Please do a bit of homework before class (and the readings as well - many, but not too difficult!):
Global Health: What is the global burden of the following infectious diseases?

Plus...4 M lower respiratory infections deaths, 700,000 measles, etc...

How does this compare to the 4 top chronic diseases (JAMA, June 2004)- the largest cause of death in the world? [PDF]

Worldwide...	Fatalities / year
Cardiovascular disease	17,000,000
Cancer	7,000,000
Chronic lung diseases	4,000,000
Diabetes mellitus	1,000,000
Total:	~29,000,000

A new idea: a non-for-profit pharmaceutical company: OneWorld Health, funded in part by the Bill and Melinda Gates Foundation, is leading the ' development, testing and manufacture of new drugs against infectious diseases that threaten millions in the undeveloped world'. (NYTimes)

Business Model - One World Health:

A Nonprofit Model For Drug Development...WHY?

"<1% of all drugs developed are designed to treat Tropical Diseases, although these diseases cause >90 percent of the total disease burden worldwide..."

Criteria for Drug Development: The 7 criteria for drug candidates at One World Health:

1. Chemically stable under tropical conditions
2. Ease/cost of synthesis
3. Low toxicity
4. Higher efficacy than currently available
5. Affordability (~$1/day)
6. Clinical need + global impact
7. Ethically developed
   
   

• 1. Nonprofit status. Adopting nonprofit status allows these groups to select development projects without regard to financial returns for investors. Nonprofit companies also are not handicapped by high marketing, advertising, and administrative costs.
  
  
• 2. Intellectual property. Nonprofit drug companies can lessen the costs of the early stages of drug development by adopting promising postdiscovery compounds that have accumulated substantial safety and efficacy data. These compounds may be licensed or donated by the pharmaceutical industry and academe, both of which produce a large number of discoveries that are never used commercially but have applications for the developing world.
  
  
• 3. Affordability and pricing. Multi-tier pricing within a developing country is an important measure to ensure the nonprofit’s sustainability and the affordability of its products. Products developed by the nonprofit for the developing world could be distributed to some sectors with a revenue return (that is, wealthier markets in the developing country), thus subsidizing the no- or low-cost provision of the new therapy for the most vulnerable.
  
  
• 4. Sources of revenue. In the early stages of any such nonprofit venture, the primary source of revenue is likely to come from philanthropies. Other avenues may open as the nonprofit becomes more sophisticated in its operations. As the nonprofit begins to market its drug, its efforts could be financed, in part, by revenues from sales of marketed drugs.
  
  
• 5. Assumption of investment risk/costly activities. By assuming the financial risk for the often early and risky drug development phase, nonprofit drug companies provide incentives for for-profit companies to apply their technical expertise toward creating drugs for neglected diseases—those with anticipated minimal financial returns.

First Success Story: Treatment of Kala-Azar by Paromomycin

• Black fever (0.2 M deaths / year) is the second-largest parasitic killer in the world after malaria (0.5 M deaths / year)
• Enlarges spleen and liver (splenomegaly and hepatomegaly), anemia, chronic fever = systemic infection, nearly 100% fatal,
• Caused by protozoan Leishmania spread by the bite of sand flies that multiply in the cow dung, sap in banana groves and bamboo stands, and thatched roofs.
• Roughly 90 percent of black fever cases worldwide are found Bihar State in India and in Bangladesh, Nepal, Sudan and northeastern Brazil.
• Antibiotic candidates existed but dropped by pharmaceutical companies in the 1960s and 1970s

(1) Problems along the way (text below from One World health and Neglected Diseases NY Times, July 31, 2006)

1. The IRS at first denied the charity nonprofit status, concerned that it looked too much like a for-profit enterprise - 3x over 10 months! (The NPR / PBS model worked!)

2. The World Health Organization, which controlled the drug, was reluctant to hand over the data needed for further development. Why? competition! At the time, the W.H.O was developing another drug for black fever with Zentaris, a large pharmaceutical company, and the Indian government.

• Paromomycin = injection, but very low cost $10 / treatment and very low side effects.
• Competing drug miltefosine = oral treatment, but GI problems in one-third of the patients, must take the full 21-day course of treatment; women of child-bearing age must use birth control; price of $100 to $200 / treatment, = out of reach for most patients and government purchasing programs.

(2) Where the money would come from! Dr. Hale and her husband, Dr. Ahvie Herskowitz put up $100,000, signed a $315,000 promissory note, used the ground floor of their house as offices, and worked without pay for two years. The Gates foundation, which at the time was primarily underwriting vaccines and other preventive strategies, eventually offered a grant of $4.2 million that grew to $46 M: Institute for OneWorldHealth awarded $46 million grant, Nov 1, 2006 = go Bill!

• Much of this latest grant will be used to develop treatments for diarrheal diseases = a leading cause of death in children worldwide, killing more than 2 million children and contributing to the deaths of an additional 4 million children each year. Diarrheal diseases are caused by a wide range of bacterial, parasitic and viral pathogens.
• December 2004 OneWorld Health received a US$42.6 million grant from the Bill and Melinda Gates Foundation
• OneWorld Health hopes to develop to treat childhood diarrhea could be sold to travelers by a for-profit drug maker in exchange for royalties that would help sustain her organization’s charitable work.

(3) And have they succeeded? YES - New cure for deadly visceral leishmaniasis (Kala-Azar) approved by Government of India Sept 8, 2006 - the first time a charity has succeeded in ushering a drug to market.

• The application was based on data from a large Phase III multi-center, randomized and controlled clinical trial of 667 adult and pediatric patients conducted in Bihar State, India, which showed that nearly all patients (94.6%) treated with Paromomycin were cured of VL.
• OneWorld Health will not profit from the drug - it has given a license to Gland Pharma, an Indian drug company that has agreed to manufacture the drug and sell it at cost when it is approved.

(4) Challenges Ahead (text from Oxymoron No More: The Potential Of Nonprofit Drug Companies To Deliver On The Promise Of Medicines For The Developing World Victoria G. Hale, Katherine Woo and Helene Levens Lipton, Health Affairs November 2005)

• Making the transition to a financially self-sustaining model. Currently highly dependent on philanthropic funders (Bill), who are understandably reluctant to fund programs indefinitely, must become financially self-sustaining without compromising the organization’s core mission. Using tiered pricing or a sliding scale reduces risk to the nonprofit and allows for multiple funding streams.
  
  
• Engaging the drug industry. Partnerships with the drug industry are vital for developing, marketing, and distributing drugs and vaccines in the developing world; industry should not be expected to shoulder the entire burden.
  
  
• Sustaining the supply of affordable medicines. Challenge of creating drugs that are inexpensive both to manufacture and to market. Manufacturing will most likely occur in endemic countries, where incentives may maintain local production of drugs with razor-thin margins, or occur through partnerships between nonprofits and large pharmaceutical companies. Innovation at all levels is essential.
  
  
• Distribution. No matter how many drugs or vaccines are developed, delivery to patients in need is cricual. The lack of an adequate public health infrastructure challenges even the most organized groups.
• Example: Paromomycin distribution - ice coolers full of paromomycin delivered on motorcycles?!? Stay tuned

"Challenging the dominant acceptance of global health inequities and promoting the right to health of the marginalized and poor of the world are basic tenets upon which the emerging nonprofit drug company sector is based. Despite the challenges that remain, this innovative model for drug and vaccine development raises hopes that a nonprofit drug company can exist successfully, both as a global health organization and as a business."

• October 02: Nature's Malaria Genome Issue
  
• Opinion: Time to eradicate malaria: Nature, 2 Oct 2002
• Feb 04: Clinical trial of new TB vaccine begins