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Background.
Because of the rapid progression of ALS, the lack of effective treatment, and the length of placebo-controlled trials relative to the median survival of patients with ALS, there has been pressure from the ALS patient community to make experimental treatments available prior to the determination of efficacy of those treatments. However, given the need to make those determinations, a compromise proposal has been to use a database of information obtained from ALS patients previously (the natural history of the disease) and presumably prior to the introduction of a putative therapy as the control group so that current patients could all receive the putative therapy. A second rationale for the use of natural history controls has been that if a putative therapy is sufficiently powerful, the use of a relatively small treatment group should demonstrate efficacy, or at least define a relatively short experimental-time to survival-time ratio so that such a therapy could be instituted in the general ALS population relatively quickly if ultimately proven efficacious.
Definition.
The term "natural history control" can be confusing when applied to clinical trial design. Some have used it as above. Some have used it to mean a wash-in period as part of a traditional parallel-group design used along with age, gender, etc., to ensure that the groups in that study are as equal as possible. Occasionally the term has been used to signify that one group in a parallel-group study is receiving no active agent--a placebo group as opposed to comparing two or more active treatments. To avoid that confusion, it has been suggested that the term "historical control" be used when we mean the control group as described in the Background section.
Methods.
Natural history databases are currently available. No further data need be generated since the debate before us is …
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