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 Developed countries
Italy
France (7 - 20%)
Spain
Denmark
UK
United States
Netherlands
Norway

Bulgaria Transitional countries

Czech Rep.
Hungary (15 - 30%)
Croatia
Poland
Estonia
Slovenia
Lithuania

Mali
Egypt
China
Indonesia
Thailand
Tunisia Developing countries
Jordan (24 - 66 %)
Argentina
South Africa

0 10 20 30 40 50 60 70

5 PAR Seminar October 2002 WHO - EDM

 Public health need
The cost of medicine is substantial - number
of working hours to pay full treatment course
Hours And the burden falls heaviest on those least able to
600
500 pay:
500 460 Developed countries: 50-90 % publicly funded
Developing countries: 50-90 % paid out-of-pocket
400
Tuberculosis
300
Shigellosis
200 120 Gonorrhoea
100 100
100 20 20 20 6 1.4 1.4 0.4
0
Tanzania Zimbabwe Thailand Switzerland

Based on average worldwide price and national

per capita income. Source: WHO/DAP
6 PAR Seminar October 2002 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% (43)
2 = 50-80% (64)
3 = 80-95% (30)
4 = >95% (41)
5 = No data available (1)

7 PAR Seminar October 2002 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 Under 5 Age 5 & over

Diarrhoeal disease
Tuberculosis
Measles
Malaria
Tetanus
Pertussis
HIV
Meningitis

NON-COMMUNICABLE DISEASES - A GROWING CHALLENGE

Heart attacks, strokes
Cancer

0 1 2 3 4 5 6

8 PAR Seminar October 2002 WHO - EDM

 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 VELO P ED C O UN TR IE S
D e n m a rk

Un ite d S t a t e s
Un it e d Kin g d o m
G e rm a n y

N e th e rla n d s

Ire la n d

P o rt u g a l

N e w Z e a la n d

J a pa n
F ra n c e

S p a in
D E VE LO P IN G C O UN TR IE S
In do n e s ia

M o ro c c o
P h ilip p in e s

0 10 20 30 40 50 60 70
% prescriptions generic
Source: DAP Global comparative pharmaceutical
expenditures and IGPA
10 PAR Seminar October 2002 WHO - EDM
 National strategies

Price differentials between generic and brand

products vary greatly among countries

Belgium 20%
Italy 20% +
Spain 25%
Germany 25% - 30%
France 25% - 35%
Canada 40% - 50%
UK
80% +
US
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
102,3
market 200

value in US 150 Other

$ billion 64,2 Originator
100
180,2
50
63,5
0
1990 2000

Source: IMS Health, customised study. Data from 52 countries/areas

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 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
High (25)
% of market 40
Middle (23)
by value 30 Low (4)
20
10
0
1990 2000

Source: IMS Health, customised study. Data from 52 countries/areas

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 National strategies
Drug sales 1990 and 2000: originator and licensed
products in high, middle and low income country markets

180
168
160
140
120
market High (25)
100 Middle (23)
value in US 80 Low (4)
$ billion 60 59
40
20
40,5 12
0 0,6
1990 2000

Source: IMS Health, customised study. Data from 52 countries/areas

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 National strategies

Rapidly changing drugs markets

Czech Republic*, 1990 and 2000

100%
8,5
90% 19,7
80%

70% 15,5 44,6

60%

50%

40% 48,6
39,8
30%

20%

10%
16,2
0%
7,1
1990 2000

Unbranded Other brands Origin/licensed status n/a

*2000 Population: 10.3 million
Source: IMS Health, customised study. Data from 52 countries/areas

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 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:
1. Supportive legislation & regulation
50 2. Reliable quality assurance
45 3. Professional, public acceptance
40 4. Economic incentives
35
30
25
20
15
10 Percent of new prescriptions, U.S.
5
0

19 PAR Seminar October 2002 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  Hungary
 Australia  Tunisia
 Canada  USA

21 PAR Seminar October 2002 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-patent-
protected 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:
• 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.

26 PAR Seminar October 2002 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:

 dissolution (in vitro)
 bioequivalence studies (in vivo)
 pharmacodynamic studies (in vivo)
 clinical trials (in vivo)

28 PAR Seminar October 2002 WHO - EDM

 Active
Drug ingredient
registration 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  Lidocaine
 Amitriptyline  Methylphenidate
 Chlormethiazole  Morphine
 Desipramine  Neostigmine
 Dextropropoxyphene  Nifedipine
 Dihydroergotamine  Nitroglycerin
 Diltiazem  Papaverine
 5-Fluorouracil  Pentazocine
 Hydralazine  Phenacetin
 Isoproterenol  Propranolol
 Labetolol  Salicylamide
 Testosterone  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 Acetohexamide Ajmaline Alprenolol Aminophylline
Amiodarone Amitryptyline Atenolol Betamethasone Bevantolol
Bromocryptine Busulfan Butriptyline Captopril Carbamazepine
Cefalexin Cefazolin Chlorambucil Chloramphenicol Chlorpromazine
Chlorpropamide Clomifene Clonazepam Clonidene Conjugated Estrogens
Cyclophosphamide Cyproterone Deslanoside Dexamethasone Diethylstilbestrol
Digitoxin Digoxin Diltiazem Disopyramide Dosulepin
Droperidol Dydrogesterone Enalapril Epinephrine Erythromycin
Ethinylestradiol Ethosuximide Ethylestrenol Felodipine Flecainide
Fluocortolone Fluoxymesterone Flupentixol Fluphenazine Flurazepam
Flutamide Glibenclamide Gliclazide Glipizide Guanfacine
Haloperidol Hydrocortisone Imipramine Isosorb.-5-mononitrate Isosorbide dinitrate
Labetalol Levothyroxine Liothyronine Lithium Carb. Magnesium sulfate
Medroxyprogesterone Mesterolone Metformin Methotrexate Methylergometrine
Methylprednisolone Metoprolol Midazolam Nadolol Nicardipine
Nifedipine Nitrendipine Nitroglycerin Norethisterone Oxandrolone
Oxprenolol Perphenazine Phenytoin Pindolol Prazosin
Procainamide Propranolol Pyrazinamide Quinidine Rifampicin
Temazepam Terazosin Testosterone Theophylline Thioridazine
Thyroglobulin Tocainide Tolbutamide Triamcinolone Triazolam
Trifluoperazine Valproate Verapamil Warfarin

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 :
Http://www.fda.gov
MULTI-SOURCE PHARMACEUTICAL
PRODUCTS, WHO GUIDELINE ON
REGISTRATION REQUIREMENTS
TO ESTABLISH EU:
INTERCHANGEABILITY, 1996

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)

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 Drug registration

Bioequivalence (3)

3 bioavailability
parameters
(including active
metabolites if
applicable):

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 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 Selection of Comparator

PRODUCTS, WHO GUIDELINE ON Pharmaceutical Product for
REGISTRATION REQUIREMENTS Equivalence Assessment of
TO ESTABLISH
Interchangeable Multi-source
INTERCHANGEABILITY, 1996
(Generic) Products,WHO, 1999

42 PAR Seminar October 2002 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 Present on List B

Yes No Yes No

Consider Innovator Consider obtaining Follow compendial Consider Market Leader

as CPP Innovator: List A standards approach

Innovator available Quality of Market Leader known and well-documented

Yes No Yes No

Consider Innovator Consider Market Consider Market Conduct comparative compendial tests
as CPP Leader Leader as CPP between Multi-source and Market Leader

Acceptable test results

Yes No

Consider Market Consider 2nd Market Leader

Leader as CPP

43 PAR Seminar October 2002 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

 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

45 PAR Seminar October 2002 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
 declare products as ‘substitutable’ or ‘non-substitutable’
 Prescriber
 write ‘no substitution’ by hand on the prescription
 Pharmacist - must substitute a generic unless:
 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

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 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)

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 National strategies

Different types of dispensing margins create

different incentives for rational dispensing

 Cost + fixed percentage

 e.g.: cost to pharmacist + 20 %
 Cost + declining percentage
 e.g.: cost + 20% for cheaper drugs, declining to 5% for
expensive drugs
 Cost + fixed professional fee
 e.g.: cost + $3 professional dispensing fee
 Cost + differential professional fee
 e.g.: cost + $4 for generics, $2 for brand name drugs

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 National strategies

Insurance coverage is everywhere rising - generic

essential drugs are needed for cost control
Established Market6
Economies
Middle Eastern 5
Crescent

Transitional Economies
4

Latin Americas 3
& Caribbean

Asia & Islands 2

Sub-Saharan Africa1

0
0 10 20 30 40 50 60 70 80 90 100
Percentage coverage
of population
Each diamond represents % of population covered in one country
Source: WHO/DAP Global pharmaceutical expenditures WHO - EDM
53 PAR Seminar October 2002
 National strategies

WHO supports generic drug use through a

variety of efforts - some examples
 Normative support
 International Non-propriety Names (INN)
 International Pharmacopoeia
 Generically-oriented drug information
 model list of essential drugs
 model prescribing information
 model formulary of essential drugs
 Regulatory support
 manual on marketing authorization
 support to national regulatory authorities

54 PAR Seminar October 2002 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