This blog post summarises the key insights from the latest Virtual Education Session (VES) led by Dr Andrew Pengilley, a public health physician with over 24 years of experience working in various areas of public health within the Commonwealth and State and Territory Governments. For the past five years he has been a Principal Medical Advisor at the Therapeutic Goods Administration (TGA), where he works as the head of the premarket evaluation section dealing with vaccines and anti-infectives. Prior to this Dr Pengilley worked in the ACT and Victorian Health Departments in areas dealing with infectious disease control, as well as in health promotion policy.

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1. The Challenge of Risk in Drug Regulation

Dr Pengilley emphasised the difference between the risk profiles for treatments used in general populations and those for life-threatening conditions, such as cancer. In oncology, for instance, patients with serious illnesses might face substantial risks from treatments, but the benefits of access to a potentially life-saving drug may outweigh these risks. This contrasts with the cautious approach often taken for vaccines given to the entire population, where safety data must be rigorous to ensure broad public health protection.

2. Provisional Registration: A Solution for Urgent Conditions

To address situations where early evidence suggests a medicine may be highly effective, the Therapeutic Goods Administration (TGA) introduced provisional registration in 2017. This system allows for the early release of promising drugs or vaccines, based on strong preliminary evidence, even if long-term data is not yet available. A key example of this was the provisional registration of COVID-19 vaccines in 2021. The urgency of the pandemic justified their availability, even before full evidence was complete. Over time, as more data was gathered, these vaccines were fully registered, illustrating the balance between quick access and ongoing safety evaluation.

3. Addressing the Limitations of Clinical Trials

While clinical trials are essential for assessing new treatments, they have limitations. They often involve highly controlled populations, exclude individuals with multiple health conditions, and focus on limited outcomes, such as survival rates. By using real-world evidence, regulators can capture a broader picture of how a drug performs in a wider range of patients, including those with complex, long-term conditions.

There was also an emphasised importance of ethics in clinical trials, with Dr Pengilley referencing historical events like the Tuskegee syphilis study and early HIV research, where ethical concerns around placebos and patient treatment were at the forefront. Modern clinical trials must now meet rigorous ethical standards to ensure participant safety and meaningful outcomes.

For example, research merit requires that a clinical trial offers potential benefit, and cannot be conducted just for the sake of scientific curiosity. Additionally, beneficence dictates that risks to patients must be justified by the likely benefits of the treatment being studied. Trials are now required to offer standard care rather than placebos when a proven treatment already exists, ensuring participants receive the best possible care.

Dr Pengilley also highlighted the ethical importance of stopping trials early if the treatment proves to be highly effective, so that all participants can benefit from the best available therapy.

4. The Importance of Patient Involvement in Defining Research Goals

Patient involvement in clinical trials goes beyond just participation. Patients living with rare conditions provide valuable insights into what constitutes meaningful outcomes. For example, in the case of a drug for a rare metabolic disorder, Dr Pengilley found that while the treatment may have seemed ineffective to outsiders, it made a significant difference in quality of life for patients. This was due to the ability to spend more time outdoors without immediate sunburn, something that would have been overlooked without the involvement of patients in defining what matters most to them.

5. Real-World Evidence: Moving Beyond Clinical Trials

Dr Pengilley also discussed the increasing reliance on real-world evidence (RWE) in medicine regulation. Traditional clinical trials often fail to represent the diversity of real-world patients, particularly in rare conditions where a standard of care may not exist. In these cases, real-world data — gathered from routine clinical practice — can offer valuable insights into how treatments perform outside the controlled environment of a clinical trial.

For rare conditions, where it’s impossible to conduct large-scale trials, real-world data can help regulators assess efficacy and safety. It also helps in situations where there is no established treatment, reducing the ethical concerns of using placebos in trials.

Real-world data is also increasingly used to assess the safety and efficacy of drugs. A notable example is the case of coxibs, a class of anti-inflammatory drugs linked to an increased risk of heart disease. Rather than conducting a traditional clinical trial, researchers used data from an insurance company’s large clinical records to establish this risk. This was made possible by the significant advances in computing power and the shift to digital health records, which now allow for large-scale, real-time analysis of clinical outcomes without needing to run a full clinical trial.

6. Clinical Registries: A Valuable Tool for Data Collection

There is a growing importance of clinical registries, which collect data from routine clinical practice. These registries provide a more accurate reflection of the patient population and help track the effectiveness of treatments over time. By supplementing clinical trial data with real-world outcomes, regulators can make more informed decisions about drug approval and use.

7. Why Trials Continue Long After a Drug’s Approval

Dr Pengilley acknowledged a significant concern for patients with rare conditions, such as those with Scleroderma: the fatigue of continuous participation in clinical trials. Because rare conditions affect such a small number of people, patients may find themselves repeatedly invited to participate in multiple trials, which can feel overwhelming or invasive. Some people may feel “trialed out” after participating in several studies or receiving frequent calls from researchers. This experience can be particularly frustrating when the trial process becomes a recurring part of a patient’s life.

Despite this, Dr Pengilley argued that ongoing clinical trials are critical. For instance, new treatments and new disease variants can alter how existing therapies should be used or how they compare to newer options. He used the example of aspirin, which was first introduced over 120 years ago and is still being studied today. Although aspirin has long been proven to have benefits for conditions like pain and inflammation, researchers continue to explore new uses and examine its efficacy in different populations. Aspirin’s ongoing trials help assess its effectiveness relative to new therapies and ensure that it remains a relevant option for patients. Hence, the same must be done for all other drugs used in medicine today.

Another critical reason for continuing clinical trials is to provide evidence for government health agencies to make informed decisions about funding and insurance coverage. In countries like Australia, where universal health care systems are in place, decisions about which treatments are covered and to what extent are often based on rigorous clinical trial data. This data helps governments and policymakers evaluate the cost-effectiveness and long-term benefits of treatments.

Without ongoing trials, it would be impossible to determine the true long-term benefits of medicines. For example, while a treatment may show significant benefits within the first year of use, it is crucial to know if those benefits are sustained in the long term (e.g., two, three, or even five years). Without this data, healthcare providers and policymakers cannot accurately assess whether continued access to the drug is justified, especially in the context of other available therapies.

8. The Biotechnology Revolution: Accelerating Drug Discovery

Looking forward, Dr Pengilley had optimism about the future of rare condition treatments, citing advances in biotechnology that are transforming the way drugs are developed. Some of the most exciting developments include:

  • mRNA Technology: A breakthrough that has already had a major impact on vaccine development and has the potential to extend into treatments for Scleroderma.
  • Genetic Therapies: Treatments for conditions like hemophilia and inborn metabolic disorders are already being used, and the technology continues to evolve.
  • Monoclonal Antibodies: These can be designed to specifically target receptors on cells, opening the door to highly tailored treatments for rare and complex conditions.

This revolution in biotechnology allows for the creation of highly specific medicines that can target the underlying biological processes of diseases. These innovations could dramatically accelerate the pace of drug discovery and offer hope for more effective treatments for rare conditions.

Dr Pengilley further highlighted an important trend in medicine: the ability to repurpose existing drugs for new indications. He shared the example of anakinra, a drug originally developed for rheumatoid arthritis. This medication works by reducing inflammation caused by a molecule called interleukin-1. Interestingly, it was found to be highly effective in treating NOMID syndrome, an extremely rare condition that causes widespread inflammation in children. Although NOMID was not the original target for anakinra, the drug proved to be a life-saving treatment for this condition.

This kind of “off-label” application of drugs is increasingly common, and Dr Pengilley pointed out that as we develop more targeted medicines, the potential for repurposing existing drugs for rare diseases will increase, leading to more treatment options for patients with little hope.

9. A New Era of Targeted Medicines

Historically, drug discovery was a slow and uncertain process. Researchers often relied on natural substances, such as plant and fungal compounds, to find potential treatments. However, modern biotechnology has changed that landscape. Today, we can identify specific biological targets within a disease and design molecules that directly influence these processes.

Dr Pengilley gave the example of sarapress, a drug being tested for fibrosis treatment. This drug works by targeting a specific receptor to inhibit fibrosis, a condition common in diseases like scleroderma. Fibrosis is a key issue in many conditions, not just scleroderma, and sarapress’s development could potentially offer a treatment option for a range of conditions that cause fibrosis.

This shift from broad treatments to highly targeted therapies is expected to increase the availability of effective treatments for rare diseases, as the technology allows for more precise targeting of disease mechanisms that are often shared across multiple conditions.

10. The Optimistic Future of Treatment

Dr Pengilley concluded with a hopeful message about the future of rare disease treatment. The rapid advances in biotechnology, including the ability to design highly specific therapies, will likely lead to faster drug discovery and more tailored treatments. This is especially exciting for rare conditions, where treatment options are often limited. 

He stressed that the ongoing collection of data through clinical trials is crucial for ensuring that these new treatments are effective and that patients can make informed decisions about their care. By continuing to invest in clinical research and gathering real-world evidence, we can ensure that Scleroderma and other rare conditions can receive the attention and treatment options they deserve.

For those living with Scleroderma, staying updated and informed can make a world of difference. Connecting with others can also be hugely beneficial. Find out more about support in your area here. 

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