alexa Endpoints in Clinical Trials: Advantages and Limitations
ISSN: 2471-9919
Evidence based Medicine and Practice

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  • Editorial   
  • Evidence Based Medicine and Practice, Vol 2(1)
  • DOI: 10.4172/2471-9919.1000e111

Endpoints in Clinical Trials: Advantages and Limitations

Leonardo Roever*
Department of Clinical Research, Federal University of Uberlandia, Uberlândia, Brazil
*Corresponding Author: Leonardo Roever, Department of Clinical Research, Av Pará, 1720-Bairro Umuarama, Uberlândia-MG-CEP 38400-902, Brazil, Tel: +553488039878, Email: [email protected]

Received Date: Dec 11, 2015 / Accepted Date: Dec 18, 2015 / Published Date: Dec 25, 2015

Introduction

Primary endpoints in clinical trials must meet 3 criteria:

A) Clinically relevant

B) Sensitive to treatment effect

C) Measurable and interpretable. Secondary endpoints could provide a more global view of the benefit of the treatment being tested and by clarifying its risk-to-benefit ratio; may be of 2 types: A) Those that, like primary endpoints, are clinically relevant and may be taken into consideration for drug indications; and B) “Feel-good” endpoints, which are not likely to lead to a new indication or a change in labelling but might provide reassurance about the primary endpoint along with new information about the disease. Some secondary endpoints might be exploratory analyses, although they might demonstrate biologically plausible effects, they remain hypothesis-generating and will need to be confirmed by additional studies. Table 1 and 2 shows the terms and definitions used in the outcomes of clinical trials [1-4].

Term Definition
Biomarker (biological marker) A characteristic that is measured and evaluated objectively as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.
Clinical end point A characteristic or variable that reflects how a patient feels or functions or how long a patient survives.
Surrogate end point A biomarker that is intended to substitute for a clinical end point, i.e., a biomarker that is expected to predict clinical benefit, harm, or lack of benefit or harm.
Intermediate end point A characteristic that is intermediate in the causal pathway between an intervention and the clinical end point.

Table 1: Shows the outcomes in major clinical trials.

Endpoints Definition Advantages Limitations
Overall Survival (OS) Time from randomization* until death from any cause Universally accepted measure of direct benefit
Easily and precisely measured
May require a larger trial population and longer follow-up to show statistical difference between groups
May be affected by crossover or subsequent therapies Includes deaths unrelated to disease
Progression-Free Survival (PFS) Time from randomization* until disease progression or death Requires small sample size and shorter follow-up time compared with OS
Includes measurement of stable disease (SD)
Not affected by crossover or subsequent therapies
Generally based on objective and quantitative assessment
Validation as a surrogate for survival can be difficult in some treatment settings
Not precisely measured (i.e., measurement may be subject to bias)
Definition may vary among trials
Requires frequent radiologic or other assessments
Requires balanced timing of assessment among treatment arms
Time to Progression (TTP) Time from randomization* until objective disease progression; does not include deaths
Time to Treatment Failure (TTF) Time from randomization* until objective disease progression; does not include deaths. Useful in settings in which toxicity is potentially as serious as disease progression (e.g., allogeneic stem cell transplant) Does not adequately distinguish efficacy from other variables, such as toxicity
Time to Next Treatment (TTNT) Time from end of primary treatment to institution of next therapy For incurable diseases, may provide an endpoint meaningful to patients Not commonly used as a primary endpointSubject to variability in practice patterns
Event-Free Survival (EPS) Time from randomization* to disease progression, death, or discontinuation of treatment for any reason (e.g. toxicity, patient preference, or initiation, of a new treatment without documented progression) Similar to PFS; may be useful in evaluation of highly toxic therapies Initiation of next therapy is subjective. Generally not encouraged by regulatory agencies because it combines efficacy, toxicity, and patient withdrawal
Time to Next Treatment (TTNT) Time from end of primary treatment to institution of next therapy For incurable diseases, may provide an endpoint meaningful to patients Not commonly used as a primary endpoint
Subject to variability in practice patterns
Overall response rate (ORR) Proportion of patients with reduction in disease burden of a predefined amount Can be assessed in single-arm trials
Requires a smaller population and can be assessed earlier compared with survival trials
Effect is attributable directly to the drug, not the natural history of the disease
Not a comprehensive measure of drug activity
Duration of Response (DoR) Time from documentation of disease response to disease progression
(Quality Of Life - QOL) Symptoms Reported by Patients Outcome self-reported by patients using wellness scales, presence of adverse effects and toxicity therapeutic Patient perspective of direct clinical benefit. Reporting sometimes incomplete
Small symptoms and signs of difficult to assess Few validated instruments Sometimes patients do not report accurately the effects adverse
Toxicity Rate of adverse effects Definition of the benefit/risk balance of therapy Sometimes patients do not report accurately the effects adverse
Other Common Endpoints Response rate (RR)Response rate measures disease size, usually using a scan or X-ray. Complete response (CR) Disappearance of all clinical evidence of disease. Partial response (PR)
At least 30% reduction in size of all measureable
Stable disease (SD) or No change (NC) Between a 30% reduction or <25% increase in the size of all detectable disease Progressive disease (PD)Patients or proportion of patients with a = 25% increase in size of disease since previous measurement Objective response rate (ORR)Percentage of patients whose disease decreased (Partial response – PR) and/or disappears (Complete response – CR) after treatment.
Disease control rate (DCR) or clinical benefit rate (CBR) Percentage of patients whose disease shrinks or remains stable over a certain time period. DCR is the sum of the complete, partial and stable disease rates. Duration of response (DR)Time from confirmation of a partial response (PR), complete response (CR) or stable disease (SD), until the disease has been shown to progress following treatment (progressive disease or PD). Performance status (PS) Measure of how well a patient with a disease diagnosis can perform ordinary tasks in daily life before, during or after treatment. Specific numeric PS scales indicate levels of disability due to disease, and/or severity of symptoms. Two main scales are.

Table 2: Outcomes in major clinical trials. *Not all trials are randomized. In nonrandomized trials, time from study enrolment is commonly used.

References

Citation: Roever L (2016) Endpoints in Clinical Trials: Advantages and Limitations. Evidence Based Medicine and Practice 1:e111. Doi: 10.4172/2471-9919.1000e111

Copyright: © 2016 Roever L. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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