Published Ahead of Print on February 17, 2016 as 10.1212/WNL.0000000000002500
EDITORIAL
Testing HLA-B*15:02 Is it worth it?
Anthony Marson, MB ChB, MD, FRCP Renzo Guerrini, MD
Correspondence to Dr. Marson: [email protected] Neurology® 2016;86:1–2
Persons carrying the HLA-B*15:02 allele (predominantly those of Asian descent) are at high risk of hypersensitivity reactions to carbamazepine, including Stevens-Johnson syndrome and toxic epidermal necrolysis.1 Having considered the data on risk, regulatory authorities, including the Food and Drug Administration and European Medicines Agency, recommend HLA-B*15:02 testing before starting treatment.2 When making a recommendation about testing, regulators will not usually consider health economic (cost-effectiveness) or wider effects on patient care, nor will they consider how such recommendations should be implemented in complex heath systems. Not surprisingly therefore, there is potential for such recommendations to have consequences on services and use of health care resources, which may not be in the best interest of patients or the wider society. In this issue, Chen et al.3 report a study in which they use economic modeling and retrospective data from 3 years before to 3 years after HLA-B*15:02 testing was recommended in Hong Kong (2008) to estimate the cost-effectiveness of the policy of recommending HLA-B*15:02 testing. The results make interesting reading for clinicians, and for those responsible for health policy, and should spark debate as to what information is required to inform policy decisions around pharmacogenetic testing and how such policies should be implemented. Data were available for 13,231 patients starting treatment for newly diagnosed epilepsy, of which 6,231 were identified in the prepolicy and 7,000 in the postpolicy period. The most commonly prescribed drugs were valproate and phenytoin. For carbamazepine, 761 were started on treatment with carbamazepine before and 230 after the testing policy. In the postpolicy period, only 553 underwent HLA-B*15:02 testing, of whom only 141 were fully compliant with policy—that is, carbamazepine prescribed after negative test or alternative antiepileptic drug (AED) prescribed after positive test. Chen et al. conclude that HLA-B*15:02 testing as implemented in Hong Kong was not cost-effective; incremental cost-effectiveness ratio (ICER) was around US $86,000 per quality adjusted life year (QALY), which
is well above the common threshold of US $50,000 per QALY. The main consequence of the policy was that clinicians opted to prescribe alternative AEDs to carbamazepine rather than test for HLA-B*15:02. Those alternative AEDs were more expensive and as a result the annual AED cost rose from US $164 before to US $205 after the testing policy. These additional drug costs were a major factor in the ICER estimate. Chen et al. estimate an ICER of $11,000 per QALY for the ideal situation of full policy compliance, in which more carbamazepine is prescribed avoiding more expensive alternatives. If testing were to be extended to phenytoin, they estimate an ICER of around US $200,000 per QALY, which is well above what any health economy can currently afford. The study by Chen et al. has a number of methodologic limitations; it is a retrospective study, and a wide range of assumptions are made in the economic modeling. The study is therefore at risk of a number of important biases that make it difficult to asses whether the policy of HLA-B*15:02 is the only (or the main) factor responsible for the changes observed. It is likely that increased awareness of risk produced a change in practice that resulted in the use of alternative AEDs to carbamazepine, as well as HLA-B*15:02 testing in a minority of patients. So, while the HLA-B*15:02 testing policy may be only one of a range of factors responsible for the observed changes, it is clear that changes in the service in Hong Kong have not been cost-effective and that scarce health care resources could have been better spent. The most reliable evidence about the clinical and cost-effectiveness of HLA-B*15:02 testing, as for any health care intervention, will come from randomized controlled trials (RCTs), although there are currently few RCTs of pharmacogenetic tests, particularly those aimed at preventing harm rather than to stratify for benefits. Recruiting to RCTs requires equipoise, and while there is likely to be equipoise about the cost-effectiveness of HLA-B*15:02 testing, there may not be equipoise about clinical benefits as clinicians and patients may express a preference to test, or choose an alternative AED with lower risk. The only likely context in which an RCT could proceed would
See page XXX From the University of Liverpool (A.M.), UK; and University of Florence (R.G.), The Children’s Hospital A. Meyer, Florence, Italy. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. © 2016 American Academy of Neurology
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
be one in which testing was not approved in routine practice, and would become so only if RCTs proved benefit. Given the risk associated with the HLAB*15:02 allele, it is unlikely that the clinicians and patients would find this approach acceptable. If there is a mandate that a pharmacogenetic test should be available, in the absence of high-quality evidence about clinical and cost-effectiveness, how would it be best implemented in clinical services? The study by Chen et al. highlights the fact that a regulatory recommendation does not miraculously result in the implementation of a well-organized and efficient service. That requires adequate planning, education, and monitoring. It may be that failure to educate physicians about the risks of adverse effects and the benefits of screening was a major factor diminishing the cost-effectiveness of the policy. In particular, risks associated with other drugs, including phenytoin, may have been overlooked. Poor adherence to the screening policy may have been caused by low confidence among clinicians and patients in the ability of genomic technology to stratify risk and help personalize treatment decisions, a problem recognized by the Food and Drug Administration.4 Many AEDs are used for indications other than epilepsy, and genetic markers of hypersensitivity reactions are likely to become available for carbamazepine and other AEDs for a range of ethnic groups. Implementation and education programs are therefore needed across a range of health care settings to facilitate the use of pretreatment genetic tests, for which
2
Neurology 86
costs and turnaround times are reducing. It is likely that the upfront cost of planning and properly implementing a service would reduce unintended consequences and avoid inefficient use of scarce resources. The study by Chen et al. highlights inadequacies in our current health systems. We need to agree what clinical and cost-effectiveness evidence is required before testing is recommended, and consider and assess how best to implement services. Failure to do so will likely result in inefficient use of health care resources and could result in poorer outcomes for patients. STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428:486. 2. US Food and Drug Administration. Information for healthcare professionals: dangerous or even fatal skin reactions— carbamazepine (marketed as Carbatrol, Equetro, Tegretol, and generics) [online]. Available at: http://www.fda.gov/ Drugs/DrugSafety/Postmarketdrugsafetyinformationfor PatientsandProviders/ucm124718.htm. Accessed November 26, 2014. 3. Chen Z, Liew D, Kwan P. Real-world cost-effectiveness of pharmacogenetic screening for epilepsy treatment. Neurology 2016;86:xxx–xxx. 4. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med 2015;372:793–795.
March 22, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Testing HLA-B*15:02: Is it worth it? Anthony Marson and Renzo Guerrini Neurology published online February 17, 2016 DOI 10.1212/WNL.0000000000002500 This information is current as of February 17, 2016 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2016/02/17/WNL.0000000000 002500.full.html
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Epilepsy/Seizures http://www.neurology.org//cgi/collection/all_epilepsy_seizures Antiepileptic drugs http://www.neurology.org//cgi/collection/antiepileptic_drugs Cost effectiveness/economic http://www.neurology.org//cgi/collection/cost_effectiveness_economic _
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2016 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
EDITORIAL
Testing HLA-B*15:02 Is it worth it?
Anthony Marson, MB ChB, MD, FRCP Renzo Guerrini, MD
Correspondence to Dr. Marson: [email protected] Neurology® 2016;86:1–2
Persons carrying the HLA-B*15:02 allele (predominantly those of Asian descent) are at high risk of hypersensitivity reactions to carbamazepine, including Stevens-Johnson syndrome and toxic epidermal necrolysis.1 Having considered the data on risk, regulatory authorities, including the Food and Drug Administration and European Medicines Agency, recommend HLA-B*15:02 testing before starting treatment.2 When making a recommendation about testing, regulators will not usually consider health economic (cost-effectiveness) or wider effects on patient care, nor will they consider how such recommendations should be implemented in complex heath systems. Not surprisingly therefore, there is potential for such recommendations to have consequences on services and use of health care resources, which may not be in the best interest of patients or the wider society. In this issue, Chen et al.3 report a study in which they use economic modeling and retrospective data from 3 years before to 3 years after HLA-B*15:02 testing was recommended in Hong Kong (2008) to estimate the cost-effectiveness of the policy of recommending HLA-B*15:02 testing. The results make interesting reading for clinicians, and for those responsible for health policy, and should spark debate as to what information is required to inform policy decisions around pharmacogenetic testing and how such policies should be implemented. Data were available for 13,231 patients starting treatment for newly diagnosed epilepsy, of which 6,231 were identified in the prepolicy and 7,000 in the postpolicy period. The most commonly prescribed drugs were valproate and phenytoin. For carbamazepine, 761 were started on treatment with carbamazepine before and 230 after the testing policy. In the postpolicy period, only 553 underwent HLA-B*15:02 testing, of whom only 141 were fully compliant with policy—that is, carbamazepine prescribed after negative test or alternative antiepileptic drug (AED) prescribed after positive test. Chen et al. conclude that HLA-B*15:02 testing as implemented in Hong Kong was not cost-effective; incremental cost-effectiveness ratio (ICER) was around US $86,000 per quality adjusted life year (QALY), which
is well above the common threshold of US $50,000 per QALY. The main consequence of the policy was that clinicians opted to prescribe alternative AEDs to carbamazepine rather than test for HLA-B*15:02. Those alternative AEDs were more expensive and as a result the annual AED cost rose from US $164 before to US $205 after the testing policy. These additional drug costs were a major factor in the ICER estimate. Chen et al. estimate an ICER of $11,000 per QALY for the ideal situation of full policy compliance, in which more carbamazepine is prescribed avoiding more expensive alternatives. If testing were to be extended to phenytoin, they estimate an ICER of around US $200,000 per QALY, which is well above what any health economy can currently afford. The study by Chen et al. has a number of methodologic limitations; it is a retrospective study, and a wide range of assumptions are made in the economic modeling. The study is therefore at risk of a number of important biases that make it difficult to asses whether the policy of HLA-B*15:02 is the only (or the main) factor responsible for the changes observed. It is likely that increased awareness of risk produced a change in practice that resulted in the use of alternative AEDs to carbamazepine, as well as HLA-B*15:02 testing in a minority of patients. So, while the HLA-B*15:02 testing policy may be only one of a range of factors responsible for the observed changes, it is clear that changes in the service in Hong Kong have not been cost-effective and that scarce health care resources could have been better spent. The most reliable evidence about the clinical and cost-effectiveness of HLA-B*15:02 testing, as for any health care intervention, will come from randomized controlled trials (RCTs), although there are currently few RCTs of pharmacogenetic tests, particularly those aimed at preventing harm rather than to stratify for benefits. Recruiting to RCTs requires equipoise, and while there is likely to be equipoise about the cost-effectiveness of HLA-B*15:02 testing, there may not be equipoise about clinical benefits as clinicians and patients may express a preference to test, or choose an alternative AED with lower risk. The only likely context in which an RCT could proceed would
See page XXX From the University of Liverpool (A.M.), UK; and University of Florence (R.G.), The Children’s Hospital A. Meyer, Florence, Italy. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. © 2016 American Academy of Neurology
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
be one in which testing was not approved in routine practice, and would become so only if RCTs proved benefit. Given the risk associated with the HLAB*15:02 allele, it is unlikely that the clinicians and patients would find this approach acceptable. If there is a mandate that a pharmacogenetic test should be available, in the absence of high-quality evidence about clinical and cost-effectiveness, how would it be best implemented in clinical services? The study by Chen et al. highlights the fact that a regulatory recommendation does not miraculously result in the implementation of a well-organized and efficient service. That requires adequate planning, education, and monitoring. It may be that failure to educate physicians about the risks of adverse effects and the benefits of screening was a major factor diminishing the cost-effectiveness of the policy. In particular, risks associated with other drugs, including phenytoin, may have been overlooked. Poor adherence to the screening policy may have been caused by low confidence among clinicians and patients in the ability of genomic technology to stratify risk and help personalize treatment decisions, a problem recognized by the Food and Drug Administration.4 Many AEDs are used for indications other than epilepsy, and genetic markers of hypersensitivity reactions are likely to become available for carbamazepine and other AEDs for a range of ethnic groups. Implementation and education programs are therefore needed across a range of health care settings to facilitate the use of pretreatment genetic tests, for which
2
Neurology 86
costs and turnaround times are reducing. It is likely that the upfront cost of planning and properly implementing a service would reduce unintended consequences and avoid inefficient use of scarce resources. The study by Chen et al. highlights inadequacies in our current health systems. We need to agree what clinical and cost-effectiveness evidence is required before testing is recommended, and consider and assess how best to implement services. Failure to do so will likely result in inefficient use of health care resources and could result in poorer outcomes for patients. STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428:486. 2. US Food and Drug Administration. Information for healthcare professionals: dangerous or even fatal skin reactions— carbamazepine (marketed as Carbatrol, Equetro, Tegretol, and generics) [online]. Available at: http://www.fda.gov/ Drugs/DrugSafety/Postmarketdrugsafetyinformationfor PatientsandProviders/ucm124718.htm. Accessed November 26, 2014. 3. Chen Z, Liew D, Kwan P. Real-world cost-effectiveness of pharmacogenetic screening for epilepsy treatment. Neurology 2016;86:xxx–xxx. 4. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med 2015;372:793–795.
March 22, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Testing HLA-B*15:02: Is it worth it? Anthony Marson and Renzo Guerrini Neurology published online February 17, 2016 DOI 10.1212/WNL.0000000000002500 This information is current as of February 17, 2016 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2016/02/17/WNL.0000000000 002500.full.html
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Epilepsy/Seizures http://www.neurology.org//cgi/collection/all_epilepsy_seizures Antiepileptic drugs http://www.neurology.org//cgi/collection/antiepileptic_drugs Cost effectiveness/economic http://www.neurology.org//cgi/collection/cost_effectiveness_economic _
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2016 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
