Final Report Summary - ATP (Access to Pharmaceuticals)
This project (Access to Pharmaceuticals, ATP) concerned issues of intellectual property (IP) management in academic environments and specialised public-private partnerships known as product development partnerships (PDP), and specifically the management of IP to enhance access to essential health technologies for the poor in developing countries. Another aspect was the use of TRIPS (Trade Related Aspects of IP Rights) flexibilities, particularly compulsory licensing (CL) to enhance access to life saving drugs that are protected by patents and unaffordable. The methodology for the research involved a) survey of background literature and analysis of new developments as they happened, b) extensive interviews and surveys conducted amongst the global stakeholder community and professionals from both the public and private sectors involved in these issues and c) compiling both qualitative and quantitative data to arrive at conclusions. The conclusions reached as described below as a summary are intended to influence policy towards access to essential lifesaving medicines in developing countries. A number of peer reviewed publications produced by the ATP consortium and a practical guide on socially responsible licensing for technology transfer professionals has far more detail and more useful for policymakers and the general public, given the complexity of these topics. These are:
• Socially Responsible Licensing Guide for Technology Transfer Offices (2013). Available through the ATP consortium website: www.accesstopharmaceuticals.org
• Loyse A, Thangaraj H, Easterbrook P, Ford N, Roy M, Chiller T, Govender N, Harrison TS, Bicanic T (2013). Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. Lancet Infectious Diseases. 13(7):629-637
• Stirner B, Thangaraj H. (2013). Learning from practice: compulsory licensing cases and access to medicines (part 2). Pharmaceutical Patent Analyst. 2(2), 195–213
• Ma J, Paul Christou P, Chikwamba R, Haydon H, Paul M, Pujol Ferrer M, Ramalingam S, Rech E, Rybicki E, Wigdorowitz A, Yang D and Thangaraj H. (2013). Realising the value of plant molecular pharming to benefit the poor in developing countries and emerging economies. Plant Biotechnology Journal. 11(9):1029-33
• Parisi C, Rodríguez-Cerezo E, Thangaraj H (2013). Analysing patent landscapes in plant biotechnology and new plant breeding techniques. Transgenic Research. 22(1):15-29
• Stirner B. (2012). Learning from practice: compulsory licensing cases and access to medicines. Pharmaceutical Patent Analyst. 1(5), 555–575
• Mahoney R. (2011). Product Development Partnerships: Case studies of a new mechanism for health technology innovation. Health Research Policy and Systems. Health Res Policy and Systems 9:33 (doi:10.1186/1478-4505-9-33)
• Busang R, Boisjoly-Letourneau K, Mulder M, Fourie B, Schiermeier A, Thangaraj H. (2011). Socially responsible licensing of health technologies: Policy practice in South Africa. Journal of the Licensing Executive Society International (les Nouvelles). June, 2011 – Volume XLVI No. 2. 69-77
• Paul M, van Dolleweerd C, Drake PM, Reljic R, Thangaraj H, Barbi T, Stylianou E, Pepponi I, Both L, Hehle V, Madeira L, Inchakalody V, Ho S, Guerra T, Ma JK.(2011). Molecular Pharming: future targets and aspirations. Human Vaccines. 7(3):375-82
• Drake PM and Thangaraj H. (2010). Patents and molecular farming. Book Chapter 1 in: Plant Derived Vaccines: Technologies & Applications. Editor: Franco M Buonaguro. Publisher: Future Medicine Group (London)
• Drake PM, Thangaraj H. (2010). Molecular farming, patents and access to medicines. Expert Review of Vaccines. 2010 Aug;9(8):811-9
Project Context and Objectives:
Project context and objectives
Equitable access to pharmaceuticals, particularly for developing countries is an essential human right. Various complex impediments hinder access, which is the subject of ongoing multidisciplinary studies. New health technologies are needed on a continuing basis for the poor in Low and Middle Income Countries (LMIC, as defined by the World Bank). Access barriers include weak health systems, the high cost of many pharmaceutical products, resource and technological capacity constraints, lack of market incentives, market failures and intellectual property (IP) barriers. In addition there are inadequate or no technologies that can potentially address specific disease burdens in LMICs. If promising technologies, such as improved drugs suited for resource constrained settings, exist they often do not progress to full commercialisation due to perceived poor returns on investment. The private sector is often unwilling to commit resources to R&D due to insufficient market demand to develop new products.
Intellectual property regimes incentivise companies and other entities to undertake risk and invest in R&D. Increasingly, public funded research organisations across the globe aim to commercialise their research, often through patent protection. This mostly involves licensing their IP rights (IPR) to a commercial entity in order to bring a technology to the market. Typically both the licensor and licensee wish to make financial returns. In the wake of an infamous case involving the licensing of an antiretroviral drug by a university to a company, wherein access to this essential drug for HIV patients in the developing world was initially limited, a number of universities woke up to the possibility that their licensing practices may hinder their public mission of making available globally essential health technologies conceived in public-funded research organisations (PSRO). A new concept “Socially Responsible Licensing” (SRL) began to evolve into policy and practices where some PSROs strove to balance financial against social goals to make technologies accessible and affordable to the poor.
In the last decade Product Development Partnerships (PDP) have emerged making important contributions to the development of health technologies. PDPs are a form of public private partnerships that focus on technology development for vaccines, pharmaceuticals and diagnostics. PDPs reflect a new era of partnerships in the history of health technology development in which the public and private sectors have found productive ways to collaborate where public sector incentives to promote global health are balanced with traditional industry-driven incentives to address the gaps in R&D for diseases relatively neglected by industry.
Due to increased harmonisation of IPR rules through multilateral trade agreements such as the Agreement on Trade Related Aspects of IP Rights (TRIPS) that also required new or enhanced protection of pharmaceutical IP, there were concerns raised on the effects on access to medicines in poorer World Trade Organisation (WTO) nations. Hence in the 2001 Doha Declaration on TRIPS and Public Health the WTO sought to strike a balance between IPRs and public health. TRIPS should be implemented in a manner supportive of protecting public health and promoting access to medicines for all by using ‘flexibilities’ provided in TRIPS. Compulsory licenses (CL) granted by Governments to allow the use of the patented innovation without the authorization of the right holder, is one of those ‘flexibilities’ which enables generic manufacture for national use. The provision has been used several times in LMICs to increase access particularly to treatments for HIV/AIDS. In 2003, a further decision was also adopted whereby WTO members may issue CLs, with a view to exporting patented medicines to countries with no or insufficient manufacturing capacity.
Objectives of the project
The main focus of our project was directed to the responsible management of intellectual property rights (IPR) and addressing IP barriers in a manner to promote access to affordable health technologies in LMICs.
Specific objectives were:
1. Early Stage Research and Development: To develop practical models and best practices for academic policy in intellectual property (IP) management and licensing, to minimize barriers for the delivery of pharmaceutical innovation to populations in need. To work with a variety of stakeholders including Technology Transfer Officers/Offices (TTO) to develop practical and implementable best practices for identification and commercialization of pharmaceutical innovations that are of importance to health problems of disadvantaged populations.
2. Product Development: To review existing and evolving practices in Public-Private or Product Development Partnerships (PDP) and to analyze their outcomes in terms of pharmaceutical development. To analyse best practices for successful pharmaceutical partnerships in the commercialization of therapies for needs that are inadequately met by traditional industry with a particular focus on IP management by PDPs.
3. Commercial Access to Pharmaceuticals: To identify problems and develop solutions aimed at simplifying processes and removing barriers to trans-national cooperation. This was targeted towards the successful adoption and practical implementation of new legislative instruments via TRIPS to increase access to generic versions of essential patented medicines by countries with or without pharmaceutical manufacturing capacity.
Description of work and results
Our main methodologies used in research consisted of comprehensive analyses of existing literature and health initiatives to improve access to essential health technologies, interviewing or other means of gathering or sharing of information such as through questionnaires stakeholders in the global health community including academics, licensing professionals, medical professionals, pharmaceutical industry representatives, PDPs, negotiators and representatives from governmental and non-governmental organisations. Simultaneously we had an additional mission to raise awareness of global issues in access to essential medicines through several fora including the organisation of stakeholder meetings, presentations at professional associations and international conferences and several peer reviewed publications.
Although SRL has been a topic of discussion and debate elsewhere, there has been very little practical implementation in most of the PSROs in both developed and developing countries to date and SRL remains largely a theoretical issue. The US based Association for University Technology Managers (AUTM) has acted as an effective medium to disseminate and spread awareness of the importance of creative licensing policy and practices for global health. Despite this, SRL is patchily adopted by few universities and even fewer in Europe. Our surveys indicate that a majority of academics and medical professionals support the concept of SRL. One of our major results was crystallisation of a group of stakeholders, primarily technology licensing and IP experts to produce a brief guide to SRL to facilitate understanding, adoption and awareness of SRL practices. It distils a set of principles rather than attempting to be a detailed guide so that TTOs can adopt new ways of facilitating access to health technologies in their licensing practice. In other words, rather than attempt to be a “how to....” guide, it encourages creative thinking and flexibility to structure license agreements that reflect the objectives of the parties involved taking into account not only immediate commercial opportunities, but also future access needs of the poor when technologies enter the global market.
The study on PDPs captured the changes in practices for IP management in the PDP field to guarantee access. To accomplish this, some PDPs were interviewed to gain insight into how they are dealing with IP management issues such as patenting and licensing practices that can enable access. Some strategies are used by PDPs in their agreements, in order to guarantee access such as: 1) negotiating with partners the exact terms of ownership for all IP generated over the course of the project (power of negotiation) 2) when the partner retains IP rights, PDP contract will require “access commitments” for the developing countries and provision of remedies - exclusive license, march-in rights 3) When there is a dual market, some PDPs have exclusive or non-exclusive license to IP to commercialize in the developing countries public market and 4) in some cases, license can be a royalty free, sub licensable exclusive one which gives to the PDP rights to distribute and sell for public markets in developing countries. The ultimate goal of “access” is the availability of the product at the lowest price to ensure a sustainable supply and widest access into a given market. But how this objective is defined in practice varies considerably. It depends on some internal and external factors such as the nature of the contributions brought by the two parties, which means power of negotiation. Generally, specific criteria for a reasonable price are set, and where possible, structures are developed to allow sales in rich markets to subsidize sales in poor markets.
We also undertook a comprehensive analysis of several case studies on select products that emerged from a number of PDPs and the strategies that PDPs used to bring these products to market. As an illustration using one case study of dengue vaccines in development we noted that: there are relatively few major IP constraints that would complicate global deployment of any of the four vaccines in various stages of clinical development. This appears to be the case for several reasons: Many of the inputs are already in the public domain. Basic technologies for developing and manufacturing vaccines are well-established, and many have been in use for well over a century. However, with the advance of biotechnology in vaccine research, development and manufacturing, IP issues may arise, depending on the type of methodologies and materials employed. Issues stemming from the use of recombinant DNA technology are the principal ones identified by us, however these technologies have enabled tremendous advances in vaccinology.
Further advancement and introduction of one or more of these vaccines will require concerted attention to certain determinants of innovation. These include further investment in dengue vaccine research and development, development of regulatory frameworks, creation of cost effective production facilities and assessment and development of domestic and international markets. Because of the relative clarity of the IP situation with respect to dengue vaccines, greatest attention should be accorded to other determinants of innovation. Much of this work was conducted through face-to-face interviews with managers in existing PDPs.
Studies on CLs resulted in the following conclusions: Increasing patent protection of pharmaceuticals worldwide may enhance the importance of the TRIPS flexibility in the future. While diseases, such as HIV/AIDS, malaria or tuberculosis receive high attention and the largest part of donor funding, the prevalence of non-communicable illnesses (NCD), such as diabetes, cardiovascular diseases or cancer will grow and require improved access to cheaper and effective treatment, and CLs for NCDs have been issued by Thailand and India. Our case analyses show that the CL mechanism can impact access to medicines in the short term through increased physical access for a limited period, and in a long-term perspective through the increased competition and subsequent price reductions. However, the various CL uses also illustrate challenges that nations with the intent to apply the instrument for public health purposes may face as discussed in the next section.
We conducted detailed analysis of the two compulsory license (CL) mechanisms introduced into international trade law, namely Article 31 of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) for the supply of the domestic market with needed pharmaceutical products and the future Article 31 bis TRIPS for the export of generic products to countries with lacking manufacturing capacities (based on the World Trade Organization General Council Decision on the Implementation of Paragraph 6 of the Doha Declaration on the TRIPS Agreement and Public Health of August 30, 2003; hereinafter “the Decision”).
After more than 9 years of existence, the Decision had been successfully used in only one case, and in another attempt the generic drug producer could not finalize the CL application. Apotex, Canada had shipped several millions of tablets for HIV/AIDS treatments to Rwanda implementing provisions under the new Canadian Access to Medicines Regulation (CAMR). The CL system has been described as functioning because of this completed implementation. However the end result is not sufficient to assess the success of legislation. There are important barriers to the effectiveness and feasibility of the CL measure that are already inherent in the Decision itself.
National implementation of the newer CL regimes varies widely ranging from complex legislation including multiple provisions as established in Canada to very vague provisions under Indian law. The first use of the CAMR displays important operational hurdles of local government implementation including the predefined drug list, the provision for mandatory negotiations for voluntary licenses that cannot be waived; and the 2-year limitation on the duration of the compulsory license. Future implementations of the Decision should refrain from similar ‘Decision-plus’ requirements that go beyond the original intention of WTO legislation. They should include a simplified process for drug quantities extensions, in case required by the importing developing countries (DCs). There is also incompatibility of the Decision’s CL system in general with the procurement practices in developing countries (DC), for example: tenders. The lack of economic viability is a major disincentive for generic manufacturers in industrialized and developing countries during implementation on a country-by-country basis. Solutions to these issues are a ‘one-license’ approach that allows the issue of a single CL for multiple countries; and further, pooled procurement of drugs by several DCs. Both avenues would increase economy of scale for generic companies making the use of the regime more attractive. The model of pooled procurement that is already included in international law should be further developed in national/regional legislation. Nevertheless, CL will remain a valuable policy instrument for DCs in the foreseeable future.
Analysing lack of access to essential medicines using specific diseases as models was essential to illustrate barriers to essential medicines. A detailed analysis was conducted that highlighted the three main essential antifungals to cryptococcal meningitis (CM). Despite being off patent for many years there is little or no generic competition due to market failures. We have helped create a Cryptococcal Meningitis Advocacy Group (CryptoMAG) involving persons from the WHO, Medecins Sans Frontieres, Centre for Diseases Control USA, Clinton Access Health Initiative and other institutions (http://www.life-worldwide.org/en/media-centre/article/access-to-diagnosis-and-treatment-for-cryptococcal-meningitis/) which held its first meeting in Geneva in March 2013. The group is actively developing strategies to further access to essential medicines and diagnostics for CM patients particularly in sub-Saharan Africa. We also have established an ongoing collaboration with Kings College, London on the role of SRL for cancer drugs as part of our wider interest in non-communicable diseases (NCD). So far SRL practice has mainly been applied to communicable diseases (CD). However LMICs face a dual burden of both CD and NCD.
Conclusions and societal impacts
Adoption of SRL practices by university technology transfer offices is a critical factor to improve access to healthcare technologies arising from public funded research. Our research reveals that a significant proportion of health technology had its origins in academic research supported by licences granted to industry. With foresight and diligence with SRL, research organisations can address unmet needs in underserved markets. And it also has benefits for the organisations and their licensees such as increased reputational goodwill and addressing corporate social responsibility, coupled with increased chances of funding from existing funders or philanthropic sources. Our recommendations include that funders of research projects including the EU Horizon 2020 program consider placing a requirement that grantees of projects of global health significance have access strategies and policies incorporated into proposals and projects including the use of IP to increase access and affordability of technological outputs. And that research organisations consider incorporating in their IP policy a commitment to safeguard humanitarian needs when out-licensing technology. Our handbook and the awareness we have created through diverse advocacy activities will, we hope, move in this direction.
PDPs have in many cases been successful in developing products that have been commercialised or in late stage of development by addressing effectively all components that determine innovation, namely a) the design and execution of research and development programs from preclinical studies to licensure b) analysis and planning for the marketing and distribution of new technologies in individual developing countries c) analysis and planning for the procurement and supply of new health technologies by the global health community d) planning and implementation of manufacturing capabilities e) establishment and implementation of regulatory systems to ensure safe and effective products and f) the establishment and implementation of intellectual property rights (IPR) management systems. According to our analyses and case studies IPRs are but one factor that may affect access to health technologies from PDPs, and very rarely an important factor. Nevertheless, PDPs have put IP management at the forefront of their overall innovation strategies, and access and affordability are a primary concern in IP management, unlike SRL practices by universities where access can be a secondary concern. We advocate wider sharing of access strategies between universities and PDPs to accelerate knowledge and adoption of SRL. Additionally we recommend that greater emphasis is placed on public private partnerships modelled along successful PDPs to address market failures for a wider range of diseases in LMICs, including non-communicable diseases. There is a worrying trend where public and philanthropic funding for PDPs is declining amidst a background of global economic difficulty and much care is needed not to derail such alternate models of product development.
Our case studies on CL reveal several obstacles to the issuing of CLs. Themes that emerged from these experiences include, for example, the varying interpretations and understandings with respect to the TRIPS CL conditions; the lack of operational capacities of IP offices in LMICs including implementing a CL procedure, or the fear and risk of retaliation from other stakeholders when granting a CL. Negotiation for a voluntary price reduction for efavirenz, an antiretroviral, by Brazil turned out to be very protracted and unproductive and forced Brazil to issue a CL. A particular challenge that needs to be addressed is the application of the newer CL system for the export of pharmaceutical products to countries without or insufficient manufacturing capacity. Only one company and country of import have used this provision, and the complexities in the systems both in the exporting and importing country has deterred the company from ever using this flexibility again. In addition Indian generic firms see insufficient incentives to use this new mechanism, particularly due to insufficient volumes potentially ordered. Ultimately national governments should have the capacity and the tools to address access barriers via CL in a legitimate manner during public health emergencies.
Our research is expected to have an impact also at various levels especially policy and practice in the management of IP and addressing IP barriers in a legitimate manner to increase access to essential medicines. These expected impacts will significantly narrow many of the access gaps to pharmaceuticals, but only if there is capacity building at several levels particularly in developing countries, not only in IP issues but also other determinants of access that are more important than case-specific IP barriers. It will also result in significant awareness and implementation of best practices, both for countries and institutions at the policy and practitioner level to address many problems of access to drugs.
List of Websites:
Contact Details for Principal Investigators of the ATP Project
1) Harry Thangaraj (project coordinator), St. George’s University of London firstname.lastname@example.org
2) Daniel Kraus, University of Neuchatel Switzerland email@example.com
3) Richard Mahoney, International Vaccine Institute, South Korea (Richard Mahoney is no longer with IVI. For essential messages, contact the project coordinator first)
4) Carlos Morel, Oswaldo Cruz Foundation, Brazil firstname.lastname@example.org
5) Rabogajane Busang, Medical Research Council, South Africa email@example.com