Advance Market Commitments for New Vaccines – Lessons from the Pneumococcal Vaccine

In global public health, we talk about a class of diseases that cause significant morbidity and mortality, but for which treatments are either unavailable, ineffective, or toxic, known as neglected tropical diseases (NTDs). One of the main problems with NTDs is that they predominantly occur in populations who lack the financial means of purchasing new drugs (which are often expensive) to treat them. Thus, there exists little financial incentive for researchers, research funders or a pharmaceutical company to invest in the development of new drugs to treat these conditions, because of the perceived lack of return on their investment.

This has long been a challenge in public health – how do we stimulate the needed research and development to address the world’s most salient public health problems, when the return on investment is likely to be poor?

There is no catch-all solution to this problem, so a number of potential solutions have emerged. The Drugs for Neglected Diseases initiative (DNDi), for example, is a not-for-profit research and development organization that works in collaboration with a long list of partners, from the pharmaceutical industry to universities and university spin-offs. As drugs are developed through the collaboration, different arrangements made by DNDi ensure that the drugs are available and affordable, using different intellectual property arrangements.

This addresses concerns for drugs being developed through the partnership, but doesn’t address the issue of poor access to drugs or vaccines already on the market.

As previously reported, pneumonia is currently the leading cause of death in children under the age of 5, accounting for about 18% of child deaths worldwide, followed by diarrhea and malaria as the second and third leading causes of death. That’s huge, and a lot of pneumonias can be prevented through the use of vaccines. However, getting vaccines to people in poorer countries is a challenge because vaccines do not fit into the contemporary model of most alternative intellectual property arrangements like compulsory licenses or the lure of cheap generic pharmaceuticals.

One problem is that vaccines are difficult to produce. The manufacturing capacity required to produce vaccines – which is quite sophisticated – is greater than what is needed to stamp out medications in tablet form. Vaccines are biologically complex, so producing them isn’t as easy as producing something like paracetamol. For this reason, there are fewer pharmaceutical companies entering into the market, and even fewer capable of producing vaccines on the cheap.

One solution, proposed by the GAVI Alliance, is something called an Advance Market Commitment (AMC), which guarantees a market for vaccine producers and provides incentive for investing in research and development by ensuring a financial return on that investment. This addresses one of the critical shortfalls, above, in the NTDs problem, where financial incentives are weak.

GAVI administers the AMC, which requires manufacturers to commit to providing a share of the targeted 200 million doses of a vaccine. Currently, the AMC states that no dose can cost more than $3.50, and this cost is covered in part by GAVI and in part by the recipient country government (in Malawi, the government is paying $0.20 per dose for the pneumococcal vaccine, which – considering the cost of treating a case of severe pneumonia – is a pretty solid return on investment). By comparison, in rich countries, the cost per dose is between $54-108.

GAVI, through it donor partners (currently: Italy, UK, Canada, Russia, Norway, and the Gates Foundation), agrees to purchase a certain number of the vaccines at a fixed price point, for a certain number of years, thus guaranteeing a market for vaccines once they are developed. The economy of scale allows manufacturers to increase their production and bring costs down, while ensuring that there is a market on the other end to buy them.

Several key questions emerge from this arrangement: is the AMC increasing access to the vaccines in a more timely manner than if the market were left on its own? Is the cost of the program, as a whole, producing the anticipated cost-reductions per vaccine?

First, let’s consider the issue of access. The vaccine currently being used  in Malawi is called Prevnar-13, manufactured by Pfizer. Prevnar-13 (which protects against 13 types of pneumococcal bacteria) was approved by the US Food and Drug and Drug Administration on November 24, 2010. For most new vaccines, the delay between when they are available in rich countries and when they’re available in low-income countries can be 10-15 years, probably because pharmaceutical companies need to recoup their investment in research and development in richer countries before introducing them in countries where the market can only sustain lower costs, and for which the market is not guaranteed. However, in the case of Prevnar-13, it was available in Nicaragua 10 months after it was introduced in the USA, as a result of the GAVI AMC. GAVI’s goal is to reach 40 developing countries with the vaccine by 2015.

This would seem to suggest that the AMC is, in fact, working as it was intended and increasing access to cheaper versions of the vaccine.

Some criticisms have emerged regarding the financing of this model, as highlighted in an editorial in Nature Medicine in 2011. The crux of the argument, basically, is that: (1) the cost per child saved under the GAVI AMC is $4,722, and immunization packages for other diseases (like polio, measles, and yellow fever) can save more children for less; and (2) The GAVI model serves the interests of the pharmaceutical companies.

These seem to be flawed arguments. The AMC model is designed with the intention of stimulating vaccine development and distribution that may otherwise be neglected, while reducing costs for new vaccines that are still under patent in rich countries (and therefore, more expensive). Arguably, this needs to be a part of a more global focus on increasing access to vaccines in general (like polio, measles, and yellow fever), however the focus of the AMC is on expediting the availability of the pneumococcal vaccine in countries like Malawi (which already has exceptionally high vaccine coverage rates for other vaccines), for whom $54 a dose is simply out of reach. If nothing else, there is an ethical imperative to provide an available vaccine to populations who are disproportionately affected by a condition prevented by a vaccine. Pitting one disease against another seems a poor argument to make.

Pharmaceutical companies clearly have an interest in generating profit from the technologies they produce. However, as has been shown repeatedly, the pharmaceutical industry rarely profits from the introduction of new drugs in developing countries, precisely because they can’t afford to purchase them at the same price point as rich countries can. Thus, pursuing patent protection and distribution in many poor countries is rarely in the pharmaceutical company’s interest, and these countries rarely factor into how they make money. Thus, these new products are rarely accessible to developing countries, and unless we start finding ways around this, it seems unlikely that this will change.

Compulsory licensing isn’t going to achieve this, for the reason that producing the vaccines is costly and it’s unlikely that a generic manufacture is willing to invest in the technology to do so.The start-up costs of having a generic company produce a vaccine are likely going to offset the cost reductions, and issuing a compulsory license (thus allowing the country to essentially ignore the patent) is a politically-charged intervention.

The AMC puts the global public health community (particularly those from the access to essential medicines community) closer to the pharmaceutical industry than perhaps we would like to be; However, it’s important to consider this in the broader context of results. Results that suggest that the pneumococcal vaccine became available quicker than most other vaccines in developing countries, and that the cost per dose remains steeply discounted from the cost per dose in rich countries.

Fundamentally, this is the hand we have been dealt. The pneumococcal vaccine has been brought to market by major pharmaceutical companies (Pfizer and Wyeth), who are the current patent holders. Producing it under a compulsory license is probably impractical and the costs of production may not result in cost-savings and certainly won’t result in saving time from when the vaccines are brought to market in the US or Canada and when they’re available in developing countries. Had the vaccine been produced through a pooled, non-profit intellectual property arrangement, we might be in a different situation; but we’re not.

For now, the AMC administered by GAVI has succeeded in bringing the pneumococcal vaccine to populations who likely wouldn’t have access to it today without the arrangement. Is it perfect? Nope. But, it is a different approach to access to new technologies that seems to be working. In global public health, it’s important that we focus on interventions that are successful (even if marginally so), and continue to refine them even further until they’re flawless and address global health problems head-on. Celebrate our successes and then make them better.

Check out:

International Vaccine Access Center Twitter: @IVACTweets and @NoMorePneumo

References:

Gabriel P, Goulding R, Morgan-Jonker C, Turvey S, & Nickerson J (2010). Fostering Canadian drug research and development for neglected tropical diseases. Open medicine, 4 (2) PMID: 21709722
Scudellari, M. (2011). Are advance market commitments for drugs a real advance? Nature Medicine, 17 (2), 139-139 DOI: 10.1038/nm0211-139

Posted in Essential Medicines, Global Health, Pneumonia, Population Health | Tagged , , , , , , , , , , , | Comments Off

Childhood Pneumonia – What’s the Problem?

An article caught my eye in last week’s Lancet. Soofi and colleagues conducted a cluster-randomised controlled trial of community case management of severe pneumonia in children aged 2-59 months in a rural district of Pakistan to try and understand how community health workers might be able to recognize and diagnose pneumonia in this population. Basically, the researchers wanted to know if community health workers, given the proper training, knowledge, and resources could diagnose and treat severe pneumonia in the community. As it turns out – they can, and this might be a viable strategy for other places where referral to higher levels of care is difficult.

This article is significant for a few reasons: First, it highlights the ongoing challenges of treating pneumonia in developing countries. Pneumonia is the leading cause of death in children under the age of 5, accounting for 18% of all under-5 deaths worldwide. Effective, accessible, and timely case management stands to save a lot of children’s lives.

Second, it highlights the fact that relatively simple solutions exist for some of the biggest problems we face in global health. Pneumonia is not a new disease, nor is it a particularly “neglected” one in the same way as other neglected tropical diseases, like leishmaniasis or schistosomiasis. For childhood pneumonia, we have effective prevention and treatment options available, but scaling them up has proven difficult and slow. Vaccines exist that provide coverage against pneumococcus and haemophilus influenzae B, which are thought to cause more than 50% of pneumonia deaths in children under 5. Even treatment options for pneumonia are fairly straightforward: amoxicillin and cotrimoxazole, both of which are drugs on the WHO Model List of Essential Medicines, and part of most NGOs’ and countries’ formularies. More broadly, improvements to the determinants of health – improvements to socioeconomic factors, improving nutrition, and so on – would significantly impact the likelihood that children get sick in the first place.

Put all of this together into a comprehensive package of vaccinations, improvements in the determinants of health, and ensuring that treatment is accessible and available for those children who do get sick, and you have a pretty robust package of health services that could really bring down the number of children who die each year from a preventable and treatable disease.

So, what’s the problem?

In population health, we like to think of health as being a complex phenomenon, impacted by influences at different levels – your health is impacted by the community you live in, the resources available to you to make healthy choices and influence healthy behaviours, as well as the economics and laws that impact what kinds of health options are available to you. Improving population health in a significant way requires what we call “multi-level interventions”: interventions that don’t just address one aspect of health, but rather simultaneously address a range of different health determinants, simultaneously. By intervening at different levels, we look for synergies that fuel change at a higher level and that leads to sustainable improvements.

Childhood pneumonia, like most global health problems, is a problem that has multiple levels of influence, and requires complex interventions to address them:  There are economic drivers of the availability of essential medicines and a sustainable and well-trained health workforce, technological factors that limit the availability of essential technologies, knowledge gaps in how to diagnose and treat different kinds of pneumonia, a lack of awareness of pneumonia as a problem among Western donors, and an absence of reliable systems and networks to provide health services to treat pneumonia.

Over the coming weeks, this blog will explore childhood pneumonia in greater depth, exploring not only the challenges, but also the successes in preventing and treating the disease in developing countries. As Soofi and colleagues (and others) have shown, effective strategies for the treatment of pneumonia in difficult-to-reach populations do exist, and with proper investment and training, these programs can make a significant impact in childhood survival.

I will be traveling to Malawi throughout February to explore how that country has responded to the need to scale up health services for the prevention and treatment of childhood pneumonia. I am traveling with the International Vaccine Access Center from the Bloomberg School of Public Health at Johns Hopkins University, who are working to improve access to pneumonia care in this country. Over the coming weeks, we will explore some of the challenges and highlight the many successes of these programs and really try and understand what works, what doesn’t, and why that is.

Reference:

Soofi, S., Ahmed, S., Fox, M., MacLeod, W., Thea, D., Qazi, S., & Bhutta, Z. (2012). Effectiveness of community case management of severe pneumonia with oral amoxicillin in children aged 2–59 months in Matiari district, rural Pakistan: a cluster-randomised controlled trial The Lancet DOI: 10.1016/S0140-6736(11)61714-5

Posted in Epidemiology, Essential Medicines, Global Health, Pneumonia, Population Health, Respiratory Therapy, Uncategorized | Tagged , , , , , , , , , , , , , , | Comments Off

Haiti’s Health System, 2 Years After the Earthquake

Today marks the two year anniversary of the 7.0 magnitude earthquake that hit Haiti in January 2010. Far from celebration of the progress made since, the anniversary has drawn criticism from a range of dignitaries and aid workers in the country and around the world. That the billions in international humanitarian assistance have failed to transform the country is not exactly news, and if anything, the media coverage this week (and beyond) should remind us that discussions of aid effectiveness and accountability should not emerge only on anniversaries of events, but rather need to continue to be brought into the spotlight regularly. Where did this money go, and who set the priorities?

Within the health sector, I have yet to see solid evidence of the international humanitarian response strengthening, rather than disrupting, the local health system following an acute event. When disasters strike, aid agencies pour in with foreign medical teams and their field hospitals (or with nothing, and are otherwise unprepared), and stand the potential to seriously disrupt the workings of the local health system that was in place beforehand. I don’t want to suggest that Haiti’s health system before the earthquake was comprehensive (or even overly functional), but the point is that Port-au-Prince wasn’t the Flintstones’ Bedrock before the earthquake, and it is disingenuous to not acknowledge the existence of the system or to capitalize on the infrastructure and human resources and expertise in place.

My biggest concern of the coverage of the Haiti recovery is exemplified in some of what Michaëlle Jean said earlier this week:

“If the reconstruction is not about creating infrastructure or jobs, what’s the point? We have to be clear, we have to be coherent. Are we trusting the Haitian government or not?”

It’s the last point that she makes that exemplifies many of the problems I witnessed: are we supporting, or replacing, Haitian capacity to provide and manage health care in Haiti, and why is that? Numerous concerns have been raised about the impact of international aid on the Haitian health system, and many can be traced back to a perception of “we know better”. From the outset of the emergency response, stories emerged of Haitian doctors being pushed out of their own clinics so that “experts” from North America or Europe (many of whom who had never set foot in the country before) could take over, or of Haitian physicians losing business (and money) because of the wide availability of free health services provided by NGOs. The message here is that while emergency medical (clinical) assistance was abundant (in some cases, there were probably too many doctors), assistance to the Haitian Ministry of Health (the Ministère de la Santé Publique et de la Population – MSPP) to build capacity to manage this response in both the acute and recovery stages was lacking, and continues to be.

A major lesson learned from the Haiti earthquake response needs to be that health systems expertise is needed at the outset of crisis response to not only coordinate the large number of NGOs providing acute care, but also to establish a strategy in partnership with ministries of health for reintegrating this assistance into the health system and, ultimately, strengthening it. It is not the role of the Health Cluster or any other agency to replace the ministry of health; rather, it ought to be our role to provide specific expertise on the coordination of disaster health services and health systems strengthening post-emergency – an expertise that few possess.

Furthermore, while clinical or curative health services are clearly needed in major emergencies, so too is investment at the ministry level to ensure that the local government has the capacity to effectively manage the system-wide health system and the hospitals where NGOs set up shop.

Looking back over the past 2 years, many of us are trying to understand whether Haiti’s health system is stronger or weaker given the aid delivered. The answer is far from straightforward: arguably, access to health services is better now than it was 2.5 years ago, but at what cost, and is it sustainable? We need to ask ourselves: if the NGOs pulled out tomorrow, what would happen to the health system in Haiti? Likely, it wouldn’t sustain itself, and it’s important to ask why that is, rather than to just lay the blame on Haiti’s weak public service. While there are weaknesses at this level, sure, there has has also been little investment in strengthening it, which brings us back to the question of how the international aid community views the Haitian government.

Several important lessons can be drawn from the earthquake response, and while coordination has been cited as the weak link, it’s more complicated than that. It’s not only coordination, it’s also information management and information delivery. We knew very little about the capacity of Haiti’s health system and health facilities post-earthquake, and we don’t know much about them now. Although the MSPP has attempted to map some of these capacities, the data are weak and the validity of the data collected should be questioned. Furthermore, there was an absence of centralized population health information or health systems in crisis expertise available post-earthquake. Coordination is critical, but so too are accurate and timely data.

In short, we need to rethink the ways that humanitarian assistance strengthens health systems of crisis-affected countries, rather than replaces or parallels them. This is one of the critical elements that needs to be drawn from the lessons learned post-Haiti, is that humanitarian assistance needs to support, rather than undermine, local authority, and place Ministries of Health in a leadership role with assistance from the humanitarian community to coordinate, and then absorb, the health services provided in the acute phase.

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The War on Drugs: Implications for the Treatment of Pain

Today, a colleague, Amir Attaran, and I have a paper published in PLoS Medicine where we discuss some of the international legal constraints that hinder the availability of one of the world’s most basic and essential medicines: morphine. The paper, titled “The Inadequate Treatment of Pain: Collateral Damage from the War on Drugs” provides a critical look at the current realities of access to morphine in low-, middle-, and high-income countries, a topic that I have explored previously on this blog (here and here).

The reality is grim: 80% of the world’s population has no or inadequate access to effective pain medications, the majority of these people living in the world’s poorest countries. Furthermore, the reasons for this inequity are complex, though have a basis in prohibitionist drug policies that seek to restrict access to these drugs for fear of diversion and illicit use, in addition to economic forces that might make some drugs available and others not (for example, fentanyl – a more expensive and potent opioid – is available in some countries where morphine – a cheaper, more basic opioid – is not).

Pain is one of the most common diagnoses in clinical medicine. Is it morally defensible to restrict access to one of the most basic therapies – pain relieving drugs – to those who need them for medical purposes, in order to prevent the relatively small risk of diversion for illicit purposes? We, along with others (notably, Human Rights Watch), argue that it is not and that the treaties (specifically, the United Nations Single Convention on Narcotic Drugs) put in place to curb illicit drug production, trafficking and use have a dual mandate to influence national governments to enact laws and policies to control and reduce illicit drugs, but also to “ensure that adequate supplies of [narcotic and psychotropic] drugs are available for medical and scientific uses”. Conflicting, no?

In our paper, we advocate the need to shift responsibility for ensuring access to controlled narcotics for medical purposes to the World Health Organization, from the International Narcotics Control Board (INCB), who are currently responsible for simultaneously restricting and ensuring access to the same drugs. Our data show that despite the treaties’ 50-year existence, virtually no low-income countries have access to adequate amounts of morphine, compared to high-income countries who have substantially (sometimes 30- to 100-fold) more.

Interestingly, a series on addiction published on January 7th in The Lancet, features a related article by Robin Room and Peter Reuter which finds that “Over the past 50 years international drug treaties have neither prevented the globalisation of the illicit production and non-medical use of these drugs, nor, outside of developed countries, made these drugs adequately available for medical use.” The authors of this paper also highlight the need to revisit the treaties, though their approach advocates that individual countries consider opting out of provisions within the treaties. Fundamentally, the authors agree that the treaties impede governments’ abilities to deliver evidence-based public health services and enact evidence-based public health policies (though they make this argument in the context of addiction treatment).

Pressure needs to be mustered to reverse the current situation of unacceptably low access to essential pain medications. Morphine, among other controlled narcotics, is listed as an essential medicine by the World Health Organization, though given the poor access to it, it appears that few share the view that it is “essential”. Organizations working on health issues that are likely to necessitate pain relief and palliative care need to address head-on this need; HIV/AIDS and cancer are but a few of the illnesses for which palliative care needs to become commonplace for those at the end of life. While many agencies choose to focus on curative care or treatment, due attention needs to be given to ensuring that quality end-of-life care is available and accessible to those who need it.

Reference:
Nickerson, J.W., & Attaran, A. (2012). The Inadequate Treatment of Pain: Collateral Damage from the War on Drugs PLoS Medicine, 9 (1) DOI: 10.1371/journal.pmed.1001153

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Haiti’s Cholera Epidemic – Cholera Vaccines

It has been just over one year since cholera emerged in Haiti, the first time in perhaps 100 years. Since then, it has wreaked havoc within the country, whose water and sanitation infrastructure was already poor before the earthquake, while the displacement of upwards of a million people after the earthquake undoubtedly contributed to its rapid spread and impact. To date, the Ministere de la Sante Publique et de la Population (MSPP) – the Haitian ministry of health – reports that there have been a cumulative total of 473, 649 cases of cholera since the beginning of the epidemic, with 6,631 deaths, and a current average of 500 new cases a day. In short: this is the largest cholera outbreak in the world, and it’s not over.

Controversy has framed much of the health and humanitarian response to the earthquake and cholera outbreaks. Understandably so. Following the earthquake there was a massive outpouring of international aid – some of it well-implemented, a lot of it not so much.

More recently, controversy around the provision of a cholera vaccine in Haiti has emerged – notably, the tension between the provision of the vaccine as opposed to spending the money on improvements to water and sanitation. This is certainly a valid point. As MSF‘s David Olson said recently: “Money spent on vaccines should not come at the expense of money spent on permanent water and sanitation measures.”

Two cholera vaccines currently exist on the market – Dukoral (manufactured by a Dutch company – Crucell N.V.) and a more recently-approved vaccine called Shanchol (manufactured by Shanta Biotechnics – a subsidiary of Sanofi). Dukoral costs around $6 a dose, while Shanchol is about $1.85. It should be noted that both are effective, and a recent study in PLoS Neglected Tropical Diseases demonstrated good efficacy data for Shanchol in a large RCT.

Rolling out vaccination to all of Haiti’s population is not just difficult, it’s probably currently logistically impossible. There are simply just not that many doses of these vaccines available. Both vaccines are oral vaccines, which require a small, yet significant, amount of preparation in order to distribute (a reliable cold chain, some water, a buffer solution for Dukoral, etc.). Furthermore, both require 2 doses, spaced apart by several days. You could safely estimate that to vaccinate everyone in Haiti would require 20 million doses – there are currently far fewer than that available.

The current proposal for vaccination in Haiti will see one section of the population vaccinated as a trial, with the ultimate goal of vaccinating the entire population. Partners in Health, one of the lead agencies taking on this role thinks universal coverage can and should be done. Step 1 is to purchase 200,000 doses in order to vaccinate 100,000 people in certain high-risk areas or populations.

The controversy stems around exactly this: Only some people are getting vaccinated, while large segments of the population continue to have poor access to clean drinking water and adequate sanitation. Anyone working in public or population health will tell you that you have to address the determinants of health, like housing and sanitation, as well as provide essential medical/clinical care. As the Commission on the Social Determinants of Health so eloquently states: “…water-borne diseases are not caused by lack of antibiotics but by dirty water, and by the political, social, and economic forces that fail to make clean water available to all…”

Moving forward, it is clear that a balanced approach continues to be needed. One that adopts universal principles for everyone in Haiti, and moves toward active case finding and aggressive treatment, reliable and safe water and sanitation systems, and greater preventative measures at the community level, including surveillance, education and community mobilization. There are no magic bullets – cholera is no exception.

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