Australian Therapeutic Goods Administration Research Articles

The entactogen 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) as a treatment aid in psychotherapy and its safety concerns.

The phenylethylamine, 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'), is the prototypical example of an entactogen. Its original placement in highly restrictive drug usage categories in the US and UK, led to an inevitable restriction on MDMA neuroscience research and treatment. The dominant pharmacological effects of MDMA are its properties of release and inhibition of reuptake of amine neurotransmitter transporters for dopamine, norepinephrine, and serotonin. MDMA is an agonist of a wide range of receptors; its mood-altering effects are mediated via 5-HT2A receptors; this receptor may also mediate its effects on body temperature, analgesia, and anxiolytic properties. The mechanisms underlying MDMA's entactogenic properties of sociability and interpersonal closeness are not known but release and involvement of oxytocin, a peptide thought by some to be involved in social bonding, has been suggested. Adverse effects of MDMA are mostly transient; acute multiorgan adverse effects occurring during raves or crowded dance gatherings include dehydration, hyperthermia, seizures, rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. Deaths following MDMA taken by itself are rare compared to fatalities following coadministration with other drugs. A recent FDA-approved phase 3 clinical trial of MDMA for post-traumatic stress disorder (PTSD) led to the conclusion that MDMA-assisted therapy represents a potential breakthrough treatment meriting expedited clinical evaluation. Despite the ongoing deliberations by the FDA and EMA for approval of MDMA treatment of PTSD, the Australian Therapeutic Goods Administration (TGA) recently announced that after an evaluation of the therapeutic value, benefits, and risks of MDMA, it will permit its prescribing for the treatment of PTSD. Further examples of regulatory relaxation toward MDMA-assisted psychotherapy are underway. These include the FDA's recently approved clinical trial to assess MDMA's efficacy in the treatment of "asociality" in patients with schizophrenia and an open trial of MDMA treatment for alcohol-use disorder which showed decreased alcohol consumption. There are also ongoing studies on the little understood startle response, anxiety associated with life-threatening illness, and social anxiety in autistic adults.

Gabapentinoids: a therapeutic review.

The Australian Therapeutic Goods Administration's approved indications for prescription of gabapentinoids are refractory focal epilepsy and neuropathic pain. Use of gabapentinoids outside of the approved indications is common, but evidence for this is limited, especially for chronic nonspecific back pain and nonradicular leg pain. Some effects of gabapentinoids encourage their nonmedical use (e.g. euphoria, sedation, disinhibition). Widespread nonmedical use has increased the incidence of accidental and deliberate poisonings. Dependence may develop with chronic use of gabapentinoids and abrupt cessation may induce withdrawal symptoms. If the indication for continued use is unclear, gradual dose tapering as a means of deprescribing is recommended. Clinicians should consider the indication, patient characteristics and harm-benefit profile when prescribing gabapentinoids. Some people, such as those with kidney disease, have an increased risk of harm when using these drugs.

899 serious adverse events including 13 deaths, 7 strokes, 211 thromboembolic events, and 482 immune reactions: The untold story of cyanoacrylate adhesive closure.

The aim was to retrieve and analyse the serious adverse events of venous occlusion systems used in cyanoacrylate adhesive closure (CAC) submitted to regulatory agencies. The Total Product Life Cycle (TPLC) database of the US Food and Drug Administration (FDA), the Database of Adverse Event Notifications (DAEN) of the Australian Therapeutic Goods Administration (TGA), and the Yellow Card database of the UK Medicines and Healthcare Products Regulatory Agency (MHRA) were reviewed. Three Freedom of Information (FOI) requests had to be submitted to the MHRA to obtain data. The TPLC contained 899 reports which included 13 cases of death, 7 strokes, 211 thromboembolic events, and 482 immune reactions. The DAEN recorded three reportable adverse events, and the MHRA recorded seven adverse incidents including one death. CAC is associated with serious adverse events including death. These events are under-reported in the medical literature and only sub-optimally reported to the regulatory agencies.

Assessment of COVID-19-related medical device regulator policies on entry to market for prioritised devices: a case study

Background/Aims In response to the COVID-19 pandemic, medical devices were given exceptional use authorisations. Medical device regulators around the world modified their administrative approach to medical device approval to ensure that relevant devices and personal protection equipment would be available to healthcare professionals and patients. Using data from medical device regulators in the US and Australia, this study assessed the impact of COVID-19-related regulatory modifications implemented to allow quick market entry of relevant equipment, and how data science techniques can help to inform future policy. Methods Data from the US Food and Drug Administration's Global Unique Device Identification Database and the Australian Therapeutic Goods Administration's Australian Register of Therapeutic Goods were used as case studies to explore the effects of policy changes. All COVID-19-related devices and personal protective equipment were identified in the data using the Global Medical Device Nomenclature system and device descriptions. A 10-day and 20-day moving average was applied to assess how many of these devices reached the market between 30 July 2019 and 24 June 2020. Results In both the US and Australian datasets, the number of market entries increased after the pandemic began. However, the impact of the Australian policy appeared to be greater than that of the US, as there was a considerable increase in the number of personal protective equipment and COVID-19-related device registrations following the declaration of the pandemic in Australia, while the impact on the US data was relatively minimal. Conclusions In general, market entry of relevant equipment increased during the COVID-19 pandemic, indicating the possible impact of policy changes. The kind of data captured in national databases greatly influences the ability to accurately track performance of regulatory policy changes. This work shows the potential of using data science in a regulatory context to assess if a policy change creates the desired effect.

Hematological and Other Cancers in People Using Clozapine: Analysis of Australian Spontaneous Reports Between 1995 and 2020.

Recent observational study evidence suggests that clozapine, unlike other antipsychotics, may be associated with a small increased risk of hematological malignancy. This study described characteristics of hematological and other cancers in those taking clozapine reported to the Australian Therapeutic Goods Administration. We analyzed public case reports for "clozapine," "Clozaril," or "Clopine" from January 1995 to December 2020 classified as "neoplasm benign, malignant and unspecified" by the Australian Therapeutic Goods Administration. Data on age, sex, dose, clozapine start and cessation dates, Medical Dictionary for Regulatory Activities reaction terms, and date of cancer were extracted. Overall, 384 spontaneous reports of cancers in people taking clozapine were analyzed. The mean age of patients was 53.9 years (SD, 11.4 years), and 224 (58.3%) were male. The most frequent cancers were hematological (n = 104 [27.1%]), lung (n = 50 [13.0%]), breast (n = 37 [9.6%]), and colorectal (n = 28 [7.3%]). The outcome was fatal for 33.9% of cancer reports. Lymphoma comprised 72.1% of all hematological cancers (mean patient age, 52.1 years; SD, 11.6 years). The median daily dose of clozapine at the time of hematological cancer report was 400 mg (interquartile range, 300-543.8 mg), and the median duration of clozapine use before hematological cancer diagnosis was 7.0 years (interquartile range, 2.8-13.2 years). Lymphoma and other hematological cancers are overrepresented in spontaneous adverse event reports compared with other cancer types. Clinicians should be aware of the possible association with hematological cancers and monitor for and report any hematological cancers identified. Future studies should examine histology of lymphomas in people using clozapine and corresponding blood level of clozapine.

Reduced gastrointestinal-related hospitalisation costs following rescheduling of over-the-counter codeine-containing compound analgesics in Australia: results of a single hospital audit in South Australia.

Codeine-containing compound analgesics (CCCAs) are associated with dependence and, when taken in excess, significant risks of harm. A previous audit showed significant costs related to admissions for gastrointestinal (GI) complications of CCCA. Based on this and other evidence of harm, the Australian Therapeutic Goods Administration changed CCCAs to prescription only in 2018. We aimed to identify the costs associated with codeine-related GI complications and whether the schedule change in 2018 led to a reduced clinical and financial strain on the health care system. We conducted an audit of GI admissions and associated costs of CCCAs at a tertiary teaching hospital in Adelaide between 2016 and 2020. Patients were grouped by 2-year time periods before (group 1) and following (group 2) schedule change. Costs for the index presentation were multiplied for subsequent presentations. Costs and outcomes were compared for groups (standard statistics; P value < 0.05 significant.) RESULTS: Three hundred forty patients (group 1, n = 164; group 2, n = 119) were identified, with the majority of these admitted due to nonsteroidal anti-inflammatory drugs (NSAIDs) only. For CCCAs (NSAID-containing), the same patients were admitted repeatedly with a reduction from 31 to eight admissions (P = 0.005), following rescheduling. The total cost of CCCA admissions was reduced from AU$ 561 691 for group 1 to AU$ 261 764 for group 2 (P < 0.001). Australian rescheduling of CCCAs in 2018 resulted in a reduction in hospital admissions and costs related to GI complications. The cost savings, even in a single hospital department, were substantial.

CGM accuracy: Contrasting CE marking with the governmental controls of the USA (FDA) and Australia (TGA): A narrative review.

The National Institute for Clinical Excellence updated guidance for continuous glucose monitoring (CGM) in 2022, recommending that CGM be available to all people living with type 1 diabetes. Manufacturers can trade in the UK with Conformité Européenne (CE) marking without an initial national assessment. The regulatory process for CGM CE marking, in contrast to the Food and Drug Administration (FDA) and Australian Therapeutic Goods Administration (TGA) process, is described. Manufacturers operating in the UK provided clinical accuracy studies submitted for CE marking. Critical appraisal of the studies shows several CGM devices have CE marking for wide-ranging indications beyond available data, unlike FDA and TGA approval. The FDA and TGA use tighter controls, requiring comprehensive product-specific clinical data evaluation. In 2018, the FDA published the integrated CGM (iCGM) criteria permitting interoperability. Applying the iCGM criteria to clinical data provided by manufacturers trading in the UK identified several study protocols that minimized glucose variability, thereby improving CGM accuracy on all metrics. These results do not translate into real-life performance. Furthermore, for many CGM devices available in the UK, accuracy reported in the hypoglycaemic range is below iCGM standards, or measurement is absent. We offer a framework to evaluate CGM accuracy studies critically. The review concludes that FDA- and TGA-approved indications match the available clinical data, whereas CE marking indications can have discrepancies. The UK can bolster regulation with UK Conformity Assessed marking from January 2025. However, balanced regulation is needed to ensure innovation and timely technological access are not hindered.

Reigniting tobacco control: returning Australia to the front of the pack.

Australia has long been heralded as a leader in tobacco control, but more than 10 years have passed since the country implemented the world's first tobacco plain packaging reforms. In late 2022, the Australian Federal Government announced it would be "reigniting the fight against tobacco addiction". The forthcoming reforms package will help modernise and re-energise Australian tobacco control. The Government has signalled that preliminary reforms will include updating graphic health warnings, standardising tobacco pack sizes and filters, and banning menthol and flavours. The recently endorsed National Tobacco Strategy 2023-2030 also opens the door to further supply-side reforms. Ten years ago, when Australia fought multiple legal challenges from the tobacco industry and established plain packaging as a best practice standard, e-cigarette or vaping products were a fringe issue with little presence in Australia. Today, vaping product use by young Australians has dramatically and rapidly increased. Easy access and marketing of cheap, flavoured, disposable, nicotine-containing vaping products are driving use. Recognising that the current approach to e-cigarette regulation is not achieving its aim of preventing children and adolescents from accessing vaping products, the Australian Therapeutic Goods Administration (TGA) launched a consultation on possible reforms in late 2022. Currently, vaping importers and retailers are exploiting an exemption for non-nicotine products in regulations, and nicotine-containing products are masquerading as non-nicotine products. The ideal public health solution would see the elimination of all vaping product sales, nicotine and non-nicotine alike, that fall outside of the TGA prescription-only access pathway. After 10 years of minimal action, it is invigorating to have three key initiatives in play to fully "reignite" tobacco control - the tobacco legislation renewal and update, the imminent national strategy release, and the TGA consultation on vaping products. Re-establishing Australia as a tobacco control leader is welcome news for public health.

A point-prevalence study of off-label medication use in an Australian adult tertiary intensive care unit

Medications prescribed for indications or at doses, frequencies or durations not approved by the Australian Therapeutic Goods Administration are considered "off- label". Critical illness makes seeking consent for off-label medication use impractical. We aimed to characterise the extent of off-label medication use in a tertiary medical- surgical intensive care unit (ICU) by auditing the electronic health records of all patients admitted over a one-month period. We found 25.4% of 2292 prescriptions made for 142 patients were off-label. Eighty-one (37.2%) of the total of 218 different prescribed medications were used at least once for an off-label indication. Medications commonly prescribed off-label included antacids (pantoprazole, esomeprazole), analgesics (fentanyl, morphine, ketamine, pregabalin), anticonvulsants (levetiracetam), antibiotics (cefazolin, erythromycin), antipsychotics (quetiapine, haloperidol), and cardiovascular agents (metoprolol, clonidine). Nearly all patients (88.0%) received at least one off-label medication during their ICU stay. Most off- label medications were used for conventional (albeit not licensed) reasons, but nine out of 81 (11.1%) were not; for example, acetazolamide for hypertension, aminophylline for oliguria, and dexmedetomidine for seizures. Recognising the challenges of formally registering an indication with the Therapeutic Goods Administration, but also the value of reducing the incidence of medications used for potentially incorrect purposes, we suggest guideline endorsement of what constitutes standard critical care practice as an alternative to regulatory control.

20 Years of Legislation - How Australia Has Responded to the Challenge of Regulating Genetically Modified Organisms in the Clinic.

•In contrast to the prior voluntary system, since 2001, gene technology in Australia has been regulated under a legislated national Gene Technology Regulatory Scheme which is administered by the Gene Technology Regulator.•The Scheme provides science-based assessment of the potential risks of gene technology to the health and safety of people and the environment.•It complements the role of the Australian Therapeutic Goods Administration which regulates all therapeutic products in Australia to ensure they are safe and effective.•Recent reforms to the Scheme contribute to, and anticipate, the continued safe development and delivery of gene-based human therapeutics in Australia as a successful model for other jurisdictions.

Initial and supplementary indication approval of new targeted cancer drugs by the FDA, EMA, Health Canada, and TGA

SummaryBackground. Previous research focused on the clinical evidence supporting new cancer drugs’ initial US Food and Drug Administration (FDA) approval. However, targeted drugs are increasingly approved for supplementary indications of unknown evidence and benefit. Objectives. To examine the clinical trial evidence supporting new targeted cancer drugs’ initial and supplementary indication approval in the US, EU, Canada, and Australia. Data and Methods. 25 cancer drugs across 100 indications were identified with FDA approval between 2009–2019. Data on regulatory approval and clinical trials were extracted from the FDA, European Medicines Agency (EMA), Health Canada (HC), Australian Therapeutic Goods Administration (TGA), and clinicaltrials.gov. Regional variations were compared with χ2-tests. Multivariate logistic regressions compared characteristics of initial and supplementary indication approvals, reporting adjusted odds ratios (AOR) with 95% confidence intervals (CI). Results. Out of 100 considered cancer indications, the FDA approved 96, the EMA 92, HC 86, and the TGA 83 (83%, p < 0.05). The FDA more frequently granted priority review, conditional approval, and orphan designations than other agencies. Initial approvals were more likely to receive conditional / accelerated approval (AOR: 2.69, 95%CI [1.07–6.77], p < 0.05), an orphan designation (AOR: 3.32, 95%CI [1.38–8.00], p < 0.01), be under priority review (AOR: 2.60, 95%CI [1.17–5.78], p < 0.05), and be monotherapies (AOR: 5.91, 95%CI [1.14–30.65], p < 0.05) than supplementary indications. Initial indications’ pivotal trials tended to be shorter (AOR per month: 0.96, 95%CI [0.93–0.99], p < 0.05), of lower phase design (AOR per clinical phase: 0.28, 95%CI [0.09–0.85], p < 0.05), and enroll more patients (AOR per 100 patients: 1.19, 95%CI [1.01–1.39], p < 0.05). Conclusions. Targeted cancer drugs are increasingly approved for multiple indications of varying clinical benefit. Drugs are first approved as monotherapies in rare diseases with a high unmet need. Whilst expedited regulatory review incentivizes this prioritization, indication-specific safety, efficacy, and pricing policies are necessary to reflect each indication’s differential clinical and economic value.

Alloreactivity of Allogeneic Mesenchymal Stem/Stromal Cells and Other Cellular Therapies: A Concise Review.

Cellular therapies, deemed live medicine, have brought a wave of new generation biological therapies to treat previously untreatable diseases such as cancers and degenerative diseases like osteoarthritis. These cellular therapies have gained significant recognition in clinical research. The area has been further strengthened with the approval of Chimeric Antigen Receptor added on T cells (CAR-T) therapies by the regulatory authorities USA's Food and Drugs Administration (FDA), European Medical Agency (EMA), the Australian Therapeutic Goods Administration (TGA), and in many countries in 2017 to treat hematological cancers. Another milestone was achieved when allogeneic Mesenchymal Stem Cell- (MSC-) based therapy was approved by the EMA to treat Chrohn's disease in 2018. Allogeneic donor-derived MSC therapies in particular hold great promise and real hope because of their ‘off-the shelf' availability and accessibility for patients in need of urgent treatment. So far, thousands of clinical trials have explored the safety and efficacy of both autologous and allogeneic cell therapies, deeming them safe, however with varying degrees of efficacy. In the current pandemic, clinical trials have begun in many parts of the world to treat severe cases of COVID with MSCs. However, the risk of tissue rejection and the development of undesirable effects due to alloreactivity of allogeneic cells are currently not adequately addressed. Therefore, this warrants careful investigation and detailed reporting of such events by clinical researchers. This review aims at discussing the current landscape of approved allogeneic MSCs along with a few other cellular therapies. We explore any possible reactivity reported to inform the readers of any safety concern and on the efficacy of such therapies.

Spinal Cord Stimulators: An Analysis of the Adverse Events Reported to the Australian Therapeutic Goods Administration.

BackgroundSpinal cord stimulators are used to treat intractable pain. Placebo-controlled trials of spinal cord stimulators typically involve short-term treatment and follow-up, so long-term safety and efficacy are unclear.AimThe aim of the study was to describe the adverse events relating to spinal cord stimulators reported to the Therapeutic Goods Administration of Australia between July 2012 and January 2019.MethodsAdverse events were coded by seriousness, severity, body system affected, type of event, action taken, and attribution of fault. Data on the number of stimulators implanted and removed were sourced from the Admitted Patient Care Minimum Data Set.ResultsFive hundred twenty adverse events were reported for spinal cord stimulators. Most events were rated as severe (79%) or life-threatening (13%). Device malfunction was the most common event (56.5%). The most common action taken in response to an adverse event was surgical intervention with or without antibiotics (80%). The ratio of removals to implants was 4 per every 10 implanted.ConclusionsSpinal cords stimulators have the potential for serious harm, and each year in Australia, many are removed. In view of the low certainty evidence of their long-term safety and effectiveness, our results raise questions about their role in providing long-term management of intractable pain.

Use of priority and provisional approval pathways by the Australian Therapeutic Goods Administration in approving new medicines: a cross-sectional study.

Objective Examine the use of priority and provisional approval pathways by the Australian Therapeutic Goods Administration (TGA) for evaluating new medicines. Methods This observational study assessed all new medicines approved by the TGA between 1 January 2018 and 18 October 2021. It examined how frequently priority and provisional approval pathways are being used, the conditions which the medicines are being approved to treat, how long medicines are spending in the approval pathways, the additional therapeutic value of the medicines being approved through these pathways and how the use of the pathways compares with similar regulatory pathways used by Health Canada. Results The TGA approved 138 new medicines in the time period under study, of which 33 were approved through either the priority or provisional approval pathways. Sixteen were approved to treat cancer. It took the TGA a mean of 130 (95% CI 118, 143) and 144 (95% 101, 188) working days for priority and provisional pathways, respectively. Therapeutic evaluations were available for 16 of these medicines and 11 offered little to no therapeutic gain over existing medicines. There was moderate agreement between the TGA and Health Canada in their use of these pathways (Kappa = 0.5458, 95% CI 0.3900, 0.7016). Conclusions The priority and provisional approval pathways are now being used by the TGA for about one-third of all new medicine approvals. Although the medicines approved in these ways are moving through the review process more quickly than those approved through the standard approval pathway, the majority of these medicines, for which an evaluation of therapeutic value is available, do not offer any substantial additional therapeutic value over existing medicines.

A Pragmatic Randomized Comparative Trial of e-Cigarettes and Other Nicotine Products for Quitting or Long-Term Substitution in Smokers.

Tobacco harm reduction has potential to improve individual and population health. However, little research exists on low-intensity interventions, such as encouraging longer-term NRT or e-cigarette use. We aimed to determine whether: (1) encouraging use of nicotine products as long-term tobacco substitutes is more effective for smoking abstinence than standard treatment, and (2) offering e-cigarettes is more effective than NRT. An open-label, parallel-group randomized trial was conducted in Australia between 2014 and 2015, with 1563 adult daily smokers, randomized to: (A) standard cessation advice and NRT: advice to use NRT short-term, (B) quit or substitute advice and NRT: advice to use NRT as a longer-term substitute for smoking if required to maintain smoking cessation, or (C) Quit or substitute advice and NRT and/or e-cigarettes. Participants were offered an initial supply of products they could then purchase for up to 7 months. The primary outcome was self-reported continuous smoking abstinence at 7 months. Point prevalence, dual use, and cigarette reduction were secondary outcomes. At 7 months, 2.8% (N = 9) of group A (N = 324) were abstinent, compared with 1.8% (N = 11) in B (N = 620) and 1.3% (N = 8) in C (N = 619) (adjusted odds ratio [ORs]: B vs. A 0.66, 95% confidence interval [CI]: 0.27-1.63; C vs. A 0.46, 95% CI: 0.17-1.21; C vs. B 0.69, 95% CI 0.27-1.73). There were no suspected unexpected serious adverse reactions associated with trial products. A free trial of NRT and first generation e-cigarettes and advice on long-term substitution was no better for smoking abstinence than usual care. The trial was registered with the Australian Therapeutic Goods Administration under their Clinical Trials Notification scheme and the Australian and New Zealand Clinical Trials Registry (ACTRN12612001210864). This pragmatic trial allowed the comparison of existing and alternative policy options under semi-realistic conditions, such as product choice and financial cost. All trial arms had low rates of smoking cessation. The findings suggest that providing unflavored cigalike e-cigarettes without additional support may not increase quitting compared with advice to use standard NRT in a general population of Australians who smoke. More intensive support and education, and/or opportunity to try a range of e-cigarette products, may be required to motivate quit attempts using e-cigarettes.

Therapies to Prevent Progression of COVID-19, Including Hydroxychloroquine, Azithromycin, Zinc, and Vitamin D3 With or Without Intravenous Vitamin C: An International, Multicenter, Randomized Trial.

BackgroundCOVID-19 is a global pandemic. Treatment with hydroxychloroquine (HCQ), zinc, and azithromycin (AZM), also known as the Zelenko protocol, and treatment with intravenous (IV) vitamin C (IVC) have shown encouraging results in a large number of trials worldwide. In addition, vitamin D levels are an important indicator of the severity of symptoms in patients with COVID-19.ObjectivesOur multicenter, randomized, open-label study aimed to assess the effectiveness of HCQ, AZM, and zinc with or without IVC in hospitalized patients with COVID-19 in reducing symptom severity and duration and preventing death.MethodsHospitalized patients with COVID-19 in seven participating hospitals in Turkey were screened for eligibility and randomly allocated to receive either HCQ, AZM, and zinc (group 1) or HCQ, AZM, zinc plus IV vitamin C treatment (group 2) for 14 days. The patients also received nontherapeutic levels of vitamin D3.The trial is registered on the Australian and New Zealand Clinical Trial Registry ACTRN12620000557932 and has been approved by the Australian Therapeutic Goods Administration (TGA).ResultsA total of 237 hospitalized patients with COVID-19 aged 22-99 years (mean: 63.3 ± 15.7 years) were enrolled in the study. Almost all patients were vitamin D deficient (97%), 55% were severely vitamin D deficient (<25 nmol/L) and 42% were vitamin D deficient (<50 nmol/L); 3% had insufficient vitamin D levels (<75 nmol/L), and none had optimal vitamin D levels.Of the patients, 73% had comorbidities, including diabetes (35%), heart disease (36%), and lung disease (34%).All but one patient (99.6%; n = 236/237) treated with HCQ, AZM, and zinc with or without high-dose IV vitamin C (IVC) fully recovered. Additional IVC therapy contributed significantly to a quicker recovery (15 days versus 45 days until discharge; p = 0.0069).Side effects such as diarrhea, nausea, and vomiting, reported by 15%-27% of the patients, were mild to moderate and transient. No cardiac side effects were observed.Low vitamin D levels were significantly correlated with a higher probability of admission to the intensive care unit (ICU) and longer hospital stay.Sadly, one 70-year-old female patient with heart and lung disease died after 17 days in ICU and 22 days in the hospital. Her vitamin D level was 6 nmol/L on admission (i.e., severely deficient).ConclusionsOur study suggests that the treatment protocol of HCQ, AZM, and zinc with or without vitamin C is safe and effective in the treatment of COVID-19, with high dose IV vitamin C leading to a significantly quicker recovery.Importantly, our study confirms vitamin D deficiency to be a high-risk factor of severe COVID-19 disease and hospitalization, with 97% of our study’s patient cohort being vitamin D deficient, 55% of these being severely vitamin D deficient, and none had optimal levels.Future trials are warranted to evaluate the treatment with a combination of high-dose vitamin D3 in addition to HCQ, AZM, and zinc and high-dose intravenous vitamin C.

Integrating Public Participation, Transparency and Accountability Into Governance of Marketing Authorisation for Genome Editing Products

Public participation, transparency and accountability are three of the pillars of good governance. These pillars become particularly important for innovative, personalised health technologies, because of the tendency of these technologies to raise distinct scientific, ethical, legal and social issues. Genome editing is perhaps the most personal of all innovative health technologies, involving precise modifications to an individual’s genome. This article focuses on the adequacy of current requirements for public participation, transparency and accountability in the governance of the market authorisation for genome edited products. Although clinical trials for genome edited products are only just underway, lessons can be drawn from the marketing approvals pathways for related gene therapy products. This article provides a broad overview of the regulatory pathways that have been adopted by the US Food and Drugs Administration, the European Medicines Authority, and the Australian Therapeutic Goods Administration for reviewing gene therapy products for marketing approval. This analysis focuses on the extent to which public participation processes and transparency and accountability of review pathways are incorporated into marketing approval policy and practice. Following this review, the article proposes the application of Sheila Jasanoff’s “technologies of humility” as a foundation for meaningfully incorporating these pillars of good governance into regulatory processes for the review of products of genome editing. We conclude by articulating clear mechanisms for operationalising technologies of humility in the context of public participation, transparency and accountability, providing a blueprint for future policy development.

Roles and Rules of Some Regulatory Agencies around the World during COVID-19 Pandemic

Objective: Collecting and synthesizing relevant data on COVID-19 from official sources of some different regulatory agencies around the world.&#x0D; Methods: The information and actions related to responding to the COVID-19 situation were collected from the websites of some regulatory agencies, including the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), Health Canada (HC), Swiss Agency for Therapeutic Products (Swissmedic), and the Australian Therapeutic Goods Administration (TGA).&#x0D; Results: All the regulatory agencies help in expediting the development of COVID-19 treatments and medical devices. These agencies also developed an international regulatory collaboration to develop cure models for the pandemic. While some of the agencies conduct the COVID-19 testing, like the US FDA, the others do not. The agencies also differ in their approaches towards resolving the pandemic. FDA and EMA are more aggressive in a way that they prioritize more testing and hospitalization coverage. However, as of the 22nd of June 2021, the FDA authorized the highest number (388) of diagnostic COVID-19 test kits followed by TGA (128), and EMA (88).&#x0D; Conclusions: Although the regulatory agencies differ in their approaches towards resolving pandemic COVID-19, all regulatory agencies help in expediting the development of COVID-19 treatments and medical devices.

Audit of high dose antipsychotics (HDA) prescribing on high dependency unit (HDU) and acute ward, Nepean Mental Health Centre, Nepean Blue Mountains Local Health District, Sydney, Australia

AimsTo measure the rate of patients receiving high dosage antipsychotics.To review the adherence to maximum recommended doses of antipsychotics as per the product information approved by Australian Therapeutic Goods Administration, product information approved by Medsafe (the New Zealand Medicines and Medical Devices Safety Authority) and Therapeutic Guidelines (Psychotropic Writing Group, 2013)BackgroundHigh dose antipsychotics or combination of antipsychotics are associated with significant adverse effects including QTc prolongation, arrhythmias, sudden cardiac death, seizures, increased incidence and severity of adverse effects, longer hospital stay and possibly increased mortality. High dose antipsychotic prescribing may arise as a result of EITHER single antipsychotic drug prescribed at a daily dose above the recommended limit (High Dose single drug) OR More than one antipsychotic prescribed concurrently where the sum of doses given expressed as a percentage of the SPC maximum of each drug exceeds 100% (High-Dose through the prescribing of multiple drugs).MethodThe data were gathered from all the drug charts for all patients admitted to HDU and Acute ward on 9th April 2019. The Audit standards were 1) Individual antipsychotic dose should be within recommended limit as 100% and 2) Combined antipsychotics should be within recommended limit as 100%ResultTotal number of patients on both the HDU and Acute wards = 33Total number of patients on antipsychotics = 30Number of patients on &gt; 100% of recommended cumulative dosage = 13/30 = 43.3%Number of patients on &gt; 100% maximum limits of regular antipsychotics = 3 = 10%Number of patients on &gt; 100% maximum limits of PRN antipsychotics = 0/30Number of patients on 2 antipsychotic = 18/30 = 60%Number of patients on 3 antipsychotic = 8/30 = 26.6%Number of patients on 4 antipsychotic = 2/30 = 6.6%ConclusionOut of the 30 patients on antipsychotics, almost half were on more than 100% of the recommended cumulative maximum limits of antipsychotics doses, almost 2/3rds were on 2 or more antipsychotic and a quarter on 3 or more. This can be associated with significant adverse effects including QTc prolongation, arrhythmias, sudden cardiac death, seizures, increased incidence and severity of adverse effects, longer hospital stay and possibly increased mortality. There is a need to review PRN antipsychotics prescribed as a norm, clear documentation and need for a protocol for increased vital sign monitoring for patients on high dose antipsychotic treatment.

Feasibility of implementing a pharmacist-led DPYD gene testing service for patients commencing 5-fluorouracil (5FU) or capecitabine.

e18644 Background: Polymorphisms in the DPYD gene, which encodes for dihydropyrimidine dehydrogenase (DPD), may impair DPD metabolism of fluoropyrimidines (FP) and cause life-threatening toxicities. The European Medicines Agency (EMA) recommend testing for DPD activity before FP therapy, but the Australian Therapeutic Goods Administration and the US Food and Drug Administration do not currently recommend this. At our hospital, pre-emptive DPYD gene screening was established in response to 7 cases of severe FP-toxicity and significant challenges for timely access to the life-saving antidote, uridine triacetate (UT), in the preceding 3 years. This study assessed the feasibility of a pharmacist-led DPYD gene testing service in an Australian cancer centre. Methods: Patients planned for FP therapy, without previous FP exposure, were referred to the Clinical Pharmacogenetics (CPGx) pharmacist for consenting, before a blood or buccal swab sample was taken. An external genomics company screened for the five Clinical Pharmacogenetics Implementation Consortium (CPIC) recommended gene variants (c.1905+1G &gt; A, c.1679T &gt; G, c.2846A &gt; T, c.1236G &gt; A and c.557A &gt; G). Dose recommendations based on CPIC guidelines and phenotype were made to the treating clinician. Patients were followed-up for toxicity (graded according to CTCAE v5.0) at 3-5 days post first FP exposure and pre-cycle 2. Results: Between 16 December 2019 and 11 December 2020, 311 patients were planned for FP therapy. Genetic testing did not occur for 13 patients, in the first two months of program implementation mostly due to unfamiliarity with procedures. Of the 298 genotyped patients (median age 59.5 years, 52.7% female, 67.8% Upper and Lower Gastrointestinal, 18.1% Breast), 274 (91.9%) were seen by the CPGx pharmacist within 1 day of referral. Median time from samples being taken to result availability was 6 days. 286 patient (96.0%) results were reported and acted upon prior to the planned cycle 1 FP commencement date. Overall, 1 patient (0.3%, 95%CI 0.1-1.9) was identified as a poor metaboliser and avoided FP therapy. Ten patients (3.4%, 95%CI 1.8-6.0) were identified as intermediate metabolisers, of which 2 patients did not receive chemotherapy due to changes in goals of care, 1 patient received only one cycle at 100% of the full dose but passed away due to disease progression, 1 patient required UT administration after cycle 2 despite 50% dose reductions for both cycles and 6 patients received an initial 50% dose reduction, where for subsequent cycles, 3 continued at this dose level, 2 had dose increases and 1 had a further dose reduction. 17 patients experienced at least one grade 3/4 toxicity pre-cycle 2; all had normal metaboliser phenotypes. Conclusions: A pharmacist-led DPYD gene testing service is feasible, with acceptable test result turnaround times and phenotype identification rates similar to that reported by the EMA.