axe ???
• Define by characteristics
• 1. use or potential use in diagnosis or treatment
  of disease
• 2. selective in their actions

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Clinical drug development occurs in stages

• Exploratory
• Phase I-II

• Confirmatory
• Phase III

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Drug Absorption, Distribution, Metabolism
and Excretion - What is Assessed and When?
Candidate Selection to FTIH
FTIH to PoC
PoC to commit to Phase III
Lead to Candidate
File Launch
Lifecycle Management
Phase 3
Phase II
Phase III
Phase IV
Phase I

• Pharmacokinetics / Toxicokinetics
• In-vitro metabolism / enzymology
• ADME in toxicology species
• Metabolite identification

• Bioanalysis for Clinical, Toxicity and
  Oncogenicity Studies
• ADME for reprotox and oncogenicity species
• Placental and milk transfer

• Identify routes of human metabolism
• Compare human and animal metabolism
• Human radiolabel study
• Bioanalysis for Clinical and Toxicity Studies

• Bioanalysis for Clinical Studies
• ADME support of alternative administration routes

Progress to definition of animal and human ADME
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Sources of Drugs
Animal Insulin (pig, cow)
growth hormone (man) Plant digitalis
(digitalis purpurea - foxglove)
morphine (papaver somniferum) Inorganic
arsenic mercury
lithium Synthetic chemical (propranolol)
biological (penicillin)
biotechnology (human insulin)
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Approaches to Drug Discovery
DRIVER IS UNMET MEDICAL NEED IN A VIABLE MARKET

• Historical cinchona (quinine) willow barks
  (aspirin)
• Study disease process breast cancer (tamoxifen)
  Parkinsons disease (L-dopa)
• Study biochem/physiological pathway
  renin/angiotensin
• Develop SAR to natural compound
  beta-adrenoceptors (propranolol), H2-receptors
  (cimetidine)
• Design to fit known structurally identified
  biological site ACEi
• By chance (serendipity) random screening (HTS)
  penicillin dimenhydramate pethidine
• Genomics identification of receptors gene
  therapy recombinant materials

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Levels of testing
DRUG receptor
transduction system (second messenger enzyme)
BINDING
functional whole or part organs
BIOCHEMICAL TESTING
ISOLATED TISSUE EXPERIMENTS
Anaesthetised or conscious animals
WHOLE ANIMAL EXPERIMENTS
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Animal Models of Efficacy

• Existing normal behaviours/effects (anaesthesia
  contraception paralysis)
• Create behaviours (fat rats hypertensive rats
  anxious rats epileptic rats)
• Find unrelated behaviour affected by existing
  drugs (Straub tail for narcotic analgesics
  learned helplessness for antidepressants)

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Clinical Testing

• Phase 0 (non-clinical)
• Phase 1 (volunteers)
• Phase 2 (patients)
• Phase 3 (large scale multi-centre)
• Phase 4 (post registration monitoring)
• phases can also be defined by the information
  you are trying to get out of the testing

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PHASE I GOALS

• Safety and tolerability of single and short-term
  (7d-14d) dosing with NCE
• Obtain the concentration-time profile of the NCE
  determine the degree of proportionality between
  dose and plasma concentrations
• Characterize relationship between dose-plasma
  exposure and appropriate markers of pharmadynamic
  effect or efficacy
• Recommend dosage regimen for Phase II

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Phase II

• To investigate the dose-exposure-response/efficacy
  relationship in the target patient population
• To select the optimal dosage regimen for Phase III

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Phase III

• Confirm Efficacy and Safety in a larger sample of
  the target population (thousands)
• Define the Risk/Benefit Ratio
• Differentiation of the drug from competitors
• Regulatory Submission of Non-clinical and
  Clinical Studies

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Phase I II. Phase III (US Japan vs Europe)
Minimum duration Studies in animals
Clinical Trial Repeat dose studies
Rodent Non
rodent Single dose 2-4w
2w lt 2 weeks 2-4w
2w 1 month 1m 1m
3 months 3m/6m 3m 6
months 6m 6m gt 6 months
6m chronic
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Lack of Efficacy accounts for the largest part of
the of the Attrition Pie
Other 14
Other 10
Efficacy 46
Efficacy 29
DMPK 7
DMPK 7
Safety 17
DMPK 40
AEs 10
AEs 16
Safety 11
Prentis et al, 1988
Kennedy, 1997
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Well-validated Surrogates

• Hypertension Blood Pressure
• Peptic Ulcers Suppression of gastric acid
  production over 24h
• Glaucoma Intraocular pressure

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Ideal Surrogate linked to clinical endpoint via
same mechanism
Treatment
Surrogate Endpoint
Disease
Clinical Endpoint
Treatment Intervention acts through pathway
affecting clinical endpoint through the surrogate
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Arterial Stiffness and Survival
LDL cholesterol and survival
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Inappropriate surrogates
Surrogate
A
Treatment
Disease
Clinical Endpoint
Surrogate
B
A Surrogate is unrelated to mechanism that leads
to clinical outcome
B Surrogate is linked to to clinical outcome via
a pathway not affected by treatment intervention
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Clinical Drug Development must have a cunning plan
15 y ago
Clinical Development
Discovery
NOW
Clinical Development
Discovery
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DRUG DEVELOPMENT

• Preclinical Studies - tissues and whole animals
• Clinical Studies
• ? Phase I healthy volunteers (20-50) - PK, PD
• ? Phase II patients (50-300) - PK, PD,
  dose-ranging, safety
• ? Phase III patients (250-1000) - formal
  clinical trial, efficacy, safety
• Granting of Product Licence
• ? Phase IV post-marketing patient studies
  (1000s), larger clinical trials
• Developing and launching a new drug - 100M and
  10 to 15 years

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GOVERNMENT
Ministry of Health
License Applications
Granted Licenses
Medicines Control Agency (MCA)
Committee on Safety of Medicines (CSM)
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Prescribing Drugs- a balance of benefit and risk
RISK
BENEFIT
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Drugs can do good or harm!

• Poisons in small doses are the best medicines
  and useful medicines in too large doses are
  poisonous
• William Withering 1789

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Study Stages Sample Sizes and Number of Sites
Phase II (n100300) 280 Sites
PreclinicalTesting
Approval
Phase III (n1,0005,000) 10100 or More Sites
Phase I (n50100) Usually Single Site
Phase IV Outcomes Research (nvariable) Variable
of Sites
Discovery
210
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1
2
3
1.5
Varies
First in Human
Time (Years)
Note For Phase III, you could test upwards of
1520,000 subjects. Trovan was over 14,000 you
might want to up that figure for Phase III
Source PhRMA. Tufts Center for the Study of Drug
Development
2.1
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US Dominates Global Market 11 Growth in 2003
US/Mil
Source IMS Health March 2003 Pharmacy
only Hospital only
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U.S. Pharmaceutical IndustryRD Continues to
Grow
Expenditures (Billions of Dollars)
PhRMA member RD and non-PhRMA member biotech
company RD (including PhRMA research
associates). Estimated
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From Laboratory to Patient The Complex Pathway
of Biopharmaceutical RD
Large-ScaleManufacturing/Phase IV
Drug Discovery
Pre-Clinical
Clinical Trials
FDA Review
1FDA ApprovedDrug
10,000Compounds
5 Compounds
250 Compounds
NDA Submitted
IND Submitted
5 Years
1.5 Years
6 Years
2 Years
2 Years
Average time in stage
Source Pharmaceutical Industry Profile, 2005,
PhRMA
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U.S. Pharmaceutical Industry Cost of Developing
a New Drug Continues to Grow
Expenditures per Rx Drug (Millions of 2000
Dollars)
Source J.A. DiMasi, R.W. Hansen, and H.G.
Grabowski, The Price of Innovation New
Estimates of Drug Development Costs, Journal of
Health Economics 22 (2003) 151-185
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World Trade in Drugs (Legal)
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Annual Personal Spend on Drugs
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Top Pharmaceutical Companies
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Use of Generics
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What Drugs Cost in Cambs (2000)

• Omeprazole (anti-gastric acid) 3.5m
• Simvastatin (cholesterol lowering) 2.4m
• Beclomethasone (asthma) 1.8m
• Fluoxetine (antidepressant) 1.5m
• Lansoprazole (anti-gastric acid) 1.4m
• Ranitidine (anti-gastric acid) 1.3m
• Paroxetine (antidepressant) 1.2m
• TOP 7 TOTAL gt13m
• Total GP drugs gt67m

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NICE (http//www.nice.org.uk/)
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Local guidelines

• GPs Cambridgeshire PCT guidelines
• Addenbrookes

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Summary

• EBM provides evidence basis for clinical practice
  based on combining clinical experience,
  scientific investigation and reviewing results of
  outcomes research
• Drug development is a long and expensive journey
  undertaken primarily by the pharmaceutical
  industry
• Roles and responsibility of individual
  prescribers in a nationalised health system to
  prescribe in a rational, unbiased manner based on
  levels of evidence and national guidelines