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More, better new drugs: five ways the system must change


Professor Paul Workman outlines five solutions to the challenge of the broken drug system of drug discovery and development, which is failing to deliver enough innovative new cancer drugs to those who need them.

Posted on 04 January, 2016 by Professor Paul Workman

As always seems to be the case across the whole of drug discovery and development, 2015 saw successes as well as disappointments in the speed of progression towards widespread use in cancer patients of drugs that we have discovered here at The Institute of Cancer Research (ICR) – or those whose development we have enabled through our laboratory research or our clinical research with our hospital partner, the Royal Marsden.

The ups and downs of drug discovery and development

We were very pleased that the ICR was named in the UK Pharmacology on the Map competition as one of four top institutions in the UK for research in drug discovery and pharmacology that has led to significant contributions to improving human health. The ICR was nominated for its pioneering research that spans the discovery of many of the world’s first chemotherapy drugs through to more recent research on molecularly targeted precision or personalized medicines and the recognition that the ICR discovers more new cancer drugs than any other academic centre in the world.

ICR discovered chemotherapy agents like busulfan, chlorambucil, melphalan and, with collaborators, carboplatin – all of which are still in use worldwide up to 50 or more years later. More recently, we have discovered – alone or with our academic and commercial partners – molecularly targeted precision medicines exemplified by the prostate cancer drug abiraterone, HSP90 inhibitors and many kinase-targeted drugs. In fact we have discovered 20 drug candidates over the decade since 2005.

The ups and downs of developing drugs once they have left the lab were very clearly illustrated by three decisions made in December by the English healthcare regulator, the National Institute for Health and Care Excellence or NICE.

Previously the prostate cancer drug abiraterone – discovered at the ICR – was approved for use in patients after they have received chemotherapy. However, the latest NICE decision is that, based on cost-effectiveness grounds, the use of abiraterone is not extended to giving the drug before chemotherapy – even though it has been shown to be beneficial at this earlier point and thus can spare men from the unpleasant side-effects of chemo.

The negative decision means that men in England and Wales will not be able to access abiraterone before chemo on the NHS – whereas in Scotland the drug has been made available to equivalent patients on the NHS there. Such inequalities in drug access across the UK are clearly inappropriate and hard to understand. It is a great achievement that abiraterone is already extending the lives of hundreds of thousands of men with prostate cancer around the world – but frustrating that many men in the UK are being deprived of the drug.

On the other hand, it is very welcome that NICE has ruled that men with prostate cancer can access another molecularly targeted drug enzalutamide on the NHS in England, without having to undergo chemotherapy first.The ICR and The Royal Marsden have carried out research that helped to develop enzalutamide for patients. The decision means that men can benefit earlier in their course of treatment. This is especially important for frail, often elderly patients for whom chemotherapy is especially challenging.

And it’s also great news that NICE has approved the use of the PARP inhibitor olaparib on the NHS for women with BRCA mutant ovarian cancer, although only once they have undergone at least three rounds of chemotherapy. The development of olaparib is underpinned by 20 years of research here at the ICR, originating when our scientists identified the breast cancer 2 gene BRCA2. ICR researchers then proposed and exemplified a new treatment paradigm – known as synthetic lethality – which exploited the vulnerability of tumour cells with the BRCA mutations to PARP inhibition.

Following initial rejection in a short space of time by both NICE and the Cancer Drugs Fund, NICE subsequently approved olaparib under the less stringent ‘end of life criteria’, which allows a higher threshold for cost effectiveness.

While I welcome the new decision by NICE which is a defining moment in the history of targeted cancer treatments – because olaparib is the first targeted therapy for genetically inherited cancers – and also a major success story for the UK in therapeutic innovation, it is still frustrating that NHS patients cannot benefit until after they have had at least three rounds of chemotherapy.

Lessons learned

At ICR we have been considering the lessons that continue to be learned about how to make innovative and effective drugs available to patients as soon as possible at affordable prices. And we feel that’s its appropriate for the ICR not only to make the discoveries that defeat cancer – including discovering and developing innovative cancer drugs – but also to use our expertise in cancer and cancer drugs to contribute to the debate on policy.

This autumn my colleague Dr Eva Sharpe – from our policy team at ICR – attended Europe’s biggest annual cancer conference, the European Cancer Congress in Vienna, to present some ideas on my behalf for how to radically reform the system for drug discovery and development – so as to deliver innovative cancer therapies at a price society can afford.

I have long held the passionate view that not enough genuinely game-changing cancer drugs are reaching patients, meaning that too many people are still left with untreatable cancer. The reasons for this are multi-faceted and highly complex, and the situation will only improve with fundamental change in every element of the baroque system governing drug development, evaluation and approval – requiring change from governments and regulators, to health services, companies and academic institutions.

Here are five recommendations for ways in which that I believe the system needs to change – and which were outlined in our presentation at the Congress.

These ideas are designed to make sure that we take fullest possible advantage of the scientific breakthroughs in our fundamental understanding of cancer – and convert these with a sense of urgency into innovative medicines for the one in two people who will suffer from cancer at some stage in their lives.

Recommendation #1: New, smarter trial designs

The pharmaceutical industry and regulators need to be more willing to consider new, smarter clinical trials that reduce the overall cost of drug development. The traditional approach of running huge, expensive clinical trials across disparate groups of patients – trusting that a few of these studies will uncover the latest blockbuster drugs – will not result in the range of innovative targeted drugs that patients need.

There are five key ways in which clinical trials need to change.

  • First of all, we need to start out with the discovery of drugs that act through novel molecular mechanisms and supported by better target validation. Companies and clinical trialists should prioritize the most promising and mechanistically novel molecules as candidates for the potential targeted cancer drugs of the future – those that bind with high affinity and with impressive specificity to the desired molecular target and modulate the intended biochemical pathway or network.
  • Next, trials must be stratified. Patients can now be selected for trials based on their cancer’s molecular profile, increasingly using genome sequencing. This enables smaller, cheaper trials to be run that include only patients who can reasonably expect to benefit from treatment. The approach requires identification of robust biomarkers for patient selection and these are currently especially lacking for drugs acting to stimulate the immune response against cancer.
  • We need well-designed, randomised phase II trials. Regulators are increasingly willing to license drugs after phase II trials, but that can only happen when studies are designed at the outset to produce good evidence of efficacy, including proper randomisation where this is needed.
  • However, in some cases – particularly in cancers with very poor survival options and where no effective treatments are available – drugs can be approved based on promising results in non-randomised trials.
  • Innovative clinical designs include so-called ‘basket trials’ in which the aim is to match patients with relatively rare mutations, regardless of tumour type/histology, to one of a group of drugs in the trial that are expected to work on the particular mutated pathways that are tested for in the lab. Adaptive randomization can be used to ensure more patients are assigned to the more effective therapies and cooperation between different companies as well as multiple academic institutions can be very important here.

Recommendation #2: Early adoption of new medicines

We need a regulatory system which allows early adoption of innovative new medicines. I would encourage licensing bodies – like the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) – to be much more flexible in giving marketing approval for new drugs based on earlier clinical trial data than has traditionally been the case.

In this way patients can gain access to drugs that can help them as soon as possible. Of course the effectiveness of drugs gaining such early approval must then be confirmed in subsequent follow-up studies and further decisions made according to the evidence gained in these.

I am also supportive of programmes which allow early access to innovative treatments prior to their licencing – especially if they work through novel mechanisms and when there is good evidence of their effectiveness and safety. An example is the Early Access to Medicines Scheme (EAMS) in the UK, which recently enabled patients to access the pioneering immune-stimulating drug pembrolizumab.

Regulators are beginning to show more willingness to use new measures of effectiveness that have been developed in recent years, such as progression-free survival – the time it takes for a metastatic cancer to progress. That’s a good thing, because the gold standard of overall survival can take years to achieve through clinical trials that delay the introduction of new and effective treatments into routine care.

But while some drugs are being licensed based on progression-free survival data, they are often falling at the next hurdle, and being turned down by NICE because of the lack of overall survival data.

So we need bodies like NICE to catch up with the science and be more open to considering earlier trial data, so that effective new treatments can be made available to patients on the NHS much sooner.

Of course as I said earlier, the full value of these innovative treatments must then be confirmed through later follow-on studies.

Recommendation #3: Innovation and evaluation

The companies which develop new drugs may not see a strong case for taking risks by being genuinely innovative if they cannot be confident that health services will pay for the drugs that result. So we need to take action to widen or remove the bottleneck in getting exciting new treatments adopted by the NHS. The NICE decisions on olaparib and enzalutamide mentioned above are examples of support for innovative treatments, unlike the turning down of abiraterone before chemotherapy.

I think the best chance of true innovation comes from new drugs that work in unprecedented ways – for example by acting on a new molecular target or by affecting an existing target in a novel way. Such drugs seem more likely to have a bigger impact than ‘me-too’ drugs that provide only more modest benefits over existing agents.

Because of this I strongly believe that NICE needs to place more emphasis on innovation when it evaluates new drugs. It needs to give more consideration to whether a drug is tackling cancer in a new way, whether it provides an opportunity where no existing treatments are available, and also importantly whether there is the potential to use it successfully in combination with other drugs with different mechanisms of action. Such combination treatments will be essential to defeat the problem of treatment-resistant disease which is the major challenge we face in curing cancer today.

But any change to NICE processes – including greater emphasis on innovation – must not come at the expense of the current end of life criteria, which are a valuable initial entry route into the NHS for innovative new medicines.

Recommendation #4: More realistic pricing, linked to benefit

If pharmaceutical and biotechnology companies are making savings from regulators and approval bodies that allow them bring drugs to patients at lower cost, it’s essential that they pass on those savings by setting more realistic prices.

This is especially important at a time when it has become very clear to almost everyone that the prices being set by companies – who are essentially testing out what the market will bear with each submission – are quite simply unaffordable for healthcare systems today.

Currently, phase III trials make up the largest cost of developing a new drug, so earlier approval based on phase II data and other smaller, stratified trials will substantially reduce companies’ outlays. Therefore we should expect that the NHS will pay less for drugs that are approved at this stage.

As more data emerge from bigger trials that show a drug is effective – and may well reveal greater benefits in patients with earlier stage cancer or when the drug is used as part of combination treatments to overcome resistance – companies could then be allowed to increase prices accordingly. In other words, the cost of drugs should reflect the level of benefit they will offer NHS patients.

Recommendation #5: Risk sharing

Developing innovative new drugs is a risky business. As with anything genuinely new, it’s impossible to know for certain that a different approach to treatment will work until you try it – and many new drugs will inevitably fail.

Pharmaceutical companies often shy away from projects with higher levels of risk, knowing that they could instead focus on developing me-too drugs which mimic the mechanisms of action of existing ones. These may bring modest benefits but as mentioned, they will not address the major challenge of drug resistance. Nor will they bring new options for types of cancer, such as those of the lung, brain, oesophagus and pancreas, for which survival is still unacceptably low.

So we need a system which is better at sharing the inherent risk in true innovation – with governments, regulators and health systems, and also academic researchers, shouldering some of the burden alongside the commercial sector. Of course this should involve sharing the reward as well as the risk.

Some academic institutions, not least the ICR, have shown a willingness to take on greater risk in drug discovery than many parts of industry – partly because as non-profits they are not under the same pressure to deliver financial results. Partnerships between academic organisations and companies can be an effective way to share risk and reward and to drive innovative new treatments into clinical trials – and even supporting clinical development as well as the discovery phase.

Some final thoughts

Now is a hugely exciting time to be doing cancer research – based on the extraordinary increase in our understanding of cancer at the genetic, molecular and whole body level, a range of genuinely innovative new treatments are emerging through the pipeline for approval by regulators and some of these are now becoming available for patients.

But too many drugs are falling at the final hurdle in the long journey from the laboratory to the clinic, and there are still far too few innovative drugs beginning on that journey.

In the UK, there is an ongoing national debate about how health services can meet the challenge of bringing new cancer drugs to patients at an affordable cost. This debate is also now happening in other countries, including the USA.

I am especially concerned that a critically important aspect of new drug approval is currently not being addressed in the current debate, which is that we should not just be considering the merits of each individual drug for the trial population on which the drug has been regulated for testing – usually patients with late stage cancers who have exhausted all available options for treatment, and are already highly resistant to treatment.

Rather, we should also be thinking about getting new therapies approved that have the potential to overcome the major scientific and clinical challenge we face – which, as I’ve emphasised above, is the emergence of drug resistant cancer cells.

Scientists at the ICR and elsewhere have shown that drug resistance develops as a process of Darwinian evolution as well as through biochemical feedback loops. Counteracting drug resistance – which is essential to extend survival from months to years and decades and to increase cure rates – will require combination therapies including established and innovative treatments, as well as their use at an earlier stage of the disease.

In order to develop these combinations and use them earlier, it’s absolutely essential that we find ways to get new treatments approved in the first place. Otherwise we are effectively blocking progress towards extending life and curing people with cancer. Blocking the availability of innovative treatments is the worst thing we can do.

I believe that now is the perfect time to be making our case for radical change to the whole system for drug discovery and development. Too many cancers remain untreatable, and only genuine innovation will overcome that.

We need to get together as a community to solve our shared problems and make change happen.


Update 2016-07-21: The number of drug candidates was updated to 20.


abiraterone olaparib DrugDevelopmentStats pembrolizumab enzalutamide HSP90 inhibitors
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