Appl Health Econ Health Policy (2018) 16:429–432 https://doi.org/10.1007/s40258-018-0393-7 COMMENTARY EMA and NICE Appraisal Processes for Cancer Drugs: Current Status and Uncertainties 1 1 1 1 • • • • Rumona Dickson Angela Boland Rui Duarte Eleanor Kotas 2 2 3 4 • • • • Nerys Woolacott Robert Hodgson Rob Riemsma Sabine Grimm 4 4 5 6 • • • • Bram Ramaekers Manuela Joore Nasuh Bu ¨ yu ¨ kkaramikli Eva Kaltenthaler 6 6 7 8 • • • • Matt Stevenson Abdullah Pandor Steve Edwards Martin Hoyle 9 10 11 • • Jonathan Shepherd Xavier Armoiry Miriam Brazzelli Published online: 28 May 2018 The Author(s) 2018 1 Appraisal Processes for Cancer Drugs Recently, Davis et al.  reported that the majority of oncology drugs approved by the EMA between 2009 and The European Medicines Agency (EMA) began operating 2013 were ‘‘…without evidence of beneﬁt on survival or in 1995 with the aim of evaluating the clinical efﬁcacy and quality of life’’ . The authors reported that, at the time of safety of new medicines prior to their entry into the EMA assessment, signiﬁcant prolongation of survival was European Union (EU) market. In addition, the EMA reported for 24 out of 68 indications (35%) and there was ensures that the beneﬁts of the medicines authorised for use an improvement in quality of life for seven out of 68 in the EU outweigh their risks by continuing to monitor indications (10%). The clinical beneﬁt of the new drugs their safety after approval through their pharmacovigilance remained uncertain for 33 out of 68 indications (49%) after programme . a median follow-up of 5.4 years post-marketing authori- sation . In England, the National Institute for Health and Care Excellence (NICE) has a mandate to appraise drugs & Rumona Dickson approved by the EMA in a timely fashion with a view to email@example.com making recommendations regarding their routine use in the Liverpool Reviews and Implementation Group, University of National Health Service (NHS) . This mandate makes it Liverpool, Whelan Building, Liverpool L69 3GB, UK necessary for NICE appraisals to be undertaken using the Centre for Reviews and Dissemination, University of York, data available at the time of, or near the point of, regulatory York, UK approval. The level of evidence that informs the EMA’s Kleijnen Systematic Reviews, York, UK conclusion of a positive beneﬁt/risk balance therefore plays Department of Clinical Epidemiology and Medical a large part in determining the level of uncertainty present Technology Assessment, Maastricht University Medical in each NICE appraisal. Center, Maastricht, The Netherlands Evidence submissions from the sponsors of new oncol- Institute for Medical Technology Assessment, Erasmus ogy drugs to NICE are critiqued by independent Evidence University Rotterdam, Rotterdam, The Netherlands Review Groups (ERGs) and subsequent recommendations School of Health and Related Research, The University of for use are made by one of the four NICE appraisal com- Shefﬁeld, Shefﬁeld, UK mittees. In this commentary, authored by representatives of BMJ Technology Assessment Group, BMJ, London, UK the nine ERGs, we report the results of our comparison of Peninsula Technology Assessment Group, University of the oncology drugs approved by the EMA between 2009 Exeter Medical School, Exeter, UK and 2013  and the appraisal decisions made by NICE in the Single Technology Appraisal (STA) process. We then Southampton Health Technology Assessments Centre, University of Southampton, Southampton, UK reﬂect on the newly revised Cancer Drugs Fund (CDF)  and highlight some of the challenges that we feel policy Warwick Evidence, University of Warwick, Coventry, UK makers may face in the future. Health Services Research Unit, University of Aberdeen, Aberdeen, UK 430 R. Dickson et al. appraisal processes that take into consideration both clini- 2 Methods cal and cost effectiveness whilst attempting to ensure that Electronic searches were conducted using the NICE guid- patients receive effective treatments in a timely manner. ance website  to identify the drugs approved by the EMA for oncology indications between 2009 and 2013. We 4 Referrals to the UK Cancer Drugs Fund then determined how many of these drugs had been con- sidered as part of the NICE appraisal process and recorded In an analysis of the UK CDF, Aggarwal et al.  (like the resultant decisions taken by the NICE appraisal com- mittee. Finally, we reviewed the CDF listings  to iden- Davis et al. ) reported a lack of clinical beneﬁt for the 29 cancer drugs approved for 47 indications that could have tify how many of these drugs were available to the NHS been accessed through the CDF in January 2015. Aggarwal through this fund. et al.  concluded that ‘‘…the majority of CDF-approved Data extracted included the NICE appraisal committee indications have been based on studies that reported min- recommendation following publication of the ﬁnal apprai- sal determination, whether there were limitations in the imal to no beneﬁt in survival.’’ However, since July 2016, there has been a signiﬁcant recommended use of the drug and if the drug was to be provided at a discounted cost in the UK (e.g. via a patient change in the CDF with the responsibility for it shifting to NHS England and NICE . In the new process, NICE access scheme). refers a cancer drug to the CDF in situations where there is a ‘plausible potential’ that, with additional data, the drug could be recommended for routine commissioning in the 3 NICE Recommendations NHS . The drug is then available to patients through the fund and further data on effectiveness can be collected to The NICE appraisal committees can issue a number of inform a new appraisal of the cost effectiveness of the possible recommendations in any given appraisal. The intervention at a future date, usually within 2 years of the recommendations can be classiﬁed into the following cat- egories : initial referral. Up until March 2018, NICE had referred a total of 36 drugs (for 53 different indications) to the CDF. • recommended for use at the stated price or at a Of the oncology treatments considered in this commentary, discounted price offered by the sponsor of the a total of 15 drugs for 16 indications approved by NICE are submission; being monitored through the CDF. • recommended for optimised use, meaning that the technology is only recommended for a subgroup of the patients listed in the EMA marketing authorisation (e.g. 5 Current Uncertainties based on factors such as disease stage or progression, or receipt of previous treatments); NICE has an important role as an assessor of both the • recommended for use within the new CDF; clinical and cost effectiveness of oncology drugs approved • recommended for use only in research; for use by the EMA. However, as outlined by Woolacott • not recommended. et al. , there are methodological challenges to assessing A summary of the decisions taken by NICE related to effectiveness when the clinical evidence available to the regulators is limited and/or immature. For example, there the 68 cancer indications for drugs that the EMA approved between 2009 and 2013 is presented in Table 1. There are a has been an increase in the number of NICE appraisals where the only clinical effectiveness data available for number of interesting issues to examine from these data. consideration comes from single-arm, non-comparative NICE awarded a positive recommendation in 45 out of the 57 oncology indications (79%) that it did appraise. Of studies that often have small numbers of patients and limited follow-up. Over the past year (i.e. March 2017 to these, eight (18%) received what is known as an optimised recommendation. In addition, of the 45 positive recom- March 2018), there have been 14 such submissions that the ERGs have been asked to critique. Having to make deci- mendations, 37 (82%) were for oncology drugs that were recommended by NICE only when they were made avail- sions based on limited data invariably leads to assumptions in economic models that consequently result in increased able at a discounted price to the NHS. Finally, NICE did not carry out an appraisal of 11 of the drugs approved by uncertainty in the cost-effectiveness results, which is often not appropriately reﬂected (i.e. not parameterised in the the EMA between 2009 and 2013. Therefore, it can be seen that the NICE appraisal process model, not sufﬁciently explored in scenario analysis). Given these complexities and the considerable uncertainty, is fulﬁlling its mandate through the application of rigorous it is not clear whether all of the positive recommendations EMA and NICE Appraisal Processes for Cancer Drugs 431 Table 1 NICE decisions for indications related to the cancer drugs approved by the EMA between 2009 and 2013 Outcome Positive Optimised Cancer Drugs Total recommendation recommendation Fund Positive recommendation (at list price) 6 2 0 8 Positive recommendation at a discounted price 15 6 16 37 Not recommended 12 No NICE recommendation 11 No company submission [n = 3] Unable to differentiate drug and indication on the NICE website [n = 3] Not referred to NICE [n = 2] Suspended or discontinued [n = 2] In progress [n = 1] Total 21 8 16 68 by NICE would be justiﬁed had more deﬁnitive data been As researchers responsible for critiquing evidence sub- available, or whether such recommendations truly resulted missions to the NICE appraisal process, we ﬁnd ourselves in improvements in patient outcomes. facing increasing uncertainty: We acknowledge that, given all of these uncertainties, it – Uncertainty in the clinical data available as we note the is becoming more challenging for NICE and other national increase in the number of NICE appraisals that are HTA agencies to make recommendations about the adop- using data from small, single-arm studies with short- tion of clinical- and cost-effective technologies. While all term follow-up. HTA agencies continue to strive to improve their appraisal – Uncertainty in the way the newly introduced CDF processes, sponsors should be encouraged not only to process will monitor the drugs approved through this collect good quality clinical evidence over the long term mechanism and how information will ﬂow back into but also to make this information routinely available to the NICE appraisal process. HTA agencies. There has been a recent victory in the – Uncertainty due to potential changes in the NICE European Court of Justice allowing for the release of appraisal process coming into effect in April 2018 that clinical data by the EMA and there are hopes that there will include new roles for the NICE appraisal committees, be further steps taken to improve the transparency of the NICE appraisal teams and the ERGs providing clinical data . critiques of the submitted evidence . In England, NICE is working hard to ensure that cancer drugs with uncertain beneﬁts are recommended for use As regulatory authorities continue to approve cancer drugs that have uncertain beneﬁts at the time of licensing, it only when accompanied by careful monitoring via the new CDF. The potential total beneﬁts to patients of early access increasingly becomes the responsibility of every national to promising new treatments will be realised more quickly HTA agency to ensure that the post-marketing survival than ever before. We welcome this approach as it means beneﬁts of these drugs are closely monitored. Indeed, that, where the beneﬁts of new cancer drugs are uncertain willingness to address these uncertainties must be a priority at the time of marketing authorisation, patient outcomes for all parties involved in HTA. can be monitored without denying patients early access to Of course, added to this, there is the uncertainty of how these new treatments. Drugs in the CDF are to be reviewed medicines will be licensed in the UK following departure usually within a period of 2 years and will then undergo from the EU in 2019, and how, in turn, this will affect the current NICE drug appraisal process . further appraisal with only cost-effective drugs with proven beneﬁts being recommended for use in the NHS. It is of Compliance with Ethical Standards note that the pathway to a CDF recommendation and design of potential data collection is currently not clearly Conﬂict of interest Rumona Dickson, Angela Boland, Rui Duarte, deﬁned. The inclusion of a formal step, in which the value Eleanor Kotas, Nerys Woolacott, Robert Hodgson, Rob Riemsma, ¨ ¨ of data collection is assessed compared to its cost and the Sabine Grimm, Bram Ramaekers, Manuela Joore, Nasuh Buyukkar- amikli, Eva Kaltenthaler, Matt Stevenson, Abdullah Pandor, Steve cost of making the new drug available through the CDF, Edwards, Martin Hoyle, Jonathan Shepherd, Xavier Armoiry and may aid in ensuring the efﬁciency of the CDF. Miriam Brazzelli have no competing interests. 432 R. Dickson et al. Funding The Evidence Review Group members that contributed to 4. McCabe C, Paul A, Fell G, Paulden M. Cancer Drugs Fund 2.0: a this editorial are funded by the UK NIHR HTA Programme. The missed opportunity? PharmacoEconomics. 2016;34(7):629–33. views and opinions expressed are those of the authors and do not 5. National Institute for Health and Care Excellence. 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Published: May 28, 2018