Clinical trial endpoints
A clinical trial’s endpoints measure the outcomes in the trial. When a trial evaluates the efficacy of a new medical product or a new use for an approved product, investigators may choose endpoints that directly measure the clinical outcome they want to study. Clinical outcomes directly measure whether people in a trial feel or function better or live longer (survival). (https://www.fda.gov/drugs/developme...point-resources-drug-and-biologic-development)
Clinical endpoints are used in clinical trials to assess validity and generalizability of the study, and the evidence they generate is important to clinicians and patients alike. Clinical endpoints also have the capacity to evaluate the outcomes of using a medical intervention to guide clinical decision making. When addressing potential treatment options with a patient, physicians look for interventions that will improve survival, reduce symptoms, restore functional capacity, or lower the chances of developing a chronic condition. These desirable effects are weighed against any negative side effects or assumed risks. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085844/)
Generally, clinical endpoints can be classified as primary, secondary, or tertiary depending on their relevance to the main research question. While primary endpoints are efficacy measures that address the question directly, secondary and tertiary endpoints may be utilized to demonstrate additional effects, support a mechanism of action, or explore less frequently occurring outcomes. For example, a primary endpoint in oncological clinical trials is usually survival: a direct, measurable outcome based on the drug’s expected effects. A secondary endpoint, such as quality of life, may be chosen to explore additional benefit the patient may gain including functional and emotional status. All other exploratory endpoints would be classified as tertiary endpoints. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085844/)
All drugs have safety risks. Therefore, the only reason that a patient would want to take a drug would be if the drug: – improved survival – resulted in a benefit that was detectable by the patient (improvement in symptoms, improvement in functional capacity), or – decreased the chances of developing a condition or disease complication that is itself apparent to the patient and is undesirable (e.g. stroke) (https://www.fda.gov/media/84987/download)
Surrogate Endpoints
A surrogate endpoint is a measure of success in a clinical trial. It is used in place of a primary endpoint to speed up approval process or prove that a drug appears to be working. For example, let’s say a new drug is tested to see if it reduces risk of death from diabetes. The drug appears to reduce high blood sugar, but it will take several years to gather mortality data. Reduced blood sugar is then used as a surrogate endpoint instead of the primary endpoint of reduction in number of deaths from diabetes — a figure which could take many years to calculate. Surrogates are often used because they are cheaper or easier to measure but are weaker than stronger indicators like survival time. (https://www.statisticshowto.com/primary-endpoint/)
Clinical trials also frequently rely on the utilization of surrogate endpoints to substitute for clinical endpoints. In the classical definition of surrogate endpoints, they are referred to as “biomarkers”, however, not all biomarkers will meet the criteria to be surrogate endpoints. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085844/)
A biomarker is a defined characteristic that is objectively measured as an indicator of normal biological processes, pathologic processes, or responses to an exposure or intervention, including therapeutic interventions. In a drug development context, biomarkers may be used for several different purposes such as identifying patients for clinical trial enrollment, monitoring the safety of a therapy, or finding out if a treatment is having the desired effect on the body. (https://www.fda.gov/drugs/developme...point-resources-drug-and-biologic-development)
In order for a biomarker to be considered a surrogate endpoint, there must be a relationship between the biomarker and the clinical outcome; a mere association between the biomarker and the pathophysiology of the disease is not sufficient. If general information about the disease pathophysiology and the intervention’s mechanism of action, surrogate endpoints are expected to predict clinical benefit or harm. While surrogate endpoints have historically been used to rapidly assess medical interventions in clinical trials, they do not have strict validation criteria. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085844/)
All-Cause Mortality
Anything that causes death is considered to be a "cause of death." Therefore, all-cause mortality is any cause of death.
While mortality can be random, patterns can often be found that result from particular behaviors. Many longitudinal studies aim to assess which risk factors lead to specific illnesses such as heart disease or cancer. A risk factor is a condition or behavior that is known to increase vulnerability to a particular disease or outcome. For instance, smoking cigarettes is a major risk factor. That behavior increases your chances of cancer and other serious conditions, which in turn could lead to death. (https://www.verywellhealth.com/what-is-all-cause-mortality-2223349) & (https://www.ncbi.nlm.nih.gov/books/NBK294300/)
My understanding: An All-Cause Morbidity study is the most ideal study as is a good measure of the effectiveness of a drug. If a drug generally reduces your chances of death, given the prevailing circumstance then it’s a good drug. For example, during the pandemic, everyone is at a higher risk of death. If a drug reduces your chances of death either from the disease or from the other ailments that may strike you as a result of catching the disease, then it’s the best drug. This is the same as if a smoker stops smoking then generally, he has better health (in the long run) than a continuing smoker and the chances of death from any cause are lower compared to those of a smoker (holding some factors constant, such as the effects of prior smoking experience).
What does this all mean from my understanding?
A clinical trial’s endpoints measure the outcomes in the trial. When a trial evaluates the efficacy of a new medical product or a new use for an approved product, investigators may choose endpoints that directly measure the clinical outcome they want to study. Clinical outcomes directly measure whether people in a trial feel or function better or live longer (survival). (https://www.fda.gov/drugs/developme...point-resources-drug-and-biologic-development)
Clinical endpoints are used in clinical trials to assess validity and generalizability of the study, and the evidence they generate is important to clinicians and patients alike. Clinical endpoints also have the capacity to evaluate the outcomes of using a medical intervention to guide clinical decision making. When addressing potential treatment options with a patient, physicians look for interventions that will improve survival, reduce symptoms, restore functional capacity, or lower the chances of developing a chronic condition. These desirable effects are weighed against any negative side effects or assumed risks. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085844/)
Generally, clinical endpoints can be classified as primary, secondary, or tertiary depending on their relevance to the main research question. While primary endpoints are efficacy measures that address the question directly, secondary and tertiary endpoints may be utilized to demonstrate additional effects, support a mechanism of action, or explore less frequently occurring outcomes. For example, a primary endpoint in oncological clinical trials is usually survival: a direct, measurable outcome based on the drug’s expected effects. A secondary endpoint, such as quality of life, may be chosen to explore additional benefit the patient may gain including functional and emotional status. All other exploratory endpoints would be classified as tertiary endpoints. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085844/)
All drugs have safety risks. Therefore, the only reason that a patient would want to take a drug would be if the drug: – improved survival – resulted in a benefit that was detectable by the patient (improvement in symptoms, improvement in functional capacity), or – decreased the chances of developing a condition or disease complication that is itself apparent to the patient and is undesirable (e.g. stroke) (https://www.fda.gov/media/84987/download)
Surrogate Endpoints
A surrogate endpoint is a measure of success in a clinical trial. It is used in place of a primary endpoint to speed up approval process or prove that a drug appears to be working. For example, let’s say a new drug is tested to see if it reduces risk of death from diabetes. The drug appears to reduce high blood sugar, but it will take several years to gather mortality data. Reduced blood sugar is then used as a surrogate endpoint instead of the primary endpoint of reduction in number of deaths from diabetes — a figure which could take many years to calculate. Surrogates are often used because they are cheaper or easier to measure but are weaker than stronger indicators like survival time. (https://www.statisticshowto.com/primary-endpoint/)
Clinical trials also frequently rely on the utilization of surrogate endpoints to substitute for clinical endpoints. In the classical definition of surrogate endpoints, they are referred to as “biomarkers”, however, not all biomarkers will meet the criteria to be surrogate endpoints. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085844/)
A biomarker is a defined characteristic that is objectively measured as an indicator of normal biological processes, pathologic processes, or responses to an exposure or intervention, including therapeutic interventions. In a drug development context, biomarkers may be used for several different purposes such as identifying patients for clinical trial enrollment, monitoring the safety of a therapy, or finding out if a treatment is having the desired effect on the body. (https://www.fda.gov/drugs/developme...point-resources-drug-and-biologic-development)
In order for a biomarker to be considered a surrogate endpoint, there must be a relationship between the biomarker and the clinical outcome; a mere association between the biomarker and the pathophysiology of the disease is not sufficient. If general information about the disease pathophysiology and the intervention’s mechanism of action, surrogate endpoints are expected to predict clinical benefit or harm. While surrogate endpoints have historically been used to rapidly assess medical interventions in clinical trials, they do not have strict validation criteria. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085844/)
All-Cause Mortality
Anything that causes death is considered to be a "cause of death." Therefore, all-cause mortality is any cause of death.
While mortality can be random, patterns can often be found that result from particular behaviors. Many longitudinal studies aim to assess which risk factors lead to specific illnesses such as heart disease or cancer. A risk factor is a condition or behavior that is known to increase vulnerability to a particular disease or outcome. For instance, smoking cigarettes is a major risk factor. That behavior increases your chances of cancer and other serious conditions, which in turn could lead to death. (https://www.verywellhealth.com/what-is-all-cause-mortality-2223349) & (https://www.ncbi.nlm.nih.gov/books/NBK294300/)
My understanding: An All-Cause Morbidity study is the most ideal study as is a good measure of the effectiveness of a drug. If a drug generally reduces your chances of death, given the prevailing circumstance then it’s a good drug. For example, during the pandemic, everyone is at a higher risk of death. If a drug reduces your chances of death either from the disease or from the other ailments that may strike you as a result of catching the disease, then it’s the best drug. This is the same as if a smoker stops smoking then generally, he has better health (in the long run) than a continuing smoker and the chances of death from any cause are lower compared to those of a smoker (holding some factors constant, such as the effects of prior smoking experience).
What does this all mean from my understanding?
- Drugs developed and tested based on direct clinical trial endpoints are the best. i.e. if a drug is designed to reduce Diabetes and the tests done tested the reduction of death from diabetes, then this is the best drug as it has tested the most critical endpoint.
- Drugs developed and tested based on surrogate endpoints may not be the most reliable as the direct endpoint has not been tested. For example, High Density Lipoproteins (HDL) can be considered a reliable surrogate endpoint for the risk of cardiovascular diseases. However, a drug that increases the HDL levels in the body may not necessarily be a good drug in preventing cardiovascular disease. This is because while it might reduce cardiovascular disease, it may increase other risks such as increased risk of ischemic stroke, worsened glycemic control amongst diabetics, increased incidence of diabetes, serious bleeding complications and trend toward increased risk of death (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829575/)
- Drugs developed and tested based on overall survival should be the very best. They measure the time from randomization/use of drug until death from any cause. This type of testing essentially answers the question of whether you are better off after taking the drug than that other person who didn’t take the drug. However, for drug development, this is difficult and costly to achieve as it requires a loooot of time (people’s lifetimes basically).