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HISTORY

Drug Discovery Story
Clinical Trials and Partnerships
Political Concerns
Distribution Challenges
Current Success and the Future

THE DRUG DISCOVERY STORY
In 1975, workers at Merck laboratories were screening compounds for therapeutic effects with the strategy of developing them for veterinary use. They received 54 samples from the Kitsato Institute in Japan including some soil samples obtained from a Japanese golf course, one of which contained a factor with significant antiparasitic effects, which they called Avermectin. The structure of the compound was of a macrocylclic lactone, which is naturally produced in soil by Streptomyces avermitilis. This structure was further modified by reducing a single double bond to decrease its toxicity in animal studies and this new compound was called Ivermectin and marketed under the name Mectizan. While studying the response of equine Onchocerca cervicalis to this compound, Dr. William Campbell, leader of the Merck team and the scientist responsible for the development of thiabendazole, recognized the properties ivermectin possessed suggested its utility against River Blindess caused by the human parasite Onchocerca volvulus. With the encouragement of P. Roy Vaeglos, M.D. president of the Merck Research Laboratories, the company began seriously to consider the potential use of ivermectin in humans.

CLINICAL TRIALS AND PARTNERSHIPS

Human clinical trials began in February 24, 1981 in Dakar, Senegal where the first patient received a single oral dose of Mectizan. Ivermectin proved to be remarkably effective in humans, leading to a hope that the cure for river blindness was possible. As soon as data on the compound's safety and effectiveness became convincing, Merck contacted the World Health Organization (WHO). At first the World Health Organization was not particularly interested in the drug due to its inability to kill adult worms and its own interests in controlling River Blindness through the use of black fly insecticides. However, the continued success of Ivermectin clinical trials and growing ineffectiveness of insecticide use changed the WHO's position so that in 1982, Merck and WHO began a collaborative ivermectin research program under the guidance of Drs. Mohammed Aziz and Kenneth Brown. In the next few years, trials were conducted in Ghana, Guatemla, Cote d'Ivoire, Liberia, Mali, Senegal and Togo. These trials demonstrated that a single annual dose of 150 to 200 micirograms/kilogram of Mectizan effectively reduced the density of microfilaria to near zero after a month and maintained low levels for up to 12 months. These efforts culminated in the approval of the Mectizan in France in 1987. (Approval was not sought in the US at the time because River blindness is not found in the United States) Since that time, ivermectin has proven to be remarkably safe and effective. Ivermectin was approved by the United States Federal Food and Drug Administration (FDA) in 1996 for strongyloidiasis and onchocerciasis. (Elgart and Meinking 2003)

POLITICAL CONCERNS

The development of Ivermectin raised major hurdles around the problem of how affected populations could receive the therapy. Three issues were considered:
1. What price, if any, should be charged for ivermectin?
2. What would be the company's liability if some previously undetected side effects occurred with widespread use?
3. Would donation of this new drug prompt a decrease in research on antiparasitic medications if companies were expected to donate the products of such research efforts?
Merck exhausted all third party payers as intermediaries for donation of ivermectin including the World Health Organization (WHO), the U.S. Agency for International Development (USAID), and the U.S. Department of State. In meetings with both the Deputy Secretary of State and Chief of Staff, Dr. Vagelos was told that the humanitarian effort was worthwhile but no money was available for the program to supply the drug at cost. U.S. Senators Bill Bradley, Frank Lautenberg, Edward Kennedy and Richard Lugar even supported congressional action to sponsor the worldwide distribution of Mectizan. However, no one offered sufficient assistance to meet the need, so at this point in 1987, Merck chairman Dr. Roy Vagelos decreed that Merck would donate Ivermectin-free of charge-to those who needed it for as long as it was needed.(Elgart and Meinking 2003) (Merck website)

DISTRIBUTION CHALLENGE
The challenge for Merck and the World health Organization then became finding a way to distribute Mectizan to millions in the 35 endemic countries that needed it - many of whom had little access to modern means of communication and lived in extreme remote regions. In 1988, Merck announced the formation of the Mectizan Expert Committee, an independent group of experts in tropical medicine and public health. The panel would review and approve applications from non-governmental development organizations, ministries of health and local health agencies for free supplies of the medicine. Applicants had to demonstrate the ability to deliver Mectizan effectively for at least three years, to report serious adverse experiences and to keep accurate records. During the years of its operations, the committee has approved Mectizan for use in 34 or 35 endemic countries in Afrca, Latin America, and Yemen. The committee continuously attempts to improve existing delivery programs. When it deems a program insufficient for approval, it works with applicants to develop a more structured program and distribution system.
In 1988, Merck established The Merck Mectizan Donation Program in conjuction with Dr. William Foege, executive director of The Carter Center in Atlanta. This program monitors the progress of community-based treatment programs approved by the Mectizan Expert Committee and promotes the development of new treatment programs and serves as a liason in the various arms of the relief effort.
From France, Merck ships Mectizan to ministries of health and NGDOs in countries where programs have been established. The logistical, shipping, and custom issues are handled by Merck's office of contributions. The job of health workers in the field of actually delivering these drugs is hampered by harsh conditions in war torn countries lacking the infrastructure to deliver treatment. Considerable work needed to be done to stress the value of Mectizan, an effort led by NGDO in partnership with the Ministry of Health. Today, NGDOs tend to be more involved in information dissemination, education, communication campaigns and overseeing distribution, but not planning or managing it.
In 1994, the board of directors of the World Bank approved a special grant program, The African Programme for Onchocerciasis Control, to raise $130 million over 12 years to help fund NGDOs and local community officials to control onchoceriasis in the 19 countries in Africa not served by the Onchocerciasis Contorl Program. To increase the efficiency and sustainability of Mectizan distribution, Community-Directed Treatment with Ivermectin (CDTI) was introduced by the African Programme for Onchocerciasis Control. This empowering effort allowed communities to organize, direct, and manage their own treatment thereby ensuring program sustainability.
In the Americas, the Onchocerciasis Elimination Program of the Americas was established in 1993 as a multinational, multidonor effort to eliminate onchocerciasis as a publich health threat in Latin America. The Pan American Health Organization believes that it may be possible to eliminate onchocerciasis as a public health problem in some parts of Latin America by 2007.

CURRENT SUCESS AND THE FUTURE
By 2001, 15 years after the program began, more than 30 million people were being treated annually with Mectizan - mainly in Africa, but also in Latin America and Yemen. Villages that were once abandoned due to River Blindness has been reclaimed. In October 1998, Merck expanded the donation of Mectizan to include lymphatic filariasis in African countries where both coexist. Donations are using the same system established for the treatment of river blindness. The Mectizan campaign represents the largest ongoing medical donation program in history. Currently, about 60 million people are being treated with Mectizan a year between the River blindness and Elephantiasis treatment programs.

Information for the history and came from the Merck Mectizan campaign website and speech by Dr. Roy Vagelos at Stanford University. For more information, please check out: http://www.merck.com/about/cr/mectizan/home.html

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