Globalization in clinical drug development for sickle cell disease

Abstract

Globalization of clinical trials, defined operationally as conduct in the international arena, has grown over the past few decades. The pharmaceutical industry is expanding its activities not only in High-Income countries but also in Low- and Middle-Income countries (LMICs).¹

For pharmaceutical companies, this shift can be associated with several benefits: a larger pool of potential participants, faster enrollment in trials, and substantial cost savings.¹ At the same time, there may be advantages also for LMICs in terms of capacity building, gaining experience, and access to innovation.²

Drug development and access to medicines in LMICs is certainly a challenge for patients with sickle cell disease (SCD), a condition that is most highly prevalent in malaria-endemic countries in the global South, but that, through the tragedy of the transatlantic slave trade and subsequent migrations, is also prominent in the global North.³

The prevalence of SCD outside Africa has accelerated the development of new medicinal products, enhanced by a conducive regulatory framework. The orphan drug legislation in the United States (US) and the European Union (EU) have provided pharmaceutical developers with special incentives (e.g., periods of market exclusivity) to counterbalance the limited market size. In addition, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have implemented special pathways to expedite the review and approval of treatments for serious and life-threatening diseases. Accordingly, in both the US and the EU, treatments for SCD can be approved based on surrogate endpoints or more flexible evidence.⁴

To assess the trends and impact of globalization on the development of SCD drugs, we analyzed data from industry-sponsored studies initiated in the time interval from 1 January 1990 through 30 June 2024 (see Appendix S1). In the study period, a total of 79 pharmaceutical active substances were tested in 156 clinical trials.

Overall, 56.4% of enrolling centers were in North America, 20.5% in Europe, 7.9% in Africa, 5.7% in Latin America, 9.1% in Asia and Middle East, and 0.4% in Australia. Temporal trends from the early 2000s to the last 5 years showed a relative decrease of enrolling centers in North America from 63.1% to 44.0%, and in Europe from 28.5% to 22.2%. By contrast, in African centers there was an increase from 0.5% to 13.2%, in Latin America from 1.1% to 9.0%, and in Asia and the Middle East from 5.7% to 11.4%. The number of Australian centers remained low over time.

Similar trends were mirrored in the drug development phases: for instance, enrolling centers in Africa increased from 2.8% in Phase 1 trials to 4.2% in Phase 2, and to 10.6% in Phase 3 and 11.9% in Phase 4 trials. Similar increases were observed in Latin America, Asia, and the Middle East (Appendix S2). When these trends are considered according to World Bank country classifications by income, we observe an expansion toward LMICs, where participating centers increased from 7.4% of all centers in Phase 1, to 15.1% in Phase 2, to 22.1% in Phase 3, to 41.3% in phase 4.

Against this background, we have detailed data from pivotal clinical trials conducted by pharmaceutical companies seeking regulatory approval for medicines for the treatment of SCD. As of December 2023, 10 trials have led to the licensing of 9 medicinal products for SCD in the US and the EU. These products range from small molecules such as hydroxyurea, L-glutamine, voxelotor, and deferiprone, to biologicals (crizanlizumab), and most recently to two potentially curative gene therapies (Table 1).

In the face of a gradual but steady tendency of clinical trials to become more global, the purpose of this article is to consider some implications of this trend: these may become even more important in the future if, as we hope, the trend continues.

The most innovative and exciting development listed in Table 1 is gene therapy: this has the promise of long-term improvement and potentially curative intervention. Despite being licensed by stringent regulatory authorities, gene therapy should probably still be regarded as experimental, since long-term follow-up data are very limited and the vectors and techniques are still being improved. The price of these new products is more than $2 million to be paid upfront, which was claimed to be warranted by comparison to the astronomic prices of other newly approved treatments ($299 000 for L-glutamine and $1.1 million for voxelotor and crizanlizumab over a lifetime).¹² In principle, there is no reason why any curative or otherwise efficacious treatment should be denied to SCD patients in LMICs: however, in these countries, this price range is simply unrealistic and therefore cannot be considered a priority.

Beyond the specific research, ethical, and public health issues discussed above, we feel that the international community has a historical responsibility toward the global South and that in the immediate future, there should be a “pay-back” at least to a small extent. Therefore, we propose that international organizations, policymakers, and the pharmaceutical industry come together to undertake a stepwise path.

First, hydroxyurea should be made available to all patients with SCD.¹³ In Africa, fixed-dose treatment with hydroxyurea at 1000 mg/day has been estimated to be $16.5–54.6 per month at the retail market.¹⁴ For quantities provided by global vertical programs—as with HIV, malaria, and TB in the context of the Global Fund—the price could even be leveraged further, toward the recently proposed goal of $0.10 per 500 mg hydroxyurea capsule (i.e., around $ 6 per month at 1000 mg/day).¹⁵ If 1% of the pharmaceutical budget for SCD in the global North were invested in purchasing hydroxyurea, such a “global tithe” could be transformative for Africa.

Second, clinical research and regulatory strengthening ought to proceed hand in hand. So far, in Africa, the latter function has been carried out by individual National Medicines Regulatory Authorities, but there is a drive to establish an African Medicines Agency (AMA) that will be able to draw from the expertise available in African Universities, Research Institutes, and Teaching Hospitals. A sound regulatory structure will make African countries more attractive for pharmaceutical companies, which may be induced to place manufacturing on the continent. Regulatory harmonization could provide substantial benefits: African countries, by coming together, could negotiate more favorable conditions, based on the very fact that they will be representing a population of up to 1.2 billion people. At the same time, pharmaceutical companies would interact with a reliable multinational system (as already in place in the US and the EU), thus streamlining global marketing efforts.

In the meantime, African Authorities should implement a holistic approach to SCD, comprising education of health workers, network development, early diagnosis, local manufacturing of essential drugs, and timely therapeutic intervention, to keep a virtuous circle active through which SCD is clearly set as a priority in the public health agenda.

Taken together, these data document a positive trend of drug development toward the global South, especially in those regions where SCD is most prevalent. When analyzing the number of enrolled participants, we confirmed that the shift is significant and will likely play an important role in strengthening the SCD ecosystem. This trend is encouraging but the shift of clinical trials for SCD toward LMICs is less evident in pivotal clinical trials, where centers from malaria-endemic regions, particularly in Africa, are still underrepresented.

Expanding industry-sponsored multinational clinical trials further into LMICs provides a great opportunity to improve clinical outcomes and local capacity.² Expanding into LMICs from the initial phases of development of a new drug could help the fine-tuning of late-phase trials that include regulatory purposes. However, the exercise might be fruitless if not supported by subsequent measures to improve access to the population once a therapy has been found effective.

In the long term, the responsibility to the health of people lies with their respective governments, who will rightly put in place those measures deemed most appropriate to address the medical needs of their citizens. In the meantime, once again we appeal to the Global Fund¹⁴: in the trail of what they have accomplished for years with respect to malaria, tuberculosis, and HIV infection, which are primarily horizontally transmissible diseases, they might choose to include SCD, which is transmissible vertically, into a global program that will supply hydroxyurea to all patients with this condition. This request has been recently and forcefully requested by a highly qualified group of African hematologists.¹⁶

The authors declare no conflicts of interest.