The Future of Health Access: Therapeutic Antibodies?
The three principles of access to health are…
equity (can the many, not the few, have ready access to the innovation)
affordability (can societies afford and will they fund innovations)
impact (will the intervention make a major difference in the societies affected).
Smart minds used to think that the 2010s would the decade of non-communicable diseases (NCDs). Coalitions were formed, and collaboratives launched. Despite initiatives like former US president George W. Bush’s Pink Ribbon Red Ribbon, and broad human papillomavirus vaccinations strategies, we are not really any the wiser about how to expand the grand access to healthcare movement that was built around AIDS, TB and malaria. Season 2 of my podcast A Shot In The Arm Podcast kicks off on December the 1st 2019, World AIDS Day. And as we face a new decade, there is still so much to be done to end the AIDS epidemic. However, it is also a good time to consider how the AIDS response can inform our response to other health priorities, particularly those with the most complex of new biomedical innovations, like cancer and autoimmune disease.
Size of the unmet medical need
The International Agency for Research on Cancer has estimated that there were 9.6 million deaths from cancer in 2018. A large proportion of these deaths were due to lung disease, and increasing rates of cancer have been seen in older people in the industrialized, with fewer dying as a result of stroke and heart attack. However, under these headlines, the data present a picture of a world still deeply divided. Incidence and mortality related to cervical cancer are significantly higher in low- and middle-income countries. While breast cancer is the leading cancer for women in many countries around the world, women in the developing world have later diagnoses, and higher mortality rates.
In the autoimmune diseases of Crohn’s disease and Ulcerative Colitis, rates of detection are rising in emerging middle-income countries. Increased rates have been reported, particularly, in China. While not at levels reported in Western Europe and North America, there is an urgent need to understand and respond to these increasing trends, beyond lifestyle changes, and the growing so-called “westernization” of behaviors and diets.
A new generation of treatment options
Since the 1970s, there has been a flourishing of research into immunological diseases, including certain cancers and autoimmune diseases. A particular triumph of medicine has been the therapeutic antibody. Therapeutic antibodies attach to individual cells or proteins in the body, so that the immune system can mount a more effective attack on those cells. therapeutic antibodies, which have either been cloned or replicated from animal or, increasingly, human cells.
The most common are monoclonal antibodies - mAbs - that attach themselves to specific cells. We find mAbs in the generic names of medicines for many immunological diseases - including bevacizumab (for the treatment of metastatic breast cancer) and adalimumab (for the treatment of a range of autoimmune diseases, including Crohn’s Disease).
The field of immunology research is exciting, but very much still in its infancy. We are learning so much, both in potential treatments and diagnostics, but also in our understanding of the immune system itself - how it can overpower hostile bodies, but also what can over-charge or undermine it.
As we enter the new decade of the 2020s, it is a safe bet to assume that innovation will continue to accelerate. However, despite the optimism of ten years ago, the world has not really made significant, and wide-ranging impact in expanding access to immunology medicines, outside of the industrialized world. While it is unlikely that the kind of intensive, complex care a person with cancer might receive at an academic research institution on the US West Coast, or in Northern Germany, this unmet medical need still speaks to the urgency of securing concrete ways to bring the fruits of innovation to patients around the world.
Increased domestic spending on health
Arguably, the most important stakeholder in improving access to health is the tax-payer. In its recent declaration on universal health access, the General Assembly of the United Nations sought to “reaffirm the primary role and responsibility of governments to determine their own path to achieving universal health care.” In fact, in the many countries around the world that elect their governments through the democratic process, the ultimate responsibility rests surely with a country’s citizens, not its political leaders or bureaucrats. Whether directly through paying taxes for national health services, or through subsidizing private health insurance providers or the actual delivery through private sector healthcare, the citizen should have a fundamental role in determining how health services are not only paid for, but prioritized.
Much of the world’s advocacy has focused on drug pricing. This is not surprising, but it is curious that more attention is not spent on the broader question - should the public sector allocate more resources to health? To my mind, there is no doubt that it should. And increases in domestic investment in health should be an over-riding priority. Since the 1980s, we have experienced decades of common political that seeks to maximize the efficiency and reduce costs in the health sector. The irony is that the US spends significantly more now on healthcare than it did in 2000. And it is certainly the case that it may not spend those healthcare dollars in the most efficient and effective ways (while, at the same time, requiring beneficiaries of its overseas aid to do so)?
It is worth reviewing what countries have done in the recent past. In 2001, the members of the African Union signed the Abuja Declaration, in which they committed to allocate at least 15 per cent of their annual budget to improve the health sector.
A decade later, in 2011, by the World Health Organization’s own reckoning, only one country (Tanzania) had delivered that target. Twenty six countries had increased the proportion of government expenditures on health, and eleven had actually reduced it. By the time the WHO appointed its new Director General Tedros Adhanom Ghebreyesus, in 2017, it reported that domestic investments in health had increased, but few had actually reached the Abuja targets. Perhaps the Abuja targets are no longer relevant, given that so many members of the AU still rely, so deeply, on donor aid, to pay for healthcare. And what is the value of an advocacy movement that calls on the governments of the world to invest a greater proportion of their annual income on health, when may of them remain unaccountable to their citizens?
These concerns notwithstanding, I strongly believe it is time to ask whether, given the rapid transformation of healthcare around us, we should be spending an order of magnitude more on health, than say, tax cuts or military expenditure. This would free us to consider how we ensure all people, regardless of geography, have improved access to the fruits of biomedical innovation.
There is cause for optimism. While, many global health advocates, myself included, were deeply disappointed at the fairly muted publicity and concrete announcements of the United Nations General Assembly Special Session on Universal Healthcare, we had cause for great celebration at the outcome of the Global Fund to Fight AIDS, TB and Malaria’s 6th replenishment conference, just a month later in October 2019. Over 14 billion US dollars were pledged by countries, rich and poor. According to the Global Fund itself, this was the largest amount ever raised for a multilateral organization, and certainly the largest replenishment commitment to the Global Fund.
The point here is that there is renewed global commitment to fight disease. And it is needed, not only because the fight against AIDS, TB and malaria is far from over. This is an opportunity to reinvigorate global interest in health, from vaccinations of newborns, to a healthy and productive workforce, to compassionate end of life care.
Obstacles to access: Cost of medicines
Cost of medications is not unique to immunology treatments. However, these medications are sharply at the top end of an already expensive field of newly developed, existing, and in some cases, older medications’ whose patents have been extended for other indications. The World Health Organization, in a review in 2018 of the pricing of cancer therapies, listed publicly known prices of key medications. Immediately, they strike you as extraordinarily expensive, even for industrialized-world markets. However, as the report notes, these list prices do not reflect the subsidies or donations that go with these drugs, making their “real world” cost to the payer (whether it be a private insurance company, or public sector healthcare funder) hard to gauge. That difficulty comes with the territory of trying to unravel healthcare costs, particularly in the USA. Nonetheless, it is equally obvious that emerging economies would have an extremely difficult, if not impossible, task of justifying anything close to the cost of these medicines.
In the early 2000s, the precedent was set in the HIV field for pharmaceutical companies to reduce significantly the prices of their medicines, as part of global access strategies. There have been further reductions in price since then, technology transfers and licenses to generic companies, and individual action by some generics companies to reverse-engineer medicines, when they could not, or chose not, to collaborate with originator companies. Many advocate organizations claim credit for this precedent, either individually or in groups. In fact, there were many organizations working on access to treatment, and while not formally connected, they collectively led to significantly improved access to HIV medicines. The first efforts by industry in 1999 and 2000, that created the accelerated access to HIV medicines initiative, demonstrated a willingness, that admittedly, varied from company to company, but which opened the flood gates for greater action, either with or without them. Some leaders in the industry believed they could contain the significant price reductions for public health emergencies, like the AIDS epidemic. Others understood that the real innovation here, was that there was no longer any acceptance, either by policy makers or by the informed general public, that cost of medicines should be a hindrance to health access, regardless of where the patient lives. They proved to be right. The hunger for increased affordability of medicines in middle and low income country has increased, not been sated.
There is precedent, therefore, for reducing the prices of medicines in immunological diseases and cancer. Despite the calls for action since 2010, this has not happened in a meaningful way. Why has that been? I think that, just as in late 1999, the executive director of UNAIDS, Peter Piot, under the imprimator of the UN Secretary General, Kofi Annan led negoitations with leading pharmaceutical companies to agree a general principle of significantly reduced pricing for developing countries, so again, immunology and cancer medications innovators need a highly-influential and respected third party, to enable them to make similar commitments, free from the threat of anti-trust behavior. As Peter Piot has noted, I participated in these negotiations. In today’s world, and for the field of cancer and immunology medications, it is not clear who, or what that third party could be. However, the need for unified multilateral support seems most useful to help companies commit to access pricing. Whether it comes from foundations and non profits, or whether it has to be a new coalition of politically credible allies from around the world, remains to be seen. But it has to happen.
Generics versus biosimilars
One other point about the experience in HIV is relevant here - the role of generics. Unlike HIV, exact copies of originator medications - “generics” can not be made, because of the complexity of the molecular structure of the therapeutic antibodies themselves. Instead, a generic equivalent term - “biosimilars” - has been coined to reflect the production of molecules that are similar enough, to bring about similar efficacy and clinical result as the original medicines, but are not exact copies. Biosimilars have tended to be much cheaper than their branded originator medicine. However, their pathway to regulatory approval is more complex, not least because, given they have, in fact, different molecular structures, the original regulatory submissions for the originator medicine cannot be used. The FDA and EMA have produced separate regulatory pathways for biosimiliars, which ease, but do not eradicate the need, for additional laboratory and clinical studies to demonstrate equivalent safety and efficacy. However, as research into smaller molecules continues, the engagement of more traditional generics’ partnerships may re-emerge as an important way forward.
Dramatic reductions in the cost of medicine alone are necessary, but not sufficient to improve access to cancer and immunology treatment around the world. However, a concerted act now by the industry, combined with continued advocacy from patient and access advocates, will either encourage, or force the hand of other funders, health care policy makers and and politicians to act, to invest in the infrastructure needed to build broader comprehensive care for cancer and autoimmune diseases, as well supporting the more effective use of these medicines.
The high cost and complexity of delivering diagnostics and treatments
One of the reasons for exploring how we might improve the quality of immunology diagnosis, treatment and care is precisely the complexity of how services are currently provided. The treatment of chronic disease, and in particular cancer and autoimmune disease can be complex, difficult to diagnose, require inpatient treatment, including surgeries and transfusions. This is not “one pill, once a day, and you are on your way.” Comprehensive screening, therapeutic and palliative care is not the norm. Cancer care, even with the promise of new therapies, is a journey, consisting of surgery, chemotherapy, radiotherapy, counseling and support. It can be hugely demanding of skilled healthcare workers and equipment. In the 1990s, public health minds thought the same about HIV. It required extensive hospitalization, and highly-educated health workers based in hugely expensive and well-equipped hospitals. How much has changed. With a new wave of immunotherapies newly approved in the US and Europe, and with further innovations in the research and development pipeline, can we expect the same simplification to happen in the treatment of cancer and autoimmune diseases?