Tag Archives: drug development

ABC steps up to fill the gaps in metastatic breast cancer care

Marc Beishon

Marc Beishon

 

The third Advanced Breast Cancer consensus conference – ABC3 – took place last month at its regular Lisbon home. ABC is the world’s only international consensus meeting devoted to the care and treatment of women and men with locally advanced and metastatic breast cancer. At each ABC conference, a large panel of experts adds and refines guideline statements for managing patients, with the aim of promoting them around the world for all countries, including those that lack the resources of developed nations.

ABC has contributed greatly to a fundamental change in thinking about metastatic disease. No longer do oncologists raise doubts about the feasibility of guidelines for treating such patients – the argument that there are too many variables among individuals is not often heard now.

And the conference has done much to unite the various parties in the advanced breast cancer community – in particular, patients and advocates participate on an equal basis with physicians (including on the consensus panel) and there is also a wide spectrum of professional expertise, again on the panel and in the conference sessions. Psycho-oncology, supportive and palliative care, health economics and survivorship all had prominent positions alongside scientific progress, and a complementary stream for advocates also allowed networking among patient representatives from many countries.

It’s not easy to break down barriers, particularly between doctors and patients, and ABC co-chair, Fatima Cardoso, reminded delegates that the conference has a mission for all to be respectful of the views of others. She also introduced the first results from a major new study sponsored by Pfizer and supported by the European School of Oncology, entitled ‘Global status of advanced/metastatic breast cancer: 2005-2015 decade report’, in which patient care perspective and public understanding have been surveyed across as many as 34 countries, and which also reports on scientific progress (disclosure – I am on the steering committee for the report).

Big gaps remain in areas such as patient communication, involvement in decision-making, and public awareness, where many people still think metastatic breast cancer can be cured, and some prefer women not to talk about it. Dian ‘CJ’ Corneliussen-James, of US group METAvivor, told the audience that prejudice is still a major problem, and that metastatic patients can be made to feel unwelcome by some advocacy groups. There are indications that overall, quality of life may not have seen much improvement.

Dian ‘CJ’ Corneliussen-James spoke about prejudice still affecting metastic breast cancer patients

Dian ‘CJ’ Corneliussen-James spoke about prejudice still affecting metastatic breast cancer patients

In the final session at ABC3, the consensus panel voted on new and changed statements in the guidelines, which will be published next year. There was heated discussion about some while others sailed through.

Briefly, there are important new statements concerning the use of objective benefit scales to assess drugs (e.g. from ESMO and ASCO), which may help to control costs, and on the need to design clinical trials that answer practical questions such as the sequence of using agents.

There are also new statements on survivorship, which is becoming more important as the number of women living with advanced disease for longer rises, and on several supportive care issues.

The consensus panel vote on new and changed statements in the guidelines

The consensus panel vote on new and changed statements in the guidelines

There has only been one new drug approved for the metastatic setting since ABC2, palbociclib, but new data on other drugs such as pertuzumab have changed some statements. The point was made in the conference that innovation in advanced breast cancer is now lagging other tumour types, such as lung cancer and melanoma.

Overall, the conference was notable for the continued integration of patients and those supporting patients into the programme. A highlight was Anna Craig, a young mother from the US, and her video, I am Anna, which was screened for delegates.

See @ESOncology and #ABCLisbon for tweets.

“The purse is closed!” – this is no way to run a hospital

Rosa Giuliani, medical oncologist, S. Camillo-Forlanini Hospital, Rome, Italy

Rosa Giuliani, medical oncologist, S. Camillo-Forlanini Hospital, Rome, Italy

 

As a medical oncologist my primary interest is in helping patients to live longer and better. The best part of my job is the integration of clinical and molecular views: see the problem in the clinic, look for answers in the lab, bring back the solution to patients. I wish it could be as simple as that.

Research & development have a price, which is often difficult to understand. Why new drugs and devices cost that much, and not a penny less, is a complicated conundrum for many of us. The EU regulatory and reimbursement systems, the lack of a universal health policy through Europe and the profound economic crisis are regularly debated.

While I was at ECCO participating in debates on the need to promote equity and defeat disparities in access to precision medicine in Europe, hospital managers where I work notified the oncology department that the budget allocated to cancer drugs expenditure was over:no “expensive” drugs could be purchased until the budget for the new year will be discussed in January. The purse was closed. Meetings followed, some very unpleasant; poor use of resources by medical staff was implied, not even too subtly. Of course, this prompted self-examination: am I a good oncologist? Am I following guidelines? Am I spending money for my pleasure to give drugs?

After this last question, I realized that I was losing my mind and luckily, I returned to my senses. I respect rules, I need rules, I love rules. I appreciate fair rules. Budget negotiations at local hospitals are as obscure as the procedure of setting prices at EU or national level. A rule, which lacks of transparency, is not fair. The fact that the rules are set and dealt by people who are not prepared to manage the process, is terribly wrong. The overwhelming gap between cancer politics at EU Headquarters, where precision medicine is being promoted, and cancer politics at local level, where the only interest is that 2+2 should be equal to 3, because 4 is already too expensive, is frightening.

Money is an important part of the equation: resources are not infinite and their rational employment is of utmost importance. The process of drug development is not cost-effective, and many managers are not, because they have not been adequately prepared to deal with a different type of economy. Cancer medicine cannot be dealt as if providing water or electricity.

The global curriculum for being a good medical oncologist has dramatically changed in the past 10 years. Medical oncologists in 2015 cannot neglect molecular biology, health policies, precision medicine and so on. The same change should happen with managers who allocate resources for health politics, especially at hospital level. Being a good accountant does not suffice anymore, just as being exclusively a good clinician is not enough. Another level of knowledge and preparation is needed. And honestly, sometimes, a little bit of emotional intelligence would not do any harm.

We welcome contributions to this blog. If you have a topic you would like to write about, please send your post to Corinne Hall – chall@eso.net You can find our guidelines here – How to write a blog

 

 

 

 

The price isn’t right, but neither is the effect

Marc Beishon

Marc Beishon

 

Concern about the high prices of cancer drugs is nothing new but there are signs now that the issue may be coming to a head. There is a flood of new agents coming onto the market and, if anything, the prices charged are still going up, with more agents reaching eye-watering levels above $100,000 a year. Global annual spending on cancer drugs has now hit $100 billion for the first time.

At the upcoming European Cancer Congress, a study by a UK pharmacologist on how much it costs to make cancer drugs such as imatinib (Glivec) will reveal that Americans in particular are paying hugely more than the manufacturing cost, but Western European prices are also high.

Just a few weeks ago, a group of more than 100 senior oncologists, mostly in the US, launched a ‘grassroots’ petition calling on the powers that be in America to address the harm that high drug prices cause patients. Writing in Mayo Clinical Proceedings, the oncologists says the average price of new cancer drugs in the US increased 5- to 10-fold over 15 years, to more than $100,000 a year in 2012 and the cost of drugs for each additional year lived (after adjusting for inflation) has increased from $54,000 in 1995 to $207,000 in 2013.

Of course, the US has particular conditions that determine drug prices – its Medicare system for older people is not allowed to negotiate prices, and the lack of a universal healthcare system means many patients are faced with huge ‘co-pays’ on drugs through their private insurers. As the Mayo article says: “For a patient with cancer who needs one cancer drug that costs $120,000 per year, the out-of-pocket expenses could be as high as $25,000 to $30,000.” In calling for people to sign the petition, the oncologists say: “The individuals most harmed and least engaged in these discussions are cancer patients because they are exhausting their energy, resources, and time fighting for their lives,” and note that advocacy proved successful in stimulating treatments for those affected by the AIDS epidemic.

Cancer drug prices are of great concern elsewhere, of course. In European hospitals and healthcare systems the pressure on budgets for new drugs is great. In the UK, for instance, there are endless arguments over reimbursement for new treatments. In 2011 the government resorted to setting up a special cancer drugs fund for England to pay for treatments that the National Health Service would not otherwise fund.

At European Union level, there are a string of initiatives, such as the new European Commission expert group on Safe and Timely Access to Medicines for Patients (STAMP), which in turn is hearing updates on various projects such as the European network for Health Technology Assessment, and the network of Competent Authorities on Pricing and Reimbursement. But joint negotiation of pricing among countries, which could lower cost, is not in the Commission’s remit, although there is a joint procurement agreement for vaccines and other “medical countermeasures”. There is though a move by Belgium and the Netherlands to engage in joint drug price negotiation, initially for orphan drugs, where small patient numbers can mean high prices, and which will also involve cooperation on registries and evaluation.

The US oncologists propose a number of actions that could help, including price negotiation, allowing drug imports, faster access to generics, a reform of the patent system, and perhaps most importantly, taking steps to include both the cost and efficacy of drugs in assessments of treatment value and in guidelines. In fact, England already has what many countries, notably the US, lack – a body that recommends reimbursement only for treatments that meets value for money criteria, namely the National Institute for Health and Care Excellence (NICE), which uses QALYs (quality adjusted life years). But the hasty establishment of the cancer drugs fund shows that the pressure to access treatments beyond NICE’s recommendations (and the NHS budget) is great, as stories about patients denied drugs flood the media.

The high price of cancer drugs would of course be less of a problem if they were more effective, but breakthroughs have been the exception not the rule. As Fatima Cardoso, co-chair of the Advanced Breast Cancer conference, has recently commented in Cancer World: “In early breast cancer the standards of care haven’t changed in more than two decades; in advanced disease median overall survival is still a dismal two to three years.”

Certainly, more can be done to add to measures of drug effectiveness. This year, the European Society of Medical Oncology introduced the first version of the Magnitude of Clinical Benefit Scale (MCBS), which grades therapies with both curative intent and palliative intent, and which its developers say is a validated tool that can be used to prioritise drugs for assessment and develop clinical guidelines founded on magnitude of benefit rather than just level of evidence. A quick check on several grade 4 (out of 5) palliative drugs in the MCBS shows they are also recommended by NICE, so there may be some duplication here, initially, although at least one with a grade 5 score, the breast cancer drug Kadcyla, was turned down by NICE owing to its very high price and is now one of several drugs cut from the NHS cancer drugs fund.

Meanwhile in the US, the American Society of Clinical Oncology (ASCO) has just launched a framework for assessing the value of new cancer therapies “based on treatment benefits, toxicities and costs”. Developed by ASCO’s Value in Cancer Care Task Force, this aims to be a “user friendly” tool that oncologists can use with patients to discuss the value of new treatments compared with standard ones, and has been out for consultation. A paper in JAMA Oncology has also looked at how applying a value-based cost can work in a drug used in metastatic lung cancer, but political forces in the US are hard to influence along these lines.

Along with efforts to pin down cost-effectiveness and to carry out more meaningful clinical trials, Cardoso says a priority is to ensure that each patient is treated according to current knowledge and guidelines, which is often not the case. And in England, Karl Claxton, an economics professor specialising in health technology, has published research that calls into question the cost-effectiveness threshold that NICE uses – saying that it is in fact too high. His study made the news, as the implication is that some money spent on cancer drugs, and particularly the drugs funded by the special fund, would be more effectively deployed across the health system, both on standard cancer care and other health conditions.

The UK’s NHS has had long battles with drug companies over price but drugs are also rejected because of lack of effect. Were the US to take similar steps to agree on what constitutes an effective new therapy then there could be a move towards more meaningful drug development as well as lower prices for patients. As the authors of the ESMO MCBS paper also say: “A key challenge for the future will be to establish whether there can be harmonisation between the different approaches to value in Europe and the US.”

 

 

 

Bold policies for progress north and south

anna portrait  picWorking in silos has long been a problem within the cancer community, as people engaged in increasingly specialised fields struggle to remain aware of the bigger picture. So it can be important, on occasion, to bring the different constituents together around a single agenda.

One might have wondered, however, whether the World Oncology Forum, which gathered almost two months ago in Lugano, Switzerland, might not have been a little over-ambitious in setting an agenda that focused on two topics that are poles apart in almost every respect, including the geographical.

The first of these, fixing the ‘broken model’ of new drug development, is a priority issue for the northern hemisphere. The second, addressing unmet need for the most rudimentary detection, treatment and palliative care, is the priority in the South. The opportunity to explore these challenges and the associated policy implications, within a single gathering, however, turned out to be remarkably constructive.

wof collage Hearing about some of the best examples of low- to middle-income countries that have taken well-planned, system-wide, sensibly financed steps to get the widest possible access to the best possible early detection, treatment and follow-up showed just how much can be achieved for cancer patients, even with modest resources, by simply getting the fundamentals right.

While hearing about the cost, both in health expenditure and overtreatment, of squeezing out additional survival benefit for patients in better resourced health systems brought home how unsustainable current approaches to developing new treatments are becoming, even for world’s wealthiest countries. The message that came out was about priorities.

  • Don’t waste resources on expensive equipment and therapies if the money can be better used getting the fundamentals right for everybody who needs them.
  • Don’t waste resources on developing new therapies unless they aim high – which means tackling resistance rather simply chasing cancer cell evolution from dependence on one mutated pathway to the next.

Bold policy initiatives that champion the public interest will be needed at international and national level to achieve what must be achieved. The task of the 35 assembled experts, leaders and innovators in their own fields, was to spell out the core elements of such initiatives.

As keynote speaker Paul Workman, chief executive of the UK Institute of Cancer Research, points out in the video below, the level of agreement among participants was remarkable, given the differences in their geographic and professional backgrounds and the strong views held by all.

The exact wording of the final policy appeal is currently being finalised. It will be published on this blog and in the March issue of Cancer World, which will carry a full report of this remarkable meeting. It will also feed into a discussion at the ‘Davos’ World Economic Forum on meeting the challenge of the global cancer epidemic, if and when the organisers confirm that the issue has made it onto the final agenda at the end of January 2015.

Slides from most of the presentations are available now on the ESO website (access requires you to register with Club ESO).

Turning targets into effective treatments. My three questions for the World Oncology Forum

 

Paul Workman

Paul Workman

This week 50 experts from across the globe involved in researching, developing, evaluating and delivering new therapies will meet to develop consensus recommendations on who needs to do what to speed the development of effective treatments. The meeting is one of a series of World Oncology Forum summits organised by ESO in collaboration with The Lancet.  

In this guest blogpost, Paul Workman, interim CEO of The Institute of Cancer Research, London, talks about the three questions he will be posing in his opening keynote speech.

AS SOMEONE WHO has spent a career in cancer drug discovery and development, in academic, biotech and big pharma settings, I find it very frustrating that we still lack the treatments we need to effectively control or cure many cancers.

So I welcome the opportunity to give the opening presentation at WOF 2014, and to ask questions about what has to happen to translate the tremendous insight and knowledge we now have about the genetics and biology of cancer into effective treatments.

I intend to open on an optimistic note.

The success of the human genome project and its application to oncology has led over the past decade to an extraordinary increase in our understanding of the causation of cancer, and has opened up a new, ‘personalised’ approach to treating cancer.

There is a feeling of positivity among cancer researchers which I certainly share. Genetics and biology are being laid open, and ideas about rational therapies are still pouring out of labs.

It’s true that, while some of the new personalised therapies have been very successful, the overall impact so far has been disappointing. But an important point I will be stressing is that we do understand what the limitations are – and based on this we can now devise scientifically rational ways forward to move us to the next level.

We now know that cancers are able to develop resistance to molecularly targeted drug treatments – just as they did to the previous generation of cytotoxic drugs. This is because cancer cells evolve over time through a sort of Darwinian ‘survival of the nastiest’.

Such evolution leads to the high level of genetic and biological variation of cancer cells within a given patient. Even worse, the treatments given can themselves act as a ‘selective pressure’ to drive further variation and resistance.

So the task ahead is ideally to design therapies that will block cancer evolution. One class of drugs that does this that we at the ICR have been heavily involved in developing – HSP90 inhibitors – are now in clinical trial. We need to find more targets of this type, for example those in epigenetic regulatory pathways.

Another important approach to overcome evolution and resistance is to develop drug combinations that can hit, for example, several different cancer targets or other alterations at the same time – a strategy which has worked well in controlling HIV.

But this is where we come up against a problem. Because, out of the 500 genes or so we have discovered that are responsible for causing cancer, we’ve only got drugs that will work against about 5% of them.

We still haven’t got any drugs that work, for instance, on RAS or on MYC or p53 – three of the big genes responsible for causing cancer. So we’re trying to find effective combinations when we have no drugs for 95% of genes that may be involved in resistance. There is a huge amount of work still to do in this key area.

Question 1
So a key question I will be posing at the World Oncology Forum will be: how do we speed up the development of innovative drugs against more of these new cancer targets?

Part of the answer to this problem involves the technical challenges to find drugs for the less ‘druggable’ targets. But in fact there is another more systematic problem which lies in the ‘ecosystem’ that governs the way new therapies are discovered, developed, brought to market and paid for. It clearly isn’t functioning as well as it should for developing personalised cancer therapies.

Most companies are working on a relatively small number of targets, maybe 20 or 30. They all tend to invest in the same group of targets and often they prefer trying to develop a slightly better version of a drug that is already out there rather than going for a new target.

Taking a higher-risk, more innovative approach and working on currently undrugged targets, rather than developing ‘me-too’ drugs, is much more likely to deliver the sort of step changes in survival that we all want to see.

The risk-aversion that predominates in the pharma industry is understandable, from their point of view. They know that historically only 5–10% of drugs that enter phase I show enough activity to be approved, so they want to be very sure about the targets they work on.

But that thinking creates an innovation gap, or what we call rather more dramatically the ‘valley of death’. There is a gap – in fact a chasm –  between early-stage research with real clinical implications, like the identification of a new target gene, or the discovery of a an early prototype drug candidate, and it being taken forward by companies to the point where a treatment can be trialled in patients.

Then there’s the problem that new drugs are being tested in settings where they are least likely to show a benefit, as single treatments given in late-stage disease which has already become drug resistant.

Even though we now have predictive biomarkers to select responsive patients, the benefit in heavily treated drug-resistant patients can be relatively small, which means that it takes more patients and a longer time to demonstrate in a clinical trial. This pushes up costs, which then means that bodies like NICE in the UK and its equivalents elsewhere may refuse to fund the drugs because they aren’t deemed sufficient value for money.

This is not helped by companies continuing to seek the maximum cost the market will bear. And once a drug has been turned down it becomes very difficult to find out what it might be capable of when used either earlier in the disease or in combination with other drugs. So great opportunities will be lost.

Question 2
So the second question I will be asking is, how can we incentivise the ecosystem to be more innovative in research and development?

I think the key to progress is all about decreasing risk aversion. Until now, the pharmaceutical industry has preferred to stick to tried and tested ways of discovering drugs and of steering them through the regulatory process – even though there may be strong scientific grounds for doing things differently when we’re dealing with rationally designed, targeted therapies and especially facing the challenge of cancer evolution and drug resistance.

It’s easy but fruitless to get into the blame game here. Pharmaceutical companies are not charities and they have a responsibility to their shareholders. Bodies like NICE have a responsibility to ensure health spending delivers value for money and regulators need to be convinced of the medical merits and safety of new therapies.

The question is how to find a way forward that works better for everybody.

If we accept that risk aversion is a big part of the problem – an assumption that is backed up by many conversations I have had and by my own experience in the industry – we have to find ways to bridge the innovation gap.

One way is to do more of the early high-risk drug discovery and development in the academic sphere, and in collaborations with Government, charities and industry.

Some organisations, such as Cancer Research UK and the National Institutes for Health in the US, are already pushing for this approach. They are beginning to provide ‘valley of death’-type funding to academic groups, including mine here at the ICR and MD Anderson and others, to help them get involved in early-stage, high-risk, innovative drug discovery and development. That can decrease the risk to industry in progressing a new approach.

I think this approach will really help, as exemplified by the breakthrough drug abiraterone that we discovered at the ICR and which was then subsequently licensed to industry and approved in late-stage prostate cancer.

We should be aware though that risk-aversion is not restricted to industry. There are many pressures at work in the academic sector – including hyper-competition, difficulties in accessing grant funding, and a preference for funding ‘safe’ rather than highly innovative approaches.

We also have to face tough questions about excessive requirements for publication which can actually slow progress and reduce efficiency. And conversely there are worries about the inability to replicate many academic discoveries in basic research which can then misinform choices about the best therapeutic targets to work on.

Question 3
So the final questions I will be pushing very hard at the end of my presentation will be: How do we de-risk innovative drug development for companies? Where will the high-risk work be done? Who will fund it? And what should we expect from companies and academia?

It is going to require concerted efforts from all parts of the ecosystem to overcome the challenges we face to overcome cancer evolution and drug resistance. We need to work together as a community to find win-win solutions.

I’m looking forward to the discussions at the Forum and believe they will help move us in the right direction.

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