ASCO 2011 Annual Meeting, June 3-7 2011, Chicago

Ethics of early-phase clinical trials

Dr Steven Joffe – Dana-Farber Cancer Institute, Boston, USA

I’ll be talking about the ethical challenges or controversies that surround phase I trials in oncology, trials that involve the very first experiments or efforts to use new potential anti-cancer agents in human subjects. These are very controversial studies for a couple of reasons from an ethical point of view with people who are both very critical of these trials on the one hand, and people who are very strong defenders of the ethics and, in fact, the therapeutic benefits of these trials on the other. Our session and my talk will be trying to navigate between these conflicting or controversial views about these trials.

So on the one side we have critics of phase I trials who say we have good evidence that the likelihood that anybody will benefit from taking part in these trials is very low; that the trials are designed to answer questions about the safety of the drugs, the appropriate dose of the drugs to use in subsequent, for example phase II, trials, not about what the efficacy of the drugs might be. And that we have good evidence that people who take part in these trials, who agree to take part, are often overestimating the likelihood of any benefits that they will receive from being in the studies and therefore we really ought to take a step back from these trials and take a very different approach, at least to the recruitment of patients for these trials. So that’s the view on the one hand.

The view on the other hand is these are patients who have exhausted all standard anti-cancer options; if they had available standard options, of course, that’s what would be offered to them instead. For patients like this, who no longer have standard options available to them, phase I trials are as good as, if not perhaps better than, any other treatment that we can offer them; that they really do have very substantial prospects of benefit, particularly seen in comparison with other options that are available to them. So we should not be shy about offering phase I trials and offering them as potentially beneficial interventions for patients. 

What’s your opinion?

My own view falls somewhere in between these two extremes, which is to say I do believe that there is a potential for benefit from joining a phase I trial, I think we have enough data to suggest that that is the case, although I also acknowledge that it’s, on average, fairly low. Now there are going to be exceptions to that, every once in a while there is a phase I trial where a very high proportion of patients have responses, life extension, things like that. Of course if one finds oneself in the middle of such a trial then the thinking is different. So I do believe, on the one hand, that there is the potential for benefit and patients should not be told that there’s absolutely no benefit from being in this trial. On the other hand, I think we have to be very careful as oncologists and investigators not to over-promise benefits from these trials and to be very careful to convey to patients that the likelihood of benefit is fairly modest, that they should be thinking carefully about the other options that are available to them, including palliative care, symptom directed care, treatment without anti-cancer kinds of agents, anti-cancer drugs, not enrolling in a clinical trial. At the end of the day, an informed patient who thinks about these various options and decides that joining an early phase trial, a phase I trial, is what that patient wants to do, I’m very supportive of that.

How do we better inform patients?

We have to be very clear in our discussions with patients, our discussions and also the forms that we give patients, the information sheets or the consent forms about the purpose of these trials. These are the first, earliest uses of these trials in human subjects, they’re the first time that we will learn anything and, in fact, our initial questions are about the safety of the drug, the dose of the drug. I think we have to give some sense of the likelihood that people will get responses or other forms of benefit from the drug. Now this is a complicated thing to communicate because if it’s the first time we’ve used the drug in people then we can’t easily estimate what the likelihood of benefit or response with this drug is, we have no experience with it. But we can extrapolate to some extent from other phase I trials that have gone before and we know that on average the response rates for phase I trials in contemporary oncology research practice are something less than 10%. So I think we can share that number with patients and we can be very careful to say the purpose of what we’re doing here is to learn something about the safety and the toxicity of this drug. Of course we hope that it benefits you in your fight against your cancer but it’s important for you to understand that at this early stage of treatment or early stage of investigation with new drugs that that’s unfortunately a rare, although not unheard of, event.

Is there any research into patients’ feelings about taking part as the trials progress?

That’s a great question and there isn’t a lot of research that follows patients through their time on a study to try to find out what their experience of being on that study has been. There is a lot of research around the initial time that people decide to join studies, around the time of the informed consent conversation, this is part of how we know that, to a fairly large extent, patients are in fact overestimating the likelihood that they will benefit. But there’s not a lot that follows them through their trial experience and that would be important information, I think, to try to understand better what the experience of being on a phase I trial is like.