Ethical Aspects of Global Care & Drug Development

Judy Stone, MD

www.conductingclinicalresearch.com

MRSA Infections

Bad Bugs No Drugs

www.idsociety.org

Rise in Drug Resistant Organisms MRSA Resistance/year http://www.cdc.gov/eid/content/13/2/236.htm

Antibiotics Approved Since 1998 Antibiotic

Quinupristin/dalfopristin Moxifloxacin Gatifloxacin

Linezolid

Cefditoren pivoxil Ertapenem Gemifloxacin

Daptomycin

Telithromycin Tigecycline Year 1999 1999 1999

2000

2001 2001 2003

2003

2004 2005 Novel MOA?

no no no

YES

no no no

YES

no no Spellbert et al, CID, May 1, 2004

Perspective The Bad News

 “The End of Antibiotics:” Why?  Clinical trials for antibiotics are more expensive  Efficacy for pathogen and site of infection  Anti-infectives are not as profitable as those for chronic illnesses or life-style drugs  Zithromax generated $2 billion in 2003 vs.

 Lipitor generated $9.23 billion

It gets worse for NTDs…

“between 1975 and 1999,

1,393 new drugs

made . . .

but only 16 were of these were meant for neglected diseases” * (Companies’) “interests are, in general, in danger of being in conflict with what are society's interests.” Pecoul, B. PLoS Medicine Vol. 1, No. 1, e6 doi:10.1371/journal.pmed.0010006

Ethical Issues in Drug Development

Ethical Principles

Nuremberg Trial=> Declaration of Helsinki “Belmont Principles”  calls for respect for: Persons  Individual’s autonomy  Voluntariness of consent 1947 Code 1964 1979

Belmont Principles

 Beneficence  Benefit to the subject/participant  “requires that we protect against risk of harm to subjects…  and be concerned about the loss of substantial benefits that might be gained from research.”  e.g., access to AIDS treatments  Access to treatment of serious and life-threatening illnesses

Belmont Principles

 Justice  That there be an equitable distribution of risks and benefits from research among different populations

Vulnerable Populations

 Institutionalized  Children  foster children and HIV trials  too vulnerable to participate vs. unethical to withhold the potential for benefit  Women/pregnant

Politics of Healthcare -Women

Shift in Perspective:  Protection vs. Paternalism  Feminism; Our Bodies, Our Selves in 1970  Protection vs. denying access to care  groups being subjected to disproportionate risks vs.

 groups being denied access to potential therapies

Politics of Health Care -Religion

 1999, 18 percent of community hospital beds in the United States had religious sponsors provided the inpatient care for more than 5.3 million people in the US.

 70 percent were Catholic  48 (or 8 percent) of these religiously sponsored hospitals are the sole providers of hosp. care

Religious Restrictions

 Contraceptives and family planning  “Plan B,” Emergency contraception  Post-rape counseling/rx  Vaccine development  Women’s participation in clinical trials is limited  Exporting policies overseas (“global gag rules”)

Ethics & Politics-Race

There are some known metabolic differences between men & women => differences in response to drugs. Also differences in intracellular metabolism (e.g., Cytochrome P 450 enzyme) between different races.

So it is important to test drugs in men and women, and different ethnic groups.

But…

Legacy of Distrust

    Tuskegee study  African-American men with syphilis were not treated to follow the “natural history” of disease Foster children/HIV trials   Providing access to best rx or “experimenting” 13,878 children in trials; only ~5% were foster children Oral contraceptives  1980s, 20% of BCP research was done in developing countries Quinacrine sterilization

Sterilization and studies…

 What is the need for new technology?

 Who defines this need?

 What are the social and cultural attitudes about contraception and pregnancy?

 What is the effect of power inequities between men and women?

 Is there coercion by medical providers or gov’t.?

AIDS study survey

 88 % of the women felt they had to participate  ~1/3 feared repercussions if they refused  Almost all unaware they could withdraw from a trial  Inherent coercion from extreme poverty and lack of alternatives, as well as power inequities “Body Hunters” Washington Post 2000

Shifting Research to Developing Countries

What is Driving Move to Developing Countries?

Costs are < 50% More readily available “naïve” patients More compliant patients* Less litigious climate *“Patients in Western countries—and in the United States especially—have an overdeveloped sense of their rights and a fear of being harmed.”

Shifting Research to Developing Countries

 Some illnesses are more common in dev. countries—e.g., meningitis belt and tropical infections  Many developing countries want the financial gains and business from conducting trials

Problems with Overseas Trials

Inadequate or more limited:  protection of human rights  community experience & understanding of research  availability of healthcare and treatment options  ability to provide informed consent  Monitoring is also more difficult.

Ethical Dilemma

Should the absolute standards of care available in more developed countries be applied even when adequate resources are not available in the host country? Or is it perhaps more realistic and ethical to conduct trials with reference to the local standard of care?

Maternal-Fetal HIV Transmission

Should the intervention be compared to the local standard, which may be to do nothing, or to provide another level of care which appears substandard to us?

Ethical Dilemma

Helsinki Declaration requirements revised in 2000, requiring uniform standards:  To provide each participant with the “best current” diagnostic tests and therapy  What if the drugs or interventions may not be the “best” in the world but are better than the locally available treatments?

Distributive Justice Dilemmas

Should gov’t research $ be directed toward basic science research (such as mechanisms of disease) rather than applications?

Should public $ be spent on future drugs or on “designer” drugs that may only benefit a small segment of the population, or on basic public health?

Distributive Justice Dilemmas

Should trials of new medicines or technologies be undertaken where the study population will not be able to benefit afterwards?

e.g., Latin American trials on surfactant Flaherty, Washington Post, 2/23/2001

Developing Countries

  By 2020, US. will have decreased to 4 percent of the world’s population Developing countries will grow to 84 percent Of $2 trillion annual health expenditures:  90% go to the top countries (US, Japan, Europe, Canada, Australia, Hong Kong, Singapore, Israel)

10% resources for 90% of global disease burden

EMBO Rep. 2003 June; 4(Supp1): S35–S38.

United States China * Russia * United Kingdom Japan France Germany India Saudi Arabia South Korea Italy Australia Brazil Canada

Military Spending in $ Billions, 2005

62.5

61.9

51.1

44.7

41.6

30.2

22 21.3

20.7

17.2

13.2

13.1

1 0.9

420.7

43% 6% 6% 5% 4% 4% 3% 2% 2% 2% 2% 1% 1% 1% 1 11 12 13 14 2 3 4 5 6 7 8 9 10

Common Features of the Neglected Tropical Diseases

      “Biblical diseases”-- afflictions that have burdened humanity for centuries Rural areas of low-income countries  2.7 billion people on < $2 per day Disabling and very deforming => stigma Poverty-promoting conditions  Child development; pregnancy; worker productivity No commercial markets for products that target these diseases Interventions, when applied, have a history of success Molyneux, Hotez, and Fenwick PLoS Med 2(11): e336 doi:10.1371/journal.pmed.0020336

Neglected Tropical Diseases



Helminth Infections

 

Soil Transmitted Helminth Infections

   Ascariasis Trichuriasis Hookworm infection

Schistosomiasis

(Bilharziasis)    Lymphatic filariasis (Elephantiasis) Onchocerciasis (River blindness) Dracunculiasis (Guinea Worm)

Neglected Tropical Diseases



Protozoan Infections

 African trypanosomiasis (Sleeping Sickness)  Chagas disease  Kala-azar (visceral leishmaniasis) 

Bacterial Infections



Trachoma

 Leprosy  Buruli ulcer

The Disability-Adjusted Life Year (DALY)

Total amount of healthy life lost, to all causes, whether from premature mortality or from some degree of disability during a period of time

Ranking of Communicable Diseases By DALYs

Disease Burden

HIV-AIDS 84.5 million Neglected Tropical Diseases Hookworm Ascaris Whipworm 56.6 million 22 million 10.5 million 6.4 million Malaria Tuberculosis 46.5 million 34.7 million Hotez, PLOS Medicine 2006; 3: e102

http://www.gnntdc.org/what/poverty.html

Neglected Tropical Diseases



Protozoan

 African Trypanosomiasis

Sleeping Sickness

50-70,000 infected (500,000 in 1998) www.stanford.edu



Chagas Disease

American Trypanosomiasis Central and South America: 16-18 million infected, 50,000 deaths/yr cardiomyopathy who.int/ map: wikipedia



Leishmaniasis

 Sandflies 12 million infected  2 million new cases/yr  1.5 mill skin  0.5 mill visceral  (Kala azar) www.who.int/ Pt. Pics: Judy Stone

Neglected Tropical Diseases



Soil-transmitted Helminths

   Ascariasis (round) Trichuriasis (whip)

Hookworm

Despommier, Gwadz, Hotez, Knirsch, Parasitic Diseases 5 th Edition and www.sabin.org/

Helminth Infections

Ascaris:

1.2 billion

people infected; 600,000 deaths/yr Trichuriasis: 800 million; 10,000 deaths/yr Hookworm: 600 million; 65,000 deaths/yr

Helminth Infections

Rx with Albendazole or Mebendazole only 1-3 x/yr improves nutrition & health=> Increased ability to learn and earn => Helping break the cycle of poverty

Why have we waited?

Lymphatic Filariasis(Elephantiasis)

 120 million cases  40% in India; 33% in Africa   5 million DALYs $2 billion+ in lost productivity  Rx: DEC + Albendazole 1x/ yr or Ivermectin + Albendazole 1x /yr

Mosquito

+

Wuchereria bancrofti

=

www.filarisis.org

www.who/int

http://www.gatesfoundation.org/GlobalHealth/Pri_Diseases/OtherInfectiousDiseases/Other_Infe c_Backgrounder.htm

Schistosomiasis

200 million people infected 200k deaths/yr => incr. in HIV Bloody urine Bladder cancer Increased susceptibility to HIV Schistosoma eggs in bladder wall (CDC) Rx: Praziquantal x 1 dose 20-25 cents Photos: www.who/int map: geo.arc.nasa.gov

Onchocerciasis

(River Blindness)

18 million people infected=> severe rash and blindness (270k blind, 500k impaired)

Rx: Ivermectin

60 million doses/yr donated by Merck (filaria and river blindness) Map from PlosMed 3(9): e371;"Africa Recovery, United Nations" www.un.org

WHO/Mark Edwards

Up to 50% of adult males may be blinded… www.who/int

Guinea Worm (Dracunculiasis)

www.who.int/ ; map tmcr.usuhs.mil

Guinea Worm



Rx: Clean water Filters

 Norsk Hydro: > 9 million pipe filters  du Pont: nylon   Larvicides (Abate)  BASF, Am Home Products, etc Manual extraction  Johnson& Johnson Very successful progress: See Carter Center for info www.cartercenter.org

NTDs-Bacteria

Leprosy Mycobacterium leprae Pic:: Judy Stone

Buruli Ulcer

Mycobacterium ulcerans Map and Photos: WHO/ Dr. Chauti ; Dr. Y. Lugor; Dr. Johnson

Trachoma

Chlamydia trachomatis ~ 10% of population is at risk 84 million with active disease (360 million in 1985) 8 million blind productivity lost est. at US $2.9 billion per year www.nei.nih.gov/photo/star/STAR09_thumb.jpg

Why America Must Care about Tropical Medicine

 Emerging infections with globalization  Cholera, Diptheria, Measles; Cyclospora/outbreaks from imported food; TB; MDR bugs, Chagas Guerrant, R. Am. J. Trop. Med. Hyg., 59(1), 1998, pp. 3–16

Emerging Infectious Diseases

http://www3.niaid.nih.gov/about/overview/planningpriorities/strategicplan/emerge.htm

2000

Why America

Must

Care…

 Exploding population, especially of the impoverished  Erosion of our humanity and moral leadership  Haves vs. have-nots Guerrant, R. Am. J. Trop. Med. Hyg., 59(1), 1998, pp. 3–16

Development Assistance as % of GNP

Guerrant, R. Am. J. Trop. Med. Hyg., 59(1), 1998, pp. 3–16

US overseas aid for development

Guerrant, R. Am. J. Trop. Med. Hyg., 59(1), 1998, pp. 3–16

“perhaps for the first time in human evolution, we can begin to perceive the

survival advantage of caring about the other person,

the poor in the tropics.” Guerrant, R. Am. J. Trop. Med. Hyg., 59(1), 1998, pp. 3–16

“Rapid Impact Package” for NTDs

Albendazole or Mebendazole Diethylcarbamazine or Ivermectin Praziquantal Azithromycin

only 4 drugs Treats 7 NTDs:

Helminths (Ascaris/Hookworm/Whipworm) Schistosomiasis Filariasis River Blindness Trachoma

+ = It’s Smart Rapid Impact Package

Including Drugs Delivery Equipment Distribution costs Health education materials Training Monitoring and evaluation and just the right thing to do…

Treating NTDs Costs: 40 cents/per person/yr

Only $200 million/yr, treats 500 million people What are we waiting for?

Molyneux, Hotez, Fenwick. DOI: 10.1371/journal.pmed.0020336.g002

Collateral Benefits 􀂃 Worm Control Skin disease Reduced 􀂃Blindness Prevented Control of Malaria and HIV/AIDS Anemia Prevalence reduced

Lower maternal-infant mortality

􀂃Nutritional Status improved Growth Enhanced Improved educational performance Improved economic performance

Less time lost from school and work Better earning capacity cost effective return on investment

􀂃 All of this, for < 50 cents/per person/year.

Why haven’t we done this?

Priorities

 Few drugs for sleeping sickness:  Suramin, Pentamidine, Melarsoprol (arsenic deriv),  Eflornithine  Aventis stopped production of IV eflornithine in 1999 due to lack of profit  2001 production resumed after agreement with WHO and Doctors Without Borders

vs:

Vaniqa ad*: “What a burden that has been lifted from my life! I feel so free now to be who I really am. I’m not at all self-conscious with people.” *Vaniqa website 9/11/2004; accessed with wayback machine 2/21/07

Vaniqa

$1-2/day for Vaniqa

Priorities

Viagra

$2-3/dose Value Pak- “Buy 3, get 1 free” “Want to improve your sex life?” AIDS Healthcare Foundation sues Pfizer 1/07 for ads promoting sex=> incr. STDs (and HIV)

Disparities

1 latte or 1 “little blue pill”

vs.

$ to feed 3 people for 1 day

Lifestyle drugs

Justice?

vs < 50 cents/ per person/ per year to control 7 major NTDs

Cosmetic Expenditures

$35 billion/yr in US Or > $100/person/yr

vs.

< 50 cents/ per person/ http://www.flickr.com/photos/yoshie231/386003324/ http://www.cfsan.fda.gov/~comm/cp29002.html

per year to control 7 major NTDs

Perspective

News Flash!

New marriage =>malaria drug combo

“ASAQ”—artemisinin + amodiaquine Adults 2 pills/day x 3 days< $1 Kids 1 pill/day x 3 days < $0.50

Partnership:

Sanofi-Aventis selling drug at cost to WHO, etc.

not seeking patents sliding scale for public Doctors Without Borders Drugs for Neglected Diseases Initiative NYTimes 3/1/2007

Bednets and Bactrim Beats Malaria

300 HIV + kids; 519 HIV – In the HIV + kids: Prophylactic Bactrim reduced malaria 35% Bednets reduced malaria 44% Bactrim + bednets => 97% reduction!

SF Chronicle 2/28/07

Why are we not doing more?

http://www.gnntdc.org/resource/conf_rsc/docs/(13a)%20PPPs%20Panel_Amazigo.pdf

-"...let us recognize that extreme poverty anywhere is a threat to human security everywhere. Let us recall that poverty is a denial of human rights. For the first time in history, in this age of unprecedented wealth and technical prowess,

we have the power to save humanity from this

shameful scourge.

Let us summon the will to do it."

-- Kofi Annan

Bill & Melinda Gates Foundation

$1.5 billion for vaccine preventable diseases 2006 new pledge: $ 68 million for: Leishmania vaccine Hookworm vaccine Leishmania and Trypanosome therapies PLoS Neglected Tropical Diseases

Whatever you choose to do, Support Research

Remember and Work for the Forces of Good

For more information, see

Global Network for Neglected Tropical Diseases http://www.GNNTDC.org

References

MolyneuxDH, HotezPJ, Fenwick A.

PLoSMedicine 2005; 2: e336 HotezPJ, MolyneuxDH, et al PLoSMedicine 2006; 3: e102 Guerrant, R. Why America Must Care about Tropical

Medicine. Am. J. Trop. Med. Hyg., 59(1), 1998, pp. 3–16

References, cont.

WHO: WHO_CDS_NTD_2006.2_eng.pdf

“Hidden successes, emerging opportunities” http://www.who.int/neglected_diseases/en/ WHO: Intensified control of NTD, 2006

Global Network for Neglected Tropical Diseases

      

http://www.GNNTDC.org

Schistosomiasis Control Initiative www.schisto.org

Trachoma Initiative Liverpool School www.trachoma.org

www.filariasis.org

Human Hookworm Vaccine Initiative www.sabin.org

Earth Institute @ Columbia University Task Force for Child Survival www.taskforce.org

Gates Foundation

The End

Extra slides if time permits:

Return on Investment of 15-30%

Cost-effectiveness of interventions: cost per DALY gained Helminth infections

Community or school-based deworming

Diarrhoea

Water supply hand pump or stand post House connections Basic sanitation

HIV/AIDS

Antiretroviral treatment Prevention US$ 6–33 US$ 94 US$ 223 US$ 270 US$ 1000 US$10 Childhood diseases Immunization (basic 6) US$ 15 David Canning, Harvard; WHO_CDS_NTD_2006.1_eng.pdf

http://whqlibdoc.who.int/hq/2006/WHO_CDS_NTD_2006.3a_eng.pdf

DOI: 10.1371/journal.pmed.0020336.t003

http://www.gnntdc.org/what/current_efforts.html

Military expenditure comparison

A comparison of the budgets for the world's greatest military spenders. Note that this comparison is done in nominal value US dollars and thus is not adjusted for purchasing power parity

Ascaris. Gnttdc.org

http://www.gnntdc.org/resource/conf_rsc/docs/(13a)%20PPPs%20Panel_Amazigo.pdf

http://www.gnntdc.org/resource/conf_rsc/docs/(16)%20WHO%20Presentation_Preventive%20C hemotherapy.pdf

http://www.gnntdc.org/resource/conf_rsc/docs/(16)%20WHO%20Presentation_Preventive%20C hemotherapy.pdf

http://www.gnntdc.org/resource/conf_rsc/docs/(16)%20WHO%20Presentation_Preventive%20C hemotherapy.pdf

Stages of Drug Development

Preclinical 1000 candidates Phase 1 5 drugs Phase 2 Phase 3 Phase 4 1 drug

    Phase 1=> safety and pharmacokinetics  20-100 pts Phase 2 => Efficacy  Hundreds of patients over 2-3 years Phase 3 =>Efficacy and Safety over broader indications  Thousands of patients over 2-4 yrs Phase 4 =>Post-marketing studies

Timeline of Drug Development

Onchocerciasis