Clinical endpoints in organ transplantation
The aim of most of the clinical trial is to estimate the endpoint and that serves as the goal of the clinical trial. e.g. response rate and survival. An endpoint in a clinical trial is a consequencewhich is measured. A clinical end point gives us a measure of how a patient feels, functions orhow long a patient lives. Surrogate end point is quantitative factor used as a replacement forend point. Intermediate end point is a factor that is in between the pathway between anintervention and end point. It could be binary like graft rejection Vs graft survival, continuouse.g. serum creatinine
(Hariharan et al,
2003)
.Sometimes to measure the endpoint a biomarker can also be used. It is an indicator of responseproduced for an intervention.End points are important in clinical trials as the have the capability to predict the outcome of the patients in the study using biomarkers or using other factors (Hariharan et al,
2003)
. Theyare safe, cost-effective and accurate as outcome could be established well before the end.
Clinical trial endpointsDisease free survival
F
or any drug, if it could improve survival rate of patients then the chances of its approvalincreases significantly and this is a gold standard for any drug to get approved. Survival isundisputed end point as no bias is possible from the side of investigator. The Disease
F
reeSurvival is used to assess the outcome of a treatment or an intervention which can lead tofreedom from disease such as surgery or surgery plus adjuvant therapy (Lachenbruch et al.,
2004)
. During the period of disease free survival disease may reoccur due to some factors butwould not lead to death. The reoccurrence of the disease could end their term of disease freesurvival but they will not die. Like some patients in survival cures will not die similarly in diseasefree survival curves only a few patients will undergo relapse of the disease and then plateauphase is attained indicating the patients in which disease did not reoccurred. Patients in whichdisease reoccurred will survive for some time and will not die as soon as disease reappeared(Lachenbruch et al.,
2004)
.
Progression free survival
R
ecently time to progression (TTP
)
has been accepted as satisfactory end point in clinical trials.Using TPP end points in trial can be obtained in short duration, second-line therapies do notcause confounding in TPP (Lachenbruch et al.,
2004)
. But TPP had to be done with greataccuracy than other trial end points. TPP gives an estimate value and can show variation as theydepend on when disease progresses and usually progression of disease is not measured andnumber of patients. The Progression
F
ree Survival is used to assess the outcomes of an
intervention or treatment for a disease which has already progressed and not is not in initialphase. Usually in progression free survival, disease becomes worse and progresses(Lachenbruch et al.,
2004)
.To get the correct outcome from the trial precise evaluation of TPP is important to evaluateeach factor at baseline and during follow up evaluation should be done using same tools andtechnology and this makes use of TPP in clinical trial very costly.
R
esponse duration
The response duration is often used in assessing the consequences for an already progresseddisease (Lachenbruch et al.,
2004)
. Usually disease reappears or relapses during the progressionof the disease. So in trials were such kinds of end points are to be studied a subgroup of patientpopulation is selected as only those patients are required for the trail who will respond andduration of response time is measured (Hariharan et al,
2003)
.
Quality of life assessment
Evaluation of patients quality of life is a significantly important end point in a clinical trial as itshows patients views about the clinical benefit (Lachenbruch et al.,
2004)
. QOL are not usedmuch as defining the variables of QOL is complex and tedious task. Quality of life can arisequestions that sometimes unrelated to the study and can have impact on the result. QOLexhibits the evaluation of symptoms of disease, toxicity and effect of the treatment and wellbeing on worldwide basis (
R
oep and Peakman,
2010)
. QOL is very difficult end points in a trialas these depends on reporting by the patients which is not always correct and it is difficult toverify the reports of each patient and to follow them over time. In order to get good resultsfrom such trials bias should be reduced by double blinding them or by using a placebo group(Lachenbruch et al.,
2004)
. They protocols, instruments and tools used should be checked.Usually QOL studies are proposition directed studies but missing data and involvement of manyend points can make the study complex and also there is a possibility that by itself improvement would have taken place (
R
oep and Peakman,
2010)
.
F
or accurate prediction of endpoint two factors are important- predictive and surrogate.
Clinical/ primary endpoints
G
ood clinical endpoint must be clinically connected and related to the clinical event of thepatient which he or she may avoid. A clinical event should be sensitive.Often consequence which is measured and is clinically important is quality of life.Predictive variable or primary end point takes into consideration the variation in endpoint e.g.kidney allograft rejection could be predicted by creatinine levels in serum or by examining the
immune system activation (elevated levels of m
RN
A
)
(Hariharan et al,
2003)
. These variables orfactors alone are not an effective way of predicting the endpoint instead if multiple variable aretaken into account the level of accuracy in prediction of outcome could be greatly enhanced.
Problems with clinical endpoints
y
It is difficult to do trials in which primary endpoint is death which is not desired from atrial.
y
W
hen the events occurring in a trial are so small, that no statistical significance could bedrawn from them.
y
Urgency is assessment of interventions which could offer radical cure can affect thetotal outcome.All the above factors make evaluation of primary clinical endpoint difficult and arises need forother endpoints which can act as substitute for primary end point.
Surrogate end points
In trials surrogate endpoints are finding increased use and have replaced true endpoints forstudying disease free survival but the role of surrogate end point in a trial is disputed as theirreliability is questionable.In order to study, eradication of disease and disease free or just survival can take long durationand high associated cost is very high. So in order to reduce duration of the trial surrogate endpoints are used and time and cost are correlated so reducing time would affect cost as well.Unlike in long term studies surrogate end point do not following of patients for long time andthis reduces chances of missing values and data as patients may skip follow up or sometimespatients are lost as they move to some other places (
R
oep and Peakman,
2010)
.Use of surrogate endpoint in a trial first requires identification of surrogate markers whichcould be measurable and are related to biology of the disease. Problems arises in the use of surrogate endpoints as surrogate markers are not easy to identify and their use is successfulonly if surrogates have high degree of relation with clinical endpoint of the disease (
R
oep andPeakman,
2010)
.Examples of surrogate endpoints are blood pressure effects or prostate-specific antigen levels.
Properties of surrogate end points
y
It is used to evaluate the effect of an intervention or treatment which can be related toclinical end point but their relationship is not sure.
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