Novel, innovative (bio)pharmaceutical drugs are an important part of our global healthcare system, offering advanced, radical new personalized and targeted therapy options to patients with life-threatening diseases, including different forms of cancer.

While advancements in the development of these novel, targeted cancer therapies, including antibody-drug conjugates or ADCs, come, in many cases, at a high financial cost, they may ultimately lead to a reduction in costs to society, longer survival and improved Quality of Life (QoL).  However, the fact remains that, often ignored as the big elephant in the room, these novel therapies show price-tags that would be unthinkable less than a decade ago.

“… It’s depressing and demoralizing that … [the]… latest [targeted and personalized] drugs … are not being used in the United Kingdom…”

According to a report published earlier this year by the IMS Institute for Healthcare Informatics, global spending on therapeutic oncology drugs have, in 2015, risen by 14.2% to U.S. $ 83.7 billion, while, at the same time, the costs of supportive care therapies increased 2.6% to U.S. $ 22.9 billion, to a combined total of nearly U.S. $ 107 billion (up from U.S. $ 75 billion in 2010). These costs continue to rise, on average, at a compounded annual growth rate between 7.5% and 10.5% through 2020, when the global oncology costs are expected to exceed U.S. $ 150 billion. [1]

According to the same IMS report, the United States is responsible for nearly half of the growth of the total global oncology costs (46%) between 2011 and 2015.  In Europe, the costs rose at an average of 5.3% annually.

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Interestingly, the costs of innovative oncology drugs, as a proportion of the overall drug costs, remain higher in Europe than in the United States. Furthermore, while Germany spends, proportionally, more than other European countries, the costs for these oncology drugs is rising faster in the United Kingdom than in the rest of Europe.

Targeted therapies
The development of novel, innovative, oncology drugs is concentrated on targeted therapies and personalized medicine, which according to IMS Institute for Healthcare Informatics make up 87% of all late phase pipeline drugs today.

Notwithstanding the high – and in some cases increasing – cost of these innovative drugs, these novel therapies are also instrumental in preventing long hospital stays and doctor visits, which, in addition to saving lives and improving QoL, also saves money, bringing value to the broader healthcare system and society in general.

But with economic pressures abound, the high costs of innovative cancer treatments has created a major battleground for national healthcare systems: between what these national health systems aspire to reimburse and what they can afford to do under public insurance programs.

As result, access to novel cancer drugs is, unfortunately, not universally guaranteed.  This means that, even in developed countries, economic pressure and priorities may result in a decline to reimburse vital cancer drugs.  And a ‘negative recommendation‘ may be more a ‘norm‘ for national healthcare systems using a cost-effectiveness assessment methodology based upon quality-adjusted life-year or QALY.  These healthcare systems may be less inclined to reimburse novel cancer drugs than those who use other assessment methodologies.

According to the authors of the IMS report, in 2015, the cost of treatment – especially of novel therapies – remained high.  On average, these costs ranged from U.S. $ 6,000.00 to U.S. $ 13,000.00 per treatment month. While the clinical benefits – measured in incremental progression-free survival (PFS) or overall survival (OS) are significant for these new oncology drugs, since ‘real world evidence,’ including QoL and adverse effects, are not systematically reported, establishing the cost- effectiveness and value assessment is complex.

Photo 1.0: Packaging brentuximab vedotin (Adcetris®; Takeda Pharmaceutical Co). Courtesy: © Takeda Pharmaceutical Co.

Brentuximab vedotin
For example, brentuximab vedotin (Adcetris®; Seattle Genetics / Takeda Pharmaceutical Co), an antibody–drug conjugate selectively targeting CD30-expressing cancer cells (recommended dose at 1.8 mg/kg administered intravenously over 30 minutes every 3 weeks) has been a game changer in the management of relapsed or refractory (r/r) Hodgkin lymphoma following autologous stem cell transplant (ASCT). In the United Kingdom it is the only approved medicine in this setting.

However, the United Kindom’s cost-effectiveness watchdog, the National Institute for Health and Care Excellence (NICE), who holds the purse strings of reimbursement of care, is not convinced that evidence for the drug’s efficacy in Hodgkin’s lymphoma is strong enough.  According to the institute’s published reports, the data is “immature” and “limited” and the price tag per patient is “not a good use of resources available to the United Kingdom’s National Health Service (NHS).” As a result, NICE does, in its draft guidance, not recommend the drug for routine use.*

Overal Survival
Relapsed or refractory Hodgkin lymphoma is a rare disease often affecting young people. As result of the relatively high level of unmet need, regulators, including the U.S. Food and Drug Administration (FDA) and the European Commission/European Medicines Agency (EMA), have, based on unprecedented Phase II trial results, approved brentuximab vedotin.**

Recently-published five-year follow-up of the pivotal study with brentuximab vedotin showed that the median overall survival (OS) for patients treated with brentuximab vedotin was nearly 3.5 years, longer than the historical survival data.[2]

In this study, a total of 38% of patients (13 of 34) who achieved Complete Response (CR) on brentuximab vedotin remained in remission 5 years later and may be cured. An additional 9 of the 13 patients (9% of all enrolled patients) have remained in long-term remission without the need of a consolidative allogeneic transplant.[2]

Current treatment options
Current first-line treatment for Hodgkin’s lymphoma is chemotherapy with or without radiotherapy, leading to long-term remission in 70–85% of people with Hodgkin’s lymphomas. Among the remainder of the population, high-dose chemotherapy followed by autologous stem cell transplant (ASCT) cures approximately 50% of people. However, ASCT may not be an option in some clinical circumstances. And after ASCT, some patients are considered to be at ‘high risk’ of residual disease.

There is no standard therapy administered after autologous stem cell transplant (ASCT) to delay disease progression. People whose disease relapses after ASCT may be treated with single or combination treatment regimens that may include chemotherapy such as gemcitabine, vinblastine, or vinorelbine (alone or in combination) or ChlVPP (chlorambucil, vinblastine, procarbazine and prednisolone). Some chemotherapy regimens are used outside their marketing authorisation.

In the United Kingdom there is currently no (final) NICE technology appraisal guidance for Hodgkin’s lymphoma.

Anger and concern
Although brentiximab vedotin is approved in Europe by the European Medicines Agency and included in the United Kingdom’s Old Cancer Drugs Fund (CDF), a fund designed pay for cancer drugs that are not available on the National Health Service (NHS), the new NICE draft guidance to not recommend the drug, has angered both physicians and patients organizations in the United Kingdom as well as Takeda Pharmaceutical Co, the drug’s co-developer and  distributor outside North America.***  They argue that, if made final in February 2017, a negative decision in England could ultimately mean that patients with relapsed or refractory Hodgkin lymphoma may be denied access to a drug that has changed the treatment option and survival outlook for many patients.

In addition, a negative decision by NICE, they contend, could lead to inequality of care in the United Kingdom as access to the initial indications for brentuximab vedotin has been approved in Scotland and Wales.

But the concern, which is not limited to NICE’s recommend for brentuximab vedotin, is widespread, going beyond the availability of innovative medicines.

Although not directly referring to brentuximab vedotion, in an interview by Julia Bradshaw published in late October 2016 in The Telegraph, Mene Tangelos, Ph.D, Executive Vice-president of AstraZeneca’s Innovative Medicines and Early Development Biotech Unit (IMED) responsible for the development of the company’s nearly 410 million (UK £ 330 million) research center in Cambridge (United Kingdom)****, noted that “If … the [United Kingdom’s] healthcare system does not adopt the most important innovations that are becoming standards of care in other countries… companies will leave and others will not come to the United Kingdom to invest.” [4]

The underlying reason is, according to Tangelos, that the assessment of novel, innovative, drugs requires a novel approach, a different methodology, a new way of looking at the benefits of these drugs. “[These drugs are truly] personalized [and targeted] agents [and] they … should not be … assessed or priced in the same way as drugs treating large populations of patients with diseases such as diabetes, cardiovascular disease or asthma,” Tangelos explained in his interview with The Telegraph’s Bradshaw.

But there is a more troubeling reason why NICE may not recommend novel drugs like berentuximab vedotin and similar advanced, targeted and personalized therapies for routine use by the NHS.  The little known fact is that the National Institute for Health and Care Excellence has not increased its threshold for paying for drugs since 1999.

Translated in real money, this means that the available funds to pay for drugs, including innovative (bio) pharmaceutical drugs, have actually fallen by nearly one third.  While other European markets, including France and Germany, spend on average, between US $ 12,000.00 – and 13,000.00 per treatment month, in contrast, England spends, on average, U.S. $ 8,500.00 per patient treatment month. As a consequence, if noting changes, this means that some of the more advance therapies may not be available to patients in the United Kingdom.

“It’s depressing and demoralizing that … [the]…  latest [targeted and personalized] drugs … are not being used in the United Kingdom,” AstraZeneca’s Tangelos concluded.

Experts believe that yet another reason why NICE may not recommend reimbursement of brentuximab vedotin is that it poses a challenge to the methodology used by Institute, which generally penalizes the absence of Phase III data which is often the case for rarer cancer medicines, including relapsed or refractory Hodgkin lymphoma.

But while the NICE recommendation is based on cost-effectiveness, many novel, target cancer drugs which have become standards of care around the world are, according to the available data, being offered at  prices comparable or even below the rest of the developed world.

The cancer cost paradox
While a high price-tag of novel, targeted and personalized therapies, can indeed be challenging for policy-makers, the irony is that advances in successful treatment options for cancer patients may further exacerbate this challenge.  Recent data confirms that today there are aproximately 10 million cancer survivors in Europe. Before the availability of many of the advanced treatment options, these patients would probably have died. And while these achievements are indeed impressive, they may, in some cases, also burden some, if not most, national health services in Europe with additional demands for continuing, supportive treatment that would otherwise not have been required.

Cancer Survival
A decision not to recommend reimbursement of innovative treatments may have grave consequences. A  comparison of cancer survival trends in 67 countries by researchers at the London School of Hygiene & Tropical Medicine, publishes in the The Lancet, revealed wide variations that were likely to be attributable to differences in access to early diagnosis and optimum treatment.[3]  These variations, in turn, were directly related to the available funds national health systems are willing and/or able to pay for medicines.

The effects are clearly seen in the United Kingdom.  According to an analysis by Macmillan Cancer Support based on the study published in The Lancer, cancer survival rates in the United Kingdom are lagging more than two decades behind those achieved in other European countries, including Italy and Austria.

These results have led to increased and often heated discussions on how to make the best possible use of limited national health services resources. But one thing is clear, the increasing pressure on national health systems responsible for approving, organizing, and funding treatment is driving cancer and the question how to pay for novel treatment options rapidly up the policy agenda in Europe.

Notwithstanding the economic pressure, the value of innovative, lifesaving medicines, including brentuximab vedotin, is undeniable and defending and ensuring patients rights and guaranteeing their access to live-saving medicines remains crucial. Unfortunately, with increased economic pressure on national healthcare systems, advancing novel, innovative, (bio) pharmaceutical drugs may not be as simple as an up- or down vote.

Later this s week, on Wednesday, November 9, 1016, following additional submission of clinical data by Takeda Pharmaceutical Co, NICE will hold second appraisal committee meeting, which will ultimately help in deciding if brentuximab vedotin will be made available on the National Health Service in the United Kingdom or not. A final decision is expected in February 2017.

Based on the analysis by researchers from Macmillan Cancer Support, the data clearly shows that much better survival rates are achievable in the United Kingdom. With cancer survival rates in the United Kingdom lagging far behind by the rest of Europe, it is fair, albeit shameful, to note that people are dying needlessly.

Hence, if NICE is serious about the importance of their role, it should be a top priority – vital – for the Institute to really commit to improving cancer survival rates and outcomes, making cancer a top health priority and help the country – once again – become a nation that matches the best in Europe and around the world.  They should be willing to fully consider all comments submitted during the consultation period and guarantee that new, innovative, medicines that are standards of care around the world, are available to patients in the United Kingdom.

For many patients, time is of the essence.

* According to NICE, an added reason for the negative recommendation is that the anti-tumour effect of the drug were measured as response rate, which is less clinically relevant than progression-free survival and overall survival.

** Brentuximab vedotin (Adcetris®; Seattle Genetics / Takeda Pharmaceutical Co) was granted conditional marketing authorization by the European Commission in October 2012. The approval was for two indications including the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option and the treatment of adult patients with relapsed or refractory sALCL. Brentuximab vedotin has received marketing authorization by regulatory authorities in 65 countries.

In June 2016, the European Commission extended the current conditional approval of brentuximab vedotin and approved the drug for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT.

***Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

**** AstraZeneca’s new research center in Cambridge (UK) will be a state of the art facility designed to stimulate collaborative scientific innovation and is s expected to play an important role in the future success of the UK life science industry.

November 8, 2016 | Corresponding Author: Peter Hofland | doi: 10.14229/jadc.2016.08.11.001

Received: October 21, 2016 | Published online November 8, 2016 | This article has been submitted for peer review by an independent editorial review board.

Last Editorial Review: November 8, 2016

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