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
 ….which will ultimately be demonstrated
in humans….
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 costeffective for publicly-funded formularies.
The Focal Point of Today’s Talk
Are Canada’s Approved Generic Drugs ‘The SAME’
as the Originator’s Drugs?
‘The SAME’ in terms of:
 Quality
 Safety
 Efficacy
But, what is meant by ‘The Same’?
How much variability can be tolerated with
‘The Same’?
Are there exceptions to Canada’s common
criteria?
What is Different or ‘The Same’?
All have ‘The Same’ purchasing power.
What is Different or ‘The Same’?
Permitted Product Content Variability
Drugs
Azithromycin
Carbamazepine ER
Doxorubicin Inject.
Doxycycline
Levetiracetam
Methylphenidate ER
Metoprolol ER
Nifedipine ER
Nifedipine
Valproic Acid
Verapamil ER
*USP 34 NF 29 Suppl 1 (2011)
Limits*
90-110
90-110
90-115
90-120
90-110
90-110
90-110
90-110
90-110
90-110
90-110
Critical Dose Drugs Content Variability
TPD Drugs
Cyclosporin
Digoxin
Flecainide
Lithium
Phenytoin
Sirolimus
Tacrolimus
Theophylline
Warfarin
*USP 34 NF 29 Suppl 1 (2011)
Limits*
90-110
90-105
90-110
95-105
95-105
NA
NA
90-110
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
Intra- and Inter-Product Content Variability
0.8
1
1.25
View of the Body??
Planck’s
Is It Like These Constants??
View of the Body??
Is It Really Variable??
The Variable Human Illustrated
Body Normal Temperature
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 Lab Values
Parameter
Serum Total T3
‘Normal Range’
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
13
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
Age, gender, size,
genetic traits,
health status, food,
etc.
 Absorption
 First-pass effect
 Liver –
 Metabolism
 Bile
 Distribution
 Excretion
Patient Response to a Drug
Blood/Int. fluid
Homeostasis
Drug
Drug
Receptor
Response
Cellular
Barrier
Biophase
Variability in Therapeutic Effect
TPD Critical Dose Drugs
Drug
Cyclosporin
Digoxin
Flecainide
Lithium
Phenytoin
Sirolimus
Tacrolimus
Theophylline
Warfarin
USP Content Limits
Therapeutic Window**
90-110
90-105
90-110
95-105
95-105
NA*
NA*
90-110
95-105
50 - 300 ng/mL
0.8 - 2.0 ng/mL
0.2 - 1.0 mcg/mL
0.8 - 1.2 mmol/L
10 - 20 mcg/mL
5 - 15 ng/mL
5 - 20 ng/mL
10 - 20 mcg/mL
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
Indistinguishable Response
Intra- and Inter-Product Content Variability
0.8
1
1.25
The Science of Comparing Two Products
A
AUC
A
AUC
B
Cmax
A
Cmax
B
Tmax
A
Tmax
B
B
 AUC

Area under the
concentration- time
curve
 Cmax

Maximum
concentration
 Tmax

Time to maximum
concentration
Bioequivalence Testing:
The Complicating Problem of Variability
Propafenone 300 mg IR; fasting study
H.H. Blume et al: Application of single dose vs. multipledose studies. Biointernational 2002
Variability Encountered With a Dose
Famotidine-Formulation A
250
250
200
200
Conc (mcg/ml)
Conc (mcg/ml)
Famotidine-Formulation B
150
100
50
150
100
50
0
0
0
5
10
Time (Hours)
15
20
0
5
10
Time (Hr)
Intra- and Inter-Individual Variability!!
15
20
Variability With the Same Product
90
Plasma Level (ng/mL)
80
Nifedipine - Adalat
70
Sub1A
60
Sub1B
50
Sub2A
40
Sub2B
30
Sub3A
20
Sub3B
10
0
0
2
4
6
8
10 12 14 16 18 20 22 24
Time (hours)
M. Spino “Non-Linear Drugs: A Pragmatic Perspective”; TPD Workshop,
2002
People/Products are Not Constant!!
Intra-Product Variability (0.25 mg Lanoxin)
People/Products are Not Constant!!
A Yacobi et al: J. Clin. Pharmacol. Ther. 21: 301-31 (1981)
Lanoxin vs Generic Digoxin: n=12 4-way crossover trial
Intra-Product Variability (5 mg Coumadin)
People/Products are Not Constant!!
A Yacobi et al: J. Clin. Pharmacol. Ther. 40: 1-10 (2000)
Coumadin vs Taro-warfarin: n=26(23completed) 4-way crossover trial
Intra-subject CV ~ 20%
Quantifying Comparative Study Results
A
AUC
A
AUC
AUC
A
B
AUC
B
Cmax A
Cmax
A
Cmax
Cmax
B
B
Tmax
Tmax
A
A
Tmax
Tmax
B
B
B
Variability as a Fundamental Issue
Inter-Subject Variability
Intra-Subject Variability
Indistinguishable Response
Intra- and Inter-Product Content Variability
0.8
1
1.25
Variability as a Fundamental Issue
Bioequivalence Limits
Inter-Subject Variability
Intra-Subject Variability
Indistinguishable Response
Intra- and Inter-Product Content Variability
0.8
1
1.25
So, what do we mean when we say a
product meets the criterion of 80125%??
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)
.
% Mean Ratio
125
100
80
This case ‘passes’: ratio
and CI is within 80125% [Bioequivalent]
This case ‘fails’:
acceptable mean ratio
but not within 80-125%
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
 Cmax average must be between 80-125%
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.