Transcript Case 8 - Pathology Colloquium

Pharmaceutical companies &
HIV/AIDS in developing settings
Omar A. Khan, MD MHS
Overview
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Disclosure
The magnitude of HIV/AIDS
Therapeutic and preventive approaches (drugs and
vaccines)
Pharmaceutical company involvement
Some ethical issues in vaccine & med trials abroad
Quick facts about HIV/AIDS
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40 Million:
– People living with AIDS
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5 Million:
– New infections last year
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3 Million:
– Deaths due to HIV/AIDS last year
AIDS drugs
"Lack of access to antiretroviral therapy (ART) is a global
health emergency. To deliver antiretroviral treatment to the
millions who need it, we must change the way we think and
change the way we act.”
-- Lee Jong-wook, Director-General, World Health
Organization
AIDS drugs & targets
Entry inhibitors
 Protease inhibitors
 Reverse transcriptase inhibitors (RTIs)
 Integrase inhibitors
 Assembly & budding inhibitors
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Entry Inhibitors
 Act to inhibit fusion
– Eg: Fuzeon (enfuvirtide / T-20)
Protease Inhibitors
– Saquinavir, Ritonavir, Indinavir, Nelfinavir, Lopinavir/
retinavir
Reverse Transcriptase Inhibitors (RTIs)
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Non-nucleoside RTIs (NNRTIs)
– Nevirapine (NVP)
– Efavirenz (EFZ)
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Nucleoside RTIs (NRTIs)
– Zidovudine (AZT)
– Didanosine (ddl)
– Stavudine (d4T)
– Lamivudine (3TC)
– Abacavir (ABC)
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Nucleotide RTIs (NtRTIs)
– Tenofovir disproxil fumarate
AIDS vaccines
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Vaccine trials ongoing, attempted to elicit
immunity by mixing surface proteins (gp120)
from 2 strains of HIV
– AIDSVAX B/B: North America & Amsterdam
– AIDSVAX B/E: Thailand
– ADVAX C: Aaron Diamond AIDS Research
Center & International AIDS Vacine
Initiative (IAVI)
Examples of AIDS care components, or , ‘what can
sponsoring organizations do?’
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Access to testing
Access to counseling
Education & provision of preventive methods
Provision of antiviral therapies
Symptom management, eg pain relief
Social support, material support
Financial and scientific support for research
towards vaccines
…...so who are these people?
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The UN’s various organizations: WHO, UNAIDS
NIH and country-specific governmental
biomedical organizations
The private foundations: eg., The Gates
Foundation, the Global Alliance for Vaccines &
Immunizations, The Rockefeller Foundation,
etc.
The pharmaceutical industry
University-based and independent research labs
…..and what do they do?
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When is 3 x 5 not 15?
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The 3 by 5 Initiative was created since
currently, 6 M people infected with HIV in the
developing world who need antiretroviral
therapy (ART) to survive, of which only 400,000
have access.
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WHO aims to coordinate the target of 3 by 5 getting three million people on ART by the end
of 2005.
…..and what do they do?
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GAVI (Global Alliance for Vaccinations &
Immunizations)
GAVI pharmaceutical partners:
– American Home Products
– Chiron Vaccines
– Berna Biotech (representing smaller vaccine
producers)
– Glaxo SmithKline
– Merck
– Aventis Pasteur
An abbreviated timeline on generic Rx
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2001: Merck & Co and Bristol-Myers Squibb saying they
will sell their anti-AIDS drugs in South Africa at or
below cost. Bristol-Myers considers giving local
companies the green light to override patent laws and
make generic versions of one of the AIDS drugs.
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2002: 5 major pharmaceutical companies reach an
agreement with Central American health secretaries to
reduce the cost of triple therapy AIDS drugs for the
region by up to 55 percent. The agreement "is a
milestone in the history of the AIDS epidemic, both in
Central America and in a global context," said the
statement.
An abbreviated timeline on generic Rx
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2003: South African Competition Commission's
finds GlaxoSmithKline (GSK) & Boehringer
Ingelheim (BI) culpable of charging excessive
prices on antiretrovirals (ARVs) [(lawsuit filed by
Treatment Action Campaign (TAC)].
An abbreviated timeline on generic Rx
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Oct. ‘03: Clinton Foundation brokers deal with 4
generic manufacturers (Aspen, Cipla, Ranbaxy,
Matrix) to start [legal] generic drug manufacturing
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Bristol Myers-Squibb gives up exclusive rights to
stavudine (d4t) in response to global protests
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The aim is for generic production of AZT, lamivudine
and nevirapine, to reduce from $10,400 to $140 per
pt per year
An abbreviated timeline on generic Rx
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Result- triomune (nevirapine and lamivudine mixed
with stavudine) produced by the Indian generic
manufacturer Cipla under WHO ‘one pill’ plan
Countries allowed to import generic medicines produced under
these agreements are: Angola, Benin, Botswana, Burkina Faso,
Burundi, Cameroon, Cape Verde, Central African Republic, Chad,
Comoros, Congo, Côte d’Ivoire, Djibouti, Equatorial Guinea, Eritrea,
Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea Bissau, Kenya,
Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius,
Mozambique, Namibia, Niger, Nigeria, Rwanda, Sao Tome &
Principe, Senegal, Seychelles, Sierra Leone, Somalia, Sudan,
Swaziland, Tanzania, Togo, Uganda, DR Congo (Zaire), Zambia and
Zimbabwe.
Issues to consider when providing antiretrovirals
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The sheer number:
– Per person, 3 meds (assuming one combination tab)
= 1 cap BID = 730 tablets per yr. For 10M positive
people = 7,300,000,000 tablets to be manufactured
+ distributed.
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Administrative details:
– Storage & transport, maintaining the cold chain
– Quality control
– Distribution, administration, DOT for AIDS?
Issues to consider when providing antiretrovirals
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Cost:
– A complex equation: cost of manufacturing relatively
low, but money for testing/development much
higher. Pharmaceutical companies use this to set the
higher (and regionally variable) prices for some of
these medications. WHO (and most of the EU, and
all of the developing world) advocates for generic
drugs, but opposed by US.
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GSK sales: $32B. Profit: $6B
Overall HIV pharm sales: $406B
Issues to consider when providing antiretrovirals
More on cost:
Global Pharmaceutical Market 2002
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Region
Revenue Forecast
North America
$169.5 billion
Europe
$100.8 billion
Japan
$45.8 billion
Latin America/Caribbean $ 30.5 billion
SE Asia/China
$ 20.1 billion
Middle East
$ 10.6 billion
Eastern Europe
$ 7.4 billion
Indian subcontinent
$ 7.3 billion
Australasia
$ 5.4 billion
Africa
$ 5.3 billion
CIS
$ 3.2 billion
% of global market
41.8%
24.8%
11.3%
7.5%
5.0%
2.6%
1.8%
1.8%
1.3%
1.3%
0.8%
Issues to consider when providing antiretrovirals
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77.9% of anticipated global pharmaceutical revenue just two
years from now will come from North America, Europe, and
Japan. Very little revenue generated from the developing
countries where HIV is most common.
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Therefore, makes good marketing sense to consider the kind
of ‘generic when needed’ deal struck for some core drugs
already
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Crucially, the changes in drug/generic policy did not affect
US policy towards Latin American or Asian countries which
also have large and growing epidemics.
Research & Development budgets by top spenders
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R&D $
2.2B
1.9B
1.8B
1.6B
1.4B
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1B
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Co.________________________
AstraZeneca
Roche, GlaxoWellcome
Merck, Novartis
Bristol-Meyers-Squibb
Hoechst Marion Roussel, Johnson & Johnson,
SmithKline Beecham, American Home Products
Rhone-Poulenc Rorer, Boehringer Ingelheim
Recent pharmaceutical industry initiatives
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Bristol-Myers Squibb, makers of Videx (didanosine) and Zerit
(stavudine), has promised $100 million to its "Secure the Future"
program: HIV prevention, treatment, and research programs in a
number of African countries.
Glaxo-Wellcome, the first to announce a price drop for ARTs in poor
countries, has offered to reduce the cost of Combivir (AZT and 3TC)
from $16/day to $2/day. This would still come to $730/year for double
therapy for a single person, which is more than the average annual
income in many countries affected by HIV.
Merck & Co. has provided $3 million to the Harvard AIDS Institute for
its Enhancing Care Initiative (ECI) in Brazil and Senegal. Soon the
program may be expanded to South Africa and Thailand. Merck has
also given $1 million to upgrade the library of the University of Cape
Town Medical School (Merck website 2000).
Recent pharmaceutical industry initiatives
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Merck & Co. has announced a $50 million gift (over 5 years) to
Botswana via the Gates Foundation (which is matching with $50
million).
In a reversal of the ‘one world, one price’ model, Merck may discount
indinavir and efavirenz (Crixivan and Stocrin) to Senegal. The
discounted price may be somewhere between $450 and $1,300.
Roche, makers of zalcitabine (ddC), saquinavir, and Viracept, has also
promised steep discounts under the UNAIDS program. However, they
have not announced any specific figures or places where this will take
place.
Abbott Laboratories developed an agreement with Tanzania in late
June 2000 and is providing "initial grants in Mbeya, an especially poor
region in southwest Tanzania where AIDS is rampant."
Recent pharmaceutical industry initiatives
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Pfizer has agreed to provide free fluconazole (Diflucan) to
South Africans who are diagnosed with cryptococcal
meningitis. However, this offer is restricted to one country
and one AIDS complication. TAC and MSF have demanded
that Pfizer broaden the offer to include treatment for
esophageal candidiasis and to include other poor
countries, or that Pfizer agree to a compulsory license for
a local company to manufacture cheap generic
fluconazole. In the meantime, TAC has imported 5,000
pills of inexpensive Thai fluconazole (Biozole), some of
which it has submitted to the government for quality
control testing.
Recent pharmaceutical industry initiatives
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Roche has begun work with the Clinton Foundation to procure
the supply of HIV- and AIDS-related diagnostic products to
certain Developing Countries.The aim is to cut the costs of key
tests by up to 80 percent for people with HIV/AIDS. The tests
will initially be available in 16 countries, with 2 million at-risk
HIVpeople will be able to benefit from the tests by the year
2008.
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Boehringer Ingelheim will offer Viramune brand nevirapine free
for a five year period to developing countries for prevention of
mother-to-child HIV transmission.
Some ethical issues of HIV drug/vaccine trials
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Testing in developing countries for vaccine
subtypes predominant in the developed world:
– Why not test the vaccine on HIV-infected
individuals in the States?
– Can individuals in other countries litigate?
Some ethical issues of HIV drug/vaccine trials
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How does one get informed consent from
poorly educated individuals?
– Explaining the science
– Equalizing the power gap between provider and
patient
– Should pregnant women/women who may become
pregnant be allowed to participate? If we decide that
they should not, this would constitute a barrier of
access of women to the benefits of trials.
– Should teenagers (currently the group at high risk
but not of a legal age to give informed consent to
trial participation) be allowed to participate?
Some ethical issues of HIV drug/vaccine trials
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What obligations do researchers have to
promote known HIV-prevention strategies
among trial participants?
– Should prevention interventions be offered to trial
participants even if this may affect the outcome of
the trial? i.e. it would not necessarily be clear if the
reduction in infection was due to vaccine efficacy or
behavior change.
Some ethical issues of HIV drug/vaccine trials
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What obligations do researchers have to provide
care to trial participants?
– Will those who become seropositive during their
participation in trials receive care?
– Will the promise of care not available in other settings
constitute undue inducement to participation? E.g.,
Should HAART be offered (Highly Active Antiretroviral
Therapy) when this is not available in the country?
– Should the standard of care offered be the best
available in the country or should it be the (higher)
standard of care available in the sponsoring country?
– Who will finance such treatment? Is it the responsibility
of the pharmaceutical company/sponsor?
Pharma companies with AIDS drugs:
Abbott Laboratories: http://abbott.com
Agouron Pharmaceuticals: http://www.agouron.com/, www.viracept.com/
Bristol-Myers Squibb Company: http://www.bms.com
Du Pont Pharma: http://www.dupontpharma.com/, http://www.sustiva.com/
Gilead Sciences: http://www.gilead.com
GlaxoSmithKline: http://corp.gsk.com
Merck Sharp & Dohme: http://www.merck.com/, http://www.crixivan.com/
Roche: http://www.roche.com/, http://www.roche-hiv.com/
Triangle Pharmaceuticals: http://www.tripharm.com/
Trimeris: http://www.trimeris.com/