Q. Can you tell us why early access to medicines is needed and how the Paediatric Bioethics Centre has approached the decision-making required in these very challenging and emotional situations?
The wider context of paediatric drug research
There has been a lot less funded research on drugs provided to children, and this problem continues, despite organisations like the Food and Drug Administration (FDA) and European Medicines Agency (EMA) trying to encourage companies into paediatric research.
For me, early access is an umbrella term used to describe the use of experimental, innovative treatments for situations that do not quite fit the constraints of a randomised trial or formal clinical research. This could be because children do not fit the entry criteria for a clinical trial, cannot geographically reach a trial site or the clinical team feel that a child might still benefit from treatment. In my setting, early access can mean reviewing a treatment which is yet to go through human testing and sometimes because it is for a disease that is so rare that you are unable to run a formal randomised controlled trial.
Our interest was in setting up an ethical process for early access that included the children (when appropriate) and families. Having parents involved with this very complex ethical decision-making has been really positive and feedback from consultants and families is that they value being a part of the process.
In order to warrant accessing a drug through an Early Access Programme (EAP), where the safety profile and efficacy have not been established, there has to be a compelling gain to the patient. An EAP isn’t something where you can say, “Well, I will try this because I don't fancy the treatment that they're offering me.” In most cases there is a high chance of the child using the licensed treatments available not surviving, and the families whom we look after are understandably desperate. The ethics guidelines help us to work through each person’s situation to determine whether early access is suitable to pursue.
Q. What particular challenges has the COVID-19 pandemic brought to the fore when it comes to paediatric access to experimental medicine?
Pre-planning for early access to COVID-19 treatments
Early on we had conversations with our drugs and therapeutics committee and infectious disease colleagues to discuss how we would treat children coming into hospital with COVID-19. We knew there would eventually be randomised controlled trials for COVID-19 but that these would not, certainly at the outset, include children. With little data on how the disease affects children, especially those with rare and complex diseases, we developed our existing rare disease innovative process to work through how we would use early access to treat children with COVID-19.
Facilitating ethics meetings
On a practical level, to ensure we could still run ethics meetings, with only one parent allowed in hospital during the pandemic, we successfully moved these onto Zoom.
COVID-19 has had a huge impact, especially in pre-clinical research. Labs have been closed and health organisations have had to prioritise clinical work during COVID-19. In addition, PhD students have been furloughed, meaning the very people who are developing cures for diseases have not been working for six months. And that’s a disaster. Ongoing clinical trials have continued in the main, but new trials have not been able to get any sort of funding, and there have been delays in trial governance, in either authorisation or ethics processes, because the only game in town is COVID.
With the scale of mortality that COVID-19 has brought, research bodies have understandably focused their resources into the COVID effort. Whilst that was completely understandable at the time, we are now going to be faced with the impact of six months and more of missed opportunities in research for children. It is vital to now prioritise getting back to a better normal for pre-clinical research.
Positives from the COVID-19 phenomenon
I really do see that some positives have arisen from COVID-19. I think it shows the ability of industry to react at speed. It has also shown great collaboration with industry and research groups coming together to make effective vaccines and that is tremendous.
Long may it continue. Children and women have been hit hardest by this pandemic, but we have an opportunity to build back better in terms of what the research society should be focused on. I know I’m biased but I would say the healthcare of children should be a priority.
Q. What are some of the unique challenges when seeking early access to promising therapies which are not yet approved?
Equity of access is a big challenge. This can be for many reasons. Not every rare disease is coded in the system, so once a clinician is aware of an EAP, identifying children who might be eligible is difficult. There can be very different opportunities for children based on who is caring for them: you might have a very active clinician interested in research and keeping up to date with new drugs that are in development and EAPs or a very passive clinician who is not as focused or engaged in that area. Similar to that, is how proactive the parents are. If you have parents who are researching on the internet, asking questions and spending time reaching the right people versus a family in challenging socio-economic circumstances, or possibly from a group with significant cultural or language barriers, equity of access becomes a real issue.
More positively, patient groups can play a big part in battling for all children. Our experiences to date have been positive with patient group representatives working with us on clinical processes to support decision-making that benefits all children.
Q. What do you see as the challenges for pharma companies operating in the space of early access and what would be your message to them?
I think the first challenge is concerns for the development implications of their drug. When using drugs that are still in the experimental stage there are risks. If the drug does not work, there are unforeseen complications outside the intended indication, or even complaints; companies can quite rightly worry this could unfairly put the whole development programme in serious jeopardy, often after significant development costs. This is where having these very robust ethics conversations and proper consenting processes can help.
Another challenge is the cost of drugs. If you are producing a drug that took billions to develop and perhaps only 20 children in the world might stand to benefit from it, that is an astonishing bit of maths and I have great sympathy for companies operating in this space.
The development of treatments for rare diseases is a precious thing and we need to support and effectively cherish those companies developing treatments in this area.
Early access is an important tool for consultants working in rare disease, and I would say to companies, let’s work together to ensure the children who need these treatments the most can reach them.
Dr Joe Brierley is also involved with the Bioethics Advisory Group (Beta Group), which is a multi-disciplinary group of experts who seek to apply ethics to early access in answering some of the hardest questions faced by companies in their EAP development. The Beta Group was provided with start-up funding by Clinigen Group and continues to operate with its administrative support covering provision of a part-time secretariat.
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Rare Revolution Editor