Pharmaceutical companies HIVAIDS in developing settings Omar A

Pharmaceutical companies & HIV/AIDS in developing settings Omar A. Khan, MD MHS

Overview n n n 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 n 40 Million: – People living with AIDS n 5 Million: – New infections last year n 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 n Protease inhibitors n Reverse transcriptase inhibitors (RTIs) n Integrase inhibitors n Assembly & budding inhibitors n

Entry Inhibitors n Act to inhibit fusion – Eg: Fuzeon (enfuvirtide / T-20) Protease Inhibitors – Saquinavir, Ritonavir, Indinavir, Nelfinavir, Lopinavir/ retinavir

Reverse Transcriptase Inhibitors (RTIs) n Non-nucleoside RTIs (NNRTIs) – Nevirapine (NVP) – Efavirenz (EFZ) n Nucleoside RTIs (NRTIs) – Zidovudine (AZT) – Didanosine (ddl) – Stavudine (d 4 T) – Lamivudine (3 TC) – Abacavir (ABC) n Nucleotide RTIs (Nt. RTIs) – Tenofovir disproxil fumarate

AIDS vaccines n Vaccine trials ongoing, attempted to elicit immunity by mixing surface proteins (gp 120) 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? ’ n n n n 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? n n n 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? n When is 3 x 5 not 15? n 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. n 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? n n GAVI (Global Alliance for Vaccinations & Immunizations) GAVI pharmaceutical partners: – American Home Products – Chiron Vaccines – Berna Biotech (representing smaller vaccine producers) – Glaxo Smith. Kline – Merck – Aventis Pasteur

An abbreviated timeline on generic Rx n 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. n 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 n 2003: South African Competition Commission's finds Glaxo. Smith. Kline (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 n Oct. ‘ 03: Clinton Foundation brokers deal with 4 generic manufacturers (Aspen, Cipla, Ranbaxy, Matrix) to start [legal] generic drug manufacturing n Bristol Myers-Squibb gives up exclusive rights to stavudine (d 4 t) in response to global protests n 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 n n 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 Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, 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 n The sheer number: – Per person, 3 meds (assuming one combination tab) = 1 cap BID = 730 tablets per yr. For 10 M positive people = 7, 300, 000 tablets to be manufactured + distributed. n Administrative details: – Storage & transport, maintaining the cold chain – Quality control – Distribution, administration, DOT for AIDS?

Issues to consider when providing antiretrovirals n 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. n n GSK sales: $32 B. Profit: $6 B Overall HIV pharm sales: $406 B

Issues to consider when providing antiretrovirals More on cost: Global Pharmaceutical Market 2002 n n n 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. 3% 0. 8%

Issues to consider when providing antiretrovirals n 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. n Therefore, makes good marketing sense to consider the kind of ‘generic when needed’ deal struck for some core drugs already n 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 n R&D $ 2. 2 B 1. 9 B 1. 8 B 1. 6 B 1. 4 B n 1 B n n Co. ____________ Astra. Zeneca Roche, Glaxo. Wellcome Merck, Novartis Bristol-Meyers-Squibb Hoechst Marion Roussel, Johnson & Johnson, Smith. Kline Beecham, American Home Products Rhone-Poulenc Rorer, Boehringer Ingelheim

Recent pharmaceutical industry initiatives n n n 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 3 TC) 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 n n 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 (dd. C), 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 n 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 n 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. n 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 n 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 n 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 n 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 n 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 Glaxo. Smith. Kline: 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/