pharmaceutical companies & hiv/aids in developing settings omar a. khan, md mhs

Pharmaceutical companies &Pharmaceutical companies &HIV/AIDS in developing settingsHIV/AIDS in developing settings

Omar A. Khan, MD MHSOmar A. Khan, MD MHS

DisclosureDisclosure The magnitude of HIV/AIDSThe magnitude of HIV/AIDS Therapeutic and preventive approaches Therapeutic and preventive approaches

(drugs and vaccines)(drugs and vaccines) Pharmaceutical company involvementPharmaceutical company involvement Some ethical issues in vaccine & med trials Some ethical issues in vaccine & med trials

abroadabroad

OverviewOverview

40 Million:40 Million:– People living with AIDSPeople living with AIDS

5 Million:5 Million:– New infections last yearNew infections last year

3 Million:3 Million:– Deaths due to HIV/AIDS last yearDeaths due to HIV/AIDS last year

Quick facts about HIV/AIDSQuick facts about HIV/AIDS

AIDS drugsAIDS drugs

"Lack of access to antiretroviral therapy (ART) is a global"Lack of access to antiretroviral therapy (ART) is a globalhealth emergency. To deliver antiretroviral treatment to thehealth emergency. To deliver antiretroviral treatment to themillions who need it, we must change the way we think andmillions who need it, we must change the way we think andchange the way we act.”change the way we act.”

-- Lee Jong-wook, Director-General, World Health-- Lee Jong-wook, Director-General, World HealthOrganizationOrganization

Entry inhibitorsEntry inhibitors Protease inhibitors Protease inhibitors Reverse transcriptase inhibitors Reverse transcriptase inhibitors

(RTIs)(RTIs) Integrase inhibitorsIntegrase inhibitors Assembly & budding inhibitorsAssembly & budding inhibitors

AIDS drugs & targetsAIDS drugs & targets

Entry InhibitorsEntry Inhibitors Act to inhibit fusion Act to inhibit fusion

– Eg: Fuzeon (enfuvirtide / T-20)Eg: Fuzeon (enfuvirtide / T-20)

Protease InhibitorsProtease Inhibitors

– Saquinavir, Ritonavir, Indinavir, Nelfinavir, Saquinavir, Ritonavir, Indinavir, Nelfinavir, Lopinavir/ retinavir Lopinavir/ retinavir

Reverse Transcriptase Inhibitors (RTIs)Reverse Transcriptase Inhibitors (RTIs)

Non-nucleoside RTIs (NNRTIs)Non-nucleoside RTIs (NNRTIs)– Nevirapine (NVP)Nevirapine (NVP)– Efavirenz (EFZ)Efavirenz (EFZ)

Nucleoside RTIs (NRTIs)Nucleoside RTIs (NRTIs)– Zidovudine (AZT)Zidovudine (AZT)– Didanosine (ddl)Didanosine (ddl)– Stavudine (d4T)Stavudine (d4T)– Lamivudine (3TC)Lamivudine (3TC)– Abacavir (ABC)Abacavir (ABC)

Nucleotide RTIs (NtRTIs)Nucleotide RTIs (NtRTIs)– Tenofovir disproxil fumarateTenofovir disproxil fumarate

AIDS vaccinesAIDS vaccines

Vaccine trials ongoing, attempted to Vaccine trials ongoing, attempted to elicit immunity by mixing surface elicit immunity by mixing surface proteins (gp120) from 2 strains of HIVproteins (gp120) from 2 strains of HIV– AIDSVAX B/B: North America & AIDSVAX B/B: North America &

AmsterdamAmsterdam– AIDSVAX B/E: ThailandAIDSVAX B/E: Thailand– ADVAX C: Aaron Diamond AIDS ADVAX C: Aaron Diamond AIDS

Research Center & International AIDS Research Center & International AIDS Vacine Initiative (IAVI)Vacine Initiative (IAVI)

Access to testingAccess to testing Access to counselingAccess to counseling Education & provision of preventive Education & provision of preventive

methodsmethods Provision of antiviral therapiesProvision of antiviral therapies Symptom management, eg pain reliefSymptom management, eg pain relief Social support, material supportSocial support, material support Financial and scientific support for research Financial and scientific support for research

towards vaccinestowards vaccines

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

The UN’s various organizations: WHO, UNAIDSThe UN’s various organizations: WHO, UNAIDS NIH and country-specific governmental NIH and country-specific governmental

biomedical organizationsbiomedical organizations The private foundations: eg., The Gates The private foundations: eg., The Gates

Foundation, the Global Alliance for Vaccines & Foundation, the Global Alliance for Vaccines & Immunizations, The Rockefeller Foundation, Immunizations, The Rockefeller Foundation, etc. etc.

The pharmaceutical industryThe pharmaceutical industry University-based and independent research University-based and independent research

labslabs

……...so who are these people?...so who are these people?

When is 3 x 5 not 15?When is 3 x 5 not 15?

The 3 by 5 Initiative was created since The 3 by 5 Initiative was created since currently, 6 M people infected with HIV in the currently, 6 M people infected with HIV in the developing world who need antiretroviral developing world who need antiretroviral therapy (ART) to survive, of which only therapy (ART) to survive, of which only 400,000 have access. 400,000 have access.

WHO aims to coordinate the target of 3 by 5 - WHO aims to coordinate the target of 3 by 5 - getting three million people on ART by the end getting three million people on ART by the end of 2005.of 2005.

… …..and what do they do?..and what do they do?

GAVI (Global Alliance for Vaccinations & GAVI (Global Alliance for Vaccinations & Immunizations)Immunizations)

GAVI pharmaceutical partners:GAVI pharmaceutical partners:

– American Home Products American Home Products – Chiron Vaccines Chiron Vaccines – Berna Biotech (representing smaller vaccine Berna Biotech (representing smaller vaccine

producers) producers) – Glaxo SmithKline Glaxo SmithKline – Merck Merck – Aventis PasteurAventis Pasteur

… …..and what do they do?..and what do they do?

2001: Merck & Co and Bristol-Myers Squibb saying 2001: Merck & Co and Bristol-Myers Squibb saying they will sell their anti-AIDS drugs in South Africa they will sell their anti-AIDS drugs in South Africa at or below cost. Bristol-Myers considers giving at or below cost. Bristol-Myers considers giving local companies the green light to override patent local companies the green light to override patent laws and make generic versions of one of the laws and make generic versions of one of the AIDS drugs. AIDS drugs.

2002: 5 major pharmaceutical companies reach 2002: 5 major pharmaceutical companies reach an agreement with Central American health an agreement with Central American health secretaries to reduce the cost of triple therapy secretaries to reduce the cost of triple therapy AIDS drugs for the region by up to 55 percent. AIDS drugs for the region by up to 55 percent. The agreement "is a milestone in the history of The agreement "is a milestone in the history of the AIDS epidemic, both in Central America and in the AIDS epidemic, both in Central America and in a global context," said the statement. a global context," said the statement.

An abbreviated timeline on generic RxAn abbreviated timeline on generic Rx

2003: South African Competition 2003: South African Competition Commission's finds GlaxoSmithKline (GSK) & Commission's finds GlaxoSmithKline (GSK) & Boehringer Ingelheim (BI) culpable of Boehringer Ingelheim (BI) culpable of charging excessive prices on antiretrovirals charging excessive prices on antiretrovirals (ARVs) [(lawsuit filed by Treatment Action (ARVs) [(lawsuit filed by Treatment Action Campaign (TAC)]. Campaign (TAC)].


Oct. ‘03: Clinton Foundation brokers deal with Oct. ‘03: Clinton Foundation brokers deal with 4 generic manufacturers (Aspen, Cipla, 4 generic manufacturers (Aspen, Cipla, Ranbaxy, Matrix) to start [legal] generic drug Ranbaxy, Matrix) to start [legal] generic drug manufacturingmanufacturing

Bristol Myers-Squibb gives up exclusive rights Bristol Myers-Squibb gives up exclusive rights to stavudine (d4t) in response to global to stavudine (d4t) in response to global protestsprotests

The aim is for generic production of AZT, The aim is for generic production of AZT, lamivudine and nevirapine, to reduce from lamivudine and nevirapine, to reduce from $10,400 to $140 per pt per year$10,400 to $140 per pt per year


Result- triomune (nevirapine and lamivudine Result- triomune (nevirapine and lamivudine mixed with stavudine) produced by the Indian mixed with stavudine) produced by the Indian generic manufacturer Cipla under WHO ‘one pill’ generic manufacturer Cipla under WHO ‘one pill’ planplan

Countries allowed to import generic medicines produced under Countries allowed to import generic medicines produced under these agreements are: Angola, Benin, Botswana, Burkina Faso, these agreements are: Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Cape Verde, Central African Republic, Chad, Burundi, Cameroon, Cape Verde, Central African Republic, Chad, Comoros, Congo, Côte d’Ivoire, Djibouti, Equatorial Guinea, Comoros, Congo, Côte d’Ivoire, Djibouti, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea Bissau, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Sao Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Sao Tome & Principe, Senegal, Seychelles, Sierra Leone, Somalia, Tome & Principe, Senegal, Seychelles, Sierra Leone, Somalia, Sudan, Swaziland, Tanzania, Togo, Uganda, DR Congo (Zaire), Sudan, Swaziland, Tanzania, Togo, Uganda, DR Congo (Zaire), Zambia and Zimbabwe. Zambia and Zimbabwe.


The sheer number:The sheer number:– Per person, 3 meds (Per person, 3 meds (assumingassuming one combination tab) one combination tab)

= 1 cap BID = 730 tablets per yr. For 10M positive = 1 cap BID = 730 tablets per yr. For 10M positive people = 7,300,000,000 tablets to be manufactured people = 7,300,000,000 tablets to be manufactured + distributed. + distributed.

Administrative details:Administrative details: – Storage & transport, maintaining the cold chain Storage & transport, maintaining the cold chain – Quality controlQuality control– Distribution, administration, DOT for AIDS?Distribution, administration, DOT for AIDS?

Issues to consider when providing antiretroviralsIssues to consider when providing antiretrovirals

Cost:Cost:– A complex equation: cost of manufacturing A complex equation: cost of manufacturing

relatively low, but money for relatively low, but money for testing/development much higher. testing/development much higher. Pharmaceutical companies use this to set the Pharmaceutical companies use this to set the higher (and regionally variable) prices for some higher (and regionally variable) prices for some of these medications. WHO (and most of the of these medications. WHO (and most of the EU, and all of the developing world) advocates EU, and all of the developing world) advocates for generic drugs, but opposed by US. for generic drugs, but opposed by US.

GSK sales: $32B. Profit: $6BGSK sales: $32B. Profit: $6B Overall HIV pharm sales: $406BOverall HIV pharm sales: $406B


More on cost:More on cost:Global Pharmaceutical Market 2002 Global Pharmaceutical Market 2002

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


77.9% of anticipated global pharmaceutical revenue just 77.9% of anticipated global pharmaceutical revenue just two years from now will come from North America, two years from now will come from North America, Europe, and Japan. Very little revenue generated from Europe, and Japan. Very little revenue generated from the developing countries where HIV is most common.the developing countries where HIV is most common.

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

Crucially, the changes in drug/generic policy did Crucially, the changes in drug/generic policy did notnot affect US policy towards Latin American or Asian affect US policy towards Latin American or Asian countries which also have large and growing epidemics.countries which also have large and growing epidemics.


R&D $R&D $ Co.Co.________________________________________________ 2.2B2.2B AstraZenecaAstraZeneca 1.9B1.9B Roche, GlaxoWellcomeRoche, GlaxoWellcome 1.8B1.8B Merck, NovartisMerck, Novartis 1.6B1.6B Bristol-Meyers-SquibbBristol-Meyers-Squibb 1.4B1.4B Hoechst Marion Roussel, Johnson & Johnson, Hoechst Marion Roussel, Johnson & Johnson,

SmithKline Beecham, American Home ProductsSmithKline Beecham, American Home Products 1B1B Rhone-Poulenc Rorer, Boehringer Rhone-Poulenc Rorer, Boehringer

IngelheimIngelheim

Research & Development budgets by top Research & Development budgets by top spendersspenders

Bristol-Myers Squibb, makers of Videx (didanosine) and Zerit Bristol-Myers Squibb, makers of Videx (didanosine) and Zerit (stavudine), has promised $100 million to its "Secure the Future" (stavudine), has promised $100 million to its "Secure the Future" program: HIV prevention, treatment, and research programs in a program: HIV prevention, treatment, and research programs in a number of African countries. number of African countries.

Glaxo-Wellcome, the first to announce a price drop for ARTs in Glaxo-Wellcome, the first to announce a price drop for ARTs in poor countries, has offered to reduce the cost of Combivir (AZT poor countries, has offered to reduce the cost of Combivir (AZT and 3TC) from $16/day to $2/day. This would still come to 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 $730/year for double therapy for a single person, which is more than the average annual income in many countries affected by than the average annual income in many countries affected by HIV. HIV.

Merck & Co. has provided $3 million to the Harvard AIDS Institute Merck & Co. has provided $3 million to the Harvard AIDS Institute for its Enhancing Care Initiative (ECI) in Brazil and Senegal. Soon for its Enhancing Care Initiative (ECI) in Brazil and Senegal. Soon the program may be expanded to South Africa and Thailand. the program may be expanded to South Africa and Thailand. Merck has also given $1 million to upgrade the library of the Merck has also given $1 million to upgrade the library of the University of Cape Town Medical School (Merck website 2000). University of Cape Town Medical School (Merck website 2000).

Recent pharmaceutical industry initiativesRecent pharmaceutical industry initiatives

Merck & Co. has announced a $50 million gift (over 5 years) to Merck & Co. has announced a $50 million gift (over 5 years) to Botswana via the Gates Foundation (which is matching with $50 Botswana via the Gates Foundation (which is matching with $50 million). million).

In a reversal of the ‘one world, one price’ model, Merck may In a reversal of the ‘one world, one price’ model, Merck may discount indinavir and efavirenz (Crixivan and Stocrin) to discount indinavir and efavirenz (Crixivan and Stocrin) to Senegal. The discounted price may be somewhere between Senegal. The discounted price may be somewhere between $450 and $1,300. $450 and $1,300.

Roche, makers of zalcitabine (ddC), saquinavir, and Viracept, Roche, makers of zalcitabine (ddC), saquinavir, and Viracept, has also promised steep discounts under the UNAIDS program. has also promised steep discounts under the UNAIDS program. However, they have not announced any specific figures or However, they have not announced any specific figures or places where this will take place.places where this will take place.

Abbott Laboratories developed an agreement with Tanzania in Abbott Laboratories developed an agreement with Tanzania in late June 2000 and is providing "initial grants in Mbeya, an late June 2000 and is providing "initial grants in Mbeya, an especially poor region in southwest Tanzania where AIDS is especially poor region in southwest Tanzania where AIDS is rampant."rampant."


Pfizer has agreed to provide free fluconazole Pfizer has agreed to provide free fluconazole (Diflucan) to South Africans who are diagnosed with (Diflucan) to South Africans who are diagnosed with cryptococcal meningitis. However, this offer is cryptococcal meningitis. However, this offer is restricted to one country and one AIDS complication. restricted to one country and one AIDS complication. TAC and MSF have demanded that Pfizer broaden TAC and MSF have demanded that Pfizer broaden the offer to include treatment for esophageal the offer to include treatment for esophageal candidiasis and to include other poor countries, or candidiasis and to include other poor countries, or that Pfizer agree to a compulsory license for a local that Pfizer agree to a compulsory license for a local company to manufacture cheap generic fluconazole. company to manufacture cheap generic fluconazole. In the meantime, TAC has imported 5,000 pills of In the meantime, TAC has imported 5,000 pills of inexpensive Thai fluconazole (Biozole), some of inexpensive Thai fluconazole (Biozole), some of which it has submitted to the government for quality which it has submitted to the government for quality control testing.control testing.


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


Testing in developing countries for Testing in developing countries for vaccine subtypes predominant in the vaccine subtypes predominant in the developed world:developed world:

– Why not test the vaccine on HIV-infected Why not test the vaccine on HIV-infected individuals in the States?individuals in the States?

– Can individuals in other countries litigate?Can individuals in other countries litigate?

Some ethical issues of HIV drug/vaccine Some ethical issues of HIV drug/vaccine trialstrials

How does one get informed consent from How does one get informed consent from poorly educated individuals? poorly educated individuals? – Explaining the scienceExplaining the science– Equalizing the power gap between provider and Equalizing the power gap between provider and

patientpatient– Should pregnant women/women who may become Should pregnant women/women who may become

pregnant be allowed to participate? If we decide that pregnant be allowed to participate? If we decide that they should not, this would constitute a barrier of they should not, this would constitute a barrier of access of women to the benefits of trials. access of women to the benefits of trials.

– Should teenagers (currently the group at high risk but Should teenagers (currently the group at high risk but not of a legal age to give informed consent to trial not of a legal age to give informed consent to trial participation) be allowed to participate?participation) be allowed to participate?


What obligations do researchers have to What obligations do researchers have to promote known HIV-prevention strategies promote known HIV-prevention strategies among trial participants?among trial participants?

– Should prevention interventions be offered to trial Should prevention interventions be offered to trial participants even if this may affect the outcome of participants even if this may affect the outcome of the trial? i.e. it would not necessarily be clear if the the trial? i.e. it would not necessarily be clear if the reduction in infection was due to vaccine efficacy or reduction in infection was due to vaccine efficacy or behavior change.behavior change.


What obligations do researchers have to provide care to What obligations do researchers have to provide care to trial participants?trial participants?– Will those who become seropositive during their participation in Will those who become seropositive during their participation in

trials receive care? trials receive care? – Will the promise of care not available in other settings constitute Will the promise of care not available in other settings constitute

undue inducement to participation? E.g., Should HAART be undue inducement to participation? E.g., Should HAART be offered (Highly Active Antiretroviral Therapy) when this is not offered (Highly Active Antiretroviral Therapy) when this is not available in the country? available in the country?

– Should the standard of care offered be the best available in the Should the standard of care offered be the best available in the country or should it be the (higher) standard of care available in country or should it be the (higher) standard of care available in the sponsoring country?the sponsoring country?

– Who will finance such treatment? Is it the responsibility of the Who will finance such treatment? Is it the responsibility of the pharmaceutical company/sponsor? pharmaceutical company/sponsor?


Abbott Laboratories: hAbbott Laboratories: http://ttp://abbottabbott.com.com

Agouron Pharmaceuticals: Agouron Pharmaceuticals: http://www.http://www.agouronagouron.com/.com/, , www.viracept.com/www.viracept.com/

Bristol-Myers Squibb Company: Bristol-Myers Squibb Company: http://www.http://www.bmsbms.com.com

Du Pont Pharma: Du Pont Pharma: http://www.http://www.dupontpharmadupontpharma.com/.com/, , http://www.http://www.sustivasustiva.com/.com/

Gilead Sciences: Gilead Sciences: http://www.http://www.gileadgilead.com.com

GlaxoSmithKline: GlaxoSmithKline: http://corp.http://corp.gskgsk.com.com

Merck Sharp & Dohme: Merck Sharp & Dohme: http://www.http://www.merckmerck.com/.com/, , http://www.http://www.crixivancrixivan.com/.com/

Roche: Roche: http://www.http://www.rocheroche.com/.com/, , http://www.http://www.rocheroche--hivhiv.com/.com/

Triangle Pharmaceuticals: Triangle Pharmaceuticals: http://www.http://www.tripharmtripharm.com/.com/

Trimeris: Trimeris: http://www.http://www.trimeristrimeris.com/.com/

Pharma companies with AIDS drugs:Pharma companies with AIDS drugs:

pharmaceutical companies & hiv/aids in developing settings omar a. khan, md mhs

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unaids n nih

entry inhibitors n act

hivaids slide

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