1. DiGiulio, Sarah

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Phase I clinical trials are an important step in the development of new anticancer therapies, Jonathan Kimmelman, PhD, Associate Professor in the Biomedical Ethics Unit/Social Studies of Medicine at McGill University, explains in a recent article in the Journal of Clinical Oncology (2017;35:135-138).

Jonathan Kimelman, P... - Click to enlarge in new windowJonathan Kimelman, PhD. Jonathan Kimelman, PhD

But, he adds: "The assertion that phase I trials offer a vehicle for pursuing cancer treatment (the 'therapeutic position') rests on weak evidence and has counterproductive implications for human protection. It also erodes the ability of oncologists to rigorously evaluate new treatments and support evidence-based practice."


His view: Phase I trials are primarily investigational.


The JCO article lays out the evidence where the 2015 policy statement from ASCO on the role of phase I clinical trials in cancer fall short (JCO 2015;33:278-284). And Kimmelman also makes a series of recommendations he says ASCO should use in their policy statement on the design and enrollment of phase I trials.


In an interview with Oncology Times, Kimmelman summed up the key points from his argument-and why defining and following the appropriate role for phase I clinical trials is so important.


1 What prompted you to write this article on phase I clinical trials now-and what are your topline reasons for disagreeing with ASCO's current policy statement?

"In 1997, ASCO issued a statement on the ethics and policy around phase I studies (JCO 1997;15:853-859). A lot of time passed before they updated that statement. And a lot has happened from 1997 to 2015-both in terms of the way phase I studies are done, which prompted the updating, but also in terms of the way people think about the ethics of phase I studies. And I was surprised at how little the updated version had kept apace with the thinking around the ethics of phase I cancer studies.


"The ASCO policy [holds the position that] phase I studies ought to be viewed as therapeutic endeavors for patients who enroll in them. And in a nutshell my response to that was-well-not exactly.


"A professional society like ASCO should state more clearly that these are primarily research endeavors, not therapeutic endeavors, and they ought to be out in front of the various ways that the implementation of phase I cancer studies could be improved.


"Some of the issues of implementation that I identify include a more proper and rigorous review of the preclinical evidence to support phase I studies. There has been a lot that's emerged in the last 10 years about the problems with the way people conduct and report preclinical studies that support phase I trials. We [could] do a lot with phase I studies by improving the way we do the preclinical studies to support them. And we could be improving the way we do consent in phase I studies, including explaining to patients that the prospect of major therapeutic benefit is highly improbable.


"To my knowledge, no one had done any kind of systematic review or meta-analysis of current phase I studies (in the past 5 years or so) to test the hypothesis that the risk-benefit analysis has actually shifted in a dramatic way. If it has shifted in a dramatic way, that's interesting-and could alter my analysis."


2 So what would you say is the role of phase I clinical cancer trials?

"The primary role of phase I to determine some basic safety features as well as dosing, and perhaps to identify promising indications or malignancies in which to advance a drug into efficacy testing.


"Here's the way an ethicist thinks about research and phase I studies: Every time you expose a patient to risk in the context of research, you want to make sure that risk is counterbalanced by some kind of benefit. And there's two different ways you can counterbalance that benefit. One is direct benefit: if the patient responds medically to an intervention that can purchase you some risk in a clinical trial. The other way is by appealing to the prospect of advancing medical science by producing information about whether a drug is promising and whether a drug ought to be developed. One benefits the patient directly; the other benefits society.


"What I have essentially argued is that when we think about risk in phase I cancer studies, we ought to be thinking about purchasing that risk with benefit to society (by learning something about the drug) as opposed to benefit to the subjects. We ought not to use the prospect of a patient benefitting as a way of justifying exposing them to the risk [of the trial].


"There can be exceptions, but we should not be presenting these [trials] to patients as therapeutic opportunities.


"There may very well be exceptional cases where phase I studies can and should be used as therapeutic endeavors-and it may very well be legitimate for some patients if they have been given proper information to regard their participation as a therapeutic opportunity for them."


3 What would you say is the bottom line that practicing oncologists and cancer care providers should know about this debate?

"The take-home message is that if you're an oncologist and if you want to refer a patient to a phase I cancer study or enroll them, you ought to present this to them as an opportunity to advance medical science-not as an opportunity to access cutting-edge therapies.


"And there is a lot we can be doing to improve the consent, design, and justification for phase I oncology studies."