The curling wheeze and tight-lipped breathing of inflammatory lung conditions (1), the severe abdominal pain and gastrointestinal disruption of inflammatory bowel disease (IBD) (2), and the arduous stiffness associated with rheumatoid arthritis (RA) (3) are common inflammatory ailments that globally prevail. Though the aetiology of each disease is not well understood, each share a similar pathophysiology of unaccounted immune cell recruitment and inflammation (1, 2, 3). With this gap in knowledge, current therapies aim at managing symptoms and preventing further damage by targeting inflammatory pathways (1,2,3). However, the toxicity associated with immune modulators has created an urgency into finding alternative therapies.

Recently, Incannex Healthcare received approval for a phase I study investigating the safety profile of IHL-675A, a novel anti-inflammatory that is indicated for the treatment of inflammatory diseases including inflammatory lung conditions, IBD, and RA (4). IHL-675A is comprised of cannabidiol (CBD) and hydroxychloroquine (HCQ) (4). Currently, CBD has only been approved for the treatment of seizure disorders (Lennox-Gastaut syndrome and Dravet syndrome) (5).

Over the years, the importance of the endocannabinoid system in controlling homeostasis and mediating metabolic and inflammatory pathways has become a popular target for pharmacotherapy (6). CBD is one of the main active cannabinoids found in Cannabis sativa (5). Cannabinoids are an exogenous molecule that share structural and chemical similarities to cannabinoids (6). Though the mechanism of action remains elusive, pre-clinical studies have shown that CBD indirectly improves anti-inflammatory pathways by inhibiting T cell proliferation, inducing T cell apoptosis, and reducing the migration and adhesion of immune cells (6).

Conversely, HCQ is a well-tolerated anti-malarial and anti-inflammatory compound that has been traditionally indicated for the treatment of RA and malaria (7). Despite the anti-inflammatory mechanism remaining unclear, studies have shown that HCQ disrupts antigen-presentation and processing, preventing activation and differential of CD4+ T cells (7). Furthermore, studies have shown that HCQ induces apoptosis of autoreactive T cells, and interferes with the activation of the humoral immune response, thus reducing the presence and production of inflammatory cytokines (7).

Despite both compounds have individually shown anti-inflammatory properties, preclinical studies conducted by Incannex into IHL-675A has demonstrated that CBD and HCQ act synergistically to inhibit the production of inflammatory cytokines (IL-1, Il-6, TNFα, IL-12, and IFN-γ) in mouse models (7). Furthermore, IHL-675A demonstrated greater anti-inflammatory properties compared to CBD by 109% to 767% from 24 hours post-drug administration (7). These preclinical studies, though minimal, show promising results for the treatment of inflammatory conditions in humans.

Though the hurdle of a phase I trial is hard to surpass, the idea of a safe and effective treatment provides silver-lining to the treacherous battle of chronic inflammatory conditions. The competitiveness of the pharmaceutical industry is the foundation of innovative drug developments.  IHL-675A has shown to be a strong competitor within this battle, and hopefully within a few years, a solution to inflammatory conditions is approved.

References:

1. Agarwal A., et al., Chronic Obstructive Pulmonary Disease, 2022. StatPearls Publishing, Available at https://www.ncbi.nlm.nih.gov/books/NBK559281/
2. McDowell C., et al., Inflammatory Bowel Disease, 2022. StatPearls Publishing, Available at https://www.ncbi.nlm.nih.gov/books/NBK470312/
3. Chauhan K., et al,m Rheumatoid Arthritis, 2022. StatPearls Publishing, Available at https://www.ncbi.nlm.nih.gov/books/NBK441999/
4. SmallCaps, Incannex Healthcare to begin phase 1 clinical trial for IHL-675A following ethics approval, Nicholaos L., 2022, Available at https://smallcaps.com.au/incannex-healthcare-phase-1-clinical-trial-ihl-675a-following-ethics-approval/ [Accessed 11AUG2022]
5. Meissner H., et al., Cannabidiol (CBD), 2022. StatPearls Publishing, Available at https://www.ncbi.nlm.nih.gov/books/NBK556048/
6. Atalay S., et al., Antioxidative and Anti-Inflammatory Properties of Cannabidiol. Antioxidants, 2020; 9(1) 20
7. Bansal P., et al., Hydroxychloroquine: a comprehensive review and its controversial role in coronavirus disease 2019. Annals of Medicine, 2021; 53(1): p. 117-134
8. Incannex, Positive In vivo results confirm strong synergistic activity of IHL-675A to inhibit inflammation, Incannex, 2020, Available at https://company-announcements.afr.com/asx/ihl/cf6be2f2-2d2b-11eb-8f4b-aa3736f8de15.pdf [Accessed 11AUG2022]

Ecopharmacovigilance

The rate at which modern medicine is progressing is astonishing. Production and usage of medicines across the globe continue to grow substantially. The global pharmaceutical market is estimated to exceed USD 1.5 Trillion in the coming years. No doubt these new medicines have improved quality of life and saved lives for some of the most terrible diseases and conditions, however their unwanted presence in the environment is raising alarm bells. As a result, a concept combining pharmacovigilance and environmental pharmacology, was first introduced as Pharmaco Environmentology in 2006 by Syed Ziaur Rahman. 

This concept has slowly evolved into Ecopharmacovigilance which is defined as “the science and activities concerning detection, assessment, understanding and prevention of adverse effects or other problems related to the presence of pharmaceuticals in the environment, which affect both human and the other animal species”.

Ecopharmacovigilance aims to ensure that significant environmental issues associated with pharmaceuticals in the environment are identified in a timely way and addressed appropriately. Ecopharmacovigilance is of significant concern these days since the unwanted presence of even trace amounts of active pharmacological ingredients in the environment may pose a risk.

There are various ways by which pharmacological pollutants may end up in the environment, such as in the patients’ excreta in the sewerage system and via release into the waste waters by manufacturers or hospitals and the terrestrial depositions. The largest release of medicines into the environment comes from the humans or animals taking them. Medicines are excreted from the body either in their unchanged form or as metabolites in faeces and urine and find their way into sewers or sewage treatment plants.

Several studies have documented the effects of pharmaceutical pollution on various animal species, such as vultures and fish. Ecopharmacovigilance is emerging as a promising approach to prevent the environmental risks posed by unwanted pharmaceutical agents ending up in the environment. However, it is impractical to implement rigorous EPV processes for all the pharmaceutical substances with complex and diversified chemical, biological or toxicological properties. Consequently, the concept of “targeted EPV” has evolved and is aimed at targeted detection, evaluation, understanding, and prevention of adverse effects of high-priority hazardous pharmaceuticals in the environment.

“Targeted EPV” implementation focusses on targeted monitoring of the presence of high-risk agents in the environment, targeted reporting of over-standard discharge, targeted management of main emission sources, targeted legislation and conduct of research on high-priority pharmaceutical pollutants, as well as targeted educational strategies for specific areas and key populations.

Although the detected concentrations of pharmaceuticals in the environment are generally low, (ng/L to μg/L) potential direct and indirect risks for human and animal populations do exist and hence should be carefully monitored. This is of further importance in the case of special populations including pregnant women, children and older patients, who may be vulnerable to even very low concentrations of medicines.

Addressing issues related to pharmaceutical pollution is one of the key current aims of Ecopharmacovigilance in managing the environmental safety of medicines. Environmental safety of medicines will be another challenge that regulators and researchers will need to face and work on collaboratively to address this vital issue and develop new strategies to minimise environmental risks.

The US, EU and Canada is already regulating in this area and undertaking Environmental Risk Assessment (ERA) in pharmaceuticals. At present there are no specific guidelines for ERA of pharmaceuticals in Japan, Australia and many other countries.

It will be important to watch this space and stay abreast of developments in this area and see what challenges and opportunities present themselves.

References:

1. Silva LJG, Lino CM, Meisel L, Barceló D, Pena A. Ecopharmacovigilance. In: Barcelo D, editor.

The Handbook of Environmental Chemistry. Germany: Springer-Verlag Berlin and Heidelberg

GmbH & Co. KG; 2012. pp. 213–42.

2. Holm, G., Snape, J. R., Murray-Smith, R., Talbot, J., Taylor, D., and Sörme, P. (2013). Implementing Ecopharmacovigilance in Practice: Challenges and Potential Opportunities. Drug Saf. 36 (7), 533–546. doi:10.1007/s40264-013-0049-3

3. Wang, J., He, B., Yan, D., and Hu, X. (2017). Implementing Ecopharmacovigilance (EPV) from a Pharmacy Perspective: A Focus on Non-steroidal Anti-inflammatory Drugs. Sci. Total Environ. 603-604, 772–784. doi:10.1016/j.scitotenv.2017.02.209

Amongst many things, the COVID-19 pandemic questioned our traditional, separated work-home lifestyle divide ingrained over generations. The paradigm shift, to working from home (WFH) promised individuals the return of and flexibility with time – no more commutes, distractions, nor concrete set hours. Initially, this “gift” from COVID provided nuclear families and co-habitants with more time together, gave flexibility and some freedoms back to the individual, and overall was beneficial to many. However, underneath the rose petals of WFH, the thorns of raised risks of cardiovascular diseases (CVDs) present a menacing and longer-term health threat.

CVDs are characterised as a group of diseases (not exhaustive) including myocardial infarction, congestive heart failure, and myocardial ischemia, which affect the heart and blood vessels¹. Currently, CVDs are the leading cause of death globally². Though pharmaceutical intervention has helped reduce CVD prevalence and mitigate the risk of mortality over the years, its pathogenesis from multifactorial causes emphasises the importance of managing behavioural risk factors². More specifically, tabacco use, alcohol, physical inactivity, hypertension, obesity, and inadequate dietary intakes are proportional to CVD risk².

The impact of predisposing CVDs on COVID infection risks and outcomes has been extensively researched. However, the relationship of COVID infection and changed behaviours on the emergence of CVDs remains a novel topic. When SARS-Cov-2 spread and lockdowns commenced, communities and people were forced to stay in their homes, the subsequent lifestyle changes posed a physiological threat. As established, physical activity has a prophylactic effect on CVD². The decrease in activity to just basal metabolic rate from removing daily activities such as commuting to work, and the consequence of increased sedentary time due to longer work hours, increases the risk of cardiovascular disease by promoting weight gain³.

Weight gain leads to increased obesity rates. Studies have suggested that 1/3 Australians gained weight during the pandemic, as well as 42% of Americans stating weight gain, with more than 16 United States of America states now having obesity rates of 35% or higher⁷. The accepted hypothesis linking obesity to CVD is centred on the ability of adipose tissue to produce pro-inflammatory cytokines, which directly impair myocardial function and contribute to the formation of atherosclerotic plaques⁸. This weight gain and consequential increased CVD risk is compounded further by irregular eating behaviours such as snacking and increased consumption of highly processed foods, which also promote atherosclerosis of blood vessels and hypertensive characteristics¹.

The complex impacts of WFH also exacerbate other pre-disposing CVD risk factors through behavioural changes¹. During lockdown, alcohol sales increased by 29% with tobacco expenditure increasing by 13%^4,5, being used by some to mitigate the psychosocial pressure of lockdown. Increased tobacco and alcohol intakes indirectly increase CVD risk through blood pressure elevation, increases in cholesterol, and increases in triglyceride levels⁶.

COVID-19 presented WFH as a lifestyle delicacy on a silver platter. However, masked by the initial charade of increased work flexibility and freedom, the menacing wave of CVD health risks threatens the community in the longer term. CVD risks are multifactorial, whereby control of the modifiable risk factors can help mitigate the risk and severity. With WFH becoming the normalised practice, community programs should be initiated to emphasise the importance of staying active, eating healthy, and reducing alcohol and tobacco intake. As a community, we were able to slow but not stop COVID-19 from taking our breath away, but individually we can stop behavioural and lifestyle changes from contributing to our community’s longer-term CVD and mortality. 

References

1. Ruan Y., et al., Cardiovascular disease (CVD) and associated risk factors among older adults in six low-and middle-income countries: results from SAGE Wave 1. Biomed Central, 2018, 18(1): p. 778
2. Muhammad D.G. et al, COVID-19 lockdown may increase cardiovascular disease risk factors. The Egyptian Heart Journal, 2021, 73(1): p. 2
3. Powell-Wiley T.M., et al, Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation, 2021, 143(21): e984–e1010
4. Huge increase in Australian alcohol sales during the COVID-19 pandemic, Meacham S., 9NEWS, 2022, Accessed 14JUL2022, Available at https://www.9news.com.au/national/covid19-pandemic-blamed-for-huge-increase-in-alcohol-sales-across-australia/b8da58fa-b7b8-4d81-87ef-2baee80148ca
5. Lee B.P., et al., Retail Alcohol and Tobacco Sales During COVID-19. Annals of Internal Medicine, 2021
6. Larsson S.C., et al., Alcohol Consumption and Cardiovascular Disease. Circulation, 2020, 13(3): e002814
7. Has the Pandemic Affected Obesity Rates?, Beaumont, [Unknown Author], 2022, Accessed 14JUL2022, Available at https://www.beaumont.org/health-wellness/blogs/has-the-pandemic-affected-obesity-rates
8. Carbone S., et al., Obesity paradox in cardiovascular disease: where do we stand?. Vascular Health and Management Risk, 2019, 15(1): p. 89-100

In a rapidly changing world where technological developments happen on a daily basis, it is only logical that advanced telecommunications and computer technologies are used to improve health care and expand access to health services. The necessity to provide high quality and accessible medical attention was highlighted with the COVID-19 pandemic where interpersonal interactions were minimised to reduce contagion. Governments needed to provide a quick response to the high-volume demand and rapidly expanded telemedicine services^4,5. Telecommunications posed a solution to harness the power of technology and connectivity to transmit knowledge from the healthcare worker right to the patient’s home⁶.

Telemedicine can be defined as “the use of electronic information and communication technologies to provide and support health care when distance separates the participants”². It consists of the virtual interaction, synchronous or asynchronous, between the physician and the patient; whereas telehealth (a term commonly used interchangeably with telemedicine) is the flow of information^6,7. One of the first telemedicine experiences can be traced all the way back to the 1860s, where the telegraph and morse code were used during war to transmit messages from wounded soldiers to the medical teams³. Major inventions followed including the radio, telephone, and television, but it wasn’t until the 20th century that they were repurposed to provide medical care (e.g., to assist sailors when at sea or to provide training to healthcare students). With the age of connectivity starting during the 2000s, telemedicine rapidly expanded with the creation of telephone networks, use of satellites and space technology, and the development of the internet. This rapid evolution allowed telemedicine companies to grow exponentially and evolve into more efficient services³.

With the dependency of telecommunication during the COVID-19 pandemic, an unparalleled opportunity has been presented to consider not only the ethical and legal issues, but also the social concerns that these services bring foward^4,6,7.

Firstly, is an informed consent needed before each telemedicine consult? Will the patient-physician relationship be altered? What are the privacy and confidentiality concerns? How do we identify patients? Do we trust that the patients are who they say they are? Is the patient’s autonomy being respected? How do healthcare providers document each consultation and where will that data be stored? What is the risk of misdiagnosing during a virtual visit? These represent some of the many ethical and legal questions posed that were overshadowed by the urgency of the pandemic.

Secondly, in terms of the main social issues that need to be address, international organisations and governments need to argue and decide whether a low socioeconomic country should spend part of their money on improving telemedicine services rather than on, for example, agricultural insecurity, water safety or education. Health equity and access is a major topic to address, especially for the elderly, disadvantaged and minorities with no access to technology or to an effective connectivity network⁴. How do we reduce these disparities, whilst agreeing on local guidelines to protect the patient’s health and information?

Several guidelines and codes of ethics have been drafted to address these concerns^1,8. However, these guidelines cannot be unanimously adopted by every country due to cultural and socioeconomic differences as well as local stakeholder’s viewpoints⁷. Not all of these questions have answers, and telemedicine services appear to be so vulnerable in every aspect. But is clear that in those countries in which telemedicine is a step forward, efforts need to be put into establishing guidelines that address quality and relationships, access, consent, and privacy; regulatory policies and regulations need to include issues of cybersecurity, licensure, liability, and malpractice⁷.

References

1. American Medical Association (2021). AMA Telehealth quick guide. Accessed 10 July 2020 from https://www.ama-assn.org/practice-management/digital/ama-telehealth-quick-guide
2. Institute of Medicine (US) Committee on Evaluating Clinical Applications of Telemedicine; Field MJ, editor. Telemedicine: A Guide to Assessing Telecommunications in Health Care. Washington (DC): National Academies Press (US); 1996. 1, Introduction and Background. Available from: https://www.ncbi.nlm.nih.gov/books/NBK45440/
3. Jagarapu J, Savani RC. A brief history of telemedicine and the evolution of teleneonatology. Seminars in perinatology. 2021;45(5). doi:10.1016/j.semperi.2021.151416
4. Kaplan B. Ethics, guidelines, standards, and policy: telemedicine, covid-19, and broadening the ethical scope. Cambridge quarterly of healthcare ethics: cq : the international journal of healthcare ethics committees. 2022;31(1):105-118. doi:10.1017/S0963180121000852
5. Kaplan B. Revisiting health information technology ethical, legal, and social issues and evaluation: telehealth/telemedicine and covid-19. International journal of medical informatics. 2020;143:104239-104239. doi:10.1016/j.ijmedinf.2020.104239
6. Nittari G, Khuman R, Baldoni S, et al. Telemedicine practice: review of the current ethical and legal challenges. Telemedicine and e-health. 2020;26(12):1427-1437. doi:10.1089/tmj.2019.0158.
7. Shafizadeh H, Larijani B, Mojtahedzadeh R, Shamsi Gooshki E, Nedjat S. Initial drafting of telemedicine’s code of ethics through a stakeholders’ participatory process. Journal of medical ethics and history of medicine. 2021;14:24-24. doi:10.18502/jmehm.v14i24.8184

World Medical Association (2020). Statement on the Ethics of Telemedicine. Accessed 10 July 2022 from https://www.wma.net/policies-post/wma-statement-on-the-ethics-of-telemedicine/

Physical activity presents as a prevention strategy for numerous chronic health conditions, including coronary heart disease, insulin resistance, hypertension and breast, colon, and endometrial cancer.¹ However, for individuals with existing chronic health conditions, evidence is growing to support the integration of regular exercise into their treatment plans.

Multiple sclerosis

Multiple sclerosis (MS) is a chronic disease that affects the central nervous system, typically resulting in progressive and gradual disability. Approximately 25,600 Australians live with MS.² Diagnosis of MS typically occurs between the ages of 20 and 40 years, and 75% of people with MS are women.² There is currently no cure for MS and current therapies are aimed at easing symptoms and modifying the progression of the disease.

A systematic review published in 2013 examined 54 studies and found strong evidence that moderate intensity exercise performed two times per week increases aerobic capacity and muscular strength in MS patients with mild to moderate disability.³ The authors concluded that exercise training is effective for improving aerobic capacity and muscular strength and may improve mobility, fatigue, and health-related quality of life for people living with MS.³

It appears that the benefits of exercise for people living with MS is not limited to functional capacity and health-related quality of life. Several studies have demonstrated a positive impact of exercise on cognitive status of people living with MS⁴, as well as a lower annual relapse rate in people living with MS.⁵   

Type 2 Diabetes

Type 2 diabetes, a condition in which the body becomes resistant to the normal effects of insulin and gradually loses the capacity to produce enough insulin in the pancreas, has strong genetic risk factors and is often associated with modifiable lifestyle risk factors. In 2017-8 it was estimated that 4.9% of Australia’s total population had diabetes and approximately 1.2 million hospitalisations were associated with diabetes.⁶ Complications associated with type 2 diabetes include stroke, lower limb ischemia, nephropathy, retinopathy, and diabetic maculopathy.⁷ There is a high incidence of other risk factors for these complications among patients with type 2 diabetes e.g., hypertension, hyperlipidaemia, and cardiac and endothelial dysfunction.⁷  

The idea of exercise as treatment for type 2 diabetes is not new, and there is an international consensus that physical activity, along with diet and pharmaceuticals, are the foundations in the treatment of type 2 diabetes.⁸ There is extensive literature demonstrating the positive effects of exercise on metabolic control, fitness, muscle strength and motivation in patients with type 2 diabetes.⁹ Furthermore, regular exercise has several documented effects that are important for patients with type 2 diabetes such as reduction in systolic blood pressure and improvements in cardiac and endothelial vasodilatory function.⁹

Dementia

Dementia describes a collection of symptoms that are caused by disorders affecting the brain. Dementia affects thinking, behaviour, and the ability to perform everyday tasks and due to the aging population, the number of people with dementia is constantly increasing.¹⁰ Estimations from Dementia Australia suggest that 487,500 Australians are currently living with dementia, and that the age of onset of dementia is gradually declining.¹¹ A major challenge concerning dementia treatment is the management of neuropsychiatric symptoms such as agitation, anxiety, and depression, all of which are associated with low quality of life and increased caregiver burden.¹⁰

A recent systematic review including 13 studies and 1925 dementia patients demonstrated that regular aerobic exercise performed three to five times per week has a positive effect on neuropsychiatric symptoms.¹¹ Interestingly the review demonstrated that combined exercise programs (aerobic and resistance exercise) did not appear to be as effective as aerobic exercise alone. Nevertheless, the study determined that resistance training programs are beneficial for dementia patients with mobility problems, with demonstrated reductions in symptoms of depression and behavioural problems.

The evidence pertaining to the benefits exercise as a treatment for chronic health conditions is growing rapidly and is not limited to the conditions discussed in this article. There is existing and emerging evidence relating to a wide range on chronic diseases including chronic obstructive pulmonary disease, asthma, osteoporosis, polycystic ovarian syndrome, obesity, Parkinson’s disease, depression, and anxiety.⁹ Indeed, further work is required to determine the efficacy and safety of exercise prescription for specific chronic health conditions. Nevertheless, perhaps a scenario where we see exercise prescription integrated into the treatment guidelines for most chronic health conditions is not too far away.

Sarah Joyce, PhD (Senior Consultant at My Medical Department)   

References

1. Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of chronic diseases. Compr Physiol. 2012;2(2):1143-211.
2. What is Multiple Sclerosis (MS)? MS Australia. https://www.msaustralia.org.au/what-is-multiple-sclerosis-ms/. Accessed July 8, 2022.
3. Latimer-Cheung AE, Pilutti LA, Hicks LA, Martin Gini KA. Effects of Exercise Training on Fitness, Mobility, Fatigue, and Health-Related Quality of Life Among Adults with Multiple Sclerosis: A Systematic Review to Inform Guideline Development. Arch. Phys. 2013; 94(9): 1800-1823.
4. Kalron A, Zeilig G. Efficacy of exercise intervention programs on cognition in people suffering from multiple sclerosis, stroke and Parkinson’s disease: A systematic review and meta-analysis of current evidence. NeuroRehabilitation. 2015;37(2):273–89.
5. Pilutti LA, Platta ME, Motl RW, Latimer-Cheung AE. The safety of exercise training in multiple sclerosis: a systematic review. J Neurol Sci. 2014; 343(1–2):3–7.
6. Diabetes. Australian Institute of Health and Welfare. https://www.aihw.gov.au/reports/diabetes/diabetes/contents/how-many-australians-have-diabetes/type-2-diabetes. Accessed July 8, 2022.
7. Goyal R, Jialal I. Diabetes Mellitus Type 2. Treasure Island (FL): StatPearls Publishing; 2022. https://www.ncbi.nlm.nih.gov/books/NBK513253/. Accessed July 8, 2022.
8. American Diabetes Association. Clinical practice recommendations. Diabetes Care. 2002:S1-s147.
9. Pedersen BK, Saltin B. Exercise as medicine – evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015; 25(S3):1-72.
10. Kouloutbani K, Venetsanou F, Markati A, Karteroliotis K, Politis A. The effectiveness of physical exercise interventions in the management of neuropsychiatric symptoms in dementia patients: A systematic review. International Psychogeriatrics. 2022;34(2)177-190.
11. Dementia Statistics. Dementia Australia. https://www.dementia.org.au/statistics. Accessed July 8, 2022.

What happens when a patient is injured in a clinical trial in Australia, will there be the care necessary to nurse them back to full health or at least to the best that they can be with their condition? Will that care be provided quickly, and will all needs be covered? Currently our understanding rests in a piece of paper, referred to in consent forms.

The most seminal session at the ARCS Conference 2022, which justifies a groundswell for further action, was bravely and respectfully discussed in person, by the injured clinical trial participant, their solicitor, the Icon Group Executive Manager for Research, Dr Sophie Mepham and the AccessCR Managing Director, Dr Janelle Bowden – the last two being long-term advocates for quality and consumer participation in clinical trials in Australia – and both well known to ARCS members.

Unfortunately, with even the safest medicine adverse events can happen, and in this case, it was a checkpoint (PD-1/PDL-1) inhibitor at the centre of a series of serious adverse events (SAEs) causing long-term injuries to a trial patient; a member of a relatively new drug class which has brought hope to many with advanced cancer, where conventional small molecule or antibody drugs no longer worked.

This blog is not a criticism of the protocol, the medicine, the care or the oversight leading up to the SAEs. It is to shine a light on an example of how the system was found wanting when used to respond to trial events that may and do happen, despite all precautions and care.

First some history and a disclosure, I was involved as a contributor to the Medicines Australian Indemnity and Compensation Guidelines, which I believe all commercially sponsored clinical trials are required to follow. My recollection was that it was drafted by Medicines Australia to set a common standard and expectation of support for the burgeoning clinical trial sector, including hospitals, in Australia. Prior to this common agreement, each protocol and trial insurance arrangements were sent to hospital lawyers to determine its acceptability on a case-by-case basis. This was time-consuming, significant work for lawyers, but a flawed system. I directly observed that two Victorian hospitals had simultaneous but markedly different advice on the same protocol and company’s insurance documentation from two solicitors at the same Victorian law firm!

Coming back to the recent past and this concerning and unfortunate case for a trial participant in the relatively recent past. The guideline requires, irrespective of consent and foreseeability, that claims be dealt with expeditiouslyand to deal with the most serious type of injury being disabling and enduring. In the recent case, the trial medicine caused an immunogenic-like reaction, affecting multiple organ systems throughout their body.

Also, worrying is that participation in a clinical trial means the usual health service arrangements for indemnity do not apply and the responsibility seems to be split between site, sponsor, insurer and HREC, though the delineation of their respective responsibilities and overall oversight of patient care and support is not abundantly clear.

In this case it was years of delay from lawyers and the insurance company for the local sponsor and later a second step of review by international lawyers for the Pharma company.

What does expeditious mean? Who pays for the tests, the assessment and the care as well as loss of earnings whilst it is being considered? Who is meant to have oversight?

Fortunately, Icon Group paid for all costs for their patient whilst the case was being considered, and I am pleased to say eventually, compensation was agreed by lawyers and the insurance company.

Let’s go back to the documents supporting clinical research in Australia. A second document, well known to our sector is the NHMRC National Statement on Ethical Conduct in Human Research (updated 2018; the National Statement; section 2.2.6(c)), states information on the “provision of services to participants adversely affected by the research” should be communicated as part of the consent process, but in many multiple years of reviewing consent forms there seems to be little or no documentation on this – is this communicated effectively?

A further scan of other documents and I note there is a May 2014 NHRMC report on Indemnity and Insurance Arrangements, which does not cover this issue. The National Statement goes on to state (sections 5.1.38-39) “…that sponsors of clinical trials have indemnity, insurance and compensation arrangements in accordance with applicable regulatory requirements.” and “…arrangements to compensate participants for harm resulting from negligence in research.” In short, neither details continuity of care whilst insurance issues are being considered, and the compensation section seems to deal more with negligence.

To me this is a call to identify and characterise if this is widespread and if it is, a call for action. For this a survey of the sector will help us identify the extent. A quick solution thereafter may be to have a no-fault Australia-wide indemnity fund, which will support patients who suffer a significant and likely-related trial injury without any admissions, until such time it can go through legal considerations.  Should it be found that it is likely related to participation in the study (whether negligent care or not), then the fund would be later reimbursed by the responsible party.

It also means there should be an independent medical umpire to rapidly consider injuries and initiate care, diagnosis, treatment and patient support until the lawyers/courts go through the details of the case. I would suggest that this may be part of a cross-jurisdictional Office for Clinical Trial Support, to be established as a body independent to hospitals/clinics, sponsors and HRECs to remove any perception of admission or bias, which can initiate these actions and keep continuity of care for the most vulnerable in our community, who are often the participants in clinical trials.

Clinical trials are a necessary and important factor in improving patient care, please join with us in calling for further improvements to make our clinical trial sector world-class in all respects.

A/Prof Adrian Bootes

Director of Drug Development & Regulatory Affairs

Sophie Mepham