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Clinical equipoise versus scientific rigor in cancer clinical trials

A critical aspect of both evidence-based medicine (EBM) and science-based medicine (SBM) is the randomized clinical trial. Ideally, particularly for conditions with a large subjective component in symptomatology, the trial should be randomized, double-blind, and placebo-controlled. As Kimball Atwood pointed out just last week, in EBM, scientific prior probability tends to be discounted while in SBM it is not, particularly for therapies that are wildly improbable strictly on the basis of basic science, but for both the randomized clinical trial remains, in essence, where the “rubber hits the road,” so to speak. Indeed, when the prior probability of a therapy working based on preclinical basic science investigations appears high, EBM and SBM should be (and are, for the most part) more or less indistinguishable.

The ethics of clinical trials, however, demand a characteristic known as clinical equipoise. Stated briefly, for purposes of clinical trials, clinical equipoise demands that at the time a clinical trial is being carried out there be a state of genuine scientific uncertainty in the medical community over which of the drugs or treatments being tested is more efficacious and safer. One reason (among many) why the Gonzalez trial was completely unethical was a lack of clinical equipose. (Lack of adequate informed consent was another.) Lack of clinical equipoise is also the reason why a prospective randomized, double-blind, placebo-controlled clinical trial testing an unvaccinated group versus a vaccinated control group to determine whether vaccines cause autism would be completely unethical. Such a trial would egregiously violate the principle of clinical equipoise because the unvaccinated group would be left unprotected against potentially life-threatening vaccine-preventable diseases, and that is completely unacceptable from an ethical perspective. Consequently, we have had to rely on on the accumulation of data from less rigorous trial designs to demonstrate that there is no correlation between vaccines and autism. Even so, the accumulated weight of such evidence is enough, and for some questions that is the best we can do because scientific rigor sometimes conflicts with human subjects research ethics. This is an extreme example of lack of clinical equipoise, but it illustrates the point. If we know (or have good scientific reason to suspect) that one treatment is better than another, it is unethical to randomize patients to the arm that receives what is, based on what is known at the time of the trial, likely to be an inferior treatment.

Sometimes, however, the question of whether clinical equipoise exists in a clinical trial is not so obvious as it is for trials proposed by cranks. This situation sometimes crops up in clinical trials for cancer. I was reminded of this issue by a front page story in the New York Times yesterday, New Drugs Stir Debate on Basic Rules of Clinical Trials. In it, reporter Amy Harmon uses a classic human interest story to highlight the issue of clinical equipoise in a clinical trial for a new drug for melanoma that shows great promise. In brief, it is the story of two cousins, one of whom is receiving the new “wonder drug” (whether it is truly a wonder drug or not remains to be seen) in a clinical trial and one of whom is receiving the current standard of care for stage IV melanoma, which, to put it bluntly, sucks in that it has very little effect in prolonging life:

And when, last year, each learned that a lethal skin cancer called melanoma was spreading rapidly through his body, the young men found themselves with the shared chance of benefiting from a recent medical breakthrough.

Only months before, a new drug had shown that it could safely slow the cancer’s progress in certain patients. Both cousins had the type of tumor almost sure to respond to it. And major cancer centers, including the University of California, Los Angeles, were enrolling patients for the last, crucial test that regulators required to consider approving it for sale.

“Dude, you have to get on these superpills,” Thomas McLaughlin, then 24, whose melanoma was diagnosed first, urged his cousin, Brandon Ryan. Mr. McLaughlin’s tumors had stopped growing after two months of taking the pills.

But when Mr. Ryan, 22, was admitted to the trial in May, he was assigned by a computer lottery to what is known as the control arm. Instead of the pills, he was to get infusions of the chemotherapy drug that has been the notoriously ineffective recourse in treating melanoma for 30 years.

Even if it became clear that the chemotherapy could not hold back the tumors advancing into his lungs, liver and, most painfully, his spine, he would not be allowed to switch, lest it muddy the trial’s results.

The melanoma drug in question, PLX4032 (RG7204) was developed by U.S.-based biotechnology firm Plexxikon, which partnered with Swiss pharmaceutical firm Roche to bring the drug to market. The drug targets a specific (but common) mutation in the BRAF proto-oncogene (pronounced “b-raf,” not “braf”) found in melanoma. Interestingly enough, I’ve actually participated in research with a collaborator who is a melanoma surgeon to develop PCR-based methods to detct this very mutation (which was at the time erroneously referred to as the V599E mutation) that results in activation of the BRAF protooncogene, but it’s been five years since I have done any work in this area. In any case, it is gratifying to see that others have developed drugs that target these activating mutations.

Melanoma, for those unfamiliar with the disease, is a cancer that develops in melanocytes, the pigmented cells in the skin. It is highly curable when it is caught early, because surgical excision and sampling of the regional lymph node basins is highly effective. It can even occasionally be controlled in the metastatic setting, resulting in long term survival, if the metastasis can be completely excised surgically. However, once melanoma is stage IV and metastatic to multiple sites or to a site (or sites) from which the tumor cannot be surgically resected, melanoma is incurable. Worse, it’s notoriously resistant to chemotherapy. The very best standard of care chemotherapy regimens include dacarbazine or temozolomide, the former of which is usually first line therapy and the latter of which is sometimes preferred because it can be given orally. Neither work very well.

So in melanoma basically what we have is a disease that is incurable and fatal when it reaches stage IV and for which, unlike the case with, for example, colorectal cancer, there is no good therapy that can markedly prolong survival. Enter PLX4032. PLX4032 is remarkable because it is a targeted agent directed at the V600E BRAF mutation that, in phase I trials, demonstrated significant activity against melanomas harboring that mutation. Since V600E is a common mutation in melanoma, being present in around 50-60% of tumors, that means more than half of patients with metastatic melanoma could potentially benefit from the drug. What do I mean by “significant” activity? In a multicenter dose-escalation phase I trial whose results were recently reported in the New England Journal of Medicine and the press, 81% of patients with V600E mutations showed tumor shrinkage of at least 30%. Moreover, side effects were not prohibitive, with cutaneous (skin) side effects, fatigue, and arthralgias (joint pain) predominating. The worst potential side effect was squamous cell carcinoma of the skin.

These results are quite impressive for a phase I study. Remember that phase I trials are not designed to detect efficacy; they are safety studies. The idea is to increase the dose in humans until dose-limiting toxicities are encountered. If tumor responses are seen, so much the better. Typically, less than 25% of subjects in a phase I trial will demonstrate measurable tumor shrinkage, making 81% very impressive indeed. Moreover, among subjects receiving the drug, the estimated median progression-free survival (PFS) has been 7 months, compared to historical controls of around 2 months. The duration of these responses was on the order of 8 months, which means that the tumors did nearly all start growing again, but, even so, this is far better than the standard of care chemotherapy for metastatic melanoma, dacarbazine, which only slowed tumor growth in 15 percent of patients for an average of two months. Of course, the results of this phase I trial are no guarantee that the apparent increase in PFS (which may or may not be real, given that there is no control arm in a phase I trial) will translate into an increase in overall survival (OS) — remember Avastin — but it is very promising, which is why this new clinical trial was begun. Indeed, I view PLX4032 as a prime example of SBM at work, starting with a basic science observation (many melanomas harbor BRAF mutations that drive their growth) and using that basic science to develop a therapy, ultimately bringing that therapy to clinic.

So here’s the question. Given the result of this phase I trial, is there truly clinical equipoise regarding PLX4032 in melanoma that has the V600E BRAF mutation? It’s not an easy question, and some physicians come down on either side of the issue, as discussed in the NYT article. First, the side arguing that drugs like PLX4032 are challenging our current cancer clinical trial paradigm:

But critics of the trials argue that the new science behind the drugs has eclipsed the old rules — and ethics — of testing them. They say that in some cases, drugs under development, PLX4032 among them, may be so much more effective than their predecessors that putting half the potential beneficiaries into a control group, and delaying access to the drug to thousands of other patients, causes needless suffering.

“With chemotherapy, you’re subjecting patients to a toxic treatment, and the response rates are much lower, so it’s important to answer ‘Are you really helping the patient?’ ” said Dr. Charles L. Sawyers, chairman of human oncology at Sloan-Kettering. “But with these drugs that have minimal side effects and dramatic response rates, where we understand the biology, I wonder, why do we have to be so rigorous? This could be one of those defining cases that says, ‘Look, our system has to change.’”

But does it? On the other side:

Defenders of controlled trials say they are crucial in determining whether a drug really does extend life more than competing treatments. Without the hard proof the trials can provide, doctors are left to prescribe unsubstantiated hope — and an overstretched health care system is left to pay for it. In melanoma, in particular, no drug that looked promising in early trials had ever turned out to prolong lives.

PLX4032 shrinks tumors in the right patients, for a limited time. But would those who took it live longer? No one knew for sure.

“I think we have to prove it,” said Dr. Paul B. Chapman, a medical oncologist at Memorial Sloan-Kettering Cancer Center who is leading the trial. “I think we have to show that we’re actually helping people in the long run.”

Both are powerful arguments. On the one hand, if drugs like PLX4032 really are far and away more effective than previous generations of experimental drugs in the pipeline to market, then rigidly sticking to the old system has the potential to result in the loss of potentially savable lives and in increased suffering that could potentially have been ameliorated. However, we have been fooled before. Drugs that look highly promising in preliminary studies have ultimately fizzled, and increases in response rates and even increases in PFS have not always translated into increases in OS. Again, remember Avastin. Then, as was suitably mentioned in the NYT article, there is the cautionary example of bone marrow transplantation for advanced breast cancer, which during the 1990s was thought to prolong survival. As a result, both physicians and patient advocacy groups lobbied, using their political muscle to persuade health insurance companies to pay for bone marrow transplants for breast cancer. However, when the careful clinical trials were done, it was found that bone marrow transplantation was no more efficacious than high dose chemotherapy and that it caused death in some cases. The history of cancer research is littered with drugs that appeared efficacious in early clinical trials and then failed when subjected to more rigorous testing. How do we know that PLX4032 isn’t one of those drugs?

We don’t. Clinical trials are how we figure out the answer to that question:

“My goal,” Dr. Chapman shot back, “is to find out as quickly as possible in as few patients as possible whether this works. If we never know, then we’re never going to be able to build on anything.”

One of the melanoma field’s senior clinicians, Dr. Chapman had lived through trial after trial of drugs that failed to live up to early promise. Almost every oncologist knew, too, of a case nearly 20 years earlier when bone marrow transplants appeared so effective that breast cancer patients demanded their immediate approval, only to learn through a controlled trial that the transplants were less effective than chemotherapy and in some cases caused death.

“Making patients’ tumors go away is gratifying,” Dr. Chapman told critics. “But that’s not the business I’m in. I’m in the business of making people live longer. That’s what I want to do.”

Which brings us back to the whole debate on whether PFS in the absence of OS is reason enough to approve a new anticancer drug, the very same question faced for Avastin. Again, we have no idea that PLX4032 even prolongs OS compared to the standard of care, although we do have an indication that it does prolong PFS. On the other hand, PLX4032 has considerably less toxicity than dacarbazine, meaning that the potential to cause harm would seem to be less, at least from what we know now. All of this leads to a critical question: Is a phase I trial with stellar results enough to claim that there is not equipoise between PLX4032 and the standard of care? Add to that information in the NYT article that describes the “Lazarus” effect observed in some patients who were clearly weeks or even days from death could get off of oxygen and out of bed after placed on PLX4032, sometimes even for months. Is this all enough information to destroy clinical equipoise for this drug and make performing a randomized trial against standard of care unethical?

One thing that puzzled me initially is why the design for this trial was chosen. It’s a straightforward open label randomized trial comparing PLX4032 against dacarbazine that does not allow patients in the dacarbazine arm to cross over if they are receiving no benefit. Originally, the principal investigator of the current trial wanted to do a test of PLX4032 versus standard of care in only the sickest patients. If, reasoned Dr. Paul Chapman, the drug did indeed show this “Lazarus effect” in some patients, it would be justification to get it approved as rapidly as possible, even before evidence of improvements in OS were shown. On the other hand, it appears that the drug company (Roche) feared that such a trial would only provide justification for approval for PLX4032 only in that small group of the sickest patients. It wanted approval for the widest indications possible, which requires a large, phase III randomized clinical trial.

In other words, economics appears to have trumped science and ethics. The best design from an ethical standpoint, one that would also be scientifically strong, would have been to do a randomized trial of dacarbazine plus or minus PLX4032. One group would receive dacarbazine plus placebo; the other dacarbazine plus PLX4032. Both groups would be receiving the standard of care, and there would still be genuine uncertainty whether the combination is better than dacarbazine alone. This is how clinical trials testing many new anticancer drugs are performed these days. Because clinical equipoise would tell us that testing a new anticancer drug versus placebo would be unethical in most cases, the two choices left are to test a new drug either against standard of care or added to standard of care. In addition, for trials in which clinical equipoise is not as clear as it should be, in general there is a built-in planned interim analysis of PFS and OS, wherein the trial is stopped if one group is doing significantly more poorly than the other group to the point where the results are so clear-cut that statistically there is no way that the addition of the remaining patients could change the results. In addition, often patients are allowed to cross over to the other group if after a certain period of time they are receiving no benefits. This can go both ways, either control crossing over to experimental drug or those receiving experimental drug crossing over to the control group. Such a design makes the analysis of the data harder to do, but it does mitigate some of the ethical concerns. Unfortunately, in this case, the investigators chose clarity rather than allowing patients to cross over.

Interestingly enough, it is the basic scientists who are most in favor of the contention that this drug should be more widely available:

Some of the strongest criticism came from laboratory researchers who study the biology of the disease and see the drug as fundamentally different from its predecessors. The previous red herrings, they argued, never had such a high response rate. Few other drugs had shrunk tumors in as high a percentage of patients with melanoma or any other solid tumor as PLX4032 had in its first human trial.

“Many of my colleagues who are outstanding clinical investigators have been able to convince themselves that this is a fair thing to do,” Dr. David E. Fisher, a leading melanoma biologist at Massachusetts General, said of the controlled trial. “My personal view is it’s nuts. I don’t know anyone who hasn’t shuddered at the concept that we can’t let patients on the control arm cross over because we need them to die earlier to prove this point.”

Quite frankly, even though I am a staunch advocate of science-based medicine, I, too, shudder at this design. On the other hand, the basic scientists seem rather cavalier to me in their belief that improvements in response and PFS will translate into improvements in OS. After all, even though the toxicities observed in the phase I trial were relatively mild, one of them was squamous cell carcinoma. As promising as PLX4032 is, there is still power to the argument that we can’t know for sure if it is superior unless we actually do the careful clinical trial, keeping the failures of promising treatments of the past in mind.

In oncology clinical trials, as in clinical trials for treatments of any life-threatening disease, there is always a tension between wanting the “cleanest” possible results versus doing the best for each individual patient. It is a balancing act that relies on the ethics of physicians and a combination of hope and altruism in the patients who become subjects in such trials. Both patients and physicians want the drugs being tested to work, but in some cases clinical trials are very much, to invoke my Star Trek geek tendencies, a case where the good of the many is weighed against the good of the few — or the one — with the balancing of these factors done using knowledge with huge gaps in it. How to maximize the good for as many patients as possible is the goal, but, as we have seen, this is a goal that is not so easily accomplished, just as clinical equipoise is a concept that is easily stated but not so easily applied. PLX4032 teaches us that.

Posted in: Cancer, Clinical Trials, Medical Ethics

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34 thoughts on “Clinical equipoise versus scientific rigor in cancer clinical trials

  1. David,

    Thanks for posting this. I read that article as well, and was dying to respond to it here, but in the midst of trying to keep my promise about posting Part 2 of the Gonzo thang before the weekend was over I didn’t have the time. You did it much better than I could have, anyway. It’s an interesting juxtaposition, this melanoma trial and Gonzo: in the former, there ain’t equipoise because the preponderance of experts in the field already believe that the novel treatment is superior to the standard; and yet, because of an almost religious allegiance to EBM, half the subjects are denied the novel treatment (I’ll admit to having overstated that slightly; I personally favor, as do you, a crossover study here). In the latter, there wasn’t equipoise because the preponderance of experts in the field already believed that the novel treatment was worthless or worse; and yet, well, you know the rest.

    With regard to equipoise, the critics of the melanoma trial are wrong to say that “the new science behind the drugs has eclipsed the old rules — and ethics — of testing them.” The old ethical rule of clinical equipoise is precisely the reason for doing what those critics want: to make the new drug available to all in the study ASAP, and to make it available to others ASAP as well. The preponderance of experts in the field may be wrong, of course, which is the argument of those favoring the trial as it currently stands, but that does not change the “old rules and ethics” regarding clinical equipoise. It seems to me that this problem can be ethically solved by a trial that allows for early crossover and that meticulously informs its subjects of the views of the various experts. The opposite, pretty much, of what was done in the Gonzalez trial.

  2. I almost forgot another ironic twist in the juxtaposition of the two trials: in the Gonzo trial, the original plan for an RCT was scrapped in favor of allowing anyone who wanted Gonzo to get him, because there were so few subjects willing to be randomized. Not so in the melanoma trial, which is why the NYT article was written. Yet another double standard involving the fool’s errand that is “CAM” research.

  3. David Gorski says:

    Perhaps you should do a post comparing the two trials in depth. :-)

  4. windriven says:

    Where is the patient’s voice heard in this debate? If someone is dying of a Colt .45 disease like melanoma and is capable of funding his or her own treatment, what is the ethical case for denying that patient PLX4032?

    If a sufficient cohort of patients take the drug, the progress of the disease can be compared (albeit imperfectly) to the historical progress among patients using other therapies. There is something to be learned here, especially if the differential survival rate is large.

  5. qetzal says:

    windriven writes:

    If a sufficient cohort of patients take the drug, the progress of the disease can be compared (albeit imperfectly) to the historical progress among patients using other therapies. There is something to be learned here, especially if the differential survival rate is large.

    True, but only if the differential survival is large. And even then, I can almost guarantee it would take longer to prove that if we relied on uncontrolled studies where wealthy patients pay for their own experimental treatment.

    I won’t claim that this trial design is necessarily the best or most ethical. But it probably is the fastest way to prove a true survival benefit for this drug. Which makes it the fastest way to get this drug on the market so everyone who might benefit will have access to it.

    I think that point is at least worth considering in the overall equation.

  6. windriven says:

    “Which makes it the fastest way to get this drug on the market so everyone who might benefit will have access to it.”

    Conducting an RCT with an informed and consenting population does not preclude others outside the RCT from using the drug without compromising the RCT.

    The ethics here seem maddeningly murky. I think I could mount a decent argument either way.

  7. David Gorski says:

    That is rather the point of my post, namely that the ethics of cancer clinical trials are anything but straightforward. I thought it particularly appropriate after Kimball’s additional discussion of the Gonzalez trial.

  8. daedalus2u says:

    Windriven, the barriers to “everyone” getting the drug are not monetary, they are regulatory. If a drug is not FDA approved for an indication, what basis is there for an MD to prescribe it, even to wealthy people who want it and can pay through the nose for it? Who protects the wealthy from being exploited?

    I could imagine an unscrupulous pharma company (or scam artist) generating a lot of hype about a “new” treatment and then dragging their heels about FDA approval while they make lots of money off of rich clients. That is exactly what all of these stem cell clinics are doing. That is exactly what Gonzalez was doing. That is exactly what the chelation scam artists were doing until the FDA stopped them.

    It is unfortunate that many of the decisions about FDA approval are based on business prospects and how much money can be made by going this route or that, and not on how to maximize benefit to patients. Unfortunately that is what happens when you rely on a for-profit pharmaceutical industry and gigantically high barriers to entry. It doesn’t select for the best drugs, it selects for the drugs that can make the pharmaceutical industry the most money.

  9. qetzal says:

    I agree you could potentially run an RCT and still allow access outside the trial. But I’ve seen that discussed before and it can create it’s own problems. For example, if the drug is easily available outside the RCT, and if the popular belief is that it works, it may be very hard to recruit anyone into a trial where there’s a chance they’ll be in the control group.

    Definitely not clear-cut, IMO.

  10. windriven says:

    daedalus2u wrote: “the barriers to “everyone” getting the drug are not monetary”

    I used the case of people purchasing their own drugs to avoid the issue of tax dollars paying for unproven treatments. In my example the risks, financial and medical, are borne by the patient.

    “Who protects the wealthy from being exploited? ”
    One man’s ‘protection’ is another man’s ‘blocking access to a potentially life-saving therapy.’ Not everyone wants to be protected and even those who do may not agree on the authority competent to do the protecting.

    One of the many interesting ethical and philosophical issues raised by Dr. Gorski’s post is the issue of what a mentally competent adult can be prohibited from ingesting and under what authority. It is one thing for an authority to say that the evidence is that reiki is nonsense or that PLX4032 is an unproven therapeutic agent with potentially serious side effects, quite another to say: thou shall not…

  11. pmoran says:

    Would there not normally be a (Phase ll or lll) case series, employing the optimum dosage found in the Phase l study, before considering the RCT that is in dispute?

    You would then have more information, such as whether the drug can produce reasonably stable complete remissions in some.

    The RCT is only clearly necessary if the expected benefit is a modest prolongation of survival in a trade-off with possible adverse effects.

  12. nybgrus says:

    windriven: I have to say that daedalus2u is right on this one – it doesn’t matter where the money comes from, there simply is no way to purchase the drug legally since it is not yet FDA approved and on the market. The answer to that would be to put a stipulation stating that in cases like these, the drug could be available for private purchase. However, that would ultimately select for a very small subset of the population – namely those that have the disease in question AND enough money to actually afford it. These would (in most cases) be such small numbers that it would do little if anything to strengthen the evidence for or against the drug (nevermind the fact that the drug company would then have to figure out what to charge for the drug, which brings me to the next step…). So then, the drug company would have incentive to make the entry cost for private purchase low enough to capture a large enough audience (and keep in mind, drugs typically cost in the hundreds of millions of $$$ to get from R&D to phase III). So now we have in place exactly what qetzal refers to – a situation where people would have the resources to knowingly refuse a treatment everyone is telling them could likely be life saving/prolonging and CHOOSE to settle for the control arm for scientific integrity. And now, we have just circumvented the entire point and may as well have just skipped ahead and approved it on the Phase I or II trials for limited use since our best data would come from a case-control study which would take years to hash out and actually determine efficacy and outcomes.

    Of course, as Dr. Gorski aptly said, this is why it is a muddled topic – it is simply not clear cut either way. I personally feel that the idea of a cross-over study that is funded sufficiently to enroll and treat as huge a number of candidates as possible all at once would be the best design. Thus the ethical issue of equipoise is mitigated and the numbers are big enough right out the gate to (hopefully) be able to grab some good data in as short a time as possible.

    Sometimes in medicine you don’t get the choice between good and bad, or even the the best of two evils. Sometimes, all you get is bad, shit, and I don’t know. IMHO, of course.

  13. nybgrus says:

    Oops! I totally skipped on the bad word filter! I apologize…. please just delete my comment, and post the re-written one below:

    windriven: I have to say that daedalus2u is right on this one – it doesn’t matter where the money comes from, there simply is no way to purchase the drug legally since it is not yet FDA approved and on the market. The answer to that would be to put a stipulation stating that in cases like these, the drug could be available for private purchase. However, that would ultimately select for a very small subset of the population – namely those that have the disease in question AND enough money to actually afford it. These would (in most cases) be such small numbers that it would do little if anything to strengthen the evidence for or against the drug (nevermind the fact that the drug company would then have to figure out what to charge for the drug, which brings me to the next step…). So then, the drug company would have incentive to make the entry cost for private purchase low enough to capture a large enough audience (and keep in mind, drugs typically cost in the hundreds of millions of $$$ to get from R&D to phase III). So now we have in place exactly what qetzal refers to – a situation where people would have the resources to knowingly refuse a treatment everyone is telling them could likely be life saving/prolonging and CHOOSE to settle for the control arm for scientific integrity. And now, we have just circumvented the entire point and may as well have just skipped ahead and approved it on the Phase I or II trials for limited use since our best data would come from a case-control study which would take years to hash out and actually determine efficacy and outcomes.
    Of course, as Dr. Gorski aptly said, this is why it is a muddled topic – it is simply not clear cut either way. I personally feel that the idea of a cross-over study that is funded sufficiently to enroll and treat as huge a number of candidates as possible all at once would be the best design. Thus the ethical issue of equipoise is mitigated and the numbers are big enough right out the gate to (hopefully) be able to grab some good data in as short a time as possible.
    Sometimes in medicine you don’t get the choice between good and bad, or even the the best of two evils. Sometimes, all you get is bad, manure-type-stuff, and I don’t know. IMHO, of course.

  14. daedalus2u says:

    Shouldn’t questions of clinical equipoise be determined by the IRB? I am worried that a pharmaceutical company could shop a clinical trial around until they found a group that would consider two treatments equivalent wink wink? Isn’t that what happened with the Gonzalez trial?

    In the melanoma example, how could a new treatment be considered “equivalent” to the current standard of care? I understand the desire to get clean data and giving both isn’t going to give clean data, but that should be secondary to the ethics of the trial.

    If you analyze it by EBM, then you can’t give just the new drug because there is no clinical trial data that says it works. If you analyze it by SBM, then the non-clinical data says it is so good you can’t give just the old drug.

    What is ethical should not be determined by who does the ethics analysis.

    It also can’t be left up to the non-medically trained subjects to balance the conflicting views of the medical experts.

  15. windriven says:

    daedalus2u wrote:

    “It also can’t be left up to the non-medically trained subjects to balance the conflicting views of the medical experts.”

    Yes, let’s go back to the good old days when some physicians didn’t feel it necessary to inform their patients of certain diagnoses. Just do what I say and if you get better, well its all good. And if you don’t, well it’s really a shame, isn’t it?

    As well-trained, deeply caring, highly motivated as most physicians are, do not lose sight of the fact that they are service providers like attorneys and CPAs. The wise client generally follows the advice s/he pays good money for. But the client, the patient, has the ultimate responsibility for his or her life.

  16. daedalus2u says:

    windriven, I was specifically talking about clinical trials where (as in the Gonzales trial) clinicians did (effectively) lie about the the relative effectiveness of the two treatment legs.

    I am not talking about avoiding informed consent, I am talking about the physician not exploiting the ignorance of the experimental subject.

    In the Declaration of Helsinki, it is not left up to the subjects to balance the conflicting views of medical experts. The medical experts need to come to a consensus on what it takes to make the two legs of the trials equivalent and then implement that in the clinical trial and not rely on the ignorance of the subjects.

    The two legs have to be equivalent. The two legs are not made equivalent just by using a random number generator to determine who gets which leg.

  17. windriven says:

    @nybgrus

    “These would (in most cases) be such small numbers that it would do little if anything to strengthen the evidence for or against the drug ”

    I’m not so much concerned about the impact on the trial as I am the rights of the patient to direct his or her own care. The scientific effort to determine the safety and efficacy of a given therapeutic agent is vital beyond question. But to a terminal patient these questions may also be moot.

  18. windriven says:

    @daedalus

    I was following the thread of your earlier comment and did not realize that you had shifted emphasis.

  19. Anecdote: I know someone who was recently diagnosed with cancer in his lungs, spine, and liver. He may qualify for a clinical trial of a promising new type of chemotherapy. (I don’t know him well, therefore don’t know the details…)

    His loved ones are very frustrated by the reality that if he is accepted into the trial, he doesn’t get to choose the new drug over the conventional therapy. They find it appallingly unfair, and I can understand their perspective.

    These conflicting protocol considerations do get muddled here on the ground with real people’s lives potentially on the line.

  20. qetzal says:

    deadalus2u wrote:

    If you analyze it by SBM, then the non-clinical data says it is so good you can’t give just the old drug.

    I don’t think you could say that based only on non-clinical data, no matter how good it was. We just don’t know enough to extrapolate from non-clinical data to actual performance in humans.

  21. stewiegriffin81 says:

    Hi Dr. Gorski,

    I agree with you completely regarding the strange reasoning to make the proposed phase III trial of PLX4032 an open label trial. However, I’m not sure I fully agree with your proposed alternative trial (dacarbazine +/- PLX4032). Although this will tell us whether or not the combination is superior, it won’t answer the question of whether or not PLX4032 alone is superior to dacarbazine.

    I was thinking that the best option would be to have a dacarbazine versus PLX4032 RCT, but to keep it double blinded by having one arm of the trial with IV dacarbazine + placebo tablet, versus the other arm of the trial with IV placebo (or fake IV) + PLX4032. This would keep it sufficiently methodological rigorous, while also answering the question of whether PLX4032 is superior to dacarbazine.

    What do you think? Is this a good option, or have I missed something?

    Cheers

  22. rork says:

    stewiegriffin81: Patients and doctor may both be able to tell who got the chemo.

    General note: You can have situations where the plots of % survival vs. time for two therapies actually cross, perhaps with the new therapy having less death early, but killing folks a bit later with more certainty (from second cancers for example). It’s an example of tough choices even if you have “perfect” knowledge.

  23. stewiegriffin81 says:

    @Rork

    You didn’t properly answer my question. My version of the RCT theoretically allows for double blinding since both arms of the trial will get both an IV infusion and a tablet.

    To an extent some of the patients and doctors will have some suspicion as to who got the dacarbazine, as the dacarbazine arm will most likely have more side effects. However, this is not guaranteed to happen (as far as I know).

    Additionally, my version will answer the question of whether or not PLX4032 is superior to dacarbazine.

    So again, is there a good reason why this version is not a good idea? (perhaps dacarbazine is so bad that all in the dacarbazine arm will have side effects to the extent that it becomes unblinded?)

  24. stewiegriffin81 says:

    Looking at the side effects, it seems that nausea and vomiting is very common, perhaps common enough to unblind such my version of the trial.

    Anyone with knowledge on the doses of dacarbazine used in melanoma care to comment?

  25. Wolfy says:

    stewiegriffin81:

    as a single agent for metastatic melanoma: dacarbazine 250 mg/m2 daily for 5 days.

    per the NCCN guidelines, dacarbazine has a high emetic risk: > 90% of patients treated with this drug (in the absence of a prophylactic anti-emetic regimen) will experience nausea.

    as you suggest, it would be a little difficult to double blind your version of the study since additional antiemetics are given with dacarbazine and probably not with PLX4032. i suppose one could double blind the antiemetics to solve this problem.

  26. stewiegriffin81 says:

    Yes, such a high proportion of nausea side effects would indeed unblind my version. I think your suggestion of given blinded prophylactic antiemetics sounds good, although it would only work if the nausea rates are substantially reduced (which I would hope they are!)

    Cheers

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