The new guidance comes as EMA recognizes that the field of Alzheimer’s disease (AD) research and development “witnessed a recent paradigm shift in the diagnostic framework of AD which is now considered a continuum with a long-lasting presymptomatic phase, with evidence of AD neuropathology, which precedes 10-20 years the onset of dementia.”
And as the discovery of new biomarkers evolves, EMA says that the possibility to detect disease changes and progression in vivo opens new regulatory scenarios including the possibility to intervene on the neuropathology before symptoms appear.
“There is now a consensus that treatment options should be evaluated in earlier disease stages before the full picture of dementia is reached,” EMA says. “While the general approach for symptomatic drug development in mild to moderate and severe AD is still valid, this draft Guidance aims at integrating the requirements for development programs which start earlier in the disease course with the necessary adaptations to the distinct manifestations of the illness at these stages.”
The draft document, which researchers can comment on through 31 July and which builds off a concept paper from 2013, specifically addresses:
– The impact of new diagnostic criteria for AD, including early and even asymptomatic disease stages on clinical trial design;
– The choice of outcome parameters and need for distinct assessment tools for the different disease stages in AD (different signs and symptoms, differences in progression rate);
– Potential use of biomarkers and their relationship with the different phases of AD in different stages of drug development (mechanism of action, target engagement, use as diagnostic test, enrichment of study populations, stratification for subgroups, safety and efficacy markers, etc.);
– Design of long-term efficacy (maintenance of effect) and safety studies.
Goals of Treatment
EMA says the main goals of dementia treatment should include:
– Prevention of symptomatic disease by intervention in suspected pathogenic mechanisms at a preclinical stage.
– Disease modification with slowing or arrest of symptom progression and correlation with evidence of delay in the underlying neuropathological process.
– Symptomatic improvement, which may consist of enhanced cognition and functional improvement (monotherapy or adjunctive therapy)
– Symptomatic treatment of behavioral and psychiatric symptoms of dementia (BPSD).
“Since a disease modifying effect correlated with a persistent delay in the underlying neuropathological process is difficult to prove without adequately validated and qualified biomarkers as outcome parameters, a slowing or delay of clinical decline (cognitive and functional) as demonstrated by innovative trial designs may be acceptable as an alternative development goal,” EMA adds.
EMA also calls on industry to establish in the early pharmacology and pharmacokinetic studies the mechanism of action by which the drug may be thought to have a therapeutic effect.
“As polypharmacy will be an important issue in this population, pharmacodynamic interactions between the test drug and other medicinal products (including psychoactive, antiplatelet and lipid metabolism agents), expected to be given concurrently with the test drug in clinical practice, should be studied as appropriate,” EMA says, also noting what should be considered in exploratory trials and how autosomal dominant AD and sporadic AD should be distinguished.
Biomarkers
In addition to the development, validation and use of reliable instruments to measure cognitive, functional, behavioral and neuropsychiatric symptoms especially in early disease stages, EMA also calls for improving the standardization and harmonization in the use of biomarkers for different purposes along the course of drug development.
EMA points to four categories of biomarkers: Diagnostic, enrichment (for reinforcing entry criteria), prognostic and predictive, noting that recently in the diagnostic area, the approval in the EU of the radiopharmaceuticals florbetapir (18F), 325 (florbetaben (18F) and flutemetamol (18F) for positron-emission-tomography (PET) imaging of beta amyloid neuritic plaques in the brain have been another step forward.
Other Tools
EMA also provides in the 35-page guidance document new information on tools for outcome assessment, particularly for objective cognitive tests, activities of daily living, global assessment of change, health-related quality of life and behavioral and psychiatric symptoms of dementia.
Meanwhile, on the clinical trial side of development, EMA offers insight into what can be considered efficacy endpoints in AD dementia, prodromal AD/mild cognitive impairment and in preclinical AD.
The agency also offers trial design features, development strategies for disease prevention, statistical considerations and an overview of different types of dementia, as well as safety evaluations that should be conducted in the context of ICH’s E1 document on clinical safety.
More Information on RAPS
More Information on Draft guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease and other dementias