NICE- information for you to use- plus direct link to no.10 petition

petitions.number10.gov.uk/CML-NICE

Over the next few days I will try to collate all the relevant points on this page for you to use in your comments to NICE/politicians/media etc.

Simon has compiled some of his comments below and has asked me to share them with you. I have added a few of my own and will try to add more as the week goes on.

Hope this helps those of you who are finding the ACD a challenge (as we all are)

Sandy

Chronic Myeloid Leukaemia – Dasatinib and Nilotinib: Appraisal Consultation Document

1 The evidence for both 2nd generation drugs’ efficacy in dealing with some of the imatinib resistant mutations that are apparent in some patients is well documented both in clinical trials of both drugs and in clinical practice and does not seem to be disputed. Both drugs are recommended by the European Leukaemia Network (ELNet) for use in Imatinib resistant/intolerant Chronic Phase CML if stem cell transplant is not appropriate.

2 The NICE appraisal committee seem to be saying that they cannot use the existing trials data to establish the relative cost and benefit of the new drugs because the data are from open label trials (i.e. the drug is clearly identified) and therefore it follows that the data are flawed because there is a possibility that the clinicians would be biased in favour of one drug over the other. I very much doubt that this would happen in CML clinics in practice.
They would prefer to see double blinded trials i.e. the drug is not identified to the clinician or the patient. However, both patients and clinicians will know. All the drugs in question have differing side effects and also nilotinib has a completely different regime of administration based on fasting 2 hours before and 1 hour after taking the dose. Others are taken with food. Double blind trials are therefore unworkable on that point alone.

3 NICE seem to have ignored the existence of mutational analysis and the clinical consequence for imatinib resistant mutations. The new drugs are designed to treat mutations that the current drug does not treat.

4 Why do they make the comparison with Interferon, when Interferon is of little use to CML patients as it does not stop disease progression for the majority (only 5% show significant cytogenetic responses)?
They note that in clinical practice Interferon alpha is very rarely used now, as very few patients have any cytogenetic responses over time and the side effects are very severe for most and disabling for many.
This is not a life saving option for the majority of CML patients but it is cheaper. However the extra costs of Interferon come in when you consider the side effects i.e. lack of quality of life, lack of ability to continue to work and all those wider social costs to society, and lack of cytogenetic response for majority and therefore low overall progression free survival rates.
Including this drug in a double blind trial with no cross over permitted is effectively condemning a proportion of the participants to almost certain death within few years when it is known that an effective drug is available.

5 Why ignore the clinical data available and instead construct a theoretical model based on several assumptions that cannot be tested?
Whilst each assumption is considered in detail and includes notes that the actual situation could be significantly different, leading to quite different outcomes, the overall outcome produced by the model is not in line with what is observed in practice. For example, there is an assumption of around 7 years progression free survival on Interferon after treatment with imatinib whereas before imatinib was available, life expectancy was only around 3-5 years. This is critically important because it makes the alternative treatments appear more expensive than they actually are.

6 CML is a rare disease. Incidence rate cited in this ACD is 560 cases in the UK each year (Executive Summary pgs 29 and 31) but this figure is questioned by clinicians amongst others. A figure of 800 cases is thought to be a realistic estimate. In the UK under-reporting of CML to the cancer registries has been well documented and incidence rates from other Eu countries seems to confirm this.

7.The numbers of CML patients who show resistance to imatinib is a fairly small proportion of the overall CML population. Again figures vary depending on sources but an estimate of between 20-25% seems realistic. This means that the overall cost of providing dasatinib and nilotinib will not be of great cost to the NHS.
Such low numbers means that any new trial/study will take a long time to produce meaningful data because only small numbers of people will be eligible in any one year. In the meantime, patients will be denied the life saving drugs already used in clinical practice.
In the real world, in real time we know these drugs are effective. CML patients know. Clinicians know.

8. The Secretary of State for Health has guaranteed that funding for cancer research will be ring fenced an will not be subject to cuts. That is good news, but what is the point of funding cancer research if cancer patients cannot access the fruits of such investement and effective therapies are denied on grounds of cost. We are not talking about a drug that might increase lifespan by a couple of months at great cost. These drugs are life saving therapies and will probably allow many years of normal quality of life.

Although 2nd generation TKI's have only been in studies for 4-5 years and long term data is not available to prove this, current best estimates by expert CML clinicians for progressions free overall survival show a likely 15-30years from diagnosis. This means that it is more than likely that the majority of CML patients will live their normal life span and will die from causes other than CML.
Quality of life with TKI therapy is so good that patients can and will continue to be fully contributing members of society.

other links that are helpful are:

From the imatinib IRIS trial in newly diagnosed patients, 15% of patients treated with imatinib over a seven year period withdrew from the study due to unsatisfactory therapeutic effect1, in other terms resistance. This equates to 2.29% of patients becoming resistant to imatinib each year.

1. O’Brien.S. et al. (2008). International randomised study of interferon versus STI571 (IRIS) 7 year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients with newly diagnosed chronic myeloid leukaemia in chronic phase treated with imatinib. Blood, 112: Abstract 186 ASH 2008.

www.nice.org.uk/nicemedia/pdf/RCPhysiciansComments.pdf

http://www.nice.org.uk/nicemedia/pdf/RCPathologistsAssessmentReportComment.pdf

Phil B's comments:

Having worked through the bulk of this, I have to say I'm finding their conclusions very strange indeed. Having rejected the manufacturers' own cost effectiveness analysis they appear to have gone out on a limb with their own analysis and ignored some very unlikely predictions it makes.

They seem to have:

1. predicted their overall survival curve based on MCyR (major cytogenetic response) response rates

2. calculated expected times on treatment from the study data

3. taken standard assumptions on length of AP and BP

4. assumed the balancing number is time in chronic phase without treatment, after the treatment in has question failed.

The results of the exercise are showing time to progression from chronic phase WITHOUT TREATMENT for the HD Imatinib and Nilotinib arms of 7 to 8 years on average.

I can't see how this can possibly make sense given that TOTAL life expectency pre TKIs was only 3 to 5 years from diagnosis.

The conclusion that dasatinib is not cost effective arises ONLY because of the effect of this 'calculated' length of treatment-free chronic phase being so much longer in their HD imatinib / nilotinib models, but the fact the the figure produced makes no sense at all in comparison with empirical data (and thus their model clearly doesn't accurately model reality) hasn't been mentioned.

On top of ignoring all the best scientific data, there are a few more sneaky things they've done.
In particular they have rigged the model so that a very large proportion of patients die of non-cml causes before or not long after they would have succumbed to CML and therefore getting minimal benefit to set against the cost.

They have done this by:
1.assuming all the patients are 60 years old to begin with;

2 exaggerating the survival times without treatment; and

3.modeling survival times on treatment as a smooth distribution tailing off rapidly when what you actually have is distinct populations of non-responders, poor responders and good responders with the bulk of this last group effectively CML-free with normal life expectancy.

If you instead model say a 40 year old with resistance due to a single kinase mutation which we know dasatinb / nilotinib works against then your best estimate of their survival time would be in line with Dr Druker's 30 year estimate for Glivec responders.
The bulk of this would be AFTER the patent expires and therefore on a cheap generic. The cost per year gained is then very favourable indeed.

You could say they have ignored patent expiry and exaggerated patient expiry!

The other big thing missing, as already mentioned below is the whole issue of mutation testing, drug level testing, etc. which in a high proportion of cases lets the doctors target the drugs to where they know they will do most good and greatly improve value for money.