Research Ethics Blog

Recently the New York Times published a story about two cousins in the US, both with a lethal form of melanoma, who were also both enrolled into a Phase III Clinical Trial to test a new, breakthrough cancer drug. The drug, PLX4032, has been shown to radically reduce the size of solid tumours in specific kinds of cancers, including intractable melanoma, in recent previous trials. Compared to the current standard drug for use in cancers like this, PLX4032 shrinks more tumours and does it much faster and more effectively than any other drug previously tested. But the drug, like many new breakthrough cancer drugs, is not yet available on the market until full clinical testing is complete. Until now, the drug used for what we refer to as the “standard of care” to treat these patients is dacarbazine, a drug that one oncologist in Massachusetts was quoted in the story as saying is “a drug we all hate and would rather never give a dose of again in our lives.”

An important point — while PLX4032 has been shown to drastically reduce the size of tumours for a limited time (compared to current drugs on the market), it is not known whether or not the drug can actually extend life, in comparison to treatments already used. The current Phase III clinical trial is being conducted to figure this out, and as the lead investigator for the trial, Dr. Paul Chapman (an oncologist at Memorial Sloan-Kettering) states, “I think we have to prove it. I think we have to show that we’re actually helping people in the long run.”

Both cousins had aggressive melanoma and both were enrolled into the Phase III clinical trial. While one cousin, Thomas, ended up randomized to the treatment arm of the trial and received the “wonder drug” PLX4032, his cousin Brandon was instead randomized to the control arm. Instead of getting the new medication (in the form of pills) Brandon received the “standard of care”, i.e. the traditional IV infusion of dacarbazine, shown to be, as the article states, “notoriously ineffective” in the treatment of melanoma. His oncologist informed Brandon and his mother that he was enrolled in the control arm with a heartfelt apology. Because each drug in this trial is delivered in a different way (one by mouth and one by IV infusions), both treating doctors and patients/participants would obviously know which arm they were enrolled in from the outset of the trial. This differs from most traditional randomized controlled trials which are “double-blinded” meaning that neither participants nor their doctors know which treatment they are receiving. Practically, that was impossible in this case so the cousins, their families and their doctors, all knew that Thomas was getting the newer, more promising drug while Brandon was getting the drug that, it seems, no one wanted.

Tragically, Brandon has since died from the cancer and Thomas is still on PLX4032. This compelling case has raised many questions and concerns from both the clinical and the research ethics communities about the rigidity of controlled trials for testing drugs for clinical use and whether or not we need to carefully examine or be more flexible with the standards in cases like this one. With the rapid development of new potentially breakthrough drugs and the proliferation of genetically-targeted cancer drugs, are controlled trials always the right way to go about getting these drugs to market safely and effectively?

Here’s a link to the article from the New York Times: New Drugs Stir Debate on Rules of Clinical Trials

…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.’ ”

Dr. Richard Pazdur, director of the cancer drug office at the Food and Drug Administration, said in a recent interview that the new wave of drugs in development — especially for intractable cancers like melanoma — might require individual evaluation. “This is an unprecedented situation that will, hopefully, be increasingly common, and it may require a regulatory flexibility and an open public discussion,” he said…

This lengthy (but well worth reading) article raises a number of serious issues and questions related to the kinds of ethical standards and regulatory practices that are in place surrounding clinical trials. I’m going to try to take apart some of these issues, one by one, in subsequent blog entries over the next week or so. But let me state them here first:

1. At this point, it’s clear that clinical equipoise, in this case, no longer exists, if it ever did. The standard of care is a drug no oncologist wants to give. It’s ineffective at both shrinking tumours in a significant way and prolonging life. So to compare (by experimental use in seriously ill patients) a clearly inferior agent to what has been proven to be a markedly better drug seems, at first glance, unethical.

2. The way that clinical trials are structured and regulated is something that is important, for many reasons. Putting new drugs on the market is not a process in which we necessarily want lots of possible shortcuts. Yet, in some cases, when a particular drug might be shown to be clearly superior in particular cases, should we be looking at different structures to support getting such a drug to market faster and being, perhaps, more flexible on a case-by-case basis?

3. This article demonstrates that the goals of care and the notion of what we might, for example, want cancer drugs to do may well differ from person to person. While some oncologists clearly support PLX4032 for use as an agent to shrink tumours, the fact that it is still unknown how much (if at all) the drug can prolong life is something others feel is just as, or even more important to demonstrate. If a drug allows a critically ill person to have significant (but perhaps temporary) relief through shrinking of their solid tumours without an additional guarantee of the prolongation of life, is that enough? Should that be a sufficient reason to push the drug to market faster?

4. Finally, the fact that this trial was never double blinded, as the article notes, “intensifies” certain tensions, specifically the tension experienced by physicians who are, at once, clinicians and researchers. Knowing your patient has been enrolled into a control arm with an inferior treatment means, to some, knowing that the patient is being provided with substandard care. While the control arm may well be the current “standard of care”, if that “standard of care” is an agent that many in the medical community agree is not beneficial relative to the newer drug, it may well feel like your patient is at risk of harm by receiving it and by not receiving the superior drug.

Each of these issues raises important questions that aren’t going to go away as newer, better drugs are developed faster. With a growing “consumerist” movement and limited access to expensive “wonder drugs”, the pressure on physicians, pharmaceutical companies and the medical and research communities to get these drugs on the market is only going to increase.

~ by Nancy Walton on October 1, 2010.

Posted in by Nancy Walton, clinical trials, ethics committees, pharmaceuticals, regulations, scientists, Uncategorized