Moving Targets in Clinical Trials

There is mounting frustration for both clinical trialists and the pharmaceutical industry with the difficulty of moving clinical trial results to patient care. Over the past 10 years, there has been a paucity of new cardiac drugs approved by the Food and Drug Administration. This drought follows a flood of drugs that came into clinical care in the previous 2 decades.

The increasing difficulty and expense of carrying out clinical trials in the United States has led to reliance on patient recruitment in Eastern Europe and Asia.

As a result, a number of the large pharmaceutical companies have withdrawn from the development of new cardiac drugs and have moved to other more fertile disease systems. At the same time, because of the current economic environment, it has been difficult to obtain venture capital funding to initiate studies of new drugs.

Nevertheless, some areas that remain “hot” targets of cardiovascular disease are receiving continued interest and support by Big Pharma. This has been particularly true in acute coronary syndromes: Although long-term mortality rates have changed dramatically, new interventional procedures and change in diagnostic criteria have provided a ready supply of patients available for recruitment.

The area of heart failure, where the 60-day mortality rate for hospitalized patients exceeds 25% in spite of advances with ACE inhibitors and beta-blockers, has also been an appealing target of research.

Although the interest in these areas is welcome, it raises some interesting issues for the clinician when interpreting the results of intervention.

In acute coronary syndromes, for which a decrease in mortality had been the major therapeutic target, mortality now represents less than 25% of all combined events in some clinical trials. As mortality became a smaller part of the end point measurement, troponin-defined reinfarction increased in both statistical and clinical significance. As we all know, reinfarction is subject to significant variation and interpretation as more sensitive biomarkers reflect smaller degrees of infarction which may be of questionable clinical importance.

The clinical relevance of reinfarction has come into special prominence as we develop more potent antithrombotic and antiplatelet agents that are associated with an increased potential for major bleeding. The benefit of achieving this combined end point, dominated by myocardial infarction determined using a biomarker, weighed against the potential of increased bleeding risk, is less obvious.

The investigation of new drugs for the treatment of heart failure, particularly in an aging population, has resulted in a search for relevant measures that truly impact a patient's life. In addition to mortality, rehospitalization is the most commonly-used measure of therapeutic success, reflecting both the clinical and economic burdens of the disease.

In young heart failure patients, subsequent hospitalization could result from a cardiac event. But as our population ages and we apply new therapies to older patients, total hospitalization has become much more heterogeneous. Rehospitalization in octogenarians, who increasingly dominate our heart failure population, may have different implications. The readmissions may be a result of noncardiac concerns such as cancer, pulmonary disease, trauma, or debilitating neurologic events.

In addition, the increasing reliance on patients from Eastern Europe and Asia to participate in clinical trials, because of economic and legal restrictions, has made the use of rehospitalization a less certain end point when applying trial results to Western Europe and North America.

The increased reliance upon these patients in both heart failure and ACS trials has become a necessity for sufficient recruitment. A recent analysis of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial revealed considerable baseline and mortality differences between patients randomized in Eastern Europe and those participants from the United States and Western Europe (J. Am. Coll. Cardiol. 2008;52:1640-8).

All of these issues have challenged designers of clinical trials to create a study that is relevant to local societal requirements. The world has not become so flat that studies in India and China can have complete relevancy to Americans when we stray from hard core end points such as mortality.

There is mounting frustration for both clinical trialists and the pharmaceutical industry with the difficulty of moving clinical trial results to patient care. Over the past 10 years, there has been a paucity of new cardiac drugs approved by the Food and Drug Administration. This drought follows a flood of drugs that came into clinical care in the previous 2 decades.

The increasing difficulty and expense of carrying out clinical trials in the United States has led to reliance on patient recruitment in Eastern Europe and Asia.

As a result, a number of the large pharmaceutical companies have withdrawn from the development of new cardiac drugs and have moved to other more fertile disease systems. At the same time, because of the current economic environment, it has been difficult to obtain venture capital funding to initiate studies of new drugs.

Nevertheless, some areas that remain “hot” targets of cardiovascular disease are receiving continued interest and support by Big Pharma. This has been particularly true in acute coronary syndromes: Although long-term mortality rates have changed dramatically, new interventional procedures and change in diagnostic criteria have provided a ready supply of patients available for recruitment.

The area of heart failure, where the 60-day mortality rate for hospitalized patients exceeds 25% in spite of advances with ACE inhibitors and beta-blockers, has also been an appealing target of research.

Although the interest in these areas is welcome, it raises some interesting issues for the clinician when interpreting the results of intervention.

In acute coronary syndromes, for which a decrease in mortality had been the major therapeutic target, mortality now represents less than 25% of all combined events in some clinical trials. As mortality became a smaller part of the end point measurement, troponin-defined reinfarction increased in both statistical and clinical significance. As we all know, reinfarction is subject to significant variation and interpretation as more sensitive biomarkers reflect smaller degrees of infarction which may be of questionable clinical importance.

The clinical relevance of reinfarction has come into special prominence as we develop more potent antithrombotic and antiplatelet agents that are associated with an increased potential for major bleeding. The benefit of achieving this combined end point, dominated by myocardial infarction determined using a biomarker, weighed against the potential of increased bleeding risk, is less obvious.

The investigation of new drugs for the treatment of heart failure, particularly in an aging population, has resulted in a search for relevant measures that truly impact a patient's life. In addition to mortality, rehospitalization is the most commonly-used measure of therapeutic success, reflecting both the clinical and economic burdens of the disease.

In young heart failure patients, subsequent hospitalization could result from a cardiac event. But as our population ages and we apply new therapies to older patients, total hospitalization has become much more heterogeneous. Rehospitalization in octogenarians, who increasingly dominate our heart failure population, may have different implications. The readmissions may be a result of noncardiac concerns such as cancer, pulmonary disease, trauma, or debilitating neurologic events.

In addition, the increasing reliance on patients from Eastern Europe and Asia to participate in clinical trials, because of economic and legal restrictions, has made the use of rehospitalization a less certain end point when applying trial results to Western Europe and North America.

The increased reliance upon these patients in both heart failure and ACS trials has become a necessity for sufficient recruitment. A recent analysis of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial revealed considerable baseline and mortality differences between patients randomized in Eastern Europe and those participants from the United States and Western Europe (J. Am. Coll. Cardiol. 2008;52:1640-8).

All of these issues have challenged designers of clinical trials to create a study that is relevant to local societal requirements. The world has not become so flat that studies in India and China can have complete relevancy to Americans when we stray from hard core end points such as mortality.

There is mounting frustration for both clinical trialists and the pharmaceutical industry with the difficulty of moving clinical trial results to patient care. Over the past 10 years, there has been a paucity of new cardiac drugs approved by the Food and Drug Administration. This drought follows a flood of drugs that came into clinical care in the previous 2 decades.

The increasing difficulty and expense of carrying out clinical trials in the United States has led to reliance on patient recruitment in Eastern Europe and Asia.

As a result, a number of the large pharmaceutical companies have withdrawn from the development of new cardiac drugs and have moved to other more fertile disease systems. At the same time, because of the current economic environment, it has been difficult to obtain venture capital funding to initiate studies of new drugs.

Nevertheless, some areas that remain “hot” targets of cardiovascular disease are receiving continued interest and support by Big Pharma. This has been particularly true in acute coronary syndromes: Although long-term mortality rates have changed dramatically, new interventional procedures and change in diagnostic criteria have provided a ready supply of patients available for recruitment.

The area of heart failure, where the 60-day mortality rate for hospitalized patients exceeds 25% in spite of advances with ACE inhibitors and beta-blockers, has also been an appealing target of research.

Although the interest in these areas is welcome, it raises some interesting issues for the clinician when interpreting the results of intervention.

In acute coronary syndromes, for which a decrease in mortality had been the major therapeutic target, mortality now represents less than 25% of all combined events in some clinical trials. As mortality became a smaller part of the end point measurement, troponin-defined reinfarction increased in both statistical and clinical significance. As we all know, reinfarction is subject to significant variation and interpretation as more sensitive biomarkers reflect smaller degrees of infarction which may be of questionable clinical importance.

The clinical relevance of reinfarction has come into special prominence as we develop more potent antithrombotic and antiplatelet agents that are associated with an increased potential for major bleeding. The benefit of achieving this combined end point, dominated by myocardial infarction determined using a biomarker, weighed against the potential of increased bleeding risk, is less obvious.

The investigation of new drugs for the treatment of heart failure, particularly in an aging population, has resulted in a search for relevant measures that truly impact a patient's life. In addition to mortality, rehospitalization is the most commonly-used measure of therapeutic success, reflecting both the clinical and economic burdens of the disease.

In young heart failure patients, subsequent hospitalization could result from a cardiac event. But as our population ages and we apply new therapies to older patients, total hospitalization has become much more heterogeneous. Rehospitalization in octogenarians, who increasingly dominate our heart failure population, may have different implications. The readmissions may be a result of noncardiac concerns such as cancer, pulmonary disease, trauma, or debilitating neurologic events.

In addition, the increasing reliance on patients from Eastern Europe and Asia to participate in clinical trials, because of economic and legal restrictions, has made the use of rehospitalization a less certain end point when applying trial results to Western Europe and North America.

The increased reliance upon these patients in both heart failure and ACS trials has become a necessity for sufficient recruitment. A recent analysis of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial revealed considerable baseline and mortality differences between patients randomized in Eastern Europe and those participants from the United States and Western Europe (J. Am. Coll. Cardiol. 2008;52:1640-8).

All of these issues have challenged designers of clinical trials to create a study that is relevant to local societal requirements. The world has not become so flat that studies in India and China can have complete relevancy to Americans when we stray from hard core end points such as mortality.