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).
Jonathan Kimmelman. "Are Trials Necessary?" Web blog post. STREAM research. 20 Sep 2010. Web. 09 Jan 2025. <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/
Are government bureaucrats keeping dying patients from getting access to possibly life saving drugs? That’s one way to read Margaret Talbot’s story in the Sunday New York Times (“Fighting for a Last Chance at Life.” May 17, 2009). Talbot describes how mother Kathy Thompson sought access to an unlicensed therapy Iplex for her Amyotrophic Lateral Sclerosis (ALS)- afflicted son, Joshua. The drug, Iplex, was not licensed by FDA for use against ALS, and an almost identical drug had failed two randomized controlled trials in patients with ALS.
Buoyed by anecdotal patient reports on web forums, Thompson sought compassionate use access from the FDA and was rebuffed. She ultimately engaged the Washington Legal Foundation to appeal FDA’s rejection of Thompson’s request for the drug. FDA relented, allowing the drug maker to run a trial of Iplex– recouping all costs from enrolled patients (about $100k/year).
There are a number of troubling features in this story. First, the article (or, at least Thomspson) makes FDA out to be a bunch of heartless bastards. Some, like the Washington Legal Foundation, view FDA’s stringency as an affront to the “civil liberties of American Business” (to paraphrase Haley Barbour). But let’s remember that, for over a half a century, FDA has played a critical role in public health by keeping unproven drugs out of the pharmacy. Grants of compassionate use seriously weaken the ability of the state to collect evidence of a drug’s safety and efficacy, because they make enrollment in clinical trials much more difficult. So there need to be some pretty compelling policy reasons- backed by persuasive evidence- to grant exemptions.
Second, the article states “Many are Campaigning for the chance to be treated with drugs whose safety and effectiveness is not yet known.” While Iplex itself hasn’t been tested against ALS, its active ingredient has been tested in two large randomized controlled trials. Both failed to show any advantage over placebo.
Third, there’s the business of allowing desperate patients to “buy” their slots in the trial approved by FDA. For starters, it’s hard to imagine that a trial that included only “several dozen patients” is going to be of any use in measuring safety or efficacy (the two failed studies involved about 180 and 300 patients). As well, there is something unseemly about a “compassionate use” exemption that is priced at $100K.
ALS is an awful disease, and I feel for people like Thompson and her son. Surely, more and better care and research are needed for ALS sufferers. But where’s the compassion in a program that ministers only all to the most wealthy and politically connected? More importantly, where’s the compassion in undermining a system that ultimately protects us all from clinics that prey on the desperation of patients, and companies that sell unsafe, ineffective, and extremely expensive drugs? (photo credit: Monster 2007)
@Manual{stream2009-100,
title = {A Cure? "Compassionate Use" and Drug Regulation},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2009,
month = may,
day = 17,
url = {http://www.translationalethics.com/2009/05/17/a-cure-compassionate-use-and-drug-regulation/}
}
MLA
Jonathan Kimmelman. "A Cure? "Compassionate Use" and Drug Regulation" Web blog post. STREAM research. 17 May 2009. Web. 09 Jan 2025. <http://www.translationalethics.com/2009/05/17/a-cure-compassionate-use-and-drug-regulation/>
APA
Jonathan Kimmelman. (2009, May 17). A Cure? "Compassionate Use" and Drug Regulation [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/17/a-cure-compassionate-use-and-drug-regulation/
Further to the therapeutic outlook on first-in-human studies at the Brugge meeting was Adrian Thrasher’s thoughtful presentation on his own X-SCID study at Great Ormand Street Hospital. Thrasher’s study was able to restore immune function in nearly all volunteers. Recently, however, his team reported a lymphoproliferative disorder like those seen in a very similar Paris study.
Thrasher stated clearly “The purpose [of X-SCID protocol] is therapeutic effect; it is not a safety study.” Fair enough: the study was in a pediatric population (standard research ethics requires clear therapeutic warrant for such risky studies), and Thrasher’s protocol did not range doses the way typical first-in-human studies do. And I should add, there is some grounds for thinking of the study as having therapeutic warrant, not the least because it was supported several unsuccessful X-SCID human studies and a successful one in Paris). Still, putting the therapy before the learning- this made me somewhat uncomfortable. Therapy might have been his (and his hospital’s) intent, but to describe the study as ontologically “therapeutic” and not “research”? Intent only gets us so far…
Thrasher revealed some unusual properties about the molecular events leading to this leukemia (see? told you it could be construed as a safety study). And now, here’s the compassion part. Thrasher was circumspect about this particular leukemia, because the patient who developed the leukemia had originally been ineligible for the protocol because he had a matched unrelated bone marrow donor. The regulatory agency made a “one-time” exception to waive the normal risk-benefit balance.
Of course, one should be very careful generalizing from this one case where “compassion” seems to have led authorities astray. And presumably, the boy’s parents were thoroughly informed about the risks going in to the protocol. Still, the example is somehow instructive. (photo credit: missinguigga 2008).
@Manual{stream2008-120,
title = {In Brugge / No Compassion (Part II)},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = nov,
day = 29,
url = {http://www.translationalethics.com/2008/11/29/in-brugge-no-compassion-part-ii/}
}
MLA
Jonathan Kimmelman. "In Brugge / No Compassion (Part II)" Web blog post. STREAM research. 29 Nov 2008. Web. 09 Jan 2025. <http://www.translationalethics.com/2008/11/29/in-brugge-no-compassion-part-ii/>
APA
Jonathan Kimmelman. (2008, Nov 29). In Brugge / No Compassion (Part II) [Web log post]. Retrieved from http://www.translationalethics.com/2008/11/29/in-brugge-no-compassion-part-ii/
“They say compassion is a virtue….” so sang David Byrne of the Talking Heads. But what about “Compassionate Use?”
This refers to the practice of giving terminally ill patients who are otherwise ineligible for early phase clinical trials access to investigational agents. At the Brugge ESGCT meeting, Finnish researcher Akseli Hemminki described providing 125 patients compassionate use access to a novel oncolytic gene transfer vector– Ad5/3-Cox2L-D24. Hemminki was not reassuring when asked by an audience member whether a concurrent clinical trial was actually testing the approach, and rumors swirled that he had charged patients for the agent.
Compassionate Use is highly controversial. Patient advocates view it as a lifeline, and over the years, drug regulators like FDA and EMEA have eased restrictions on patient access to untested agents. In late 2006, for example, the FDA proposed new rules that would make it easier to provide untested agents to groups of patients (rather than individuals); the rules would allow companies to recover manufacturing costs from patients seeking access. A related set of proposed new rules would allow companies to charge patients for entering early phase clinical trials.
Compassionate Use raises troubling questions for ethics and policy. With respect to the former, is it really an act of compassion to offer terminal patients a completely untested composition of matter? If the answer is “yes,” well, that makes any future clinical trial that will randomize some patients to standard of care (which, for terminal patients, is nothing) diabolical. That leads me to the policy concerns: if you can get access to a drug outside a study, why enter the trial at all? Compassionate use potentially complicates the collection of rigorous data about the safety and efficacy of new interventions, and thus has public health implications. As for the idea of actually charging patients for access– whether on or off a trial: that’s plain wrong.
According to the American Cancer Society, no records are available on the number of agents provided through compassionate use, the volume of patients who receive drugs through compassionate use, or their outcomes. Regardless of where one stands, the practice would seem a policy black box. (photo credit: fgm878, 2007).
@Manual{stream2008-121,
title = {No Compassion},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = nov,
day = 27,
url = {http://www.translationalethics.com/2008/11/27/no-compassion/}
}
MLA
Jonathan Kimmelman. "No Compassion" Web blog post. STREAM research. 27 Nov 2008. Web. 09 Jan 2025. <http://www.translationalethics.com/2008/11/27/no-compassion/>
APA
Jonathan Kimmelman. (2008, Nov 27). No Compassion [Web log post]. Retrieved from http://www.translationalethics.com/2008/11/27/no-compassion/
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?
