The Bill & Melinda Gates Foundation is stepping up its commitment to helping solve the complex chemistry, manufacturing and control (CMC), regulatory, financial, and distribution challenges of providing quality medicines for developing countries.
In the effort to open the CMC pathways and expand access to essential medicines for those most in need, the foundation is partnering with the pharmaceutical industry, non-profits, family agencies, governments, and a growing network of subject matter experts and contract organizations.
Engraved on the building at the entrance of the Gates Foundation visitor’s center are the words: “Every person deserves the chance to live a healthy, productive life.” Since being formed in 2000, the foundation has focused its mission on “working together” to advance biomedical research and make medicines available in those areas of the world where there is the greatest mismatch between disease burden and available care.
Now the largest philanthropic organization in the world, the foundation added more focus and resources to its work by opening the doors of the Gates Medical Research Institute in early 2018. “Gates MRI” is essentially a non-profit biotech company, with a focus on catalyzing the development, manufacturing, and distribution of new therapies to address the world’s most devastating diseases – particularly malaria, tuberculosis, and enteric/diarrheal illnesses.
At conferences where the pharma industry, regulators, and academia are meeting to discuss global CMC/quality-related issues, senior Gates leaders have been sharing what they do, and how and why they do it, in the effort to broaden the foundation’s global collaborative network.
Leveraging Modern Manufacturing for Global Health
During the opening session on “Advancing the Understanding & Control of Manufacturing Processes” at the 2018 IFPAC Annual Meeting held in February in Bethesda, Maryland, Gates Foundation Global Health Division CMC Senior Program Officer Niya Bowers reviewed the role Gates is striving to play in “leveraging modern manufacturing for global health.”
Bowers began by describing the 18-year history of the foundation, emphasizing its humanitarian, global healthcare roots. At present, she said, there is a total endowment of over $40 billion with philanthropic investments of over $5 billion last year alone. The efforts of about 1,500 employees worldwide are harnessed in support of about 1,900 grantees – making it by far the largest philanthropic organization in the world.
Bowers explained that a major benefit of the foundation’s legal structure – being a private, family-owned organization – is that it can take risks that others can’t or won’t. As such, Gates can channel resources into the development of medicines for which there has been little financial motivation among pharmaceutical companies.
Further, she pointed out, unlike corporations that must closely guard proprietary information and trade secrets, the foundation is able to freely share discoveries, processes, data, and other information for the benefit of underserved countries and populations.
Bowers went on to emphasize the importance of discovering and developing affordable vaccines, drugs, and diagnostics for people in the developing world. The foundation’s programs are focused on infectious diseases, including enteric and diarrheal diseases, pneumonia, neglected tropical diseases, malaria, HIV, and tuberculosis.
She noted that 90% of the world’s infectious disease burden is in developing countries, while fewer than 20 of the 1,500 medicines licensed since 1975 have been for diseases that primarily affect developing countries.
In her February 2018 presentation, Bowers explained that CMC is part of the “integrated development” arm of global health at the Gates Foundation, and at that time involved a handful of Gates employees working with about 25 non-profit and for-profit partners on about 60 active programs in development.
Leveraging “an army of consultants” to provide technical and strategic guidance is essential, Bowers commented. So is working closely with grantees. “We are not looking for a return of our money in five years. We are not looking for a five-year exit plan. What we are looking for is impact.”
With $5 billion in investment, there is a vigorous program strategy review, because “we have to focus on the greatest need and increase the impact that we can make,” she said. The need is great for cost-effective, affordable, and yet more complex products to compensate for the deficiencies in healthcare systems and infrastructure, including supply chains, transportation, and electricity.
“The majority of our products are not white pills,” but in complex formats, Bowers stressed – providing as examples a longer duration implant for HIV prevention, a long-acting oral delivery drug with the potential to provide seasonal malaria prevention and intervention, and a take-it-home, simple-to-use injection device for birth control.
Bowers shared the foundation’s aspiration of improving manufacturing efficiency to reduce costs.
She emphasized a commitment to supporting continuous manufacturing, including the API cost reduction model being driven by the Medicines for All Institute at Virginia Commonwealth University, as well as new manufacturing technology to produce stabilized semi-synthetic artemisinin, crucial to the current malaria treatment. [A link to Bowers’ full remarks at the IFPAC session is provided below.]
A New Paradigm for Translational Vaccine Development
A keynote presentation was made by Gates MRI CEO Penny Heaton on her recently established institute and its goals, which include creating “a new paradigm for translational vaccine development,” at the 2018 CASSS WCBP Symposium that took place in Washington, D.C. at the end of January.
The presentation encompassed: ● her own journey in global health ● the Gates Foundation and MRI ● the mission, mantras, and process of the institute ● diarrheal diseases and rotavirus ● a case study of developing a vaccine and its impact, and ● the pathway ahead.
Prior to joining the Gates Foundation in 2013, Heaton’s journey encompassed an early interest in infectious disease as a child, to work at the Center for Disease Control, followed by a 15-year career in industry.
She emphasized that Gates Foundation itself has been a “funder” – not involved in wet labs, plants, or running trials – with the work done through partners.
The best way to think about Gates MRI, by contrast, is as a non-profit biotech company, she suggested. “The idea is to take advantage of what has been happening in the biotech and big pharma space – the explosion of new discoveries, new technologies, new approaches to translational medicine. The idea is, let’s harness that, and let’s apply that to diseases of the poorest.”
Located in Cambridge, MA, with a small group in Seattle, Gates MRI is a wholly owned and funded subsidiary of the foundation, but “a separate entity,” and is actually doing translational medicine and R&D. “We have a 15-year business plan with a check-in at 10 years,” noted Heaton. The ultimate goal is to have about 100-120 employees.
While progress has been made in global health – for example, in polio, meningitis, and AIDS – challenges remain and the number of deaths is “staggering,” with enteric/diarrheal diseases, malaria, and tuberculosis together resulting in four deaths every minute. The Gates MRI priorities, aligned with the foundation, are: ● a world free of malaria ● accelerating the end of the tuberculosis epidemic, and ● eradicating diarrheal deaths in children.
Gates MRI Will Bring Experts to Bear on Freeing Up Bottlenecks
MRI is still in its early stages as a “non-profit biotech,” Heaton explained. Although her presentation focused heavily on the development of a vaccine for rotavirus to illustrate how MRI would operate, she emphasized that the organization is “not wed to a given technology platform. We are not wed to a given approach. What we really want is the solutions to meet our goals.”
In focusing on the translational space, the institute’s model will be “looking at starting development in that late discovery, early preclinical space. We will take it through confirmatory preclinical and nonclinical type studies to Phase 1 and Phase 2 in humans – GxP studies enabling clinical trials – with the goal of demonstrating proof of concept in our target population. At that point we envision that we may be handing off to a late-stage development partner. We are envisioning remaining a relatively small organization, and we don’t envision doing late-stage development and commercial manufacturing.”
In considering the important capabilities needed for Gates MRI, Heaton commented that she drew on her past industry experience in assessing where the bottlenecks and problems have been – especially in vaccine development. In addressing them, the institute will be applying the latest approaches and technologies, and engaging expertise in translational and quantitative science, CMC, and bioassays to advance various modalities, including small molecule therapeutics, diagnostics/biomarkers, vaccines, and biologics.
The focus will be on sharing the learnings across these product types in responding to the diseases in focus – taking “learnings from one and applying them to the other.”
Heaton has found CMC to be “the number one bottleneck in the translational space, both in the private sector and in my time at the foundation. So I am making sure that we have strong CMC expertise.”
She spoke about the “mantras” she developed for Gates MRI – urgency, collaboration, innovation, and rigor – and added a fifth one to the list – courage. In looking ahead, she noted that “progress will only come through partnership” in early research, and translational and late-stage development, allowing the benefits to be applied across the whole of the global health ecosystem. [A link to Heaton’s full remarks at the WCBP conference is provided below.]
Q&A Probes into Scope of MRI’s Work
The Q&A that followed provided Heaton an opportunity to offer some additional insights into the scope of the foundation’s work.
Asked about MRI’s involvement with monoclonals, she responded that the institute would indeed be working on developing them and that it was important to build expertise in-house. She noted that they would also be working on the process itself, “so that we can make smaller batches less expensively for experimental medicine trials.”
The intention, Heaton explained, is to use small batches of monoclonals with different constructs, infect them with malaria, see if any do protect against the disease, then use them both as a “bridge” treatment, and, through reverse engineering, as a basis for the development of a vaccine in the long-term.
The next audience question moved the focus from malaria to TB.
Noting that the current TB vaccine has been in use for nearly 100 years, Heaton explained that three recent developments are giving her hope: ● a number of studies showing remarkable efficacy of Bacillus Calmette-Guerin (BCG) when given intravenously, leading MRI to use that model to try to identify correlates – “and we are really making some progress there” ● a cytomegalovirus (CMV) replicate vector-based vaccine that is showing remarkable results that ”we have never seen before in non-human primate models,” and ● MRI’s investigation of granulomas.
Heaton explained that in any given monkey all the granulomas are different and that “some of them regress and control the disease.” Noting that this was “starting to look a lot like cancer,” she suggested that “the answer to TB may come from a very different area than what we have ever dreamed.”
The final question of the session was about the potential conflict between MRI’s focus on “rigor” and the imperative of “urgency.”
Heaton acknowledged the conflict, but affirmed that rigor was the priority. As an example, she emphasized that it was critically important to invest adequate attention on dosing.
“One thing I think is super important is getting the dose right,” she said, “and taking time to do the dose managing. I have seen that mistake over and over again, and…there are real implications for not moving out from the beginning with the two-dose regimen or one-dose regimen for low-income countries.”
Heaton concluded by noting that the urgency is not just developing drugs or “checking the box” of objectives to be accomplished. The real urgency is “time to impact,” and the question she asks herself is “what can we do early on to actually speed up the back end?”
Global Regulatory Approach to Improve Health Care
At The Organization for Professionals in Regulatory Affairs (TOPRA) Annual Symposium in October 2017 in London, Gates Foundation Integrated Development Deputy Director and Global Regulatory Systems Initiative Lead Murray Lumpkin provided the keynote on “Global Regulatory Approaches to Improve Health Care: Collaborations, Strategies & Solutions.”
Lumpkin reviewed: ● the disparities between high and low income countries in population, disease burden, medical care and the functioning of their regulatory systems, and ● the regional and global initiatives to strengthen regulatory processes.
He opened his presentation with the adage that “the patient is waiting.” However, he challenged the audience to think about who those patients are, and not to lose sight of those in most need from areas of the world where there is the greatest mismatch between disease burden and available medical care, biomedical research, manufacturing capacity, and regulatory infrastructure.
Sounding a “call to action,” he stressed that “there is a great need for participation. There is a great need for people with regulatory expertise and with a wide perspective on using the opportunities that we are given to improve healthcare.” Using powerful graphics to illustrate, he went on to say that, “when we start thinking globally, there are some significant differences in disease burden in various parts of the world, and there are significant differences in the access to effective, safe, quality products.”
Lumpkin, who had an extended career in leadership positions at FDA before joining the Gates Foundation, shared his insights on “the good, the bad and the ugly” of medical product regulation:
● Regulation done well – “the good” – “facilitates access and impact by assuring that the products available are quality products whose claims are backed by independent evaluation of good science.”
● Regulation done poorly – “the bad” – “retards access to quality products and has a negative impact on public health.”
● The absence of regulation – “the ugly” – simply “creates chaos both in public health and in the market place where products are of questionable quality and are not backed by science.” As Lumpkin points out, “patients are exploited in a ‘buyer beware’ dynamic that is a ‘rush to the bottom’ when it comes to product quality, efficacy, and safety.”
Regulatory approval, he stressed, “is not the holy grail of our work.” What is needed is access to these medicines after the approval process. Yet, there can be delays of up to years in some developing countries due to many factors, including procurement, delivery of product, and surveillance challenges – for example, product safety and supply chain integrity.
Collaborative work is ongoing to address these challenges in global health product access and impact for developing countries, Lumpkin explained.
Much of this is being driven by the World Health Organization (WHO) in working to advance a pre-qualification collaborative process and other strategic approaches for these countries in terms of registration and product suitability. For example, Lumpkin explained, “is it stable in the climate? Will it be stable under transport conditions? Is it labeled in a way that will be effective in communicating to the populations who will be receiving this?”
Lumpkin also highlighted the role being played by the African Medicines Regulatory Harmonization (AMRH) initiative in responding to the issues and challenges in registering medicines in the region. The AMRH vision is to guide the 55 countries and six regional economic groupings in Africa toward a unified “African Medicines Agency” (AMA) that would be similar to the European Medicines Agency (EMA).
In May 2018, the African Ministers of Health voted in favor of proposing a treaty for the establishment of the AMA, which will “seek to ensure the coordination and strengthening of continental initiatives to harmonize medial products regulation, provide guidance and technical support to improve access to quality, safe and efficacious medical products and health technologies on the continent.” Ratification of the treaty has been under discussion among the African Union members in January.
Lumpkin finished with a review of some of the other key initiatives going on around the world in regulatory systems that impact global health, including the work being done by the TB Alliance to evolve CMC requirements and make more therapies available in low and middle income countries. [A link to Lumpkin’s full remarks at the TOPRA session is provided below.]
[Editor’s Note: In a follow up story, IPQ will explore further the collaborative efforts now advancing – with the support of organizations like Gates and WHO – to understand, evolve and harmonize the regulatory processes and standards in the developing world.]
MRI’s Manchanda Sheds Additional Light on Institute Activities
As a part of Gates’ outreach to the biopharmaceutical community, MRI Innovation Portfolio Leader Raj Manchanda spoke at a “Biomanufacturing Summit” coordinated by the University of Massachusetts Lowell in Boston in September. Manchanda had joined MRI only a few weeks before. He has held senior management positions in development and CMC at both small start-up and large established pharma companies, including Biogen.
Manchanda began by giving a brief overview and history of biomanufacturing – from plasma fractionation to recent work on mABs – and the lessons learned. He then addressed current innovations and the future of biomanufacturing – from the small company perspective, where the focus is on the development and proof of concept of new modalities, to the large company perspective, where the focus is on CMC and scaling up production.
In the second part of his talk, Manchanda offered the Gates MRI perspective, with its focus on developing a portfolio of different drugs for their three top priorities – TB, malaria, and enteric/diarrheal diseases.
He noted that the institute is heavily invested in understanding human disease biology and the biology of the drugs that treat them. MRI’s interest, he said, is in translational medicine – pre-clinical testing, developing CMC processes, and running global trials to come up with suitable paradigms for the target populations.
[A link to the later part of Manchanda’s presentation on MRI is provided below.]
Diagnostics Also on MRI’s Radar Screen
During the Q&A following his presentation, Manchanda commented that of all the enteric and diarrheal diseases that are devastating young and old populations in Africa, the institute is currently most focused on Shigella.
Explaining that MRI will not be doing any manufacturing, he reiterated that the institute relies on partnerships, that they are open to all modalities, and they encourage innovation in the CMC realm. “If we do proof of concept and they are our manufacturing partner, we can incentivize them [to innovate] by providing the funding,” he said.
Asked if MRI was focusing on injectables, Manchanda responded that the institute was not married to any modality.
“For TB there are orals available,” he noted. “But the problem is you have to take the drug every day for six months. As soon as you stop for even a couple of days you have lost the whole advantage of the benefit you had. It all depends on the disease and the infrastructure that exists. So what is that model that can be applied to Africa? If we are going with an oral, you have to have a really long half-life so the patient doesn’t need to be on a six-month regimen.”
Manchanda also emphasized the institute’s interest in diagnostics.
“There is definitely a shortfall in TB diagnostics,” he said. “For TB the only diagnostic we really have is the active disease. The way TB works is that you get infected, but you may not have active TB for years. You are carrying the pathogen, but there are no symptoms. So, can we diagnose that early, or do we have to wait for the active disease?”
Active disease is currently diagnosed using a cell culture, which takes a couple of weeks. “We are looking at different options. There is a paper out there right now looking at PET. And there are urine tests coming out that look for pathogens in the urine, so we don’t actually have to take a lung sample, which is invasive.”
Asked about timed-release vaccines, Manchanda noted that MRI is “looking at subcutaneous depots, long-lasting vaccines, looking at how the immune response can be delayed as well. And for drugs, we are looking at the same thing. But again, it depends on what you are targeting and how does the immunity sustain? For malaria that is a problem. You can vaccinate, but the immunity is short-lived because the parasite is changing as well. There are multiple factors, but that is what we are looking at.”
In line with the other recent talks, Manchanda invited industry to partner with Gates MRI.
In response to a question about grant funding to support projects, Manchanda explained that MRI had not yet given out grants but that its parent, the Bill & Melinda Gates Foundation, had done a lot in that regard – funding alliances, consortiums, and biotechs large and small. “We are reaching out to companies to explore if they are willing to have a partner like Gates MRI,” he said.