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.