Clinical Researcher—February 2018 (Volume 32, Issue 2)
Gary W. Cramer
Editor’s Note: As an illustration of a complex project management challenge, Clinical Researcher is pleased to present the following Q&A with:
|Mark Sullivan, Managing Director of Medicines Development for Global Health (MDGH)|
|Craig Rayner, a Senior Vice President with Certara Strategic Consulting®|
MDGH, a not-for-profit global health company, recently submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration for moxidectin as an oral treatment for river blindness (onchocerciasis). A drug development team from Certara has been an integral part of MDGH’s development program and NDA for moxidectin.
Q: How was the connection first made between Certara and MDGH to partner on this project?
A: The moxidectin collaboration grew from Mark’s relationship with the Melbourne-based Certara team and awareness of the drug development reputation of that organization.
Q: What kind of critical expertise was being looked for in a partner by MDGH for this work?
A: In common with many companies, MDGH develops new medicines using a virtual model with a particular emphasis on in-house project management and leadership. As such, MDGH needed integrated, model-informed drug development expertise in the areas of clinical pharmacology, translational medicine, and regulatory science to dovetail with our own skill set. We found great alignment between Certara’s and MDGH’s global health and infectious diseases expertise, and there was the added benefit that Certara has team members based in Melbourne who specialize in those areas. Finally, there was an excellent cultural alignment between the organizations.
Q: Does it make a difference in project management on Certara’s end of the project that MDGH is a not-for-profit entity vs. a commercial sponsor?
A: Certara believes that there should be global equity in access to medicines. Certara and its consultants are excited to be collaborating with MDGH to develop moxidectin for onchocerciasis patients in sub-Saharan Africa. Certara employs a broad range of contract structures across its client portfolio—ranging from hourly, milestone, and full-time equivalent retainer contracts to structures aligning performance, value creation, and risk share. MDGH, although a not-for-profit organization in structure, operates as a social enterprise rather than a charity. For examples like MDGH, which involve a long-term collaboration and alignment of company culture and purpose, Certara uses creative deal structures that may include a volume discount and value-based payments linked to the delivery of agreed project milestones.
Q: Can you give examples of particular challenges that the nature of the disease being targeted raised during the conduct of clinical trials for moxidectin?
A: Onchocerciasis is caused by the filarial worm Onchocerca volvulus, which is transmitted through the bites of infected black flies. Each adult female worm, which can live for up to 15 years in the human body, produces millions of microfilariae that migrate through the skin, eyes, and lymph nodes. Symptoms include severe skin inflammation, intense itching, enlarged lymph nodes, and, in some patients, visual impairment that can ultimately lead to blindness.
The World Health Organization (WHO) estimates that at least 16 million people are infected with Onchocerca volvulus worldwide. Of those people, 300,000 are blind and 800,000 have some degree of visual impairment. About 123 million people are at risk of becoming infected with the parasite.
In sub-Saharan Africa, where onchocerciasis is endemic, the current standard of care (ivermectin) is administered once or twice a year as part of mass drug administration programs. Ivermectin has been donated by Merck, Inc. for decades, but this generous provision of an important medicine also greatly diminishes incentive for follow-up treatments to be developed. The issue is that modeling has shown that ivermectin alone is unlikely to achieve the 2012 London Declaration on Neglected Tropical Diseases goal of eliminating onchocerciasis in 80% of endemic countries by 2025, and that alternative treatment options are needed.
Population health policy, lack of infrastructure, and, particularly, health infrastructure, added to regional conflict all provided challenges when designing an executable development program for moxidectin. The WHO Special Programme for Research and Training in Tropical Diseases (TDR) executed the onchocerciasis clinical development program to regulatory standards despite these logistical complexities. They built and equipped the clinics to conduct the studies and provided the necessary training and support to the dedicated staff. Further, the chronic nature of the disease and extended time required to achieve clinical outcomes created additional complexity from the development perspective. Therefore, guidance on optimal dose and re-treatment intervals both required significant support from modeling and simulation approaches.
Q: How and why were modeling and simulation techniques applied to the research goals in this project?
A: Moxidectin provides an excellent example of the power of an integrated, model-informed drug development program. Pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation was applied throughout the program to expand the development team’s knowledge of moxidectin. Specifically, the team used population PK/PD models to support the therapeutic dose rationale and to understand the potential impact of intrinsic (e.g., body composition, gender, age, disease burden) and extrinsic (e.g., concomitant medications, food, formulation) factors on moxidectin dosing and use.
Modeling and simulation methods also informed clinical trial design, conduct, and analyses. Those trials included a concentration QT and selection of doses for a pediatric Phase II study. Moxidectin may have utility in a number of other diseases, including scabies, and a Phase II study in scabies currently being planned integrates a model-based approach.
MDGH and Certara also collaborated with teams from TDR and Imperial College London, to combine PK/PD modeling with epidemiological and health economic modeling for exploring public health strategies that could accelerate the elimination of onchocerciasis. This modeling demonstrated that moxidectin could significantly shorten the time to elimination of this disease when compared to current ivermectin strategies, delivering a potentially enormous public health benefit.
Q: If the NDA is approved, what comes next? How soon and in what manner would the treatment be available to affected populations?
A: Once approved, moxidectin will be made available to nongovernmental organizations working on onchocerciasis programs. The intention is to donate moxidectin to the affected communities. MDGH is also committed to continuing moxidectin development for other indications, including scabies, lymphatic filariasis, soil-transmitted helminths, and strongyloides, which are all neglected tropical diseases affecting up to 1 billion people. The relationship with Certara will continue to achieve these goals.
Gary W. Cramer (firstname.lastname@example.org) is Managing Editor for ACRP.