“Unrealistic optimism” and participation in early-stage clinical trials

There is an excellent article by Pauline Chen in today’s New York Times. It is focused on the mindsets of patients who willingly participate in the very earliest clinical trials of  new drugs for the treatment of cancer, and on ethical issues related to enrollment of patients into these trials.

Phase I (and some Phase II) clinical trials are almost never about the effectiveness of a new cancer therapy. They are entirely focused on identifying the potential for toxicity and the maximum safe doses of the drug that can be given to sick patients. It is fair to say that few of the patients who are enrolled really benefit significantly from participation in these very early-stage trials — perhaps no more than about 5 percent.

In her article, Chen discusses a recent research study by Jansen et al. that appears in the highly specialized journal IRB: Ethics and Human Research.

Between August 2008 and October 2009, Jansen and her colleagues asked 70 patients enrolled in several early-phase cancer trials  about their expectations and understanding of the trials they had agreed to take part in. It is clear that a significant majority of these patients fully appreciated that the goal was to advance research, not to treat them. However, the patients also tended to demonstrate what the research team described as “unrealistic optimism” with respect to their personal expectations about the trial outcome for them as individuals. Most of the trial participants believed that they were different, that the new drugs would work for them, and that they would just “do better” than the average patient in their trial.

There are all sorts of interesting and important ethical challenges associated with this issue. But it is also worth remembering that the sort of person who is willing to participate in such early stage trials tends, already, to be unusual. Such patients have commonly, previously, participated in one or more other trials. Many have a “glass half full” mentality about life and are willing (rightly or wrongly) to try pretty much anything to extend their lives — because of how much value they place on another week with their children or a desire to see a grandchild graduate from high school.

If you have ever participated in a clinical trial yourself, or you have been thinking about it — particularly if it is a very early stage trial of a completely new drug — Dr. Chen’s article is well worth reading.

6 Responses

  1. ‘Many have a “glass half full” mentality about life and are willing (rightly or wrongly) to try pretty much anything to extend their lives.’

    Is this a surprise to anyone? It’s not to me. Why do you think people get screened for prostate cancer when it has never been proven to decrease PCSM? It’s the exact same reason. People don’t want to die from cancer and they will try just about anything that they think will give them a better chance of survival. Everyone hopes to be that one exception to the rule. What other option do you have when you’re diagnosed with cancer?

  2. Dear Chris:

    I think you are missing the point. People enrolling in Phase I trials of utterly untested drugs when they have very late stage cancer (e.g., a man with advanced prostate cancer who has already failed hormone therapy, Taxotere-based chemotherapy, an abiraterone trial, cabazitaxel, and perhaps some other trial, and who has mCRPC with a PSA of 600) are invariably advised that there is almost no chance at all that such drugs will offer any clinical benefit whatsoever … let alone “a better chance of survival.”

    This issue being raised by this research paper and by Chen’s article is an important ethical one. How does one actually know whether these people have really heard what they are being told?

  3. OK. You are right. I am missing the point. Not to be a smart a??. If these drugs have “almost no chance at all that such drugs will offer any clinical benefit whatsoever,” then I have two questions:

    (1) Why are the drugs being tested at all then?
    (2) Why are the patients eligible to be in the trial in the first place?

    It is that exact slight chance that the drug may help them that these people are hanging on to. When you are being told you are going to die and there is no hope, a lot of people start to try anything. Again having been diagnosed with cancer, this is not surprise to me. I would have agreed to be incontinent the rest of my life if it could guarntee me a cure.

  4. In answer to question (1) … In a Phase I clinical trial, drugs are being tested to see if they are tolerable, and if so at what dose. They are not being tested to see if they are effective at all. As you are well aware, lots drugs appear to work in laboratory tests and in lab rats and mice, but sooner of later one has to see if they can be given to and tolerated by humans. And if they are going to be used in patients with cancer, one needs to see if they can be tolerated by people with cancer, even for short periods of time. As a result, drugs are rarely given in Phase I trials for a long enough period to know that they would be effective. The researchers are just trying to find out whether people can manage to deal with the drugs at all, and if so at what dose. Lots of drugs that go into Phase I trials never make it to Phase II because either the patients can’t tolerate them at all or the drug can’t be tolerated at a high enough dose to have any chance of being clinically effective.

    In answer to question (2) … The whole point of testing these drugs in people with extremely late stage cancers is that the risks associated with trying such drugs in these people is minimal because the patients are already near to death. This is carefully explained to them. They are advised, with great care, that what they are doing is volunteering to help science, and that the chance of any particular drug having any clinical effect in them is minimal.

    To all intents and purposes, volunteering as a cancer patient to participate in a Phase I clinical trial is not dissimilar to donating one’s body to science after you die — but just slightly earlier. Is there a chance that you might have a response? Yes there is. Maybe 1 in 20. But even if you have a response, you are already so far advanced that the response is not likely to be clinically significant.

    Because I was trained as a biochemist, and I have worked in the biological sciences almost all of my life, I have asked myself on many occasions whether I would participate in a Phase I clinical trial of a cancer drug under appropriate curcumstances. I am as sure as I can be that the answer is yes, I would … but only once I knew that I had exhausted all reasonable opportunities to extend and enjoy any further life, and only in order to be able to help others by assisting to find out if a new drug was actually tolerable. My expectation of any survival benefit would be nil.

  5. I have participated in many clinical trials, and will continue to do so. I have both sons and grandsons who may benefit from the science gained from such work. Not all clinical trials are carried out on advanced patients.

    Even phase I trials may provide some benefit to some of the patients, and that places those who received no benefit in Phase I ahead of the rest for a phase II trial. Look how Dendreon froze the blood of patients (ACP8015F) who received a placebo and give them an infusion of the loaded Provenge after the trial of other patients was complete.

    The question here is why is this “ethics” question is even being asked? Getting volunteers for these trials is tough enough.

    The New York Times wrote that oncologists make 50% of their income selling drugs to patients. Clinical trials provide free drugs. Also, the time required to research and then explain the clinical trials to patients is not compensated. Now we have ethics to deal with? How many will not do clinical trials because of reading this article?

    When I was at the National Institutes of Health Clinical Center doing a trial, there were patients in the waiting room so sick you wondered if they would make it out of that room alive. The will to live is strong and clinical trials offer some hope if not for the patient then those who will follow them.

    Not everyone just wants to lay down and die without helping as much as possible.

  6. It is completely unclear to me what Bob’s point is. No one is suggesting that clinical trials shouldn’t be done. The only point being made in the article above is that apparently a significant percentage of patients participating in Phase I (and some Phase II) clinical trials of investigational cancer therapies appear to have an unreasonably optimistic set of expectations about the potential of their personal outcomes from these trials. This is very clearly an ethical issue, as anyone who has ever studied the ethics of clinical trials would recognize immediately. However, as Dr. Chen and the original study authors carefully pointed out … what to do about it is a much more difficult question to deal with.

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