Are Trials Necessary?

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Today’s New York Times ran a heartbreaking story by Amy Harmon about two cousins who developed melanoma. One was entered into a cancer clinical trial and received the investigational drug PLX4032. The other was ineligible for the trial, and therefore unable to access the experimental drug. Guess which cousin died?


The article is one in a series of Harmon articles that seems to raise questions about whether rules governing drug testing and research are depriving desperately ill patients timely access to curative therapy. In this article, the narrative takes aim at two practices: 1- the practice of including control groups within trials, and randomly determining that some patients will receive standard care that is widely regarded as inadequate; 2- excluding patient access to drugs that have not yet demonstrated unequivocal therapeutic advantage.

As with many of my blog entries, I preface this one by saying that I am not a cancer doc, and therefore not in a position to evaluate whether PLX4032 is the wonder drug this story makes it out to be. I also preface my comment on this article by acknowledging the incredible pain and anxiety that patients suffer when denied access to a trial, or when denied access to a preferred drug within a trial. These disclaimers aside, I found the tenor of this article very problematic.

First, the reason investigators randomly determine treatment choice in trials is because, at the outside of a well designed trial, there is genuine uncertainty about whether the new drug is better, the same, or worse than the (inadequate) standard treatment. Many doctors participate in trials because they fervently believe the new regimen is better than the standard one. But the evidence shows, again and again, that on average, new drugs outperform old ones in a small portion of instances (maybe around 15-20%). It is just as likely that new drugs will underperform standard treatments- making patients sicker perhaps, or failing to deliver as much punch. So one concern about the article is the premise that doctor’s personal beliefs about which cancer drug will perform better in a randomized controlled trial carries some moral weight. The evidence shows doctors in the aggregate haven’t a clue- which is why functional healthcare systems run trials.

A second troubling premise here is that there is no harm to allowing public consumption of drugs that are not yet validated in rigorous clinical trials. CEOs of many pharmaceutical companies perhaps may share this view. But the historical record shows otherwise: in fact, many patients are severely harmed when drugs are introduced into clinical use before they have been established as safe and effective. Perhaps a few readers out there may be familiar with thalidomide? Or autologous bone marrow transplantation for breast cancer? Ever considered the price tag on these new cancer drugs, and do you want your government or insurance company purchasing a potentially useless drug?

Still, article zeros in on an ethical tension that is very difficult to eradicate from clinical research. Patients want- and are entitled- to be treated as individuals. Physicians also prefer to treat patients as individuals. Clinical trials, however require that patients be treated as tokens of larger populations- that they be treated, in a sense, as “stand ins” for future patients. Randomization has not been shown to deprive patients of access to life preserving drugs. However, it does rob patients of fulfilling their desire to be treated as individuals and to exercise personal choice. And this is one of the reasons why the field of research ethics is endlessly fascinating, important, and nettlesome. (photo credit: travelingMango 2008).

BibTeX

@Manual{stream2010-59,
    title = {Are Trials Necessary?},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = sep,
    day = 20,
    url = {http://www.translationalethics.com/2010/09/20/are-trials-necessary/}
}

MLA

Jonathan Kimmelman. "Are Trials Necessary?" Web blog post. STREAM research. 20 Sep 2010. Web. 21 Jul 2017. <http://www.translationalethics.com/2010/09/20/are-trials-necessary/>

APA

Jonathan Kimmelman. (2010, Sep 20). Are Trials Necessary? [Web log post]. Retrieved from http://www.translationalethics.com/2010/09/20/are-trials-necessary/


Testing Testing…: Personal Medicine, Breast Cancer, and Policy

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Personalized medicine is supposed to usher an era in which treatments are tailored to individuals. And HER2 testing has long been seen as heralding the promise of personalized medicine: tumors that test positive for an amplified HER2 gene are more likely to be responsive to drugs, like trastuzumab, that block the HER2 receptor.


Some may see HER2 testing as foreshadowing a perfect future in which treatment decisions are coupled to molecular diagnostics. But Gina Kolata in the New York Times instead tells a story of shadows. Like all medical tests, HER2 testing is error prone: some tumors test positive when they are in fact negative, and others test negative when they are in fact positive. And some results are just plain ambiguous, with parts of the tumor being positive and other parts being negative. Kolata describes the challenges that women and their physicians confront when interpreting test results.

Most troubling in this story is the role, or lack thereof, played by regulatory agencies like the FDA. Quoting Kolata: “there is a proliferation of laboratories offering tests without F.D.A. oversight. But, for now, the agency has no specific plan to regulate the tests, in part because of lack of money.” If FDA is not prepared to regulate tests because of resource constraints, and prescription decisions are likely to be increasingly coupled to diagnostic tests, it logically follows that FDA is not prepared to regulate the approval and use of newer generation, test-based drugs. In other words, FDA seems unable to establish the validity of labeling indications for drugs that rely on diagnostic tests. This can’t be a good thing for patients, physicians, or third party payers (but is great for the makers of drugs and diagnostics, who thrive in this kind of clinical and regulatory uncertainty!) (photo credit: crafty dame, breast cancer cells, 2009)

BibTeX

@Manual{stream2010-68,
    title = {Testing Testing…: Personal Medicine, Breast Cancer, and Policy},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = apr,
    day = 20,
    url = {http://www.translationalethics.com/2010/04/20/testing-testing-personal-medicine-breast-cancer-and-policy/}
}

MLA

Jonathan Kimmelman. "Testing Testing…: Personal Medicine, Breast Cancer, and Policy" Web blog post. STREAM research. 20 Apr 2010. Web. 21 Jul 2017. <http://www.translationalethics.com/2010/04/20/testing-testing-personal-medicine-breast-cancer-and-policy/>

APA

Jonathan Kimmelman. (2010, Apr 20). Testing Testing…: Personal Medicine, Breast Cancer, and Policy [Web log post]. Retrieved from http://www.translationalethics.com/2010/04/20/testing-testing-personal-medicine-breast-cancer-and-policy/


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