Time
to Event analysis has expanded beyond the traditional term of survival analysis
even though the term of survival analysis may still be used in oncology trials and time to event analysis remain as the primary tool in oncology
clinical trials. In oncology area, depending on the type of the cancer and the
regulatory requirement, the primary efficacy endpoint may be one of the
following 'time to event' variables: overall survival (time to death),
progression free survival (time to progression), disease free survival (time to
disease occurrence), event free survival (time to event occurrence),… In the
non-oncology area, we also often need to perform 'time to event' analysis. Except in oncology area where the terms 'overall survival', 'progression free survival' are used, all 'time to event' endpoints will be
labelled with ‘time to something’. Here are some of the examples of 'time to
event' variable in non-oncology areas:
Endpoint
|
Indication
|
Time to hemostasis (time to stopping the bleeding)
|
Adjunct
to Hemostasis after various types of surgeries using fibrin sealant or
thrombin
COPD, Bronchiectasis |
Time to first pulmonary exacerbation |
|
Time to healing of the primary lesion complex (loss of
crust from vesicular [classical] lesions)
|
Recurrent Herpes Labialis |
Time to clinical worsening
|
Pulmonary arterial hypertension
|
| Time to parasite clearance Time to recurrent infection |
Malaria
|
For
all 'time to event' variables, the EVENT of interest must be clearly pre-defined. Sometimes,
defining an EVENT is not easy. In many situations, the EVENT of interest may
need to be adjudicated by an event adjudication committee (EAC) or by central
reader (if an Event of interest is determined by imaging).
Depending
on the definition of the ‘event’, the 'time to event' variable could be a hard
end point or a surrogate (soft) endpoint.
Overall
survival (time to death) is usually considered as a hard end point because death
is a definite event.
Time
to first hospitalization, time to lung transplantation,… may be considered as a
hard endpoint. However, the hospitalization and lung transplantation could be
impacted by the health care resources and might be different depending on the
countries/regions.
If
there is a composite endpoint that includes the 'time to MI', 'time to Stroke', you
might think that the event MI and Stroke are definite endpoints. You might think that myocardial infarction (MI) is an event that can be easily
identified/diagnosed until you realized that the myocardial infarction could be
determined based on cardiac markers such as tropolin level. Whenever we deal
with a laboratory test, we will run into the issue of the assay sensitivity, the measurement
error, and the cut point for defining the event. Stroke might also be considered
as identifiable event, but if the stroke event includes the transient ischemic
attack (TIA), TIA may not be easily identifiable.
'Time
to event' variables may depend on the pre-specified schedules for checking the
EVENT of interest. For example, in malaria studies, ‘time to parasite clearance’ was assessed by taking blood
samples and examining it by light microscopy prior (0 hour) and during
treatment at 4, 8, 12 hours and then 6 hourly until two consecutive negative
blood slides. If the pre-specified time points for taking blood samples
are different, the ‘time to parasite clearance’ variable will also be different.
For Progression Free Survival or Time to Progression variables, the disease
progression will need to be clearly defined. For the solid tumor, the progression
is usually defined using Response
Evaluation Criteria In Solid Tumors (RECIST) criteria that is usually
based on the radiological and imaging (CT, MRI) results to measure the changes
in tumor size (or target lesions).
Many
women with early-stage breast cancer undergo breast-conserving surgery followed
by whole breast irradiation, which reduces the rate of local recurrence. Radiotherapy
to the chest wall and regional lymph nodes, termed regional nodal irradiation,
which is commonly used after mastectomy in women with node-positive breast
cancer who are treated with adjuvant systemic therapy, reduces locoregional and
distant recurrence and improves overall survival. In early stage breast cancer studies, Disease Free Survival (DSF) measures the length of time after
primary treatment to the re-occurrence of any signs or symptoms of
the cancer. DFS may also be called relapse-free survival or RFS. It will be
a surrogate endpoint since the determination of the re-occurrence of any signs
or symptoms may not be accurately detected.
In oncology studies, Event-Free Survival (EFS) measures the length of time after primary treatment to the
re-occurrence of certain complications or events that the treatment was intended
to prevent or delay. These events may include the return of the cancer or the
onset of certain symptoms, such as bone pain from cancer that has spread to the
bone. For example, in neoroblastoma studies, Event-Free Survival was used and the EFS was defined as the time from study
enrollment (which occurred after transplantation) until the first occurrence of relapse, progressive
disease, secondary cancer, or death or, if none of these events occurred, until
the last contact with the patient. It will also be a surrogate end point since the
determination of relapse, progressive disease, and secondary cancer may depend on
when the patients are examined and how the imaging results are examined.
In
summary, for time to event variables, it is critical to have criteria to
determine the Event of Interest. If the determination of the Event of
Interest is soft, it may require a third party (independent of the sponsor and the investigator) to
determine the Event of Interest. If the radiological and imaging techniques are
used, a central reader is usually needed. For other 'time to event' variables
where the determination of the event is soft, an independent Event Adjudication Committee (EAC) is usually needed. For the studies in the same indication, it is
ideal to have standardized criteria to determine the Event of interest so that the study results across different
sponsors may be compared. For example, in breast cancer area, people are trying
to use a STEEP
system to standardize the criteria for clinical trial end points.
References:
