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Improving Global Access to New Vaccines: Intellectual Property, Technology Transfer, and Regulatory Pathways Sara Eve Crager, MD
The 2012 World Health Assembly Global Vaccine Action Plan called for global access to new vaccines within 5 years of licensure. Current approaches have proven insufficient to achieve sustainable vaccine pricing within such a timeline. Paralleling the successful strategy of generic competition to bring down drug prices, a clear consensus is emerging that market entry of multiple suppliers is a critical factor in expeditiously bringing down prices of new vaccines. In this context, key target objectives for improving access to new vaccines include overcoming intellectual property obstacles, streamlining regulatory pathways for biosimilar vaccines, and reducing market entry timelines for developing-country vaccine manufacturers by transfer of technology and know-how. I propose an intellectual property, technology, and know-how bank as a new approach to facilitate widespread access to new vaccines in low- and middle-income countries by efficient transfer of patented vaccine technologies to multiple developing-country vaccine manufacturers. (Am J Public Health. 2014;104:e85–e91. doi:10.2105/AJPH.2014. 302236)
Vaccine rollout in low- and middle-income countries (LMICs) routinely lags far behind rollout in high-income countries. As of 2010— a full decade after its introduction—87% of high-income countries included the pneumococcal conjugate vaccine in their immunization schedules, compared with only 2% of lowincome countries.1 Although the Haemophilus influenzae type b (Hib) vaccine was being widely used in wealthy countries by the early 1990s, Hib vaccine coverage in Africa was estimated at 24% as of 2006.2 Twenty years after licensure of the hepatitis B vaccine, vaccine coverage was estimated at 90% in the Americas as opposed to only 28% in Southeast Asia, where hepatitis B is endemic.1 These timelines, unfortunately, are the norm rather than the exception for adoption of new vaccines in LMICs. The inequities of this situation are all the more indefensible because the vast majority of mortality from vaccine-preventable diseases occurs in LMICs3; it is estimated that more than 90% of deaths from pneumococcal disease,4 95% of deaths from Hib,5 and 80% of deaths from hepatitis B5 occur in developing countries. In May 2012, the 65th World Health Assembly endorsed the Global Vaccine Action
Plan (GVAP),6 a document that sets ambitious vaccination goals for the upcoming decade. The GVAP reflects the growing recognition by governments, international agencies, and civil society of the importance of vaccines not only for achieving international health priorities but for addressing global issues such as poverty, hunger, education, and gender equality.7 One of the key objectives outlined by the GVAP is for all immunization programs to have sustainable access to universally recommended vaccine technologies within 5 years of licensure. There is an enormous gap between this goal and the current reality of new vaccine rollout in LMICs, and the GVAP recognizes that innovative mechanisms will be needed to support scale-up of new vaccines within the proposed timeline. The Decade of Vaccines collaborative that created the GVAP has proposed the goal of achieving universal vaccine access by 20208; it is estimated that this goal will cost more than US $57 billion, with new vaccines responsible for over half the cost.9 Although there are numerous social and logistical obstacles to the adoption of new vaccines in LMICs, a clear consensus has emerged that one of the greatest barriers is
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vaccine pricing.10---15 This problem is being compounded by the increasingly high costs associated with recent vaccine innovations. The newly developed human papillomavirus (HPV) vaccine, for example, is the most expensive vaccine in history16; this is particularly problematic because the overwhelming majority of cervical cancer cases occur in developing countries.17 Like many new vaccines, the high cost of the HPV vaccine will be most prohibitive in exactly the places it is most needed, and it is unlikely that expensive new vaccines such as the HPV vaccine will become widely accessible in LMICs without extensive external funding. Currently, the most important source of external funding for vaccines in low-income countries is the Global Alliance for Vaccines and Immunizations (GAVI). GAVI’s critical role in the introduction of new vaccines to lowincome countries, most recently with its commitment to introducing the HPV vaccine,18 cannot be overstated; however, there are significant limitations inherent in this support. First, new vaccine introduction is only 1 component of GAVI’s vaccination programs, and the decision to introduce a new vaccine is based on numerous factors, which inevitably include the price of the vaccine and GAVI’s current financial status. In 2010, GAVI was facing a serious budget shortfall of over $4 billion, which threatened to limit future plans to introduce new vaccines.19 GAVI was able to raise sufficient funds to overcome this budgetary crisis; however, the shortfall highlights concerns regarding the long-term stability of GAVI’s subsidies for the future introduction of new vaccines. In any event, LMICs that are not eligible for GAVI funding are likely to have difficulty financing new vaccines without assistance,12 and the GVAP notes that innovative pricing strategies will be particularly important for those LMICs that do not have access to GAVI pricing and procurement mechanisms. In
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addition, the subsidies provided by GAVI to finance new vaccines are intended to be limited to a 5-year period, with the expectation that, over that time, prices will fall, allowing donors and national governments to continue vaccine financing. To date, however, this expectation has not been realized. Once it became apparent that vaccine prices were not dropping rapidly enough, GAVI was forced to revise its support timelines. Thus, a critical limitation to GAVI’s role in promoting access to new vaccines is the failure to establish mechanisms ensuring sustainable vaccine pricing once the initial period of support has ended. There is an emerging consensus that the most important factor in achieving sustainable vaccine pricing is the market entry of developing-country vaccine manufacturers (DCVMs).1,20---23 I propose an intellectual property, technology, and know-how (IPTK) bank as a novel strategy to enable early market entry of multiple DCVMs to facilitate rapid rollout and sustainable pricing of new vaccines in LMICs.
OVERCOMING ACCESS BARRIERS FOR NEW VACCINES In January 2010, a consultation meeting convened by Médecins Sans Frontières and Oxfam brought together experts from around the world to discuss strategies for improving access to vaccines in LMICs.20 New vaccines were a major focus of this meeting, which included representatives from key players such as the Netherlands Vaccine Institute, the International Vaccine Institute, Third World Network, Program for Appropriate Technology in Health, and the World Health Organization (WHO). The consultation meeting report concluded that although organizations such as the Pan American Health Organization Revolving Fund—which effects reduced prices through bulk procurement systems—are key players in improving vaccine access, such entities have not proven sufficient to ensure affordable prices for new vaccines. The report further noted that success with tiered pricing approaches has been mixed and has not consistently resulted in sustainable prices, particularly for new vaccines. It concluded that future strategies to improve access to new vaccines will need to include (1) streamlining regulatory
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pathways for biosimilar vaccines, (2) addressing intellectual property barriers, and (3) reducing the barriers and timelines to the entry of multiple new suppliers by transfer of technology and know-how. Before addressing each of these strategies in detail, I will briefly discuss the implications of the fact that vaccines are biologics rather than small-molecule drugs.
Vaccines as Biologics and Implications for Access Strategies The presence of multiple DCVMs has been identified as a critical factor in generating sustainable vaccine prices. It is now widely recognized that the advent of generic drug production, but more importantly the market entry of multiple generic drug suppliers, is the best mechanism for rapidly achieving dramatic price reductions. The major expansion of HIV/ AIDS treatment in LMICs, for example, was made possible through the entry of generic manufacturers in countries such as India and Brazil; with the advent of robust generic competition, prices of first-generation antiretroviral drugs fell by more than 99%, from $10 000 annually per patient in 2000 to less than $70 in 2014. Strategies to improve access to medicines have thus coalesced around the goal of enabling generic production. This has led many of these efforts to focus on patent protection as a key barrier to the availability of affordable generic medicines. A crucial assumption that underlies this strategy is that it is fairly straightforward to reverse engineer a given drug; in concept, the problem is not that generic drug manufacturers would be unable to exactly replicate a drug, it is that they are prohibited from doing so by patent law. Although this is generally the case for smallmolecule drugs, this basic assumption does not hold true for biologics, including vaccines. The majority of medications in common use are small-molecule drugs, which are generally low-molecular-weight organic compounds synthesized by chemists. Biologic drugs, a category that includes vaccines, are generally produced by living cells and are significantly larger and structurally more complex than small-molecule drugs. To successfully reverse engineer a small-molecule drug, it is not necessary to precisely duplicate the manufacturing process in order to guarantee an identical product. In the case of vaccines, however, an identical
product is not necessarily guaranteed if an alternative production process is used. The details of the vaccine production process can affect variables such as 3-dimensional structure and posttranslational modifications, which are important determinants of vaccine immunogenicity. Detailed information on vaccine production processes is usually not patented. Instead, this information is protected by trade secret law, under which it is never made publicly available because, unlike patent protection, there is no scheduled expiration after a preset term.24 This perpetual monopoly prevents replication of the production process, thus precluding straightforward duplication of the vaccine.25 Furthermore, because vaccine manufacturing is often highly complex, significant know-how may be required to reproduce a vaccine, necessitating direct input from the original product developer. In sum, although patent protection remains the major barrier to the production of affordable small-molecule generics, access to trade-secret--protected information and know-how present major additional obstacles to generic production of vaccines. A successful vaccine access strategy that relies on early production by multiple DCVMs will need to address all of these issues.
Streamlining Regulatory Pathways for Biosimilar Vaccines To bring a generic drug to market, a company must go through an abbreviated approval pathway established by national regulatory agencies such as the US Food and Drug Administration. Because of the high degree of manufacturing complexity and the difficulties inherent in reverse-engineering biologics, no abbreviated approval pathway existed for biologics until very recently. Over the past several years, a number of governments have created new regulatory frameworks for abbreviated approval of generic biologics (referred to as “follow-on biologics” or “biosimilars”). The European Union was the first to establish such guidelines,26 and in 2010 the United States passed the Biologics Price Competition and Innovation Act27 as part of the Affordable Care Act. The WHO has also now published guidelines for the approval of biosimilars28 modeled on EU guidelines, and the Indian Department of Biotechnology recently introduced a similar set of guidelines.29
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To date, the debate regarding implementation of abbreviated approval pathways for biosimilars has focused on the category of therapeutic proteins, and implementation has yet to be discussed in the context of vaccines. This is partly because therapeutic proteins are far more lucrative for the pharmaceutical industry; the global market for therapeutic proteins was valued at US $93 billion in 2010 and is predicted to reach more than $140 billion by 2017,30 whereas the global vaccine market is currently valued at a little more than $2 billion.31 It is, however, also partly because of the recognition that there are fundamental differences between vaccines and therapeutic proteins that will require special regulatory consideration.32 It will be important for regulators to consider how abbreviated approval pathways for biosimilars should be implemented specifically in the context of vaccines. The major safety concern surrounding approval of biosimilars is their potential immunogenicity. Immunogenicity, which refers to the tendency of a drug or vaccine to elicit a response from the body’s immune system, can be either a desirable property (in the case of vaccines) or an undesirable property (in the case of therapeutic proteins). Safety concerns related to biosimilars immunogenicity is best exemplified by the oft-cited example of a minor manufacturing change to a therapeutic protein product that resulted in a number of cases of severe anemia thought to be caused by increased product immunogenicity.33 A similar incident is improbable with vaccines because microbial antigens are far less likely to induce an immune response that cross-reacts with endogenous proteins. Another key issue in the debate over biosimilars is the extent to which additional clinical trials will be necessary for approval. Here as well, special consideration needs to be taken for vaccines, particularly with regard to the potential use of correlates of protective immunity to define appropriate clinical trial endpoints. Defining a validated correlate of protective immunity could allow clinical trial evaluation of biosimilar vaccines to be accomplished more rapidly and at lower cost than will likely be necessary for most therapeutic proteins.34 A precedent for using correlates of protective immunity in this manner was set during clinical trials of the HPV vaccine; Merck
conducted a bridging study to a younger age group (in which the use of cervical intraepithelial neoplasia as an endpoint was infeasible) by comparing antibody responses to those in the older cohort in whom efficacy had been previously established.35 GlaxoSmithKline has used a similar metric in a noninferiority trial of Cervarix after a manufacturing change, using antibody titers as the major trial endpoint.36 The WHO has set similar precedents; for example, convening a series of expert consultations with the objective of establishing antibody reference values related to clinical efficacy outcomes for the pneumococcal vaccine.37 Issues of the safety and efficacy of biosimilar vaccines, however, will ultimately need to be evaluated on a case-by-case basis. Now that various national governments and international agencies are establishing abbreviated approval pathways for biosimilar biologics, approaches to streamlining a pathway for abbreviated approval of biosimilar vaccines should be explored in detail.
Addressing Intellectual Property Barriers Although patent protection may not be the sole barrier to the production of biosimilar vaccines, it remains a major obstacle. This is especially true in the era of broad enforcement of the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights,38 which significantly limits the ability of countries like India (the “pharmacy of the developing world”) to produce medications still under patent protection in high-income countries.39 Gardasil, 1 of 2 recently developed vaccines for HPV, provides an example of the complex patent landscape that can be expected to surround new vaccines. To date, 81 US patents for Gardasil have been granted to a total of 18 different organizations.40 Such a morass of intellectual property clearly has the potential to be a significant impediment to any access strategy that relies on the early entry of new suppliers. In addition, intellectual property barriers will likely apply to new formulations of existent vaccines (e.g., noninjectable delivery systems or improved vaccination schedules), a precedent that has been set by the new intranasal influenza vaccine.41 This could become particularly relevant if an organization
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wished to apply a technology for adapting delivery methods to the manufacture of a new vaccine (e.g., to produce a noninjectable HPV vaccine). An access strategy that may be particularly relevant to patent-related barriers to generic production of new vaccines is the Medicines Patent Pool (MPP). The MPP,42 established with the support of UNITAID in 2009, aims to enable the affordable production of HIV drugs still under patent protection by obtaining voluntary licenses from patent holders and making these licenses available to generic companies in LMICs. Through the MPP, licenses to all patents required to produce a given end product are provided as a package to multiple generic manufacturers on a nonexclusive basis. These manufacturers must meet quality, safety, and efficacy standards, and must have access to markets that are large enough to achieve economies of scale and generate major price reductions. Royalties will be paid to patent holders, and generic licenses will be for use only in LMICs, thereby avoiding infringement upon the main target markets of brand-name manufacturers. Although the MPP was established only recently, the response of the pharmaceutical industry has been encouraging thus far.43 To date, the MPP has negotiated licenses with the US National Institutes of Health, Gilead Sciences, Bristol-Myers Squibb, Roche, and ViiV Healthcare, and is currently engaged in discussions with a number of other major pharmaceutical companies.
Reducing Timelines to New Supplier Market Entry A vaccine access strategy that relies on the rapid market entry of multiple DCVMs must address the issue of intellectual property rights12; however, there are multiple additional barriers that must be surmounted to allow generic companies to efficiently and costeffectively duplicate a vaccine.44 Access to manufacturing process information protected by trade-secret law, as well as access to technology and know-how held by the innovator company, will likely be necessary. A strategy to incentivize companies to disseminate process secrets and know-how to DCVMs would be a major step toward increasing vaccine access in LMICs.45 Such a strategy would require the relevant actors to work together to find
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a balance between the need to allow DCVMs to produce vaccines for lower-income markets and the need of innovator firms to recover sunk costs from higher-income markets.45 Transfer of technology and know-how to DCVMs has been identified as a key factor allowing affordable vaccines to reach the market rapidly,20 and innovative technology transfer mechanisms could play a central role in improving vaccine accessibility. It is important to note in this context that most technology transfer licenses cover both patents and trade secrets.46 The WHO has recognized the importance of DCVM technology transfer in their response to the recent crisis in global production capacity of the influenza vaccine.47 In 2007, the WHO created a technology transfer hub as a strategy to rapidly increase the number of influenza vaccine producers in LMICs. In this model, a publicly funded institution provides a base to bring together all necessary manufacturing, clinical, and regulatory expertise to create a comprehensive documentation package with corresponding training modules. This package is then transferred to various DCVMs, allowing them to efficiently and cost-effectively reproduce a vaccine. The technology transfer hub model recognizes the inefficiencies of currently prevalent one-to-one technology transfer involving a single provider and a single recipient, and the WHO’s technology transfer hub has been highly effective in rapidly expanding DCVM influenza vaccine production capacity48; since its inception, it has facilitated the establishment of 14 DCVMs producing pandemic influenza vaccines.49 It is important to take note of not only the large number of DCVMs that are now producing the vaccine, but also the rapidity with which this was achieved. The WHO is expanding on this concept with their Technology Transfer Initiative, a project to create “centers of excellence” capable of transferring other manufacturing processes to multiple recipients.49 Although technology transfer hubs could provide a highly effective avenue for achieving rapid market entry of multiple DCVMs, they have a critical limitation: this model can only be used with vaccines for which no intellectual property barriers exist in both the country hosting the hub and the country receiving the
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technology. This requirement will effectively preclude using technology transfer hubs to accelerate the market entry of DCVMs for vaccines still under patent protection. Functionally, then, the technology transfer hub model cannot be applied to new vaccines. Unfortunately, this is exactly the situation in which such a model could prove most useful because it is these vaccines that are the most expensive and thus could benefit most from the early market entry of multiple DCVMs.
A STRATEGY TO IMPROVE ACCESS TO NEW VACCINES Patent pools and technology transfer hubs are 2 approaches that are being successfully employed to improve access to medicines by increasing the number of developing-country generic suppliers; however, neither will be able to resolve the problems facing access to new vaccines. Patent pools do not incorporate mechanisms to provide access to manufacturing process information and know-how necessary to duplicate a vaccine. Technology transfer hubs, on the other hand, explicitly exclude patented vaccines, making this model inapplicable to essentially all new vaccines. Therefore, neither patent pools nor technology transfer hubs are individually equipped to enable widespread access to new vaccines through reducing the barriers and timelines to the entry of new DCVMs. The focus of the access-to-medicines movement on small-molecule drugs—driven partly by the HIV/AIDS epidemic—has resulted in a proliferation of innovative intellectual property strategies converging around patent protection. At the same time, organizations that specifically promote access to vaccines have traditionally focused on expanding access to existent vaccines and strengthening national immunization systems rather than ensuring access to new vaccines; GAVI’s inception in 2000 was significant partially because one of its priorities was to expand access to new vaccines; however, this did not include the development of novel upstream mechanisms for rapidly achieving sustainable pricing for new vaccines. There is no intrinsic reason that mechanisms for addressing patent protection and those for addressing technology transfer must remain distinct. Licensing agreements
combining rights to patents with rights to technology and know-how are actually quite common.50 I propose a strategy that would integrate key aspects of both these models, creating a structure capable of facilitating access to new vaccines by establishing an entity that pools all relevant intellectual property, technology, and know-how: an IPTK bank. An IPTK bank would bring together the necessary intellectual property rights, manufacturing process information, know-how, and regulatory expertise into a single platform that could be licensed as a package with associated training modules; it could also offer assistance in navigating vaccine registration with national regulatory authorities. A licensing approach similar to that used by the MPP would be employed to address intellectual property barriers by creating a structure whereby the patented technology could be disseminated to multiple DCVMs, each paying royalties to the patent holder. The manufacturing process information, know-how, and regulatory expertise would be brought together through the organization hosting the IPTK bank, which would closely mirror the organizational model of the WHO technology transfer hub.
Barriers to Creation of the Proposed Banks Funding, inevitably, will be a major barrier to the creation of IPTK banks. IPTK banks would require an initial period of funding in order to acquire and then disseminate the vaccine technology. Once a critical mass of DVCMs began producing the vaccine, however, provision of affordable vaccines would be self-sustaining, with reliance on market forces to ensure appropriate price declines. IPTK banks thus would not be as subject to the vagaries of sustained donor funding as organizations like GAVI, but would rather need to raise enough money to support the initial acquisition and dispersal period for each new vaccine technology. Given that projected spending on new vaccines necessary to achieve the GVAP goals is estimated at nearly US $30 billion, it may ultimately be more cost-effective to invest in upstream mechanisms to rapidly achieve sustained price reductions for new vaccines. The greatest barrier to the creation of IPTK banks is the need for close cooperation with
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innovator companies. Fundamentally, engaging with an IPTK bank would be similar to the technology transfer arrangements that multinational pharmaceutical companies frequently enter into with individual DCVMs to expand their regional vaccine production and distribution. The major departures from a traditional technology transfer agreement would include licensing terms that allow the IPTK bank to grant nonexclusive licenses to multiple DCVMs and the transfer of technology to a hub organization at a publicly funded institution rather than directly to a DCVM. Because an IPTK bank strategy depends on significant involvement from innovator companies, creating appropriate conditions that incentivize their participation is key to the success of this model.
Engagement With Innovator Companies Multinational pharmaceutical companies frequently engage in successful technology transfer with DCVMs, and this trend appears to be growing. According to an International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) spokesperson, Technology transfer in medicines and vaccines were growing rapidly in the past decade, benefiting both pharmaceutical companies and the health of recipient countries’ population alike.51
In fact, so much interest has developed around this topic that the IFPMA recently issued a research paper titled “Technology Transfer: a Collaborative Approach to Improve Global Health—the R&D Pharmaceutical Industry Experience.” In addition to providing numerous case studies of technology transfer partnerships, the paper identified 8 conditions that the pharmaceutical industry considers necessary for successful technology transfer relationships: 1. a viable and accessible local market, 2. political stability and good economic governance, 3. clear economic development priorities, 4. adherence to high regulatory standards, 5. availability of skilled workers, 6. adequate capital markets, 7. strong intellectual property rights and effective enforcement, and 8. a high-quality relationship between industry and government, and their ability to work together effectively for long periods of time.
An IPTK bank as a technology partner would fulfill most of these criteria. The fact that an IPTK bank would almost certainly be based in a high-income country would also address a number of these issues. In this context, there should be relatively little concern over issues such as political stability and good economic governance, and most industrialized-country governments are generally considered to have relatively good relationships with industry and a long history of working together effectively. These conditions may not be guaranteed to the same degree in all countries that receive technology from an IPTK bank, but that risk would not be directly borne by the company and would be distributed over multiple potential technology partners. In addition, high-income countries generally have well-established systems of strong intellectual property rights with effective enforcement. Again, this may or may not be true to the same extent in all countries that are recipients of IPTK bank technology; however, industry has already shown itself willing to discuss licensing arrangements with the MPP that would involve licensing intellectual property rights to a central organization, which would then provide nonexclusive licenses to multiple other entities in countries that may not have similarly strong enforcement of intellectual property rights. Regarding access to viable local markets, although the IPTK bank itself would not directly have such access, licenses would be granted only to partners with demonstrable access to local markets large enough to achieve economies of scale such that significant price reductions could be generated (as occurs with the MPP). Finally, if the IPTK bank is based at an institution such as the Netherlands Vaccine Institute or the International Vaccine Institute, availability of skilled workers should be more than adequate. Basing the IPTK bank within such organizations would provide a strong base of experience in adherence to high regulatory standards that would be passed on to IPTK bank technology recipients. Overall, IPTK banks would fulfill the criteria that the IFPMA has identified as being critical to the decision of multinational pharmaceutical companies to engage with a technology transfer partner. The major departure from the technology transfer arrangements described in the IFPMA report would be use of a licensing
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covering all necessary intellectual property modeled on the MPP licenses rather than the traditional sublicense negotiated between pharmaceutical companies and their technology partners. Companies have demonstrated their willingness to enter into negotiations involving such licenses with the MPP, providing a precedent that this may not present an insurmountable barrier to companies engaging in technology transfer agreements with an IPTK bank. Although an IPTK bank would require a high degree of commitment and cooperation from innovator companies, it seems possible that industry might be willing to consider engaging in discussion regarding this approach to expanding vaccine access.
Unique Benefits of the Proposed Banks While IPTK banks are a new and untested model for improving access to vaccines in LMICs, this strategy is firmly based in previously established and successful organizational models. IPTK banks would not be a fundamental departure from these models; rather, by combining them to improve access to new vaccines, they would create possibilities that neither patent pools nor technology transfer hubs could generate individually. Bringing together all necessary intellectual property, technology, know-how, and regulatory expertise under a single umbrella organization with the power to efficiently disseminate this package to multiple DCVMs could facilitate a framework for biosimilar vaccine production capable of mimicking generic competition. In addition, although IPTK banks would require an initial period of substantial funding, the impact on pricing for an individual vaccine would ultimately be self-sustaining. A major drawback for pharmaceutical companies is that the vaccine prices currently offered through their tiered pricing schemes are almost certainly higher than could be achieved through competition.52 At the same time, an IPTK bank model could offer several unique benefits for partner companies. It would allow a company to reap some of the benefits of expanding to developing-world markets without taking the risk of making the large investments necessary to build additional production capacity. A company could similarly accomplish this through traditional technology transfer, but this process also involves
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a significant investment of time and resources from the innovator company. Engaging in technology transfer with an IPTK bank could to some degree mitigate the risks potentially associated with licensing directly to a single producer in a developing country. In addition, companies licensing technologies with an IPTK bank would receive royalties from multiple licensees with the same input of time and resources that, in traditional one-to-one technology transfer arrangements, would only result in receipt of royalties from a single company. In fact, royalty percentages required from any single company could be lower than those negotiated in traditional one-to-one technology transfer agreements, while overall still generating more royalties than the originator company would receive from engaging in technology transfer with a single partner.
CONCLUSIONS To achieve the goal set out in the GVAP for all immunization programs to have sustainable access to universally recommended vaccine technologies within 5 years of licensure, innovative new approaches will be necessary. The crucial role of generic competition and the importance of developing-country manufacturers in expanding drug access is unequivocal. In the case of vaccines, a clear consensus is emerging that market entry of multiple DCVMs is a critical factor in bringing vaccine prices down to sustainable levels, and that technology transfer will be key to expediting this process. For this approach to significantly improve the timeline for access to new vaccines, issues of both intellectual property rights and transfer of vaccine technology and know-how must be addressed. It is not clear that any single strategy currently in use will be able to accomplish this. An IPTK bank is one possible approach that integrates components of previously established successful models in order to allow rapid transfer of new vaccine technologies to multiple DCVMs efficiently and cost-effectively. In the future, a version of this model could be particularly relevant in bringing together the necessary intellectual property, technology, and know-how required to create adapted formulations of new vaccines that would be better suited to the needs of LMICs. A further avenue that merits exploration is how the
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newly established regulatory pathways for abbreviated approval of biosimilars may be applied to vaccine technologies. Finally, the global community needs to recognize the growing importance of biologic medications in the treatment of noncommunicable diseases such as cancer in LMICs. The HPV vaccine was a breakthrough partially because it was the first vaccine designed specifically to prevent cancer. Now that numerous strong links between other viruses and cancer are becoming increasingly clear, there may be hope for more “cancer-prevention” vaccines on the horizon; it is estimated that 16% of new cancer cases globally are attributable to infections, with a significantly higher proportion in less-developed countries.53 As noted by the WHO’s Technology Transfer Initiative, The concept of creating centers of excellence able to establish and transfer manufacturing processes to multiple recipients is currently being applied to other medical products including monoclonal antibodies and other biologics.54
This is an important move forward; however, in its current form it would not be applicable to new biologic products. Because many of the most promising new cancer treatment advances are biologics, and most of the global cancer burden is now carried by developing countries,55 the inapplicability of this model to new biologics poses a significant problem. The unacceptably long delays to vaccine access in LMICs must not be perpetuated with future vaccine innovations. Mechanisms that have been successfully used to improve access to small-molecule drugs cannot be similarly invoked to increase the availability and affordability of vaccines and other biologics. IPTK banks are one possible strategy to rapidly bring down vaccine prices to sustainable levels, one with the potential to be applied to all biologics. j
About the Authors Sara Eve Crager is with the Department of Emergency Medicine, University of California, Los Angeles. Correspondence should be sent to Sara Eve Crager, University of California Los Angeles, Emergency Medicine, 924 Westwood Blvd, Suite 300, Los Angeles, CA 90025 (e-mail: [email protected]). Reprints can be ordered at http://www.ajph.org by clicking the “Reprints” link. This article was accepted July 22, 2014.
Acknowledgments I appreciate contributions to this work from Rachel Kiddell-Monroe, board president, Universities Allied for Essential Medicines, and from Kevin Outterson, professor of health law, bioethics and human rights, Boston University School of Law.
Human Participant Protection Human participant protection was not required because no human participants were involved in this study.
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14. Outterson K. Will HPV vaccines prevent cervical cancers among poor women of color? Global health at the intersection of human rights and intellectual property law. Am J Law Med. 2009;35(2---3):247---252. 15. Cervical Cancer Action. Panama conference sponsored by PAHO, the Panama Ministry of Health, and PATH. June 2010. Available at: http://www. cervicalcanceraction.org/newsletters/2010-07/ CCA_news_July10.html#bolivia. Accessed January 25, 2012. 16. Outterson K, Kesselheim AS. Market-based licensing for HPV vaccines in developing countries. Health Aff (Millwood). 2008;27(1):130---139. 17. Pagliusi SR, Teresa Aguado M. Efficacy and other milestones for human papillomavirus vaccine introduction. Vaccine. 2004;23(5):569---578. 18. GAVI Alliance. GAVI offers new support for vaccines against cervical cancer and rubella. 2012. Available at: http://www.gavialliance.org/library/news/ press-releases/2012/new-vaccine-support-againstcervical-cancer-rubella. Accessed June 18, 2012. 19. Financial Times examines how GAVI’s $2.6 billion shortfall might affect new vaccine programs in developing countries. The Medical News. June 16, 2010. Available at: http://kff.org/news-summary/financial-timesexamines-how-gavis-2-6b-shortfall-might-affect-newvaccine-programs-in-developing-countries. Accessed August 25, 2012. 20. Improving Access and Stimulating Vaccine Development for Use in Resource-Poor Settings. Consultation Summary. Geneva, Switzerland: Médecins Sans Frontières and Oxfam Consultation; January 26, 2010. 21. McElligott S. Addressing supply side barriers to introduction of new vaccines to the developing world. Am J Law Med. 2009;35(2---3):415---441. 22. GAVI Alliance. Procurement reference group report to the GAVI Board. 2007. Available at: http://www. gavialliance.org/resources/2007GaVIreport.pdf. Accessed January 20, 2010. 23. Gollin M, Friede M, Suresh J, Iverson E, Khanna R. Building vaccine capacity in LMICs. Paper presented at: BIO International Convention; May 3---6, 2010; Chicago, IL. 24. Westby JR. “Trade Secrets.” International Guide to Privacy. Chicago, IL: American Bar Association; 2004. 25. Roger SD, Goldsmith D. Biosimilars: it’s not as simple as cost alone. J Clin Pharm Ther. 2008;33(5): 459---464. 26. Generics and Biosimilars Initiative. The EU guidelines for biosimilars. Available at: http://www.gabionline. net/Guidelines/EU-guidelines-for-biosimilars. Accessed May 10, 2014. 27. US Food and Drug Administration. Biosimilars: draft guidances. Available at: http://www.fda. gov/drugs/developmentapprovalprocess/ howdrugsaredevelopedandapproved/approvalapplications/ therapeuticbiologicapplications/biosimilars/default.htm. Accessed May 11, 2014. 28. Generics and Biosimilars Initiative. WHO guidelines on biosimilars: case studies and discussion highlights. Available at: http://www.gabionline.net/Reports/WHOguidelines-on-biosimilars-case-studies-and-discussionhighlights. Accessed May 10, 2014. 29. Jayarman K. India’s biosimilar regulations. Nat Biotechnol. 2012;30:815.
30. GBI Research. Therapeutic proteins market to 2017—high demand for monoclonal antibodies will drive the market. Market Research Report. September 11, 2011. 31. Kobayashi TH. Vaccine does make sense, until used [in Japanese]. Yakugaku Zasshi. 2011;131(12): 1743---1744. 32. Corbel MJ, Cortes-Castillo L. Vaccines and biosimilarity: a solution or a problem? Expert Rev Vaccines. 2009;8(10):1439---1449. 33. Casadevall N, Nataf J, Viron B, et al. Pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346(7):469---475. 34. Palmer KE, Bennett-Jenson A, Kouokam JC, Lasnik AB, Ghim S. Recombinant vaccines for the prevention of human papillomavirus infection and cervical cancer. Exp Mol Pathol. 2009;86(3):224---233. 35. Frazer I. Correlating immunity with protection for HPV infection. Int J Infect Dis. 2007;11(suppl 2): S10---S16. 36. GlaxoSmithKline. Human papillomavirus (HPV) vaccine consistency and non-inferiority trial in young adult women. Study ID: NCT00337818. Results first received: November 12, 2009. Available at: http:// clinicaltrials.gov/show/NCT00337818. Accessed January 18, 2012. 37. Ginsburg A, Nahm MH, Khambaty FM, Alderson MR. Issues and challenges in the development of pneumococcal protein vaccines: a two day international symposium. Expert Rev Vaccines. 2012;11(3):279---285. 38. Agreement on Trade-Related Aspects of Intellectual Property Rights. Annex 1C of the Marrakesh Agreement establishing the World Trade Organization, signed in Marrakesh, Morocco on April 15, 1994. Available at: http://www.wto.org/english/tratop_e/trips_e/t_agm0_ e.htm. Accessed August 29, 2014. 39. Médicins Sans Frontières. Access briefing: how a free trade agreement between the European Union and India could threaten access to affordable medicines for millions of people worldwide. Available at: http://www. msfaccess.org/sites/default/files/MSF_assets/Access/Docs/ Access_Briefing_HowFTAthreatensmeds_ENG_2012.pdf. Accessed May 10, 2014. 40. Padmanabhan S, Amin T, Sampat B, Cook-Deegan R, Chandrasekharan S. Intellectual property, technology transfer and manufacture of low-cost HPV vaccines in India. Nat Biotechnol. 2010;28(7):671---678.
46. Jorda KF. Trade secrets and trade-secret licensing. In: Krattiger A, Mahoney RT, Nelsen L, et al., eds. Intellectual Property Management in Health and Agricultural Innovation: A Handbook of Best Practices. Davis, CA: PIPRA; 2007: 1043---1058. 47. Friede M, Serdobova L, Palkonyay MP, Kieny MP. Technology transfer hub for pandemic influenza vaccine. Vaccine. 2009;27(5):631---632. 48. Palkonyay L. Status of the WHO Influenza Vaccine Technology Transfer Programme. Paper presented at: World Health Organization, Initiative for Vaccine Research (IVR) 3rd Meeting With International Partners on Prospects for Influenza Vaccine Technology Transfer to Developing Country Vaccine Manufacturers; May 5---6, 2010; Nha Trang, Vietnam. 49. World Health Organization. Public health, innovation, intellectual property and trade: technology transfer for health related products. Available at: http://www. who.int/phi/programme_technology_transfer/en. Accessed December 14, 2013. 50. Mukherjee S, Bhattacharjee S. Technology transfer and the intellectual property issues emerging from it—an analysis from a developing country perspective. J Intellectual Property Rights. 2004;9:260---274. 51. People’s Daily Online. Pharmaceutical technology transfer growing rapidly in past decade: IFPMA. March 9, 2011. Available at: http://english.peopledaily.com.cn/ 90001/90782/90880/7312820.html. Accessed January 20, 2012. 52. Wilson P. Giving developing countries the best shot: an overview of vaccine access and R&D. April 2010. Campaign for Access to Essential Medicines, Médecins Sans Frontières. Available at: http://www.msf.org.uk/ sites/uk/files/Vaccine_Report_201005111518.pdf. Accessed August 26, 2014. 53. de Martel C, Ferlay J, Franceschi S, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13 (6):607---615. 54. World Health Organization. Technology transfer for health related products: Technology Transfer Initiative. Available at: http://www.who.int/phi/programme_ technology_transfer/en/index.html. Accessed August 25, 2014. 55. Ferlay J, Shin HR, Bray F, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893--2917.
41. Blumenstyk G. U. of Michigan sells patent royalties from FluMist for as much as $35-million. Chron High Educ. July 12, 2007. Available at: http://chronicle.com/article/Uof-Michigan-Sells-Patent/39220. Accessed August 29, 2014. 42. Medicines Patent Pool. About the Medicines Patent Pool. Available at: http://www.medicinespatentpool.org. Accessed January 20, 2012. 43. Medicines Patent Pool. Company engagement. Available at: http://www.medicinespatentpool.org/ company-engagement. Accessed May 11, 2014. 44. Crager SE, Guillen E, Price M. University contributions to HPV vaccines and implications for access in developing countries: potential models for improving access to university discovered vaccines. Am J Law Med. 2009;35(2---3):253---279. 45. McElligott S. Addressing supply side barriers to introduction of new vaccines to the developing world. Am J Law Med. 2009;35(2---3):415---441.
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Improving Global Access to New Vaccines: Intellectual Property, Technology Transfer, and Regulatory Pathways Sara Eve Crager, MD
The 2012 World Health Assembly Global Vaccine Action Plan called for global access to new vaccines within 5 years of licensure. Current approaches have proven insufficient to achieve sustainable vaccine pricing within such a timeline. Paralleling the successful strategy of generic competition to bring down drug prices, a clear consensus is emerging that market entry of multiple suppliers is a critical factor in expeditiously bringing down prices of new vaccines. In this context, key target objectives for improving access to new vaccines include overcoming intellectual property obstacles, streamlining regulatory pathways for biosimilar vaccines, and reducing market entry timelines for developing-country vaccine manufacturers by transfer of technology and know-how. I propose an intellectual property, technology, and know-how bank as a new approach to facilitate widespread access to new vaccines in low- and middle-income countries by efficient transfer of patented vaccine technologies to multiple developing-country vaccine manufacturers. (Am J Public Health. 2014;104:e85–e91. doi:10.2105/AJPH.2014. 302236)
Vaccine rollout in low- and middle-income countries (LMICs) routinely lags far behind rollout in high-income countries. As of 2010— a full decade after its introduction—87% of high-income countries included the pneumococcal conjugate vaccine in their immunization schedules, compared with only 2% of lowincome countries.1 Although the Haemophilus influenzae type b (Hib) vaccine was being widely used in wealthy countries by the early 1990s, Hib vaccine coverage in Africa was estimated at 24% as of 2006.2 Twenty years after licensure of the hepatitis B vaccine, vaccine coverage was estimated at 90% in the Americas as opposed to only 28% in Southeast Asia, where hepatitis B is endemic.1 These timelines, unfortunately, are the norm rather than the exception for adoption of new vaccines in LMICs. The inequities of this situation are all the more indefensible because the vast majority of mortality from vaccine-preventable diseases occurs in LMICs3; it is estimated that more than 90% of deaths from pneumococcal disease,4 95% of deaths from Hib,5 and 80% of deaths from hepatitis B5 occur in developing countries. In May 2012, the 65th World Health Assembly endorsed the Global Vaccine Action
Plan (GVAP),6 a document that sets ambitious vaccination goals for the upcoming decade. The GVAP reflects the growing recognition by governments, international agencies, and civil society of the importance of vaccines not only for achieving international health priorities but for addressing global issues such as poverty, hunger, education, and gender equality.7 One of the key objectives outlined by the GVAP is for all immunization programs to have sustainable access to universally recommended vaccine technologies within 5 years of licensure. There is an enormous gap between this goal and the current reality of new vaccine rollout in LMICs, and the GVAP recognizes that innovative mechanisms will be needed to support scale-up of new vaccines within the proposed timeline. The Decade of Vaccines collaborative that created the GVAP has proposed the goal of achieving universal vaccine access by 20208; it is estimated that this goal will cost more than US $57 billion, with new vaccines responsible for over half the cost.9 Although there are numerous social and logistical obstacles to the adoption of new vaccines in LMICs, a clear consensus has emerged that one of the greatest barriers is
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vaccine pricing.10---15 This problem is being compounded by the increasingly high costs associated with recent vaccine innovations. The newly developed human papillomavirus (HPV) vaccine, for example, is the most expensive vaccine in history16; this is particularly problematic because the overwhelming majority of cervical cancer cases occur in developing countries.17 Like many new vaccines, the high cost of the HPV vaccine will be most prohibitive in exactly the places it is most needed, and it is unlikely that expensive new vaccines such as the HPV vaccine will become widely accessible in LMICs without extensive external funding. Currently, the most important source of external funding for vaccines in low-income countries is the Global Alliance for Vaccines and Immunizations (GAVI). GAVI’s critical role in the introduction of new vaccines to lowincome countries, most recently with its commitment to introducing the HPV vaccine,18 cannot be overstated; however, there are significant limitations inherent in this support. First, new vaccine introduction is only 1 component of GAVI’s vaccination programs, and the decision to introduce a new vaccine is based on numerous factors, which inevitably include the price of the vaccine and GAVI’s current financial status. In 2010, GAVI was facing a serious budget shortfall of over $4 billion, which threatened to limit future plans to introduce new vaccines.19 GAVI was able to raise sufficient funds to overcome this budgetary crisis; however, the shortfall highlights concerns regarding the long-term stability of GAVI’s subsidies for the future introduction of new vaccines. In any event, LMICs that are not eligible for GAVI funding are likely to have difficulty financing new vaccines without assistance,12 and the GVAP notes that innovative pricing strategies will be particularly important for those LMICs that do not have access to GAVI pricing and procurement mechanisms. In
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addition, the subsidies provided by GAVI to finance new vaccines are intended to be limited to a 5-year period, with the expectation that, over that time, prices will fall, allowing donors and national governments to continue vaccine financing. To date, however, this expectation has not been realized. Once it became apparent that vaccine prices were not dropping rapidly enough, GAVI was forced to revise its support timelines. Thus, a critical limitation to GAVI’s role in promoting access to new vaccines is the failure to establish mechanisms ensuring sustainable vaccine pricing once the initial period of support has ended. There is an emerging consensus that the most important factor in achieving sustainable vaccine pricing is the market entry of developing-country vaccine manufacturers (DCVMs).1,20---23 I propose an intellectual property, technology, and know-how (IPTK) bank as a novel strategy to enable early market entry of multiple DCVMs to facilitate rapid rollout and sustainable pricing of new vaccines in LMICs.
OVERCOMING ACCESS BARRIERS FOR NEW VACCINES In January 2010, a consultation meeting convened by Médecins Sans Frontières and Oxfam brought together experts from around the world to discuss strategies for improving access to vaccines in LMICs.20 New vaccines were a major focus of this meeting, which included representatives from key players such as the Netherlands Vaccine Institute, the International Vaccine Institute, Third World Network, Program for Appropriate Technology in Health, and the World Health Organization (WHO). The consultation meeting report concluded that although organizations such as the Pan American Health Organization Revolving Fund—which effects reduced prices through bulk procurement systems—are key players in improving vaccine access, such entities have not proven sufficient to ensure affordable prices for new vaccines. The report further noted that success with tiered pricing approaches has been mixed and has not consistently resulted in sustainable prices, particularly for new vaccines. It concluded that future strategies to improve access to new vaccines will need to include (1) streamlining regulatory
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pathways for biosimilar vaccines, (2) addressing intellectual property barriers, and (3) reducing the barriers and timelines to the entry of multiple new suppliers by transfer of technology and know-how. Before addressing each of these strategies in detail, I will briefly discuss the implications of the fact that vaccines are biologics rather than small-molecule drugs.
Vaccines as Biologics and Implications for Access Strategies The presence of multiple DCVMs has been identified as a critical factor in generating sustainable vaccine prices. It is now widely recognized that the advent of generic drug production, but more importantly the market entry of multiple generic drug suppliers, is the best mechanism for rapidly achieving dramatic price reductions. The major expansion of HIV/ AIDS treatment in LMICs, for example, was made possible through the entry of generic manufacturers in countries such as India and Brazil; with the advent of robust generic competition, prices of first-generation antiretroviral drugs fell by more than 99%, from $10 000 annually per patient in 2000 to less than $70 in 2014. Strategies to improve access to medicines have thus coalesced around the goal of enabling generic production. This has led many of these efforts to focus on patent protection as a key barrier to the availability of affordable generic medicines. A crucial assumption that underlies this strategy is that it is fairly straightforward to reverse engineer a given drug; in concept, the problem is not that generic drug manufacturers would be unable to exactly replicate a drug, it is that they are prohibited from doing so by patent law. Although this is generally the case for smallmolecule drugs, this basic assumption does not hold true for biologics, including vaccines. The majority of medications in common use are small-molecule drugs, which are generally low-molecular-weight organic compounds synthesized by chemists. Biologic drugs, a category that includes vaccines, are generally produced by living cells and are significantly larger and structurally more complex than small-molecule drugs. To successfully reverse engineer a small-molecule drug, it is not necessary to precisely duplicate the manufacturing process in order to guarantee an identical product. In the case of vaccines, however, an identical
product is not necessarily guaranteed if an alternative production process is used. The details of the vaccine production process can affect variables such as 3-dimensional structure and posttranslational modifications, which are important determinants of vaccine immunogenicity. Detailed information on vaccine production processes is usually not patented. Instead, this information is protected by trade secret law, under which it is never made publicly available because, unlike patent protection, there is no scheduled expiration after a preset term.24 This perpetual monopoly prevents replication of the production process, thus precluding straightforward duplication of the vaccine.25 Furthermore, because vaccine manufacturing is often highly complex, significant know-how may be required to reproduce a vaccine, necessitating direct input from the original product developer. In sum, although patent protection remains the major barrier to the production of affordable small-molecule generics, access to trade-secret--protected information and know-how present major additional obstacles to generic production of vaccines. A successful vaccine access strategy that relies on early production by multiple DCVMs will need to address all of these issues.
Streamlining Regulatory Pathways for Biosimilar Vaccines To bring a generic drug to market, a company must go through an abbreviated approval pathway established by national regulatory agencies such as the US Food and Drug Administration. Because of the high degree of manufacturing complexity and the difficulties inherent in reverse-engineering biologics, no abbreviated approval pathway existed for biologics until very recently. Over the past several years, a number of governments have created new regulatory frameworks for abbreviated approval of generic biologics (referred to as “follow-on biologics” or “biosimilars”). The European Union was the first to establish such guidelines,26 and in 2010 the United States passed the Biologics Price Competition and Innovation Act27 as part of the Affordable Care Act. The WHO has also now published guidelines for the approval of biosimilars28 modeled on EU guidelines, and the Indian Department of Biotechnology recently introduced a similar set of guidelines.29
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To date, the debate regarding implementation of abbreviated approval pathways for biosimilars has focused on the category of therapeutic proteins, and implementation has yet to be discussed in the context of vaccines. This is partly because therapeutic proteins are far more lucrative for the pharmaceutical industry; the global market for therapeutic proteins was valued at US $93 billion in 2010 and is predicted to reach more than $140 billion by 2017,30 whereas the global vaccine market is currently valued at a little more than $2 billion.31 It is, however, also partly because of the recognition that there are fundamental differences between vaccines and therapeutic proteins that will require special regulatory consideration.32 It will be important for regulators to consider how abbreviated approval pathways for biosimilars should be implemented specifically in the context of vaccines. The major safety concern surrounding approval of biosimilars is their potential immunogenicity. Immunogenicity, which refers to the tendency of a drug or vaccine to elicit a response from the body’s immune system, can be either a desirable property (in the case of vaccines) or an undesirable property (in the case of therapeutic proteins). Safety concerns related to biosimilars immunogenicity is best exemplified by the oft-cited example of a minor manufacturing change to a therapeutic protein product that resulted in a number of cases of severe anemia thought to be caused by increased product immunogenicity.33 A similar incident is improbable with vaccines because microbial antigens are far less likely to induce an immune response that cross-reacts with endogenous proteins. Another key issue in the debate over biosimilars is the extent to which additional clinical trials will be necessary for approval. Here as well, special consideration needs to be taken for vaccines, particularly with regard to the potential use of correlates of protective immunity to define appropriate clinical trial endpoints. Defining a validated correlate of protective immunity could allow clinical trial evaluation of biosimilar vaccines to be accomplished more rapidly and at lower cost than will likely be necessary for most therapeutic proteins.34 A precedent for using correlates of protective immunity in this manner was set during clinical trials of the HPV vaccine; Merck
conducted a bridging study to a younger age group (in which the use of cervical intraepithelial neoplasia as an endpoint was infeasible) by comparing antibody responses to those in the older cohort in whom efficacy had been previously established.35 GlaxoSmithKline has used a similar metric in a noninferiority trial of Cervarix after a manufacturing change, using antibody titers as the major trial endpoint.36 The WHO has set similar precedents; for example, convening a series of expert consultations with the objective of establishing antibody reference values related to clinical efficacy outcomes for the pneumococcal vaccine.37 Issues of the safety and efficacy of biosimilar vaccines, however, will ultimately need to be evaluated on a case-by-case basis. Now that various national governments and international agencies are establishing abbreviated approval pathways for biosimilar biologics, approaches to streamlining a pathway for abbreviated approval of biosimilar vaccines should be explored in detail.
Addressing Intellectual Property Barriers Although patent protection may not be the sole barrier to the production of biosimilar vaccines, it remains a major obstacle. This is especially true in the era of broad enforcement of the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights,38 which significantly limits the ability of countries like India (the “pharmacy of the developing world”) to produce medications still under patent protection in high-income countries.39 Gardasil, 1 of 2 recently developed vaccines for HPV, provides an example of the complex patent landscape that can be expected to surround new vaccines. To date, 81 US patents for Gardasil have been granted to a total of 18 different organizations.40 Such a morass of intellectual property clearly has the potential to be a significant impediment to any access strategy that relies on the early entry of new suppliers. In addition, intellectual property barriers will likely apply to new formulations of existent vaccines (e.g., noninjectable delivery systems or improved vaccination schedules), a precedent that has been set by the new intranasal influenza vaccine.41 This could become particularly relevant if an organization
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wished to apply a technology for adapting delivery methods to the manufacture of a new vaccine (e.g., to produce a noninjectable HPV vaccine). An access strategy that may be particularly relevant to patent-related barriers to generic production of new vaccines is the Medicines Patent Pool (MPP). The MPP,42 established with the support of UNITAID in 2009, aims to enable the affordable production of HIV drugs still under patent protection by obtaining voluntary licenses from patent holders and making these licenses available to generic companies in LMICs. Through the MPP, licenses to all patents required to produce a given end product are provided as a package to multiple generic manufacturers on a nonexclusive basis. These manufacturers must meet quality, safety, and efficacy standards, and must have access to markets that are large enough to achieve economies of scale and generate major price reductions. Royalties will be paid to patent holders, and generic licenses will be for use only in LMICs, thereby avoiding infringement upon the main target markets of brand-name manufacturers. Although the MPP was established only recently, the response of the pharmaceutical industry has been encouraging thus far.43 To date, the MPP has negotiated licenses with the US National Institutes of Health, Gilead Sciences, Bristol-Myers Squibb, Roche, and ViiV Healthcare, and is currently engaged in discussions with a number of other major pharmaceutical companies.
Reducing Timelines to New Supplier Market Entry A vaccine access strategy that relies on the rapid market entry of multiple DCVMs must address the issue of intellectual property rights12; however, there are multiple additional barriers that must be surmounted to allow generic companies to efficiently and costeffectively duplicate a vaccine.44 Access to manufacturing process information protected by trade-secret law, as well as access to technology and know-how held by the innovator company, will likely be necessary. A strategy to incentivize companies to disseminate process secrets and know-how to DCVMs would be a major step toward increasing vaccine access in LMICs.45 Such a strategy would require the relevant actors to work together to find
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a balance between the need to allow DCVMs to produce vaccines for lower-income markets and the need of innovator firms to recover sunk costs from higher-income markets.45 Transfer of technology and know-how to DCVMs has been identified as a key factor allowing affordable vaccines to reach the market rapidly,20 and innovative technology transfer mechanisms could play a central role in improving vaccine accessibility. It is important to note in this context that most technology transfer licenses cover both patents and trade secrets.46 The WHO has recognized the importance of DCVM technology transfer in their response to the recent crisis in global production capacity of the influenza vaccine.47 In 2007, the WHO created a technology transfer hub as a strategy to rapidly increase the number of influenza vaccine producers in LMICs. In this model, a publicly funded institution provides a base to bring together all necessary manufacturing, clinical, and regulatory expertise to create a comprehensive documentation package with corresponding training modules. This package is then transferred to various DCVMs, allowing them to efficiently and cost-effectively reproduce a vaccine. The technology transfer hub model recognizes the inefficiencies of currently prevalent one-to-one technology transfer involving a single provider and a single recipient, and the WHO’s technology transfer hub has been highly effective in rapidly expanding DCVM influenza vaccine production capacity48; since its inception, it has facilitated the establishment of 14 DCVMs producing pandemic influenza vaccines.49 It is important to take note of not only the large number of DCVMs that are now producing the vaccine, but also the rapidity with which this was achieved. The WHO is expanding on this concept with their Technology Transfer Initiative, a project to create “centers of excellence” capable of transferring other manufacturing processes to multiple recipients.49 Although technology transfer hubs could provide a highly effective avenue for achieving rapid market entry of multiple DCVMs, they have a critical limitation: this model can only be used with vaccines for which no intellectual property barriers exist in both the country hosting the hub and the country receiving the
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technology. This requirement will effectively preclude using technology transfer hubs to accelerate the market entry of DCVMs for vaccines still under patent protection. Functionally, then, the technology transfer hub model cannot be applied to new vaccines. Unfortunately, this is exactly the situation in which such a model could prove most useful because it is these vaccines that are the most expensive and thus could benefit most from the early market entry of multiple DCVMs.
A STRATEGY TO IMPROVE ACCESS TO NEW VACCINES Patent pools and technology transfer hubs are 2 approaches that are being successfully employed to improve access to medicines by increasing the number of developing-country generic suppliers; however, neither will be able to resolve the problems facing access to new vaccines. Patent pools do not incorporate mechanisms to provide access to manufacturing process information and know-how necessary to duplicate a vaccine. Technology transfer hubs, on the other hand, explicitly exclude patented vaccines, making this model inapplicable to essentially all new vaccines. Therefore, neither patent pools nor technology transfer hubs are individually equipped to enable widespread access to new vaccines through reducing the barriers and timelines to the entry of new DCVMs. The focus of the access-to-medicines movement on small-molecule drugs—driven partly by the HIV/AIDS epidemic—has resulted in a proliferation of innovative intellectual property strategies converging around patent protection. At the same time, organizations that specifically promote access to vaccines have traditionally focused on expanding access to existent vaccines and strengthening national immunization systems rather than ensuring access to new vaccines; GAVI’s inception in 2000 was significant partially because one of its priorities was to expand access to new vaccines; however, this did not include the development of novel upstream mechanisms for rapidly achieving sustainable pricing for new vaccines. There is no intrinsic reason that mechanisms for addressing patent protection and those for addressing technology transfer must remain distinct. Licensing agreements
combining rights to patents with rights to technology and know-how are actually quite common.50 I propose a strategy that would integrate key aspects of both these models, creating a structure capable of facilitating access to new vaccines by establishing an entity that pools all relevant intellectual property, technology, and know-how: an IPTK bank. An IPTK bank would bring together the necessary intellectual property rights, manufacturing process information, know-how, and regulatory expertise into a single platform that could be licensed as a package with associated training modules; it could also offer assistance in navigating vaccine registration with national regulatory authorities. A licensing approach similar to that used by the MPP would be employed to address intellectual property barriers by creating a structure whereby the patented technology could be disseminated to multiple DCVMs, each paying royalties to the patent holder. The manufacturing process information, know-how, and regulatory expertise would be brought together through the organization hosting the IPTK bank, which would closely mirror the organizational model of the WHO technology transfer hub.
Barriers to Creation of the Proposed Banks Funding, inevitably, will be a major barrier to the creation of IPTK banks. IPTK banks would require an initial period of funding in order to acquire and then disseminate the vaccine technology. Once a critical mass of DVCMs began producing the vaccine, however, provision of affordable vaccines would be self-sustaining, with reliance on market forces to ensure appropriate price declines. IPTK banks thus would not be as subject to the vagaries of sustained donor funding as organizations like GAVI, but would rather need to raise enough money to support the initial acquisition and dispersal period for each new vaccine technology. Given that projected spending on new vaccines necessary to achieve the GVAP goals is estimated at nearly US $30 billion, it may ultimately be more cost-effective to invest in upstream mechanisms to rapidly achieve sustained price reductions for new vaccines. The greatest barrier to the creation of IPTK banks is the need for close cooperation with
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innovator companies. Fundamentally, engaging with an IPTK bank would be similar to the technology transfer arrangements that multinational pharmaceutical companies frequently enter into with individual DCVMs to expand their regional vaccine production and distribution. The major departures from a traditional technology transfer agreement would include licensing terms that allow the IPTK bank to grant nonexclusive licenses to multiple DCVMs and the transfer of technology to a hub organization at a publicly funded institution rather than directly to a DCVM. Because an IPTK bank strategy depends on significant involvement from innovator companies, creating appropriate conditions that incentivize their participation is key to the success of this model.
Engagement With Innovator Companies Multinational pharmaceutical companies frequently engage in successful technology transfer with DCVMs, and this trend appears to be growing. According to an International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) spokesperson, Technology transfer in medicines and vaccines were growing rapidly in the past decade, benefiting both pharmaceutical companies and the health of recipient countries’ population alike.51
In fact, so much interest has developed around this topic that the IFPMA recently issued a research paper titled “Technology Transfer: a Collaborative Approach to Improve Global Health—the R&D Pharmaceutical Industry Experience.” In addition to providing numerous case studies of technology transfer partnerships, the paper identified 8 conditions that the pharmaceutical industry considers necessary for successful technology transfer relationships: 1. a viable and accessible local market, 2. political stability and good economic governance, 3. clear economic development priorities, 4. adherence to high regulatory standards, 5. availability of skilled workers, 6. adequate capital markets, 7. strong intellectual property rights and effective enforcement, and 8. a high-quality relationship between industry and government, and their ability to work together effectively for long periods of time.
An IPTK bank as a technology partner would fulfill most of these criteria. The fact that an IPTK bank would almost certainly be based in a high-income country would also address a number of these issues. In this context, there should be relatively little concern over issues such as political stability and good economic governance, and most industrialized-country governments are generally considered to have relatively good relationships with industry and a long history of working together effectively. These conditions may not be guaranteed to the same degree in all countries that receive technology from an IPTK bank, but that risk would not be directly borne by the company and would be distributed over multiple potential technology partners. In addition, high-income countries generally have well-established systems of strong intellectual property rights with effective enforcement. Again, this may or may not be true to the same extent in all countries that are recipients of IPTK bank technology; however, industry has already shown itself willing to discuss licensing arrangements with the MPP that would involve licensing intellectual property rights to a central organization, which would then provide nonexclusive licenses to multiple other entities in countries that may not have similarly strong enforcement of intellectual property rights. Regarding access to viable local markets, although the IPTK bank itself would not directly have such access, licenses would be granted only to partners with demonstrable access to local markets large enough to achieve economies of scale such that significant price reductions could be generated (as occurs with the MPP). Finally, if the IPTK bank is based at an institution such as the Netherlands Vaccine Institute or the International Vaccine Institute, availability of skilled workers should be more than adequate. Basing the IPTK bank within such organizations would provide a strong base of experience in adherence to high regulatory standards that would be passed on to IPTK bank technology recipients. Overall, IPTK banks would fulfill the criteria that the IFPMA has identified as being critical to the decision of multinational pharmaceutical companies to engage with a technology transfer partner. The major departure from the technology transfer arrangements described in the IFPMA report would be use of a licensing
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covering all necessary intellectual property modeled on the MPP licenses rather than the traditional sublicense negotiated between pharmaceutical companies and their technology partners. Companies have demonstrated their willingness to enter into negotiations involving such licenses with the MPP, providing a precedent that this may not present an insurmountable barrier to companies engaging in technology transfer agreements with an IPTK bank. Although an IPTK bank would require a high degree of commitment and cooperation from innovator companies, it seems possible that industry might be willing to consider engaging in discussion regarding this approach to expanding vaccine access.
Unique Benefits of the Proposed Banks While IPTK banks are a new and untested model for improving access to vaccines in LMICs, this strategy is firmly based in previously established and successful organizational models. IPTK banks would not be a fundamental departure from these models; rather, by combining them to improve access to new vaccines, they would create possibilities that neither patent pools nor technology transfer hubs could generate individually. Bringing together all necessary intellectual property, technology, know-how, and regulatory expertise under a single umbrella organization with the power to efficiently disseminate this package to multiple DCVMs could facilitate a framework for biosimilar vaccine production capable of mimicking generic competition. In addition, although IPTK banks would require an initial period of substantial funding, the impact on pricing for an individual vaccine would ultimately be self-sustaining. A major drawback for pharmaceutical companies is that the vaccine prices currently offered through their tiered pricing schemes are almost certainly higher than could be achieved through competition.52 At the same time, an IPTK bank model could offer several unique benefits for partner companies. It would allow a company to reap some of the benefits of expanding to developing-world markets without taking the risk of making the large investments necessary to build additional production capacity. A company could similarly accomplish this through traditional technology transfer, but this process also involves
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a significant investment of time and resources from the innovator company. Engaging in technology transfer with an IPTK bank could to some degree mitigate the risks potentially associated with licensing directly to a single producer in a developing country. In addition, companies licensing technologies with an IPTK bank would receive royalties from multiple licensees with the same input of time and resources that, in traditional one-to-one technology transfer arrangements, would only result in receipt of royalties from a single company. In fact, royalty percentages required from any single company could be lower than those negotiated in traditional one-to-one technology transfer agreements, while overall still generating more royalties than the originator company would receive from engaging in technology transfer with a single partner.
CONCLUSIONS To achieve the goal set out in the GVAP for all immunization programs to have sustainable access to universally recommended vaccine technologies within 5 years of licensure, innovative new approaches will be necessary. The crucial role of generic competition and the importance of developing-country manufacturers in expanding drug access is unequivocal. In the case of vaccines, a clear consensus is emerging that market entry of multiple DCVMs is a critical factor in bringing vaccine prices down to sustainable levels, and that technology transfer will be key to expediting this process. For this approach to significantly improve the timeline for access to new vaccines, issues of both intellectual property rights and transfer of vaccine technology and know-how must be addressed. It is not clear that any single strategy currently in use will be able to accomplish this. An IPTK bank is one possible approach that integrates components of previously established successful models in order to allow rapid transfer of new vaccine technologies to multiple DCVMs efficiently and cost-effectively. In the future, a version of this model could be particularly relevant in bringing together the necessary intellectual property, technology, and know-how required to create adapted formulations of new vaccines that would be better suited to the needs of LMICs. A further avenue that merits exploration is how the
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newly established regulatory pathways for abbreviated approval of biosimilars may be applied to vaccine technologies. Finally, the global community needs to recognize the growing importance of biologic medications in the treatment of noncommunicable diseases such as cancer in LMICs. The HPV vaccine was a breakthrough partially because it was the first vaccine designed specifically to prevent cancer. Now that numerous strong links between other viruses and cancer are becoming increasingly clear, there may be hope for more “cancer-prevention” vaccines on the horizon; it is estimated that 16% of new cancer cases globally are attributable to infections, with a significantly higher proportion in less-developed countries.53 As noted by the WHO’s Technology Transfer Initiative, The concept of creating centers of excellence able to establish and transfer manufacturing processes to multiple recipients is currently being applied to other medical products including monoclonal antibodies and other biologics.54
This is an important move forward; however, in its current form it would not be applicable to new biologic products. Because many of the most promising new cancer treatment advances are biologics, and most of the global cancer burden is now carried by developing countries,55 the inapplicability of this model to new biologics poses a significant problem. The unacceptably long delays to vaccine access in LMICs must not be perpetuated with future vaccine innovations. Mechanisms that have been successfully used to improve access to small-molecule drugs cannot be similarly invoked to increase the availability and affordability of vaccines and other biologics. IPTK banks are one possible strategy to rapidly bring down vaccine prices to sustainable levels, one with the potential to be applied to all biologics. j
About the Authors Sara Eve Crager is with the Department of Emergency Medicine, University of California, Los Angeles. Correspondence should be sent to Sara Eve Crager, University of California Los Angeles, Emergency Medicine, 924 Westwood Blvd, Suite 300, Los Angeles, CA 90025 (e-mail: [email protected]). Reprints can be ordered at http://www.ajph.org by clicking the “Reprints” link. This article was accepted July 22, 2014.
Acknowledgments I appreciate contributions to this work from Rachel Kiddell-Monroe, board president, Universities Allied for Essential Medicines, and from Kevin Outterson, professor of health law, bioethics and human rights, Boston University School of Law.
Human Participant Protection Human participant protection was not required because no human participants were involved in this study.
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