Opening Pandora's box in the UK: a hypothetical pharmacogenetic test for clozapine
Transcript of Opening Pandora's box in the UK: a hypothetical pharmacogenetic test for clozapine
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Opening Pandora’s box in the UK: a hypothetical pharmacogenetic test for clozapine
Benjamin W J Spencer1,2, Barbara Prainsack3, Dan Rujescu4, Ina Giegling4, David A Collier3,5, Fiona Gaughran1,2, James H MacCabe1,2, Cathy L Barr6,7, Engilbert Sigurdsson8,9, Henrik Stovring10, Anil K Malhotra11,12, Sarah R Curran1,2
And the CRESTAR Consortium.
This is not the final version! For final version please see: http://www.futuremedicine.com/doi/abs/10.2217/pgs.13.182
Citation: Spencer BWJ et al. Opening Pandora’s box in the UK: a hypothetical pharmacogenomics test for clozapine. Pharmacogenomics 14/15: 1907-1914.
1. South London and Maudsley NHS Foundation Trust, London, UK 2. Institute of Psychiatry, King’s College London, London, UK 3. Department of Social Science, Health and Medicine, King’s College London, London, UK 4. Dept. of Psychiatry, University of Halle, Germany 5. Eli Lilly and Company Ltd, Erl Wood, UK 6. The Toronto Western Research Institute, Toronto, Ontario, Canada 7. The Hospital for Sick Children, Toronto, Ontario, Canada 8. University of Iceland, Reykjavik, Iceland 9. Department of Psychiatry, Landspitali-University Hospital, Reykjavik, Iceland 10. Department of Public Health, Aarhus University, Denmark 11. The Zucker Hillside Hospital, Glen Oaks, NY, USA 12. Hofstra North Shore-LIJ School of Medicine, Hemptead, NY, USA
Keywords
clozapine, legal, ethics, antipsychotic, psychiatry, schizophrenia, capacity, probabilistic, licensing, pharmacogenetic
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Abstract
Clozapine is a uniquely efficacious antipsychotic drug in treatment resistant schizophrenia. Its use is restricted due to adverse effects including a rare but dangerous reduction in neutrophils (agranulocytosis) and the mandatory haematological monitoring this entails in many countries. We review the statistical, ethical, and legal issues arising from a hypothetical pharmacogenetic test for clozapine, using the UK as an exemplary case for consideration.
Our key findings include: a consideration of the probabilistic results that a pharmacogenetic test may return; the impact on drug licensing; and the potential for pharmacogenetic tests for clozapine being used without consent under the UK’s legal framework. We make recommendations regarding regulatory changes applicable to the special case of pharmacogenetic testing in clozapine treatment.
Introduction
Pharmacogenetic testing has created much expectation, such as the potential for a ‘tidal wave that would sweep away the old patterns of healthcare’ [1]. In psychiatric research efforts have been considerable, but with limited applications in clinical practice so far, in contrast to areas such as HIV treatment (see for example Lai-Goldman and Faruki 2008 regarding adoption of a pharmacogenetic test to predict hypersensitivity to abacavir [2]).
The task of developing useful pharmacogenetic markers may be particularly challenging in psychiatry owing to multiple factors: the complexity of psychiatric diseases and need to rely on diagnostic manuals such as the DSM-IV [3] and ICD-10 [4] with their inherent difficulties; comorbidity is the rule rather than an exception in most mental disorders; there are no valid and reliable diagnostic and prognostic biological markers, in contrast to other disorders such as type 2 diabetes (e.g. blood glucose, elevated blood pressure, low HDL cholesterol, and elevated triglycerides)[5] for or atrial fibrillation (e.g. ECG, troponin and natriuretic peptides)[6] ; the need for very large samples with comparable clinical data; and last but not least the scarcity of genetic markers that have been related to psychiatric diseases with medium to large effect sizes.
Clozapine is the only antipsychotic drug with consistently proven efficacy in treatment resistant schizophrenia [7]. In the UK, the National Institute for Health and Clinical Excellence (NICE) recommends that clozapine be offered to ‘people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs’ [8]. This is equivalent to the US licence for the use of clozapine in ‘the treatment of
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severely ill patients with schizophrenia who fail to show an acceptable response to adequate courses of standard antipsychotic drug treatment’ (US Food and Drug Administration). Therefore, if a patient has a treatment-resistant psychosis, then clozapine is the only evidence based drug treatment. Clozapine has also been shown to be effective as a first line treatment for schizophrenia [9]. However, it is rarely used in this context because treatment can be complicated by a range of side-effects which include diabetes, diabetic ketoacidosis, severe constipation, ileus (which can be fatal), sialorrhoea, seizures, sedation, marked weight gain, myocarditis, and cardiomyopathy [10, 11]. Of particular salience is the rare but potentially fatal side effect of agranulocytosis, which has resulted in mandatory haematological monitoring within many regulatory systems including the UK and USA, thus limiting the licensing of the drug to treatment resistant patients.
There is substantial evidence that clozapine is underused in the UK, with an average delay of five years [12], although the reasons for this have not yet been fully explored, and existing research suggests that they are multi-fold and complex (see for example Howes et al. 2012 [13]). In the USA, clozapine use remained flat at 2-3% in the period from 1999-2006, in contrast to the rapid rise in use of other atypical antipsychotics [14]. Regardless of cause, this underuse and delay results in patients not receiving treatment with potentially significant beneficial effects. A successful pharmacogenetic test could lead to earlier treatment or relax the very stringent haematological monitoring regulations, with a profound impact on patient care and save valuable health-service resources. At the same time, it raises a few substantial ethical and legal issues.
Due to the difficulties in using the highly effective antipsychotic clozapine in clinical practice, research into the pharmacogenetics of this drug has been given a particular focus in the CRESTAR consortium, a consortium recently funded by the EU [15].
In this paper we review the ethical and legal challenges surrounding a putative pharmacogenetic test specific to clozapine treatment in schizophrenia. We address how it might operate in practice; the potential ethical issues around its clinical use; and the current legal framework as exemplified by the UK. In conclusion we make suggestions for future regulatory considerations and research, specifically pertaining to changes to drug licensing and legal provisions for the protection of those unable to consent.
Pharmacogenetic testing for clozapine
Pharmacogenetic research can study adverse outcomes or tolerability of drugs (‘safety pharmacogenetics’) or the efficacy of drugs (‘efficacy pharmacogenetics’) [16, 17]. Both can be investigated through predicting the pharmacokinetics of the target drug (the metabolism of the drug), or the pharmacodynamics (the effects of the drug in terms of the efficacy and adverse effects). For treatment with clozapine, an ideal pharmacogenetic test would predict treatment response, predict non-response
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to alternative antipsychotics, predict side-effect burden, and crucially, predict risk of agranulocytosis.
To date the most studied aspect of pharmacogenetics in schizophrenia has been in the pharmacokinetic domain [18]. This is because of the well characterised major metabolic pathways, the cytochrome P450 system, and the relatively easily measurable serum drug levels following a given dose of the target drug [19]. The blood level of clozapine is influenced by the many environmental factors influencing the pharmacokinetics of a drug. A simple example for this is smoking and diet (for a review see Arranz and Kapur 2008) [19]. There are limitations to the utility in clinical practice of a test predicting plasma levels for a given dose, as plasma levels are easily and inexpensively measured and the dose adjusted accordingly, and environmental factors such as smoking can have a profound impact on the pharmacokinetics of the drug [20]. Evidence suggesting an optimal plasma level of clozapine, either for prevention of adverse events or treatment efficacy is mixed [21]. Commercial pharmacogenetic tests designed for evaluating the P450 system have to date not been successful [18], perhaps in part due to the lack of prospective studies to assess their utility in clinical practice. There continues to be interest, however, in their use with other older antipsychotics [22] and antidepressants [23] where therapeutic windows are narrow.
Pharmacodynamic genetics research is still in its infancy in mental health. Psychiatry faces particular challenges due to the lack of objective biomarkers, difficulties in reliably classifying the clinical phenotype [24], and the complexity of gene environmental interactions in both clinical phenotypes and in treatment response [25]. Given this, purely genetic data is unlikely to provide a ‘gold standard’ treatment-response prediction of around 80-90% [19] and the predictive values are likely to be much lower, requiring clinical and other context for useful application [18, 19].
There has been some success in finding genetic loci that increase risk of agranulocytosis in clozapine-treated patients, but the utility of these markers remains limited. The cumulative incidence of agranulocytosis defined as an absolute neutrophil count ≤0.5×109/L [26] on clozapine at one year is 0.8% [27], making it a rare adverse outcome. Assuming a prevalence of 0.8% the sensitivity and specificity of the test need to be extremely large for it to be clinically useful (see box 1). The low positive predictive value (PPV) led to the failure of a commercially marketed test for the human leucocyte antigen (HLA) allele HLA-DQB1 associated with agranulocytosis [28, 29, 30], and very high negative predictive values (NPV) would be needed to have an impact on the haematological monitoring.
[box 1 about here]
It seems likely that any clozapine pharmacogenetic test either for efficacy or rare adverse drug reactions would return probabilistic results that would not lead to an answer that would clearly direct treatment. For example it would lead to tests with low PPVs in rare adverse events (such as agranulocytosis), and it would predict marginally increased odds of common outcomes (such as weight gain). Many experts have considered that to make a pharmacogenetic test meaningful it would
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need to incorporate clinical data as part of a computational algorithm and therefore return complex probabilistic results [18, 31]. Indeed, several authors using genotypic data to predict response to clozapine have all shown how including clinical variables with genotypic data can improve predictive accuracy with both logistical regression [32, 33] and neuronal network modelling [34]. Such algorithms would be seen as a constitutive part of the test and subject to regulatory framework and evaluation of the test itself [1]. However current algorithms have inadequate positive and negative predictive values and insufficient validation to be clinically useful and have not been widely adopted.
Probabilistic decision-making
There is ample evidence that statistical literacy amongst clinicians is limited (see for example Gigerenzer et al. 2008 [35]). It is also established that the means by which probabilistic information is presented to clinicians and patients has a significant effect on their treatment decisions, even where the facts are equivocal (i.e. frequencies vs percentages) [35] (see also Kahneman and Tversky 1984 [36]). For complex decisions heuristic algorithms (a heuristic is a simple rule or strategy to arrive at a decision) outperform clinicians, as they ignore distractors (see box 2 for an example heuristic for treatment decision making in clozapine) [37].
[box 2 about here]
This leads to a dilemma: how much detail should be presented to the clinician and patient, and in what form should it be presented? How much authority should we lend to a clinical decision making algorithm given that individual concerns about adverse effects may differ? The decision making process is complicated further by the fact that clozapine may be the only treatment likely to be efficacious in many patients. How do we weight side-effect burden and risk of catastrophic outcomes such as agranulocytosis compared to relative efficacy? These questions are key in setting thresholds for any algorithm or clinical guidance. Questions over who should set such thresholds, however, such as NICE or the UK medicines licensing body (Medicines and Healthcare products Regulatory Agency; MHRA), and the relevant expertise needed, are particularly difficult to answer and may in fact vary depending on perspective. For example the views of a patient may differ from those of their carer, their clinicians and the funders.
Ethical Implications for pharmacogenetic testing with clozapine
Licensing
In the UK, clozapine is only licensed for use with strict monitoring procedures of white cell count to minimise the risk of clozapine induced neutropaenia or
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agranulocytosis. Licensing, however, is not static; there have been some alterations to licensing, with the mandatory monitoring criteria relaxed for individuals who have benign ethnic neutropaenia (BEN) [38]. The severity of BEN can be such that extreme measures have to be taken to allow treatment with clozapine, such as the use of immunomodulatory drugs [39]. The risk of agranulocytosis in BEN is no different to those without BEN, so a pharmacogenetic test for clozapine could reduce the need to artificially boost neutrophil count and pave the way for even lower cut-off neutrophil levels where the risk of clozapine-related agranulocytosis is negligible. Potentially, therefore it could open up the possibility for treatment for those who are currently ineligible due to their constitutively low neutrophil count.
It is also possible that the MHRA could make pharmacogenetic testing a mandatory requirement for commencing clozapine treatment. The MHRA reviews licensing conditions every five years. In a landmark report that still represents a point of reference in debate today, the British Nuffield Council on Bioethics (NCOB) considered it a possibility that the MHRA imposes mandatory pharmacogenetic testing for drugs already licensed [40], although this has not happened so far.
It could be argued that in the right clinical context, it would be reasonable to prescribe clozapine off label without haematological monitoring (or with increased monitoring in the high risk group). Such practice however would transfer the legal risk to the individual practitioner if harm occurs. Given the medico-legal pressures to practice defensively, the potential benefits that off label use could give to the patient are unlikely to be fully realised. However, if a pharmacogenetic test with sufficient predictive value existed, that risk would diminish considerably.
Licensing decisions would be further complicated in a situation where a patient meets the criteria for treatment resistance, but has a pharmacogenetic test result that returned a high probability of agranulocytosis (but not one which was determinative). A pharmacogenetic test could thus perversely lead to fewer patients who might benefit from clozapine being offered it.
In the case that a pharmacogenetic test for clozapine had sufficient predictive value to influence the licensing conditions and/or the haematological monitoring regulations, we would recommend that the possibility to prescribe clozapine without a pharmacogenetic test should remain under the current licence.
Empowerment and Equity
The aforementioned NCOB report reflected on the key principles of consent, privacy, and confidentiality. It also discussed pharmacogenetic testing as a double-edged sword: while such tests may predict susceptibility to disease, they may also ‘engender feelings of powerlessness’ [40]. Although it is important to not conflate diagnostic genetic tests with pharmacogenetic tests, and these concerns may apply more to the former, there is an overlap between the two. Furthermore, pharmacogenetics may inspire hope in terms of treatment options, or resentment if
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treatment is refused based on pharmacogenetic testing. What are the implications of this for testing in clozapine?
A pharmacogenetic test as a decision-making tool for treatment with clozapine could have mixed potential for use by health insurers. Its utility would depend on the framework in which it was interpreted: a result that indicated treatment with clozapine as opposed to other antipsychotics would suggest that individual had a more treatment resistant illness, and implicitly worse prognosis. In countries where genetic non-discrimination legislation [41], or voluntary moratoria by the insurance industry [42] does not prevent this, insurers could use this information to infer that the patient in question is not a desirable client, potentially leading to restriction of cover or reduced premiums. A result that advised against treatment with clozapine would be very difficult to interpret, as its interpretation would depend on whether the decision was based on other antipsychotics being reasonably efficacious as well, or whether there would be a significant risk of agranulocytosis. Therefore access to the detailed and contextual information associated with the test would be necessary. If this proved possible the identification of clozapine ‘non-responders’ could have profound impact on health insurance providers [43]. In some jurisdictions the result for these non-responders could be that they are classified as uninsurable.
The NCOB report sees potential benefits if private healthcare services directed funding for treatments deemed necessary by a pharmacogenetic test [40]. Efficacy predictions could be used to help allocate resources between groups requiring expensive versus cheaper drugs [40]. In the antipsychotic field where many drugs are relatively inexpensive and off patent at present, this would have limited impact. Efficacy predictions could however be used by NICE to develop treatment recommendations [40], not just with drugs but other non-pharmaceutical treatments known to have an impact in schizophrenia. This could mean that treatments such as Cognitive Behavioural Therapy for psychosis [44] and Cognitive Remediation Therapy [45] (psychological interventions to decrease distress and improve neurocognitive functioning in schizophrenia respectively) could be targeted to those who would show poor response to clozapine.
Buchanan et al. take the view that insurance or more restricted state funding may also limit the range of drugs eligible for reimbursement as pharmacogenetic testing may restrict treatment to a ‘ “high response” or “safe response” genotype’ [31]. These issues are analogous to licensing concerns and have been discussed above. Morley and Hall considered genotypic information as a criterion for liability not just in terms of health insurance but also on future research [24]. Rather more significant is the potential for market stratification based on pharmacogenetic testing to return increased rates of ‘orphan illness’ (illnesses which are rare or for which there is little market desire to develop treatments for) and therefore limit future development of drugs [40]. The genetic determination of clozapine non-responders could lead these individuals to exclusion from research trials and reinforce the ‘orphan illness’ status of clozapine resistant schizophrenia.
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Vulnerable Patients: Consent to Treatment and Individual Choice
Mental Capacity
The patients using pharmacogenetic testing for clozapine would belong to the most vulnerable patient groups in clinical care [24]. The prevalence of psychiatric inpatients lacking the capacity to make decisions regarding treatment is high (median 29%) [46]. Given the complexity of the issues in pharmacogenetic testing, whether to test or not could be expected to be a more cognitively demanding decision than decisions regarding ‘treatment as usual’, although this is by no means certain as treatment decision making decisions regarding clozapine retain complex issues regarding risks and benefits in the face of treatment resistance.
In the UK, the Mental Capacity Act 2005 [47] leaves it at the discretion of the clinician advocating an intervention to assess the capacity for making a decision. There is deliberately no definition as to the level of knowledge and understanding required - deficits are particularly common in schizophrenia [48]. Again in the UK, for those who lack capacity to make a decision, surrogate decision-making takes place through an assessment of ‘best interests’. A pharmacogenetic test that improves the level of knowledge in making a clinical decision might not be considered too controversial, however any decision under best interests would need to factor in the ethical implications of testing as previously described, significantly complicating the issue. There is no literature on the rates of incapacity to make treatment decisions in those offered clozapine treatment, but given that these individuals by definition would have treatment resistant illness, it is not unreasonable to assume that this rate is above the base rate.
The UK Mental Health Act 1983
The Care Quality Commission (CQC) reported that under the Mental Health Act 1983 (MHA 1983) [49], 48,631 patients were detained in hospital between 2011-2012 [50]. The MHA 1983 also regulates treatment for these detained patients. Under section 63 of the MHA 1983, patients can have ‘treatment for mental disorder’ without consent. Treatment with medicines falls under section 58 requiring the use of Second Opinion Approved Doctors to concur with the treatment plan following three months of detention if the patient is refusing treatment or is incapable to make a decision.
A subcategory of treatment, section 58A, allows capable refusal of treatment under the MHA 1983, and requires a second opinion when incapable. It also allows for refusal of treatment when this has been previously expressed as an advance decision of refusal of treatment. Currently only Electroconvulsive Therapy falls under this remit. Other interventions, such as Naso-Gastric Tube feeding, treating self harm injuries, or even a caesarean section have been interpreted to fall under the powers of section 63 (although this is certainly not devoid of controversy [51]).
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Treatment with clozapine is currently regulated by section 58, but the associated haematological monitoring falls under the remit of section 63. The CQC has the power to allocate new treatments to fall under the remit of section 58A, but pharmacogenetic testing could be considered to be separate and regulated by section 63. Although not commented on in detail, the NCOB report suggested that genetic testing could fall under ‘treatment for mental disorder’ under the MHA 1983 [52]. As the law stands, for the detained inpatient, it is possible that pharmacogenetic testing could be performed without consent of a capable patient under section 63.
Against this backdrop, we would strongly recommend that pharmacogenetic testing be considered by the CQC to fall under section 58A of the MHA 1983 given the added safeguards. This would mean that a capable detained person under the MHA could refuse pharmacogenetic testing, and that such testing could be refused under an advance decision of refusal of treatment.
Conclusion
The adoption of pharmacogenetic tests for clozapine into routine clinical care raises significant issues: the probabilistic nature of the results it would return and the interpretation of these; the ethical implications of this form of testing on medical decision making; and the legal framework under which the testing takes place. Clozapine presents a unique challenge in that any pharmacogenetic test that can predict the likelihood of agranulocytosis may have an impact on the mandatory haematological monitoring regulations and licensing in some countries. Reduction of haematological monitoring frequency may have important benefits to some patients, although regular contact with services to meet haematological monitoring requirements over the first year may be relevant to the superior efficacy of clozapine compared to other antipsychotic drugs. However, reluctance to prescribe in high-risk individuals may lead to avoidance of treatment with the only drug with proven efficacy in treatment resistant schizophrenia. Complex probabilistic data can be easier to interpret through the use of heuristics. Such an approach would in all likelihood result in handing over decision making to another party, and may make it difficult to take into account complex but important clinical and individual factors. Ironically this could lead to a move away from ‘personalised medicine’, with the potential to reduce choice for clinicians in the treatment of high-risk patients, while on the other hand it may make the drug available and more cost-effective for patients who are scored as low-risk for agranulocytosis on the basis of the test.
The voluntary nature of the test is also a concern, as patients may consider that the only means to have access to a drug is through testing, or done under ‘best interests’ or as treatment for mental disorder under the MHA 1983. This, however, is not specific for pharmacogenetic testing for clozapine.
We have focused in this review on these issues with a deliberate focus on the UK, to facilitate a discussion of the licensing regulations and law surrounding consent to
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treatment. Most other regulatory systems involve similar mandatory haematological monitoring and law of consent, and therefore we would submit that the same issues are relevant also to the rest of Europe and the US.
At present there are no data on how patients and other stakeholders view this form of testing and the possibility of its implementation in the clinic. Systematic empirical research is needed in particular on the perspectives of patients, carers, and clinicians so as to ensure that if Pandora’s box is opened with a clozapine pharmacogenetic test in an outpatient clinic, we, like Pandora, will find that hope remains for all.
Future perspective
Clozapine is a unique case when considering the issues that a hypothetical pharmacogenetic test may raise, and the potential impact on licensing and treatment without consent is particularly salient. We predict that there will be further developments over time, as our ability to detect genetic and other biomarkers improves with technological advances, with increasing ability to predict stereotyped outcomes, such as agranulocytosis. If any such test is to have a real impact in patient care, licensing changes must follow. Consideration as to the legal and ethical issues surrounding pharmacogenetic testing for treatment with clozapine needs to be made in advance, and the views of stakeholders and consumer groups is crucial, to ensure informed consideration by the relevant regulatory body.
Acknowledgements
Dr Benjamin Spencer is employed on an Academic Clinical Fellowship award from the National Institute for Health Research. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.
The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 279227.
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Disclosures
David A Collier is a full time employee of Eli Lilly and Company Ltd.
Anil K Malhotra is a Consultant to Genomind, Inc.
Box 1 – The challenge of predicting rare events
The negative predictive value (NPV) of a test defines the proportion of subjects that test negative who are true negatives. I.e. for agranulocytosis it would return the proportion of people who test negative to develop agranulocytosis that would not actually develop agranulocytosis.
It is intrinsically linked to disease prevalence, with extremes of disease prevalence having the dominant effect on the negative predictive value: With a disease prevalence similar to agranulocytosis in clozapine to have a test with a negative predictive value 0.99992 (i.e. 100 times less likely than baseline to develop agranulocytosis), would require a Sensitivity = 0.99, and a Specificity = 0.99.
The HLA-DQB1 test for agranulocytosis returned a high Specificity of 0.984, however the low Sensitivity of 0.215 gave a NPV of 0.9936 (i.e. 1.25 times less likely than baseline to develop agranulocytosis).
Box 2 – Simple heuristic tool for decision making in clozapine. This tool shows how complex pharmacogenetic data can be used to make simple heuristic tools. This example uses the risk of agranulocytosis and efficacy of clozapine over alternative treatments as the key decision points deciding whether to offer treatment with clozapine or not.
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Executive Summary
1. Research in pharmacogenetic testing for clozapine is underway, given that it is the only antipsychotic with proven efficacy in treatment resistant schizophrenia, but is associated with serious but rare adverse events such as agranulocytosis. Mandatory haematological monitoring is currently part of the terms of the licence to reduce this risk in clinical practice.
2. A pharmacogenetic test for clozapine is likely to return probabilistic data, posing complex challenges for interpretation and communication. An alternative is to provide results via a heuristic algorithm with the issues of disempowerment and threshold setting. This produces difficult questions regarding who could, or should design these and set the thresholds.
3. We recommend that any changes to the licensing of clozapine based on a pharmacogenetic test should still allow for treatment under the current licensing criteria if a pharmacogenetic test is refused by the patient.
4. Patients with mental disorder can be considered to belong to one of the most vulnerable groups in clinical care, and there are complex legal issues surrounding the use of this testing including the possibility of testing without consent. We would recommend that clozapine pharmacogenetic testing be regulated under section 58A of the Mental Health Act 1983 by the CQC.
Risk of agranulocytosis > baseline (0.008%)?
Predicted ef=icacy of clozapine superior to
alternative antipsychotics?
Offer clozapine
Decline clozapine
Decline clozapine
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5. There are substantial ethical issues surrounding the use of clozapine pharmacogenetic testing in clinic, and we would recommend further research into the views of relevant actors and stakeholders (including clinicians, patients, carers).
Glossary
BEN Benign Ethnic Neutropaenia
CQC The Care Quality Commission
MHA 1983 The Mental Health Act 1983
MHRA Medicines and Healthcare products Regulatory Agency
NCOB British Nuffield Council on Bioethics
NICE The National Institute for Health and Clinical Excellence
NPV Negative Predictive Value
PPV Positive Predictive Value
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