The Cancer Drug Fund 1 year on—success or failure?

The Cancer Drug Fund 1 year on—success or failure?

Comment After prospective validation of the three molecular risk groups, defined by gene expression and/or immunohistochemical analysis of LIN28 and O...

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Comment

After prospective validation of the three molecular risk groups, defined by gene expression and/or immunohistochemical analysis of LIN28 and OLIG2, and their prognostic effects have been confirmed, health-care providers might be able to tailor treatment decisions in the future. Such validation should ideally be done in patients with hemispheric CNS PNET who are treated homogenously and have complete clinical information available. Moreover, new molecular targets such as WNT and SHH signalling, which are also relevant in medulloblastoma,10 might be considered as treatment targets, especially in patients with high-risk CNS PNET. Another multicentre effort is needed to collect as many samples as possible to investigate and delineate molecular groups of CNS PNETs of the brain stem or spinal cord— which are less common than are hemispheric CNS PNETs—to better understand the clinical and molecular features of this heterogeneous cancer.

I declare that I have no conflicts of interest. 1

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André O von Bueren

Picard D, Miller S, Hawkins CE, et al. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncol 2012; published online June 11. DOI:10.1016/S1470-2045(12)70257-7. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumours of the central nervous system. Lyon: IARC Press, 2007. Korshunov A, Remke M, Gessi M, et al. Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes. Acta Neuropathol 2010; 120: 253–60. Paulus W, Kleihues P. Genetic profiling of CNS tumors extends histological classification. Acta Neuropathol 2010; 120: 269–70. Li M, Lee KF, Lu Y, et al. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell 2009; 16: 533–46. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011; 29: 1408–14. Russo C, Pellarin M, Tingby O, et al. Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer 1999; 86: 331–39. Pfister S, Remke M, Toedt G, et al. Supratentorial primitive neuroectodermal tumors of the central nervous system frequently harbor deletions of the CDKN2A locus and other genomic aberrations distinct from medulloblastomas. Genes Chromosomes Cancer 2007; 46: 839–51. Miller S, Rogers HA, Lyon P, et al. Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma. Neuro Oncol 2011; 13: 866–79. Gilbertson RJ. Medulloblastoma: signalling a change in treatment. Lancet Oncol 2004; 5: 209–18.

University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany [email protected]

The Cancer Drug Fund 1 year on—success or failure? Published Online June 29, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70273-5 See Online for appendix

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On Oct 1, 2010, the English Government introduced ring-fenced funding for procurement of cancer drugs not funded by the National Health Service (NHS). These funds—worth an additional GBP£650 million during 3·5 years—were developed as “a means of improving patient access to cancer drugs”1 and as the start of “plans to address the disparity in patients’ access to cancer drugs in England compared to other countries”.2 They are collectively known as the Cancer Drug Fund (CDF), are additional to existing NHS funding flows, and are allocated regionally through strategic health authorities (SHA). Some feared that demand would outstrip funding,3 others that the so-called postcode lottery would worsen.4 In December, 2011, however, a national newspaper claimed that millions had not been spent and that patients were “paying the price”.5 So what is the real effect of the CDF? Here, we examine actual drug use and compare such use with expectations.

CDF funds are actually spent on only a few drugs. Five—bevacizumab, cetuximab, everolimus, lapatinib, and sorafenib—constituted 59% of applications between April, and December, 2011, with each one the subject of more than 350 applications.6 Use of these drugs has greatly increased since the introduction of the CDF, as recorded in data obtained by IMS Health from almost all English hospitals (figure 1). Mean volumes dispensed within SHAs in the year to November, 2011, were significantly higher than were those in the year before the CDF was launched (p<0·05). Variation between SHAs also declined (figure 2), and differences between the tenth and 90th percentile for each drug seem to be of magnitudes described as normal in previous reports of variation in the uptake of cancer drugs approved by the National Institute of Health and Clinical Excellence (NICE).7 However, growth is less than what would be expected. If every application to the CDF led to a treatment dose and duration similar to those used in clinical trials or in www.thelancet.com/oncology Vol 13 August 2012

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Proportion of amount used in year to July, 2010

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studies describing intended treatment, growth should be almost four times higher than what has been reported for sorafenib, more than double for bevacizumab, and about 1·3 times higher for lapatinib and cetuximab. Similar results are obtained when information about dose and duration collated by IMS Health from questionnaires describing clinical practice in the year to March, 2011, are used (appendix). Actual growth is again lower than expected (p<0·05) for all drugs apart from lapatinib (appendix). Two potential factors could explain this difference between actual and expected growth—a decreased duration of treatment than is expected and a switch of funding from the NHS to the CDF—but raise several important questions about the value of the CDF, funding of cancer drugs, and data necessary to improve understanding of use of cancer drugs. In our analysis, the differences between actual and expected growth are derived from the assumption that dose and duration of treatment are similar to either those used in clinical trials or those declared in studies describing the intended treatment. However, if we assume that a shorter duration of therapy or a reduced dose is used in practice, the recorded growth rates would be as expected and the Department of Health’s assessment that the cost per quality-adjusted life year (QALY) gained of drugs funded through the CDF would be twice as high as would that of other drugs reimbursed by the NHS (£50 000 vs £25 000) might have to be challenged. The difference was calculated to lead to a net health loss to the NHS worth £646 million8 (estimated as an additional 25 840 QALYs that could have been generated if the money had not been spent by the CDF). Our analysis suggests that drugs funded by the CDF might be used for shorter periods of time or at a lower dose than has been reported in clinical trials— which form the basis for the Department of Health’s calculations. In clinical practice, the most likely causes of decreased treatment duration or reduced dose are early disease progression or adverse events. If these are the explanation for the difference between actual and expected volume growth, then the cost per QALY of drugs funded by the CDF is probably higher than was anticipated in the assessment. Although decreased duration of treatment leads to reduced drug cost, such a decrease is unlikely to compensate for the loss of survival benefit or the increased frequency or effect

Figure 1: Growth in use per head in England of five cancer drugs after the launch of the Cancer Drug Fund in October, 2010 Proportions calculated with amount in mg used in year to July, 2010, used as the index value.

of adverse events. The health loss to the NHS would be thus even greater. This conclusion has implications for access to cancer drugs when the CDF closes in 2014, and when valuebased pricing is introduced. If the cost per QALY for drugs funded through the CDF is higher in clinical practice than was originally assumed, access to cancer drugs might be maintained only if health gains for people with cancer are valued more than twice as highly as are others. A switch of funding for these agents from the NHS to the CDF could also explain the difference. In this case, not all CDF applications would generate additional growth. Growth in one area would be cancelled out by losses in another. Guidance from the Department of Health in England states that the CDF should be “additional funding for new activity”,1 which would prevent any such switch. However, before the launch of the CDF, anecdotal evidence suggested that at least some of these drugs were funded by some primary care trusts via individual funding requests or commissioning policies. A negative NICE appraisal could have forced a review of such individual funding requests or commissioning policies, causing funding by these primary care trusts to cease and be replaced 755

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Figure 2: Per-head use of five cancer drugs by strategic health authorities in 12-month periods before and after the launch of the Cancer Drug Fund Proportions calculated with amount in mg used in England overall. Bevacizumab and cetuximab are combined because high use of one appeared to lead to reduced use of the other in some strategic health authorities.

by the CDF. Sorafenib, bevacizumab, and everolimus all received negative NICE decisions for specific indications in the period reviewed, although the same cannot be said for cetuximab or lapatinib. IMS Health data do have some limitations, which are discussed elsewhere.7 For example, IMS is unable to gather information from all home-care providers,7 and so might miss some growth. Whatever the reason for the differences, more complete data are needed to understand how cancer medicines are used in NHS England and what their real effect is, particularly on clinical outcomes. This view is reinforced by the differences in volume of use per head between England and other European countries. In the year to November, 2011, England spent less than 20% of the average per head for the five drugs of four European countries combined, with population and price differences taken into account (France, Germany, Italy, and Spain; data not shown). At one time, such differences could have been caused by reimbursement barriers in England that were not present in other systems. Such considerations have, however, been removed for these drugs in their licensed indications with the introduction of the CDF. 756

Are we in England less willing to offer chemotherapy or accept its associated toxicities than are others? Or are the differences in volume due to use earlier or later in treatment, fewer eligible patients, off-label use, or use outside guidelines? As yet, we cannot identify the drivers, and improved data are urgently needed, some of which may be provided by the newly commissioned audit of the CDF and the roll out of the systemic anticancer therapy dataset. However, the CDF has clearly had a significant effect on access to new cancer drugs and has reduced the postcode lottery between SHAs, although all CDF funds might not be being spent on new activity. Nevertheless, total usage remains much less than what is reported in some countries in Europe, raising the question of whether or not NHS England wishes to continue to measure itself against such countries without a precise understanding of the details of usage in these countries. The final question that remains is what will happen to the access of patients with cancer to these drugs when the CDF closes in 2014? The only answer that we can give is that if access to new cancer drugs is to remain at their present level, society will have to consider whether it values effective treatments for cancer more than twice as highly as those for other disorders. *Peter Stephens, David Thomson IMS Health, 7 Harewood Avenue, London, NW1 6JB, UK (PS); WHO Collaborating Centre for Pharmacoepidemiology and Pharmaceutical Policy Analysis, Utrecht Institute for Pharmaceutical Sciences, Utrecht, Netherlands (PS); and Yorkshire Cancer Network, Harrogate, UK (DT) [email protected] PS is employed by IMS Health, which provided data free of charge. IMS Health is funded through sales of information services to both industry and government, including all the companies whose products are described in this report. DT is employed by the Yorkshire Cancer Network and is involved in the CDF clinical panel in the Yorkshire and Humber SHA. DT has received consultancy payments in the past 3 years from Amgen, BMS, Boehringer Ingelheim, GlaxoSmithKline, MSD, Novartis, and Sanofi-Aventis; payment for lectures including service on speakers bureaus from Roche and Pfizer; and travel, accommodation, and meeting expenses unrelated to the activities listed above from Roche and Pfizer. We thank Aukje Mantel-Teeuwisse (WHO Collaborating Centre for Pharmacoepidemiology and Pharmaceutical Policy Analysis, Netherlands) for her comments on this report and IMS Health for providing the data. 1

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Keogh B. Interim cancer drugs funding: dear colleague letter. July 28, 2010. http://www.dh.gov.uk/en/Publicationsandstatistics/ Lettersandcirculars/Dearcolleagueletters/DH_117996 (accessed June 13, 2012). Department of Health. £50m kick starts greater access to cancer drugs. Oct 1, 2010. http://www.dh.gov.uk/en/MediaCentre/Pressreleases/ DH_120037 (accessed June 13, 2012).

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Cancer Network Pharmacists Forum. Response to the governments’ £50 million Interim Cancer Drugs Fund. Sept 8, 2010. http://www. bopawebsite.org/contentimages/publications/Position_Statement_on_ CancerDrugFund.pdf (accessed June 13, 2012). Dehnel T. Primary Care Trusts refuse to play NICEly. Lancet Oncol 2012; 13: e7. Hope J. Cancer fund betrayal: it promised £200m for vital drugs, but millions haven’t been spent—and patients are paying the price. Dec 26, 2011. http:// www.dailymail.co.uk/health/article-2078575/Cancer-Drugs-Fund-Millionshavent-spent--patients-paying-price.html (accessed June 13, 2012). Rarer Cancers Foundation. The Cancer Drugs Fund (CDF)—an overview of progress so far. http://www.rarercancers.org/images/stories/news/0112/ cdf_overview_of_numbers_and_treatment_requests_-_ december_2011_2.pdf (accessed June 13, 2012).

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Richards M. Variations in usage of cancer drugs approved by NICE Report of the Review undertaken by the National Cancer Director http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@ dh/@en/documents/digitalasset/dh_4083895.pdf (accessed June 13, 2012). Department of Health. Impact assessment of proposal for a Cancer Drug Fund. Oct 26, 2010. http://www.dh.gov.uk/prod_consum_dh/groups/ dh_digitalassets/@dh/@en/documents/digitalasset/dh_120930.pdf (accessed June 13, 2012).

Will the medical student in the team please stand up?

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that they do not find educational, but also that an opportunity for clinical learning based on real patient cases and evidence-based medicine is being missed. We presented four hypothetical scenarios to students and asked them to rate them as ways to increase the educational value of multidisciplinary team meetings for students and trainees: a mock meeting for three to four students to run for other students about typical cases following guidelines; a short session after the meeting for students to ask questions and exchange views; signalling of the cases that are most typical for students to focus on; and a list of web links at the end of the meeting to give background on specific cases. In all three countries surveyed, students consistently rated the idea of a short session after the meeting and a signalling of the cases to focus on as good (34–54%) or very good (25–40%). Finally, students were asked for their own suggestions to improve the educational value of the multidisciplinary team meetings that they attend. The most frequent suggestion was increased participation by students in the meeting. Students also suggested having a pre-meeting to make educational cases available for discussion and to draw attention to the key learning points in advance. Although cancer will affect one in three individuals in countries such as the UK, oncology learning is very poorly represented in medical school curricula, sometimes totalling 2 days or less of clinical training in the core syllabus. This under-representation has prompted the UK Joint Council for Clinical Oncology to set up the Undergraduate Curriculum Working Group in June this year to try to address this national deficit. Its primary aim is to produce a national core curriculum to define basic competency in cancer medicine for medical students. Furthermore, if medical students are not inspired to study

Mark Thomas/Science Photo Library

Multidisciplinary team meetings have become routine in many developed countries to establish the standard of cancer care for individual patients. These meetings can improve communication between team members and enhance coordination and continuity of care.1 For example, evidence shows that multidisciplinary teams can increase resection rates,2 reduce treatment variance,3 and improve health outcomes after discharge.4 Although the participation of medical students is encouraged and can be mandatory during several clinical attachments, the educational value of such participation has not been examined. Multidisciplinary team meetings are focused on clinical decision making, but the information proffered during these meetings is not always accessible to students for learning. Furthermore, core members of the team might object to extra time being spent on educational points during the meeting, potentially affecting the effectiveness of the team in reaching clinical decisions. We asked for the opinions of 161 medical students in three countries—Brazil, England, and Belgium—and received 100 responses via a web-based questionnaire in English. 96 students attended multidisciplinary team meetings regularly as part of their clinical training. Students were asked if they thought that such meetings were educational: 65% said yes in Brazil (17 of 26) and 62% in Belgium (24 of 39), compared with just 26% in England (nine of 35). This finding might relate to cultural differences in the perception of clinical experiences in different medical schools, or to the amount of time allowed within multidisciplinary team meetings to discuss complex cases, which can be very limited in the UK.5,6 The finding raises concerns since it not only suggests that medical students are being forced to attend meetings

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