Hi Itsa, I think from a psychological viewpoint many across the community, ie science, investment lay, etc currently feel more comfortable with placebo.
So from one perspective, a placebo arm is appealing as it offers some visual validation, and it can be a real validation.
A 3 arm trial such as below has an appeal.
"The practice of using an additional natural history group as the trial's so-called "third arm" has emerged; and trials are conducted using three randomly selected, equally matched trial groups, Reilly[5] wrote: "... it is necessary to remember the adjective 'random' [in the term 'random sample'] should apply to the method of drawing the sample and not to the sample itself."
The Active drug group (A): who receive the active test drug.
The Placebo drug group (P): who receive a placebo drug that simulates the active drug.
The Natural history group (NH): who receive no treatment of any kind (and whose condition, therefore, is allowed to run its natural course).
The outcomes within each group are observed, and compared with each other, allowing us to measure:
The efficacy of the active drug's treatment: the difference between A and NH (i.e., A-NH).
The efficacy of the active drug's active ingredient: the difference between A and P (i.e., A-P).
The magnitude of the placebo response: the difference between P and NH (i.e., P-NH).
It is a matter of interpretation whether the value of P-NH indicates the efficacy of the entire treatment process or the magnitude of the "placebo response". The results of these comparisons then determine whether or not a particular drug is considered efficacious.
Natural-History groups yield useful information when separate groups of subjects are used in a parallel or longitudinal study design. In crossover studies, however, where each subject undergoes both treatments in succession, the natural history of the chronic condition under investigation (e.g., progression) is well understood, with the study's duration being chosen such that the condition's intensity will be more or less stable over that duration. (Wang et al. provide the example of late-phase diabetes, whose natural history is long enough that even a crossover study lasting one year is acceptable.[6]) In these circumstances, a natural history group is not expected to yield useful information."
Natural history studies can provide other benefits over a standard placebo/drug trial though as discussed below, such as inclusiveness in the trial of all boys (in DMD) to receive drug treatment and hopefully benefit, and if nothing else, hope.
17-Jul-2019 By Melissa Fassbender
Natural history studies are essential for rare disease research and can potentially replace placebo arms in clinical trials, among several other benefits, says industry expert.
(the above has copyright so you will have to copy and paste link to read, short read)
So in hindsight without great insight into the efficacy potential of a drug about to be trialed, in general, I would run a placebo. But given the DMD boy's futures are short and limited and often lack hope, I would consider a natural history arm so all could receive potential therapy. That said, a trial is complicated, and figuring out if all boys are being given the drug with beneficial outcomes versus all boys being given the drug with some negative outcomes requires much thought.
In the scenario of DMD, that we are familiar with, if the safety record and prior clinical results provide strong data for no or low chance of negative safety issues I would strongly consider natural history.
And the longer the trial the more weight I would give to NH.
Eg a month trial may not be life-altering during the trial, (8 year old 0.69%) but a 12-month trial with a 12-month+ follow-up (8 year old 13.89%+) then becomes a large percentage of a 20-year lifespan and an even greater percentage of the lifespan left of a 10-year-old that will live to 20.
It is difficult when you think about it, and science ethics and life practicalities start to be more relevant.
A placebo is a good component of a 3 arm trial, ie people who may still live to 70+ and if it's not life-threatening then I think that would be the way to go.
As discussed, short-term life spans bring in new aspects.
Would i have done a placebo in the 2a trial that went for 6 months on 9 boys with no follow up period, difficult, but most likely i would have since the data may have been seen to be more compelling therefore opening up a quicker path to bring an effective drug therapy to DMD boys en masse.
But there are many considerations. Its not really black and white or binary, it can be difficult to know the best decision.
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