Guest post by Larry Gilman.
In the latest issue of The Journal of Infectious Diseases, Drs. M. Kearney and F. Maldarelli (K&M) have “strong words,” as Paul Sax puts it, for doctors prescribing antiretrovirals for XMRV/MLV-positive ME/CFS patients. K&M write:
At this time, such an approach is premature and medically indefensible outside the secure oversight of a well‐controlled clinical trial. “Real world” coping with severe diseases like chronic fatigue syndrome and prostate cancer creates understandable desperation on the part of patients, caregivers, and health care professionals. Such pressures are not justification for testing of therapies in an uncontrolled manner. Indeed, because they are of no help whatsoever to other patients, physicians, pharmaceutical companies, or regulatory agencies, such uncontrolled therapy works directly against the goal of providing effective therapy to the million or more individuals experiencing these serious conditions.
Unfortunately, this righteous reprimand is riddled with fallacies.
(1) Off-label prescription of drugs (prescription for conditions not named in FDA approvals) is legal and common. One can slight such usage as “uncontrolled” — and it is, in the rarified sense that it is not overseen by an Institutional Review Board (as it would be in a research trial) — but it is not necessarily unreasonable, unethical, or ineffective.
(2) It is also normal to prescribe therapies despite uncertainty about whether they will work for a given patient. Even approved treatments always carry some burden of uncertainty. It is clearly defensible to attempt any therapy for any patient if an informed judgment has been made jointly by patient and doctor that the likely benefits outweigh the risks. K&M, in condemning ad hoc treatment of retrovirus-positive ME/CFS with antiretrovirals found effective in vitro, imply that flawed risk-benefit judgments are being made. But in which cases? Flawed how? They haven’t said. Nor, so far as I know, has any other critic of these efforts.
(3) Observations of statistically insignificant numbers of patients (e.g., clinical experience, pilot studies) often inform the design of large, rigorous studies. Far from preventing or impeding scientific studies, small-scale experience commonly stimulates them. Every rigorous study begins with an educated guess; clinical experience with small numbers is often part of the education. Researchers should try to learn from the nonsystematic but clinically reasonable use of antiretrovirals with ME/CFS, not shame it out of existence.
(4) It is not true that ad hoc treatment of a few patients with particularly dire ME/CFS outside of randomized, controlled clinical trials “works directly against the goal of providing effectual therapy” to other patients. The number of patients receiving ad hoc treatment — even if it grew to the tens of thousands, which it seems unlikely to do — is far too small to impede the conduct, now or later, of large, strictly designed trials, which have an ME/CFS population of at least a million (judging by CDC studies) to draw from in the US alone. K&M do not say how, they think, scattered ad hoc efforts will impede research — and I don’t think they can. The vanishingly tiny fraction of ME/CFS patients that receives antiretroviral treatment will simply be excluded from studies using such drugs, with no harm done.
(5) Most seriously, K&M—like other critics of ad hoc treatment — seem to me to confound research ethics with clinical ethics. Researchers are obliged to gather the most objective, accurate scientific knowledge they can while doing, so far as is humanly possible, no harm: clinicians are obliged to do all the good they can for the people in their care, period. In the clinic, only the individual patient’s well-being, not the advancement of science, may be consulted. The patient has a right to demand, and the doctor a duty to provide, any treatment that in their joint judgement may improve the patient’s overall condition. Far from being obligatory, it is forbidden for a doctor to consider the advancement of science in deciding whether to withhold any reasonable therapy from a patient who wants it. The idea that patients must—or even may—be denied treatment in order to advance science is nothing short of a Tuskegee mentality. Thus, even if it were true that ad hoc antiretroviral treatments are somehow impeding rigorous research (which they aren’t), it would still be unethical to urge the blanket denial of such treatments for the sake of the research.
Strong words, yes—for radically wrongheaded condemnation of the treatments now being attempted.
The ethical shoe is really on the other foot. Doctors prescribing antiretrovirals for retrovirus-positive ME/CFS are making a reasonable attempt to help very sick patients. Those who argue that doctors should never do any such thing because it might somehow (how?) slow the gathering of scientific knowledge show a disturbing tendency to view patients as a source of scientific information, rather than as people deserving the best care possible—even in the midst of uncertainty.
My essay comparing the recent controversy over XMRV/MLV to an earlier controversy in bioscience, the maize transgene flap, is here. I blog sporadically on science-related issues here. Professional website here, religion-and-science blog here.