Generics and public health
Andrew Creese - Valerio Reggi
Department of Essential Drugs and Medicines Policy - EDM
Health Technology and Pharmaceuticals Cluster
World Health Organization
May 2002
Definitions
Generics are pharmaceutical products that
contain well-established drugs.
They are:
intended to be interchangeable with the
original product,
usually manufactured without a licence from
the original manufacturer,
marketed after the expiry of patent or
other exclusivity rights,
marketed either under a non-proprietary
name (INN or other approved name) or under
brand names ("branded generics").
2 PAR Seminar October 2002
WHO - EDM
The worldwide role of generic pharmaceuticals
Public health need
National strategies
Social responsibility
3 PAR Seminar October 2002
WHO - EDM
The worldwide role of generic pharmaceuticals
Public health need
National strategies
Social responsibility
4 PAR Seminar October 2002
WHO - EDM
Public health need
In poor countries drugs are largest household
and second largest public expenditure for health
Pharmaceutical spending, as % of total health spending
Greece
Germany
Italy
France
Spain
Denmark
UK
United States
Netherlands
Norway
Developed countries
(7 - 20%)
Bulgaria
Czech Rep.
Hungary
Croatia
Poland
Estonia
Slovenia
Lithuania
Transitional countries
(15 - 30%)
Mali
Egypt
China
Indonesia
Thailand
Tunisia
Jordan
Argentina
South Africa
Developing countries
(24 - 66 %)
0
5 PAR Seminar October 2002
10
20
30
40
50
60
WHO - EDM
70
Public health need
The cost of medicine is substantial - number
of working hours to pay full treatment course
600
500
400
Hours
500
460
And the burden falls heaviest on those least able to
pay:
Developed countries: 50-90 % publicly funded
Developing countries: 50-90 % paid out-of-pocket
Tuberculosis
300
200
Shigellosis
120
100
Gonorrhoea
100 100
20
0
Tanzania
Zimbabwe
20
20
6
Thailand
Based on average worldwide price and national
per capita income. Source: WHO/DAP
6 PAR Seminar October 2002
1.4 1.4 0.4
Switzerland
WHO - EDM
Public health need
Despite the potential health impact and expenditure,
too many people still lack access to essential drugs

>1/3 of world’s
population lacks
regular access

320 million in Africa
have <50%

Problem worsens
with economic
pressures
Percentage of populations and number of countries with regular access to essential drugs:
1 = <50%
2 = 50-80%
3 = 80-95%
4 = >95%
5 = No data available
7 PAR Seminar October 2002
(43)
(64)
(30)
(41)
(1)
WHO - EDM
Public health need
Millions of children and adults still die from
diseases readily treated with generic essential drugs
Developing Country Deaths (millions) 1990
INFECTIOUS & PARASITIC DISEASES
Respiratory infections
Age 5 & over
Under 5
Diarrhoeal disease
Tuberculosis
Measles
Malaria
Tetanus
Pertussis
HIV
Meningitis
NON-COMMUNICABLE DISEASES - A GROWING CHALLENGE
Heart attacks, strokes
Cancer
0
8 PAR Seminar October 2002
1
2
3
4
5
WHO - EDM
6
The worldwide role of generic pharmaceuticals
Public health need
National strategies
Social responsibility
9 PAR Seminar October 2002
WHO - EDM
National strategies
As of the mid-1990’s, few countries had
achieved large generic coverage
D E V E LO P E D C O UN T R IE S
D e nm a rk
Unit e d S t a t e s
Unit e d Kingdo m
G e rm a ny
N e t he rla nds
Ire la nd
P o rt uga l
N e w Z e a la nd
J a pa n
F ra nc e
S pa in
D E V E LO P IN G C O UN T R IE S
Indo ne s ia
M o ro c c o
P hilippine s
0
10
20
30
40
50
60
% prescriptions generic
Source: DAP Global comparative pharmaceutical
expenditures and IGPA
10 PAR Seminar October 2002
WHO - EDM
70
National strategies
Price differentials between generic and brand
products vary greatly among countries
Belgium
Italy
Spain
Germany
France
Canada
UK
US
20%
20% +
25%
25% - 30%
25% - 35%
40% - 50%
80% +
50% - 90%
Source: IMS, Pharma Strategy Group
11 PAR Seminar October 2002
WHO - EDM
National strategies
Drug sales 1990 and 2000: originator and licensed
products grew from 50% to 64% of world market value
300
250
market
value in US
$ billion
102,3
200
Other
150
100
64,2
50
63,5
180,2
Originator
0
1990
2000
Source: IMS Health, customised study. Data from 52 countries/areas
12 PAR Seminar October 2002
WHO - EDM
National strategies
Drug sales 1990 and 2000: market share of
originator and licensed products in high, middle
and low income country markets
70
60
50
% of market
by value
High (25)
Middle (23)
Low (4)
40
30
20
10
0
1990
2000
Source: IMS Health, customised study. Data from 52 countries/areas
13 PAR Seminar October 2002
WHO - EDM
National strategies
Drug sales 1990 and 2000: originator and licensed
products in high, middle and low income country markets
market
value in US
$ billion
180
160
140
120
100
80
60
40
20
0
168
High (25)
Middle (23)
Low (4)
59
40,5
1990
12
0,6
2000
Source: IMS Health, customised study. Data from 52 countries/areas
14 PAR Seminar October 2002
WHO - EDM
National strategies
Rapidly changing drugs markets
Czech Republic*, 1990 and 2000
100%
19,7
90%
80%
15,5
70%
8,5
44,6
60%
50%
48,6
40%
39,8
30%
20%
16,2
10%
0%
1990
Unbranded
7,1
2000
Other brands
Origin/licensed
status n/a
*2000 Population: 10.3 million
Source: IMS Health, customised study. Data from 52 countries/areas
15 PAR Seminar October 2002
WHO - EDM
What are the potential benefits of generics?
Better access to needed medicines.
Well chosen generics make government or household
spend less without loss of quality or safety
1998 study by US Congressional Budget Office:
average generic medicine prescription price was less
than one third of average price of single-source
innovator brand drug
16 PAR Seminar October 2002
WHO - EDM
What are the potential benefits of generics?
Impact on the price of non-generics through
competition:
generics may be the only way to bring price
competition to a market that is based on product
differentiation, patent protection and heavy brand
promotion to both prescribers and patients access
to needed medicines.
17 PAR Seminar October 2002
WHO - EDM
Why are generics less expensive?
Not because they are inherently different in
composition from patented drugs,
but mainly because of the structure of the generics
market: competitive, free from IPRs, often without
the R&D and particularly the marketing cost that
goes into branded proprietary drugs
18 PAR Seminar October 2002
WHO - EDM
National strategies
Building a large generic market takes time
- and requires a combination of strategies
National strategies for generics:
50
45
40
35
30
25
20
15
10
5
0
5
8
19
19 PAR Seminar October 2002
1.
2.
3.
4.
Supportive legislation & regulation
Reliable quality assurance
Professional, public acceptance
Economic incentives
Percent of new prescriptions, U.S.
6
8
19
7
8
19
8
8
19
9
8
19
0
9
19
1
9
19
2
9
19
*
3
4
9
9
9
19
1
WHO - EDM
National strategies
1. Supportive legislation and regulation





product development authorized during patent life
abbreviated marketing authorization
differential registration fees
generic labeling
generic prescribing and substitution
20 PAR Seminar October 2002
WHO - EDM
National strategies
Product development during patent period
varies among countries

Examples of “early workings” for generics





access to innovator product safety and efficacy data
production tests on a patent-protected product
laboratory tests for marketing approval
– e.g. bioequivalence
production and stockpiling prior to patent expiry
Countries with some early workings provisions



Argentina
Australia
Canada
21 PAR Seminar October 2002
Hungary
 Tunisia
 USA

WHO - EDM
National strategies
2. Reliable quality




substitution / non-substitution lists
national regulatory capacity
enforcement of good manufacturing
practices (GMP)
distribution system inspection and
enforcement
GMP
22 PAR Seminar October 2002
WHO - EDM
Drug registration
Requirements for abridged marketing
authorization application (i.e. without pre-clinical
and clinical data)






product information previously approved,
active ingredient previously approved,
route of administration, strength and dosage form equal
to those of previously approved product,
adequate information on analytical methods,
manufacturing process, manufacturers of finished
product and starting materials,
stability studies,
proof of therapeutic equivalence with previously
approved product.
23 PAR Seminar October 2002
WHO - EDM
Drug registration
Definitions (1)
Pharmaceutical equivalents:
Products that contain the same amount of the same active
substance(s) in the same dosage form; meet the same or
comparable standards; are intended to be administered by
the same route.
Pharmaceutical equivalence does not necessarily imply
therapeutic equivalence as differences in excipients
and/or manufacturing process can lead to differences in
product performance.
24 PAR Seminar October 2002
WHO - EDM
Drug registration
Definitions (2)
Generic (multi-source):
 pharmaceutical equivalent of a non-patentprotected product (comparator product)
whose safety and efficacy are well
established;
 can be marketed under its INN or a brand
name;
 may or may not be interchangeable with its
comparator product.
25 PAR Seminar October 2002
WHO - EDM
Drug registration
Definitions (3)
Comparator product:
•
•
•
26 PAR Seminar October 2002
product with which a generic is expected to
be interchangeable;
product whose safety and efficacy studies
are well established and will be the basis
for approval of all its pharmaceutical
equivalents;
product that often has the largest market
share.
WHO - EDM
Drug registration
Definitions (4)
Therapeutic equivalents:
pharmaceutical equivalents whose bioavailability
or dissolution profiles, after the same molar
dosis, are similar to such an extent that their
safety and efficacy can be assumed to be
substantially equal. Therapeutic equivalents are
interchangeable.
27 PAR Seminar October 2002
WHO - EDM
Drug registration
Therapeutic equivalence
Depending on active ingredient and formulation:




28 PAR Seminar October 2002
dissolution (in vitro)
bioequivalence studies (in vivo)
pharmacodynamic studies (in vivo)
clinical trials (in vivo)
WHO - EDM
Drug registration
Active ingredient and formulation
characteristics affecting dissolution/absorption
Particle size: digoxine, griseofulvine, nitrofurantoin
Crystal form (different forms with equal internal structure, different internal
structures, solvates) : riboflavine, cimetidine, erithromycine, clortalidon,
chloramfenicol, cefalexine
Wettability: phenytoin
Dependence on pH: aspirin, ketoconazol, sulfonamides
Excipients: nystatin, sulfadimidine with PVP or gelatin, phenytoin  with con
lactose
29 PAR Seminar October 2002
WHO - EDM
Drug registration
Examples of drug with high first-pass metabolism












Alprenolol
Amitriptyline
Chlormethiazole
Desipramine
Dextropropoxyphene
Dihydroergotamine
Diltiazem
5-Fluorouracil
Hydralazine
Isoproterenol
Labetolol
Testosterone












Lidocaine
Methylphenidate
Morphine
Neostigmine
Nifedipine
Nitroglycerin
Papaverine
Pentazocine
Phenacetin
Propranolol
Salicylamide
Verapamil
FA= 0.5 or less. From: Pond, S.M. and Tozer, T.N. : First-pass elimination. Basic concepts and
clinical consequences. Clin Pharmacokinetics 1984; 9:1-25
30 PAR Seminar October 2002
WHO - EDM
Drug registration
Examples of drugs with “possible” BA/BE
problems (104 substances)
Acebutolol
Amiodarone
Bromocryptine
Cefalexin
Chlorpropamide
Cyclophosphamide
Digitoxin
Droperidol
Ethinylestradiol
Fluocortolone
Flutamide
Haloperidol
Labetalol
Medroxyprogesterone
Methylprednisolone
Nifedipine
Oxprenolol
Procainamide
Temazepam
Thyroglobulin
Trifluoperazine
Acetohexamide
Amitryptyline
Busulfan
Cefazolin
Clomifene
Cyproterone
Digoxin
Dydrogesterone
Ethosuximide
Fluoxymesterone
Glibenclamide
Hydrocortisone
Levothyroxine
Mesterolone
Metoprolol
Nitrendipine
Perphenazine
Propranolol
Terazosin
Tocainide
Valproate
Ajmaline
Atenolol
Butriptyline
Chlorambucil
Clonazepam
Deslanoside
Diltiazem
Enalapril
Ethylestrenol
Flupentixol
Gliclazide
Imipramine
Liothyronine
Metformin
Midazolam
Nitroglycerin
Phenytoin
Pyrazinamide
Testosterone
Tolbutamide
Verapamil
Alprenolol
Betamethasone
Captopril
Chloramphenicol
Clonidene
Dexamethasone
Disopyramide
Epinephrine
Felodipine
Fluphenazine
Glipizide
Isosorb.-5-mononitrate
Lithium Carb.
Methotrexate
Nadolol
Norethisterone
Pindolol
Quinidine
Theophylline
Triamcinolone
Warfarin
Aminophylline
Bevantolol
Carbamazepine
Chlorpromazine
Conjugated Estrogens
Diethylstilbestrol
Dosulepin
Erythromycin
Flecainide
Flurazepam
Guanfacine
Isosorbide dinitrate
Magnesium sulfate
Methylergometrine
Nicardipine
Oxandrolone
Prazosin
Rifampicin
Thioridazine
Triazolam
Sources: too many to list
31 PAR Seminar October 2002
WHO - EDM
Drug registration
¿In vitro or in vivo? (1)
Different criteria exist:
US-FDA:
WHO :
MULTI-SOURCE PHARMACEUTICAL
PRODUCTS, WHO GUIDELINE ON
REGISTRATION REQUIREMENTS
TO ESTABLISH
INTERCHANGEABILITY, 1996
Http://www.fda.gov
EU:
Http://www.eudra.org
32 PAR Seminar October 2002
WHO - EDM
Drug registration
¿In vitro or in vivo? (2)
US-FDA’s Biopharmaceutic Classification System
In vivo BE waiver based on solubility and permeability
Peff = Qin (Cin – Cout) / Cout * 2rl
Unfortunately, permeability is not easy to
measure and published data are scarce
Waiver probably never used in practice
33 PAR Seminar October 2002
WHO - EDM
Drug registration
Bioequivalence (1)
Compare two formulations to determine whether
they provide substantially the same amount of
active substance at a comparable rate.
It is applied for authorizing :
- ‘scaling up’
- post-approval changes
- generics
Almost no product is marketed in the same
formulation used in phase I, II, and III clinical trials.
34 PAR Seminar October 2002
WHO - EDM
Drug registration
Bioequivalence (2)
Design:
 12-36 healthy volunteers (males, age 18-36)
 possible effects of disease/age/sex assumed identical for
the 2 formulations
 each volunteer receives at least one dose of each
formulation after suitable washout period
Specific designs (~100 FDA, USP)
35 PAR Seminar October 2002
WHO - EDM
Drug registration
Bioequivalence (3)
3 bioavailability
parameters
(including active
metabolites if
applicable):
36 PAR Seminar October 2002
WHO - EDM
Drug registration
Bioequivalence (4)
Evaluation:
•AUC:
•90% CI of ratio of average AUC of the 2 products
(both directions),
• 90% confidence interval should generally be within
80 to 125% (EEUU, UE, Canadá, Australia)
•Cmax:
wider acceptance criteria
•Tmax:
considered only when clinically relevant
37 PAR Seminar October 2002
WHO - EDM
Drug registration
Bioequivalence (5)
1962:
FDA establishes BE requirement, implementation ‘from now on’,
AUC and Cmax of TD/RD must be between +/-20% in majority of
subjects
1977:
75/75-125: 75% of subjects must fall within 75-125%
1979:
First Orange Book
1991:
90%CI must fall within 0.80-1.25
1999:
Biopharmaceutics Classification System - BE waiver in selected
cases.
38 PAR Seminar October 2002
WHO - EDM
Drug registration
Bioequivalence (6)
Practical implementation of BE study requirement:
manufacturer selects one batch for BE study and
study for submission,
after approval, only dissolution is used for following
batch releases and lower limits are based on BE batch
data (i.e. data of one single batch).
39 PAR Seminar October 2002
WHO - EDM
Drug registration
Bioequivalence (7)
Implementation seems good enough because:
reports of clinical failures due to BA/BE problems are
anecdotal

US-FDA claims “there are no documented examples of
generic products manufactured to meet approved
specifications that could not be used interchangeably with
the corresponding brand-name drug” http://www.fda.gov/cder/news/nightgenlett.htm

Innovative industry and patients’ associations in US
claim that no documented cases of “patient-formulation”
interaction exist FDA hearing 23 September 1999

40 PAR Seminar October 2002
WHO - EDM
Drug registration
Bioequivalence (8)
Other elements to consider:
- apparently-identical drugs of the same brand but
manufactured and marketed in different countries are not
necessarily bioequivalent
- transitive property of bioequivalence (different
formulations of same product or different products)
- change in labelling resulted in reports of 20% ‘therapeutic
failures’ (Glaxo, 1990)
- superbioavailability  reformulation (first always best?)
- WHO guidelines on interchangeability and comparator
product
41 PAR Seminar October 2002
WHO - EDM
Drug registration
WHO Guidelines
What are the practical implications of requiring new
BE studies in each country even for drugs from
reliable source meant for use in non-chronic courses?
MULTI-SOURCE PHARMACEUTICAL
PRODUCTS, WHO GUIDELINE ON
REGISTRATION REQUIREMENTS
TO ESTABLISH
INTERCHANGEABILITY, 1996
42 PAR Seminar October 2002
Selection of Comparator
Pharmaceutical Product for
Equivalence Assessment of
Interchangeable Multi-source
(Generic) Products,WHO, 1999
WHO - EDM
How to Identify Comparator Pharmaceutical Product: Decision Tree
Comparator Pharmaceutical Product (CPP)
Quality/Safety/Efficacy known
Innovator known
Yes
No
Available on local market
Yes
Present on List B
No
Consider Innovator
as CPP
Consider obtaining
Innovator: List A
Innovator available
Yes
Consider Innovator
as CPP
No
Consider Market
Leader
Yes
No
Follow compendial
standards approach
Consider Market Leader
Quality of Market Leader known and well-documented
Yes
Consider Market
Leader as CPP
No
Conduct comparative compendial tests
between Multi-source and Market Leader
Acceptable test results
Yes
No
Consider Market
Leader as CPP
43 PAR Seminar October 2002
Consider 2nd Market Leader
WHO - EDM
Drug registration
Some ‘free’ considerations on BE
BE is a scientifically sound concept that has been
applied with varying criteria in different regulatory
systems over the last 38 years
 at the same time, industry has mainly used
dissolution as an indicator of uniformity of
biopharmaceutical characteristics of products at lot
release
 during all this time, reports of ‘therapeutic failures’
have been scarce
 it is likely that implementation of strict BE
requirements is not high priority for countries that do
not fully assess the quality part of MA applications, have
no full market control, cannot ensure GMP compliance,
and cannot monitor raw materials

44 PAR Seminar October 2002
WHO - EDM
National strategies
3. Professional and public acceptance






45 PAR Seminar October 2002
involvement of professional groups
phased implementation
all training by generic name
use of generic names in clinical manuals
brand-generic / generic-brand indexes
public promotional information and activities
WHO - EDM
National strategies
Stages in Generic Substitution - legislative support
for generic substitution may evolve over time
1. No substitution
2. Substitution permitted


brand dispensing assumed
generic may be requested
3. Substitution encouraged


generic dispensing assumed
brand may be requested
4. Substitution required
Increasing generic support
46 PAR Seminar October 2002
WHO - EDM
National strategies
Generic substitution laws can give each party a
voice

Regulatory authority


Prescriber


write ‘no substitution’ by hand on the prescription
Pharmacist - must substitute a generic unless:




declare products as ‘substitutable’ or ‘non-substitutable’
prescriber or patient forbid substitution
retail price of generic is higher than the brand
product has been declared not substitutable
Patient

may forbid generic substitution
47 PAR Seminar October 2002
WHO - EDM
National strategies
Pocket manuals put generic names and brand-generic
lists at health professionals’ figure-tips
 100+ countries have treatment guidelines, formularies
48 PAR Seminar October 2002
WHO - EDM
National strategies
Public education campaigns help professional and
public acceptance to reinforce each other



Posters and brochures
Radio and TV messages
Other media
49 PAR Seminar October 2002
WHO - EDM
National strategies
4. Economic incentives




price information for professionals and the public
retail margins favorable to generics
use of generics for insurers / reimbursement
development of generic industry
50 PAR Seminar October 2002
WHO - EDM
National strategies
Price information - enlightens health
professionals and empowers consumers




relative / absolute price
information in clinical manuals
drug pricing guide
publication of pricing surveys
Using ATC/DDD-based system
to compare prices (e.g. Italy,
Netherlands, Tunisia)
51 PAR Seminar October 2002
WHO - EDM
National strategies
Different types of dispensing margins create
different incentives for rational dispensing

Cost + fixed percentage


Cost + declining percentage


e.g.: cost + 20% for cheaper drugs, declining to 5% for
expensive drugs
Cost + fixed professional fee


e.g.: cost to pharmacist + 20 %
e.g.: cost + $3 professional dispensing fee
Cost + differential professional fee

52 PAR Seminar October 2002
e.g.: cost + $4 for generics, $2 for brand name drugs
WHO - EDM
National strategies
Insurance coverage is everywhere rising - generic
essential drugs are needed for cost control
Established Market6
Economies
Middle Eastern
Crescent
5
4
Transitional Economies
Latin Americas
& Caribbean
3
Asia & Islands
2
1
Sub-Saharan Africa
0
0
10
20
30
40
50
60
70
80
Percentage coverage
of population
Each diamond represents % of population
covered in one country
Source: WHO/DAP Global pharmaceutical expenditures
53 PAR Seminar October 2002
WHO - EDM
90
100
National strategies
WHO supports generic drug use through a
variety of efforts - some examples

Normative support



Generically-oriented drug information




model list of essential drugs
model prescribing information
model formulary of essential drugs
Regulatory support


54 PAR Seminar October 2002
International Non-propriety Names (INN)
International Pharmacopoeia
manual on marketing authorization
support to national regulatory authorities
WHO - EDM
The worldwide role of generic pharmaceuticals
Public health need
National Strategies
Social responsibility
55 PAR Seminar October 2002
WHO - EDM
Social responsibility
Generic pharmaceutical manufacturers and
distributors also have a social responsibility



priority on essential generic drugs
adherence to WHO ethical criteria for drug promotion
help to assure supply of “abandoned” essential drugs



ether for anesthesia
oxaminiquine, metrifonate for schistosomiasis
suramin sodium, pentamidine isethionate for African
trypanosomiasis
56 PAR Seminar October 2002
WHO - EDM
Conclusions
Generics can play an important role in public
health
This role can be optimized through:
-
supportive legislation and regulations
capable and credible regulatory authorities
favorable economic environment
information and advocacy initiatives
Professional and public acceptance
57 PAR Seminar October 2002
WHO - EDM