The way I see it, a clinical trial is a bridge between research and the patient, this is an opportunity to access the latest treatment out there to get the best outcome possible, which is what it’s all about, right? So, in order to find out more about how it all fits together, I’m talking to Ian Davis who is the chair of ANZUP, a group of medical experts who look after clinical trials for below-the-belt cancers. Here is what we cover in this conversation:
- The Guinea Pig myth
- Are clinical trials safe?
- When is placebo given (if at all)
- Clinical trials as decision support tools
- Why you should ask about one now
- and much, much more!
Joe: Ian, it’s such a pleasure to meet you and to talk to you about clinical trials. I’m really excited about it because to me, really, clinical trials are the front line to fighting cancer. It’s making a huge difference for folks out there. Unfortunately, most people don’t realise how important this is and the critical role it plays in fighting cancer. What’s your perspective on that?
Ian: Yes, thanks, Joe, for the chance to talk to you and to talk about clinical trials. It’s very important. Every time you go to your doctor to get your blood pressure medication, or the medicine for your cholesterol, or even if you’re going to go and buy some vitamins from the chemist and you think that’s going to help you, you do that because you got some information about it. You know that, here is a treatment that might help you in your condition or might not. You’ve got information about how safe it is. When you should use it and when you shouldn’t use it. You might not be aware you got that information but it’s there. That exists because clinical trials have been done in all of those situations.
Every time you go to the doctor and you have cancer and you’re having a discussion about what sort of treatment might be appropriate for you, the advice that’s being given to you is being given in the context that a clinical trial has been done and it’s given you evidence. Now, we hope that that’s the case. The reality is, for many of the clinical situations we find ourselves in, the evidence is not there, we’re extrapolating from what we know or from the basic science, or from our understanding of the condition but there might not be a clinical trial to guide us in decision-making.
In that situation, it becomes a whole lot harder to make recommendations for people. That’s why we need to continue to push this agenda of doing more clinical trials, doing them better, so that we can get more information, help people, and support them in their decision-making.
Joe: Absolutely. Yes, that’s fantastic, Ian. There are so many myths and misconceptions about it, I think it’s really important to be really clear about that. A lot of them is that clinical trials are administered as a last resort, is that true?
Ian: No, it’s absolutely not true. Sometimes it’s appropriate to think about taking part in a clinical trial as a very first treatment. We do a lot of those clinical trials here, at our hospital and through ANZUP Cancer Trials Group, where we do clinical trials for genitourinary cancers. Many of the trials we’re doing are sometimes the first treatment that someone might have had from their disease. Definitely not a last resort. People should understand that if they’re going on a clinical trial, they’ll always get the best possible treatment.
Joe: Yes, absolutely. I think that implies that it’s an experiment, this has been thoroughly researched and it builds on this body of knowledge that already exists out there.
Ian: That’s right. There are different types of clinical trials. When you’re first taking a promising treatment into the clinic to see if it works. They don’t even know how to give these medications, sometimes they might never have been given to humans before. We don’t know what the side-effects are, we don’t know what the safe doses are, don’t know how frequently to give these medications. Early phase clinical trials help us to answer those sorts of questions and to give us some indication about how active it might be.
We usually have some clues about these things from earlier experiments in the lab and elsewhere, but you really have to ask these questions in humans. Then, as you go on further in the development, process, then you start to compare the clinical trials against the best standard treatment that’s available to see is it better in some way? Does it make people live longer? Is it better tolerated? Is it cheaper? Is it easier to give? Are there other sorts of benefits besides survival that we might be looking for, for our patients?
Joe: Yes, absolutely, like quality of life.
Joe: Cool. I’ve heard that there’s a placebo involved. Is that true? How does it work?
Ian: Yes, a placebo is an inactive treatment. Sometimes it’s appropriate and necessary to do that. The way I pitch the discussion to people who are talking about this is, there are certain situations where it’s not necessary to jump straight in and have another active treatment. Let’s say, for example, you’ve got a certain type of cancer, you know it’s there, it’s growing very very slowly, it’s not causing you any problems, it’s not likely to cause any problems in the near term, and there might not be any treatment that’s out there and known to be effective, or there are treatments, but they’ve got side-effects and perhaps it’s not the right balance for you to go down that pathway at the moment.
In that situation, the best approach for that person might be to say, we’re not going to give you any treatment now, we’re going to watch and see how the cancer grows and at some point, in the future, you might need to have some treatment. Now, that’s not saying no treatment, that’s about the timing of treatment. For that person, the best treatment for them right now might be nothing at all. In that situation then, it’s entirely okay to use an inactive treatment like a placebo because people getting the placebo treatment would be getting what they would ordinarily do anyway.
So then you might ask, why have it at all? The reason for that is that cancers are sneaky things and the treatments that we test are sometimes difficult to evaluate. So someone with a cancer that’s complaining of tiredness, or they get a rash, or they grow a second head or something like that, how do you know that’s a side-effect of the treatment, or maybe something that was going to happen as a result of the cancer growing anyway? A lot of the clinical trials that have been done with some of the new treatments suggest, for example, let’s take kidney cancer for example, one of the most common side-effects was tiredness. You might thing, okay, these drugs cause tiredness, but then you look at the people who got placebo and they’ve got tiredness, as well.
So you have to understand what the baseline levels of these things are in order to really understand what the impact of the active treatment is that you’re testing. But the converse is also true. If we know that there is an active effective treatment for your cancer, and that’s what you should be getting now ordinarily, then it’s completely unethical to do a placebo in the trial because those people will not be getting the treatment that you know they should be having.
As I said before, if you go on a clinical trial, you know that you’re going to be getting the very best of care. If you go on a clinical trial, which is comparing a standard treatment versus a new treatment, then the new treatment may or may not be better, the other people in the arm are getting the standard treatment that we know is best. Sometimes the standard treatment is no treatment. Then those people might be receiving a placebo but they’re not missing out. They’re getting exactly what they would ordinarily do. They’re being watched very closely, they’re getting the very best possible care.
Joe: Yes, I think what you’re saying is, in any case, you’re in safe hands and you’re getting the best solution out there.
Ian: That’s right.
Joe: Ian, what’s the process for putting together a clinical trial? How does it come about and how does it evolve?
Ian: Well, I guess there are two broad answers to that. When people think about clinical trials, they think about things that are run by drug companies. They are the commonest sort of clinical trials that we do. A big drug company out there with armies of people working in their labs come out with new treatments, and they think, here’s something that looks promising and we’re going to make zillions of dollars out of this and cure cancer and our shareholders are going to be happy. Nobody is going to be angry at that company if they cure cancer and I’d be delighted if they put me out of business. In that situation, they will then come to people like me who do clinical trials and say, “Are you able to find people to go into this clinical trial.” We look at the science behind it, we look at the clinical trial and the safety and the ethical aspects of it and say whether that’s something that we do.” That’s something that comes from externally.
The other broad group of clinical trials are what we call: Investigator initiated trials. This might be where someone who’s experienced in the field says, look, there’s a real clinical need here. These people are not doing as well as we would want them to do, the treatments we’ve got are not as good as we would like them to be. Here’s an idea about how we might improve things. In that situation, the idea has come from that person, that’s why it’s called investigator initiated. That might be a very small-scale trial that’s done in just one or two places. Or it might be quite a large-scale trial. ANZUP, for example, has led several international clinical trials that have totalled several thousand patients. These are investigator-initiated trials. These are ideas that we came up with and have developed with our local and international collaborators and rolled out hopefully to change practice in the future.
In that situation, you bring together a team of people to look at the science, look at the treatment, experienced in clinical trial design and all of the operational and ethical aspects behind all of that. Some of the practicalities that people might not think about, like how do you ship the drug and how do you dispose of it when it’s expired and what do you do about the safety reporting and all of those sorts of questions.
We always try to add value to it, as well. Are there other questions we can ask? Can we understand the science a bit better by collecting tissue or blood samples? Can we look at people’s quality of life and see if this treatment is having effects on that? Can we look at some of the health economic issues around this treatment, as well? This treatment we’re testing might work just as well as the old one, but it might be a much more cost-effective way for the community to spend its health dollars. We always try to add extra value to our clinical trials in that way.
Joe: It makes so much sense. You mentioned change of practice, so who decides whether the treatment has worked and if it’s to become a part of standard protocol?
Ian: That’s a really interesting question. There are several levels to that. The first answer is the look shiny thing response. We’re humans and we love to see novel things come through. Our initial reaction is, something comes through, it’s new, it’s got some exciting science behind it, it must be better. Sometimes it is, sometimes it isn’t, sometimes it’s just the same as the old treatment, sometimes it’s actually worse and we use the previous one. That’s going to alter practice in that way. In practical terms, if we’re talking about drug treatments in particular, it really comes down to making that treatment available in wherever you might be. Different regions around the world have got different ways of approving and reimbursing drugs.
In the United States for example, if you get FDA approval, then you can access that drug. You might have to pay for it and that’s a whole separate question. In Australia, there are two levels of approval. It needs to be approved by the Therapeutic Goods Administration, that way we can legally prescribe it in Australia. Really, it’s how it’s taken up into practice that needs to be reimbursed through the Pharmaceutical Benefits Scheme. That’s a much more difficult hurdle to jump over because the government has to tip money into supporting these things and they’re often expensive treatments. Once that has happened, then treatments are far more likely to be taken up.
Some treatments, though, are using old drugs in new ways. An example recently is in prostate cancer, where a few years ago some evidence came out that using a relatively old chemotherapy drug in a different way, much earlier in the disease course, translated into far better outcomes in terms of survival. That information came through at exactly the time that that drug was derestricted on the Pharmaceutical Benefits Scheme, so it was cheap and easy to use. Uptake of that information happened literally overnight. The next day after the conference, people were getting that treatment in Australia, it was taken up very rapidly.
Joe: Wow, that’s fantastic. You mentioned also different scales. You said that sometimes there’s a small group of patients who go through clinical trials, sometimes there’s a bigger group. How is that decided, and does it depend on a drug? Does it depend on the treatment, how does it work?
Ian: That really comes down to the question that you’re trying to answer. If you are early in the development of the drug and you’re looking for information about how to use it, how often to dose it, what doses to use, what the side-effects are, phase one of clinical trial, you often require only a few patients to get that information.
A phase two clinical trial would be where you are rolling it out into a group of people, all with the same sort of disease and you’re trying to see how effective this treatment might be. You need larger numbers, but it might be 50/100/200 patients typically on a study like that. If you’re trying to do a phase three clinical trial where you’re now putting it up against the standard treatment to say, is this actually better or at least as good as the previous treatment, then you often need hundreds or even thousands of patients. Particularly, if you’ve already got very effective treatments, it might be quite hard to prove to yourself that you’ve got something that’s doing even better than that. That might require a lot of people followed for a long period of time before you get that information. It really does come down to the questions you’re trying to answer in that specific trial.
Joe: Absolutely. Then there’s another area that’s fairly recent, is the online interventions, and I just wanted to talk to you and get your perspective about how does that work? How does it get implemented across the world if it goes to plan?
Ian: We’ve been talking about clinical trials in the usual sense that people think of them, in terms of here’s a new drug, let’s test it. Of course, there are other sorts of clinical research that can be done, as well. Clinical trials might involve surgical devices. It might not involve any sort of typical medical intervention. As an example, ANZUP did a clinical trial a few years ago of a supportive care intervention for men with prostate cancer. This was a psycho-oncology study led by one of our researchers, Professor Suzanne Chambers from Queensland, now New South Wales. This was a study using a behavioural therapy to try help them and their partners deal with the issues around prostate cancer.
There are other sorts of clinical studies, as well. ANZUP is running something called e-TC, which is a web-based approach where men with testicular cancer can login and find out information about testicular cancer to meet their own needs. If they want to work through all of the modules on their website, they can do so. If they’ve got a specific question, they can target in and answer that information. That will help you in terms of provision of information and it might steer you to other support systems, as well. Those sorts of systems also lend themselves to other types of research.
We can also collect information from people using systems like that, that can help answer other types of questions. For example, what is the information that people with testicular cancer need to understand? What are the most common sorts of issues they need in terms of supportive care or other sources of provision of information? There are other types of research that can be done through those sorts of online interventions.
Joe: There’s typically, I understand, a group of people that are possibly from different disciplines that are working on putting together a clinical trial, is that true?
Ian: ANZUP is a very multidisciplinary organisation and I think that’s one of our strengths. We are made up of clinicians and researchers from all types of medical and other disciplines involved in the care of people with these types of cancers and in research of these condition, as well as community representatives and other stakeholders too. We think that we get most value out of these sorts of trials when we’ve got people coming at them from a whole range of different perspectives. That’s what I was talking about earlier when I said we’re trying to add extra value to these clinical trials.
We don’t want to know just how safe this drug is, or this intervention is, or whether it improves survival, that’s important information. If we’re making people live twice as long and they’re three times as miserable, then we’re not doing anyone any favours. We have to understand those sorts of questions, as well. wherever possible, we try to get that broad base consultation and trial design right from the beginning, so that we can collect the information that really is going to make a difference. In many cases, coming back to your earlier question, that sort of information might make the difference as to whether a treatment really is adopted as a standard therapy or not.
Joe: Yes, absolutely. You mentioned there are different trials but there is definitely a progression from different stages through how its designed. Does every treatment for cancer go through a similar process? With those different check points and different stages?
Ian: In broad terms, yes. There has to be the first time that you try this treatment in humans and you have to work out how best to give it. Sometimes the process is accelerated. If you’ve got a magic treatment that makes your cancer disappear, then that’s going to go through the process quite quickly, all the way through to approval and it might skip some of those stages along the way. In general terms, there is a steady progress through these phase one, two, three clinical trials.
Then after a drug is approved, there’s often phase four clinical trials, which is basically post-marketing surveillance. That’s when you’re going to find out what the real-world experience is in the community and do these drugs perform as advertised? Are we starting to see the really, really unusual and rare side-effects that you wouldn’t have picked up in the smaller numbers in the earlier phase clinical trials?
Joe: Got you. Where does the money for clinical trials come from?
Ian: This is a perennial question. If it’s a drug company sponsored clinical trial, then they will provide the drug and the resources for doing the study. That money is spent at the hospitals, not on me, it doesn’t go into my pockets. It’s spent on paying the salaries of the research nurses, the costs of giving the treatment. Now, if it’s intravenous treatment, or if it’s requiring time in hospital, or those sorts of issues where you need to actually use some resources to give the treatment, that’s where the study costs go. Paying for ethical review, paying pharmacy costs, all of those sorts of things behind the scenes.
For an investigator initiated clinical trial, then it becomes much more complex. An example of ANZUP, we received some federal government infrastructure money through Cancer Australia, which provides us with some infrastructure support. That helps us pay some of our salaries in the office and keeps the lights on and puts paper in the photocopier, but we’re not allowed use any of that money to actually run a clinical trial.
Every time we’ve got a clinical trial, we have to find the resources for that separately. If I came up with a cure for prostate cancer today, and as I’m speaking, it is the end of July 2018, then the earliest I’d be able to put in a grant application to the NHMRC will be early next year. I’ll find out the result of that at the end of next year. I’ll have maybe a ten percent chance of success for funding to start in 2020. That’s 18 months away from now and I just told you I had the cure for prostate cancer. 18 months before I can even start doing that, if I’m relying on that. We’re always looking for other creative ways of supporting this sort of research. ANZUP has got a fundraising arm to it, so we can try to at least initiate some of these studies off our own back while we’re waiting for grant funding.
We often do work with pharmaceutical companies, the difference there is, though, we are the sponsor of the study, not them. We control and own the data and not the company. They get benefit from it because we’re testing their treatment, but this is our trial, they’re not driving it. There’s a level of independence from the drug company there. That’s a model that’s worked very well. The companies like it, as well, because they get very high-quality data in a short time on questions that they might not otherwise be studying. It’s a perennial problem for us. Clinical research is expensive and it’s slow and difficult, but really important.
Joe: Yes. Ian, I know you have a perspective on these magic cures for cancer, as well, so are we likely to get a cure for let’s say prostate cancer or testicular cancer or kidney cancer?
Ian: You’ve listed three interesting cancers there. That’s three that have great interest to me. For people that might not know, testicular cancer is almost always curable right now. That gives us a challenge. It’s going to be difficult to improve upon that. Prostate cancer and kidney cancer, if it has spread beyond where it started, is usually not curable. Our treatments are aimed to controlling to disease, hopefully shrinking it down, hopefully making people live longer and live better, but understanding that we might not be able to get rid of the cancer.
Your question is about whether we’re ever going to be able to cure these cancers. I don’t know. A lot of very famous people have gone on record of saying silly things. Man will never be able to travel faster than 45mph. They’ll be one IBM computer in every city one day. Silly comments have been made. I’m not going to make any rash predictions. The challenge for us, though, we use terms like cancer, like prostate cancer, as though this is just one entity. That’s not the case. Even within a single person’s cancer, there’s literally billions of different cells and many of them are genetically distinct and behaving in different ways.
Even in that one person, you might have some cancer cells that are sensitive to a treatment and some that are not. We’re trying to think of clever ways around that, so some of the new immune-based treatments that work by stimulating the immune system have their effects, not by acting on the cancer but by stimulating normal cells, trying to get the immune system to reject the cancer like it would reject my kidney if I put it into your body. That’s attractive and is looking very promising in a number of cancer types.
It’s been seen by many in the community as a really significant step forward, and it is, but to our disappointment, it doesn’t work in every type of cancer. We’ve still got to understand why. I think we’ve still got a long way to go, unfortunately.
Joe: Cool, got you. Ian, I know you’re passionate about people having a mindset, when they would go into hospital about to start treatment, to be asking whether there’s a clinical trial that’s possibly available to them. Can you talk about that?
Ian: That’s my dream, that we get rid of this guinea pig mentality that people go along, and they’ll have the conversation with their doctor and say, okay, I understand what the standard treatment options are, are there any clinical trials that might be suitable for me? There might or there might not be, but if there are, then I would hope that people would consider taking part in those sorts of things. We’ve very excited about that. We’re trying to build that sort of capability. It’s difficult and it’s often seen in health services as something that’s in addition to the usual clinical service provision. I don’t think that’s true at all. I think that clinical research and clinical trials are absolutely integral to what we do and should be part and parcel of our everyday work and therefore, part of our everyday treatment, as well.
Joe: Fantastic. If you’re a patient, how do you find out about that? Do you go to ask a specific doctor? Do you keep track online? What do you do? How do you understand about how it works?
Ian: Probably the best starting point is to talk to the specialist that’s looking after your condition. GPs are often well-informed in general terms about clinical trials but might not know the details of the specific clinical trials. Your specialist should understand that and should be able to point you in the direction of where these clinical trials are happening, or where to find out more information. For people who just want to find general information, there’s a number of sources. You can go to Cancer Counsel websites, there is an Australian and New Zealand clinical trial registry, ANZCTR, if people Google that, that will come up.
There’s a site based in the U.S. called clinicaltrials.gov. Which is also good. Some of these are in more technical terms, though. ANZUP and other trial groups have an app that you can download for Apple devices or Android devices called the ANZUP ClinTrials Refer App. That’s really fantastic because it will tell you in the case of ANZUP, for example, all the trials that we’re doing and whatever disease, where they’re open, some information about the trial and where to go for more information. That’s pitched at not just clinicians but anyone in the community. It’s a fantastic resource.
Joe: Fantastic. Ian, if someone wanted to start treatment for cancer and they were considering a clinical trial and they’ve never heard about it, what would you tell them?
Ian: The way I approach this is, I try to explain everything I can about the condition to this person and what the current standard options would be for them. If there is a clinical trial that’s appropriate and suitable for them. I then put it into that context. If this is someone who’s thinking about having some form of active treatment and as a clinical trial, that’s when I would then bring this in as an alternative for them to be thinking about. People need to understand, they don’t have to do this, this is completely voluntary.
If there is a trial that’s suitable for you and someone is recommending it for you, they will give you information about it. We encourage people not to make snap decisions. We like you to go away and have a think about it, take this written information away, read it, scribble on it, talk about it with whoever they want to, then come back and tell us what their thoughts are. They might say at the end of that, look, this sounds interesting but it’s not for me. In which case, that’s absolutely fine. It doesn’t affect our relationship with you at all and we’ll continue to do what we’re going to do anyway.
If the clinical trial looks like it might be something that they’re interested in, then generally what we do is get them to sign the consent form. That consent form is not a mortgage. What that means is, they are agreeing to take part in the next steps of the clinical trial. That means also that they allow us to collect information about them, that’ll eventually be published somewhere, but not in a way that they can be identified. It allows us to use a treatment that might not otherwise be approved for use in Australia and all of the other information that’s in the consent form.
I also point out to them that if someone goes under a clinical trial and at any point they want to or need to come off that treatment, they can. They’re not locked into something. We encourage people not to and this is a good reason, but if there is a good reason, then of course, that takes priority. People’s best interests are always paramount when we’re giving any sort of treatment and in particular when people are on a clinical trial.
Joe: Yes, that’s fantastic, Ian. I love that there is no pressure, that as a patient, you still feel in control of the process
Ian: That’s absolutely right.
Joe: Cool. If someone wanted to find out more about ANZUP, maybe even find a way to contribute, what would you do?
Ian: They could go to our website which is: www.anzup.org.au. There’s a lot of information there about what clinical trials are, in general, and also specific information about our clinical trials. If people want to contribute financially, and some people are very interested in doing that, then there’s also information on that website about how people can contribute in terms of financial contributions, but also in terms of raising awareness about clinical trials and what we do.
Joe: Fantastic, Ian. Thank you so much.
Ian: Thank you very much.