As (para)medical personnel we share the same goal: to improve and maintain health. As a clinician I work towards this goal by treating individual patients. As a PhD student I do research to improve treatment with anticoagulants. Pharmaceutical companies join in to “work together towards a healthy world”(1) and pursuit “helping people achieve their best health”(2). On the highest level, the World Health Organisation (“build a better, healthier future for people all over the world”) takes up this role(3).
With all these skills and resources combined, our research system must be very well adapted to optimise global health, mustn’t it? I want to expl ore the shortcomings of our current research system, and improvements, using the example of neglected tropical diseases (NTDs).

NTDs are diseases that strike over a billion people, almost exclusively in low-income countries, and attract little attendance and funding. Examples are schistosomiasis (a helminthic infection), Chagas disease (caused by protozoa), Buruli ulcer (a bacterial disease) and dengue (a viral infection). Their combined impact is huge: it exceeds that of tuberculosis in sub-Sahara Africa(4) and that of malaria world-wide(5), yet much less funding is available for them(6). They trap millions of people in poverty(4).
These diseases still have such a catastrophic impact for two reasons: a lack of available drugs, and a lack of access to drugs that are available.

Lack of drug research

According to pharmaceutical companies, they are the most innovative sector to date. Indeed, they spend gigantic amounts of money on research and development(7). However, these funds are improperly allocated: 90% of the money is spent on only 10% of global disease burden(8). Pharmaceutical research is lacking in creating new pharmacological compounds for treatment of NTDs. Between 1975 and 1999, only 13 new chemical entities were marketed, which is only one-eleventh of what would be expected based on burden of disease(9). Even in more recent years, research output aimed at NTDs is extremely low: 1% of chemical entities and 1% of RCTs(10). No research is carried out towards Buruli ulcer, trachoma, cysticercosis, syphilis, cholera and giardiasis, while they have all been identified as needing attention(11). Why aren’t pharmaceutical companies more involved?

Pharmaceutical companies generally do not disclose which areas they research. Pharma research has involved into a commercial (and the Fortune 500’s most profitable(12)) business, so it can be guessed that the biggest incentive is profit. While making money obviously is no shame, this could lead to pharmaceutical companies shifting their research towards more profitable targets: chronic ailments prevalent in high-income countries. Because why invest in people without money, or in a short treatment course? Pharmaceutical companies all want a piece of the pie of chronic diseases, and that’s where much of the research money is going. More than half to almost 90% of drugs does not provide therapeutic benefit(9,12–15); so-called me-too-drugs.

The public/not-for-profit sector on the other hand is doing better. Universities and biotech (spin-off) companies are more innovative(16). Publicly funded research (e.g. National Institutes of Health) results in disproportionally more products, with a higher chance of being granted priority review (i.e. being judged as offering major advances in treatment) by the Food and Drug Administration(17). Their research is better aligned with disease burden(18). Non-profit organisations such as the Drugs for Neglected Diseases initiative (DNDi) have made great progress for developing countries(19).

Inaccessibility of existing drugs

Another problem emerges when existing drugs do not reach the intended patients. This can have many reasons: conflict, poor disease surveillance and management from a weak government, poor infrastructure(20) and stigma(21). Another important reason is treatment cost: in Ghana, the cost of care for one patient with Buruli ulcer exceeds annual earnings(22); treatment for dengue haemorrhagic fever costs more than a month’s income in Vietnam and Thailand(22). This showcases how low income and high drug prices work in tandem to create a vicious circle. Tackling either will be difficult due to vested interests(23), but it’s our duty as medical researchers to keep the (global) public interest in mind and combat drug unaffordability.

This can be done! The most famous example is that of HIV/AIDS medication, summarised in the impressive documentary Fire in the Blood(24). A cocktail of three antiretroviral drugs was available in the United States for $10,000 to $15,000, rates unaffordable in the most disease-stricken areas. As Ugandan physician Peter Mugyenyi asked the audience of a big conference: “Where are the drugs? The drugs are where the disease is not. Where is the disease? The disease is where the drugs are not.”(24) It took years of public outrage, thousands of deaths, a generic pharmaceutical manufacturer willing to produce the drugs for one dollar a day(25) and Yale students to pressure their university’s license deal with Bristol-Myers Squibb(26) to make HIV medication accessible, saving millions of life in sub-Sahara Africa. And this is far from the only example: child immunisation costs increased 68 times, mostly due to a price hike in the pneumonia vaccine (that already generated $36 billion in profits for the pharmaceutical companies involved)(27). And once again it took public pressure to change it, be it only for humanitarian organisations. But this is not a real solution: the need for new drugs creates a “treatment time bomb”(28).

Access to medicines is not only a problem in low-income countries: costs of new cancer drugs are skyrocketing(29) and the “thousand dollar pill” sofosbovir strains healthcare budgets in wealthy nations(30). And here, too, we see exuberant price hikes for medicines to treat toxoplasmosis (+5,000%)(31), anaphylaxis (+500%)(32) and parasitic disease for immunocompromised patients (+5,000%)(33).

But why are these drugs so expensive? Does it really costs a thousand euros to produce one tablet of sofosbuvir? Of course not: pharmaceutical companies justify charging high prices using an unspecified amount of $2.6 billion to develop one approved drug(34). This number is probably a huge overestimation: it is based on the 20% most expensive drugs, and consists of around 50% “unreal” costs (opportunity costs calculated using extreme return on investment) and 25% cost paid by taxpayers(12,35). And while R&D cost has increased over the years, it is still more than fifteen-fold less than marketing spending(12,36), and profits have increased six fold quicker(12).
In reality, market exclusivity allows pharmaceutical companies to charge whatever they want. This provides perverse incentives for competing pharmaceutical companies to “invent” me-too-drugs and for the originator company to put research into new indications or other evergreening(37) strategies to prolong market exclusivity long after the initial R&D has been paid off (an example was AZT, an antiretroviral drug discovered in 1963 but directly and indirectly under monopoly for 54 years(24)). This causes me to doubt pharma’s mission statements from the introduction, as it’s clear that pharmaceutical companies are putting money first: patents over patients.

Alternatives

Fortunately, there are plans and ideas to improve our pharmaceutical research system. Examples are restructuring the financial risk of clinical trials in order to make it easier to fund them(38), requiring a drug to have therapeutic benefit to be approved on the market(12), and a patent-pool for HIV(39), a voluntary licensing mechanism for HIV medicines. A recent report from the Lancet Commission on Essential Medicines recommends this idea for all essential medicines(40).

Another —very interesting but controversial(41)— alternative is called “de-linkage”(42). It separates the “research market” (R&D) and the “product market” (drug sales). Ideally, research could be directed by public or not-for-profit funds (who already make a big contribution to research(8)) based on (future) disease burden. Cooperation could be stimulated by sharing research data and rewarding “milestones”. This would allow smaller players, who now lack the funding for clinical trials, to contribute(43). Alternatively, the funds could take the risk by providing funding up-front. Variants of these push and pull mechanisms(9) are already being used(40), and can also be used for tuberculosis(44), antimicrobial resistance(43) and many more.

Conclusion

The current pharmaceutical research system disregards the needs of the world’s poorest. Pharmaceutical research is insufficiently aligned with global disease burden. When drugs do exist, they may be inaccessible due to many reasons (e.g. drug prices).
Non-profit organisations are stepping in to fill the gap; prominent health advocates made actionable recommendations about essential medicines and sustainable health gains worldwide(40); and university students are rallying to change the research aim and licensing in universities(45).
Let’s hope this is the dawn of a revolution for health worldwide.

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