Ethics and the public good: the race to find a treatment for Ebola
With world attention focused on the Ebola outbreak, debate continues about whether experimental treatments should be given to patients when no other option exists. Leanne Orchard examines the implications of fast-tracking clinical trials.
The struggle to find a balance between ethics and the greater public good in fast-tracked clinical trials is not a new one. Certainly the need to fast-track clinical trials to provide treatment in dire circumstances has been recognised by the law and the medical community globally. Indeed, the US Food and Drug Administration (FDA) has introduced a number of expedited approval programmes with the aim of accelerating the availability of treatment for serious or life-threatening medical conditions.
Despite the clear rationale for expedited approval programmes, however, they are not without opposition. Arguments regarding ethics and safety have received fresh attention recently as the world turns its attention to the Ebola outbreak in West Africa.
Availability
The Council for International Organizations of Medical Sciences clearly states in its International Ethical Guidelines for Biomedical Research Involving Human Subjects that '[g]roups or communities to be invited to be subjects of research should be selected in such a way that the burdens and benefits of the research will be equitably distributed.' That is to say that, in order to be ethical, a body that develops a vaccine must then market it at a price that makes it available to the communities in which it was tested.
In cases such as Ebola, the afflicted are predominantly in poorer, third-world countries, giving a relatively low return on investment (ROI) from a cure. Indeed, though Ebola was first identified in 1976, it has not received significant global attention until the 2013 outbreak. As James Surowiecki explains in his article on Ebolanomics, the norm for pharma is to allocate R&D to drugs that are most likely to deliver high ROI, typically those affecting wealthier people in the developed world who can afford to pay a lot for their product. As Surowiecki explains, '[a] drug for Ebola looks like a bad investment.'
However, there are counter-arguments. Kevin Outterson, a co-director of the health-law programme at Boston University, says one reason to invest in vaccines with little expected ROI is positive publicity: 'Every drug company cares about their reputation, and various companies have had various hits to their reputation over the past decade, so if they can do something that's clearly helping with an urgent global public-health need at a reasonable cost, it's a good move for everybody'.
Furthermore, fast-track clinical trials often centre on diseases for which there is no known treatment and as such provide an opportunity to employ innovative clinical trial models that could hold the key to reducing the cost of future drug development. Thus the tools used to explore these new treatments and their potential applications in other therapeutic areas become the real marketable product for these companies and their incentive to invest.
Safety
In addition to worries relating to the availability of treatment trialled in developing countries there are concerns over the safety of the agent itself. An inherent risk of fast tracking is that the drug has not been subject to the same safety monitoring as usually expected and could consequently cause as yet unknown adverse reactions.
Indeed a 2014 study published in Health Affairs found that after the Prescription Drug User Fee Act (PDUFA), which allowed for fast-track trials, there was a higher incidence of drugs receiving black box warnings and even being taken off the market completely. According to this study, 34 of every 100 drugs were either pulled from markets by their companies or had additional warnings attached.
There is also a history of fast-track trials going seriously wrong; in 1996 a trial into the drug Trovan left 11 children in Nigeria dead and dozens disabled, and in 2006 a study into TGN1412 also resulted in disaster when all six of the healthy male volunteers in the first human study suffered massive multi-organ failure.
Such outcomes are not unknown, even in thoroughly researched agents. After 20 years of development, in 2007 a phase II HIV vaccine trial yielded results that suggested the vaccine actually increased the risk of contracting the disease compared to a control group.
Then there is the question of access to the drug; even in fast-tracked trials it is generally considered standard practice to conduct a Randomised Clinical Trial (RCT) in which a control group is used. Concerns arise as to whether it is ethical to deny patients the right to an agent that could ultimately save their lives, in the interest of maintaining a control group.
"It is problematic to deny patients a chance at intervention when the mortality rate of the disease can be as high as 70 per cent when treated with conventional care"
The Ebola trials are a case in point: it is problematic to deny patients a chance at intervention when the mortality rate of the disease can be as high as 70 per cent when treated with conventional care. Also, with infectious diseases such as Ebola, it is often not only the patients at risk; as of October last year, one in 50 Liberian Health Care workers was infected with the disease. These care workers had access to adequate protection; the number is estimated to be much higher where this was not the case.
The next question is who should be the first to trial the vaccine? The target population which is most likely to contract a disease, or those who need to deal with high volumes of infected people day in, day out?
Not including a placebo control group raises further concerns, especially in trials concerning indications with a high mortality rate. It could be argued that, without the results from a placebo group for comparison, serious and harmful adverse effects of an agent could go undetected, and the data could therefore be unreliable. Luciana Borio of the FDA further supports this view, stating that, without a control group, there is a "significant risk of not generating interpretable data".
Moreover, some think that providing an experimental drug to the patient population at large without a comparative control group would contradict the ultimate aim of the trial by promoting the best interests of patients over public health in the long term. In his article Carl Coleman argues that it is 'wrong to prioritise current patients' desire for access to unproven medications at the expense of generating the kind of reliable evidence that will benefit the public in the long run.'
Methodology
RCT models in fast-track clinical trials undertaken in the target populations, such as those suggested for the Ebola vaccine, are further complicated by the fact that the healthcare infrastructure is incredibly varied, making it difficult to compare the control group across sites. As Judy Stone explains in her article for Forbes, 'while every patient can receive an experimental medicine, the results will likely, at best, only show differences in crude mortality, and it will be much harder to detect adverse events and safety concerns.' Without finding a way to control these differences any data gained from these RCT may not be interpretable.
So, perhaps one of the ways to address a balance in ethics and the public good is to reassess the trial model. Addressing the need for a placebo control group in the standard RCT can allay some of the aforementioned concerns. Certainly, this seemed to be the attitude of many speakers at the Advancing Ethical Research conference in December last year. For example, it has been suggested that an Adaptive Trial method be adopted in human trials on the Ebola vaccine. Adaptive Trials, as the name suggests, can be readily changed as new information regarding treatment becomes available. So, should drug X show positive results against a placebo then further studies into the efficacy of drug Y will be tested against drug X in place of a placebo, eliminating the need for placebo completely.
Though perhaps a stretch for the highly competitive pharma industry, the use of a Master Protocol by several sponsors could not only mitigate some of the issues surrounding placebo use, but also address problems stemming from uninterpretable data by providing a standardised method of data collection. This would not only provide more comparable results across different agents but, as only one control group would be needed, fewer patients would be involved, lowering the chances of patients receiving a placebo.
Ultimately it appears that the best way to target efforts to preserve ethics in reaching for a greater public good is by looking with fresh eyes at the methodology of clinical studies; through trials conducted correctly using methods such as the Adaptive design and/or Master Protocol we can hope to limit needless casualties. This, in combination with the shifting attitudes of pharma companies to developing treatments, could provide a brighter future for ethically-balanced fast-track clinical trials.
About the author:
Leanne Orchard is a Language Solutions Executive in SDL's Life Sciences Solutions division.
SDL is a top-three provider of language, technology and business intelligence solutions to international pharma and medical device companies and contract research organisations.
Leanne can be reached on lorchard@sdl.com or +44 (0) 1142 535 337.
Have your say: What is the best way to balance swift access to drugs with patient safety?
Read more on the Ebola situation from SDL:
