The Plea To Be Allowed To Make It Up As You Go Along: The Quandary of the N=1 Clinical Trial

The Plea To Be Allowed To
Make It Up As You Go Along: The Quandary of the N=1 Clinical Trial


Leonard Zwelling

         This Sunday’s NY Times
 is devoted to Cancer—that’s with a capital C.

         This article by Pulitzer Prize winning author and oncologist
Sid Mukherjee outlines the vexing puzzle faced by today’s cancer doctors. Where
once the protocol was king in research, now the individualization of therapy is
the choice experimental treatment pathway. But is this ethical? Is it even
research in the sense that we can generalize what we learn from one patient to
any others?

         It is definitely research. It is also ethical, but to assure
both will require some new thinking.

         This is actually not a new dilemma at all. Leading oncologists
at major cancer centers were always having new ideas about how to treat
patients with cancers resistant to conventional chemotherapy, but whose
clinical status was still quite good. If a patient is walking into your office,
you can’t be expected to tell the patient you have nothing to offer him or her.
He or she is a patient. You are a doctor. There needs to be some assuaging of
disease and suffering if the 5000 year social contract between the diseased and
those to whom they have come for healing is to be sustained.

         The problem is not only what to do, but how. I will let Dr.
Mukherjee delineate the what to do part, which he does very well, indeed. I
want to focus on the how, because that is what concerns me most and that is
what I spent nine years of my life overseeing.

         The how is the current system of human subjects research
under which we physicians have agreed to operate once we take on the added
burden of being experimentalists. And even if we don’t agree to it, the federal
government has both mandated and codified how clinical research in the US will
be done.

patient is more than a patient. He or she is a human subject and must be
approached differently, with greater care even than a regular patient. We, the
treating physicians, are more than just docs. We are scientists using instinct
and knowledge in an effort to save or at least prolong the life of an afflicted
cancer patient, but doing so under humanistic rules of engagement that cannot
be violated if the integrity of the human subject is to be preserved.

         When human subjects were lumped together in groups (e.g.,
stage 2 breast cancer), this could be dealt with using broad-based protocols.
Now that it looks like every patient is an N of one, this becomes quite a

         I am going to argue for something that Dr. Mukherjee hints
at in his article—single patient protocols. If the parameters of ethics (e.g.,
informed consent) can be met and oversight by an institutional review board
guaranteed, I see no reason that a trial that includes exactly one patient
cannot constitute useful clinical science.

         What’s the hypothesis?

         How does the proposed research and clinical manipulation
address the question?

         What will be measured?

         How will you gauge success or failure?

         If that needs to be done in just one unique individual, I do
not see why a rapid approval process cannot be devised and why the FDA cannot
grant the authority to oversee such a process to major, NCI-designated cancer

         If we agree, as Dr. Mukherjee suggests, that our level of
understanding of cancer’s complexity has reached a profound point of “don’t
know” where the many pathways and genes and epigenetics are impacting what we
see clinically in ways that we need to explore, let’s get on with it and not
let red tape stand in the way.

         Let’s grant the power of that often used term “compassionate
use” back to the doctors and patients as suggested by Dr. Freireich and develop
local oversight to assure ethics are preserved.

         Here are my caveats (you must have known there would be

         There can be ABSOLUTELY NO conflicts of interest involved in
this research. The institution, all its personnel and all its caregivers MUST
be free of any connection with the sponsor of the agent being tested. Period.
No exceptions.

         Next, payment must be figured out. If this is experimental
and the drug company or insurance company chooses not to pay, this must be
respected. The institution should cough up the cost if the question is that vital
and ethics have been preserved. Society cannot make private insurers pay for
experiments like this, nor will governmental programs like Medicare likely pay
for it unless the infrastructure under which the work is being done is
NCI-sanctioned and then Medicare ought to pay. The private insurers will likely
fall in line.

         For now, it may be the best we are going to be able to do if
we are really to pursue the origins of cancer and ways to reverse its deadly
toll. If the best of trials have an N = to one, we may be able to figure out
more in less time using fewer human subjects and wouldn’t that be a good idea?

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