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      Creative use of the priority review voucher by public and not-for-profit actors delivers the first new FDA-approved treatment for river blindness in 20 years

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          Abstract

          Neglected tropical diseases (NTDs) represent a significant disease burden, feeding a vicious cycle of permanent disability and poverty [1]. Better treatments and treatment access could break this cycle, but the significant financing requirements for development are a barrier, despite the public-health imperative. Traditional incentives for development and supply of new and/or innovative drugs, diagnostics, and vaccines—such as return on investment—do not apply, leaving philanthropy and government financing as the dominant mechanisms supporting new products for NTDs. The evidence of this “market failure” is damning: just 2% of the total research and development (R&D) spent is on diseases affecting 33% of the global population [2]. Time trends show no significant improvement, with a mere 1% of all new chemical entities approved between 1975 and 1999 [3] and between 2000 and 2011 [4] being for tropical diseases (NTDs and malaria) and tuberculosis. More diverse and sustainable mechanisms are required. In 2007, the United States of America Congress created the priority review voucher (PRV) program [5] to encourage development of new products for certain “tropical diseases” (rare pediatric diseases and medical countermeasures were later added). If a “new drug application” (NDA) for an eligible indication is approved by the US Food and Drug Administration (FDA), the applicant is awarded a PRV. The PRV permits priority review of a subsequent NDA for a drug that the FDA would otherwise assign to standard review, thus reducing time-to-market by four to six months. This means gaining a competitive advantage, more sales, and greater profitability. The voucher can be redeemed by the same applicant or can be sold [6]. The impact of the PRV on the development of innovative and affordable medicines for “tropical diseases” and the intended public-health gains is questionable [7,8]. Here we show how the prospect of the voucher facilitated FDA approval of a new treatment for onchocerciasis, a milestone towards its availability to affected populations that otherwise might not have been achieved. Onchocerciasis (river blindness) is one of the 22 PRV-eligible “tropical diseases.” It is caused by the parasitic worm Onchocerca volvulus, transmitted to humans by the blackflies Simulium spp. Around 185 million people are at risk of infection, [9] which leads to severe itching, disfiguring skin conditions, and visual impairment, including blindness. More than 99% of infected people live in 31 African countries [10]. Ivermectin, the drug on which current onchocerciasis control and elimination programs are based, is donated and distributed as preventive chemotherapy to entire populations living in transmission areas [11,12]. Screening and development programs for NTDs, initiated at the Special Programme for Research and Training in Tropical Diseases (TDR; hosted by the World Health Organization) in the 1970s, identified moxidectin as a candidate for clinical development [12]. TDR entered into arrangements with the pharmaceutical company owning moxidectin for co-development and registration for onchocerciasis. Moxidectin, like ivermectin, is a macrocyclic lactone with extensive history of veterinary use. In Phase II [13] and III [14] clinical trials, moxidectin proved superior to ivermectin in reducing skin levels of the parasite life stage (microfilariae), which causes disease symptoms and is taken up by blackflies resulting in transmission. Fewer people with skin microfilariae (and fewer skin microfilariae) for longer—compared with ivermectin—should not only reduce morbidity but also parasite transmission and thus time to onchocerciasis elimination. Following withdrawal of the co-development partner in 2011, TDR sought another partner, without whom registration could not be achieved. Medicines Development for Global Health (MDGH) is a not-for-profit biopharmaceutical company founded in 2005 to tackle health inequity by developing and registering medicines for neglected diseases. The PRV program was pivotal to completing moxidectin’s development and registration: MDGH leveraged the PRV for a US$13 million investment by the Global Health Investment Fund (GHIF), making this the first social impact investment raised specifically on the potential value of a PRV. The funds were used to complete manufacturing and nonclinical and clinical development activities necessary for regulatory compliance as well as to write the regulatory dossier for submission to the FDA. In total, MDGH and TDR each contributed around US$15 million to repurpose moxidectin from animal to human health (relevant investment by TDR’s previous for-profit partner is unknown but very likely exceeds US$20 million). The FDA approved moxidectin for onchocerciasis on 13 June 2018 and awarded MDGH a PRV [15]. Moxidectin fulfils several PRV objectives: the NDA was genuinely new because moxidectin had not been registered elsewhere and is the first onchocerciasis treatment approved by the FDA in 20 years (30 years after ivermectin registration in France in 1987). Furthermore, proceeds from the PRV sale will stay in the neglected disease sector, supporting access to moxidectin through subsidies and funding further R&D on moxidectin and other products for NTDs; finally, it brings new prospects for the onchocerciasis endgame. The moxidectin story illustrates how partners motivated not by profit but by public good can use the PRV program, designed around the market forces motivating the for-profit sector, to meet its intended objectives. To do this, certain elements must converge: public funds and public-health priority setting, not-for-profit drug development and regulatory know-how, and commitment to invest PRV gains into furthering affordable access and additional R&D for NTDs. Threats to the PRV scheme achieving its objectives are becoming increasingly obvious, not least of which is oversupply of PRVs [16]. So far, 23 vouchers have been issued, including 5 in 2018 to date. These numbers reflect the PRV extension to “rare pediatric diseases” and “medical countermeasures”: only 7 out of 23 PRVs were for “tropical diseases” indications. With increased numbers, the PRV market valuation has dropped from peak US$350 million in 2016, via an average US$130 million in 2017 to US$81 million for the last recorded sale in 2018 [6]. We concur with Ridley and Régnier [16] that a PRV value below US$100 million no longer incentivizes drug development for “tropical diseases”. This is particularly the case for nonprofit organizations that depend on public or philanthropic funding and/or need to raise money from “investment” funds. Moxidectin is a case in point: even though repurposing is comparatively cheap, the estimated total cost to bring moxidectin to FDA registration may well have exceeded US$50 million. In contrast to public and/or philanthropic funders, investment funds inevitably require reimbursement and significant return on investment. This substantially reduces the proceeds from the PRV sale available for additional work required to bring the drug to the target countries, including registration, additional studies to inform guidelines and policy, and finally, to make it available and affordable to those who need it. Another weakness of the PRV program is that companies granted a PRV have no obligation to make the FDA-approved product available at an affordable price. While MDGH is committed to subsidize procurement of moxidectin as needed, experience with other drugs for which a PRV was granted shows that without such obligations, the PRV program will not achieve its ultimate objective, i.e., improved treatment for NTDs. The inherent weaknesses of the PRV program risk the viability of an initiative that we have shown can indeed make an important contribution to addressing market failure. Codifying access and pricing obligations is an essential change that would help preserve this important incentive program.

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          Drug development for neglected diseases: a deficient market and a public-health policy failure.

          There is a lack of effective, safe, and affordable pharmaceuticals to control infectious diseases that cause high mortality and morbidity among poor people in the developing world. We analysed outcomes of pharmaceutical research and development over the past 25 years, and reviewed current public and private initiatives aimed at correcting the imbalance in research and development that leaves diseases that occur predominantly in the developing world largely unaddressed. We compiled data by searches of Medline and databases of the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products, and reviewed current public and private initiatives through an analysis of recently published studies. We found that, of 1393 new chemical entities marketed between 1975 and 1999, only 16 were for tropical diseases and tuberculosis. There is a 13-fold greater chance of a drug being brought to market for central-nervous-system disorders or cancer than for a neglected disease. The pharmaceutical industry argues that research and development is too costly and risky to invest in low-return neglected diseases, and public and private initiatives have tried to overcome this market limitation through incentive packages and public-private partnerships. The lack of drug research and development for "non-profitable" infectious diseases will require new strategies. No sustainable solution will result for diseases that predominantly affect poor people in the South without the establishment of an international pharmaceutical policy for all neglected diseases. Private-sector research obligations should be explored, and a public-sector not-for-profit research and development capacity promoted.
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            The drug and vaccine landscape for neglected diseases (2000-11): a systematic assessment.

            In 1975-99, only 1·1% of new therapeutic products had been developed for neglected diseases. Since then, several public and private initiatives have attempted to mitigate this imbalance. We analysed the research and development pipeline of drugs and vaccines for neglected diseases from 2000 to 2011.
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              Single dose moxidectin versus ivermectin for Onchocerca volvulus infection in Ghana, Liberia, and the Democratic Republic of the Congo: a randomised, controlled, double-blind phase 3 trial

              Summary Background The morbidity and socioeconomic effects of onchocerciasis, a parasitic disease that is primarily endemic in sub-Saharan Africa, have motivated large morbidity and transmission control programmes. Annual community-directed ivermectin treatment has substantially reduced prevalence. Elimination requires intensified efforts, including more efficacious treatments. We compared parasitological efficacy and safety of moxidectin and ivermectin. Methods This double-blind, parallel group, superiority trial was done in four sites in Ghana, Liberia, and the Democratic Republic of the Congo. We enrolled participants (aged ≥12 years) with at least 10 Onchocerca volvulus microfilariae per mg skin who were not co-infected with Loa loa or lymphatic filariasis microfilaraemic. Participants were randomly allocated, stratified by sex and level of infection, to receive a single oral dose of 8 mg moxidectin or 150 μg/kg ivermectin as overencapsulated oral tablets. The primary efficacy outcome was skin microfilariae density 12 months post treatment. We used a mixed-effects model to test the hypothesis that the primary efficacy outcome in the moxidectin group was 50% or less than that in the ivermectin group. The primary efficacy analysis population were all participants who received the study drug and completed 12-month follow-up (modified intention to treat). This study is registered with ClinicalTrials.gov, number NCT00790998. Findings Between April 22, 2009, and Jan 23, 2011, we enrolled and allocated 998 participants to moxidectin and 501 participants to ivermectin. 978 received moxidectin and 494 ivermectin, of which 947 and 480 were included in primary efficacy outcome analyses. At 12 months, skin microfilarial density (microfilariae per mg of skin) was lower in the moxidectin group (adjusted geometric mean 0·6 [95% CI 0·3–1·0]) than in the ivermectin group (4·5 [3·5–5·9]; difference 3·9 [3·2–4·9], p<0·0001; treatment difference 86%). Mazzotti (ie, efficacy-related) reactions occurred in 967 (99%) of 978 moxidectin-treated participants and in 478 (97%) of 494 ivermectin-treated participants, including ocular reactions (moxidectin 113 [12%] participants and ivermectin 47 [10%] participants), laboratory reactions (788 [81%] and 415 [84%]), and clinical reactions (944 [97%] and 446 [90%]). No serious adverse events were considered to be related to treatment. Interpretation Skin microfilarial loads (ie, parasite transmission reservoir) are lower after moxidectin treatment than after ivermectin treatment. Moxidectin would therefore be expected to reduce parasite transmission between treatment rounds more than ivermectin could, thus accelerating progress towards elimination. Funding UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                15 November 2018
                November 2018
                : 12
                : 11
                : e0006837
                Affiliations
                [1 ] UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization (WHO), Geneva, Switzerland
                [2 ] Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
                [3 ] Medicines Development for Global Health (MDGH), Melbourne, Australia
                University of Florida, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist. PLO, ACK, CMH, and JCR are staff members of the World Health Organization (WHO). MS is founder and managing director of Medicine Development for Global Health. The authors alone are responsible for the views expressed in this publication and do not necessarily represent the decisions, policy, or views of WHO.

                Author information
                http://orcid.org/0000-0003-3049-1034
                Article
                PNTD-D-18-01139
                10.1371/journal.pntd.0006837
                6237288
                30439940
                46db7089-afff-4cc8-8112-7121e8bef290
                © 2018 Olliaro et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Page count
                Figures: 0, Tables: 0, Pages: 4
                Funding
                The author(s) received no specific funding for this communication.
                Categories
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                Medicine and Health Sciences
                Parasitic Diseases
                Helminth Infections
                Onchocerciasis
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Onchocerciasis
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Medicine and Health Sciences
                Tropical Diseases
                Medicine and Health Sciences
                Pediatrics
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                Public and Occupational Health
                Global Health
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                Pharmacology
                Drug Research and Development
                Social Sciences
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                Clinical medicine
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                Phase II clinical investigation
                Medicine and health sciences
                Pharmacology
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                Clinical trials
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                Infectious disease & Microbiology
                Infectious disease & Microbiology

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