Céline Courtay-Cahen, Senior Manager, Regulatory Affairs at Boyds, recently wrote about bringing new treatments to people suffering from neglected diseases. The following article was published in Regulatory Rapporteur.
Neglected diseases continue to cause significant morbidity and mortality in the developing world, as they account for 11% of the global disease burden. Yet, very few of the approved medicines are targeting neglected diseases. Drugs for Neglected Diseases initiative (DNDi) is a collaborative, patients’ needs-driven, non-profit drug R&D organisation using an alternative model to bring cost-effective treatments to those suffering with diseases that fall outside the scope of market-driven development. DNDi’s first focus was the development of drugs adapted to their target population, for the treatment of malaria and African trypanosomiasis (sleeping sickness). In pursuing these goals, DNDi enabled networks built on global collaboration with industrial partners and regulatory agencies, leading not only to adapted, effective treatments but also to support and technology transfer towards the countries were those diseases are endemic.
When medical charity Médecins Sans Frontières (MSF; also known as Doctors without Borders) won the Nobel Peace Prize in 1999, its members decried the lack of lifesaving drugs for diseases of the poor, and used the Nobel Prize money to kick-start the DNDi (Drugs for Neglected Diseases initiative).1
Dr Bernard Pécoul, who had been with MSF for 20 years, took the helm when the initiative launched in Geneva, Switzerland, in 2003. However, pharmaceutical executives were sceptical. Drug development is an expensive, complex, decade-long endeavour. For more than three decades, economists at the Tufts Center for the Study of Drug Development in Boston, Massachusetts, have collected proprietary data from pharmaceutical companies, and used it to calculate the average cost of developing a new drug. The most recent estimate is $1.4 billion.2
Malaria treatment – Product profile of a simple, patient-adapted treatment
DNDi’s team started with a safe project. In 2001, the World Health Organization had called for malaria drugs that combined ingredients to slow the spread of resistance to the single best available agent, artesunate. But the poverty of most people who need malaria drugs meant that the private sector had little incentive to create and test such combination therapies. In response to that call, MSF, along with other partners, established the Fixed-Dose Artesunate Combination Project (FACT).
With the aim of getting affordable, adapted treatments to patients as quickly as possible, combinations of existing treatments were considered because of previously documented evidence of use and advantageous price. After a series of clinical trials sponsored primarily by WHO-TDR (Special Programme for Research and Training in Tropical Diseases), The Wellcome Trust and Epicentre (research branch of MSF), the decision was taken to develop two combinations of artesunate, one with amodiaquine (ASAQ) targeted for use in Africa, and one with mefloquine (ASMQ) principally for Asia and Latin America.
An extensive body of human pharmacological data already existed for both artesunate (AS) and amodiaquine (AQ): they have distinct mechanisms of action and their pharmacokinetic/pharmacodynamics characteristics are complementary. AS rapidly and substantially reduces the parasite burden and has very short half-life (20–45 minutes), whereas AQ has a much longer half-life ensuring that it works long enough to kill all the remaining parasites. AQ has been in use since the 1970s for the treatment and prophylaxis of malaria, notably in travellers. The drug was included in the WHO Essential Drug List (EDL) in 1977, removed in 1979 to be re-instated in 1982 and removed again in 1988 in view of safety concerns during prophylaxis use. When used at high doses and prophylactically, AQ had been associated with severe hepatitis and severe neutropenia, including some deaths. By contrast, field experience suggested these toxicities were not evident when malaria patients were treated. Given AQ’s difficult history, its toxicity was a focus for the FACT team’s vigilance, and a specific risk management plan (RMP) as implemented for the project.3
With patients’ needs in mind, a target product profile for ASAQ was developed for a simple to use treatment with a fixed-dose, fast-release, oral formulation for adults and children from six months old. The product had to be properly adapted for field use:
- A single daily dose to maximise adherence to treatment across all age groups
- Minimum excipient quantity to keep the tablet small
- Rapid disintegration in liquids to facilitate administration to infants and small children
- Formulation suitable for extended stability in tropical conditions
- Labelling understandable by patients and caregivers who may lack reading skills
- Cost not superior to US$1 to ensure widespread access.
FACT: an innovative public and private partnership
The FACT project pioneered the Product Development Partnership (PDP), a form of public-private partnership, by bringing together a number of malaria and pharmaceutical development experts – from pharmaceutical companies (large and start-up), non-governmental organisations, academia, private and public sponsors who operate in the disease-endemic countries or globally – to collaborate in a flexible, “virtual” model. The FACT team led and ensured continuity throughout the project, which involved almost the full range of activities associated with drug development, from formulation work through to post registration pharmacovigilance. Initial funding was provided by the EU INCO-DEV Program with other funding bodies involved as the project evolved. Specific subgroups met to oversee the various activities, and input was sought from the WHO, country malaria control programmes, and the Pan-African Conference Against Malaria (APAL P). Experts were brought in on an ad hoc basis as needs arose. The direct, open dialogue between partners who normally do not work together promoted creativity and “out of the box thinking” required to overcome the many challenges that arose.3
A key element to the success in developing ASAQ was the partnership, from December 2004 onwards, with the industrial partner, Sanofi.2 Once a stable formulation had been identified, the FACT team needed an industrial partner to shoulder the required R&D efforts and to register, manufacture, and distribute the product. Initial discussions had been held with Pfizer, who had generously donated some AQ at the beginning of the development. Sanofi had already initiated a programme to develop a fixed dose combination of AS and AQ in 2002, but were still looking for developable formulations with sufficient stability. Also, the company had already been providing AS (branded as Arsumax), AQ (Flavoquine) and an AS+AQ co-blister (Arsucam) to African countries.
One of the key components of the agreement between DNDi and Sanofi, signed in December 2004, was that the treatment would be made available at prices lower than those available at the time, ie, less than one US dollar for an adult treatment (the cost of Arsucam, artesunate-amodiaquine) and less than US$0.50 for a paediatric treatment in the non-profit public sector. Sanofi did not seek any patent protection in the FACT Project, in a decision made to be consistent with DNDi‘s intellectual property policy to develop drugs as public goods whenever possible, and with both partners’ determination to make the new medicine as widely available as possible to patients in greatest need. Sanofi agreed to pay DNDi 3% of the net private sector turnover over a period of seven years. DNDi later used these royalty payments to support the ASAQ RMP.
The starting point for the ASAQ clinical strategy was the extensive information on the safety and efficacy of non-fixed dose AS/AQ that was already available from 37 studies.3 This body of data was derived from around 10,000 patients who had received AS and AQ in various doses and ratios. Evidence of the safety of the Sanofi AS+AQ combination was also available from a number of studies. In the largest of these, performed in Senegal in over 3,000 patients, no adverse events requiring in-patient hospitalisation were reported.4
However, despite the large body of evidence on the use of AS and AQ it was necessary to provide a formal registration file for use in endemic countries for ASAQ fixed dose combination. A Phase I crossover study in Malaysia of ASAQ fixed dose combination (2004–2005), compared to non-fixed ASAQ, was conducted in healthy volunteers to confirm comparable exposure of the two formulations.5 Sanofi sponsored an additional Phase I study (in 2006) to compare fasting and fed subjects, which resulted in a recommendation not to use the drug with a high-fat meal.6 The FACT development project carried out a large pivotal Phase III trial with the support of the CRO Cardinal Health Inc for data management and final report generation. This Phase III study was conducted over two malaria seasons from October 2004 to February 2006 in Burkina Faso, and recruited 750 children aged between six and 60 months (but weighing >5 kg). ASAQ fixed dose combination achieved a cure rate of 92.1%, a result that was non-inferior to the loose combination.7
The FACT team was confident that the clinical data from the Phase I and III studies, which demonstrated that both formulations were essentially equivalent, was sufficient for filing for registration. However, the MHRA in the UK advised the addition of a direct comparison with artemether lumefantrine (Novartis, authorised in China since 1992 and in EU, with UK as reference member state (RMS), for the treatment of acute uncomplicated malaria since 1999). Therefore, a second, multicentre, Phase III study (ATAQ EASY), sponsored by Sanofi, was conducted from March to December 2006 in adults and children >10 kg in Senegal, Cameroon, Mali, and Madagascar. A total of 941 patients were recruited and non-inferiority was demonstrated between ASAQ fixed dose combination and the reference artemether lumefantrine.8
Registration and distribution (ASAQ Winthrop)
Distribution and marketing were the sole responsibility of Sanofi. The role and experience of Sanofi in the regulatory process was instrumental in achieving registration. The established presence of the company in many African markets was also a determinant. Hundreds of millions of treatments have now been distributed worldwide.
The initial plan had been to register ASAQ simultaneously in Europe and in malaria-endemic countries. However, European registration was problematic because artesunate was not yet registered in the EU and was therefore considered a new chemical entity, despite its widespread use. Therefore ASAQ was initially submitted for registration in Morocco in 2005, where it was manufactured in a GMP-compliant, Sanofi-owned plant. To date ASAQ fixed dose combination has been registered in 35 countries by Sanofi, of which 33 are in Africa.
In 2008, ASAQ was granted WHO prequalification. WHO medicines prequalification is a programme which seeks to expand access to quality-assured medicines by ensuring medicines are safe, appropriate and meet stringent quality standards. Product dossiers or master files are assessed, manufacturing and clinical sites are inspected and quality control testing of products is organised. The standards used to evaluate products and their manufacturing sites are based on the same principles and practices agreed by the world’s leading regulatory agencies and adopted by the WHO Expert Committee on Specification for Pharmaceutical Preparations. As a consequence, since its inception in 2001 in response to the HIV/AIDS pandemic, the WHO prequalification programme has helped increase access to affordable and good-quality treatments in low-income countries. The scheme supports manufacturers, regulators and quality control laboratories to reach their public health objectives.9 Obtaining WHO prequalification enabled ASAQ to access Global Fund tenders and also allowed its purchase by international funding bodies.
The non-restrictive agreement between DNDi and Sanofi has allowed other generic companies to also manufacture ASAQ fixed dose combination products. Several of those companies have now been granted WHO prequalification status. One of the consequences of having a large volume of quality fixed dose product on the market at an affordable price was the reduction of poor quality/counterfeit treatments available. Another consequence is the contribution to the prevention of emerging AS resistance on the African continent.
A post-registration programme to monitor ASAQ efficacy and safety in the field was developed as an RMP, the first of its kind to be submitted to the WHO in 2009. One of the considerations for post-marketing surveillance was that ASAQ would be used in resource-poor countries whose pharmacovigilance systems might under-report adverse drug reactions. During 2005–2006, adverse events had been collected following the use of various AS + AQ formulations manufactured in Ghana by a local manufacturer.3 For comparison, quality efficacy and safety data for ASAQ fixed dose combination were gathered through a variety of proactive studies performed by Sanofi, DNDi, and partners and constituted the RMP. One of these studies was a large trial, involving 1,000 adults and children patients and led to regulatory approval in Liberia.10,11 Another study was an extensive Phase IV field programme to assess the real-life safety and efficacy of ASAQ in Côte d’Ivoire, involving 15,000 patients over two to three years. All data from this pharmacovigilance programme are pooled in a common database with the goal of providing extensive information on the medicine’s efficacy and safety. ASAQ efficacy data sets are shared with the Worldwide Antimalarial Resistance Network (WWARN), while the safety data are shared with the Liverpool School of Tropical Medicine.3
Conclusion on the development of ASAQ
The overall costs at DNDi for developing and monitoring the implementation of ASAQ were €12.5 million, over an overall time span of 12 years. ASAQ did not require early discovery and is based on well-established drug substances, decreasing the number of preclinical data to be documented by new studies. Yet, ASAQ still required testing in Phase I and III trials. These expenditures did not include investments made in parallel by Sanofi prior to registration and to support its implementation.
The development of ASAQ FDC has been characterised by several innovations:
- The innovative approach to developing this product with public and private partners
- The innovative partnership with a major pharmaceutical company, Sanofi, including agreement to develop ASAQ FDC as a non-patented product at cost-plus a small margin, as a public good
- The innovative implementation strategy – manufacturing ASAQ FDC at Sanofi’s facility in Morocco and registering it 33 endemic countries in Africa
- The innovative RMP with Sanofi and MMV, the first of its kind to be submitted to the WHO and to be entirely undertaken in Africa, which has strengthened its implementation in endemic countries
- The choice of a regulatory strategy which involved the WHO and aimed to expedite access in endemic countries, so minimising delays (and therefore loss of life) in bringing this important drug to malaria patients who need it most.
Sanofi and DNDi received the Corporate Social Responsibility Excellence award from the Association of Strategic Alliance Professionals (ASAP) in March 2014. The award recognises the significant and measurable “positive social impact” of ten years of public-private partnership in the fight against malaria.
Sleeping sickness treatment – The next step
The process has since been replicated to develop other therapies. One of the diseases targeted was sleeping sickness, for which existing treatments consisted of multiple intravenous infusions and which are invariably fatal without appropriate treatment. That form of treatment is really problematic in countries where clean needles can be hard to find and long hospital stays are often impossible. Drug development from scratch is too expensive, so the DNDi searches for promising leads in compound libraries generated by biotechnology and pharmaceutical companies. Many companies are willing to share these libraries because the diseases that the DNDi targets will not result in blockbuster drugs. The DNDi then contracts high-throughput screening centres, such as those at the Institute Pasteur Korea in Seongnam and the University of Dundee, UK, to test them. In 2007, such efforts identified fexinidazole, a compound that had shown promise against single-celled parasites but was pulled from development before reaching clinical trials. The DNDi turned it into a tablet, and passed it to its clinical-development team two years later.
The DNDi approached Sanofi again and promised to take care of the clinical trials if the company could file for regulatory approval. Human trials would not be easy, because sleeping sickness is not common and people affected tend to live in remote, unstable regions. But with existing therapy being so impractical, the DNDi argue that fexinidazole would bring such substantial benefit that even small-scale trials would be enough to show improvement to the patient. Multiple small-scale trials were conducted in the Democratic Republic of the Congo and the Central African Republic. The studies were fraught with logistical challenges, civil war and rebel groups robbing the clinics, but the final trials concluded in 2016. Results of the trials were published in November 2017,12 showing equivalence of efficacy and safety to the nifurtimox (oral)/eflornithine (infusion) combination therapy (NECT).
The aim is now to use fexinidazole as first-line treatment, with NECT as second-line treatment. The results already obtained enable Sanofi to proceed with steps towards regulation approval through the EMA, using the Article 58 procedure. This procedure was introduced in 2004 to allow the EMA to give opinions, in cooperation with WHO and relevant non-EU regulatory authorities, for the evaluation of certain medicinal products that are intended exclusively for markets outside the EU. Eligible products are usually vaccines or medicines used to prevent or treat public health priority disease and medicines for maternal and newborn healthcare. Since 2005, products successfully accepted through that procedure include HIV treatments, malaria vaccine and treatment, and umbilical cord infection treatment. The EMA supports the medicine development and registration process from an early stage: developers are encouraged to seek scientific advice on questions concerning quality, nonclinical and clinical aspects in the context of intended markets outside the EU. Developers also have the opportunity to request a business pipeline meeting to discuss their development strategy and to identify, at early stage, the need for specific guidance throughout the procedure. A company requests eligibility for Article 58 by submitting an application for scientific review to the EMA. The scientific assessment is conducted using the same standards and procedures as for medicines marketed in the EU. If the product receives a favourable opinion, the WHO may include it in its public health recommendations and the developer can seek marketing authorisation in non-EU countries. RMPs and follow-up measures have to be implemented. However, because the Article 58 procedure does not allow access to the European market, it is better designed for innovative products destined for low- and middle-income countries. For established medicines, developers usually prefer to use the WHO prequalification programme followed by national assessment.
The DNDi has established regional disease-specific research platforms, or networks, that support and build local capacity to conduct clinical trials in centres close to patients. Infrastructure and training are provided to ensure international standards are met. In this way, DNDi accelerates drug development and bring down the costs. Short-term strategies aim to provide existing treatments, while long-term development strategies focus on brand-new “breakthrough” drugs.
The DNDi admits to enjoying perks that pharma does not have. It keeps overhead costs low because its organisation is virtual. The research organisations that it contracts probably charge the group less than they would a for-profit company. The DNDi also relies on scientific consultants who work for low pay because they relish the chance to make lifesaving drugs without considering competitors, investors and marketing. Still, the organisation reckons that such in-kind contributions account for just 10–20% of its expenditure. It saves much more through efficient collaboration (avoiding duplicated effort by screening pooled libraries, for example) and a focus on desperately needed drugs.
Policymakers have taken notice, too. In 2015, the WHO asked the DNDi to consider antibiotics for drug-resistant infections in the developing world; in May 2016, the initiative announced that it would start the GARDP (Global Antibiotic Research and Development) partnership with US$2.2 million in seed funding. GARDP was launched to repurpose and combine existing antibiotics to treat sepsis and sexually transmitted infections, most notably gonorrhoea and infections in newborn babies. GARDP’s objectives in its 2017–2023 Business Plan are to deliver up to four new treatments and build a robust pipeline of pre-clinical and clinical candidates by 2023. To reach these objectives, GARDP is building key partnerships and harnessing the technical and strategic support from its parent organisations, the WHO and DNDi. GARDP could become a kind of experiment to see if the DNDi model could also work for more cost-effective development of drugs in the Western world.
- DNDi. Available at: dndi.org/about-dndi/.
- A Maxmen. ‘Busting the billion-dollar myth: how to slash the cost of drug development’, Nature. 2016 Aug 25;536(7617):388-90.
- The successful development of a fixed dose combination of artesunate plus amodiaquine antimalarial. October 2015 Report. Drugs for Neglected Diseases Initiative.
- P Brasseur, P Agnamey, O Gaye et al. ‘Dosing accuracy of artesunate and amodiaquine as treatment for falciparum malaria in Casamance, Senegal’, Trop Med Int Health, 2009 Jan;14(1):79-87.
- V Navaratnam, S Ramanathan, M S Wahab et al. ‘Tolerability and pharmacokinetics of non-fixed and fixed combinations of artesunate and amodiaquine in Malaysian healthy normal volunteers’, Eur J Clin Pharmacol, 2009 Aug;65(8):809-21.6. S Fitoussi, C Thang, E Lesauvage et al. ‘Bioavailability of a co-formulated combination of amodiaquine and artesunate under fed and fasted conditions. A randomised, open-label crossover study’, Arzneimittelforschung, 2009;59(7):370-6.7. S B Sirima, A B Tiono, A Gansané et al. ‘The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum’, Malar J, 2009 Mar 16;8:48.8. J L Ndiaye, M Randrianarivelojosia, I Sagara et al. ‘Randomized, multicentre assessment of the efficacy and safety of ASAQ–a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria’. Malar J, 2009 Jun 8;8:125. doi:10.1186/1475-2875-8-125.9. WHO. Available at: https://extranet.who.int/prequal/10. B Schramm, P Valeh, E Baudin et al. ‘Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia’, Malar J, 2013 Jul 17;12:250.11. B Schramm, P Valeh, E Baudin et al. ‘Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non-inferiority trial’, Malar J, 2013 Jul 17;12:251.12. V K B K Mesu, W M Kalonji, C Bardonneau et al’Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial’, Lancet, 2018 Jan 13;391(10116):144-154.
This article was taken and adapted from the original published in Regulatory Rapporteur, Volume 15, No 6, June 2018.