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Pharmacovigilance in Singapore - harnessing IT and genomics to detect safety signals

This article was originally published in SRA

Executive Summary

Yvonne Koh, Adena Lim, Liesbet Tan, Ang Pei San, Tan Siew Har, Dorothy Toh and Chan Cheng Leng of Singapore’s Health Sciences Authority explain how they monitor and manage the safety of medicines on the market and discuss their plans for enhancement.

With more than 5,300 pharmaceuticals, 15,000 medical devices, 130,000 cosmetics and 9,500 Chinese proprietary medicines available in Singapore, managing potential safety and quality issues arising from these products is a significant task.

With regards to medicines, Singapore has implemented a number of post-market surveillance initiatives over the years to ensure that the benefit-risk balance of drugs remains favourable throughout their lifecycle. Over the past 11 years, the number of adverse event (AE) reports for marketed pharmaceuticals, herbal medicines, health supplements and cosmetics received by Singapore’s Health Sciences Authority has risen almost 40-fold, from 627 in 2001 to 23,724 in 2011 (see Figure 1). The HSA was recently one of the first regulators in Asia to detect serious cutaneous reactions suspected to be associated with the osteoporosis drug strontium ranelate. In addition, Singapore has taken the world lead in terms of the number of valid individual case safety reports per million inhabitants submitted to the World Health Organization's global database; Singapore has submitted just under 2,000 ICSRs per million inhabitants, the US has submitted around 1,400 and New Zealand around 1,100 ICSRs per million inhabitants.

Despite progress by the HSA on the pharmacovigilance front, there is still room for enhancements and the agency is working on initiatives to this end. When the Health Products Act together with its subsidiary legislation becomes fully implemented over the next two years, there will be greater additional legal empowerment for post-market vigilance activities.

The Vigilance Branch

The Health Products Regulation Group – one of three professional groups within the HSA – ensures that healthcare products in Singapore meet internationally benchmarked standards of safety, efficacy and quality.

Residing at the HPRG is the Vigilance Branch, whose core function is to help protect public health by identifying drug safety signals, assessing the benefit-risk profile of drugs, elucidating pre-disposing factors and communicating benefit-risk analyses to stakeholders, who include healthcare professionals (HCPs), companies and patients. As well as covering post-market "western" pharmaceuticals, biologicals, advanced therapeutics such as cell and tissue therapies and complementary health products including traditional Chinese medicines, the Vigilance Branch is also stepping up post-market surveillance for medical devices. The Vigilance Branch consists of five core functions that support post-market surveillance activities. These five functions are namely: AE monitoring; risk assessment and management; risk communication; environmental scanning and case management; and pharmacogenetics-based pharmacovigilance.

Over the years, the Vigilance Branch has expanded its capabilities in the detection and assessment of safety signals arising from the use of healthcare products, taking into consideration both local and international safety signals. Ensuing from this assessment process, the Vigilance Branch calls on companies to develop and customize risk management plans (RMPs) that suit the local clinical setting to mitigate potential risks associated with targeted products.

The Vigilance Branch team uses a life-cycle approach to product safety by actively involving itself in the pre-market stage of product evaluation. By doing so, it can take a more anticipatory role by following up with any identified safety concerns before a product is launched in the market. The process of assessing the benefit-risk profile of a product continues throughout the drug’s market lifetime, and its intensity is governed by the strength of the drug safety signals. Once the Health Products Act – the implementation of which began in 2007 – and its subsidiary legislation becomes fully implemented, the HSA will have the legal mandate to direct a registrant of a healthcare product to implement an RMP to minimise risks relating to the unsafe and inefficacious use of therapeutic products. Although the HSA can already ask companies to develop an RMP, the added legal sanctions are expected to further enhance compliance by the companies.

Singapore is known for its IT connectivity and health information technology and the HSA has established a robust and effective communication system as an important component of its pharmacovigilance system to ensure the timely dissemination of important safety information to all stakeholders. By harnessing the country's IT network and infrastructure, the agency has been able to reach out effectively to Singapore's HCPs when there has been key safety information to be communicated and disseminated. The importance of continuing to integrate IT into Singapore’s health system is recognised and is a priority for the government.

AE monitoring

The Vigilance Branch uses various AE reporting channels to detect local drug safety signals promptly and take the necessary actions to safeguard public health. The HSA's AE monitoring programme draws on the network of local HCPs, who actively report AEs to the agency. Over the years, various channels for submitting spontaneous AE reports by HCPs have been established in addition to the traditional ways of submitting spontaneous AE reports, ie via hard copy forms that are mailed via the post, emailed or faxed and through the agency's web-based reporting portal.

A reporting initiative that has simplified the reporting of AEs from healthcare institutions to the Vigilance Branch is the Critical Medication Information Store (CMIS). The CMIS, which was introduced in 2006, serves as an electronic data repository for structured medical alert, drug allergy and adverse drug reactions. While its primary function is to allow enquiry and reporting by physicians, its secondary function transfers the information on AEs directly to the Vigilance Branch. It makes the reporting of AEs to the agency fairly seamless, as the HCP only needs to enter AE information once into the patient’s electronic medical record and does not need to fill out separate AE reporting forms.

The introduction of the CMIS has increased the number of AE reports received by the Vigilance Branch exponentially – from 1,185 reports in 2005 before the initiative was implemented to 10,685 reports in 2006 and 23,724 reports in 2011.

The CMIS is leveraged on the Electronic Medical Record Exchange (EMRx) system that the Singaporean government implemented to enable secure health information exchange between clinicians in the public sector1.

The implementation of EMRx has been phased in over the years with increasing numbers of HCPs from the various hospitals submitting AE reports to the HSA through this gateway. Although the quality of reports received could be improved, it is a very useful way of detecting: clusters of AEs that may provide insights for batch-related issues; AEs from the introduction of new products; or any increase in AE trends from products that are under close surveillance.

A recent example of the value of the CMIS was the HSA's prompt detection of serious cutaneous reactions suspected to be associated with strontium ranelate in 2011. After detecting the reactions, the HSA released early interim communications to HCPs in August 2011. In addition, a full benefit-risk assessment of the drug was performed and presented to the HSA’s Product Vigilance Advisory Committee (PVAC) in 2012.

Regular efforts are in place to reach out to HCPs as they are key partners in the vigilance of health products. The HSA provides HCPs with information on the different ways they can report AEs; they are also given access to the agency's national AE database (www.hsa.gov.sg/ae_online), which contains all anonymised individual local case reports. Information identifying both the patient and reporter is not visible to HCPs viewing these reports. The ability to view the local AE information in a national database with aggregated information provides signals that healthcare providers may not observe in their practice, and should encourage them to report and track AEs in the interest of safeguarding public health.

In addition to the AE reports for western pharmaceuticals, there is an increasing number of reports associated with the use of complementary health products that may be adulterated with western pharmaceuticals such as steroids and non-steroidal anti-inflammatory drugs. Such products are sent to the HSA’s laboratories to ascertain whether they are indeed adulterated. Any tests that register positive for adulterants are followed up with further investigations, which may result in raids and prosecution actions. Appropriate communications and press releases are issued to alert HCPs and members of the public.

Efforts are in place to mine the AE report data in Singapore's databases for potential safety signals. Since the local population is largely Asian, we do not rule out the possibility of finding safety signals that may be applicable to the local and Asia region and which may not be apparent from information in the databases of our Caucasian counterparts.

Active surveillance

The Vigilance Branch began its first active surveillance programme three years ago during the H1N1 pandemic, in a move that saw it shift its regulatory paradigm from collecting AEs solely based on spontaneous AE reporting. A sentinel site was set up at the nation’s largest women and paediatric hospital to monitor H1N1 vaccine AEs in paediatrics and pregnant women2,3. The infrastructure established by the sentinel site is very relevant for the active monitoring of AEs following childhood immunisation. This active surveillance effort has enhanced the detection of vaccines-related AEs and has reinforced post-marketing surveillance systems by providing data that is of local relevance.

Risk assessment and management

As Singapore has an island economy of around only five million inhabitants, there is a need for constant vigilance of any safety signals that emerge from countries with larger populations. The HSA assesses global safety signals gleaned from international sources such as scientific literature and company reports. It also assesses safety signals detected by other drug regulatory authorities or that emerge from clinical studies. The agency launches an initial impact analysis to prioritise the importance of the identified signals and determines whether the issues have the potential to alter the benefit-risk assessment of the health product. Full risk assessment will be conducted for significant safety issues, with the development of risk mitigation strategies.

In a full benefit-risk assessment, the local usage pattern of the product, current RMPs (if any), periodic safety update reports and clinical study reports from ongoing or completed clinical trials are reviewed. As part of the assessment, relevant expert opinions will be sought and presented to the PVAC. In addition, the Vigilance Branch leverages on the various international collaborations to exchange information on safety alerts with other regulatory agencies. This interaction provides reassurance that proposed regulatory actions are relevant and can stand up to scrutiny.

For products that have known safety issues but may continue to benefit a selected group of patients with no suitable therapeutic alternatives, the Vigilance Branch has implemented a scheme called the Restricted Access Programme. The key features of this programme includes the signing of an undertaking by prescribing doctors to indicate that they: (i) are aware of the potential adverse reactions associated with the use of the product; (ii) will only prescribe the product to patients whom they have assessed to have no other suitable therapeutic alternatives; (iii) will obtain informed patient consent on the use of the product after counseling them on the potential risks involved; and (iv) will monitor patients closely for adverse reactions and report any serious adverse reactions encountered to the HSA. The Restricted Access Programme also requires the product licence holder to submit regular sales data for the HSA to track the usage of the product, and also updated lists of doctors who have signed the letter of undertaking to participate in this scheme. Examples of drugs on this scheme include tegaserod (Zelmac), aprotinin (Trasylol) and rosiglitazone-containing products (Avandia, Avandamet).

Product risk communication

Communication of safety alerts plays a crucial role in the entire spectrum of vigilance activities, serving to deliver important information to stakeholders pertaining to the regulatory decisions made, new signals detected, and to solicit AE reports.

The HSA harnesses the efficiencies of IT connectivity to optimise its risk communications processes and ensure the timeliness and speed of delivery of important regulatory messages to stakeholders. The agency's risk communications team currently makes use of information software designed to send out emails, faxes and text messages to mobile devices to all HCPs. This system allows for timely mass dissemination of letters and circulars to about 13,000 registered HCPs, including all locally registered doctors, dentists and pharmacists within just a few hours. According to the preference of the recipient, the communication can reach them in the form of emails, letters through the post or via fax. In particularly dire situations, the software can be activated to send out text messages to the mobile devices of targeted groups of HCPs so that they will be alerted to urgent information that requires their immediate attention. In addition, as part of its comprehensive communications coverage, the risk communications team sends out separate emails to the senior management of public and private health institutions so that the communication can be cascaded down to the relevant HCPs in their institutions. This ensures a two-pronged approach to disseminating important information and achieving a vast reach of the target population.

Besides the use of electronic systems, the risk communications team also employs other channels of communications such as posting up alerts on the HSA website to complement those being actively disseminated to stakeholders. When relaying important safety information and advisories to members of the public, press releases and educational campaigns are usually employed, depending on the nature of the issue and the target audience. For example, in 2008, the Vigilance Branch received a cluster of reports associated with the use of an illegal product called Power 1 Walnut. This product was adulterated with glibenclamide and sildenafil. A demographic survey indicated that many victims were foreign workers who did not read mainstream newspapers or tune into Singapore's television or radio news. The HSA reached out to these workers through the operators that ran the dormitories where these workers were living and via the local contractor association. Print advertisements were also placed in the popular tabloid papers to target this population. In addition, posters in Bengali and Thai, two languages not used in the HSA's communications but spoken by the targeted group of foreign workers, were put up at the dormitories. These proved to be effective as the reports of adverse drug reaction relating to Power 1 Walnut declined significantly following these efforts.

Common vigilance

The environmental scanning and case management function at the Vigilance Branch, facilitated by the Common Vigilance Unit, was established in 2010 to bring about a concerted and timely response to local and global signals of safety and quality issues, which have immediate impact on patient safety in Singapore. This function involves conducting environmental scanning of news pertaining to health products. Prior to setting up the CVU, scanning of health product-related issues was conducted by various HPRG departments and information was stored non-optimally in separate systems. This resulted in a lack of process consistency and work duplication. With the CVU, the information received is streamlined through a common vigilance process and escalated to the relevant department within the HPRG for relevant review. Other sources of information include product defect reporting by companies, feedback from HCPs and heads-up information sharing by other regulatory authorities.

This common vigilance initiative provides a knowledge repository that captures information from safety alerts and quality issues. It also allows for the development of a case management system that facilitates a holistic and co-ordinated approach by the HSA's pre-market and post-market divisions when mitigating potential risks associated with healthcare products. These efforts contribute towards greater consistency and transparency in the risk management process. Despite its short history, the common vigilance function has enhanced synergies and strengthened collaborations between multiple units and branches to ensure that appropriate regulatory decisions are made and actions successfully carried out.

Pharmacogenetics team

Rapid developments in genotyping technologies and decreasing genotyping costs have enabled more extensive research into the human genome, making it possible to uncover new pharmacogenetic associations that could impact drug safety. The HSA's pharmacogenetics team was formed in 2007, together with a Pharmacogenetics Expert Panel, made up of key experts from the academic, research and clinical sectors, to guide the HSA in these efforts.

The team reviews pharmacogenomic associations as part of the risk assessment of selected drugs, recommends product label changes where appropriate and communicates important pharmacogenomic associations to HCPs. One recent example leveraged a publicly accessible genomic databases to assess the risk of irinotecan toxicity associated with UGT1A1*6 and UGT1A1*28 variants. The analysis revealed the prevalence of high-risk UGT1A1 genotypes in the local population, especially among the local Indian population. This led the HSA to request for an update of the package inserts of all irinotecan products with cautionary statements to reflect the safety information4. The team explored the development of tools to measure the extent of differentiation in genes important for drug response among Singapore’s three major ethnic groups5.

The pharmacogenetics team has also embarked on research studies in collaboration with local hospitals to investigate possible genetic associations behind serious adverse drug reactions, including serious skin reactions and drug induced liver injury. For pharmacogenetics associations that are well supported by research data, the evaluation of the cost-effectiveness of incorporating pharmacogenetic testing in clinical practice is also carried out in partnership with academic institutions to support recommendations for prospective screening of patients to identify those at risk of developing the serious adverse drug reactions associated with targeted drugs6.

The future

Over the past few decades, there has been a series of high-profile incidents around the world in which widely used drugs were found to cause harm that justified their withdrawal from the market (eg Merck's Vioxx (rofecoxib)) or suspension or restriction in use (eg rosiglitazone-containing medicines)7,8. As a result of this, there has been extensive discussion over placing greater emphasis on post-market drug vigilance activities and pharmacovigilance is a growing discipline9.

The HSA's Vigilance Branch takes pride in its mission to protect public health and ensures that the benefit-risk profile of health products continues to remain favourable after they are marketed in Singapore. As a science-based organisation, the HSA recognises the importance of harnessing technology and innovative capabilities to prospectively detect drug safety signals so as to advance the safer use of medicines in Singapore. It is important to expand our electronic systems to receive, process and analyse AE reports for health products. The use of data mining is needed to enhance the post-market surveillance system to better detect drug safety signals for drugs, vaccines, biologicals and medical devices.

With the growing volume of genomic data and pharmacogenomic associations, we are now able to utilise population genetic information to supplement evaluations of drug products pertinent to the country’s ethnic demography. This includes tapping into additional resources such as the Singapore Pharmacogenomics Portal in the local context that will facilitate gene comparisons for almost the entire genome between Singapore ethnic groups and other reference populations from around the world, such as Caucasians and the Japanese. The evidence that genetic differences in our populations leads to different responses to a therapy holds promise and we will be further collaborating and engaging different stakeholders to identify genetic markers that are useful in predicting the risk of drug-induced serious AEs. This may also provide insights into the mechanisms that lead to serious AEs.

We anticipate leveraging on these advances in the science of risk assessments and communication to provide clear, timely and accurate information to stakeholders, including HCPs and the public, to empower them to make the best decisions about health and safety.

Reference

1. Lee CE, Lim BK, Peter Tan CS, Singapore Health Information Technology Case Study, http://www.pacifichealthsummit.org/downloads/hitcasestudies/economy/singaporehit.pdf

2. Soh S, Tan WC, Tan B, Lim A, Toh D, Chan CL, H1N1 Vaccination and Pharmacovigilance in Singapore, Scrip Regulatory Affairs, 22 April 2010

3. Chan CL, Soh S, Toh D. Safety monitoring of H1N1 vaccines in Singapore during the H1N1 pandemic, Epidemiological News Bulletin, April-June 2010, 36(2)

4. Sung C, Lee PL, Tan LL, Toh DS, Pharmacogenetic risk for adverse reactions to irinotecan in the major ethnic populations of Singapore: regulatory evaluation by the health sciences authority, Drug Safety, 2011, 34(12):1167-75

5. Chen J, Teo YY, Toh DS, Sung C, Interethnic comparisons of important pharmacology genes using SNP databases: potential application to drug regulatory assessments, Pharmacogenomics, 2010, 11(8):1077-94

6. Dong Di, Sung C, Finkelstein EA. Cost-effectiveness of HLA-B*1502 genotyping newly diagnosed adult epilepsy patients in Singapore, Neurology, 2012; 79(12):1259-67

7. Merck announces voluntary worldwide withdrawal of Vioxx, 30 September 2004, http://www.merck.com/newsroom/vioxx/pdf/vioxx_press_release_final.pdf

8. FDA Drug safety Communication: Updated risk evaluation and mitigation strategy (REMS) to restrict access to rosiglitazone-containing medicines including Avandia, Avandamet and Avandryl, 18 May 2011, website accessed on 14 August 2012, http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm

9. Borg JJ, Aislaitner G, Pirozynski M, Midfsud S. Strengthening and rationalizing pharmacovigilance in the EU: Where is Europe heading to?, Drug Safety, 2011, 34(3):187-197

The authors are all officers at Singapore's Health Sciences Authority. Dr Yvonne Koh and Liesbet Tan are senior regulatory specialist and regulatory specialist, respectively, of the Product Risk Management Unit of the Vigilance Branch. Also from the Vigilance Branch are Adena Lim, deputy director, Product Risk Communication Unit, Ang Pei San, regulatory consultant, Common Vigilance Unit, Tan Siew Har, senior regulatory specialist, Adverse Event Monitoring Unit, and Dorothy Toh, the branch's director. Chan Cheng Leng is division director (vigilance, compliance, enforcement) and deputy group director of the Health Products Regulation Group. Email: dorothy_toh@hsa.gov.sg.

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