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There is to be a review of bosutinib by the Cancer Drugs Fund

We were notified a few days ago of yet another review at the end of July of many of the drugs in the Cancer Drugs Fund (CDF).

Some people may recall the re-evaluation exercise at the end of last year that resulted in dasatinib and bosutinib being delisted for the treatment of blast phase CML. This time all four of the remaining CDF bosutinib patient populations are affected: They are:

(i) Chronic phase patients exhibiting resistance to nilotinib or dasatinib

(ii) Chronic phase patients unable to tolerate both dasatinib and nilotinib

(iii) Accelerated phase patients unable to tolerate dasatinib and nilotinib

(iv) Accelerated phase patients exhibiting resistance to nilotinib or dasatinib.

It is very important to stress that patients currently being treated with bosutinib, as a result of their clinicians making successful applications to the Fund, will not be affected and will continue to receive treatment with bosutinib until this is not considered an appropriate treatment option by their clinician and themselves. Secondly, as the CDF is only operative in England, this does not affect patients in Scotland, Wales and Northern Ireland.

CMLSg find this development deeply disturbing if the decision to review bosutinib has been taken on clinical or cost grounds, since it is only six months ago that the last review resulted in the following: ‘.....an overall score which was sufficient for a decision by the CDF panel to allow retention of the use of bosutinib treatment in CP CML for patients who were resistant to nilotinib/dasatinib. This decision also applied to patients with CP CML intolerant of nilotinib/dasatinib as set in the current CDF approval form.

’ http://www.england.nhs.uk/wp-content/uploads/2015/01/ncdf-summ-bosutnb-c... ‘ .... an overall score which was sufficient for a decision by the CDF panel to allow retention of the use of bosutinib treatment in AP CML for patients who were resistant to nilotinib/dasatinib. This decision also applied to patients with AP CML intolerant of nilotinib/dasatinib as set in the current CDF approval form.

’ http://www.england.nhs.uk/wp-content/uploads/2015/01/ncdf-summ-bosutnb-a...

The obvious conclusion people arrive at is that something must have happened over the last six months that raises large enough questions about the clinical or cost effectiveness of bosutinib to prompt this review. The puzzle is that there is no significant new clinical trial evidence available and the publicly available cost remains the same. We also know that evidence from patients being routinely treated with bosutinib in the NHS, what is called ‘real world’ evidence, will not be considered in the review because this data is not of sufficient quality and quantity for it to be considered. Over two thirds of the drugs in the CDF will be reviewed in July and many of these were also reviewed last year, so bosutinib is not alone in facing this challenge.

However what is different about the three of the five drugs for CML treatment that are funded via the CDF is that they are capable of securing a near natural life expectancy for patients who respond well to treatment. This contrasts markedly with most of the other drugs in the CDF where increases in survival are in no way comparable to those seen in CML.

One problem for CML drugs is their very success pushes up the ‘median drug cost per patient’ compared to other drugs in the CDF. This figure represents the total average cost for a patient’s treatment over the time treated. The average age at diagnosis for CML is around 55, so successful treatment can amount to 25 years or more of drug treatment which obviously results in a very high cost figure compared to a few months treatment with other CDF drugs for other diseases. We don’t know the impact this factor has because the calculations involved remain confidential. However it seems a perverse, unintended consequence of the cost analysis mechanism is that it penalises drugs that can secure long term clinical benefit. This would seem to contradict an overarching strategic objective of the NHS, which is to secure long term benefits for patients.

We have argued for a number of years that the underlying problem is that the evaluation processes, that result in a decision to recommend a drug for routine use in the NHS, are dated and no longer fit for purpose. This is because the drug development process is producing more and more drugs, like TKIs, that are designed for small patient populations. This in turn makes it very difficult to carry out the kind of clinical trials that were common during the last century, when the aim was to develop 'blockbuster' drugs for very large patient populations. The evaluation processes that were appropriate for these drugs are clearly not so for these new drugs.

This is one reason for their being a CDF which was always viewed as a temporary arrangement (or ‘bridge’ as it known) which would be replaced by a re-designed evaluation process. Despite five years of promises this remains an ambition rather than a reality.

Drugs for CML, and the means used to monitor their effectiveness, represent the cutting edge of 21st century pharmaceutical innovation and have spectacularly increased life expectancy for the overwhelming majority of the patient population over the last 15 years, making CML a chronic rather than a life threatening disease with a poor outcome. Each successor generation of TKIs has gradually reduced the number of patients unable to gain an effective response to ever smaller numbers, with the numbers of patients potentially needing treatment with bosutinib and ponatinib being very small indeed. This is a fact that the CDF panel seem to accept, but are somehow unable to grasp its significance. By that, we mean we had hoped that NHS England would recognise the vanguard role these targeted therapies represent and that this is the future for other types of cancer where a patient population is divided into sub-groups, often but not always defined by the presence of a mutation, which a particular drug targets.

A decision to withdraw access to bosutinib via the CDF, (and possibly to reject an application for the more extended use of ponatinib other than for patients with the T315i mutation) seems ‘Canute like’ and contradicts broader policy, which is to accelerate access to life saving drugs. It is to be hoped that engagement between Pfizer, the manufacturer of bosutinib, and NHS England will result in some sense being restored with bosutinib remaining accessible via the CDF.

For our part we intend to seek permission to submit a statement to the review panel and apply to attend the review hearing at the end of July. We will of course update this post as and when we have any additional information.

I sincerely hope you are able to put forward the arguments you have listed here. I for one am grateful for Bosutinib as it was the last option available to me having failed Glivec, Dasatinib, Nilotinib and Ponatinib and i was faced with the real possibility of a transplant. Bosutinib has certainly put off that scenario and hopefully it will stay that way for many years to come but, as you say, it is the success of these drugs in keeping us alive that could ultimately mean we are unable to access them. I would say it is ironic but that really doesn't cover it. Anything i can do to help please let me know. Best wishes. Karen

I said I would report back to our members on the NHS England meeting, held on the 7th September and on any subsequent activity taken by the coalitions of the patient organisations CML Support Group are members of. The delay in my doing this is because it was widely expected that NHS England would publish details of the consultation on the ‘successor model’ to the Cancer Drugs Fund (CDF) the week following the NHS England meeting, and when that did not occur, the week after that.

The other reason for my delay was that I had hoped to have some news from Pfizer, the manufacturer of bosutinib, about whether they planned to appeal the decision to remove bosutinib from the CDF list (the 20 day window to do so expired at the end of last week) or take advantage of other opportunities on offer to manufacturers in this situation.

Pfizer have responded to my inquiry with what I would describe as a ‘holding position’ saying:

 "Pfizer is committed to ensuring that cancer patients can gain access to its medicines, and to this end we will continue to work with the CDF, NHS England and Government to help find a long-term solution to the fundamental challenges that exist in assessing more specialist medicines.”

Assuming the company has not appealed the decision (which is understandable given the very limited grounds for appeal) they have until 4th November to conclude a successful negotiation with NHS England to prevent bosutinib being removed from the national CDF list. This would almost certainly pivot around a negotiation on price and the level of discount necessary to remain on the list. As the Pfizer statement quoted above mentions, the real issue is to develop and implement a new assessment methodology and process for drugs like bosutinib.

These drugs, which in the case of CML are the tyrosine kinase inhibitors (TKIs) -although there are other equally sophisticated classes of drugs for other cancers tend to be for small patient populations with diseases that exhibit a particular target, against which the drug is active. This makes them expensive on a cost per patient basis, but more discriminating in usage because of their limited suitability.

The Government, NHS and other relevant public bodies, including NICE, accept this is the credible future for pharmaceutical interventions for cancer, but they have consistently failed to develop and agree a methodology and process for their assessment.

In that context, the CDF was supposed to be a stop gap measure (expiring in 2014) until a new long term solution was developed to assess drugs like bosutinib and other second and third generation TKIs.

Over the last five years the abandonment of two proposals - ‘Value Based Pricing’ and its successor ‘Value Based Assessment’- that were supposed to usher in a new era for the evaluation of drugs like bosutinib speaks volumes about the inability and/or unwillingness of Government to act decisively.

The delay in publishing the consultation on a successor mechanism to the CDF indicates perhaps that we are about to witness more of the same.

As for the coalitions CML Support are members of, their handling of this issue could hardly be described as their finest hour.

As a consequence, a group of blood cancer patient organizations are meeting later this month to establish common ground and explore the possibilities for future action. I will report back after this meeting.

David Ryner