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An efficacy endpoint is an outcome that is tested during the course of a clinical trial. This assessment is based on a pre-specified event or measure that is expected to change over time. There is a difference between events and measures. An event is something that happens, e.g. losing the ability to walk independently.

Measures are scores given to certain activities. For example, timed function tests measure how fast a child runs/walks a certain distance, how fast he gets off the floor, how fast he can take four steps, etc. Because the natural history (progression) of Duchenne is pretty well understood, researchers at different study sites can test functions over time using testers who do things in the same way (called inter-rater reliability) and end up with quantitative data whether there was improvement.

Types of Clinical-Benefit Efficacy Endpoints

There are two main types of efficacy endpoints: clinically meaningful and surrogate.

  • Clinically meaningful endpoints relate to how a patient feels, functions, or survives. These endpoints have obvious value for the patient, such as ambulatory activity (the ability to walk a certain distance or for a specific period of time).
  • Surrogate endpoints are well-established, validated endpoints or substitutes that are able to predict clinical benefit. Surrogate endpoints may have no immediate value to the patient. They may be qualitative or quantitative, and aim to capture the effect of a certain treatment (such as forced vital capacity (FVC) or lung function) on the real endpoint.

There is also an accelerated approval surrogate endpoint that applies to Duchenne. This is a surrogate endpoint that is considered reasonably likely to predict clinical benefit. The surrogate endpoint, combined with primary and secondary endpoints, are used to obtain conditional approval of a drug for a serious or life threatening condition where there is currently little to no treatment. One example of this is the CK blood test, which measures creatine kinase, an enzyme that normally lives inside muscles. Boys with Duchenne often have CK levels 10 to 100 times the normal range. Elevated CK levels indicate muscle damage, although a high CK does not confirm a diagnosis of Duchenne.

What is the ideal event or measure of drug efficacy?

Ideal events or measures have four basic criteria: 

  • Regulatory utility: Meets criteria to support drug registration 
  • Disease utility: Informative and useful in study population 
  • Practical and analytical utility: Simple and cost effective 
  • Pharmacodynamic utility: Provides important support for drug utility

What are some of the endpoints (with events or measures) associated with Duchenne?

  • Survival–based on the natural history of the condition
    • Wheelchair dependency 
    • Ventilatory failure 
    • Cardiac failure 
    • Death 

  • Strength–these are all ways to measure muscle strength: 
    • Manual muscle testing (MMT) by a person with a stop watch 
    • Quantitative muscle testing (QMT) done using computers 
    • Hand-held myometry to measure grip strength

  • Scales designed to measure strength include:
    • Timed function test 
    • Brooke scale 
    • Gross motor function 
    • Motor function measure 
    • North Star neuromuscular assessment 

  • Ambulation (walking ability)
    • 6 minute walk test 
    • Step activity monitor 

  • Disability–measures degree of disability:
    • Functional independence measure 
    • Barthel index 

  • Pulmonary function–measures lung function:
    • Forced vital capacity (FVC) volume of air on forced expiration 
    • Peak cough flow measures strength of cough 

  • Quality of life–measures quality of life (how the individual and caregiver feel about quality):
    • PedsQL 
    • CHQ-CF/PF-87 

  • Pharmacodynamic–Biochemical data used to check on action of the drug and potential toxicity:
    • In vivo muscle dystrophin protein and mRNA (biopsy) 
    • In vitro myoblast dystrophin expression (myotube assay) 
    • Muscle enzymes (CK, Aldolase, etc.) 
    • Cardiac enzymes 
    • Nitric oxide 
    • Urinary creatinine/ 3 methyl-histidine 
    • Imaging (DEXA/MRI) 
    • Bioelectrical impedance 

Learn more about How We Know When Something Works.

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