Pharma often finds its global commitments to fighting infectious disease outbreaks and chronic health crises attacked or dismissed as inadequate-but the realities of market economics, fiduciary duty, and murky regulatory systems must be factored into the equation

 last year, Nicole Hassoun, a professor of philosophy at Binghamton University-State University of New York, and head of the Global Health Organization, cited a World Health Organization (WHO) report stating that a third of the world’s population cannot access important medicines for some of the globe’s most devastating diseases. Hassoun wrote, “I believe that [pharmaceutical] companies have a moral and legal obligation to ensure access to essential medicines.” 

	When companies set high prices, lobby to extend patent protections on important medicines, and do not develop enough new drugs for neglected diseases, she went on, they fail to live up to these obligations.

 While Hassoun expressed her arguments soberly, zealous contingents of activists prefer to use more drastic measures to make their points. In April of last year, seven naked people representing ACT UP London-a “diverse, non-partisan group of individuals united in anger and committed to creative action to end the HIV pandemic”-stormed the headquarters of Gilead Sciences in London with “#PharmaGreedKills” scrawled on their backs. One of their spokesmen railed that “more than two billion people do not have regular access to the critical medicines they need” and that, “every year, 10 million people die from diseases because drug pricing blocks access to effective treatments.”

	The merits of these arguments are, of course, arguable, but they stand uneasily with statistics such as those featured in this year’s

 Pharmaceutical Industry and Global Health: Facts and Figures

 report, released by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). According to the report, between 2011 and 2014, drugs and vaccines against malaria saved the lives of 1.14 million African children. Between 2000 and 2014, immunization campaigns helped reduce the number of deaths from measles in Africa by 79%. And in 2014, the pharma industry was the third-largest funder of neglected disease research, investing over $534 million.

	As the IFPMA report also points out, the private sector produces nearly all the medicines and vaccines on the market. But the industry is not immune to external or indeed internal pressures; pharma is dealing with rising R&D costs, more stringent testing, stricter reporting requirements, and a volatile wave of political and pricing pressures in its established markets. Similarly, there is always the need to appease stockholders and sustain growth in the face of corporate social responsibility (CSR) obligations and efforts to address health crises in low-income countries. 

	To maintain its drive, IFPMA observes, the industry has had to adopt new models of innovation, such as joint ventures between pharma companies and partnerships with the public sector, collaborations that “facilitate the sharing of expertise, know-how, and technologies.”

	One example where collaboration is essential to reach a health-crisis solution is the race to find a vaccine for the Zika virus, which raised worldwide alarm following reports of an outbreak of babies born with microcephaly in Brazil in 2015. Takeda is one of several companies partnering with the US’s Biomedical Advanced Research and Development Authority (BARDA) to develop a vaccine to support the Zika response in the US and affected regions around the world. 

	Rajeev Venkayya, president of Takeda’s global vaccine business unit, told 

 that such programs are not sustainable by pharma companies alone. For infectious diseases for which there is an established epidemiology and an established market, he says, companies are more likely to make investments at risk, but the Zika program “is quite different from a program with a competitive dynamic.” 

	Venkayya explains: “There is inherent risk in an emerging infectious disease program that you will develop a product and the disease will not be there, or the recommendations will not fit with the profile of the vaccine that 

you have been developing, or there will be a lot of competition in the market. There are lots of things that make it hard for companies to justify such a program.” 

	Therefore, the financial “de-risking” of the Zika program-in the form of the US government’s commitment to fund its R&D expenses-is essential for such endeavors. With BARDA taking care of much of the financial investment, it is “an easier program to take on, even if the vaccine ultimately has uncertain uptake because of changes in epidemiology or other factors,” says Venkayya. 

	There have to be different mechanisms to support preparedness for unknown or low-probability, high-impact outbreaks of disease, he explains. “It is essential for governments to take on this challenge because it is not something that companies are going to be able to do on their own. That de-risking gives us the ability to go to our governance bodies and to the stockholders of Takeda and say this is a program that represents the right thing to do on behalf of public health.”

	This does not mean Takeda isn’t making substantial investments itself in the program. “We’re committing our facilities, our people, our know-how, our technology platforms,” says Venkayya. And even government support does not eliminate all risk. Earlier this year, it was reported that Sanofi had pulled out of its Zika vaccine partnership with BARDA, the company citing BARDA’s decision to cut its funding. This followed months of increasing tension between Sanofi and its government partners about pricing guarantees. 

	Takeda’s Venkayya admits that when the decision-making on the progression of a program is shared by the partners, it adds a level of complexity. But, for his part, he adds that Takeda’s position was well understood from the outset. 

	“From the time we applied to BARDA, we knew that it was an options-based contract, subject to performance against pre-specified milestones as well as the overall context,” he says. “When we entered into this agreement, we agreed on the vaccinology approach that we’d be taking and also agreed on a high-level development strategy.”

	Venkayya adds: “We are basically in execution mode and we don’t really have the time or luxury of adjusting our plan based on what others are doing; the most important goal for us and for BARDA is to get a

 safe and effective vaccine to people who need it as soon as possible and that is what we’re focused on.”

	At the moment, the Takeda–BARDA Zika vaccine program has a US focus and is in its early stages. A major near-term milestone is the commencement of Phase I clinical trials, which are expected to begin before the end of the year. Beyond that, Takeda “has an aspiration to make a safe and effective Zika vaccine available to all populations who need it,” although Venkayya notes that this will require additional work and investment.

	While outbreaks such as Zika fuel emergency responses, the industry’s efforts to combat more widespread and ongoing global health crises continue apace. Despite the claims of the anti-pharma activists, the industry has played a significant part in reducing the number of worldwide AIDS-related deaths from a peak of 2.5 million in 2005 to an estimated 1.1 million in 2015. As IFPMA reports, pharma has developed more that 35 antiretroviral treatments (ARVs) for HIV/AIDS, which have been essential to control the epidemic. Also, industry programs to supply generic drugs, to provide education, and to build capacity are helping to erode the barriers that restrict access to medicines, contraceptives, and sexual health awareness among low-income populations. 

	At the forefront of the fight against HIV/AIDS is Mylan, which currently supplies ARV medicines to 6.4 million people with the disease in more than 100 low-income countries. In its 2015 Social Responsibility report, Mylan nobly announced that “we refuse to allow the thin margins earned in such countries to dissuade us from fighting the good fight. In fact, we continue to invest in additional capacity to expand 

access.” Key to building this capacity was Mylan’s 2007 acquisition of India-based Matrix Laboratories, one of the world’s largest suppliers of active pharmaceutical ingredients (APIs), including those used for HIV/AIDS drugs. Ten years on, Mylan has a 40% to 45% share of the API market for generic ARVs for the treatment of HIV/AIDS in some low-income countries. 

	In September, a consortium including the governments of South Africa and Kenya, the Joint United Nations Program on HIV/AIDS (UNAIDS), the Bill & Melinda Gates Foundation, and Unitaid announced a pricing agreement to accelerate the availability of the first affordable, generic, single-pill HIV treatment regimen containing dolutegravir (DTG) to public sector purchasers in these countries. Mylan is one of the program’s two suppliers, and has made a further three-year commitment to bringing down the price of the treatment. 

	“Fighting the good fight,” however, cannot be done with corporate abandon. Rajiv Malik, formerly CEO of Matrix and now president of Mylan, has significant experience in running a low-margin, high-volume business model, adept at supplying vital treatments for patients in low-income countries, while also committing to long-term company growth and sustainability. He told 

: “Sometimes you are forced to think about how far and how deeply you can continue with these commitments. There is always a fear from a business point of view, because there is competing demand for the capital. It’s a balancing act.”

	But while Mylan experienced significant challenges in the US market last year, this did not affect what the company is doing in the developing nations. In fact, it expanded. For example, through its Indian subsidiary, Mylan acquired a women’s healthcare business from Famy Care, a specialty company with global leadership in generic oral contraceptive products.

	“We are now working with partners like the J&J Foundation to continue to provide access to such products for women in Africa and are part of the UN’s Family Planning 2020 commitment,” says Malik. “And last year we launched a generic treatment for hepatitis C in India, where roughly 12 million people are infected with the virus. So, we are doubling our efforts. We continue to raise the bar and continue to invest in these critical treatment areas.” 

	 India’s importance to Mylan’s activities is paramount. Mylan’s acquisition of Matrix in 2007 was the largest ever takeover in India pharma. More than half of the company’s workforce is based in India, making the country its largest product-sourcing base. India is also key to securing future long-term growth and profitability in its low-margin global health activities. 

	“It is a huge country from an R&D and supply chain perspective,” says Malik. “It is also the hub of our business for products we produce for many developing countries; it is where we conduct our selling and marketing operations to reach patients in these underserved areas.” 

	Over the last five years, Mylan has begun to focus on India as a market itself, first with HIV drugs, then oncology (particularly breast cancer, building affordable cancer care through several CSR programs), and latterly in the hep C space. “We have tried to keep the focus on the disease states in India that need a lot of attention,” says Malik. “Financially, we just broke even, but we don’t invest in India and other rest-of-world (ROW) markets just from the perspective of returns. It is a case of building a base that is going to funnel the growth of our business. These markets may not drive your bottom line in a significant way, but they can definitely give you top-line growth and are a source of durable cash flow.”

	Using the platforms established by low-margin business models and philanthropic/CSR initiatives as a base to secure further growth, reach, and stability across low-income and developing nations is also a long-term objective of Merck & Co.’s Merck for Mothers. A 10-year, $500 million program focused on improving the health and well-being of mothers during pregnancy and childbirth in the US, India, Zambia, Senegal, and Uganda, Merck for Mothers was established in 2011 to address an urgent problem: 800 women a day-one woman every two minutes-were dying from preventable causes and complications from pregnancy and childbirth. 

	Since its inception, Merck for Mothers has “managed to reach over six-and-a-half-million women and improve their access to both quality maternity care services and quality modern contraception,” Dr. Mary-Ann Etiebet, Merck for Mothers’ executive director, told

. The program’s primary purpose, of course, is to improve the health of mothers and to save lives; in the longer term, says Etiebet, it is about “how we use this type of investment to strengthen healthcare systems” and how it “can actually benefit, more broadly, countries and other companies working in these areas.”

In Senegal, for example, Merck has helped to establish and transition to government ownership a “transformative, well-functioning supply chain system that is already improving access to critical medicines to all people.” A major barrier to family planning in Senegal was a lack of availability of contraception. Products were procured, but sat inside central warehouses, often failing to reach the “last mile” primary care facilities where women of reproductive age sought care. 

	In response, Merck for Mothers partnered with the Gates Foundation, IntraHealth International, and the government of Senegal to scale up a supply chain model adapted from the private sector, which, says Etiebet, has improved the logistics, forecasting, and delivery of contraceptives at health facilities throughout the country. 

	“The Senegal supply chain project has an impact that is wider than on maternal mortality alone,” explains Etiebet. “By improving the performance of the supply chain for contraceptives in Senegal, we were able to extend that model so that the government is now using it to supply over 90 essential medicines. By working on this one issue, we have been able to strengthen the health system in the country. This is the way we like to think about Merck for Mothers-how we can make sure our investments have broader, longer-term impacts.”

	The supply chain issue faced by Merck for Mothers in Senegal is symptomatic of a litany of challenges facing pharma’s activities in global health. Obstacles, ranging from underdeveloped infrastructures and disparate healthcare systems to poor transportation and lack of clean water and sanitation facilities, must be negotiated and overcome to establish effective access to medicines in low-income countries. 

	Not the least of these problems are the widely varying standards for market entrance and regulation. Malik admits that some companies could do more for global health “if in this part of the world we could have a harmonized framework of sustainable regulations. That would go a long way to motivating industry to come in and make a change.”

	In global health, “fighting the good fight” cannot happen without a number of enabling conditions that involve more than reducing the price of medicines. As the IFPMA report highlights, addressing the issues of regulation, corruption, logistics, poverty, and wealth inequality is a “complex challenge that requires long-term commitment from government, civil society, and the private sector.” Added to that is a pharma company’s fiduciary duty to maximize shareholder value and secure its own long-term survival. 

	The investment banker Lawrence Perkins wrote back in 2001 that “at the end of the day, the company’s future existence depends on the bottom line of the income statement. Pharmaceutical companies are no different.” While this observation may conveniently sidestep some of the more complex ethical considerations of the global health agenda, it remains an essential truth of the market-driven industry. 

s European and Online Editor. He can be reached at 

	1. Nicole Hassoun, “How can we get pharma companies to do more for global health?” 

	2. International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), 

The Pharmaceutical Industry and Global Health: Facts and Figures 2017

	3. Lawrence Perkins, “Pharmaceutical companies must make decisions based on profit,” 

Articles

Features

Pharm Exec details the latest approaches to combating disease and health crises on a global scale-including industry perspectives from those involved on the front lines.

Global Health: Fighting the Good Fight

Amid a widening net of global health threats, alliances in research and response may be more crucial than ever 

	The right business partnership can be critical to any company’s success. Specifically, in the pharmaceutical industry, partnerships between pharma or biotech companies and nonprofit organizations or foundations prove that theory-because by pooling their resources, these entities are working together to combat some of the world’s most serious health problems. 

	Polio, antibiotic resistance, AIDS, and Ebola are just a few of the global problems these partnerships are helping to fight.

 spoke with said pharma companies are key partners, because they specialize in what is needed to create and deliver new solutions to global health challenges. Pharma’s essential expertise, such as translating science into products that save lives, safely and effectively testing these treatments, and then manufacturing them in the required quantities, are critical to achieving global health goals.

	These types of partnerships are all unique and can make a big difference. Often, the relationships are not just centered around one-off projects. For example, last year, Bayer worked with the CDC Foundation to assist with two critical aspects of the Zika virus response in Puerto Rico. Those included providing women and their partners who want to delay or avoid pregnancy during the Zika outbreak with improved access to a range of contraceptive methods, and giving additional protection to families who want to sleep under mosquito-repelling bed nets. Bayer did this by providing the CDC Foundation with significant product donations of intrauterine devices (IUDs) and oral contraceptives, as well as concentrated mosquito insecticide tablets and insecticide-treated bed nets.

	At the time, Dr. Judith A. Monroe, president and CEO of the CDC Foundation, said in a press release, “This is a comprehensive public-private partnership aimed at helping CDC extend its Zika virus response. … To get ahead of this potentially devastating new threat, we must continue harnessing the resources and expertise of private 

sector partners to boost our national and local response efforts.”

	According to the CDC Foundation, 138,000 women in Puerto Rico were, at the time, at risk of unintended pregnancy and were not using one of the most effective or moderately effective forms of contraception. Bayer’s donation included up to 50,000 IUDs and 40,000 oral contraceptive units. In addition, the company provided 10,000 bed nets for use in Zika prevention kits for pregnant women and more than 700,000 mosquito-control tablets, which can be used to treat bed nets, curtains, and other household items to repel mosquitoes.

	Partnerships span across all diseases and can be especially helpful in the treatment of rare or orphan drug conditions. Take neglected tropical diseases, for example, which are a diverse group of communicable diseases that prevail in tropical and subtropical conditions in 149 countries.

	Most recently, a three-pronged partnership struck between the World Health Organization (WHO), the Mundo Sano Foundation, and Chemo Research, a division of Insud Pharma, is helping to make an essential antiparasitic medicine for the treatment of Chagas disease widely accessible to children. Treatment with benznidazole in the early stages of infection can cure this potentially life-threatening condition, but, currently, very few people are able to access diagnosis and treatment services, according to WHO. 

	Benznidazole, manufactured by Chemo Research, is commonly used as a first-line therapy for Chagas disease. Although it has existed for more than 40 years, the drug was not registered by any world regulatory agency until August of this year, when the FDA approved it for the treatment of children aged 2 to 12. It marked the first-ever approval of a therapy for Chagas disease in the US, where, reportedly, at least 300,000 people are estimated to be affected by the illness. 

	“We are working to enhance access to this medicine to people who need it the most,” said Silvia Gold, president of the Mundo Sano Foundation, in a press release. “We are proud to have Insud Pharma as a reliable industrial partner capable of expanding quality-assured affordable benznidazole. Our hope is to transform the dynamic of access to treatment for Chagas disease patients throughout the Americas and beyond.”

	About six to seven million people worldwide are estimated to be infected with 

, the parasite that causes Chagas disease.

	With some rare diseases, a medicine donation program is a popular type of partnership. One expert at WHO told 

 that often the product being donated has existed, but the market was very small. So instead of carving out numerous small markets, filled with patients unable to afford the medication, companies agree to work with a foundation or nonprofit who has direct access to the patient populuaton, and create a donation program. 

	It’s great to have partnership programs in place for the treatment of global diseases, but what if more of these international health epidemics were completely preventable? That’s the goal of the Coalition for Epidemic Preparedness Innovations (CEPI), a public-private coalition launched at the beginning of the year whose goal is to stop future epidemics by speeding the development of new vaccines. 

	According to CEPI, vaccine development needs to start long before an epidemic so that final clinical trials or emergency deployment can begin swiftly in an outbreak. However, needed vaccines in many such cases aren’t being developed often enough or quickly enough. And contributing to matters are the traditional difficulties in designing vaccines that work and are safe. 

	CEPI was founded by the Bill & Melinda Gates Foundation, the governments of India and Norway, the medical research charity Wellcome, and the World Economic Forum. It’s an alliance between governments, industry, academia, philanthropy, intergovernmental institutions such as WHO, and civil society.

	“We exist to finance and coordinate the development of new vaccines to prevent and contain infectious disease epidemics,” CEPI states on its website. “As epidemics disproportionately affect low-income countries, CEPI will ensure that the vaccines we help to develop are affordable, so that price is never a barrier to access, and they are available to populations with the most need.”

	Efforts around vaccine development are strong examples of how pharma companies, governments, and nonprofits are partnering together for a common cause. This is something Rajeev Venkayya, president of the vaccine business unit at Takeda, knows a lot about. Prior to joining the company in 2012 to launch its global vaccine business, building upon a longstanding business in Japan, Venkayya served as director of vaccine delivery for the Global Health Program at the Gates Foundation. There, he was responsible for the foundation’s efforts in polio eradication and new vaccine introduction, and a grant portfolio of $500 million a year. While at the foundation, Venkayya served on the Board of the Global Alliance for Vaccines and Immunization. 

	Venkayya explains that when it comes to vaccines, public and private entities need each other. In general, nonprofits or governments that have tried to launch their own vaccine have been unsuccessful. By leveraging knowledge from the pharma industry, it could help vaccine R&D advance at a faster pace, Venkayya believes.

	Vaccines are pretty well-established, straightforward investments for companies, but that doesn’t mean there aren’t challenges involved. This is especially true with emerging infectious diseases. Developing a vaccine can take eight to 12 years, or more, and the associated costs are steep. Partnering with a group like CEPI, or a foundation, can help eliminate that burden. 

	It’s that knowledge piece of the puzzle that drives Mei Mei Hu, co-founder and CEO of United Neuroscience. Hu is passionate about developing vaccines that treat and prevent neurological disorders. Her company has built a translational platform to rapidly design and develop targeted immunotherapeutics, leveraging the organization’s endobody vaccine technology. United Neuroscience’s proprietary technologies have successfully commercialized over three billion doses to date in multiple indications and launched one of only a handful of licensed vaccines against an endogenous host protein in the world. 

c, could not have been accomplished without partnerships, having enlisted what she says are some of the smartest researchers across the globe. 

	“Those collaborations are important, because you don’t want to miss out on the expertise of people outside your immediate ecosystem,” says Hu. 

	That knowledge network could encompass everything from strategic partnerships with academic institutions to informal informational meetings with groups like the Michael J. Fox Foundation about the latest advancements in Parkinson’s disease. Hu is a big proponent of open sourcing and sharing information, acknowledging, like many in her field, that most of the major health issues facing the world today, such as Alzheimer’s, cannot be solved by one person, or a company alone. 

	Those from both the public and private sectors that 

spoke with about the value of forming relationships between nonprofits and industry all stressed that such efforts can make a significant difference in global health. They point to pursuits to almost eradicate polio worldwide as an example of how true global partnerships between governments, nonprofits, foundations, and pharma companies can make an impact. And how those paths paved by global coalitions such as CEPI will be critical to ensuring a worthy battle against future health threats. 

’s Senior Editor. She can be reached at 

Amid a widening net of health threats worldwide, alliances forged in research and response may be more critical than ever to stem the tide.

Global Health: Partnerships Hold the Key

	In November, the FDA approved the first “digital medicine system” from Otsuka and Proteus in the form of Abilify MyCite, Otsuka’s antipychotic medication embedded with an ingestible sensor from Proteus that can show if a medication has been digested. The sensor had been “approved” since 2012 by the FDA to be included in the clinical trials, but in the drug’s public debut, interesting opinions emerged. 

“First Digital Pill Approved to Worries About Biomedical Big Brother” (view 

 and the article did bring up legitimate questions, specifically around ethics, compliance, and trust, as well as some interesting views around the patient population.  

	For example, while you can’t argue that medication adherence in the schizophrenic population is not stellar-with overall rates roughly at 50% and ranges from 20% to 89%-for the first drug with a sensor that transmits electrical signals outside the body, maybe it wasn’t an inspired choice from the standpoint of the population, whose symptoms include “hearing voices, believing other people are reading their minds or controlling their thoughts, and being suspicious or withdrawn.”

	Said Dr. Paul Abppelbaum, director of law, ethics, and psychiatry at Columbia University’s psychiatry department, in the article: “A system that will monitor their behavior and send signals out of their body and notify their doctor? You would think that, whether in psychiatry or general medicine, drugs for almost any other condition would be a better place to start than a drug for schizophrenia.”

	Leaving that aside for now, the article did profile compliant patients using medications for schizophrenia. One, in the trial for MyCite, didn’t like the rash from the patch (which is worn to collect the data), and says he won’t take it because he is compliant. Another compliant patient explained that he also wouldn’t consider the digital avenue for the medication, but he said those that don’t take their pills unsupervised have to get the medication via a shot. For those individuals, he said, the ingestible sensor alternative might be the way to go.

	Adherence for debilitating illnesses such as schizophrenia clearly has benefits for the patient, caregivers, and society. Medication adherence from an overall population health standpoint can be found in the numbers that are most-oft referenced from 2012 data: lack of adherence causes nearly 125,000 deaths, 10% of hospitalizations and costs the US healthcare system between $100 billion to $289 billion a year. The cost of non-adherence to a pharmaceutical company is a loss of $188 billion in potential US sales in 2015, and $637 billion globally. 

	For the patient, adhering to medicine is a decision around cost and mindset or behavior. For the former, that is one reason pharma invests in access programs for patients, whether in the form of rebates, hubs, or physician education around patient-specific co-pays and tiers because non-adherence is often a decision made around the pocketbook. For the latter, that revolves around patient education and the more trending “patient journey.” This means getting to the core of the patient’s perceptions around their disease, and recognizing clear goals for adherence, whether it’s being able to take a walk with their grandchild without getting winded or preventing future kidney disease and being immobilized by dialysis.

	There are quite a number of technologies used to promote adherence. They are as sophisticated as the Proteus IEM technology or AiCure’s facial recognition via smartphone, to apps or text messaging systems that send reminders, to blister packs or bottle caps integrated with chips, to wirelessly transfer open data. The more simplistic technologies can’t measure actual medication ingestion, further blurring the lines of compliance. In the limitations of use for Abilify MyCite, it states that patient compliance improvement has not been established. At the end of the day, any technology must be endorsed by the user. You can opt-out of text messaging services, or disable an app. And you can decline to share data collected via MyCite sensor.

	In a statement, Otsuka said that the product launch will be conducted in a limited rollout to select health plans and providers, to identify a group of the most appropriate patients. The hope is to gain feedback and learning for Otsuka’s broader go-to-market plan. 

	Some initial learnings may come from the views in 

article. Potentially, the use of the digital adherence technology could lead to what Otsuka mentions in the release: an opportunity to facilitate a more open dialogue and clarity to better inform medication decision-making for physicians and their patients around benefit, risk, compliance, and behavior.

From the Editor

FDA's approval of the first-ever digital medicine, while sparking legitimate concerns around ethics and trust, could signal improvements ahead to the much-chronicled woes in drug adherence and compliance.    

First Foray into Digital Adherence

	There are numerous examples of the impact the pharmaceutical industry has had on improving global health, as evidenced by our feature coverage in this month’s issue. However, one example seemed to stick out the most at 

 28th Annual General Assembly early this month: “We have taken AIDS from a death sentence to a chronic disease.” 

	That sentiment could have resonated with the hundreds of pharma professionals who gathered from across the world  simply because the event, “Pharma’s Commitment to Global Health,” was held on World AIDS Day, Dec. 1. But it was much more than that. It marked an example of public, private, and government groups coming together to conquer a public health problem, one that not only created a lethal threat to people’s lives, but also instilled a sense of fear that  affected wealthy communities in Beverly Hills to remote villages in the middle of Africa. 

	“Everything that has happened in [healthcare] in recent times has created a better place-not a perfect one, but a better one,” said Dr. Andrin Oswald, director of life sciences partnerships for the Bill & Melinda Gates Foundation. “And we are working to make it an even better place 20 years from now.” 

	Accomplishing this, forum speakers noted, will take commitment, partnership, and the ability of various entities to work in unison on multiple fronts. 

	“It requires a lot of different stakeholders coming together,” said Oswald. 

	For the Gates Foundation,  the potential of such efforts go well beyond just the funding aspect. As a trusted nonprofit, the Foundation sits in a unique position to bring a variety of healthcare influencers to the table.

	“We have the ability to convene a bridge between government and other partners,” said Oswald. “The barriers that shouldn’t be there in the first place are broken down. The Foundation believes that the private sector has an important role to play in global health. Making a profit while doing good should be supported.” 

	This is why partnerships are so vital when it comes to protecting global health. Take the Ebola virus, for example. Michael Nally, president of global vaccines at Merck & Co., and a 2016 

 Emerging Pharma Leader, explained that the company knew Ebola was never going to be a significant commercial opportunity, but, at the same time, it was aware that only a handful of organizations could translate the science to make the vaccine. 

	“Without collaborations around the world, we would have never gotten far enough with a vaccine,” he said. “[The pharma industry] has a broader obligation to global health. Shame on us if we are not working together with the global health community to find innovations. We are a science-based company. We cannot rest on just new innovation, and we have to work with the broader healthcare community to make our industry a more reputable public health partnership.”

	While foundations or government agencies can provide as much funding as possible, it’s that science from pharma and biotech companies that they lean on the most.  

	“Those in the nonprofit sector are not going back to the stockrooms and creating miracles in a test tube,” said Ambassador Sally G. Cowal, senior vice president, global cancer control, at the American Cancer Society. “We need your industry.” 

	And, in turn, the industry should depend on nonprofits. However, there needs to be a better short-versus-long-term balance in these relationships, those in industry expressed at the event. “Organizations struggle with what that model is that allows a fair return, but also can have maximum global impact,” said Nally. 

	Advocates pointed to noncommunicable diseases as the next area of global health that must be addressed. Doing more in cancer was especially brought up as an example.

	“The tsunami of cancer threatens lives and livelihoods around the globe,” Cowal said. “Cancer is undermining people’s abilities to support their families.” 

	She pointed out that, on average, cancer strikes people at the prime of their work life, ages 40-60. The disease’s economic impact-from premature deaths to  disability costs-can hurt the bottom lines of all companies. 

	Such realities, however callous in comparison, illustrate that global health is not just about the health of people, but the health of economies, businesses, resources, and ecosystems across the world.

Columns

Figuring out the right formula to address global health-for the better.

Global Health: Messages of Hope

	In recent months, biopharma companies won FDA approval of several truly breakthrough drugs that modify human cells to treat and potentially cure deadly disorders, and more are on the way. Novartis led with CAR-T therapy Kymriah for patients with relapsed acute lymphoblastic leukemia, followed by Yescarta from Gilead’s Kite Pharma for a similar condition. Spark Therapeutics’ Luxturna promises to cure a rare genetic

	Related discoveries are spurring development of antisense drugs and RNA treatments that can modulate immune pathways, such as Biogen’s Spinraza (nusinersen), approved a year ago as the first treatment for spinal muscular atrophy, which is often fatal for infants. And researchers reported success last month in utilizing gene therapy to create healthy skin to treat a life-threatening genetic skin-blistering disorder, raising expectations that genetically modified skin may treat open wounds and related conditions. 

	FDA reports that some 40 companies are developing CAR-T technologies for multiple indications and that it is monitoring more than 600 active investigational new drug applications (INDs) related to gene and cellular therapies. Scientists also are optimistic about developing vaccines to prevent and treat chronic illnesses as well as infectious diseases such as malaria and AIDS. A new report from the Pharmaceutical Research and Manufacturers of America (PhRMA) cites more than 100 vaccines in development to prevent cancer, HIV, allergies, and other serious conditions. 

	FDA support for biomedical innovation is a prominent theme in these discussions, and one championed by Commissioner Scott Gottlieb. Since taking the helm of the agency in May, Gottlieb has rolled out multiple initiatives to bolster biomedical R&D, demonstrating in the process that FDA does not impede approval of new life-saving therapies for patients. Priority efforts are to speed up orphan drug designations, spur development of complex generic drugs, streamline clinical trials through expanded modeling and simulation, and help patients gain early access to experimental therapies for serious conditions.

Digital health also is a prime FDA challenge, with Gottlieb unveiling an R&D plan last June to encourage new device and software development. In September, FDA approved the first mobile medical application to help treat substance use disorders, and last month the first digital pill came to market, a version of antipsychotic drug Abilify from Otsuka Pharmaceutical. It contains a tiny chip able to send a signal to an adhesive patch that informs a smart phone when the pill is ingested. 

	FDA’s new Oncology Center of Excellence (OCE), formally established in January 2017, is facilitating approval of dozens of new cancer therapies and additional indications. The latest challenge is developing drugs for patients with certain cancer biomarkers, as opposed to disease affecting specific body organs, as seen in the recent approval of an added indication for Merck & Co.’s Keytruda based on this technology. 

	The 21st Century Cures legislation approved at the end of 2016 supports many of these initiatives, plus a new program for developing regenerative medicine advanced therapies (RMAT). The new Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics Evaluation and Research (CBER) has established a process for designating and overseeing RMATs, including gene and cellular therapies that fall under this umbrella. Last month, FDA unveiled a RMAT regulatory framework with guidances for expediting development and review of these promising treatments. 

	Additional resources provided by the FDA Reauthorization Act (FDARA) fund many of the initiatives for spurring development and efficient oversight of cutting-edge therapies. Of particular note is the expansion of FDA’s Office for Combination Products (OCP), which advises sponsors on whether a new combination therapy should be regulated as a drug, biologic, or device. This process increasingly involves gene and other advanced therapies that incorporate prefilled syringes or autoinjectors to deliver treatment. OCP’s staff faces a growing volume of queries on combo product development programs, along with commitments to update guidances and prepare additional advisories on labeling issues and bridging studies, among others. 

	Although the long-term effects of new gene and cellular therapies are unknown, these initial successes have spurred optimism about further development of treatments for both rare and more prevalent serious conditions, particularly neurological diseases such as ALS, Alzheimer’s, and Huntington’s disease. At the same time, safety issues have sidelined some promising therapies, such as a  CAR-T candidate from June Therapeutics that was linked to severe brain toxicity that led to patient deaths in clinical trials. 

	Policymakers are taking note of these developments, along with related ethical and safety issues raised by the potential to treat serious diseases by editing genes more precisely using CRISPR and cas9 technology. A hearing before the Senate Health, Education, Labor and Pensions (HELP) Committee last month addressed 

the possibilities for preventing conditions such as sickle cell disease and blood disorders and the need for appropriate regulatory oversight of technologies able to change the human genome or to develop biological weapons. Experts agreed that the current FDA regulatory framework, plus oversight by the HHS Recombinant DNA Advisory Committee and institutional review boards (IRBs), can adequately assess the science and ethics of genome editing, and that stricter rules might discourage research or shift it overseas. 

	Sponsors and researchers also recognize the need to better understand which individuals face higher risks from new gene therapies and the potential for severe side effects. But with R&D pipelines full of innovative drugs, the future looks promising for continuing gains in discovering important new treatments for life-threatening diseases. 

’s Washington Correspondent. She can be reached at 

In 2017, patients gained access to the first gene therapies and more orphan and breakthrough drugs.

A Year of Transformation for Science & Medicine

Groundbreaking treatments involving adoptive cell transfer, such as CAR -T drugs, call for innovative commercialization strategies

	The approval of the first genetically modified cell therapy in the US-Kymriah™ by Novartis-made headlines in late August of this year, receiving marketing approval in North America for the treatment of B-cell acute lymphoblastic leukemia (ALL) in children and young adults with limited treatment options. Less than two months later, Kite Pharma received approval for Yescarta™ for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Both breakthroughs are chimeric antigen receptor T-cell (CAR-T) therapies that involve adoptive cell transfer (ACT). Over the next decade, we can expect other ACT therapies to change the field of oncology dramatically, particularly in some of the more difficult-to-treat cancers. 

	In parallel, biopharmaceutical manufacturers of ACT therapies will need to alter their traditional commercial models just as dramatically. First, ACT therapies are not drugs in any traditional sense; rather, they are medical procedures that require individualized, 

 processing and highly specialized healthcare professionals and facilities. If these first two market entrants are trendsetters, future treatments will be expensive and on a scale well beyond all other oncology treatments to date. ACT therapies will require a very different approach to pricing and market access than anything that has come before. 

	The CAR-T cell therapies Kymriah and Yescarta are produced by deriving cells from the patient, reengineering them in a laboratory to recognize and kill cancer cells, and then multiplying them and infusing them back into the patient (see chart).

	Investment in CAR-T drugs is strong, with more than 270 trials underway in this space. Of the approximately 40 companies developing CAR-T cell therapies, the leading players currently include Novartis, Kite Pharma (now part of Gilead Sciences), Juno Therapeutics (in association with Celgene), Bluebird Bio (also in association with Celgene), and Cellectis (in collaboration with Pfizer). According to Coherent Market Insights, the global CAR-T cell therapy market is estimated at $72 million today, with projected growth at a staggering CAGR of 46.1% between 2019 and 2028.  

	Payers will be facing a number of difficulties in evaluating and covering ACT therapies-challenges that biopharma companies must actively address in their commercialization strategies. 

Limitations in assessing clinical benefit 

	At the time of launch, the evidence base for ACT therapies will likely be immature and may not support conclusions on their potential long-term benefits. Indeed, many of these treatments may be approved on the basis of Phase II trials in relatively small patient samples, without long-term, real-world follow-up. It is safe to assume that payers will be unwilling to make the leap of faith on long-term benefit without some kind of 

proof or guarantee. However, they are unlikely to expect data from ~10-year-long trials. Payers also want to be able to compare the efficacy of a new product with the standard of care, although, in most cases, the data on newly launched ACT therapies will likely not be robust enough for such comparisons. 

	As with other immuno-oncology treatments, ACT therapies are likely to work well for a portion of patients, providing remission for a number of years. In Kymriah’s case, 83% of patients achieved complete remission or incomplete response with blood count recovery within three months of infusion. Payers (along with the entire medical community) will be eager for more insights into which subgroups of patient will benefit from the treatment. 

	As mentioned, ACT therapy is typically developed though an individualized process for each patient, and treatment is provided in the hospital, similar to stem-cell transplants. 

	This means that in the US, the manufacturer’s customer is the hospital system/provider, and only a small number (perhaps 10 to 15) of centers of excellence are likely to be capable of offering the treatment. Payers must negotiate contracts with these facilities and be prepared to address policy issues around access and funding, in particular for patients who do not live near one of these centers. 

	In the major five European markets (France, Germany, Italy, Spain, and the UK), treatment will likely be covered by the hospital funding mechanisms, such as are in place for organ transplants. Funding is typically based on a single, fixed-price per patient to cover costs from the date of admission to a certain number of months post-transplant. There may be no existing mechanism for funding any additional, and costly, services related to ACT treatment.  

	Currently, a one-time treatment with Kymriah is priced at $475,000-a price that has pierced prior-cost barriers. (In contrast, a one-year course of treatment with a programmed death cell protein 1 [PD-1] targeted antibody is priced around $180,000). Initially, even at this price, Kymriah will present payers with limited budget impact, as it is indicated only for ALL that is refractory or in second or later relapse in children and young adults (up to 25 years of age). However, the impact on payers will change if/when Kymriah is approved for other more prevalent indications and certainly when other ACT therapies enter the market. Yescarta is priced lower than Kymriah, at $373,000, but it will serve a considerably larger patient population

 in which the unmet need may not be as high. 

	While the downstream benefits of ACT therapy are likely to last for many years, the very high cost will be concentrated at the time of treatment. In the US, where patients tend to change medical insurers on average every two to three years, how can the cost be borne, and the benefits enjoyed, equitably? There may be a disincentive to cover such therapy if another entity yields the benefits. 

	So, how will ACT therapies fit into the existing funding structure? How will payers respond? Their approaches will be different by country and region, but we can expect that they will take a conservative approach when data packages are limited. Particularly in the Euopean Union (EU), payers can prolong their drug listing/formulary decision-making process as approvals work their way through national, regional, and then hospital-level bodies. It is not unusual for this process to take as long as two years. As an example, access decisions on the multiple myeloma drug Farydak® took around two years in both France and Italy. Ultimately, they can restrict or deny access based on the price.

Offsetting uncertainty with innovative contracting options 

	Experience suggests that some payers will not cover such novel and expensive therapies based on immature evidence without a way to either share the risk or curb or delay the budget impact.  They will look for manufacturers to enter into innovative agreements such as: 

 To our knowledge, this has not yet been tried, but such an arrangement would allow payers to stagger their payments, perhaps upon completion of specific steps in the treatment process. One payment might be made, for example, when the therapy was prescribed, another when the patient was infused, and another at a certain point posttreatment when outcomes could be assessed. The final payment could even be spread out over a number of years. 

 Such pay-for-performance or risk-sharing agreements are increasingly common in the EU where the single-payer system results in stable patient populations for payers. Now, the model is coming to the US. In a novel deal, Novartis has entered into an outcomes-based agreement with the US Centers for Medicare and Medicaid Services (CMS) through which the agency need only pay for Kymriah in instances in which the patient responds after a month. CMS, which has praised the arrangement, plans to publish guidance for other companies interested in exploring innovative contracts. 

Managed-entry agreements/coverage with evidence.

 This is the coverage equivalent to approvals with risk evaluation and mitigation strategies (REMS). Under these agreements, the product is covered upon market entry, albeit conditional on a postmarketing assessment to revisit pricing. Usually, a registry is created to generate evidence that is later evaluated by the payer. 

 In the future, it is possible that access will be funded by such means as annuity payments, bonds, credit, mortgages, and risk pooling. 

Manufacturers, start your commercial engines 

	We know that, in general, payers have little appetite to accept uncertainty. A study performed by the UK’s National Institute for Health and Care Excellence (NICE) revealed that even when they had a five-year dataset (which is greater than most therapies have at launch), payers were concerned about low subject numbers and the use of a single-arm study. To secure access in this environment, manufacturers of ACT therapies will need to:

 In terms of evidence generation, payers should be considered just as important as regulators. Payer-relevant endpoints (e.g., overall survival) for a new cell therapy should be included in early-stage trials; if planned properly, these data can be mature by launch, providing outcomes data over a long period. 

Continue following patients after trial close.

 Trial participants should be followed after the close of the pivotal trial via long-term follow-up to gather data on overall survival. (Novartis’s initial Kymriah patient is still alive five years post-treatment). 

 In the EU, new funding pathways and contracts will likely be required, and manufacturers can help ensure that they are in place and workable. And in the US, contracts must be in place between treatment centers and payers before treatment can begin. Drug manufacturers can engage with their customers to ensure that they have all that they need to support the contracts.

Develop and share data on the burden of disease. 

To appreciate fully the economic benefit of ACT therapy, payers should be given data on the costs that are averted. These could include an organ transplant, other associated treatments and costs for families in missed work and stress, etc. 

Establish launch pricing based on value. 

Manufacturers should take into account epidemiology data, the degree of therapeutic unmet need in the market, and the product’s clinical value in comparison to that of competitors.  

Help payers understand which patients are the right candidates for treatment.

 Payers may benefit from education on the type of patients who are best suited for treatment (e.g., biomarkers) and from epidemiology data on the prevalence of specific diseases. This will help payers in their budgeting and may allay their concerns, as the number of eligible treatment candidates may be smaller than what they fear. 

Competition will increase in this space, and ACT therapy manufacturers should choose their trial populations with care, limiting their focus to those patients for whom the greatest payer-perceived benefit can be demonstrated. 

	ACT therapies are so new that most payers have not yet updated their systems, policies, or budgets to accommodate them. Thus, it is impossible to know exactly how to meet their requirements, but manufacturers with ACT therapies in the pipeline should be actively exploring this. It seems clear that early manufacturers of ACT therapies need to consider unique strategies toward evidence generation, working to understand how ACT therapies will require different payer policies, and planning new types of agreements with payers that will afford access to patients. 

is Senior Consultant, Pricing and Market Access; 

is VP, Project Management, Oncology; and 

is Principal, Pricing and Market Access; all with ICON plc  

Groundbreaking treatment approaches call for innovative commercialization strategies.

Access and Reimbursement for Adoptive T-Cell Transfer Drugs

	A massive improvement in the health of Europe’s citizens is within reach, boldly asserted the European Alliance for Personalized Medicine (EAPM) on the eve of its conference in Belfast at the end of November. The ambitious claim is spelled out by EAPM across some 25 pages of a position

 released in advance, and is backed up by extensive arguments about the opportunities that targeted therapies can offer patients, health services, and society.

	It is not the first time such a claim has been made in Europe. The rather halting European journey towards personalized medicine dates back more than a decade now, and a plethora of organizations have pitched their approaches to make it work.

	Currently, a high-powered inter-governmental effort known as IC-PerMed is laboring toward establishing an action plan. The European Personalized Medicine Association is planning to fund scholarships in education and training of future healthcare professionals with a focus of using diagnostics and patient engagement and empowerment centered on personalized medicine. The private-public partnership of the Innovative Medicines Initiative is running a series of projects related to personalized medicine, including its ADAPT-SMART platform exploring how regulation can be better aligned to the development of targeted therapies. And Europe is still struggling to find ways of putting into effect the conclusions of ministers at the December 2015 health council to “take personalized medicine into account in the broader context of the future framework for sustainable European Union collaboration on patient safety and quality of care.”

	What distinguishes this EAPM approach-as was noted by half-a-dozen members of the European Parliament in the foreword they have penned-is that the alliance is aiming to make a reality of building the frequently-evoked broad coalition among health stakeholders, a familiar slogan in any discussion of making progress in exploiting the wide-ranging scope of personalized medicine. The alliance emphasizes the need for “a clearer understanding among Europe’s policymakers and decision-takers that a paradigm change is needed, with new 

forms of cooperation, collaboration, and awareness across multiple domains and stakeholders.”

	EAPM has identified many of the barriers that need to be overcome to enable such a “paradigm change.” They include a limited evidence base; the absence of personalized healthcare in most cure pathways; a lack of consensus on clinical utility; varying standards and quality of provision; low awareness, particularly among healthcare professionals and patients; and insufficient coordination among policymakers and regulators.

	The position paper deals in some detail with many of these challenges. But on one-and that is payment, the one that might be considered the biggest stumbling-block of all at present-it limits itself largely to generalizations: “Radical changes in thinking at the highest policy level in relation to public health generally will enhance the measurement of value for health interventions and adapt payment systems accordingly,” it states blithely. But will it, and how will it, and how soon will it?

	In Europe, as in the US, one of the central elements of the personalized medicines debate-the issue of pricing-remains as challenging as ever. Everyone admits that the challenge exists, and particularly for the more expensive innovative products that are most likely to usher in new approaches to therapy. But admitting the challenge is only a first step toward finding solutions-and at the moment Europe is still very much at the first step.

	The European Medicines Agency’s Guido Rasi warned last month that the speed of advance in the world of therapy is impeding planning. “It is absolutely impossible to predict what new technology will be inserted into the production system for medicines and therapies and the integrated systems that come with them,” he said. Italy is introducing a legislative framework for some form of postmarketing appraisal of new drugs in a bid to improve cost-effectiveness, but already there are questions over its criteria and methodology. Portugal has just updated its out-of-date 2006 framework for granting access to new drugs for rare diseases, but with little provision for better funding. Even in prosperous Germany, officials at its G-BA insurance organization recognize that the price of orphan drugs is too high in relation to extent of additional benefit, and are urging tighter controls. 

	If the authorities in Europe are aware of the problems from their side, drug firms operating here are even more acutely sensitive to deficiencies in the current arrangements. Pfizer complained in mid-November that Ireland is “one of the slowest countries in Europe” to fund the use of innovative medicines. Roche CEO Jens Grueger described to a recent conference the dilemma faced by companies developing multiple potential combinations involving new immunotherapies and personalized drugs. The healthcare systems and health technology assessment (HTA) bodies needed to assess the value of such innovations-and to make sure they are paid for so that patients can receive them-simply do not exist yet, he said.

	Shire CEO Flemming Ornskov sees in the not-too-distant future the model shifting to outcomes-based payments, and “not just for rare diseases, but for all diseases.” But he told a recent conference in London that his excitement at that prospect was tempered by concerns over current European moves in a contrary direction: “What we are not excited about is an initiative to take some of these incentives away,” he warned. A senior official in the UK’s National Audit Office fretted in public over the ability of the National Health Service (NHS) to cope with change. Robert White, who is director for health value for money, said the rising costs of expensive, specialist drugs and medical devices are a concern and a worry for NHS sustainability. And Sir Andrew Dillon, head of the UK’s HTA body the National Institute for Health and Care Excellence (NICE), said recently that companies with expensive new technologies like CAR-Ts will need to work together with the NHS and think “more creatively” about payment structures.

	In the US, pharma is enjoying some sunnier weather under the Trump administration, as more and more pro-industry (and often ex-industry) figures are appointed to senior posts and start to tweak the rules in the interests of drugmakers. Joe Grogan, associate director for health programs in the Office of Management and Budget, pushed back recently on a discount scheme that allows hospitals and health clinics to obtain cheaper medicines. He described it as “incredibly flawed,” and said the administration wants to explore new pricing mechanisms that could “create more freedom” for payers to seek creative deals with pharma companies. Otherwise, products like CAR-T drugs “will bankrupt the system and people can’t access them,” he said.

	However, even there, companies are looking over their shoulders apprehensively at potential downsides from current tax reform proposals, which could hit foreign income from intellectual property wherever it is legally held, and threatens to remove or reduce tax credit for conducting clinical trials of rare disease drugs.

	The comprehensive view of an effective strategy for drug innovation is conspicuous by its absence on both sides of the Atlantic. And EAPM, for all its vision, has little to offer in terms of solutions to the central dilemma of pricing. “National authorities, HTA bodies, and pricing and reimbursement agencies should be open to reconsidering how they get best value for patients and society out of public health spending,” it says. But “should” is easily said. More than that is needed to start to extricate pharma innovation from its currently closed circuit of frustration among drug developers and recrimination among those who pay for drugs. 

New action plan urges tighter alignment of public health policy with the development of targeted therapies.       

Will Europe Turn a Corner in Personalized Medicine?

From researcher to globe-trotting commercial leader, Ruud Dobber, now president of AstraZeneca US and executive VP of the company’s North American business, speaks with Pharm Exec about his career path and his core mission today: steering the big pharma giant’s US course as it navigates the complexities of a fast-moving therapeutic market

’s annual Pharma 50 listing this year, with 2016 worldwide prescription sales of $21 billion and R&D spending of $5.6 billion. Its top-selling drugs globally were Crestor, Symbicort, and Nexium. In 2017, AstraZeneca gained US approval for Imfinzi for bladder 

cancer and Faslodex for expanded use in breast cancer-and possible approvals for Lynparza, also in breast cancer, and Imfinzi for lung cancer loom in 2018. Dr. Ruud Dobber, president, AstraZeneca US, and executive vice president, North America, is leading his team’s efforts to realize the full commercial potential for these important therapies. 

	Dobber has been heading the region for the big pharma company since August 2016. He is responsible for the activities of close to 6,000 people, leads AstraZeneca’s commercial operations in North America, and represents the region as a member of the company’s Senior Executive Team. In these capacities, Dobber is accountable for driving growth and maximizing the contribution of North America to AstraZeneca’s global business, of which the US represents roughly 40% of the organization’s global product sales. 

	Most recently, Dobber was executive vice president, Europe, and oversaw business functions in the 28 European Union (EU) member states. Prior to that, he was regional vice president of AstraZeneca’s European, Middle East, and African division; regional vice president for the Asia-Pacific region; and interim executive vice president, global product and portfolio strategy. Dobber also was a member of the Board and Executive Committee of the European Federation of Pharmaceutical Industries and Associations (EFPIA) and earlier was chairman of the Asia division of Pharmaceutical Research and Manufacturers of America (PhRMA). 

Drawing from his research roots and the leadership lessons gained in melding business and culture in geographies across the globe, Ruud Dobber is busy steering AstraZeneca’s US course as it navigates the complexities of a fast-evolving therapeutic market.

Pharmaceutical Executive-12-01-2017