The Lancet Global Health
Oct 2014 Volume 2 Number 10 e550 – 615
http://www.thelancet.com/journals/langlo/issue/current
Ebola: the missing link
Zoë Mullan a
“Liberia is facing a serious threat to its national existence.” So said the country’s Defence Minister, Brownie Samukai, earlier this month. For a nation that has only just seen the UN Refugee Agency withdraw after a 14-year civil war in which a quarter of a million people perished, Samukai’s words are chilling. Ebola virus entered the country from Guinea in the early part of 2014, and has since killed at least half of the 2218 people reported to have died in the west African outbreak as of Sept 7. After doing little more than spectate for almost 6 months, the world has now risen from the bleachers and set about some action.
The inadequacy of the international community’s initial response to this unusually fast-spreading urban outbreak has been lamented at length, as have WHO’s weakened capacity in the face of budget and staff cuts, and the lack of an emergency response fund and centralised global command and control structure to enable swift deployment of resources and trained personnel. However, at least we have now caught up with what is actually happening and have begun to monitor it. WHO’s regular situation reports have become a must-read and the agency’s prediction of an exponential increase in the number of new cases of Ebola virus disease in Liberia is proving tragically accurate. WHO’s Ebola Response Roadmap is a useful document and is hard to fault for its practical advice. Donor commitments are starting to arrive. But will data, directions, and donations be enough?
Respected voices such as those of Médecins Sans Frontières (MSF) and Ebolavirus co-discoverer Peter Piot have called for a military response to the coordination of supplies and the building of health centres, for UN peacekeeping forces to be deployed, and for individual Western governments to encourage and enable health workers to offer their assistance on the ground. In the case of Liberia, WHO has warned of the need for “non-conventional interventions”, whatever they may be. Amid scenes of men, women, and children prostrate outside treatment centres with no beds; of the exhaustion of national and international health workers alike; and in the face of what seems to be the infuriatingly ponderous nature of global health institutions, it is hard not to issue an empassioned plea for someone, somewhere to “do something”.
However, provision of military assistance or even well trained Western medical staff is not a panacea. The imagery conjured up by foreigners in biohazard suits or army camouflage can be powerfully negative, and even associated with the bringing of disease, rather than its banishment, as happened with cholera in Haiti. What is also vital in west Africa right now is the interface between the essential efforts of the international community and the needs of the populations affected: the entity that converts funds into care, information into understanding, and precautions into safety. In other words, the national governments of Liberia, Sierra Leone, and Guinea.
Some of the governments’ responses to the current crisis have been badly misjudged. Most notably, Liberia’s efforts to quarantine an affected community in West Point township in the capital Monrovia had disastrous consequences, with a heavy-handed security presence leading to the fatal shooting of a 15-year-old boy. Sierra Leone has threatened a 2-year gaol term on anyone found to be hiding a patient with Ebola virus disease. And, back in Liberia, President Ellen Johnson-Sirleaf’s declared 90-day state of emergency included “the suspensions of certain rights and privileges”, without stating what these were. None of these actions engenders the trust that is so crucial to the containment of the epidemic. Without trust, families will continue to hide sick loved ones, and health workers and mortuary staff will continue to be attacked.
Liberia, Sierra Leone, and Guinea are some of the poorest nations in the world, and two are still in the early stages of recovery from a devastating conflict. The international community must therefore do everything possible to assist with resources, staff, and logistics in the face of this humanitarian catastrophe. But what must not be forgotten is the responsibility of the national authorities to direct and communicate in a way that protects the human rights of those they have been elected to lead. The people of Liberia, and those of other affected countries, must be able to rely on the commitment, transparency, and cohesion of their own governments in times of national crisis.
Rethinking the development of Ebola treatments
Rajesh Gupta a
In response to the current outbreak, the international community has endorsed the clinical use of unregistered treatments for Ebola.1 Even with this accelerated pathway to in-human testing and use, radically novel approaches to drug development will be needed to improve the likelihood that a treatment is realised. Bypassing steps in development does not alter the probability of success, and historical patterns in drug development suggest that there is a slim probability of success with the current portfolio of potential Ebola treatments (all of which are were in preclinical development prior to the outbreak).
First, preclinical research in drug development can suffer from a lack of replicability, which contributes to high development failure rates.2 Second, if preclinical development is successful, the likelihood of successful regulatory approval of all investigational drugs reaching phase 1 is only 10•4%.3 Third, these patterns and low rates are based on therapeutic areas with: (a) robust preclinical and clinical data collected (often) over decades from hundreds to thousands of research and development activities spanning the globe, and (b) socially and politically acceptable clinical development programmes spanning large populations, mainly in resource-wealthy settings with strong clinical trial infrastructure. Ebola stands in stark contrast to such therapeutic areas; thus, one could expect that the likelihood of successful regulatory approval for an Ebola treatment would be lower than these estimates.
Repurposing (use of approved drugs for new indications) or repositioning (use of drugs whose development was not continued for new indications) of existing drugs has been put forward as a method to overcome some of these issues.4 Indeed, drug repositioning and repurposing could lead to higher rates of success, with lower costs of development, in a faster timeframe than de novo discovery approaches.5 However, these potential advantages are far from certain. Furthermore, drug repurposing/repositioning in and of itself does not remove the need for certain preclinical studies and clinical trials. Drugs still need to be validated and studied in the indications for which they are proposed.
In silico approaches might hold a key to overcoming some of these obstacles. Use of bioinformatics-based high-end computing to simulate drug—disease biological processes provides the ability to bypass time-consuming and costly in vitro and in vivo studies and increase the probability of success of clinical trials.6 For Ebola treatments, in silico approaches might offer two specific means to improve the current process and help address some of the critical preclinical and clinical concerns raised at the WHO meeting of international experts to discuss Ebola therapeutics on Sept 5.7 First, the number of preclinical compounds already containing clinical data for other therapeutic indications could be considerably increased. Although traditional repositioning methods using in vitro screening have led to initial discoveries for Ebola,8 computational screening could provide the needed efficiency to identify candidates more rapidly and accurately than de novo discovery methods. Second, virtual clinical trials could alleviate some of the logistical and ethical issues surrounding the clinical use of unregistered Ebola treatments, including the balance between generating safety data and the need to introduce treatments as soon as possible.9 This method would permit non-interventional assessments of pharmacokinetic-pharmacodynamic parameters and allow precise and efficient clinical trial design10 (the latter being particularly important because the epidemiology and infrequent emergence of Ebola often provides a narrow window of opportunity and limited population size to assess an intervention). There is at least one caveat, though. In silico approaches are dependent on drug and disease process data. Therapeutic Ebola research is heavily funded by the US government under the auspices of threats to national security,11 and international activities are limited to a few research groups. To allow for greater participation of researchers globally, real-time accessibility of crucial data is necessary.7
In silico methods are still in development and rapidly evolving, but have been successful in identifying potential candidates for various diseases and the risk of using such methods are very low. Their ability to affect, at scale, drug development processes, costs, and timelines is unknown but likely to be considerable given the private sector’s strong interest and investment in this area. Equally likely is that these approaches will be able to affect a wide range of diseases. Although these approaches are currently directed towards diseases with clear revenue streams (eg, inflammatory bowel disease and cancer), such approaches could be used for unprofitable diseases that affect the most underserved populations of the world.
The inequities already posed by a disease of poverty such as Ebola become further exacerbated when novel technologies are used first to explore diseases that are viable commercial opportunities. This does not have to be the pattern moving forward, and Ebola might provide the opportunity to apply new technological approaches to drug development (such as in silico methods) for traditional “market failure” diseases. If the global community is truly committed to rapidly developing a new drug for Ebola, multiple novel approaches, methods, and technologies will need to be used to beat the inherent hurdles of drug development.
1 Enserink M. Debate erupts on repurposed drugs for Ebola. Science 2014; 345: 718-719. PubMed
2 Begley C, Ellis LM. Drug development: raise standards for preclinical cancer research. Nature 2012; 483: 531-533. PubMed
3 Hay M, Thomas DW, Craighead JL, Economidies C, Rosenthal J. Clinical development success rates for investigational drugs. Nature Biotechnol 2014; 32: 40-51. PubMed
4 Editorial. New approaches for Ebola therapeutics. New York Times Aug 24, 2014.
5 Institute of Medicine. Drug repurposing and repositioning: workshop summary. Washington, DC: National Academies Press, 2014. http://www.iom.edu/Reports/2014/Drug-Repurposing-and-Repositioning.aspx. (accessed Sept 5, 2014).
6 Dudley JT, Deshpande T, Butte A. Exploiting drug-disease relationships for computational drug repositioning. Brief Bioinform 2011; 12: 303-311. PubMed
7 WHO. Statement on the WHO Consultation on potential Ebola therapies and vaccines. http://www.who.int/mediacentre/news/statements/2014/ebola-therapies-consultation/en/. (accessed Sept 8, 2014).
8 Johansen LM, Brannan JM, Delos SE, et al. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Sci Transl Med 2013; 190: 90ra79. PubMed
9 Arie S. Ebola: an opportunity for a clinical trial?. BMJ 2014; 349: g4997. PubMed
10 Holford N, Ma SC, Ploeger BA. Clinical trial simulation: a review. Clin Pharmacol Ther 2010; 88: 166-168. PubMed
11 Enserink M. Ebola drugs still stuck in lab. Science 2014; 345: 364-365. PubMed
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