Abstract
Over a period of 25 years only 1 % of new drugs were approved specifically for so-called neglected diseases, which represent over 12 % of the global disease burden in terms of mortality and chronic disability.
The authors briefly describe the Drugs for Neglected Diseases initiative (DNDi) model set up to address this gap, and give an example of the paediatric HIV project that has been undertaken in support of the needed HIV response. The role that research networks (such as PENTA, IMAACT and GRIP), public-private partnerships and strategic mobilization of key stakeholders have played in drug development and drug/formulation access for children has been highlighted. The effective achievements obtained in scaling up deployment of antiretroviral drugs in resource limited settings show the importance of consolidating public and private partnership (WHO, innovative research intensive and generic pharmaceutical companies and international agencies working with partners from countries where diseases are endemic).
Keywords
- Resource Limited Setting
- Paediatric Drug
- Paediatric Formulation
- Strengthen Research Capacity
- Marketing Authorization Holder
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Background
Just 20 years ago, research and development (R&D) for the treatment of diseases disproportionately affecting developing countries was negligible. Over a period of 25 years (1974–1999) only 1 % of new drugs were approved specifically for so-called neglected diseases, which broadly indicates diseases prevalent chiefly in low-income countries or other low-resource settings and for which no or limited health technologies are available or in development [1], despite the fact that these diseases represented over 12 % of the global disease burden in terms of mortality, chronic disability and poverty [2, 3]. The need for greater political commitment to fight these conditions has been recognized by the United Nations and included in the Millennium development goals (target 8E) [4].
Over the past decade, several major initiatives and innovative research and development (R&D) models have emerged to address neglected diseases. Despite objective progress and acceleration in new drug development, there is still a major gap between the needs and the treatments available for these diseases. Of the 850 drugs and vaccines approved (40 % new chemical entities) from 2000 to 2011 only 4 % were for neglected diseases. Furthermore, of the 150,000 clinical trials registered for new therapeutic compounds, only 1 % were for these disease areas and less than 0.5 % of them included children [5].
The lack of R&D investment for neglected diseases and for paediatric drugs has been attributed to the very low financial return for pharmaceutical companies. However, public institutions also failed to establish effective enabling policies and have not prioritized neglected diseases and thus also share responsibility for the current situation [6]. New approaches and alternative R&D models to address market and policy failures have been launched and include a broad range of actors, including academic groups, pharmaceutical companies, governments from disease-endemic countries and emerging economies, and others [2]. One of the results of this evolution was the not-for-profit product development partnership (PDP) model, an example of which is the Drugs for Neglected Diseases initiative (DNDi).
In this chapter, we briefly describe the DNDi model, and give an example of the paediatric HIV project it has undertaken in support of the HIV response. We highlight the role that research networks, public-private partnerships and strategic mobilization of key stakeholders have played in drug development and drug/formulation access for children.
Looking Back: A Brief Sketch of Public Health Achievements in Antiretroviral Drugs
One of the most successful achievements in the history of public health intervention has been the rapid implementation and use of antiretroviral drugs (ARVs) in countries with high HIV prevalence. In Africa, the region with the highest HIV burden, an estimate of nearly ten million people were receiving ARV treatment at the end of 2013, compared with only 50,000 a decade earlier [7]. However, only about 25 % of African children in need of ARVs are receiving them today [7]. There are major challenges in the implementation of early infant diagnosis and in the development and provision of appropriate paediatric formulations. Thus far, the progress made in scaling up ART for Africa has been enabled by an effective ‘model’ of public and private partnerships, which have mobilized international organizations, multilateral partners, research networks, non-profit organizations, philanthropic entities and industries in high- and low-income countries (see also Chap. 3).
The DNDi Model
DNDi, an independent international non-profit, patient-needs driven R&D organization, was established in 2003 to fill R&D gaps for neglected diseases [8]. Its mission is to deliver new treatments for its targeted diseases by developing entirely new drugs and re-formulations or new combinations of existing drugs, to optimize treatment and improve outcomes. In doing so, it also aims to develop sustainable research capacity in disease endemic countries and advocates for public responsibility globally [8] (see Chap. 18).
In 10 years of activity, DNDi was able to deliver six new treatments for neglected diseases and establish a solid drug pipeline including 13 new chemical entities in pre-clinical and clinical development. With its many partners, DNDi has conducted more than 25 clinical studies from phase I to phase IV, including implementation and pharmacovigilance studies, enrolling more than 33,000 patients often in very remote and unstable areas. To do that, DNDi established partnerships with a wide range of organizations including funders, academia, public sector research institutions and networks, pharmaceutical companies, non-governmental organizations and governments worldwide (including some 350 collaborations in 43 countries, 20 pharmaceutical and biotechnology companies, and 50 universities and research institutes). North-south and south-south technology transfer projects and disease specific clinical research platforms were formed to strengthen research capacity in neglected disease-endemic countries. In 2010, while maintaining its core focus on the three most neglected tropical diseases, DNDi responded to a call by various organizations, including Médecins sans Frontières, WHO, and the global health initiative UNITAID, to apply its expertise to the development of paediatric HIV drug formulations. Although from the R&D perspective, HIV is not seen as a neglected field, the fact that paediatric HIV has been virtually eliminated in wealthy countries has left pharmaceutical companies little incentive to develop child appropriate formulations [9]. While the same neglect can be seen to apply to the development of paediatric formulations in general, the lessons learnt in the paediatric HIV field are worth documenting and may provide insight to paediatric drug development in general.
The ‘AIDS Response’
The AIDS exceptionalism in the west rose in the 1980s and ended at the end of 1990s when technical solutions of testing and antiviral treatments were made available. However, the same struggle for access to treatment in developing countries did not happen at the same time. In 1996, during the International AIDS Conference in Vancouver, the first studies showing how combination antiretroviral therapy (ART) can reduce HIV disease progression were presented. This scientific breakthrough was, however, restricted to high-income countries which had all the needed financial and health care resources to mobilize and control the epidemic. Realizing the gap in response and the imminent rise in the HIV/AIDS epidemic in sub-Saharan Africa, the issue gained momentum in the international community and in 2001, UN Secretary General Kofi Annan called for a ‘war chest’ of $7–10 billion to address the global HIV/AIDS crisis. Mobilization from different angles such as price of treatment which is linked to intellectual property rights, positioning of the inequity of treatment access as an international human rights cause, implementation of successful treatment programmes in resource poor countries, setting up of the Global Fund to Fights AIDS, Tuberculosis and Malaria in 2002 and President’s Emergency Plan for AIDS Relief in 2003 all led to the needed access to treatment in many developing countries, and sub-Saharan Africa in particular. The story is very compelling and almost unique for a single disease. A subset of this story is the one experienced by children living with HIV/AIDS [10].
Despite the success in bringing antiretroviral treatments to the developing countries, efforts are mainly concentrated on adults, while children with HIV/AIDS suffered the neglect of tools (diagnostics and medicines) and political will in the early years. As early as 1982, cases of children with HIV were reported in North America and Europe, a few months after AIDS had been described as a new disease in the adults by the US Centers for Disease Control. When the epidemic heightened in the 1990s in sub-Saharan Africa, so did the perinatal transmission of HIV to the babies. Many deaths in children with HIV/AIDS were not accounted for and many children were orphaned as a result of losing their parents to the same disease. Today, thanks to the effective implementation of the use of ARV during pregnancy for prevention of mother to child transmission of HIV, perinatal transmission in the developed countries including some emerging countries such as Thailand and Brazil, has been eliminated [11]. However, despite a decrease in the number of new cases, the number of children living with HIV/AIDS continue to be highest in sub-Saharan Africa and treatment coverage remains low, at 25 %, half that of adults [7].
When the ART scale-up started in developing countries, treatment programmes struggled with demonstrating feasibility of such programmes in resource poor settings. It was a major challenge to treat children with HIV partly because of lack of diagnostic facilities and optimal drugs. Infants and children infected with HIV had to take large amounts of liquid formulations and to use split adult tablets. When fixed-dose combinations (FDCs) were made available for adults, some programmes resorted to breaking these adult tablets for use in children due to the simplicity it offers to the caregiver and management of drug supply as liquid formulations are bulky, difficult to store and may cause stigma in the community. There was a clear need to develop adapted paediatric HIV formulations for developing countries but it was a gruelling battle to fight against the disincentive that the paediatric HIV market offers the pharmaceutical industry. Ninety percent of children living with HIV are in sub-Saharan Africa. It was not one but a series of actions or initiatives by a collective number of actors representing a wide range of organizations and companies which made it possible. The story of access to HIV medicines for children is a fascinating one to tell, with many lessons learnt which can provide a useful case study for other diseases as well.
Role of HIV Treatment Guidelines for Developing Countries
Treating children with HIV through a normal programmatic approach proved challenging in the early 2000s. There was a lack of trained skilled health personnel and expertise in treating children with HIV. Diagnosing and treating children living with HIV appeared to be complex due to the lack of simplified guidance for resource limited settings. The first Guideline on Scaling up ARV Therapy in Resource Limited Settings was published by the World Health Organization in 2002 [12]. The guideline was aimed at scaling up ARV treatment using a public health approach which promoted rational and safe use of medicines. This technical guidance was developed with the support of US National Institutes of Health which recommended standardized regimens and simplified monitoring. The first guidelines included a section on diagnosis and treatment of children with HIV, but at that time there was a clear lack of diagnostic tools and drugs to enable treatment scale-up and achieve global targets.
Despite these simplified guidelines, programmes struggled to implement paediatric care because of poor capacity among health care workers who had limited experience in treating children and were hesitant starting treatment in those in need. Additional challenges were offered by the almost complete lack of age-appropriate paediatric ARV formulations suitable to supply in resource limited settings; no FDCs were available for children, no simplified dosing procedures had been provided to ease dose adjustment and provision by health care workers, paediatric ARV formulations were remarkably expensive and diagnosis in infancy was impeded by the lack of simple and affordable HIV-diagnostic tests for children under 18 months [13]. One of the leading implementers of HIV programmes in resource limited settings, Medecins Sans Frontieres, described the challenges faced between 2001 and 2005 in treating children with adult FDCs. These tablets had to be broken or crushed and dosing were provided based on weight bands. Programmes had no access to HIV viral loads assays at that time but, reassuringly, survival and clinical or immunological outcomes were similar to those observed in adults.
The revised 2006 WHO recommendations [14] were subsequently collected in stand-alone comprehensive guidelines that focused on providing care and treatment to infants and children. This guideline introduced more detailed information to guide diagnosis and management of children living with HIV including drug dosages, side effects, WHO staging and classification of HIV/AIDS in children. The paediatric formulation dosages were particularly complex and the need was apparent for development of a simplified weight-based dosing approach to facilitate prescribing by non-specialized personnel (see Chap. 6). The development of a generic tool to combine different drugs based on the US Food and Drug Administration (FDA) approved target dose enabled, for the first time, the establishment of a pragmatic approach to dosing and the development of FDCs containing 2 or 3 drugs in the same tablets [15]. Validation of these products that were developed in response to WHO recommendations by generic companies (via an advisory board of experts, the Paediatric ARV Working Group) occurred through the efforts of a research network committed to investigating feasibility, acceptability and PK of these products as nested sub-studies of bigger paediatric trials underway in resource limited settings.
The ‘treatment 2.0 initiative’ that included a key pillar, ‘treatment optimization’, leveraged these concepts and promoted further efforts in developing normative guidance that could result in simplification and harmonization of the deployment of more effective and less toxic drugs. Alignment of paediatric with adult treatment options and the development of these key products has been one of the central messages emerging from the WHO 2013 consolidated guidelines [16]. These guidelines, significantly forward looking, have called for urgent development of key paediatric formulation that would be critical to allow country implementation, such as the ‘4-in-1’ FDC that includes LPV, RTV, 3TC and ABC or AZT as optimal regimen for children less than 3 years.
While the development of the WHO guidelines entails a very rigorous evidence-based approach that takes into account feasibility and cost implications, these guidelines also provide a powerful advocacy tool to catalyse attention and mobilize resources towards development of new paediatric drugs and formulations for resource limited settings.
Development of Adapted Formulation for Children Living With HIV
The last decade has been hailed as the golden decade of ARV development despite claims that the HIV drug pipeline is drying up [17]. An impressive 34 % of the new drugs or combinations (16/49) were approved by US FDA since 2000, representing an active pipeline. However, of the ARVs which are approved by US FDA, only 12 are approved for use in children below 2 years of age [18].
Paediatric studies are required as part of new drug application to US FDA since 1997 and incentives for pharmaceutical companies are offered through marketing exclusivities. The European Parliament in 2007 issued the Paediatric Regulation, requiring the marketing authorization holder to present a Paediatric Investigation Plan (soon after the results of phase 1 trials in adults) to be evaluated by the Paediatric Committee at the EMA, including paediatric studies to be developed (see Chap. 10). Although this process is compulsory for new marketing authorization holders, EMA offers an incentive by granting patent extensions. These legislative measures have forced and incentivized R&D companies to plan early paediatric development strategies.
In an analysis of the time needed from adult ARV approval to granting of paediatric exclusivity following submission of all US FDA required paediatric studies, there was an average of 6.5 years (range <1 year to 14.9 years) [17]. Since drug studies in children are usually done in a de-escalating age bands, evidence-based treatment takes longest to reach the youngest age groups. The formulations were initially formulated in syrups and intended for the developed world. However, it became evident very quickly that the majority of HIV infected children are living in sub-Saharan Africa and that health care workers and caregivers in these countries were struggling with the burden of managing bulky syrups from the supply chain perspective as well as difficulties in administering multiple syrups with different dosages. Soon activists were calling for FDCs for children. Some started to use adult FDCs by breaking or cutting them.
In response to the need for paediatric FDCs, a WHO/UNICEF consultation in 2004 established a priority list of missing formulations and discussed ways to encourage pharmaceutical companies to produce them [19]. As a result of this WHO developed a generic weight band dosing tool to facilitate the development of paediatric FDCs in 2006. The fact that the WHO Expert Committee on the Selection and Use of Essential Medicines recommended and endorsed the use of such products and encouraged their development since 2005 also helped countries to prioritize selection of FDCs in national formularies. From the technical perspective, since paediatric combinations usually do not often exist in the original formulations, further guidance was needed to assist generic manufacturers in developing them, especially with regard to dosages and dosing. The WHO Paediatric ARV Working Group was tasked to do this and in 2007 issued a report prioritizing preferred ARVs for treating HIV in younger children and grading them as ‘urgent’, ‘high’ and ‘important’ in order to give guidance to manufacturers [20]. The entry of Indian generic manufacturers into the paediatric HIV market started around this time and UNITAID started to fund paediatric HIV commodities in 2006. In August 2007, the first paediatric FDC (d4T/3TC/NVP) was tentatively approved by US FDA. The commitment from UNITAID to fund this market was the main driving force for the entry of generic manufacturers. In an analysis of the global paediatric ARV market, UNITAID was the largest donor for paediatric ARV products with 97–100 % market volume in 2008–2009 [21].
From the regulatory perspective, it was important to note that the WHO Prequalification Program (WHO PQ) was set up in 2001 to facilitate access to medicines that meet unified standards of quality, safety and efficacy for HIV/AIDS, malaria and tuberculosis. Regulatory dossiers from manufacturers can be submitted to WHO PQ and this has helped UN agencies to buy quality medicines and countries with limited regulatory capacity, to expedite the dossier review process. In parallel, the US FDA set up a similar initiative which allowed ARVs to be reviewed and receive ‘tentative approval’ under a special programme associated with the President’s Emergency Plan (PEPFAR) even if products have intellectual property protection in the country. As a result, the use of generic ARVs under PEPFAR increased.
By 2012, there were 33 paediatric ARV formulations used in developing countries [22]. This created market fragmentation and clinical confusion since multiple dosage forms exist for the same ARV. Due to the small volume of certain paediatric ARVs and the small purchasing volume of certain countries, there is a considerable delay in the production of needed ARVs. A few initiatives were taking place at the global level to protect this market. The Paediatric ARV Procurement Working Group was formed by UNITAID, the Global Fund, PEPFAR, UNICEF and other stakeholders to align procurement, promote product optimization, secure financing, engage with manufacturers and provide in country support. In May 2011, a special paediatric working group from the Interagency Task Team on Prevention and Treatment of HIV Infection in Pregnant Women, Mothers and Children produced a list of optimized paediatric ARV formulations to guide donors, ministries of health and procurement agencies to prioritize purchase of paediatric formulations.
Figure 13.1 summarizes how an efficient drug development process for FDC can be achieved. The first step includes the identification of the right target dose to be included in the FDC in different age groups. This is often not a straightforward exercise since entities with different PK/PD profiles are being combined. Biostability and PK studies are then needed before a prequalification approval is sought. In order to be successful a comprehensive collaboration of different stakeholders including WHO, researchers, pharmaceutical companies and international organization is needed. An important role is also played by clinical research networks who are the ones producing the scientific evidence.
Role of International Clinical Research Networks
Multi-centre international collaboration has been vital for paediatric HIV research, at least in most industrialized countries, where a large number of clinical centres each care for a relatively small number of children. In the early nineties both in the United States and Europe large independent clinical trials network, such as PENTA in Europe and PACTG/IMPAACT in the United States, were established to undertake trials to address questions about ART in HIV infected children where answers could not be extrapolated from trials in adults. The activities and the studies run by these networks have been essential for the implementation and scaling up of ARV treatment in developing countries.
The Paediatric European Network for Treatment of AIDS (PENTA) was established in 1991 as collaboration between paediatric HIV centres in Europe Core funding for PENTA activities have been provided by the European Commission for more than 20 years through several research programmes [23]. Additional support for specific research activities were given by governmental and regional bodies in France, the United Kingdom, Italy, Spain and Germany and from pharmaceutical companies. Since early 2000 PENTA activities extended beyond clinical trials, to include cohort studies collaboration, pregnancy studies (including phase 1 trials in pregnant women), treatment guidelines and training/ educational programmes. The PENTA network now comprises more than 80 clinical centres and research laboratories in 22 countries in Western and Eastern Europe, Africa, Asia and the Americas able to recruit and follow HIV-infected children both in clinical trials and cohorts carried out according to good clinical practice. By 2014, 16 major clinical trials had been completed and almost 2000 children had been enrolled. Most trials aimed to address strategic questions not just on specific drugs or drug combinations, but on what is the optimal strategy for treating HIV infection in children. Large studies on structured treatment interruptions, simplification strategies, management strategies and best initiation approaches have been carried out. Also, several PK studies have been performed allowing identification of the right dosing for paediatric patients in different age groups [23].
The National Institutes of Health (NIH) funded International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network [24] is a global collaboration of investigators, institutions, community representatives and other partners organized for the purpose of evaluating interventions to treat and prevent HIV infection and its consequences in infants, children, adolescents and pregnant/postpartum women through the conduct of high quality clinical trials. IMPAACT has a comprehensive research agenda including: (a) evaluation of new and existing anti-HIV drugs and formulations, (b) novel approaches for addressing tuberculosis in HIV-infected or at-risk populations, (c) biomedical/behavioural interventions to prevent mother-to-child HIV transmission, (d) immunogenicity, safety and efficacy of high priority vaccines, (e) potential for HIV cure through therapeutic interventions, (f) new drugs and drug combinations to treat hepatitis in HIV-infected populations and (g) development and validation of methods to prevent and manage complications of HIV infection and its treatment. More than 40 studies have been completed and several are ongoing in more than 90 sites from 14 countries worldwide.
Studies run by PENTA and IMPAACT, which included sites in both developed and developing countries have been very informative and instrumental for the implementation of the use of ARV in developing countries and key publications for the development of WHO guidelines (2002–2013) [12, 14, 15]. Also the involvement of clinical sites in resource constrained settings in clinical trials has an important role in ‘capacity building’.
Community participation and engagement are critical in the conduct of scientific research especially in developing countries settings. There is mutual benefit to communities and researchers when both parties work together throughout the scientific research process. Both in the PENTA and IMPAACT networks community participation occurs throughout the network, community and site levels through various mechanisms that include representation on the network committees, protocols teams and cross-network community activities.
Beyond specific disease research networks other more general initiatives/networks focusing on paediatric drug research have an important role in facilitating the development and safe use of medicine in children in both developed and developing countries. With this mission the Global Research in Pediatrics – Network of Excellence (GRiP) was funded by the European Commission in 2010 [25]. The main reason for the existence of GRIP is the recognized lack of appropriate testing of paediatric drugs, with most marketed drugs having inadequate information about dosing regimen, dose adjustment and administration. The GRIP consortium is currently made up of 21 main partners from Europe, Asia and North America, including academia, research networks, regulatory agencies (EMA), international organizations (WHO, NIH) and parent advocacy groups. By linking the existing paediatric research networks, GRIP involves and mobilizes more than 1000 institutions worldwide including many active in developing countries. Partners are working to build and maintain an infrastructure matrix, which has the core aim of reducing the current fragmentation of efforts to achieve safe and effective use of medicine in children. The GRiP infrastructure matrix promotes the sharing of best practices, strategies and plans. Key points of these efforts are to harmonize methodologies and standardize research recommendations. GRiP produces guidelines reflecting the needs of researchers (including those in industry) and patients, facilitating interoperability in paediatric research to improve efficiency in clinical research in both HIC and LMIC settings. New protocol designs, procedures and methodologies for clinical trials in children are also explored and validated to fill the important ‘gaps’ that currently exist in paediatric medicine.
Paediatric studies require well-trained researchers, investigators and other experts in greater number and capacity than currently exist. Since the project aims to reduce fragmentation, one of the key components of GRiP is the development and implementation of a Joint Paediatric Clinical Pharmacology Training Program in collaboration with international stakeholders. This will include a Master Program in Paediatric Pharmacology which is to be launched in November 2014. The training programme will build on the existing experience and capacity of the partners and will aim to prepare more highly qualified personnel in paediatric clinical pharmacology able to work both at regulatory and clinical research levels in a variety of settings.
Conclusion
In this chapter we have described different experiences and networks that were involved in the successful implementation of the scaling up of ARVs in developing countries. We have presented the activities of DNDi a very efficient and innovative model for the development of new and affordable medicine for neglected diseases and have described its role in developing new ARV formulations. We briefly reviewed the fundamental role of WHO in coordinating efforts of various organizations to develop integrated guidelines to facilitate the scaling up of ART in resource constrained settings. Finally, we have described two different types of clinical and research networks: those HIV-specific, such as PENTA and IMPAACT, and the more general, focusing on the challenges of paediatric therapeutics, such as GRiP.
The common thread lacking in these initiatives is the development of a new global framework to stimulate research on paediatric drugs, prioritizing the specific needs of children in developing countries at the start of the drug development process. The important and effective achievements obtained in scaling up ARV deployment in resource limited settings shows the importance of consolidating public and private partnership, including WHO, both innovative research intensive and generic pharmaceutical companies, and international initiatives such as DNDi, to work with partners from countries where diseases are endemic. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases said a few years ago that ‘We need to use HIV networks to study other disease’. We believe that we should continue to emphasize this statement and to use the HIV networks as effective models to ensure that the output of new drug development will reach people and particularly children in need.
Abbreviations
- 3TC:
-
Lamivudine
- ABC:
-
Abacavir
- ART:
-
Antiretroviral therapy
- ARVs:
-
Antiretroviral drugs
- AZT:
-
Zidovudine
- d4T:
-
Stavudine
- DNDi:
-
Drugs for Neglected Diseases initiative
- EMA:
-
European Medicines Agency
- FDA:
-
US Food and Drug Administration
- FDCs:
-
Fixed-dose combinations
- GRiP:
-
Global Research in Pediatrics – Network of Excellence
- IMPAACT:
-
International Maternal Pediatric Adolescent AIDS Clinical Trials
- LPV:
-
Lopinavior
- NIH:
-
US National Institute of Health
- NVP:
-
Navirapine
- PDP:
-
Not-for-profit Product Development Partnership
- PENTA:
-
Paediatric European Network for Treatment of AIDS
- PEPFAR:
-
President’s Emergency Plan for AIDS Relief
- R&D:
-
Research and Development
- RTV:
-
Ritonavir
- SRA:
-
Stringent regulatory authority
- WHO PQ:
-
WHO Prequalification Program
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Lee, J.S.F., Penazzato, M., Lallemant, M., Giaquinto, C. (2015). Promoting Drug Development and Access: The Role of International Networks and Organizations. In: MacLeod, S., Hill, S., Koren, G., Rane, A. (eds) Optimizing Treatment for Children in the Developing World. Adis, Cham. https://doi.org/10.1007/978-3-319-15750-4_13
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