Re-engineering pharmaceutical research, a scientist’s opinion
Interview with Dr Denis Lacombe, Director General of the European Organisation for Research and Treatment of Cancer (EORTC).
Can you tell me a bit about the European Organisation for Research and Treatment of Cancer (EORTC)?
We are a non-governmental, not-for-profit organisation established for 60 years, focusing on survival and quality of life of cancer patients. We are active in approximately 37 countries, and have 240 people in our office in Brussels. The current situation is that when a drug is on the market, we really know nothing. Often the control used or the patient population used to test the drug are not good, and the regulators approve drugs with low ambition, with small datasets. We should be more ambitious for patients. For example, tumour shrinking, referred as a surrogate end-point, may be used as a clinical trial end point – but this is a drug related endpoint, this doesn’t mean the patient is going to live longer, have a better quality of life, or experience less toxicity. These are the clinically relevant end-points.
Approximately 10-14% of investigational new drugs do not receive licensing approval. What are your thoughts on this, and why do you think so many drug development programmes are failing?
Particularly in the complex field of oncology, this attrition rate is certainly nothing new. One of the main reasons is that as the drugs go through the development process, they first start off with very selected patients in the first trial, the ‘perfect’ sample to demonstrate a response rate. In the second, phase 2, trial, the sample size and population will be enlarged a bit, and response rate might be a bit lower. Then at the phase 3, when the population sample is widened again, the response rate is lost. The jump from small trials to real life trials are too large, and it is happening too fast with too many risks. Biology is much more complex than this. In fact, more drugs should be stopped from getting through the development process, and we should be more ambitious for the patients from the beginning. There are too many ‘me too’ drugs with no public health benefit. We should have a stronger focus on early clinical research. The problem is that we don’t know how to fully optimise the drugs we already have – there is probably maybe even enough drugs out there already to double cancer patient’s survival rate but with so many drugs coming on the market we are killing true innovation. We should be utilising drugs and combinations of drugs to their best potential effect based on the understanding of biology. So many questions remain surrounding our current drugs regarding their optimal duration of use, side effects, and toxicity. Everyone is searching for these ‘breakthrough drugs’ that happen very rarely, while we could be using what we already have to a much better degree.
Some changes to the drug development system might be needed, for example adaptive clinical trials. Similarly, real world data and real world evidence have been gaining more attention recently. What do you think the future holds?
What often occurs is that real world evidence is thought of separately from clinical trials, while this should not be the case. Real world data should be seen as a tool or resource, to use incorporated within the methodology, which is robust clinical trials. Of course, everyone likes big data, but what really needs to be asked is ‘what is it?’, ‘what is it for?’, and ‘what questions or hypotheses should be answered by it?’. Real world data can be seen in three scenarios – 1) for diagnostics, 2) for monitoring and 3) for treatment decisions. In diagnostics, there is a role for AI, machine learning, and big data for example in imaging, but for treatment decisions we need something different. Using a tsunami of data will not provide much here – what will most likely come out will just be the habits of the prescribers. There needs to be a concise hypothesis, we need to know beforehand what the questions are. Indeed, we need research on how to research with big data and how to use it. We can probably learn a lot from real world data – but it needs research and understanding and adapting current methods. Real world evidence can produce robust, reproducible methodology and evidence, but we haven’t seen this yet in oncology.
Pragmatic trials are those that are performed in populations that are as representative as possible of the general public and which ask clinically relevant questions such as duration of treatment, survival, or quality of life. They are characterised by relaxed eligibility and could be conducted and randomised within the healthcare system. Adaptive clinical trials are ones in which the trial is refined as you learn, adapting more to what is seen while still maintaining the robust methodology, and should evolve like this in the real world setting.
What could the EU institutions potentially do to improve drug development?
What the EU could do to help would be to provide a place where data and science can be discussed, where drugs post-marketing can be assessed, and where innovation can be stimulated. I am not worried about drugs failing to progress through to licenced approval – stop as many drugs as needed – but those that we do have, let’s assess them independently, and build key treatments that will be clinically meaningful to society. When immunotherapy came into the healthcare system, it was not questioned for how long the treatment should last, and this wastes incredible amounts of money. If a treatment could be shortened, this would save not only money but also patient side effects and potential toxicity. If there were an EU independent body to assess these situations, we would have the answers. We need a mandate in which, for example, pragmatic clinical trials with simply one inclusion criteria (i.e. a participant has to simply have the disease in question) take place, where all participants are randomised on treatment either for one year or indefinitely, and then a conclusion can be given back to everybody. We are not ambitious enough at the beginning of drug development, resources are being spoilt and things are not being addressed correctly. Billions are spent on immuno-oncology treatment and it has still not been answered how long should the optimal treatment last. Simply, EORTC has issued a manifesto in partnership with the EU Parliament STOA to claim that such mechanism should exist to ensure that key public health questions are identified, and the money is put on the table to answer them, and this would in fact save a lot of money, through the performance of patient centered development and access programs. Our systems do remain drug centered.