John McEwen

Reporting of adverse events following immunization in Australia

Abstract:  It is an important component of any immunization programme that vaccine safety is monitored by carrying out surveillance for adverse events following immunization (AEFI). Such surveillance can be active or passive. Active surveillance will detect more AEFI, but the vast majority will be minor events. Passive surveillance is probably more appropriate for routine AEFI surveillance, while active surveillance can be used to monitor a new vaccine or to test whether a specific severe event is significantly associated with immunization. Australia has a predominantly passive surveillance system. The system has recently been centralized, providing useful national data on vaccine safety.

Risk management from an Asian/Pacific Rim regulatory perspective.

This article reviews the state of adverse drug reaction monitoring in five Asian/Pacific Rim countries (Australia, Japan, Malaysia, New Zealand and Singapore). Each country has an active pharmacovigilance programme managed by a national regulatory agency. Current methods for assessing risks and current methods used for risk management and communication are compared with the ‘tools’ used by the US FDA. Major positive attributes of the programmes in all five countries include active involvement of independent expert clinical advisory committees in identifying and evaluating risks through the assessment of reports of serious and unusual reactions, and regular communications about risks from the national agencies to doctors and pharmacists by means of pharmacovigilance bulletins. Most components of the risk-management toolbox are currently used, in some instances without legislated support. Variations in the way risk-management tools are implemented within individual national health systems are illustrated.

Widespread Hyoscine Hydrobromide Toxicity Due to Contract Manufacturer Malpractice The Travacalm Episode

An outbreak of hyoscine hydrobromide toxicity was detected through the Australian pharmacovigilance system. The unexpectedly wide variation in hyoscine hydrobromide content between individual tablets within single packets created difficulties in initially explaining the clinical experiences. Strict time requirements for review of incoming adverse drug reaction reports and close involvement of the highly skilled national drug regulatory laboratory resulted in early identification of the cause of the outbreak and led in turn to the identification of malpractice by the contract manufacturer.

Pacific Island Pharmacovigilance: The Need for a Different Approach

Many Pacific Island countries (PICs) are recipients of funding support from the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund). However, most of these countries cannot be expected to meet Global Fund and World Health Organization (WHO) minimum requirements for a functioning pharmacovigilance (PV) system. We argue that a different approach is required to move PV forward in such countries. Although the long-term aim is to build adequate national PV capacity, we propose an approach in which resources are focused initially towards ensuring a proper system for the reporting of “problems with medicines” such as substandard and counterfeit products. The limited health system resources in these countries require that PV will be supported by some of the organizations also giving funding aid for the supply of medicines.

Author’s Reply to Bompart: “Artesunate- and Amodiaquine-Associated Extrapyramidal Reactions: Information Gained from an African-Based Risk Management Plan”

To restrict postmarketing surveillance to a ‘‘Potential risk: to be quantified in large-scale studies’’ [1] is unusual as it excludes routine pharmacovigilance, no matter how limited that may be perceived. My study [2] showed that a lessdismissive attitude to Sub-Saharan pharmacovigilance is warranted. It appears that until late 2011, Sanofi did not give weight to the published Anglophone (from 1976) and Francophone (2004) case reports referenced in my paper associating extrapyramidal reactions with amodiaquine and the repeated advice (2010 and 2011) of the WHO’s Advisory Committee on Safety of Medicinal Products (ACSoMP) that reporting to the Uppsala Monitoring Centre supported a clear association with artesunate amodiaquine combination products [3, 4]. These followed progress reports to ACSoMP of my ongoing analysis. ACSoMP recommended that the details be published and shared with the manufacturer for a possible update of the Summary of Product Characteristics [3]. It is unclear whether any of the notifications mentioned by Dr Bompart [5] that led to Sanofi’s acceptance of the association came from the large-scale studies. If some did, details should be published and an estimate of incidence disclosed. Acknowledgments The views in this reply are strictly the personal views of the author. His conflicts of interest disclosed in the published paper [2] remain unchanged.

Co-Dispensing of Contraindicated Drugs with Cisapride

To measure the rate of co‐dispensing of contraindicated drugs with cisapride 12 months prior to and 12 months after a period of publicity; and to assess the impact of the publicity, the ‘Dear Healthcare Professional letters‘, changes to the product information and pharmaceutical benefits subsidy restrictions.

Australian Drug Evaluation Committee (ADEC) 40th Anniversary

The 40th anniversary of the Australian Drug Evaluation Committee, commonly known as ADEC, occurred in late July 2003. ADEC first met on Thursday 25 July 1963, under the Chairmanship of Dr Edgar Thomson, in the boardroom at the Royal Prince Alfred Hospital, Sydney. The Committee was composed of seven members eminent in the fields of clinical medicine and pharmacology. ADEC has met regularly since and its August 2003 meeting was its 229th meeting. Australia was centrally involved in the recognition of the teratogenicity of thalidomide. William McBride’s letter published in the Lancet in December 1961 attracted the world’s attention. In 1963, to a large extent as a result of the thalidomide experience, discussions took place between the Australian Department of Health and senior Australian clinicians on ways and means of more effectively exerting control over drugs causing serious adverse effects. The thalidomide experience had brought home to Australian health officials that there were not only benefits but also potential risks from the use of therapeutic compounds. As a result of these discussions, the then Minister for Health established an independent body, the ADEC, to advise on the safety of new drugs being imported into Australia and to formulate measures for the evaluation of possible adverse affects of drugs that were being used in Australia. The functions given to the new Committee were: • to make medical and scientific evaluations of such therapeutic substances that the Minister referred to it for evaluation; • to make medical and scientific evaluations of other therapeutic substances if, in the opinion of the Committee, it would be desirable to do so; and • to furnish such advice to the Minister as the Committee considered necessary related to the importation into, and the distribution within, Australia of therapeutic substances that were the subject of evaluations made by it. ADEC met three times during 1963. These meetings laid the foundations for what would become the evaluation process for new drug substances in Australia. General topics discussed at these early meetings included the functions of the ADEC, the definition of a new drug, details of the future Australian drug evaluation process using comparisons with international practice at the time and the role of the individual medical practitioner in drug safety surveillance. Standards for submission of data for importation of medicines into Australia were introduced as a result of the early recommendations of the Committee. The Committee also sought to ensure that companies were required to provide information about risks, as well as benefits, in promotional material for health professionals. The early ADEC made a number of important decisions in relation to individual product groups. Drug substances discussed by the Committee in 1963 included Enovid® 1, the first oral contraceptive approved by the US FDA, which was of great interest to the pharmaceutical industry at the time. In the wake of thalidomide, any drug with such widespread potential use in women of childbearing years encountered a rather cautious regulatory environment. ADEC advised of the need for medical supervision of patients using oral contraceptives. Interestingly, ADEC was not convinced of a cause and effect relationship between use of oral contraceptives and thrombosis at that time. It was 3 or 4 years later before studies in Europe showed convincingly the link between high-dose oestrogens and thrombotic events. The early ADEC also acted to discourage the use of some long-acting sulphonamides, which were widely used in general practice at the time. These sulphonamides were causing StevensJohnson syndrome, especially in children. There had been 19 cases reported in Australia, mainly in children, with four deaths. In 1964, ADEC undertook a detailed review of five Australian reports to it of deaths in patients using sympathomimetic drugs to treat severe asthma. Subsequently, the Committee published a warning in the January 1965 issue of the Medical Journal of Australia. This warning was an important stimulus to studies in the UK and elsewhere of the association between pressurised