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Table 2 Steps involved in methodological approach

From: A methodological framework for drug development in rare diseases

Steps

Approaches

Methods

Step 1

Use available knowledge

Bibliography

(i) Pathophysiology, diagnosis, therapeutics, pharmacology

(ii)Discursive and mathematical models for the disease

(iii)Discursive and mathematical models for the drug effect(s)

Individual epidemiological and RCT databases

(i) Statistical approaches for analysis

(ii) Identify prognostic biomarkers

(iii) Identify N potential drugs (or therapeutic strategies) for evaluation in phase III RCTs

(iv) Identify predictive biomarkers for these N drugs (e.g. interactions between patient characteristics and drug efficacy)

(v) Validate drug-disease models

Step 2

Drug-disease modeling for the N treatments identified above

Treatment 1: (Disease model + Drug effect model 1)

Treatment i: (Disease model + Drug effect model i)

Treatment N: (Disease model + Drug effect model N)

Step 3

Drug-disease modeling for the N treatments above in patients whose characteristics may interact with drug efficacy

Treatment 1: (Disease model + Drug effect model 1) in patients whose specific characteristics interact with treatment effect 1

Treatment i: (Disease model + Drug effect model i) in patients whose specific characteristics interact with treatment effect i

Treatment N: (Disease model + Drug effect model N) in patients whose specific characteristics interact with treatment effect N

Step 4

Experimental RCT design modeling (including orthogonal approaches) for N conditions above

P experimental designs *N situations

Step 5

Simulate these N*P options

Results ordered in terms of potential efficacy, adverse events, number of needed patients, cost (including trial duration)

Step 6

Identify the most relevant drugs to be evaluated in phase III RCTs and the RCT design to be used for each of them

Multiple-criteria decision analysis approaches