The ‘Innovation in Urology’ day
The ‘Innovation in Urology’ day organised by Tom McNicholas and Rik Bryan and sponsored by The Urology Foundation (TUF) on Friday 26 February 2016 was aimed at illustrating current innovations, exploring the process for generating ideas, their implementation and development by industry or funding bodies and how those championing new developments should interact with the regulatory process, especially NICE.
In the drug session Rob Jones, Professor of Clinical Cancer Research, Glasgow, reviewed existing targeted therapies in urological malignancies with an update on the new immune checkpoint inhibitors (view Professor Jones’ video highlights). Traditional cytotoxic therapy has never really been successful for renal cell cancer, but mTOR inhibitor therapy for non-clear cell renal cancers and the VEGF inhibitors for the majority of clear cell cancers are increasingly important.
Although there are no current targeted treatments for prostate cancer, there is currently a trial of PARP inhibition. Bladder cancer chemotherapy remains a better option than any targeted therapy. Treatment for testicular cancer has been so successful that targeted therapies would only have a place if shown to be cheaper or if they led to fewer side-effects.
All cancer cells are infiltrated by CD8T killer cells, but the malignant cell alters either receptors or their ligands (PD-1 and PDL-1) to protect those cells against the immune system, whereas the immune checkpoint inhibitors switch the immune system back on and allow the CD8T killer cells to become effective again. Cost is an issue, e.g. sipuleucel-T (Provenge) shows a clear immunological benefit but is too expensive in most of the western world, impossible in poor countries and even too expensive for the US healthcare system. Overall, immune therapies appear to make cancer a chronic condition, if not always curable.
Introducing new drugs is phenomenally expensive (between $2.6 billion and $11 billion), partly due to the complex clinical trials required. Matt Sydes, Senior Scientist and Senior Medical Statistician at the MRC clinical trials unit at UCL explored the realities of trial set-up and management, and opportunities for making the whole trial process efficient and cheaper, e.g. by applying resources to accurate and complete data capture – 10% loss of data per year may add three years to the cost of a trial. Targeted monitoring of trial sites should also reduce costs.
The ‘multi-arm multi-stage’ (MAMS) trial method is best illustrated by the STAMPEDE trial. Interim analysis of failure-free survival results was a reasonable indicator of the more important but long-term overall survival figures. Analysis of the earlier data allowed closure of non-efficient arms and opening or addition of new arms as new therapeutic options became available. The subjects in the study could be distributed between arms. There are risks in this new approach and the possibility of an ‘early’ review missing a worthwhile later effect was acknowledged.
Chas Bountra, Professor of Translational Medicine and Chief Scientist in the Structural Genomics Consortium at Oxford University, captivated the audience with a stunning slideless presentation, reviewing the difficulties, inherent restrictions and perverse incentives of the current system of drug discovery and how that vital process could be improved and made less expensive to allow more rapid development of treatments (view Professor Bountra’s video highlights). Only half of drugs currently provide clinically meaningful benefit. New drug development costs range from $2.68 billion (TUF) to $11 billion (Forbes magazine). Many drugs are only ‘me toos’! Overall only 7% of cancer drugs and only a third in phase 3 trials reach market. Professor Bountra’s philosophy was to pool resources to reduce risk; to only work on completely novel proteins (including those seen by others as ‘impossible to use’); to develop new target molecules to give away ‘free’ to collaborators in an attempt to reduce the wasteful duplication of effort currently occurring; and to improve the delivery of novel, effective, affordable and hopefully more rapidly available therapeutic molecules.
Exploring genomics and diagnostics, Kathie Wong from Guy’s and St Thomas’ proposed a personalised approach to the management of cystinuria by the use of genetic profiling, and Maggie Knowles, Head of the Section of Experimental Oncology at the University of Leeds, presented an overview of the molecular genetics of urological malignancies. Using bladder cancer as her main example, Professor Knowles pointed out the immense heterogeneity of genetic processes in transitional cell cancer, discussing developments and pointing out that molecular subtyping is increasingly available, getting cheaper and should allow the identification of patient groups that were either more or less likely to respond to existing chemotherapy or future drug developments. There is the potential for localised delivery of treatments targeting particular genetic or epigenetic processes directly into tumours.
Marc Tischkowitz, Reader in Medical Genetics at Cambridge, reviewed the importance of ‘clinical genomics’ in current cancer treatment (especially breast, ovary, colonic and renal cancers), but also the developing areas, e.g. in male prostate cancer and the relevance of the BRCA1 and BRCA2 genes. As testing becomes cheaper, diagnostic genetic testing will increasingly devolve to practising clinicians. He suggested that cancers in patients under 50 were more likely to have a genetic or hereditary element and that certain religious or racial groups were more likely to have certain genetic predispositions (Ashkenazi Jews and BRCA). Practical illustrations of the value of the regional genetics lab were discussed, particularly Lynch syndrome and the BRCA genes and prostate cancer. VHL was proposed as a success story. Though sceptical about commercial gene tests, he thought an NHS panel in development might be more relevant.
In the afternoon session, a proven innovator and two senior medics in the NICE regulation process discussed the challenges and best practice for device development, approval and implementation. Josh Makower, Professor of Entrepreneurial Medicine at Stanford University, co-founder of Stanford’s Biodesign Innovation Programme and the founder of multiple medical technology device companies, illustrated that the process of medical innovation could be taught and outlined ways to maximise the chances of successful development. Biodesign by Zenios, Makower and Yock is recommended reading.
Josh Makower and Jonathan Watkins, Senior IP and Licensing Manager at the University of Birmingham, agreed that ‘people are critical – it is a team process’. British innovators need to protect their own ‘intellectual property’ (IP). Go and see your IP person if you have a novel idea!
Tom Clutton-Brock, practising Anaesthetist and Chairman of the NICE Interventional Procedures Advisory Committee gave possibly the first ever interesting and amusing review of regulatory processes! There are 29 000 device companies in Europe compared to just 29 pharma companies. Generally small device companies face a challenge getting through the regulatory process with enormous costs, wastage of effort and likelihood of failure. Device spending in the NHS is going up (75% of the drug spend) as we age and bits need replacing. Investigations of device failures suggested that one third had been used improperly, one third were true device failures and one third were indeterminate failures.
Peter Groves, a Cardiologist and Chairman of the NICE Medical Technologies Advisory Committee (MTAC), reviewed the MTAC and the MTEP (medical technology and evaluation programme) process. MTA guidance has to be taken up by the NHS within three months, but there is no such requirement for the MTEP guidance. Both NICE speakers were committed to improving the uptake of beneficial new technologies by streamlining a transparent regulatory process with appropriate coding and reimbursement. The delay in incorporating NICE assessments into NICE guidelines reduced NHS patients’ access to effective new treatments.
Rounding up the day with a look to the next 5 and 10 years, Mark Speakman, President of BAUS, gave his view on ‘the urologist of the future’ over the next 5 years. Outlining known challenges to our practice and those in the near future, he asked what trainees wanted from BAUS and the RCS – if anything. Tim O’Brien from Guy’s gave a speculative presentation on the next 10 years and explored a remarkable range of possibilities, many involving a smart phone and a range of ‘wearable technologies’. Tim’s futurology made him sound increasingly like Britain’s own Erik Topol.
Tom McNicholas concluded: most treatment advances made small improvements. For localised solid cancers, surgery was still the most likely curative treatment but new therapies could make cancer a chronic disease. Diagnostics and genetic developments had been reviewed and the role of clinical genomics outlined. New devices should be developed in a more efficient streamlined and essentially ‘teachable’ way. The UK NHS is close to having the best system of encouraging new developments, but with some remaining reimbursement glitches, although at least the audience now knew what to do if they had a good idea. (View Professor McNicholas’ video highlights.)
The next RSM urological day is on cancer and will be held on Friday 22 April 2016. Click here for further details and to register or contact firstname.lastname@example.org to register or to enquire about reduced rates for trainees.
For a fuller account of the day go to http://www.tommcnicholasurology.com/Blog/index.php
Tom McNicholas, President Section of Urology RSM