Balancing scientific rigor versus patient good in 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 (me too), 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 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 a prospective randomized, placebo-controlled clinical trial testing an unvaccinated group versus a vaccinated control group to determine whether vaccines cause autism would be completely unethical is that it egregiously violates the principle of clinical equipoise. 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 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. The drug targets a specific (but common) mutation in melanoma in an oncogene (BRAF–pronounced “b-raf,” not “braf”). Interestingly enough, I’ve actually participated in research with a collaborator who is a melanoma surgeon to detect this very mutation (which was at the time erroneously referred to as the V599E mutation) that results in activation of the BRAF oncogene using PCR-based methods, 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 testing of the regional lymph node basins is highly effective. It can even occasionally be controlled, resulting in long term survival, in the metastatic setting if the metastasis can be completely excised surgicall. However, once it’s stage IV and metastatic to multiple sites or sites from which the tumors cannot be surgically resected, melanoma is incurable. Worse, it’s notoriously resistant to chemotherapy. The very best, standard of care chemotherapy regimens including 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 verus 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 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 a case of, 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 easy stated but not so easily applied. PLX4032 teaches us that.