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Info Service on Health Issues (Jun23/02) Sangeeta Shashikant (London) – Access by affected countries to Ebola treatments is at a “standstill”, more than two years since their approval and five outbreaks of Ebola virus disease (EVD) later. This was exposed by MSF Access Campaign in its recently launched report titled “Ensuring Access to New Treatments for Ebola Virus Disease”. Decisions concerning availability and affordability are left to the goodwill of corporations and rich countries, despite research and development (R&D) of the treatments only made possible with public funding and collaborative effort, the report states. It further reveals that the U.S. government has set up its own emergency stockpile of Ebola virus disease (EVD) treatments which contains nearly all currently available treatments, deploring that “these treatments have not been adequately rolled out as lifesaving public health tools for people in countries where outbreaks occur and are instead retained primarily as biosecurity tools”. The European Union (EU) and other actors, also appear interested in setting up stockpiles as part of their pandemic preparedness efforts, the report adds. The inequity narrated by the MSF report is now a recurring occurrence during a health emergency resulting in unnecessary suffering and deaths in developing countries. In 2005, developing countries, especially South-East Asian countries hardest hit by the H5N1 outbreaks, failed to get access to vaccines developed using the flu strains circulating in affected countries, as supplies to rich countries were prioritized by manufacturers. Similarly, the inequity observed during the global pandemic of COVID-19 was staggering. According to UNCTAD, while each resident of high-income countries benefited, on average, from about US$10 per month of imports of COVID-19 related products, middle income countries only had access to about US$1 of COVID-19 products, and lower still for low income countries – a mere US$0.10. In other words, per capita imports of the medical goods essential to mitigate the COVID-19 pandemic have been about 100 times larger in high income countries in comparison to low income countries. The Ebola story and the many instances of inequity underscore the need for developing countries to negotiate a comprehensive, effective multilateral access and benefit sharing mechanism that will, among others, contractually commit manufacturers to fair and equitable benefit sharing in the two intergovernmental negotiations on WHO convention. These are negotiations on an agreement or other international instrument on pandemic prevention, preparedness and response (WHO CA+), and on amendment of the International Health Regulations (2005). Treatments for EVD As with other neglected diseases, EVD also suffered from the absence of investment in R&D, even though it was first discovered in 1976. Around 2003, motivated by bioterrorism concerns, the U.S. government especially provided some R&D funding. During the 2014-2016 EVD outbreak in West Africa, no pharmaceutical products were available, as was the case in previous outbreaks. The MSF report notes that, “It was during the epidemic in West Africa, when wealthier countries faced the threat of the outbreak reaching their borders, that funding for R&D increased dramatically. It was also during this time that the first real clinical trials were set up with the aim of helping develop better tools to tackle EVD.” More than 40 years after the virus was first discovered, in November 2018 the first-ever multidrug randomised controlled trial (RCT) for EVD treatments was launched in the Democratic Republic of the Congo (DRC). The PALM trial tested the safety and efficacy of four investigational treatments: three monoclonal antibody (mAb) therapies (mAb114, REGN-EB3, and ZMapp) and an antiviral (remdesivir) through an international research consortium coordinated by the WHO, and co-sponsored and co-funded by the Institut National de Recherche Biomédicale (part of the DRC Ministry of Health) and the National Institute of Allergy and Infectious Diseases (part of the U.S. National Institutes of Health). Of the 4 investigated, mAb114 and REGN-EB3 were considered effective. In October 2020, the U.S. FDA approved REGN-EB3 (marketed by Regeneron as Inmazeb) as the first EVD treatment and later in December approved a second product mAb114 (marketed by Ridgeback Biotherapeutics as Ebanga). Thereafter, in August 2022, WHO issued a “strong recommendation for treatment with mAb114 or REGN-EB3 for patients with confirmed EVD and for neonates of unconfirmed EVD status, 7 days or younger, born to mothers with confirmed EVD”. MSF in its report argues that WHO’s guidelines does not go far enough, and that the “treatments could and should be used in a more liberal way to prevent disease and reduce mortality based on the available evidence regarding the efficacy of mAbs against EVD”, further adding that “[c]urrently, due to the limited availability of these drugs, post-marketing investigations for use in other indications, including post exposure, has not been feasible.” mAb114 (Ebanga) According to MSF’s report, mAb114 was developed from a sample drawn by NIH in 2006 from one survivor (out of two survivors in a family of 15) of an outbreak in DRC in 1995. Thereafter immune cell isolation and antibody cloning was performed by the Institute for Research in Biomedicine in Switzerland. R&D and manufacturing of mAb114 was made possible with public funding and collaboration especially from the US and the DRC, the MSF report states. In the U.S., public entities were involved in the R&D and provided funding for development and manufacturing including for preclinical and clinical studies. DRC including its Ministry of Health and other organizations (WHO, NGOs) confirmed the efficacy of mAb114 through the PALM trial. The MSF report finds Ridgeback’s contribution to the development of mAb114 to be nominal with limited in-house capacity, outsourcing of production, and yet is a key beneficiary (financially and otherwise). mAB114 is patented by the Vaccine Research Centre of the US National Health Institutes (NIH). In December 2018 it licensed the patent to Ridgeback Biotherapeutics, a private U.S.-based pharmaceutical corporation, a very small company with no in-house production. The license which was originally non-exclusive was converted in 2021 into an exclusive license. Ridgeback outsourced to Emergent Bio Solutions, supply of mAb114 to the North American market, while Ridgeback continues to be the only supplier of mAB114 for the rest of the world. The U.S. Department of Health and Human Services which hosts NIH is holding a patent with broad claims “covering four variants of the antibody, their respective fragments, their cell lines, and antibodies which bind to the same epitope as the antibody and its variants”. Availability & Affordability Access to affordable mAb114 remains a challenge as it depends on the goodwill of Ridgeback. Production solely outsourced to Emergent BioSolutions is aimed at U.S. and Canada markets with no new doses expected before 2024, while the US may have already a stockpile, according to the MSF report. Apparently, discussions on procurement and access between Ridgeback and the WHO have thus far failed to result in any concrete agreement, particularly as Ridgeback has no plans to produce the treatment in the short term. Instead, Ridgeback has initiated a limited donation programme in DRC, presumably consisting of leftover doses from the PALM trial, the MSF report adds, failing to respond to needs of other treatment organizations. Though unavailable, the report also estimates the manufacturing costs of mAb114 ranges from US$250 for small-scale production to US$625 for large-scale production. The costs could be much lower over time with the advent of newer technologies. Regn-EB3 (Inmazeb) This treatment is a combination of three human Ebola mAbs (atoltivimab, maftivimab, and odesivimab). It was developed by Regeneron using sequence information from a West African gene sequence. Humanized mice were exposed to synthesized pieces of an Ebola virus, a strain, called C15 or Makona, isolated in 2014 from the clinical sample of a 28-year-old woman from Guinea, who survived the outbreak, while two of her brothers did not. Reportedly no consent of the survivor or the Guinean government appears to have been obtained. Her sample was exported to Europe where researchers at the Bernhard Nocht Institute in Hamburg sequenced the strain found in the woman’s sample, uploaded to the GenBank database that is part of the U.S.-E.U.-Japanese government-funded “open access” International Nucleotide Sequence Database Collaboration (INSDC). Regeneron accessed the sequence and synthesized portions of the virus. The MSF report notes that Regeneron holds broad patents in the U.S. and other countries that cover the antibodies themselves, their production methods, antibodies which bind to the same epitope as the antibodies covered by the patent, and their use in combination with other antivirals or vaccines. To date, Regeneron has not engaged in any licensing or technology transfer agreements with entities in endemic countries, the report adds. The successful development of REGN-EB3 is the direct result of public funds provided especially by the US government and collaboration of treatment providers in DRC, including the Ministry of Health, NGOs and WHO that executed the trial which confirmed efficacy of REGN-EB3. Availability and Affordability Access to REGN-EB3 for affected countries remains very uncertain, very much dependent on the ad hoc donations of the U.S. government or benevolence of Regeneron. The U.S. appears to have access to the treatment, estimated to be at the cost of US$6,900 per treatment course. At this prohibitive price, MSF argues that “the ambitions for the size of the UN/WHO stockpile would likely need to be considerably reduced”, adding that the present situation “leave WHO and others in a challenging position when responding to future outbreaks if the U.S. government is not willing to share these doses in a timely and appropriate manner”. MSF estimates the manufacturing costs of REGN-EB3 to range from US$750 for small-scale production to US$1875 for large-scale production. The report further reveals that “Regeneron has systematically declined our requests to disclose its supply details for REGN-EB3” and has yet to respond to WHO’s multiple requests for quotations. Winners and Losers The two obvious winners are two U.S.-based companies Ridgeback and Regeneron. Ridgeback received US$34.2 million from the US government for R&D and manufacture of mAb114 and has obtained an exclusive license to patent claims over mAb114. Regeneron is the recipient from the U.S. government of US$45.9 million for the anti-Ebola antibody therapeutics development program, and up to US$756.4 million contract for national stockpiling. Both have also significantly benefitted from tax credits under the Orphan Drug Subsidies Act and priority review voucher (often worth more than US$100 million). The U.S. government also gains, as “it is expected to be by far the largest purchaser of the new EVD treatments”, MSF notes. It adds that the U.S. Strategic National Stockpile (SNS) has approximately US$600 million per year to purchase medical products. It has already entered into agreement with Regeneron, with production initiated of up to 50,000 treatment courses for U.S. stockpile. The U.S.’s access to mAb114 is also secure. “Emergent BioSolutions is expected to be supported via a grant by BARDA (Biomedical Advanced Research and Development Authority), leading to their purchase by the U.S. government by 2025”, MSF states, adding that “[h]owever, there is a possibility that a small number of treatment courses has already been stockpiled by the U.S. government”. Other developed countries such as the E.U. have also indicated interest in stockpiling. Meanwhile affected countries, WHO and humanitarian organizations operating in affected countries, that have been central to the development of EVD treatments continue to struggle to obtain timely access to affordable EVD treatments. “For now, the treatments can be accessed only through ad hoc donations by companies or the U.S. government”, MSF adds. Access and benefit sharing (ABS) for Equitable Access to Treatment Achieving equitable access requires that manufacturers take on legally binding commitments for production in, and supply to, developing countries. Therefore, in the ongoing negotiations in the WHO CA+, the Africa Group and several other developing countries have called for an effective access and benefit sharing mechanism. The Africa Group has proposed that biological materials and their sequence information should be subject to fair and equitable benefit sharing. The benefit sharing shall comprise of monetary contributions to WHO by entities that financially benefit from the sharing of materials and sequence information. The contribution shall in turn be used for improving preparedness and response of public health emergency of international concern and pandemic. The Group also proposes two standard material transfer agreements (SMTA) to be agreed at the multilateral level. The first SMTA governs the use of material and sequence information shared by a WHO Member with the recipient WHO designated laboratory, including terms such as the receiving laboratory shall not seek intellectual property rights over any form or use of the shared biological material and sequence information. The second SMTA is between WHO and the manufacturer that accesses biological material and sequence information shared by WHO members. The Africa Group has proposed that the recipient manufacturer should inter alia commit to:
These proposals, if adopted, have the potential to avoid inequitable situations that have arisen with respect to mAb114 and REGN-EB3, and other health emergencies as the benefitting manufacturer would be contractually bound to provide in-kind contributions to WHO as well as to license the technology and know-how to developing country manufacturers for supply to affected developing countries. The proposal clearly builds on the success of the ABS mechanism agreed in the context of the Pandemic Influenza Preparedness Framework (PIP Framework) as well as lessons learned in its implementation and from the inequity observed during the COVID-19 pandemic. The PIP Framework was adopted following the inequity that emerged during the H5N1 outbreak in 2005. Then Indonesia with the support of other developing countries insisted that any sharing of the biological materials and sequence information be subject to fair and equitable benefit sharing. Accordingly, the PIP Framework elaborates terms and conditions including SMTAs that govern access to biological materials including sequence information. Under the PIP Framework, manufacturers have to provide monetary contributions (as of March 2023, US$283 million has been collected) which is set aside for pandemic preparedness and response. According to WHO, 131 countries have improved their laboratory systems and that “COVID-19 response has benefited from PIP’s country-focused capacity strengthening investments” with at least 35 countries using the capacity developed, made possible by the monetary contributions “as a basis to develop their COVID-19 vaccine deployment plans”. Further, through SMTAs with manufacturers including with six of the largest flu vaccine manufacturers, such as GSK, Sanofi and CSL Sequirus, WHO has already secured over 400 million doses of vaccines from manufacturers (i.e. 10 of every 100 doses of vaccine manufactured, of which 8 will go to WHO on a donation basis), 10 million treatment courses of antivirals, 250,000 diagnostic test kits, and 25 million syringes, to respond in the event of a flu pandemic. Reuters reports WHO as saying, “mechanisms were being developed “so that countries can work together – not in competition with each other” to respond to such a crisis and that it was “fully confident” manufacturers and member states would meet their obligations.” In the parallel International Health Regulations amendment process, in response to proposals by developed countries stressing on the sharing of biological materials and sequence information, the Africa Group has emphasised that the “sharing of genetic sequence data or information shall only be considered after an effective and transparent access and benefit sharing mechanism with standard material transfer agreements governing access to and use of biological material, including genetic sequence data or information relating to such materials as well as fair and equitable sharing of benefits arising from their utilization is agreed to by WHO Member States, is operational and effective in delivering fair and equitable benefit sharing”. Several other developing countries such as Bangladesh and Brazil have also supported establishment of an ABS mechanism. Weak WHO CA+ Bureau Text on ABS Concrete ABS proposals of the Africa Group that can bridge the inequity gap are absent from the Bureau text (A/INB/X/X) that has been presented to the drafting group of the Intergovernmental Negotiating Body (INB) that meets in Geneva for a week, beginning 12 June. ABS is addressed in Article 12 of the Bureau’s text with two flawed options that include proposals to delink access from benefit sharing, thereby undermining the well-established and globally recognized principles of ABS endorsed by 193 parties of the Convention on Biological Diversity (CBD) and 137 Parties of the Nagoya Protocol on access and benefit sharing. [The CBD is premised on the notion that States have sovereign rights over their own natural resources and conditions access to biological resources to prior informed consent (PIC) of the Contracting Party providing the resources. The CBD requires fair and equitable benefit sharing arising from the commercial and other utilization of genetic resources with the Contracting Party providing such resources. Following the same premise, Nagoya Protocol elaborates on the access and benefit sharing aspect of the CBD.] The first option (Option 12.A) postpones development of details of the ABS mechanism to a later time after the conclusion of the WHO CA+. While the option states that the “system shall be operational no later than xxx” there is no guarantee that such a system will be developed, with agreement on concrete and meaningful benefits. The second option (Option 12.B) presented in Article 12 of the Bureau’s text is severely wanting. The proposed benefits are too general, vague, and optional, lacking the robust and concrete ideas contained in the Africa Group proposal on ABS, which have actual potential to deliver equity for pandemic prevention, preparedness and response. For instance, Bureau’s text in Option 6(c)X on benefit sharing states that obligations by manufacturers of pandemic-related products “will include” “collaboration with manufacturers from developing countries and WHO initiatives to transfer technology and know-how”. Such text, at best is nothing more than a weak suggestion of possible collaboration. Options 6(c)Y and 6(c)Z erroneously present benefit sharing as commitments of State parties rather than commitments of manufacturers that access the biological materials and sequence information. They are also open-ended, imprecise, voluntary and thus ineffectual in providing certainty that timely affordable access will be provided to affected countries. Further in paragraph (e) the option upholds intellectual property over pathogens with pandemic potential (which could pose a barrier to production and supply of pharmaceutical products such as vaccines and diagnostics). Option 12.B also lacks details. While it refers to monetary contribution, particulars on the formula for such contribution is missing. The option also refers to SMTAs, but no text has been provided (even though the Africa Group and Bangladesh have proposed detailed SMTA text), suggesting the intent of developing SMTAs at a later stage. Without agreement on the details of SMTAs, the ABS mechanism will remain hollow and ineffective. WHO Members should learn lessons from the World Trade Organization (WTO) negotiations, which highlight why agreement on the details of the ABS mechanism, a crucial mechanism for operationalizing equity, should not be postponed or delayed. On 17 June 2022, WTO Members agreed to a Ministerial Decision on the TRIPS Agreement, with a scope limited to COVID-19 vaccines (at the insistence of the U.S.), with the understanding that within 6 months, the decision would be extended to COVID-19 diagnostics and therapeutics. However to date, no agreement has been reached and the deadline has been extended indefinitely, with no resolution in sight.+ Note: The Bureau ignored the proposal on the WHO Pathogen Access and Benefit Sharing System (PABS system) by the Africa Group, which contains two detailed standard material transfer agreements (SMTA). The Africa Group proposal on the sharing of monetary benefits was as follows: “Any entity including manufacturers of diagnostics, vaccines, therapeutics and other medical products using or benefitting from the PABS System, shall make an annual monetary contribution to WHO for improving preparedness and response of public health emergency of international concern and pandemic. It is decided that the sum of annual contribution shall be x% of total annual revenue for each product or service developed and commercialized using the PABS System. Annual revenue includes all financial benefits such as income from sales and royalties.” However, these are not considered in the Bureau’s text.
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