Transcript Globalization and Research Ethics in the Multinational

Drug Companies in
Developing Countries: What
Should We Expect?
Joel Lexchin MD
Law 6867
Osgoode LLM Health Law
What is the Nature of a Drug
Company?
Why Are Drug Companies in
Developing Countries?
“I would just be talking rubbish if I
were to say that the multinational
companies were operating in the less
developed countries primarily for the
welfare of those countries . . . They are
not bishops, they are businessmen.”
Spokesperson for the
British pharmaceutical
industry
Outline
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The ethics of clinical trials in developing
countries
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Examples from Nigeria, Latin America
Provision of existing drugs - eflornithine
The research agenda
Promotion of drugs
Intellectual property rights and drug prices
Exporting of pharmaceuticals to developing
countries
Growing Level of Research in
Developing Countries
Clinical Trials in Developing
Countries
Current estimate is 18,000 - 24,000 trials in low
and middle income countries per year
SOMO. Ethics for drug testing in low and middle income countries:
considerations for European Market Authorisation. February 2008
Why Are More Trials Being Done
in Developing Countries?
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Larger pool of sick people
Less red tape & oversight
People sign up faster because of lack of alternatives
Use of placebos--easier to show treatment effect
Research personnel are paid less
Research in India is 50 – 60% less expensive than in
the US
Other estimates are that trials in a first-rate centre in
India are 1/10 the cost of trials in a second-rate
centre in the US
Ethical Approval - Developing
& Developed Countries
Percent of respondents
Developing
Developed
countries
countries
Ethics
committee in
institution
Review body
in institution
58.9
94
41.4
75
Contemporary Clinical Trials 2007;28:677-83
Differences Between IRBs in
Developing Countries and US
Option
Raised by
developing
country IRB
Raised by US
IRB
Need for local language
consent form
72/124 (58%)
27/32 (84%)
Need for letters of approval
from developing country
representatives
53/114 (47%)
26/33 (79%)
Confidentiality protections
for participants not
adequate
22/121 (18%)
13/31 (42%)
On 10 other items no differences between IRBs in developing
countries and US - J Med Ethics 2004;30:68-72
Pfizer, Trovan, Meningitis and
Nigeria
The Body Hunters: As Drug
Testing Spreads, Profits
and Lives Hang in
Balance
Washington Post, Dec. 17, 2000
Pfizer, Trovan, Meningitis and
Nigeria
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Study planned in 6 weeks versus
expected 1 year in USA
Drug never tested before on children
Oral form used
Usual treatment in USA is intravenous
drugs
Company has no signed consent forms
Surfaxin and Latin America
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Discovery Laboratories, Doylestown PA
Synthetic surfactant (Surfaxin)
4 surfactants already on market (first in
1990)
Associated with 34% relative reduction
in neonatal mortality
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“Without doubt the most thoroughly
studied new therapy in neonatal care”
(NEJM)
Surfaxin and Latin America
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“Further placebo controlled trials of synthetic
surfactant are no longer warranted”
(Cochrane Collaboration)
FDA: “Conduct of a placebo controlled
surfactant trial for premature infants with RDS
is considered unethical in the USA”
European trial: Surfaxin vs. approved
surfactant
Surfaxin and Latin America
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Proposed locations for study: Mexico,
Peru, Bolivia, Ecuador
Design: Surfaxin vs placebo (vs
approved surfactant in some settings)
Trials of Natural and Synthetic
Surfactant: 1985-2000
9
8
7
6
No. of trials vs
another surfactant
No. of placebo trials
5
4
3
2
1
0
85 986 987 988 989 990 991 992 993 994 995 996 997 998 999 000
19
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
After 1992 only 2 trials against placebo
Other Trials with Ethical
Problems
Organizations involved range from local
companies to large multinationals
Provision of Existing Drugs Eflornithine
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First developed in France in 1970s by Merrell
1979 usefulness in treating African sleeping sickness
recognized
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About 500,000 infected annually
Subsequently tested by subsidiary of Aventis for use
as cancer agent but results negative
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Only other drug available melarsoprol - caustic arsenical kills 5% of those who receive it
1999 production discontinued
Then found to be effective depilatory for women in
topical form (Vaniqa) & marketing started by BristolMyers Squibb
BMS & MSF reached agreement to supply drug for
sleeping sickness
Drugs for Neglected Diseases 1975-2004
•1556 NCEs
introduced
•21 for
neglected
diseases
Lancet 2006;367:
1560-1
MSF, DND Working Group. Fatal imbalance: the crisis in R&D for
drugs for neglected diseases, 2001
Industry Initiated Research in the
Developing World, 2005
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5 of the top 12 multinationals do not
conduct any research into neglected
diseases
These 5 companies do not want to, and
will not, go back into neglected disease
R&D no matter what incentives are
offered
Moran et al. The new landscape of neglected disease drug development, 2005
WHO Commission on Macroeconomics and Health
The Model is Wrong
"You can't expect for-profit organisation to do
this [produce new drugs for developing
countries] on a large scale. If you want to
establish a system where companies
systematically invest in this kind of area, you
need a different system.”
Daniel Vasella
CEO Novartis
Promotion
IFPMA Code of Pharmaceutical
Marketing Practices
Self-Regulation of Pharmaceutical Promotion:
The international pharmaceutical industry is
committed to the improvement of the health of
mankind through research and development of new
medicines and the production and marketing of
pharmaceutical products of reliable quality, in
accordance with internationally defined standards of
good practice
Code of Marketing Practices
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Introduced 1981, most recent revision 2006
At same time WHO had just passed
International Code of Marketing of Breastmilk
Substitutes & talk of doing same for
pharmaceuticals
Harry Schwartz (defender of industry):
Code an attempt to repel “a coming WHO
effort to impose unacceptable controls over
all pharmaceutical commerce in the Third
World”
IFPMA View of Advertising
IFPMA Web Site:
“Advertising and promotions are an
essential means of alerting prescribers of
the availability and use of new drugs and
new uses for existing medicines”
Promotional Material Collected by
a Malaysian GP in One Month
6 updates on drugs or
treatments, 10 pens, 9
notebooks, 24
brochures, 2 clinical
manuals, 1 plush toy,
multiple packs of two
different drugs, 3
articles, 4 plastic
folders, 5 event
sponsorships and
dinners, 5 small gifts,
1 screening program
Contents of Ads in Medical Journal in
Developing and Developed Countries
Type of
information
Percent of ads containing
information
Developed
Developing
countries
countries
Indications
89
87
Contraindications
61
28
Warnings
55
29
Side effects
64
29
Herxheimer. International Journal of Health Services 1993;23:161-72.
Analysis of Ads to Thai
Doctors, 2003
Percent of ads with information
(n = 207)
Brand
name
Generic
name
100
90
ADR
Cautions References
information
for claims
23
25
52
36/207 ads judged to provide balance of information
38/207 ads misleading
Kiatying-Angsulee et al. Presentation at Second International Conference
on Improving Use of Medications, Thailand, 2004
Comparison of Information in United
States and Brazil Drug Compendia - 44
Top Selling Drugs in Brazil
Criteria
Percent of times criteria missing
United States
(PDR)
Brazil
(DEF)
Adverse effects
5.6
57.2
Interactions
38.8
41.7
Indications
2.3
13.8
Contraindications
8.3
30.5
Overdose
11.1
38.8
Mechanism action
13.8
55.5
Pharmacologic
effect
5.5
41.6
de Barros. Pharmacoepidemiology & Drug Safety 2000;9:281-7
Indian Journal of Dermatology, Veneralogy, Leprology 2005 vol. 71,
Issue 6
IFPMA Code
“It is understood that national laws and
regulations usually dictate the format and
content of the product information
communicated on labelling, packaging,
leaflets, data sheets and in all promotional
material. Promotion should not be inconsistent
with locally approved product information”
Self-Regulation
“IPFMA will continue to support
self-regulation as the most
appropriate mechanism for
regulating marketing and
promotional practices by
companies”
What’s the Penalty?
Adverse Publicity!!!
Intellectual Property Rights
(Patents)
Jonas Salk discoverer of
Polio vaccine
"There is no patent. Can
you patent the sun?"
IFPMA & Intellectual Property
Rights
“Strong patent and other
intellectual property rights are
vital incentives and protection for
innovation, especially in the
pharmaceutical sector”
A Shortsighted View of History
International Prices AIDS Drugs (Circa 1999)
Drug
USA Zimbabwe Tanzania Uganda
Zidovudine
$1.69
$0.91
$2.29
$1.26
Didanosine
$1.82
$1.34
$1.89
$1.31
Zalcitabine
$1.88
$2.00
—
—
Stavudine
$4.56
$4.85
$5.07
$3.15
Lamivudine
$4.33
$3.52
—
$2.74
Nevirapine
$4.25
$5.18
$3.44
$4.72
HIV/AIDS Treatment Need in
Relation to Drug Expenditure
WHO. World
Medicines
Situation, 2004
Generic Competition and the
Price of HIV/AIDS Drugs
TRIPS Agreement & Patents
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20 years protection from time patent
filed
However, provisions in TRIPS for
compulsory licensing
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Ability to produce drug by other companies
while product still protected by patent
Compulsory Licensing & Drug
Prices
Price of lopinavir/
ritonavir offered to
Thailand by Abbott
IFPMA on Compulsory
Licensing
“Compulsory licensing benefits nobody
except the fortunate commercial entity that is the
beneficiary of the largesse offered by such licenses.
In the medium and long-term, it is patients who will
lack new treatments for serious diseases that suffer,
as researchers will undoubtedly stay away from
targeted disease groups subject to CL policies”
Harvey Bale, Director General IFPMA
April 1999
U.K. Commission on
Intellectual Property Rights
“Higher IP standards should not be
pressed on developing countries without
a serious and objective assessment of
their development impact”
IFPMA Response to CIPR
“Most importantly, the report fails
to underline the real needs of
developing countries to have
strong intellectual property
protection”
Canadian Efforts to Promote Generic
Exports to Developing Countries
September 2003
 Canada announced initiative to allow
Canadian generic companies to export to
developing countries
 Response from Harvey Bale, head of IFPMA:
“It won’t solve a thing . . . [It will be a]
negative black eye for Canada [that will] very
well affect the investment climate”
Costs of AIDS Drugs Will
Go Up
Source: DST/AIDS
Estimates of No. of People in
Developing Countries Needing
Second-Line Therapy
Global Disease Burden
WHO - World Health Report 2003
Bullying Developing Countries
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1999
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39 companies launch lawsuit against South Africa
arguing that new medicines law is unconstitutional
because it allows for compulsory licensing
2006
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Novartis challenging Indian patent law that
prevents patenting of trivial improvements of
known molecules
Claimed not consistent with TRIPS
Drug Exports to Developing
Countries
German Drug Exports to
Developing Countries
1321 drugs 1310 drugs 1417 drugs 2179 drugs 2534 drugs
70
67
61
60
53
50
47
39
40
30
61
58
42
39
33
20
10
0
1984/85
1988
1991/92 1997/98
2003
German drugs: poor choices for poor countries. BUKO PharmaKampagne, 2004.
Percent irrational
Percent rational
Some Examples
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Aspirin (Bayer)
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Lesterol (Aventis)
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Germany: “Not for use in children under the age
of 12” (risk of Reye’s syndrome - often fatal liver
disease)
Brazil: Specifically promoted for children
Withdrawn in USA in 1995, in Germany in 1998
Continued to be sold in Brazil until May 2004
Dipyrone (Boehringer Ingelheim)
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Not sold in Canada, Sweden, UK, USA
Marketed in Brazil, Central America, Mexico,
Pakistan, South Africa
Irrational, Non-essential or
Hazardous Drugs, India 1999
Rank
Brand name
Producer
Company
Headquarters
Description
1
Becosules
Pfizer
United States
Irrational vitamin mixture
3
Corex
Pfizer
United States
Irrational cough mixture
9
Liv-52
Himalaya
India
Useless liver drug
11
Dexorange
FrancoIndian
India/France
Blood tonic
12
Digene
Abbott
United States
Needless antacid
17
Combiflam
Aventis
France
Irrational analgesic mixture
20
Polybion
E Merck
Germany
Irrational vitamin mixture
21
Glucon-D
Heinz
United States
Useless nutrients
22
Evion
E Merck
Germany
Irrational vitamin mixture
25
Revital
Ranbaxy
India
Oral ginseng tonic
National Commission on Macroeconomics – Access to Essential Drugs and Medicine
What Should We Expect?
Just what we get!
The primary obligation of pharmaceutical
companies is to their shareholders NOT
to the people of the developing (or
developed) world
I hear a pharma justifying its actions on the grounds
of Humanity, Altruism, Duty to Mankind, I want to
vomit . . . It’s because I’m reading at the same time
how the US pharma-giants are trying to extend the life
of their patents so that they can preserve their
monopoly and charge what they damn well like and
use the State Dept to frighten the Third World out of
manufacturing their own generic products at a
fraction of the price of the branded version.
John LeCarré
The Constant Gardener