Personalised medicine and accelerated access

Once upon a time a new cancer drug achieved marketing authorisation after randomised controlled trials demonstrated effectiveness treating carefully calculated numbers of patients with a given disease or condition. The critical patient outcome for the trials was a comparison between the experimental and control arms using a measure of patient survival which gave a high degree of statistical significance. It was also important that safety was demonstrated and that side effects were tolerable and manageable.

We are entering an era where a drug with a specific mode of action for a specific genetic alteration can achieve marketing authorisation in an accelerated process after small clinical studies, offering no comparative data, using endpoints where patient benefit is unclear, and without long term measurement of issues such as survival or side effects. 

We made this transition, seemingly without open debate amongst stakeholders. The move is justified by the term “personalised medicine”, which in its fullest sense would include radiotherapy and surgery but is usually focussed exclusively on drugs. It has been carried along by enthusiasm and hype and it requires genetic testing, the demand for which is driving costs down. Technology is proving disruptive.

But patients have lost something in this transition. The science behind repeating studies, using control arms, good statistical practice, endpoints with real meaning etc has been built-up over years. It is robust good practice and provides a very high level of certainty that authorised drugs deliver patient benefit safely. Based on the data at registration these new drugs promise hope for a few but uncertain patient benefit overall.

It is important to acknowledge that when a treatment has a high probability of treating a disease effectively then practice needs to change so that relevant patients can be treated without delay.  We are now recognising that in doing so we lose important evidence which is very relevant to patients and society, even if it is less important to pharmaceutical companies.

What about dose determination, treatment sequencing, duration of treatment, combination therapies, toxicity management, quality of life, patient compliance? They all get forgotten in the rush to get the treatment into routine practice where we are reassured that any problems which arise will be handled by doctors. Perhaps, but their experience is not shared and collectively analysed as it would be in a study. Evidence based medicine it is not. Nor is it truly personalised medicine, it is simply drug-centred medicine.

However, patients want it. They want the tests and if they are eligible they want the treatment.

Some patients will be denied by cost. These drugs are expensive. Larotrectinib, approved by the FDA for a rare mutation in a wide range of cancers based on data from 55 patients, is estimated to cost over $330,000 a year – assuming anyone lives for a year. Compassionate and discounted programmes are available but no major HTA body has yet got into discussion with the drug company. There will soon be tales of patients selling homes and using crowd-funding to raise the money for drugs like this.

We must move fast to apply scientific process and rigour to personalised medicine. It is not about denying treatment to anyone. Drug companies must not determine what happens, much as they might wish to. At present they are succeeding. We must change the balance. Put patient interests at the centre of drug regulation, not pharma interests.

So what are our interests? Safety (the minimum effective dose), side effects (nature, treatment, duration), duration of response to treatment (combination therapy, therapy sequencing), longevity (real life outcomes), quality of life (in all its dimensions), holistic issues of care, cost.

Establishing this kind of treatment optimisation is a theme supported by European research organisations, professional associations, patient groups and by a considerable body of influential MEPs. The move calls for protocols to guide treatment and for data to be gathered centrally for all treatments which use an accelerated approval process. By gathering data prospectively according to a protocol we can avoid bias and a picture can emerge dynamically as a treatment gathers numbers of patients. Quite separately the FDA has suggested a form of ‘synthetic’ control group based on historical data to empower comparison. 

This might result in treatments which are not effective, and we might see treatments which patients dislike, using patient reported outcomes. These treatments could be withdrawn, that would be an innovation. This kind of treatment optimisation approach importantly provides a framework for testing lower dose levels than were used in the trials for drug registration. This is not a favoured idea of drug companies either.

Support Treatment Optimisation, it is in our interests as patients.

Sarcoma diagnosis – a new challenge emerges  

Conversations at the recent British Sarcoma Group conference in London (an excellent event) brought up a growing problem with a recent change in the guidance for GPs considering potential cancer symptoms. The idea is that when a GP has suspicions about a soft-tissue lump he can order a direct ultra-sound scan.  When I questioned the chair of the NICE Guideline Group during its development I was assured they had considered all outcomes and my concerns were dismissed. As far as I am aware no specific sarcoma expertise was consulted during the development process.

The question which needs answering is whether the new approach is working for the benefit of patients and/or the NHS.

Prior to the change three years ago a GP was advised to make a 2-week referral to a specialist centre if certain clinical symptoms existed.  More patients were actually being diagnosed from non-urgent secondary care referrals or other routes than from the 2-week system. Hence the change, which made direct access to x-rays (for suspected bone sarcomas) and ultra-sound (for soft-tissue tumours) available to GPs so they can diagnose non-malignant tumours or determine uncertainty which requires expertise.

The problems arise because sarcomas are rare, diverse in their histology and can appear in any location on the body – in fact ‘typical’ is not an adjective applicable to sarcoma. The ratio of benign soft tissue tumours to malignant sarcomas is over 100:1. The rarity means ultra-sound imaging technicians have little familiarity with sarcoma although for bone tumours X-rays can be definitive.

We are finding that ultra-sound imaging reports will err on the safe side. Some tumours are clearly benign but if they have any doubt they are likely to say that they cannot be certain.  So what do GPs do with this uncertainty?  Their uncertainty boundary has shifted so they make a 2-week referral to a specialist centre, even for a tumour which under the old guidance would have been recognised as benign.

Thus specialist sarcoma centres are being overwhelmed by urgent referrals for ‘uncertain’ tumours. Diagnostic expertise is now being exercised by nurses operating triage clinics. This allows their consultant colleagues to spend longer with the fewer potentially malignant cases who come through the triage.  The people with sarcoma who would benefit from urgent attention are being hidden in a cloud of benign conditions until a late moment in the process. GPs are allowed to opt out of responsibility for diagnosing the benign condition, hiding behind the ‘uncertain’ ultra-sound. Those with benign conditions suffer a journey to a regional specialist cancer centre only to be told by a nurse that their highly qualified GP must re-consider their case.

Patients are not being respected. The problem is not the principle of the new guidance, but the implementation which has shifted the workload inappropriately. Those picking up the pieces are the specialist centres overloaded with diagnostic work. The new guidance was intended to help them and it is doubtful whether this is leading to earlier diagnosis of malignant tumours either.  The whole approach needs review in the light of the experience the sarcoma centres are reporting and any review must be in collaboration with them, rather than imposed by a committee led from primary care.