Evidence-Based Regulation—A Personal View
Authors: Malcolm Brenner
Journal: Molecular Therapy (2002)

An extraordinarily large amount of medical practice is based on a mixture of tradition, speculation, and a priori reasoning based on false assumptions. Over the past decade there has been a movement towards “evidence-based medicine” (EBM), in which a clinician's approach to health care practice is determined by an awareness of the scientific evidence in support of his or her clinical practice and the strength of that evidence. In EBM, the current best evidence is used to make decisions about the care of individual patients. I would like to propose that regulation of clinical research in general, and of gene therapy in particular, meet equivalent requirements. A small number of well-publicized disasters in clinical research over the past few years have led to a major expansion in the regulatory oversight applied to investigators. In EBM terms this would be the equivalent of modifying the entire practice of medicine based on a few anecdotal case reports, the antithesis of what EBM is about. But how can anyone argue against providing the highest possible level of protection to clinical research subjects? The problem is that avoidance of one set of risks simply exposes our patients (or “research subjects”) to a new set of perils. To illustrate this point with a banal example, a requirement for increased or prolonged follow-up of gene therapy patients exposes these individuals to the risks associated with extra travel to their doctor's appointments. This risk is real: one of my own patients was ejected through the windshield of the family pickup on his way to the clinic. Now I am not claiming that this anecdote is any more valid than the anecdotes that led to the implementation of this rule in the first place, but in evidence-based regulation there would need to be an evidential basis that our patients could benefit from these additional journeys. More generally, and of more profound importance, the increasing requirement that academic investigators provide industrial strength manufacturing and clinical research practices for early phase clinical studies demands more and more resources for fewer and fewer studies. This inhibits the introduction of novel therapeutic strategies, with the greatest effect on orphan diseases of limited commercial relevance. There is little doubt that if information technology were regulated in the same way as gene therapy, our laptops would be larger than our living rooms, 30 people would be required to run each program, and every time the system crashed, five different agencies and committees would need to be informed in triplicate. Working in pediatric oncology, I find it deeply dismaying to have to continue to treat children with therapies that EBM tells us are poisonous, mutilating, and often ineffective, while delaying introduction of newer approaches based only on risk perception and not on risk evidence. None of us wants to do clinical studies that are ill-designed, dangerous, or futile. But regulation to the level of total stasis is equally undesirable. So I would suggest imposing a moratorium on new regulation and charging one (or perhaps even all) of the entities involved in the regulation of clinical research and gene therapy with the production of a handbook of evidence-based regulation. This guide would assess the relative risks and benefits of each regulation based on scientific and clinical evidence. In this way, investigators and regulators would use the current best evidence to make decisions about the requirements appropriate for studies in individual patients. In the absence of such an evidential basis, we risk discovering that current clinical trial regulation will turn out to be of no more benefit to our patients than the pre-EBM therapies of “purge and bleed.”