Doing More with Less

The concept of conducting clinical trials in resource-limited settings isn’t new. In fact, we’ve been doing it for many decades. What has changed over the last couple of decades is the nature of that work. Until about 25 years ago, most complex multi-center clinical trials were carried out in developed countries by commercial entities. Essentially, pharmaceutical companies funded their own research with the objective of bringing a new intervention to the market. But then, we started to see a shift – even the most complicated trials began to be conducted in low- and middle-income countries (LMICs). Why? Three reasons: internal validity, convenience, and neglected conditions.

Internal validity refers to the fact that new interventions must be tested in different populations. Differences in characteristics like ethnicity can change a patient’s therapeutic response to a particular drug – and differences in healthcare infrastructure can impact the drug’s effectiveness.

Convenience is a less pleasant concept. It refers to the possibility that an unscrupulous sponsor will conduct research in poor countries because it may lower costs, simplify ethical or regulatory review, and make recruitment easier by involving socially vulnerable populations. People with few resources often see clinical trials as a way to access free medical care – and that makes them more likely to involve themselves in research without asking too many questions about the potential risks.

The third reason, neglected conditions, deals with our growing awareness that many health problems are mainly or exclusively prevalent in LMICs, and are not yet sufficiently addressed. In the past few years, we’ve seen a number of positive initiatives, like new Product Development Partnerships (PDP) for research into new antimalarial treatments to compensate for the lack of efficacy of older treatments. Other new public-private partnerships conduct research into neglected tropical diseases that desperately need effective, safe and easy-to-use prevention and treatment tools. So we’re really seeing clinical trials go global these days!

Shifting studies

We have always had some trials conducted in academic environments, but nowadays, more and more big trials are being carried out by noncommercial entities, which makes a significant difference to both rich and poor countries. There are some research questions that simply won’t be addressed by the private sector. An example from my group’s work is a comparative study prospectively comparing the safety and efficacy of existing antimalarial treatments in pregnant women. Such a study would hardly be carried out by a pharmaceutical company – after all, what if the company’s product proved inferior? That’s why we need independent, noncommercial research.

This kind of research also looks at fields that are less likely to turn a profit. Tropical diseases are one such area (and the reason why public-private partnerships like the Drugs for Neglected Diseases Initiative are so vital); pediatric oncology, which traditionally has low patient numbers, is another. With some laudable exceptions, commercial research is by its nature mainly profit-driven, so whenever a research question doesn’t offer a significant monetary return on investment, we rely on public funding and noncommercial entities to step up. The role they play is absolutely vital, and the more they take the lead in clinical trials, the more benefit resource-limited countries will gain.

The downside?

For science and medical professionals, the problem with noncommercial trials is that they’re often under-resourced in comparison to those self-funded by pharmaceutical companies. Working in LMICs only exacerbates the problem, which often means stretching your personnel, equipment and supplies as far as they will go. More specifically, as a noncommercial sponsor, you will need to compete for external funding that is always in short supply; work in small teams where individuals may have to play multiple roles; adjust procedures according to local constraints; and maintain the highest quality, reliability and ethical compliance in your work even as you tackle these obstacles.

Let me walk you through an example – the challenge of developing new in vitro diagnostic tests for neglected tropical diseases. You would likely face a number of obstacles along the way:

Funding

To successfully compete for grants, you’ll need to convince the funding agencies that your consortium is scientifically sound and can deliver quality results. At this point, you’ll also need to start considering benefit-sharing – or, in other words, discovering how you can fully involve your colleagues from the LMICs in which you intend to work. How can you provide those colleagues with an equal partnership, starting from writing the grant application together? How can you ensure that your work will build their capacity to conduct independent research in the future?

Infrastructure

When you discuss working “in Africa,” people often envision lifeless deserts, ramshackle buildings, starving people in rags. But in fact, our work contexts can vary widely, from state-of-the-art tertiary hospitals in large cities all the way to remote rural settings with poor medical infrastructure and no research capacity at all. You may need to begin by creating or upgrading the local infrastructure; in particular, labs that can provide routine medical care don’t necessarily have the procedures in place to meet research demands. Making them suitable for research requires significant effort and investment – but if you don’t do it, you can’t move forward.

Recruitment

In clinical research, we consider vulnerable populations to include children, the elderly, the incapacitated, and so on. But vulnerability may be much more widespread, especially (but not exclusively) in LMICs. Often, resource-limited settings lack social security systems and accessible healthcare, which is why many patients view clinical trials as a way to obtain free treatment. It’s difficult – but vital – to ensure that you’re not unintentionally exploiting that vulnerability when recruiting a patient population. You must also ensure that those who aren’t eligible for the trial are not treated as “second-line” patients and still receive some benefit from its presence – for instance, by upgrading local laboratories so that everyone receives better care.

Engagement

Not every researcher is a born communicator – and dialog becomes even more complex when you have to translate into local languages. I’ve seen many studies regarding patients’ capacity to understand research, but very few that closely examine the researchers’ ability to explain it. I think we need to ensure that researchers are trained in empathetic communication (see “The Missing Piece of the Puzzle”), and what’s more, I agree that we need to familiarize ourselves with local customs and cultures early on – perhaps with the aid of a social scientist. Unfortunately, there’s rarely budget for that type of groundwork – and there isn’t always the time. But we need to prioritize it much more than we currently do, and we need to make sure that we’re engaging the community throughout our research projects.

The long term

Previously, and in a western context, “post-trial access” referred to ensuring that clinical trial participants could continue to receive the experimental treatment in the window between the trial completion and medicine registration. In LMICs, the problem is more complex: how can the country retain access to the medicine? Many treatments, upon reaching the market, are priced beyond the reach of these countries. There are positive examples of “access strategies,” but they’re all chosen by the research sponsors themselves. There’s currently no system in place to ensure early and continued access at an affordable price to those in the host countries who need it – but, in my opinion, there should be.

Overcoming operational obstacles

In the end, many problems – and their solutions – come back to project management. In small academic groups, when we want to develop the capacity for clinical research, we invest in scientific and clinical practice skills. We often fail to prioritize investment in project management and administration – but those are the skills that make your research more efficient, and even more ethical. Without project management, your budget may be missing essential elements (such as preliminary cultural studies or the resources to upgrade existing facilities or engage the community) – and you can’t amend your external budget after the fact, so you need to make sure it’s correct from the start. Once your study is underway, you still need administrative skills. If you want to send samples overseas for testing, you’ll need fair and transparent material transfer agreements. If you want to share your data, you’ll need contracts that protect your rights, and the rights of your research partners and study population. These are all complicated matters, and they’re all too easily overlooked if you don’t have administration and legal experts. Never underestimate the value of good management!

And speaking of management, we have to remember that – unfair though it may be – some of us wield more power than others in our collaborations, and it’s up to us to fight for those with less. When researchers from highly developed countries work with LMICs, we must not “take charge.” It’s the local scientists and doctors who have spent their lives getting to know the patients, the diseases, and the available resources – so why aren’t we making sure they are the driving force in decision-making? And not just scientists and doctors; if you’ve spent any time in the field, you’ll know that the people on the ground – nurses, community health workers, interpreters, data entry clerks – are all equally important. We can’t view them as so many cogs in a machine. We need to support and involve them, and offer access to training and networking, so that they can continue to do their jobs and sustain their fundraising and research capacity, long after we’ve left.

Raffaella Ravinetto is a senior researcher at the Antwerp Institute of Tropical Medicine (ITM)’s Public Health Department, chairperson of the Médecins Sans Frontières Ethics Review Board, and former head of the ITM’s Clinical Trials Unit.

This piece is based on material previously published in international peer-reviewed journals.