In the latest Global CardioVascular Clinical Trialists (CVCT) Workshop", one of the topics was "How to assess the disease modification in pulmonary arterial hypertension". the academic and industry representatives discussed the definition of disease modification and if the various individual drugs met the criteria as disease modifiers.
Disease modification requires that the intervention have an impact of the underlying pathology and pathophysiology of the disease. For regulatory purposes, a disease modifying effect is when an intervention delays the underlying pathological processes and is accompanied by improvement in clinical signs and symptoms of the disease. The opposite of the disease modifying effect is symptomatic improvement which is defined as "may improve symptoms but does not affect the long-term survival or outcome in the disease, for example, use of diuretics in PAH".
- a drug targeting the underlying pathophysiology
- distinction should be made from the "symptomatic treatment" (do not affect underlying pathophysiology)
- Can achieve the goal of remission (partial or complete)
- endures sustained clinical benefit (referred to as DMA).
The randomized withdrawal design was originally proposed as an approach to enrich the study and reduce the sample size. The randomized withdrawal design (if it is feasible to implement) can be used to evaluate the long-term disease-modifying effect.
In FDA's guidance "Early Alzheimer’s Disease: Developing Drugs for Treatment", the randomized-start or randomized-withdrawal trial design was suggested:
In the FDA’s webinar on “Draft
Guidance For Industry On Alzheimer’s Disease: Developing Drugs For The
Treatment Of Early-Stage Disease”, the FDA presenters discussed the randomized start design or withdrawal design:
“… If there is a significant
effective treatment that couldn't serve as the basis of approval, we do not
believe that that argument in and of itself does not demonstrate. This is where
biomarkers come in. We learned in the trial results, the effect on up Alzheimer
disease biomarker, it is still very and clear. Where the biomarker has been
altered but there is no clinical effect. The clinical outcome was the opposite
of what you want to see. The bottom line is that that understanding and how it
relates to the clinical outcome still needs a bit of work. We would not be
willing to accept the effect on the biomarker, as a basis for a circuit --
Sarah get approval. For
that to be the case, it would be a fundamental itself in the disease process.
In addition to biomarkers there are other ways to show disease modification, a randomized start design, or
withdrawal design. These are based on clinical endpoints. These are
difficult studies to design, and conduct, and interpret. We are open to use
these approaches to show modification, let me show you what I mean by
randomized start design. One would be on .8, the other will be on placebo, the
patients on group to will be switched over to active treatment, patients in
group 2 will be caught up to group 1, they will have a systematic effect of
treatment. Patients that were switched to never really caught up to the first
group, can argue for an effect on the disease, this is challenging to do, but
we are open to the approach. It is a devastating condition, and an epidemic make
-- particularly in late stages, the field is moving to conduct trials in early
stages of the illness. As I pointed out they will pose regulatory challenges.
We hope that's where our guidance will come in and suggest pathways forward.
Thank you. I will have Russell Katz, come up and talk for the rest of the
webinar.”
In one of the EMA presentations “The scientific and regulatory approaches to facilitating disease-modifying drug development and registration in a global environment”, the delayed start design (or randomized start) and randomized withdrawal design were mentioned.
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