The use of herbal preparations to treat our ills dates back to the earliest human history, and about 80 percent of the world’s people still use plant-derived medicines for basic healthcare needs. Even among modern medicines, some of our most potent therapies have their origins in natural products like plants or soils. Ironically, though, many Western pharmaceutical companies have abandoned the exploration of natural biological products.
The emergence of newer, highly efficient techniques in industrial drug discovery, including high throughput screening and combinatorial chemistry, along with too few recent successes by major pharmaceutical companies in natural product screening, are major reasons for the trend away from natural compounds. What is more, linking external bioprospecting with in-house drug discovery programs is a highly complex process, demanding combinations of a broad range of scientific disciplines. Managing these interfaces inevitably implies longer timelines compared to research activities driven exclusively by synthetically derived compounds. Finally, legal uncertainties surrounding international agreements governing bioprospecting and biodiversity have led some pharmaceutical companies to terminate their natural product exploration programmes. Whether from natural or synthetic sources, drug development is expensive. The research and development process for bringing a new drug to market can take 10 to 12 years and cost up to USD 1.5bn, and only one out of 10,000 compounds, on average, will clear all the hurdles to become commercially available.
One of the major provisions of the Convention is to encourage those who develop and use natural biological resources to responsibly share the benefits with countries and populations from which they get those resources. From the outset, Novartis has been a strong supporter of this provision. Today, in discussing how best to ensure access and benefit-sharing, among other concerns, the natural products research community faces a call for more stringent regulations to govern CBD implementation. Novartis believes the best way to achieve the CBD’s access and benefit-sharing provisions is for countries to introduce national laws facilitating access to their genetic resources and for users and providers to reach agreement on how to share the benefits. This approach would provide governments with the necessary flexibility to preserve their national interests while allowing users to reach agreements suited to individual circumstances.
We believe, however, that a too rigorous regulatory framework would create an additional burden for industrial natural products groups to justify their existence within a portfolio of competing drug discovery technologies. While implementation of the Convention is mandatory and clear rules are needed, our experience with the responsible development of natural products suggests that overregulation would hinder future medical discoveries based on natural sources and, as a consequence, would run counter to the spirit of the CBD. Companies must make large investments and take significant risks in new drug exploration. Success in these types of innovations requires an environment that encourages flexibility, skill and trustful partnerships. Novartis and its predecessor companies, Ciba-Geigy and Sandoz, have developed natural product-based therapies for the past 90 years. Today, Novartis is one of only four major Western pharmaceutical companies with a strong natural product screening and development programme in drug discovery. We continue to build on that tradition with wide-ranging partnerships for sourcing potential biological agents in China, Latin America, Thailand, and parts of Europe and North America.
Public discussions around such programmes often focus unduly on the financial arrangements, such as milestone payments or royalties, while insufficient consideration is given to the importance of capacity building or education. In our experience, it is exactly the latter that are central during the exploration phase of a potential sourcing collaboration. At Novartis, we place a strong emphasis on the education of involved scientists and technicians not only to ensure high quality deliverables but, also, to foster a profound knowledge base at the partner institutes. Whether by organizing drug discovery seminars with Novartis scientists, inviting partners to our natural products research facilities in Switzerland, on-site training courses, or implementing dedicated database systems or analytical technologies, we ensure that capacity building in the countries where we have partnerships is sustainable. We want scientists there to benefit adequately from natural products related knowledge well beyond the expiration of any active collaboration partnership.
Leading by example One such collaboration — with Chinese scientists and the Chinese government — demonstrates the potential benefits of implementing CBD principles in developing new medicines from biological sources. The Novartis product Coartem® — an anti-malaria therapy derived from traditional Chinese medicine — is an extraordinary story of responsibility and commitment. The beneficiaries are millions of malaria patients.
For much of the 20th century, malaria was in decline, thanks to pesticides, mosquito netting and new drugs. However, infection rates began to increase in the 1990s due to growing resistance to existing drugs, reduction in prevention efforts, and deteriorating healthcare systems in some parts of the developing world. More than a million people now die of the disease each year, mostly in Africa. The young are most vulnerable — a child under the age of five dies of malaria every 30 seconds in Africa.
Coartem combines a synthetically created substance called lumefantrine and artemether, a chemically modified active extract derived from Artemisia annua, a herb used to treat various diseases in China beginning more than 2000 years ago. In 1971, this traditional medicine was rediscovered by Chinese scientists and found to be effective in killing the parasite responsible for a particularly virulent form of malaria. It was subsequently combined with lumefantrine to slow the development of drug resistance, and the new product was registered as a single agent in 1992 in China.
Today, Coartem is registered in 81 countries. Funding for developing countries to purchase the treatment at cost has come from the Global Fund to fight AIDS, Tuberculosis and Malaria (1), with the World Health Organization (WHO) managing the distribution. Today, Coartem is a critical component of the WHO Roll Back Malaria Partnership (2).
Sharing the benefits From the outset, Novartis and its Chinese partners realized that benefit-sharing would be at the heart of the Coartem programme. We knew that the greatest need for this medicine would be among the poorest of the poor — so it would need to be provided at cost. We also understood that a unique collaboration would have to be developed among a public organization (WHO), a private company (Novartis), and commercial partners to grow the plants, extract the raw ingredient and manufacture the active substances.
During the development and product rollout of Coartem, more and more farmers were enlisted to cultivate and harvest Artemisia annua. We expanded our circle of partners to include thousands of farmers in China and Africa — enhancing their incomes and standards of living, as well as the economic well-being of their communities. Benefits in technology and knowledge transfer also sprang from the Coartem effort. For example, in the early years of the partnership, capabilities were virtually non-existent in China to extract the active ingredient using good manufacturing practices. Technicians and scientists had to be trained. Over time, knowledge transfer to local partners also occurred in multiple other areas, including chemical production and health, safety and environmental standards.
Once Coartem was approved and technical issues were overcome, the scope of the world’s malaria threat called for a very significant scale-up in the number of treatments produced. Funding for developing countries to purchase the treatments at cost has come from the Global Fund to Fight AIDS, Tuberculosis and Malaria, with the WHO managing the distribution.
A success story The WHO put Coartem on its Model List of Essential Medicines in 2002 and by 2005 large orders began coming in. That year, 9 million treatments were delivered. With a steep increase in investment and capacity, the number rose to 62 million in 2006, helping to save the lives of an estimated 200 000 malaria patients. Pre-financing by Novartis was necessary since Coartem takes 14 months to produce, from the first seed in the ground to tablets coming off the production line. By October 2007, a total of 130 million treatments had been delivered since the beginning of the programme in 2001 — of which 75% are for infants and children. In the first 9 months of 2007, 52 million treatments have been shipped — continuing to save hundreds of thousands of lives.
The Coartem experience demonstrates the value of natural products and the potential for equitable benefit-sharing. We are delighted that our partners in China, both in government and the commercial sector, have understood the need to make this biological resource available at low cost. We are also delighted to have shared the benefits, building up local economies and providing new sources of income for thousands of families.
We have continued to invest vigorously in knowledge transfer, equipment, training, state-of-the-art analytical technologies and good clinical practices to build local capacity. As a result, some of our partners have been able to use the knowledge gained from Coartem for other products and for partnerships with other companies. In China, we continue to collaborate with our initial partner, the Shanghai Institute of Materia Medica, to seek new possibilities for healthcare advances through biodiversity explorations.
Continuing the journey Nature remains a nearly inexhaustible source for new pharmacologically active molecules. We believe that sophisticated new discovery technologies can be used to enhance natural product screening efforts, rather than replacing them. We have learned a great deal from the Coartem experience. We continue to research the next generation of malaria drugs because resistance remains a challenge. And we continue to expand our energies in natural product screening in China, Thailand and elsewhere.
Most importantly, through the Coartem project, we have created a legacy of trust and commitment that goes beyond any financial arrangement. Diseases like tuberculosis and dengue fever still cry out for innovative and effective treatments. We hope to use our knowledge and work with our partners to look for new medical answers from nature. We have helped build capacity, sustainability and a sound future for a number of scientific institutions, commercial enterprises and individuals around the world. But much more than that, we have delivered life-saving medicine to desperate patients in dire need of our help. That is where biodiversity development — done well — can make the greatest difference.
Dr. Frank Petersen is Senior Unit Head, Natural Products and
Dr. Thomas Kuhn is Project Manager, Global Chemical Operations,
Novartis.
(1)
TheGlobalFund.org (2)
Roll Back Malaria Partnership