Managing expectations of emerging therapies

Chapters

[0:00] Introduction & Speaker Background
[1:17] Presentation Overview: Managing Expectations
[3:58] The Ultimate Goal: A Functional Cure
[5:04] The Long Road from Lab to PBS
[6:58] Phase 1, 2 & 3 Clinical Trials Explained
[10:25] Regulatory Approval: TGA vs. PBS
[12:51] The PBS Cost-Benefit Negotiation
[15:08] Compassionate Access & Company Programs
[17:35] The Different Pathway for CAR T-Cell Funding
[19:41] The Need for Patient Advocacy
[21:49] “Real World” vs. Clinical Trial Results
[25:01] Key Questions to Ask About Any New Treatment
[27:12] Considering Practicalities & Hidden Costs
[28:35] The Current Status of CAR T-Cells in Australia
[32:47] Why Governments Fear the Cost
[34:10] The Status & Cost of Bispecific Antibodies
[35:18] Clinical Trials as the Primary Access Route
[36:02] How to Find & Enrol in a Trial
[37:06] The Screening & Consent Process
[40:01] Downsides & Commitments of Trial Participation
[42:13] The Benefits & “Concierge” Care of Trials
[43:12] Q&A: Accessing Trials from Rural Locations

Transcript

[0:00] I have the pleasure of introducing our next speaker, Dr. Wojtek Janowski. Wojtek sees patients with thrombotic and other general haematological problems, as well as those with leukaemias, lymphomas, myeloma, myeloproliferative neoplasms and myelodysplasia. His main interests are the diagnosis and treatment of haematological malignancies and he is the clinical lead for trials in multiple myeloma and CLL at the Calvary Mater. He works on protocol development and the rapid translation of cancer research into the clinical setting.

He’s involved at every level of medical training and has spoken at various GP events. After completing his training in Melbourne, Wojtek joined the haematology team at the Calvary Mater in 2014. He started in private practice in 2015 and has relocated to the Hunter Cancer Centre at Gateshead to provide a more comprehensive service. Wojtek’s presentation is called ‘Managing Expectations of Emerging Therapies’. Thanks, Wojtek.

[1:17] Thanks very much, Danielle. And what a talk to follow Peter! Thank you for that. Even I learned something. So, as Danielle said, I’m a haematologist in both public and private practice in Newcastle. As time has gone on, most of my work is now on treating people with myeloma and particularly on trying to attract more clinical trials to regional centres. We’ve been fortunate to have excellent partners and we were the first centre outside a capital city to administer CAR T-cells in a clinical trial about eight weeks ago. A huge achievement by our staff.

I’m very excited about what this new era of medications brings. Peter talked about extremely exciting therapies and I 100% agree. When Myeloma Australia asked me to give this talk, I wasn’t overly enthusiastic because I felt I was being asked to rain a little on the parade. But I realised it’s all very well hearing about these therapies, but if you can’t get access to them in a timely fashion, is it false hope? We have to be realistic about when we will get them into routine practice in Australia.

We work hard to get them here on trials, but only a tiny minority of patients benefit from trials directly. In the end, our goal is ultimately the cure of myeloma. I am extremely excited by the progress made in the last 15 years; people with myeloma live longer. But ultimately, we want a treatment of limited duration where you are done with this disease, life is back to normal, and your life expectancy is what it would have been without myeloma. There’s still a great deal of work to do.

[4:58] Today, I will talk about the long road from conducting a clinical trial to PBS prescribing. How complicated that process is. Why our expectations of a medication might not match the ‘real-world’ PBS experience. And then, since I will encourage participation in trials, talk about the maze of accessing them.

[5:57] How does a medication get from a good idea to the PBS? There are many steps. Before the Phase 1 first-in-human study, there’s years of research at universities and biotech companies. That phase can take a very long time. The first concept of a CAR T-cell was in 1987; the first human dose was 15-16 years later; the first registration took another decade.

[7:04] When it comes to people receiving medications, the company first does high-risk Phase 1 studies on a very small number of people—the first humans to ever receive it. These are done in large centres with a lot of support, for people who have no better option left. Many medications fail at this stage.

If it looks promising and safe, the company moves to larger Phase 2 studies with about 50 patients. Here they try to optimise the dose, combine it with other treatments, and look for synergy and unexpected side effects.

[9:08] If it still looks promising, they need to prove it works compared to what we already have. These are the Phase 3 studies. This is often the first time there’s randomisation—patients agree to participate not knowing if they’ll get the standard treatment or the new experimental one. These are crucial because not every new treatment is a good idea. Some may have worse side effects or be no better than existing options.

These studies take a long time. Often, even the ‘control arm’ (the standard treatment in the trial) is better than what we can give on the PBS in Australia right now.

[10:52] Once all research is done, you approach regulatory authorities. In the US, the FDA can approve based on Phase 2 data—they ask: is it safe and does it work? That allows the company to market and sell it. The TGA in Australia is similar; they will accept an early application. This allows the company to sell the medication here, but it has nothing to do with government funding via the PBS.

[12:51] The challenge is the PBS. They manage the pharmaceutical budget and look at all the clinical trial data to quantify the benefit to the patient. They try to determine, for example, how many patients we need to treat for one to gain an extra year of life. They look at that benefit and the price the company is asking, and decide if it’s cost-effective. They don’t have a firm line, but it depends on the disease and other options.

The first price is rarely approved. It’s extremely unusual for the PBS to approve a high-cost cancer medication on the first attempt. This process can take several years. We are a small market (26 million) compared to the US (360 million). Getting medications here is a priority, but not their top priority.

[15:08] Companies can choose to make a medication available early once they have TGA approval. They can sell it at a price, or offer cost-offset programmes (like ‘buy four, get four’), or very occasionally provide it free on a compassionate basis. But there’s no rule saying they have to.

[17:35] It’s slightly different for CAR T-cells. They are a cell therapy, regulated like a medical procedure. They are assessed by MSAC (Medical Services Advisory Committee), not the PBS. The basic principles are similar, but it’s a more complicated funding discussion because the federal government must share costs with state governments.

[19:41] This is all extremely frustrating for doctors and patients. I encourage you to advocate as a community. Myeloma Australia has been phenomenal in driving this. Write to your MP, write to the PBS and MSAC. The government recognises it’s a problem and is reviewing how they fund medications, but reviews take time. They have a limited budget and many competing priorities. I would argue that for a country as rich as Australia, we should have earlier access.

[21:49] Sometimes our expectations of medications may not match reality. The treatment might not be as good as we thought. It’s important to understand this, especially if considering buying your own medication. You need a clear idea of what it may offer in benefit and side effects.

The world of clinical studies is a bit artificial. Patients in trials are on average younger, have fewer health problems, and often have slower-moving myeloma. People with very aggressive disease often can’t wait to enrol. Studies are done in larger hospitals and more affluent countries; the population is different. Also, on a trial, patients are followed extremely closely.

[25:01] When looking at a new treatment, ask: Did the people in the study look like me? Were they a similar age and fitness? Were they as sick as I am? What prior treatments did they have? After considering that, are my expectations realistic? Is this treatment, with all its side effects, worth it?

[26:16] It’s not just about the medication. For example, with BCMA-targeting bispecific antibodies, people will likely need ongoing intravenous immunoglobulin replacement, which means being at a hospital regularly. That’s a practical consideration.

[27:12] Ask: How often do I need treatment and where? How long does it go for? (Most are indefinite). What are the realistic chances this will work for me, and if it does, for how long?

[28:35] We’ve been talking about CAR T-cells for years. Where are we? CAR T-cell therapy (cilta-cel) is the only one registered for myeloma by the TGA. The first application to MSAC was deferred—they said the data was immature and it was too expensive. A second application was considered last November. Huge progress was made, but the government essentially said it’s still too expensive.

[31:27] The publicly available minutes show the government acknowledges these work for late-line patients, but the cost remains the barrier. The company (Janssen) says they’ve reduced the cost by 40% over five years, but until the government recognises it’s a really good treatment, they’re stuck. The latest was a ‘deferral’, not a rejection, so hopefully, more discussions happen soon.

[32:47] Why is the government hesitant? The cost scares them. The all-in cost of CAR T-cell therapy can be around a quarter of a million dollars per patient. If even 10% of Australians diagnosed with myeloma needed it, you’re talking hundreds of millions per year. The entire PBS budget is about $15 billion, and myeloma is less than 2% of cancers. It’s a frightening cost.

[34:10] For bispecific antibodies like teclistamab: there is no Phase 3 data yet, and the PBS needs that. The current cost if you purchase it is approximately $7,000 per dose. The official schedule is once a week, though studies now use less. The company offers a ‘four for four’ programme, halving the effective price. But you might spend $28,000 before knowing if it works. Frightening stuff.

[35:18] For many new medications, the only practical way to access them (if you’re not wealthy) is to participate in a clinical study.

[36:02] First, you have to find a study. A useful website is ClinicalTrials.gov. Always ask your clinician: “Are there any studies nearby or in a hospital I could travel to?”

[37:06] It’s not straightforward. We first check the study’s inclusion/exclusion criteria to see if you might qualify—we don’t want to raise false hope. If you look like a candidate, you’ll be told about the study and receive a long consent form outlining everything involved and all potential risks.

If you agree and sign, you enter a screening phase with many tests to confirm you fit all criteria. This can take up to four weeks. If you pass and it’s a randomised study, that’s when the randomisation happens. Then treatment starts.

[40:01] There are potential downsides to trials. The newer thing isn’t always better. There can be unforeseen side effects. The treatment schedule is more rigid than routine PBS care (e.g., travelling overseas can be complicated). You will have more blood tests, scans, diaries, quality-of-life forms, and unfortunately, more bone marrow biopsies. It is a bigger time commitment.

[42:13] But the personal upsides are access to treatments you might not otherwise have. Being on a study is like having a concierge service from the trial coordinators; you always have a point of contact and are watched carefully by a team. Participating in a trial is how you help make those expectations closer to reality for future patients.

[43:12] Thanks, Wojtek. That was really interesting. We have time for one question: How can somebody in a rural or remote location access clinical trials?

[43:54] I would love for this to be simpler. The reality is a lot of the time, regional patients travel for studies. Often, the pharmaceutical company will reimburse travel and accommodation costs. The time aspect is harder. There’s a lot of talk about ‘tele-trials’ to bring studies to smaller centres. My colleagues and the Australian Leukaemia & Lymphoma Group are working hard on this, but it’s complicated logistically and regulatorily.

The best way is to participate in any studies your local regional centre has. Prove there are patients who need them, which helps build capacity to attract more studies in the future. It’s about building slowly.

[45:41] Thanks, Wojtek. Thank you for your time and for presenting during National Myeloma Month.

[45:58] Thanks for inviting me.