In early February, an article appeared in the Toronto Star that described the plight of a woman named Adrienne Lotton, who is dealing with Stage IV melanoma. After relapsing on various treatments, Lotton was entered into a Phase 3 trial of nivolumab, a monoclonal antibody candidate from BMS.
Unfortunately for Lotton, she was randomized to the placebo arm of the study. “She pulled the short straw,” said her mother Marilyn.
Lotton withdrew from the trial and petitioned the company to provide her the drug on compassionate grounds. BMS denied her request, citing insufficient information on its therapeutic use in clinical practice.
Aside from the human tragedy of Lotton’s experience, the story highlights what is likely to be a growing problem for the pharmaceutical industry as companies search for and study compounds for later-stage diseases, particularly in the realm of cancer. The story, and others like it, becomes a public crucible into which we throw questions about the moral and ethical challenges to the clinical trials process.
I will write more about this process in the June 2014 special feature that focuses on cancer, but the question stands: what is the purpose of a clinical trial?
From the scientific perspective, these studies are designed to establish benchmarks for a compound’s performance and safety versus a placebo or standard of care. It is the dispassionate division of patients into one of two (or more) groups, only one of which will receive the study drug. An effort to determine, with as much scientific rigor as possible, whether patients in group A or group B do better. It is statistics.
From the individual patient’s perspective, however, that is not the way it is being sold.
If you look at the clinical practice guidelines of a variety of diseases, and again particularly in oncology, you will see a specific guidance crop up time and again, often at the dead end of a branch of an if/then algorithm statement (I use that phrase very specifically). It is the guidance to “enter clinical trial.”
In essence, the oncologist has told the patient there is little or nothing left in the armamentarium of known clinical practice to treat his or her disease and that the last hope lies in the undiscovered country of a new, un- or modestly tested drug.
I have every confidence that somewhere in the middle of the conversation about the clinical trial, the oncologist included a note about the patient having a 50-50 chance of being randomized to the placebo or standard-of-care arm. But in the midst of a conversation about the potential end of your life, how many patients believe that they will be chosen not to receive the experimental therapeutic?
From the patient’s perspective, what was the point of going into the clinical trial if not to receive his or her last chance, the Hail Mary therapeutic?
In the Toronto Star item, healthcare ethicist Francoise Baylis from Dalhousie University answered this question.
“The purpose of participating in a trial is not access to treatment,” she said. “The purpose of participating in a trial is to contribute to knowledge production.”
The patient needs to understand he or she is being asked to take one for the team.
I apologize if that sounds glib or insensitive, but I believe it is true. For the purposes of the larger study, when a patient enters a clinical trial, he or she ceases to be an individual and instead becomes part of a statistical analysis.
Is she part of the 42 percent who saw improvement versus the control arm, or part of the control arm?
Is he one of the 95 percent who did not suffer Grade 3 neutropenia on treatment, or one of the 5 percent whose life was threatened by treatment?
I am not suggesting that the clinical trials process is flawed. At a macro level, I don’t know any other way to do this.
Nor am I suggesting that companies indiscriminately release candidate therapeutics on compassionate grounds whenever a request is made. Only the company and its medical team are in a position to make that decision.
What I am suggesting is that as the industry moves further along the clinical practice algorithms—further away from primary diagnosis and closer to “here be dragons” territory—the louder the questions and demands will become regarding individuals desperate for a ray of hope.
And that ray of hope quickly becomes a harsh spotlight under which companies will be grilled for answers.
Perhaps it is time for companies to make a stronger effort to educate patients—and probably healthcare specialists—on the idea behind and the need for clinical trials, both from the perspectives of the hopes they offer and, more importantly, the limitations under which they must operate to be effective and meaningful.