Not everyone in the world has enjoyed the benefits of the medical advances now available. There exists a tremendous gap between those in established, industrialized countries and those in developing nations. Many people worldwide lack access to the most basic healthcare, with this burden being greatest in countries overwhelmed by poverty. The difference in the impact of diseases between industrialized and developing nations can be huge, and is compounded by poor healthcare infrastructure and a lack of resources.

Conditions that predominantly inflict severe health burdens on the world’s poorest people are often described as “neglected diseases,” implying the lack of attention that has been paid to tackling them. The World Health Organization (WHO) has estimated that more than one billion people suffer from one or more neglected diseases.¹ Yet, according to figures cited by the TB Alliance, R&D for neglected tropical diseases receives only $1 out of every $100,000 spent worldwide on biomedical research and product development.² This unfortunate situation has attracted much negative media coverage; major pharmaceutical companies now find themselves publicly criticized for not doing more to develop medicines in this area.

Rob Don, director of Drug Discovery and Preclinical Research at the Drugs for Neglected Diseases Initiative (DNDi), outlined how this situation developed: “There was a lack of commercial viability, either as a push (e.g. funding) or pull (e.g. prizes or advance purchasing commitment).”

The industry focus on blockbuster development is also a factor. Dr. Reinaldo Menezes Martins, scientific consultant at Bio-Manguinhos/Fiocruz in Brazil, said, “Drugs for neglected diseases are mainly for underdeveloped countries or poor populations, and do not promise the high return on investment being sought by the multinational companies.”

Professor Charles Mgone, executive director of the European and Developing Countries Clinical Trials Partnership, has a similar view. “Most of these products are destined for disease-endemic countries whose economies are struggling and constitute very little profit, if any, for the pharmaceutical countries to invest cost-effectively in them,” he explained. “This therefore creates lack of commercial interest and motivation from the private sector to develop these products. Ultimately, the main driver for most pharmaceutical companies to develop these products is to bolster their corporate image.”

Derek Ambrosino, a spokesperson for the TB Alliance, gives tuberculosis (TB) as an example. He remarked, “Although TB exists in every country in the world, the majority of cases and mortality occur in the developing world. Since TB is not perceived to be a major health threat in wealthy countries, the market incentives to develop new tools — such as drugs, vaccines, and diagnostics — have been very weak. Therefore efforts to develop urgently needed products to address global health crises like TB were essentially non-existent.”

The Rise of PDPs

Nowadays neglected disease research has become a thriving area, involving collaborative projects across the world. “Many initiatives have come together over time and influential personalities have highlighted the importance of the area,” said Dr. Akira Homma, president of the Policy and Strategy Council at Bio-Manguinhos/Fiocruz.

This view is shared by Dr. Christian Burri, head of the Department of Medicines Research at the Swiss Tropical & Public Health Institute. “A series of events happened, especially in the early 2000s, and that created the right environment for things to fall into place,” he explained. “For example, we had the launch of the Bill and Melinda Gates Foundation and the Millennium Goals being set. There was fantastic momentum in this decade.”

“One of the ways in which progress has been made is through the establishment of Product Development Partnerships (PDPs), such as the TB Alliance,” said Mr. Ambrosino. “PDPs advance products for global health and diseases of poverty by promoting partnerships between the public, private and academic centers. The model is being used for a number of neglected diseases and has lowered the barrier for many organizations, including the pharmaceutical industry, to get involved.”

“No one can still claim that the pharmaceutical industry is avoiding the area of neglected diseases,” stated Dr. Luis Augusto Russo, chief executive officer of CCBR-SYNARC Brazil and president of the APCB-Brazilian Society of Investigators. “Companies are investing a lot of energy, time and money in these partnerships.” Dr. Menezes Martins agreed, noting that R&D in emerging countries has received a new boost from industry involvement.

“EDCTP is already engaging with pharmaceutical partners ranging from Small and Medium Enterprises (SMEs) to big pharma. This relationship has grown from strength to strength and a number of EDCTP projects have been conducted in partnership with the private sector in the period 2008-2010,” said Prof. Mgone. “Because of their central role in pharmaceutical development, the private sector constitutes an important and logical partner for EDCTP to fulfil its primary objective.”

New drug development is a risk-intensive and costly process. According to Tufts Center for the Study of Drug Development (CSDD), the cost of developing a new drug is now about $1.3 billion.³ Therefore it is crucial to involve pharmaceutical companies in PDPs, as they have a track record of being able to transform initial investments into real products. Furthermore, they have systems to measure productivity and are well accustomed to global regulatory processes. “While biotechs are considered nimble for discovery, big pharma are best for full programs,” explained Dr. Burri. “They definitely have the best knowledge of regulatory systems in the northern hemisphere and they are good with logistics.”

Prior to the introduction of PDPs, between 1975 and 1999, the annual rate of new product approvals for neglected diseases stood at 1.8. However, between 2000 and 2009, an era where PDPs became highly active, the annual rate of new product approvals for neglected diseases rose to 2.6.⁴ The impact is also reflected by the fact that, during this period of time, PDPs accounted for a growing share of all regulatory approvals to treat neglected diseases, increasing from 15% to 46%. PDPs have now brought to market 12 products to combat malaria, sleeping sickness, cholera, Japanese encephalitis, meningitis, visceral leishmaniasis and TB in low- and middle-income countries.5 PDPs remain centers of promise, with there being an estimated 150 candidates in their development pipelines, including 32 in late-stage clinical trials.⁵

“Within PDPs, initially, there was a need for other parties to understand how pharma worked — it was never a case of good guys and bad guys,” said Dr. Burri. “Companies have a definite role and the boundaries perceived in the past no longer exist. There are academics who have moved into pharma and pharma people who have moved into PDPs. Tachi Yamada at the Bill & Melinda Gates Foundation is a prime example of this dynamic.” Now president of the Global Health Program at the Foundation, Dr. Yamada was previously a member of the board at GlaxoSmithKline.

The TB Alliance represents an example of how these types of partnerships have prospered. “Previously, pharmaceutical companies were hardly involved in TB R&D on any scale. However, over the past decade, we’ve seen the pharmaceutical industry significantly ramp up their involvement,” said Mr. Ambrosino. “Today, the TB Alliance partners with many of the leading pharmaceutical companies, including Bayer Healthcare, Johnson & Johnson/Tibotec, AstraZeneca, GlaxoSmithKline and Novartis.”

The TB Alliance is also reassessing the R&D approach to TB drug development. It believes that regimen development, where novel combinations of drugs — not single drugs — are developed together to create the best regimens, will become the “gold standard” for rapid, safe and efficient development and testing of new TB treatment regimens. This approach offers the potential to reduce the time previously needed to develop a novel treatment regimen by as much as 75%, shortening the clinical development from decades to years.

Through its partnership with industry, academia and NGOs, DNDi has built a large R&D portfolio for African sleeping sickness, Chagas’ disease, visceral and cutaneous leishmaniasis, pediatric HIV, filariasis and other neglected diseases. “An example of a short-term initiative was the development of fixed dose combination treatments for malaria; one such combination (ASAQ), now available in many African countries, provided 50 million treatments last year,” explained DNDi’s Mr. Don. “The Phase II clinical trials being conducted in Bolivia for the treatment of Chagas disease represent a longer term initiative for us. They involve a drug candidate we licensed from Eisai, which was originally in development as an antifungal drug.”

Within the Swiss Tropical and Public Health Institute, clinical research has evolved into a service provider model. It includes academic teaching, consultancies and CRO-type operations to conduct and project manage clinical trials. This blend of functions has enabled the organization to work internationally. “We had a traditional core of work in Tanzania and the Ivory Coast, but this has extended to run projects all around the world,” related Dr. Burri. “In Africa, we also work in the Democratic Republic of the Congo, Ghana, Uganda and Kenya. We’re also active in southeast Asia, with projects in Laos, Vietnam and Thailand, and we have started preliminary work in India.”

The European and Developing Countries Clinical Trials Partnership (EDCTP) was established by the European Union in 2003 in response to the global health crisis caused by the three major poverty-related diseases (PRDs): HIV/AIDS, tuberculosis and malaria. This is part of the EU’s commitment to achieving the Millennium Development Goals (MDGs). EDCTP supports clinical trials against those major diseases in sub-Saharan Africa.

“Currently, the main focus of the program is to support clinical trials, especially of Phase II and III and to strengthen capacity in sub-Saharan Africa to ensure this takes place using best practice in a sustainable manner,” outlined Prof. Mgone. “For the future, the changes proposed in the second phase of the program (EDCTP-II) include extending the scope to encompass all phases of clinical trials (Phase I to IV, including health service optimization research), and broadening the disease burden scope to include other Neglected Tropical Diseases (NTDs).” EDCTP II is expected to begin in 2014.

It is also important to recognize the involvement of companies from emerging markets in these partnerships, such as in Brazil. “Bio-Manguinhos/Fiocruz is collaborating with a number of international partners, including GlaxoSmithKline, Sanofi-Pasteur and Chembio, but also some Cuban institutions,” said Dr. Menezes Martins. “We have several ongoing projects to develop drugs, vaccines and diagnosis kits for neglected diseases, such as malaria, dengue fever, yellow fever, leishmaniasis, filariasis and schistosomiasis.”

EDCTP is playing a very important role in encouraging the proliferation of partnership-centred networks that transcend the traditional north-south ties and the opening up of new joint ventures. “This initiative has funded the first African Regional Networks of Excellence for clinical trials,” stated Prof. Mgone. “Additionally, EDCTP supports strengthening and in some cases establishing National Regulatory Authorities and ethics review capacities in many African countries, and establishing the Pan-African Clinical Trials Registry (PACTR) as an African initiative funded by EDCTP, which is now officially recognized as a WHO Primary Clinical Trials Registry.”

Other Obstacles

While R&D into neglected diseases is resulting in new treatments, there is no guarantee that patients in countries affected will be able to gain access to them. WHO has estimated that one-third of the world’s population lacks access to essential drugs, with around 50% of people in Africa and Asia lacking access to even the most basic essential drugs.⁶

“Access is a critical issue, as there is absolutely no value in developing a new drug only to have it sit in a warehouse,” stated Mr. Don. “There needs to be buy-in from all those involved in the treatment of patients.” DNDi achieves this through the formation of “independent disease platforms,” a group of people who include representatives from ministries of health, disease control programs, physicians and NGOs in disease endemic countries together with other PDPs and WHO. “We work with these platforms to define target product profiles for the new treatments,” he explained. “They also play a role in training for clinical research and are involved in drug development with DNDi. By doing this we develop appropriate treatments and the end users are comfortable to take on the new treatment.”

Mr. Ambrosino shares a similar view. “The drug development and access equation is a 360° dynamic. Information about patient and provider behaviors, the TB drug market, and attributes of products that drive access must be considered on the R&D side as well,” he argued. “For the TB Alliance, this means we must be developing products that have attributes desired by patients and care providers and that can be properly administered in the context of the health systems of TB-endemic countries.”

“An increased commitment to patients with neglected diseases in their countries is needed, but I am cautious about singling out specific countries because a few comments would not be inclusive of all of the issues regarding access to treatment,” added Mr. Don. “Yet only a very small fraction of patients with Chagas’ disease are treated with existing drugs in Latin America and only a fraction of patients in the Indian subcontinent receive treatment for leishmaniasis. In general, the problem in African countries is more related to poverty and conflict with respect to the diseases in our portfolio.”

There are also other factors to address, as Prof. Mgone noted: “There is very limited networking among scientists and institutions in the disease endemic (developing) countries. Such networking is important in addressing local needs and encouraging more optimal or cost-effective ways of using resources, including co-sharing of facilities and human resources.”

Regulatory Incentives

The introduction of more attractive regulatory mechanisms, to encourage drug development for neglected diseases, has long been argued for. Aside from trying to reduce review timelines, novel regulatory mechanisms are also being developed by some agencies. This has turned out to be a tricky area, since it results in commercial incentives for pharmaceutical companies, and these do not always find favor with the public and media.

For example, FDA can now award a priority review voucher (PRV) to any company obtaining approval for a product that prevents or treats a neglected disease.^7,8 The concept was introduced as part of the 2007 FDA Amendments Act. These vouchers can then be used to accelerate approval of another drug in any disease indication that would not have normally qualified for priority review (Table 2). The financial potential for a company is considerable as use of the PRV could eliminate months from the standard FDA review and this translates into millions of dollars by leading to earlier market entry.^8,9

“It’s an interesting regulatory incentive, as this voucher is transferable and can even be sold to another company,” explained Dr. Burri. “Yet despite the obvious advantages, many companies do not know about this regulatory mechanism. The European Medicines Agency has implemented the so called Article 58 procedure to review marketing applications for products intended to be used only outside the European Community. Whereas this mechanism is very helpful, the incentive to industry is certainly less strong.”

Article 58 dates from 2004 and enables the EMA to give a scientific opinion, in cooperation with the WHO, for the evaluation of medicinal products intended exclusively for markets outside the European region.¹⁰ Products that would qualify for this procedure are those used to prevent or treat diseases of major public health interest, such as for neglected diseases. Even though this regulatory mechanism exists, there have been calls for a European priority review voucher system for neglected diseases along the lines of the U.S. version.¹¹

Duke University economists estimated that in the U.S., the PRV approach could reduce the FDA review process by seven to 12 months, and valued the expedited review at more than $300 million in pre-tax revenues.⁹ The commercial implications caused initial unease among some observers that companies might barter the PRVs in confidential deals and that R&D decisions would not be focused on patient need for new drugs.⁹ Others expressed concern that use of the PRV would not fit the original intention of the priority review designation, since it had been introduced to encourage development of novel drugs where no adequate therapy existed.⁹ They believe that it could be used to accelerate approval for drugs for which there was little or no clinical urgency, while slowing down the approval process for more important drugs on the priority review list.^9,12 Furthermore, eligibility to receive a PRV was not affected if the sponsor decided not to market the product concerned.⁷

In 2009, Novartis benefitted from the PRV system for its anti-malarial drug Coartem (an oral combination of artemether and lumefantrine). The product had been developed in 1996, and had not been previously submitted to FDA.^13,14 There was some criticism in the media that it was subsequently put forward for approval by FDA to take advantage of the PRV mechanism. However, some organizations lobbying for greater research into neglected diseases praised Novartis for submitting the product for approval.¹³ They viewed this as an important step for the new regulatory mechanism to be put into practice. It was recently reported that Novartis had used its PRV to obtain priority review of a supplemental biologic application (sBLA) for Ilaris (cana-kinumab), a humanized antibody.¹⁴ Unfortunately, FDA recommended against approval of the proposed new indication for gouty arthritis.^14,15 This setback has dampened some of the media speculation in the U.S. about excessive commercial gain from use of the PRV mechanism by the pharmaceutical industry.¹⁶

Muted Optimism

Given the progress to date in developing drugs for neglected diseases, it is surprising to find that many experts consider the current situation to be fragile. Bureaucracy and financial commitment from governments and funding organizations are a growing concern for those involved in neglected disease partnerships.

“Slow decision-making at each step is compounding the problem,” worried Dr. Burri. “You almost have to complete your research before receiving funding along the lines of the traditional academic model, but that sort of structured approach won’t work.” In Dr. Burri’s view, this thinking is beginning to affect some of the organisations that have shaped the field. “Even at the Bill and Melinda Gates Foundation, the approach to project evaluation has become slower and narrower,” he commented. “There seems to be an impatience for quick results, but you often need to pursue the project in the hope that it might work. It’s a pity that many of the funders are no longer risk takers.”

DNDi’s Mr. Don remains upbeat about the current challenges regarding neglected disease R&D.
“I am an eternal optimist and believe that we can look forward to elimination of some of these diseases,” he stated. “Nevertheless, I think that a very important issue is sustainable funding. Most funding sources can commit to one-to-three-year timelines and new drug development is a 10-plus-year enterprise.”

These concerns about long-term financing are shared by others. “We are confident in our abilities to overcome the many scientific challenges associated with TB drug development, but in some respects the financial challenges are more imposing,” concluded Mr. Ambrosino. “The past decade’s work has built a global portfolio that includes 10 TB drug candidates undergoing clinical development. Our success has brought us to the more expensive stages of the process. To ensure that today’s innovative science becomes tomorrow’s life-saving technology, we need sustained political will, cross-sectoral engagement and financial support.”

“I’m concerned that in five to 10 years we will lose momentum because of the situation with the global economy,” added Dr. Burri. “Big pharma companies need a lot of money to drive their mainstream R&D, but in the current climate they are suffering and will need to make cuts. They supply a lot of money to the PDPs, but it will be hard for them to justify to investors that this is a core part of their business.”

“Although the situation is improving, there is need to reinforce collaboration among funding agencies, industry and public-private partners,” stated Prof. Mgone. “The development of local capacity in disease endemic countries must to be prioritized by developing countries governments and funding agencies.”

Among those based in emerging markets, some are cautiously optimistic. “I think the picture for neglected diseases is perhaps not so bleak,” said Dr. Luis Augusto Russo. “From a Latin American basis I see very hopeful signs for Brazil, Peru and Colombia in tackling these diseases.”

Dr. Homma sees some opportunity for greater involvement of companies in emerging markets. “Strong economic growth in countries such as Brazil, China, India, Indonesia and South Africa could lead to greater commercial interest from companies to develop drugs for diseases that overlap geographically,” he suggested. “Nevertheless, each country will have to establish their priorities, develop capacities in those areas and decide on feasible partnerships.”

This view is shared by Dr. Luis Augusto Russo, provided that incentives are created. “Emerging markets will need to decrease bureaucracy, such as in their regulatory systems, and offer tax discounts if they want companies to involve themselves in this complex field.”

Whether the momentum to maintain research into neglected diseases at the current level across the world may be slowing, there can be absolutely no doubt that the unmet medical need remains.

“Failure is not an option,” concluded Mr. Ambrosino. “Tackling neglected diseases is not only a moral imperative, but is at the core of some of the world’s foremost questions and concerns, such as global economic development and national security. This is not charity, but an investment in human capital that presents a potential ROI that is off the charts. The key to sustaining our momentum will be the widespread understanding of what global health truly means to the future of our world.”  

References
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2    Anon (2008). Ending the R&D Crisis in Public Health: Oxfam Briefing Paper. http://www.oxfam.org/sites/ www.oxfam.org/files/bp122-randd-crisis-public-health.pdf  
3    CSDD (2011). Drug Developers Are Aggressively Changing the Way They Do R&D. http://csdd.tufts.edu/news/complete_story/pr_outlook_2011
4    Tufts Center for the Study of Drug Development (TCSDD). 2009. “Drug Approvals for Neglected Diseases Increase Along With More R&D Funding.” Impact Report 11 (6), November/December 2009.
5    Anon (2010). Innovative Product Development Partnerships. Policy Brief 26. IAVI. http://www.iavi.org/Lists/ IAVIPublications/attachments/eb7b4247-6816-4094-9f54-9f2f2b99e95a/IAVI_Innovative_Product_Development_Partnerships_2010_ENG.pdf
6    Elliott WS (2006). Access to Medicines and Innovation for Neglected Diseases. UNU. http://www.ias.unu.edu/ sub_page.aspx?catID=35&ddlID=23
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ucm080599.pdf
8    Anon (2011). Priority Review Vouchers. BIO Ventures for Global Health. http://www.bvgh.org/What-We-Do/Incentives/Priority-Review-Vouchers.aspx
9    Kesselheim A (2008). Drug Development for Neglected Diseases — The Trouble with FDA Review Vouchers. N Engl J Med; 359:1981-1983. http://www.nejm.org/doi/full/ 10.1056/NEJMp0806684
10    EMA Article 58. http://regulatoryreference.com/IND/ ema_article_58
11    Ridley DB and Calles Sánchez A (2011). Introduction of European priority review vouchers to encourage development of new medicines for neglected diseases. http://faculty.fuqua. duke.edu/~dbr1/research/eu-prv-pre.pdf
12    Waltz E (2008). FDA launches priority vouchers for neglected-disease drugs. Nature Biotechnology 26: 1315 – 1316. http://www.emilywaltz.com/FDA_priority_review_vouchers___IP_sharing_report_-_Dec_08.pdf
13    Anon (2009). Coartem Earns First Priority Review Voucher. The Global Network for Neglected Tropical Diseases. http://globalnetwork.org/press/2009/4/20/coartem-earns-first-priority-review-voucher
14    Anon (2011). Novartis Plays its PRV Card. BIO Ventures for Global Health. http://www.bvgh.org/News/Blog/PostID/71.aspx
15    Anon (2011). FDA rejects Novartis’ Ilaris for gouty arthritis. Inpharm. http://www.inpharm.com/news/160467/fda-rejects-novartis-ilaris-canakinumab-gouty-arthritis
16    Karst KR (2011). Priority Review Vouchers – Not Much Bang
for the Buck. FDA Law Blog. http://www.fdalawblog.net/ fda_law_blog_hyman_phelps/2011/07/priority-review-vouchers-not-much-bang-for-the-buck.html

Faiz Kermani, Ph.D. is president of the Global Health Education Foundation (www.globalhef.org), a 501(c)(3) a non-profit organization that seeks to rectify the basic inequalities that exist in healthcare across the world. He can be contacted at faiz.kermani@globalhef.org.