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Examining the Quality, Safety, Efficacy of Generic Drugs
Jake J. Thiessen, Ph.D.
Founding Director, School of Pharmacy,
University of Waterloo
Professor Emeritus, Leslie Dan Faculty of Pharmacy, University of Toronto
Canadian Government Mandate(Health Canada)
To ensure that the Canadian public gets medicines that are (therapeutically) safe, effective and of high quality.
To ensure that manufacturers provide suitable scientific and clinical evidence -- Obviously this implies safety and efficacy in humans…. ….which will ultimately be demonstrated in valid
clinical trials… The Canadian government does not assess whether
a drug is superior to similar therapeutic agents, nor does it determine whether the new drug is cost-effective for publicly-funded formularies.
The Focal Point of Today’s Talk
‘The SAME’ in terms of:QualitySafetyEfficacy
But, what is meant by ‘The Same’? How much variability can be tolerated with
‘The Same’? Are there exceptions to Canada’s common
criteria?
Are Canada’s Approved Generic Drugs ‘The SAME’ as the Originator’s Drugs?
What is Different or ‘The Same’?
All have ‘The Same’ purchasing power.
What is Different or ‘The Same’?
Permitted Product Content Variability
*USP 34 NF 29 Suppl 1 (2011)
Drugs Limits*
Azithromycin 90-110
Carbamazepine ER 90-110
Doxorubicin Inject. 90-115
Doxycycline 90-120
Levetiracetam 90-110
Methylphenidate ER 90-110
Metoprolol ER 90-110
Nifedipine ER 90-110
Nifedipine 90-110
Valproic Acid 90-110
Verapamil ER 90-110
Critical Dose Drugs Content Variability
*USP 34 NF 29 Suppl 1 (2011)
TPD Drugs Limits*
Cyclosporin 90-110
Digoxin 90-105
Flecainide 90-110
Lithium 95-105
Phenytoin 95-105
Sirolimus NA
Tacrolimus NA
Theophylline 90-110
Warfarin 95-105
Reported Product Variability
A Yacobi et al: Clin. Pharmacol. Ther. 65: 389-394 (1999)Carbamazepine data: 200 mg Taro Carbamazepine vs Tegretol
Content Variability - -Within and Between Products
It is impossible for all capsules/tablets in a prescription to be identical and to contain the exact amount on the label.
It is impossible for all batches from the same manufacturer to be identical.
A quality product (originator or subsequent entry, i.e. generic) meets regulatory requirements when its variability is within an approved range (e.g. most commonly 10% of label claim).
The permitted variability is really a ‘probability’ or ‘confidence limit’ that a tested sample meets the quality specification and that now all the tablets in the lot also meet that criterion.
Variability as a Fundamental Issue
0.8 1 1.25
Intra- and Inter-Product Content Variability
View of the Body??
Is It Like These Constants??
Planck’s
View of the Body??
Is It Really Variable??
The Variable Human Illustrated
13
men women overall
oral 35.7–37.7 °C 33.2–38.1 °C 33.2–38.2 °C
rectal 36.7–37.5 °C 36.8–37.1 °C 34.4–37.8 °C
typanic (ear canal) 35.5–37.5 °C 35.7–37.5 °C 35.4–37.8 °C
axillary (armpit)
35.5–37.0 °C
Body Normal Temperature
Body Normal Lab Values
Parameter ‘Normal Range’
Serum Total T3 75-220 ng/dL
SGOT 11-47 IU/L
Uric Acid 3-8 mg/dL
Serum Albumin 3.6-5 g/dL
Platelet Count 150-450 x109 /L
Serum DHEA 130-1200 ng/dL
Serum Uric Acid (Male) 4.0-8.5 mg/dL
Sources of Inter – and Intra-Human Variability
Source: Goodman & Gilman's The Pharmacological Basis of Therapeutics - 11th Ed. Figure 4-1; Originally by E. S. Vesell
Understanding Physiologic Realities After Administering a Drug
Sources of Variability
Absorption
First-pass effect
Liver –
Metabolism
Bile
Distribution
Excretion
Age, gender, size, genetic traits, health status, food, etc.
Patient Response to a Drug
Cellular
Barrier
Biophase
Blood/Int. fluid
Drug Drug
Receptor
Homeostasis
Response
Variability in Therapeutic EffectTPD Critical Dose Drugs
Drug USP Content Limits Therapeutic Window**
Cyclosporin 90-110 50 - 300 ng/mL
Digoxin 90-105 0.8 - 2.0 ng/mL
Flecainide 90-110 0.2 - 1.0 mcg/mL
Lithium 95-105 0.8 - 1.2 mmol/L
Phenytoin 95-105 10 - 20 mcg/mL
Sirolimus NA* 5 - 15 ng/mL
Tacrolimus NA* 5 - 20 ng/mL
Theophylline 90-110 10 - 20 mcg/mL
Warfarin 95-105 2.2 + 0.4 mcg/mL
* Not Available in the USP** Health Canada or elsewhere
Evaluating Drugs Effect or response in the body is relatively
insensitive for most drugs --Frequently one is unable to distinguish a
difference when the dose is doubled.Even though blood concentrations change by
50%, as usually occurs between doses, one usually cannot tell the difference in effect.
Blood concentrations are a much more sensitive way of evaluating the entry or presence of drugs in the body.
Variability as a Fundamental Issue
0.8 1 1.25
Intra- and Inter-Product Content Variability
Indistinguishable Response
The Science of Comparing Two Products
B
A
AUCA
AUCB
Oral Concentration Versus Time Curve
0.000.200.400.600.801.001.201.401.601.802.002.20
0 6 12 18 24
Time (hr)
Cmax
Tmax
AUC
AUC Area under the
concentration- time curve
Cmax
Maximum concentration
Tmax
Time to maximum concentration
Propafenone 300 mg IR; fasting study
H.H. Blume et al: Application of single dose vs. multiple-dose studies. Biointernational 2002
Bioequivalence Testing: The Complicating Problem of Variability
Famotidine-Formulation B
0
50
100
150
200
250
0 5 10 15 20
Time (Hours)
Co
nc
(m
cg
/ml)
Famotidine-Formulation A
0
50
100
150
200
250
0 5 10 15 20
Time (Hr)
Co
nc
(m
cg
/ml)
Variability Encountered With a Dose
Intra- and Inter-Individual Variability!!
Variability With the Same Product
0
10
20
30
40
50
60
70
80
90
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
Plas
ma
Leve
l (ng
/mL)
Sub1A
Sub1B
Sub2A
Sub2B
Sub3A
Sub3B
People/Products are Not Constant!!
Nifedipine - Adalat
M. Spino “Non-Linear Drugs: A Pragmatic Perspective”; TPD Workshop, 2002
Intra-Product Variability (0.25 mg Lanoxin)
A Yacobi et al: J. Clin. Pharmacol. Ther. 21: 301-31 (1981)Lanoxin vs Generic Digoxin: n=12 4-way crossover trial
People/Products are Not Constant!!
Intra-Product Variability (5 mg Coumadin)
A Yacobi et al: J. Clin. Pharmacol. Ther. 40: 1-10 (2000)Coumadin vs Taro-warfarin: n=26(23completed) 4-way crossover trialIntra-subject CV ~ 20%
People/Products are Not Constant!!
Quantifying Comparative Study Results
B
A
AUCA
AUCB
AUC
AUC
A
B
Cmax
Cmax
A
B
Tmax
Tmax
A
B
Variability as a Fundamental Issue
0.8 1 1.25
Intra- and Inter-Product Content Variability
Intra-Subject Variability
Inter-Subject Variability
Indistinguishable Response
Variability as a Fundamental Issue
0.8 1 1.25
Intra- and Inter-Product Content Variability
Intra-Subject Variability
Inter-Subject Variability
Indistinguishable Response
Bioequivalence Limits
So, what do we mean when we say a product meets the criterion of 80-
125%??
What is this ‘confidence interval’ criterion all about?
Bioequivalence Confidence Intervals It is a reasoned measure of product comparison It is quantitative limit of the in vivo performance of a
test product relative to a reference product (ie in a controlled clinical test)
The estimate is a “probability” [eg 90%]: Based on the results of a completed study Applies mostly to AUC, which defines the comparative
fraction of the dose absorbed A forecast or projection of what the average (eg
AUCtest/AUCref) would be if literally millions of people/patients were enrolled in a similar bioequivalence trial
For most products this range is 80-125%
Bioequivalence: Mean Ratios and Confidence Intervals (CI)
.
125
100
80
% M
ean
Rat
io
This case ‘fails’: acceptable mean ratio but not within 80-125%
This case ‘passes’: ratio and CI is within 80-125% [Bioequivalent]
This case ‘fails’: unacceptable 90% CI
Health Canada’s Criteria: Apply to generic and innovator companies Apply to all products, with a few exceptions -
AUC must meet the 90% confidence limits of 80-125% Cmax average must be between 80-125%
Exceptions: Critical dose drugs (cyclosporin, digoxin, flecainide,
lithium, phenytoin, sirolimus, tacrolimus, theophylline, warfarin)
AUC must meet the 90% confidence limits of 90-112% Cmax must meet the 90% confidence limits of 80-125% Fasting and Fed studies
Rapid onset of action drugs Common requirements, plus The relative mean AUCReftmax of the test to reference
formulation should be within 80 to 125%
Concluding Comments Bioequivalence requirements are a robust
international standard for designating products as ‘The Same’. They are the primary basis for decisions about interchangeability.
The requirements apply to both the originator and generic companies. Originators who make changes in formulations, sites of
manufacture, etc. Generics who seek to create competitive products.
Interchangeability means that products can be switched with no change in therapeutic response.
The public is well-served by the bioequivalence requirements.