Tuesday, September 15, 2015

Time to Event End Points

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: 

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

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. 


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