| 4. In which ways is the initiative creative and innovative?
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*Staff Training
At the time of initiation of the project, research and pharmacogenetics (PGx) were relatively new to HSA, and there was a need to build the PGx team’s knowledge and capability in these areas. HSA invited key experts from academic, research and clinical sectors to form a Pharmacogenetics Expert Panel (PEP) to provide guidance on setting up the infrastructure in the area of PGx. Foreign experts who had conducted similar PGx studies were consulted for their input. The PGx team also organized a 12-week course “Principles of PGx for Drug Regulators” consisting of weekly lectures by PEP members and other local experts on various topics related to PGx to develop HSA staff knowledge in this emerging field.
*Case-Control Collection
HSA initiated collaborations with four public hospitals to recruit and collect DNA samples from patients who had experienced SJS/TEN. Samples were also obtained from drug-tolerant controls, patients who had taken the same drug but had not experienced an ADR. HSA also established a partnership with biobanking facilities that could extract and store coded DNA and plasma samples. High-resolution genotyping was performed through collaboration with the Singapore Immunology Network (SIgN). The results confirmed that carriers of HLA-B*1502 had a 181-fold higher risk of developing SJS/TEN when given CBZ compared with non-carriers.
*Cost-effectiveness study
Concurrent with the case-control collection, HSA undertook a study in collaboration with the Duke-NUS Health Services and Systems Research Program to evaluate the cost-effectiveness of genotyping new epilepsy patients prior to selecting an antiepileptic drug. The analysis concluded that genotyping new epilepsy patients in Singapore for HLA-B*1502 is more cost effective than prescribing or avoiding usage of CBZ without knowledge of the genotype.
*Extensive stakeholder consultations
Consultations with physicians highlighted that cost and turnaround time were barriers to adoption of genotyping. These were resolved through the establishment of a centralized HLA-B*1502 genotyping facility. HCPs were informed on 30 April 2013 that “genotyping for HLA-B*1502 allele prior to initiation of CBZ therapy in new patients of Asian ancestry is now considered the standard of care” and that a 75% subsidy for the genotyping test was available for subsidized patients at public clinics and hospitals. As of 30 September 2014, a total of 1057 blood samples have been tested for HLA-B*1502 genotype, and 110 (10.4%) samples were positive for the presence of the HLA-B*1502 allele.
It is noteworthy that HSA received 131 local serious reports of CBZ-induced SJS/TEN (an average of 15 reports of CBZ-induced SJS/TEN per year) between 2003 to 2012. In contrast, HSA has not received any reports of SJS/TEN associated with the use of CBZ in patients screened for the HLA-B*1502 allele in the 21 months since issuing the new guidelines on HLA-B*1502 genotype screening. One of the advantages of testing is that patients who are not carriers of HLA-B*1502 have a very low risk of SJS/TEN. Now physicians have greater confidence prescribing CBZ, a very inexpensive anti-epileptic drug, to test-negative patients. This is an economic benefit to epilepsy patients who may have to take medication for the rest of their lifetime.
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| 5. Who implemented the initiative and what is the size of the population affected by this initiative?
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The HSA PGx Team consists of staff of the Vigilance and Compliance Branch (VCB) under the Health Products Regulation Group (HPRG). Chan Cheng Leng (CCL) is Group Director HPRG; Dorothy SL Toh (DSLT) is Director 1 VCB. The HSA PGx Team additionally consists of Cynthia Sung, PGx Team Leader (CS), Liesbet L. Tan (LLT), Celine Loke (CL), Michael Limenta (ML) and Tan-Koi Wei Chuen (TKWC). Study design was conceived by CS, DSLT, CCL, LLT; Clinical sites were set up by CS, DSLT, LLT, CL; Monitoring of clinical sites was performed by LLT and CL. The entire PGx team was involved in consultation sessions with scientific and clinical community.
Clinical collaborators who recruited cases or controls are from four public hospitals:
➢ NUH: Derrick C.W. Aw, Aisha Lateef, Chan Yee Cheun, June Tan,Teoh Hock Luen
➢ SGH: Pang Shiu Ming, Lim Shih Hui, T. Thirumoorthy, Lee Haur Yueh, Koh Hong Yi, Lui Nai Lee, Wong Siaw Ing, Chong Yong Yeow and Chan Choong Meng
➢ CGH: Tay Yong Kwang, Tan Siew Kiang, Archana Vasudevan, Lee Shan Xian
➢ NSC: Lim Yen Loo, Heng Yee Kiat
Clinical research coordinators assisting with patient recruitment and data collection:
➢ NUH: Seow Lih Jen, Serene Ng, Eric Seow
➢ SGH: Goh Poh Kuan, Ei Mon Soe
➢ CGH: Low Li Fang, Geraldine Lim, Candy Yang
➢ NSC: Jolene Ong, Kwa Jie Si
STN staff assisting with development of electronic case report forms: Lee Yan Lim, Tzer Jing Seng
Other collaborators include
➢ Edmund JD Lee (Department of Pharmacology, NUH) chaired the HSA PEP that advised the PGx Team on this initiative.
➢ Ren Ee Chee (Singapore Immunology Network) performed the high resolution HLA typing of the samples.
➢ Evelyn S.C. Koay (MDC, NUH) established the centralized laboratory of a validated genotyping test for HLA-B*1502.
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| 6. How was the strategy implemented and what resources were mobilized?
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This initiative was funded by the HSA Reinvestment Fund, which was used to pay for part of the salaries of clinical research coordinators at the public hospitals, for transport of samples to the biobanking facility and for DNA and plasma extraction and storage. Since inception, HSA has spent approximately S$51,000 to date on this initiative, in addition to 1.5 FTEs per year of HSA staff time.
The cost-effectiveness analysis was performed for free by a graduate student at Duke-NUS for a thesis project. Genotyping costs for the case-control samples were contributed in kind by the Singapore Immunology Network. Validation costs for the clinical genotyping test were absorbed by the Molecular Diagnosis Center.
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| 7. Who were the stakeholders involved in the design of the initiative and in its implementation?
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This initiative successfully created a network of clinicians at public hospitals and researchers that HSA could rely upon to assist in studying ADR cases and applying a new technology to reduce ADR incidence. The clinicians had registries of patients who had suffered such serious skin reactions, and the nurses took the time and effort to trace and contact these patients to ask if they would like to participate in the study. In addition, the clinicians were dedicated in recruiting new SJS/TEN patients from their hospitals to take part in this study.
HSA undertook a study in collaboration with the Duke-NUS Health Services and Systems Research Program to evaluate the cost-effectiveness of genotyping new epilepsy patients prior to selecting an antiepileptic drug. The study found that genotyping new epilepsy patients in Singapore for HLA-B*1502 is more cost effective than prescribing or avoiding usage of CBZ without knowledge of the genotype. This report played an important role in deliberations by MOH and other stakeholders as they formulated new practice guidelines and approved a subsidy for low income patients.
Translation of PGx into patient care is challenging because it involves changing established medical practice. In this instance, the evidence that the genetic marker HLA-B*1502 was very strong based not only on international data, but local data as well. Nonetheless, there were issues of costs and availability of a testing facility to offer this service to screen patients for the HLA-B*1502 marker. The establishment of a single centralized laboratory offering the test was considered the most effective way to reduce both the turnaround time and genotyping cost. In addition, the availability of the subsidy was instrumental in the success of this initiative. All these factors contributed towards smooth adoption of the new standard of care – that genotyping for the HLA-B*1502 allele prior to the initiation of carbamazepine therapy in new patients of Asian ancestry would be the new standard of care. With the new guidelines, patients at high risk of SJS/TEN with CBZ are offered alternative anti-epileptic drugs, while test-negative patients can be prescribed a low cost, effective medicine with very low risk of developing SJS/TEN. The most gratifying output of this programme is the elimination of cases of CBZ-associated SJS/TEN when genetic testing is done.
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| 8. What were the most successful outputs and why was the initiative effective?
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Regular audits and visits were conducted at the different centers to ensure accuracy of the data collected and to address operational issues. Letters were sent to the clinicians after every visit to keep them informed on the progress of the study and whether there were any issues with the conduct of the study. Periodic reminders were sent to the clinical research coordinators to stay alert for cases of SJS/TEN so that the program would steadily accrue cases for the study.
The HSA PGx team has convened 6 meetings of the Pharmacogenomics Expert Panel (PEP) and met more frequently with the PEP Chairman to update our advisors on the progress of the program and receive their input on implementation issues and advice about other stakeholders HSA should involve or consult. Progress reports on the PGx initiative were included in annual reporting to senior management.
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| 9. What were the main obstacles encountered and how were they overcome?
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The PGx team established a partnership with the Singapore Tissue Network (STN) as the centralized repository for patient samples and clinical data. STN was selected because it operated independently of any one hospital and had achieved ISO9000 quality certification. However, in 2011 the parent organization of STN (by then renamed the Singapore Biobank) decided to close the facility. HSA had to review the various options for biobanking facilities in Singapore, and then transfer all the samples and data to the newly selected facility, the NUH Tissue Repository.
When it became evident that the genetic association between HLA-B*1502 and SJS/TEN among new CBZ users was very strong for the local population, and that it was cost effective to perform genotyping before prescribing or avoiding usage of the drug from an overall healthcare system perspective, HSA sought input from clinicians on how to implement genetic testing into clinical practice. From the consultations, HSA learned that the cost of the test (at the time S$350) would be a significant obstacle to patients, especially low-income patients. Through the discussions, consensus was reached that having a centralized laboratory would reduce costs through economies of scale. The Molecular Diagnostic Centre (MDC) of NUH took up this role and was able to reduce the genotyping test to S$200 and reduce turnaround time to 2 to 4 days, down from 7 days. At this juncture, the Ministry of Health lent its support by providing a 75% for subsidized patients at public clinics and hospitals. The public consultation session allowed HSA to understand barriers to adoption of a new practice guideline and to proactively find a solution to the problems. This ensured better acceptance and smoother implementation of the new clinical practice.
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