Defining 'disease modification effect', 'disease modification therapy (DMT)' or 'disease modifier'

The concept of "disease modification," "disease modification therapy (DMT)," and "disease modifier" has been a focal point in the realm of drug development for chronic diseases. The distinction reaches a heightened significance when a drug under development qualifies as a true disease modifier. Disease modification is a default for acute diseases (for example, the acute infections) and for gene therapies, transplants, some surgeries. The focus of our discussion about the disease modification is mainly for chronic diseases. 

Disease modification entails interventions or treatments designed not solely to alleviate symptoms but also to actively influence the trajectory of the disease, effectively impeding or halting its progression.

It's important to note that a unified definition for disease modification does not exist. The nuances of the term, as well as what qualifies as a disease modifier, can vary across different diseases. The understanding and criteria for disease modification may differ, reflecting the intricacies inherent to each specific medical condition.

In a review paper by Vollenhoven et al "Conceptual framework for defining disease modification in systemic lupus erythematosus: a call for formal criteria", authors put together a table summarizing various definitions for disease modification in different disease areas: 

As we are doing the clinical trials, the spectrum of treatment response can be listed as the following: 

Harm -> No Response -> Modest Response -> Strong Response -> Disease Modifying -> Cure. For most chronic diseases, the ultimate outcome of a 'cure' may not be achievable. A therapy with a disease modification effect will be desirable. 

There was a proposal to classify the disease modification into five different levels: 

Level 1: Slowing decline

Level 2: Arrest decline

Level 3: Disease improvement

Level 4: Remission

Level 5: Cure

In a review article for Alzheimer's disease, "Trial Designs Likely to Meet Valid Long-Term Alzheimer's Disease Progression Effects: Learning from the Past, Preparing for the Future", the changes in the level of functioning across time were depicted as the following. 'Slowing progression' would be considered as 'disease modification'. 

In a paper by Morató et al "Symptomatic and Disease-Modifying Therapy Pipeline for

Alzheimer’s Disease: Towards a Personalized Polypharmacology Patient-Centered Approach", the following was said about the disease modification therapy in Alzheimer's disease:

A disease-modifying treatment (DMT) is defined as an intervention that produces an enduring change in the clinical progression of AD by interfering with the underlying pathophysiological mechanisms of the disease process that lead to neuronal death. Consequently, a true DMT cannot be established conclusively based on clinical outcome data alone, such a clinical effect must be accompanied by strong supportive evidence from a biomarker program.

In 2011, there was an FDA advisory committee meeting to discuss Teva's Parkingson's drug for disease modification indication. According to the FDA briefing book, to demonstrate the disease modification effect, three hypothesis tests are needed to analyze the data from the study with a delayed start design (even though the disease modification claim was voted down): 

The study was to be analyzed according to three hypotheses, in the following order: 

• Hypothesis 1-the contrast between the slope of drug and placebo response at Week 36 (using data from weeks 12-36; Linear Mixed Model with random intercept and slope) 
• Hypothesis 2-the contrast of scores between baseline and Week 72 (Repeated Measures) 
• Hypothesis 3-a non-inferiority analysis of the slopes of the ES and DS patients from weeks 48-72 (Linear Mixed Model with random intercept and slope) 

The first hypothesis was designed to determine that a difference between treatments emerged in Phase 1, the second hypothesis was designed to determine that there was a difference between ES and DS patients at the end of the study, and the third hypothesis was to determine that an “absolute” difference between the ES and DS patients persisted during Phase 2 (that is, even though a difference between groups at the end of the study might have existed [what was 4 tested by Hypothesis 2], it was important to show that the two groups were not approaching each other). 

To delve into the realm of disease modification therapy research, it is imperative to establish a standardized definition for disease modification, particularly tailored to the nuances of a specific disease area. This foundational step serves as a compass guiding subsequent investigations. Following the definition, the identification of endpoints to measure the disease modification effect becomes paramount. Given the nuanced nature of disease modification effects, the conventional clinical trial designs may prove insufficient. Hence, a specialized approach involving clinical trial designs (such as delayed start design and randomized withdrawal design) with multiple hypothesis tests becomes a requisite. Such a methodological shift is essential to comprehensively capture and validate the nuanced impacts of disease modification therapies.