Pharmaceutical companies

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Pharmaceutical companies HIV/AIDS in
developing settings

• Omar A. Khan, MD MHS

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Overview

• Disclosure
• The magnitude of HIV/AIDS
• Therapeutic and preventive approaches (drugs and
  vaccines)
• Pharmaceutical company involvement
• Some ethical issues in vaccine med trials
  abroad

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Quick facts about HIV/AIDS

• 40 Million
• People living with AIDS
• 5 Million
• New infections last year
• 3 Million
• Deaths due to HIV/AIDS last year

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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

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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

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Reverse Transcriptase Inhibitors (RTIs)

• Non-nucleoside RTIs (NNRTIs)
• Nevirapine (NVP)
• Efavirenz (EFZ)
• Nucleoside RTIs (NRTIs)
• Zidovudine (AZT)
• Didanosine (ddl)
• Stavudine (d4T)
• Lamivudine (3TC)
• Abacavir (ABC)
• Nucleotide RTIs (NtRTIs)
• Tenofovir disproxil fumarate

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AIDS vaccines

• 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)

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Examples of AIDS care components, or , what can
sponsoring organizations do?

• 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

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...so who are these people?

• The UNs 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

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..and what do they do?

• When is 3 x 5 not 15?
• 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.
• WHO aims to coordinate the target of 3 by 5 -
  getting three million people on ART by the end of
  2005.

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..and what do they do?

• 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

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An abbreviated timeline on generic Rx

• 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.
• 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.

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An abbreviated timeline on generic Rx

• 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).

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An abbreviated timeline on generic Rx

• Oct. 03 Clinton Foundation brokers deal with 4
  generic manufacturers (Aspen, Cipla, Ranbaxy,
  Matrix) to start legal generic drug
  manufacturing
• Bristol Myers-Squibb gives up exclusive rights to
  stavudine (d4t) in response to global protests
• The aim is for generic production of AZT,
  lamivudine and nevirapine, to reduce from 10,400
  to 140 per pt per year

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An abbreviated timeline on generic Rx

• 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 dIvoire, 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.

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Issues to consider when providing antiretrovirals

• 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.
• Administrative details
• Storage transport, maintaining the cold chain
• Quality control
• Distribution, administration, DOT for AIDS?

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Issues to consider when providing antiretrovirals

• 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.
• GSK sales 32B. Profit 6B
• Overall HIV pharm sales 406B

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Issues to consider when providing antiretrovirals

• More on cost
• Global Pharmaceutical Market 2002
• Region Revenue Forecast of global
  market
• North America 169.5 billion 41.8
• Europe 100.8 billion 24.8
• Japan 45.8 billion 11.3
• Latin America/Caribbean 30.5 billion 7.5
• SE Asia/China 20.1 billion 5.0
• Middle East 10.6 billion 2.6
• Eastern Europe 7.4 billion 1.8
• Indian subcontinent 7.3 billion 1.8
• Australasia 5.4 billion 1.3
• Africa 5.3 billion 1.3
• CIS 3.2 billion 0.8

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Issues to consider when providing antiretrovirals

• 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.
• Therefore, makes good marketing sense to consider
  the kind of generic when needed deal struck for
  some core drugs already
• 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.

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Research Development budgets by top spenders

• RD Co.________________________
• 2.2B AstraZeneca
• 1.9B Roche, GlaxoWellcome
• 1.8B Merck, Novartis
• 1.6B Bristol-Meyers-Squibb
• 1.4B Hoechst Marion Roussel, Johnson Johnson,
  SmithKline Beecham, American Home Products
• 1B Rhone-Poulenc Rorer, Boehringer Ingelheim

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Recent pharmaceutical industry initiatives

• 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).

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Recent pharmaceutical industry initiatives

• 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."

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Recent pharmaceutical industry initiatives

• 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.

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Recent pharmaceutical industry initiatives

• 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.
• Boehringer Ingelheim will offer Viramune brand
  nevirapine free for a five year period to
  developing countries for prevention of
  mother-to-child HIV transmission.

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Some ethical issues of HIV drug/vaccine trials

• 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?

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Some ethical issues of HIV drug/vaccine trials

• 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?

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Some ethical issues of HIV drug/vaccine trials

• 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.

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Some ethical issues of HIV drug/vaccine trials

• 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?

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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.c
  om/ Gilead Sciences http//www.gilead.com
  GlaxoSmithKline http//corp.gsk.comMerck
  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.co
  m/ Trimeris http//www.trimeris.com/

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