If you have read this blog regularly you will know that I am not entirely comfortable with what is going on in cancer clinical research at the moment. I can appreciate innovation and recognise that scientific developments which may benefit patients need to be tested in clinical trials. However, stresses are showing.
When I started learning about cancer research, things were fairly simple. That wonderful teacher Derek Stewart defined patient involvement as learning to balance benefits and burdens. We needed to listen, question, challenge when appropriate, and when we had experience or information which was relevant, to make our voice heard, politely. These are fine principles and experienced patient advocates everywhere recognise them.
Targeted drug therapies have been challenging established models of research. The pinnacle of a drug’s journey to market used to be a Phase 3 Randomised Controlled Trial (RCT). Regulatory approval followed trial success and started the process of getting a new treatment into standard clinical practice. When involved with RCTs the concept of equipoise was an important one for us to understand; learning about endpoints, outcome measures, inclusion and exclusion criteria, side effects and their management was all do-able provided you were prepared to learn. Then you learned about ethics, you got into discussion about placebos, early stopping rules, systematic reviews – the list grew and grew. There were plenty of people happy to help with all the learning.
When you needed to look at research in a more strategic manner, as happens when you work on a programme of research or developing clinical guidance, you find that there are new issues. Questions can be harder to define and not always asked or answered in the systematic reviews. You need to ask questions in order to discover the real questions you need to ask. You find the professionals take certain knowledge for granted and may not see why it should be questioned.
So what is it which worries me about clinical cancer research today?
Results from Phase 2 studies now unlock registration leading to NICE opening up interim approval and funding for NHS use. The Cancer Drugs Fund (CDF), soon to be extended as an Innovative Medicines Fund, enables drugs which have not been tested in an RCT to be evaluated within standard clinical practice. Evidence on that experience can open up full regulatory approval. This journey is replacing the RCT.
Perhaps the most challenging current research is the work on genetically modifying T-cells, the body’s natural immunotherapy. There has been a lot of publicity for the technique, which has benefited a few patients, although the long-term benefits are completely unknown. CAR T-cell, as it is known, is a complex technology, very well explained on the NHS website if you need to know more. It is also very expensive.
The NHS centres conducting the CAR T-cell studies on diffuse large B-cell lymphoma (DLBCL), have been charged by NICE with reporting on their work by March 2021. An initial report was presented at the recent ASH Convention in Florida and the results so far are disappointing. Sadly trials in a lot of targeted drugs and immunotherapies are disappointing.
This is where questioning comes in. This is the pinnacle of personalised medicine. These patients have advanced cancer which is untreatable with standard therapies. An assessment of how long patients survive and what other treatments achieve are questions which need an answer, together with a proper appraisal of quality-of-life. There are further questions about biomarkers which could predict response, predict side effect problems, even perhaps predict a cure. All these are questions which the scientists involved know about and will try to answer without an RCT.
But there are bigger questions. Should these therapies be tested at an earlier stage of disease? Would similar sums spent on maintenance therapies which hold relapse at bay deliver better and more patient-centred care? Never mind value-for-money. Are we being dazzled by our own cleverness?
We have seen that with these new treatments a truly prospective RCT may not be feasible. We need a new rigour in our system which can unlock patient benefit. I believe the answer lies in the NHS itself. We have 150 cancer hospitals using the same data standards for recording cancer clinical performance. We must engage the real world of clinical practice more widely in the research challenge. There are many cancer treatments where research in the real clinical world could add value for both patients and the NHS. We can gather data in a structured manner on every new treatment. Consent for treatment allows your data to be used for research.
This is an environment where we can go further. We could construct prospective studies, without relaxing our research consent practices. We should be looking at the sequencing of new drugs where more than one is available for any condition, accruing patients into the studies from any hospital. We should be looking at studies of combination therapy, new-with-new and new-with-old. We should be looking at the ‘minimum effective dose’ of a drug rather than blindly accepting (as we do) the developer’s recommendation based on ‘maximum tolerated dose’. We could be looking at studies using known effective drugs earlier in the course of disease, or as maintenance therapies when there is no disease present. We could look at new indications for approved drugs. We should build studies like these with patient involvement, questions defined by patients should be answered. Patient Reported Outcomes should be at least co-primary endpoints, we might even get ‘patient preference’ accepted as a standard outcome.
Industry has no real interest in running studies of this kind. Their interest is commercially driven despite high-sounding words about better patient outcomes. Their real world studies that lead to converting interim drug approval into full and funded NHS approval are run in their commercial interest. Their studies receive funding through the Cancer Drugs Fund, guaranteeing the manufacturer an income, but there is no automatic funding for real world NHS research with a patient-led focus. That funding has to be found. As therapies are already funded through CDF or NICE approval treatment would not be a study cost. A study will all be about prospectively gathering and analysing data. The NHS is capable of doing it and is in the NHS’s interest to get such results.
A focus on high technology in cancer research is important but it must not be the primary focus. It is great for creating headlines and makes wonderful TV but we have seen that very few patients benefit and costs are phenomenal. I am not saying we should not do it but I am saying that we are failing to do the other things which the NHS is uniquely capable of delivering. Cancer research is doing a dis-service to everyone, not just to cancer patients, if it does not shout about this challenge.
We need routine research within clinical practice, we need real world evidence, we need it to be driven by patient reported outcomes. Given the growing cost of drugs I believe that every penny invested in such research could be returned in value to the NHS.