2018 – A Year of Important Change ?

As we prepare to step out into 2018 it is time to reflect on the past year and consider what the New Year might bring.

For me the highlight of 2017 which summed up so much was the statement by Dr Janet Woodcock, the FDA’s Director of the Center for Drug Evaluation and Research that the clinical trials system is “broken”. She said this to an academic conference on ‘real world evidence’ in September. She also looked ahead and said that clinical research networks and ‘master protocols’ must be the shape of the coming future. She noted that there has been “very little historical use of real world experience in drug regulatory decisions about effectiveness.”

She is not alone in voicing the comment ‘broken’ about cancer research. The rare cancer community has been saying it for some years and to their credit the regulators have been listening. The recent approval of oloratumab for advanced sarcoma was very welcome. It came on evidence from a randomised Phase 2 study but it is a 2-year interim approval while a Phase 3 RCT is concluded. ‘Real world evidence’ (RWE) will also be gathered.

The challenge of the RWE agenda is gathering data prospectively, facing down the long-standing belief it can only be retrospectively gathered. Those same beliefs support the double-blind randomised controlled trial (RCT) with an endpoint of Overall Survival (OS), as the ‘gold standard’ in cancer research. However, the ways through which we gather evidence are changing. The biggest change is that targeted therapies are having their targets proven in pre-clinical studies using cell-lines and in Phase 1 dose/safety studies. What goes into Phase 2/3 is a drug with confidence that there will be a high level of targeted responses. This can make selection crucial and randomisation ethically difficult. It has meant studies with cross-over from placebo, randomisation between different doses or methods of delivery, and choice of questionably appropriate comparator arm treatments. Because time is needed to reach the OS median and because successive lines of different treatment may be given to patients, so-called surrogate endpoints such as PFS (Progression Free Survival) are used. All these patches on the traditional RCT are making proper analysis and effective regulation difficult. It has already been shown that many approved cancer drugs drop out of standard therapeutic use very quickly because the promise of the study is not realised in the real world.

There is growing agreement that ‘real world evidence’ is an issue which must be addressed and this will mean new methodologies. That is probably the single most pressing agenda in cancer research. We have moved to the point where traditional trials cannot give us the evidence of value which we need without good RWE data to support it. In rarer cancers getting all the evidence in a timely way is also important. We cannot define the value of a treatment without RWE and we are in increasing danger of reaching the point where drug costs will be politically and socially unsustainable unless we can prove value. A research project at Oxford University has demonstrated that arguments about the ‘price of a life’ etc cut little ice with the general public so politicians may find they are on strong ground for limiting access to high cost drugs for cancer.

One of the best sources of RWE data is ‘quality of life’ studies. This is the patient-centred focus on a new treatment which complements the clinical/medical data. There are proven methodologies which give good data. Too often the QoL data gathered in a research study of a new treatment is not analysed or published. It seems to be used if it supports conclusions the researchers want to see and gets hidden away if it doesn’t. This must change. But the QoL tools we have are each unique, their data cannot be compared easily and cannot be aggregated to provide a bigger picture. This must change too. There is work to do.

So what about Dr Janet Woodcock’s comments about networks and master protocols. Formalised networks maximise patient numbers when study inclusion has to be selective, as with targeted therapies. Networks are also the best way of gaining experience in using statistical tools such as Bayesian probability and in developing the skills of investigators in new approaches to clinical research. In rare cancers networks already exist – SARC in the USA, EORTC in Europe for example – but in the more common cancers they are less formalised internationally although in the UK we have the structures of NCRI and NIHR. Master protocols are protocols which cover a range of studies eg one drug in several diseases or targeted indications, or one disease/indication with several drugs. Such protocols are increasingly being employed. Academic networks are also building protocols which allow multiple drugs with variation in the sequence these can be taken following relapse. Such studies need the independence of academic investigators plus the provision of drugs by pharma. They can take time to negotiate but their value in eliminating poor performers is huge.

In non-drug studies the blinded RCT will still dominate the evidence base for clinical decision-making. It is the surest way of reducing, even eliminating, bias although as statistical techniques and practice evolves we will find probability statistics playing a greater part. However if we grow reliance on QoL to inform the definition of value and influence regulatory practice with new drugs we can expect the same standards to apply to non-drug studies. A growth in QoL will create massive volumes of data so I would predict that this is the next background step necessary, a ‘big data’ project bringing together QoL data from across the research spectrum, providing analyses which can inform change in clinical practice and which will give patients better quality information.

We seem to be on the cusp of important change in clinical cancer research. What Dr Janet Woodcock will say in September 2018 may not be massively different from 2017 but I hope she will be identifying the beginnings of change which brings new methodologies in clinical research, together with robust QoL tools which provide reliable (and comparable) data on real world experience, and which can all be brought together to allow us to define value in a practical way which society can accept and pay for.


We Are Stronger in Partnership

This theme is often the sub-text behind a conference combining patients and clinicians on the same agenda, but these are usually patient-led conferences and the theme rarely makes its way into professional events. When it happens it is done very cautiously, patient contributors are usually sought at the last minute, and even though the audience feedback is almost always appreciative the repeat event does not do it any better.

Out with the old and in with the new, that was the approach taken by the Rarer Cancers Europe project when developing a training course for both patients and professionals with ESMO and ESO. It was held in early December in Milan and it was a great success.

An initial plenary session on the Saturday included talks from professionals (Jean-Yves Blay, Paolo Casali, Paolo Dei Tos, Rolf Stahel) and patients (Kathy Oliver from IBTA and Francesco Di Lorenzo of ECPC). Questions came almost equally from patients and professionals in the audience.

Separate professional and patient sessions started after lunch on the Saturday. The patient programme focussed on Advocacy Issues in Rarer Cancers. The Saturday and Sunday sessions covered clinical issues – diagnosis, surgery, oncology and research. Individual clinicians and scientists came from the professional event to talk for 20-30 minutes on a defined topic and to answer questions. These sessions were lively with lots of issues and new ideas put forward by the speakers, and plenty of challenges from the advocate audience to keep them on topic and on their toes.

Meantime the professional session looked at some specific tumour types. Patients from the advocacy group attended sessions of personal interest, often raising questions which some of the professionals attending would have liked to ask but because they did not want to look ill-informed in front of their peers were too nervous to do so.

The advocacy research session was particularly lively when Dr Paolo Bruzzi (a statistician) and Dr Paolo Casali (medical oncologist) came together to talk about probability statistics in a joint session. At one point they put forward a hypothetical trial of intercessory prayer, examined how probability would affect its results, and how it would compare with a study of a more usual medical therapy. The subject of combination therapy was raised, which caught both scientific speakers unprepared. A humorous moment. It was followed by a stimulating talk from Eric Low OBE, a very experienced advocate, looking at the social, cultural, political and medical pressures to change research models and rely more on real world evidence.

The final session on Monday looked at advocacy issues, drawing on the long experience as an advocate which some members of the group had. The presentations included case studies of activities successfully undertaken by patient advocacy groups. These were listened to carefully by a couple of senior clinicians, sitting quietly at the back.

A closing short plenary summarised the weekend. These was agreement that it was a great success. Dr Casali, who led the event, deserves congratulations. The combined audience recognised the value of a parallel conference for clinical specialists and patient advocates which sets out to make maximum use of the skills and experiences of each group for the benefit of the other group. Both the planned and the unplanned interchange of audience members according to personal choice was truly valuable.

I look forward to seeing similar structures evolve in professional events everywhere. Let conference companies take note.


Time for Change

In early November I attended the NCRI Conference in Liverpool. I was offered a bursary by NCRI to cover my expenses and as I was speaking in a session on Quality of Life my delegate fee was waived.

It was an event which I enjoyed, as I have every other NCRI Conference since it started in 2005, although I missed a couple because I was having treatment at the time. It is a valuable way of maintaining contact with people across the spectrum of cancer research, scientists, clinicians and patients. Of course that social element is not the main reason for having the event, which includes a large amount of exhibition space. What is noticeable is that large pharma companies do not exhibit and that clinicians are few in number, those attending being ones with a significant research responsibility. Laboratory science dominates and NCRI has little to do with laboratory science. The main conference sessions are a bit formulaic – three ‘levels’ of plenary, symposium and parallel session, the latter with three or four speakers and the content mostly fixed months beforehand – leaving little opportunity to reflect ‘breaking’ news.

The ambition for joining everyone up, which Professor Sir Alex Markham expressed in 2005 (he was then NCRI Chair), has withered and it is a very one-sided event with token recognition of what NCRI actually does. The structures also fail to recognise that NCRI is not the NCRI of fifteen years ago. It is now an independent charity with its charity funder/members working together to develop cancer research at a policy and strategic level, not to fund it, educate its staff or evaluate the science.

One of the stresses is that the NCRI Conference is underwritten by Cancer Research UK, and all credit to them for carrying the venture forward. It is intriguing that as Cancer Research UK has started to bring its weight to bear on policy and strategic issues, very effectively, it has failed to ensure that these issues are represented properly in the NCRI Conference. They are trapped by the rigidity of programming structures which cannot respond to current events. CRUK, also to its credit, is a significant funder of NCRI.

It is becoming clear that things have changed and the Conference is overdue for a re-launch in new colours. It does not reflect NCRI’s activities or the needs of NCRI itself that could be met through having a proper national event to consider policy and its implementation, new initiatives (such as the current Survivorship partnership) and the steps being taken by member charities which could be better if joined up. Change is never easy, or comfortable, but it is needed. Clearly there will be funding issues and a re-launch would need to be carefully positioned.

A critical part of that positioning is the relationship with pharma. While the industry self-regulatory system fails to recognise that patients have a valued role to play in the design and development of research, pharma cannot fully participate in the way that it should. One of NCRI’s core principles is the involvement of ‘consumers’ – patients and carers. It is easy for NCRI to ensure that patients attending its conference are ‘accredited’ research representatives, whether they work with NCRI or with charities such as Cancer Research UK. The failure to recognise this by the pharmaceutical industry is an indictment of its shambolic, legalistic and patronising approach to patient involvement. Until that changes pharma attempts at patient involvement in research can only be tokenistic and trivial.

So there is much that needs change and as patients we can point it out and pressurise for it.

Roger Wilson is a member of the NCRI Consumer Forum and its longest serving consumer/patient. He was an NCRI Board Member 2004-2007 and closely involved with the first three NCRI Conferences. He is also a Member of Cancer Research UK.