These decisions mean that women with BRCA mutation-positive ovarian cancer will be denied access to a pioneering medicine that improves quality of life and extends periods of remission. We know that this type of drug is highly valued by cancer patients and their families, and this delay will affect about 450 women annually in England.
This is especially frustrating because the development of olaparib as a cancer treatment is underpinned by 20 years of ground breaking research here at The Institute of Cancer Research in London.
Olaparib is the first of a new class of drugs called PARP inhibitors. They are particularly innovative as they target a genetic mutation specific to some cancer types. In fact, olaparib is the first cancer drug targeted at an inherited genetic fault to be approved by the European Medicines Agency and the US Food and Drug Administration (FDA).
In the 1990s, scientists at the ICR identified the breast cancer 2 gene, BRCA2, and mutations in it that greatly increase the carrier’s risk of developing breast cancer and other cancers. They went on to show that the protein produced by the BRCA2 gene plays a role in repairing damaged DNA, providing a completely new approach to treatment by exploiting a specific genetic weakness of cancer cells.
Cells with mutations in the BRCA1 or BRCA2 genes can survive DNA damage using an alternative repair pathway involving PARP proteins. By inhibiting PARP with drugs such as olaparib, research at the ICR showed that we can block this second pathway, effectively killing cancer cells with BRCA mutations by limiting their ability to repair damaged DNA, but leaving normal cells which have a working BRCA repair system unharmed. This is an example of an exciting new therapeutic approach known as ‘synthetic lethality’.
In October last year, the European Medicines Agency recommended that olaparib be approved for women with ovarian cancer who have a BRCA mutation, which we welcomed at the ICR as the first step in getting the drug to patients on the NHS, particularly as the decision was based on Phase II trial data and would mean that patients could have access to the drugs earlier.
But before drugs can be made available to patients routinely on the NHS, both the clinical benefit and cost-effectiveness of the drug must be considered.
Because of this requirement, olaparib was evaluated in parallel by NICE – to see whether it could be made routinely available – and also by NHS England to determine whether its use could be covered on the Cancer Drugs Fund. It was a real blow when it was turned down for both effectively at the same time, leaving no way of paying for the treatment on the NHS.
A decision from NICE
On Monday, NICE released draft guidance announcing its decision not to recommend olaparib for BRCA mutation-positive ovarian cancer, because the estimated costs of the drug were above the range normally considered cost-effective, and they also had some uncertainty over whether, and to what extent, olaparib increases overall survival as the data are still immature.
I am very disappointed that NICE has not been able to recommend use of olaparib in these patients, as the evidence is clear that it is an effective treatment that delays disease progression and is also a well-tolerated drug – which NICE agreed with.
For me, this decision highlights how the current system of drug evaluation and pricing needs reform – in particular to reward the development of innovative drugs that address unmet need in cancer treatment and which have additional, further potential.
The clinical effectiveness results were based on a Phase II clinical trial, in 265 people with ovarian cancer. I’ve long been advocating that for really innovative and effective drugs like olaparib, it is really important to be making initial approval decision based on early trial results, as it means they can reach patients more quickly, rather than waiting for the results of larger Phase III trials which may take many years. Meanwhile, the clinical trials can continue and deliver more definitive, mature results in due course.
So I am really pleased that NICE considered earlier Phase II trial data as part of the appraisal. But the downside is that some of the longer term data such as overall survival of the people on the trial is still immature. To address this, the published trial results look at other measures of clinical effectiveness such as progression-free survival – which is the time before someone’s cancer starts to progress.
Obviously, decisions for approval should be based on sound evidence. There has been a lot of discussion over the best measure of clinical effectiveness. I think it is important, especially for innovative drugs, that their effectiveness is not judged solely on the ability to extend overall survival, as this could limit the number of important and effective drugs which reach patients. What I’d really like to see is NICE being able to have the flexibility to approve a drug before overall survival data is available, so patients can benefit from drugs that are so clearly effective as early as possible.
However, such a flexible approach would not necessarily tackle the difficult issue of cost-effectiveness. So, in return for this earlier approval, I would encourage flexibility on the part of the drug company involved. For example, one possibility I have suggested is that pharmaceutical companies cut the prices of drugs during this initial approval period, with prices rising later as benefits are shown in bigger trials in more patients. Such a flexible approach to licencing would allow patients to benefit earlier, reward innovation, and at the same time be affordable.
Cancer Drugs Fund
The other recent negative decision came from NHS England who had been looking at whether to include olaparib on the list of drugs available through the Cancer Drugs Fund. This decision was based on the same trial data and they judged olaparib to show ‘sufficient clinical benefit to be potentially included in the Cancer Drugs Fund’. However, when this was considered alongside cost-effectiveness it was determined to be of insufficient overall value currently to justify including it on the fund.
Of course I acknowledge that the NHS is cost-constrained, and that no decisions on availability of drugs or technologies can be taken without some reference to their cost.
However, the UK government originally set up the fund to pay for cancer drugs which had either been turned down by NICE on the grounds of cost, or had not yet been appraised by NICE. With both NICE and NHS England carrying out cost-effectiveness analyses at the same time, it’s hard to believe that there isn’t some duplication in the processes, and this risks the outcome we see here, which is to deny patients the latest and, in many cases the only, treatments available for their cancers.
We need to ensure that decisions over drugs to be included on the Cancer Drugs Fund list use different price thresholds to those applied by NICE, otherwise they will be unable to approve any drugs that are rejected by NICE on cost grounds.
I’ve blogged before about how we need a sustainable, long-term appraisal system for introducing new drugs into the NHS. This doesn’t mean separating out cancer drugs as a special case, but it does ask that we ensure the appraisal system as a whole rewards innovative cancer medicines the priority they deserve.
The really substantial long-term patient benefits are most likely to come from the most innovative drugs acting on previously unprecedented targets – or those that act on established targets but in very new ways. We have to reward those companies and academic institutions that take risks in drug discovery – because if innovating is not rewarded then no one will do it, and we will miss out on the breakthrough treatments that we desperately need.
So what’s next for olaparib?
The development of olaparib as a cancer treatment was underpinned by research carried out by scientists at the ICR and other investigators – and the ICR also ran the early clinical trials of PARP inhibitors with our partner hospital, The Royal Marsden NHS Foundation Trust. It represents a real scientific breakthrough that involved a creative partnership in the UK between academia, biotech, a pharmaceutical company and charitable funders. For our work to make a difference to cancer patients, we now need to see this drug prescribed on the NHS.
The decision NICE announced this week is draft guidance, and it has now gone out for public consultation. Later in the month the committee will meet again to discuss any additional information that comes in. We’ll be responding to the consultation along the lines discussed here and we and will follow what happens closely.
In the longer term, larger clinical trials in ovarian cancer are ongoing, and we are confident that PARP inhibitor drugs like olaparib will become available for subgroups of women with ovarian cancer – and ultimately patients with other cancers too. Emerging research has also found benefits for patients with BRCA mutations who have other cancer types, such as breast and prostate cancer.
It is our hope that olaparib really will make a difference to many patients worldwide.
The double knock-back is a stark reminder that if we want to make the biggest breakthroughs and get them to patients soon, then we need to look carefully at how the approval processes work, and find a way to remove blocks which prevent us from making innovative treatments available to patients.
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