Nonindustrial Pharmaceutical Research in the BRIC Countries: Lessons for Drug Discovery Partnerships with Academic and Governmental Institutions
Promega Corporation, Madison, WI, USA
Early drug discovery is growing in academic and governmental organizations. The convergence of two powerful drivers has resulted in a shift in early drug discovery from private pharmaceutical companies to academic and governmental organizations. The first is the lack of new chemical entities coming from the existing industrial framework [1], and the second is the desire of governmental agencies to fund translational bioscience research [2]. The outcome has been an explosion in nonindustrial small molecule screening facilities, as well as a number of new government-financed drug discovery programs at public research institutions [3]. These medicinal science resources are often designed to support basic research investigators that have expertise in an important protein target class, but little knowledge of the methods used to develop small molecule modulators of their targets. As these nonindustrial drug discovery programs mature, they have begun to face difficulties related to bringing projects into the drug development pipeline. Challenges related to intellectual property, conflicting organizational missions, transfer of projects to industrial partners, and financial support, are now becoming bigger issues for the public institutions and the industrial partners that are collaborating to bring this new paradigm of therapeutics development to fruition.
BRIC Countries Can Provide a Model for Drug Discovery in Nonindustrial Institutions
While a number of academic laboratories in western industrialized countries have developed new therapeutics, many of the successful drugs were the result of serendipitous discovery by scientists working on more esoteric basic research projects. As public research laboratories take a more deliberate approach in their drug discovery programs lessons can be learned from countries such as Brazil, Russia, India, and China (BRIC) that have a long history of governmentally funded drug programs. Historically, the majority of pharmaceuticals in these countries were produced by government-managed organizations. In the case of Brazil and India, there have been true government-driven drug discovery and development programs since at least the 1950s. In Russia and China, much of the historical investment was in generic drug production; more recently, their interest has shifted to include developing innovative medicines.
The issues faced by the governmental institutions in the BRIC countries trying to develop drugs may be predictive of the ones that will be faced in western countries in the future. These include challenges around managing governmental bureaucracies, developing transition plans to industrial partners, and aligning stakeholder objectives with the expectations of funding sources. The goal of this article is to provide a brief overview of government-financed drug discovery in the BRIC countries in the hope that it provides an understanding of how drug discovery can be performed outside of the industrial process. As western countries look to new models of drug development that include partnerships between industrial and nonindustrial collaborators, the experience of BRIC countries may help model best practices.
Common Drug Development Activities across the BRIC Countries
Before discussing programs in the specific countries, it is useful to understand some of the commonalities across the BRIC countries in terms of their nascent innovative pharmaceutical industries. One key theme in the BRIC countries is that the governments have been the major drivers for developing the pharmaceutical sciences. This is different from western countries, where private companies have driven the evolution of the drug discovery industry. The strategy executed by BRIC countries has resulted in cheap generic drugs being widely available, but has stunted the development of innovative drugs. Recently, all of the BRIC countries have come to understand the importance of having the capability to discover, develop, and produce new pharmaceutical drugs. To provide a competitive opportunity for their programs, the BRIC countries have typically focused their funding efforts on diseases with significant prevalence in their region, or on discovery of drugs from natural products unique to their country. Because the BRIC countries have historically managed their drug development programs within nonindustrial institutions, they are at the forefront of a move by western countries to transfer early discovery research to academic and governmental laboratories.
India
India Was a Pioneer in Nonindustrial Drug Discovery
The first prime minister of independent India, Jawaharlal Nehru, felt that the pharmaceutical industry should be funded by the public sector. To support that strategy, he established the Central Drug Research Institute (CDRI) in Lucknow and Indian Drugs & Pharmaceuticals Limited (IDPL) near New Delhi. Together they were designed to help free India from a dependence on the profit-driven pharmaceutical industry. While the lofty goals set out by Nehru have not been fully accomplished, these two institutions have been successful in laying the groundwork for an indigenous Indian pharmaceutical industry. India has also established a number of other pharmaceutical research institutes designed to provide collaborative opportunities for industrial partners while educating the next generation of drug discovery scientists.
The pharmaceutical industry in India is rooted in its strength in medicinal chemistry related to the manufacture of small molecule generic drugs. This expertise has resulted in India becoming a global center for contract synthesis of new chemical entities with more FDA-approved manufacturing facilities than any country, other than the United States. [4].
IDPL Demonstrates Some of the Challenges Faced by a Publicly Owned Pharmaceutical Company
IDPL was created in the 1960s to provide a publicly owned manufacturing capability for pharmaceuticals important to public health. This has included responding to a plague epidemic in 1994 with the production of tetracycline, and the manufacture of chloroquine to combat a rise in malaria the mid-2000s. In addition, IDPL has been a source of low-cost birth control pills for women and rehydration solutions. Their challenge has been trying to compete in a free market economy against private companies that are not impeded by governmental work rules and political funding decisions. IDPL was envisioned to be financially self-sustaining but has required additional governmental funding support on multiple occasions. An interesting twist is that IDPL created much of its own competition as chemists from its organization moved to private pharmaceutical companies. In fact, IDPL was a key catalyst for the generics industry in India. Today IDPL is operating at significantly reduced capacity relative to its peak when it was India’s largest publicly held corporation [5]. The absence of an academic research component created a lack of purpose for IDPL when it struggled to compete in the marketplace with private companies. It also was unable to garner financial support from programs that have supported basic research missions at other public drug discovery institutions. In the end, IDPL was very successful, if unintentionally, in driving success for the private pharmaceutical industry using public funds. It seems likely that the dollars used to create IDPL have been returned many times over to the Indian government through the taxes generated by private companies that have benefited from the pioneering work done at IDPL.
CDRI Shows the Promise of Publicly Financed Drug Discovery
CDRI was established in 1951, soon after Indian independence, with the intention of creating an indigenous drug research institute that could compete with private pharmaceutical companies. While the full vision may not have been realized, CDRI has been one of the most productive innovative drug discovery institutions in India, private or public, in terms of the number of new drugs developed. More importantly, CDRI’s mission to drive the education of new drug discovery scientists has fertilized many of India’s academic translational research programs and provided the nucleus for innovator drug development in Indian pharmaceutical companies. A number of the scientists trained at CDRI that had done overseas training have now returned to drive early discovery services at contract research organizations (CROs) based in India.
As outlined on the CDRI website, researchers at CDRI have participated in the discovery and/or development of at least 11 existing therapeutic treatments. Drugs developed at CDRI include Centchroman, a nonsteroidal oral contraceptive, Centbucridine, a local anesthetic, and Arteether, an antimalarial. Another outcome of CDRI research has been to bring drug development processes to the study of traditional herbal medicines. This has included the development of a “Standardized Herbal Remedy” termed Bacosides Enriched Standardized Extract of Bacopa (BESEB) that will be marketed as a memory aid and sold under the brand name Memory Sure.
The original strategy of CDRI was to develop compounds up to, and including, early-stage clinical trials. The significant upfront resources required to fund clinical trials, along with the high-risk nature of the investment, limited the number of clinical trials that were sponsored by CDRI. With the construction of their new campus in Lucknow, it appears their focus will be on early discovery and preclinical development.
Public funding for CDRI is through the Council of Scientific & Industrial Research (CSIR). Since the mission of CDRI includes investigating the basic sciences of biological processes important to drug discovery, their contribution is not just measured by pharmaceutical products produced. Scientists at CDRI have produced key publications in medicinal chemistry [6], natural products discovery [7], and preclinical toxicology models [8].
Access to compounds developed at CDRI, or various drug discovery services, are available to collaborators through their business development function. Past collaborations have included western drug companies, Indian pharmaceutical companies, the World Health Organization (WHO), and other public research institutions. CDRI represents one of the more mature organizations available in the BRIC countries for managing public–private partnerships. With a history of successful public–private collaborations, CDRI provides a potential model for other nonindustrial institutions trying to commercialize products developed internally.
Other Academic Drug Discovery Institutions in India Include NIPER and IICT
The National Institute of Pharmaceutical Education and Research (NIPER) has evolved into a multisite program focused on research and education in the pharmaceutical sciences. A central 100+ acre campus is located 250 km north of New Delhi in Mohali. In addition, satellite campuses have been built in Hajipur, Hyderabad, Kolkata, Rae Bareli, Guwahati, and Ahmedabad. Together they provide a national infrastructure to ensure that India has the technology and manpower to be competitive in the global pharmaceutical industry. NIPER is an autonomous institute housed within the Department of Pharmaceuticals, which is in the Ministry of Chemicals and Fertilizers of the government of India. Collaborations between the academic scientists of NIPER and external industrial companies are encouraged. The central animal facility can provide services for approved outside collaborators.
The Indian Institute of Chemical Technology (IICT) in Hyderabad has the broad mission of advancing all the chemical sciences, including medicinal chemistry. A number of scientists at the institute are actively involved in internal drug discovery programs or collaborations with outside companies. IICT actively solicits business development opportunities related to the synthesis of drugs or drug intermediates. Previous clients have included Sami Labs, Nicolas Piramal, Civenti, and Dabur Research Foundation.
Brazil
The Brazilian Technology System (SIBRATEC) Provides a Framework for Public–Private Partnerships in Brazil
Historically, Brazil’s health-care research programs have been heavily invested in improving public health, not developing innovative pharmaceuticals. This has resulted in Brazil becoming a global leader in producing affordable treatments for infectious diseases, especially HIV/AIDS. As per capita income has risen in recent years, the spectrum of health-care issues has shifted to include “western” diseases such as cancer, cardiovascular disease, and diabetes. With these changes has come a realization that the Brazilian government should encourage new drug discovery.
In an attempt to expand Brazil’s efforts in translational research, the government has funded a comprehensive science and technology initiative (SIBRATEC), which includes, as one component, a program for drug discovery. The intention is to help fund the development of promising compounds from academic laboratories through Phase 1 clinical trials, thereby bridging “The Valley of Death.” While the program is too young to have significant completed projects, it does represent a new direction for Brazilian research, one that could help transition the country into a strong contributor to innovative drug discovery.
Brazil’s Drug Discovery Programs Focus on Natural Products Chemistry and Neglected Diseases
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