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Cardiovascular Drug Development: Protocol Design and Methodology
BOOK REVIEW Cardiovascular Drug Development: Protocol Design and Methodology, edited by Jeffrey S. Borer and John C. Somberg, Marcel Dekker, Inc., New York, 1999, 248 pages, ISBN: 0-8-2471927-1, $130.00 (hardback) For almost 20 years the authors have organized an annual symposium entitled “Advances in Cardiovascular Pharmacology: Protocol Design and Methodology.” This symposium has involved members of the regulatory community, the pharmaceutical industry, as well as leading academic investigators. Since 1990 they have added a second annual symposium that addresses international drug development issues. The current book represents a compilation from symposia conducted in the United States and abroad between 1996 and 1997. The structure of the book follows the format for the symposium. Brief formal presentations are made followed by panel discussions. These have been edited by the authors. The book starts with an overview of drug discovery and development by Dr. John Somberg. The historical perspective is excellent and illustrates the development of pharmaceutical research and development over the past century. In particular there is a nice discussion of the evolution of biotechnology and genetic therapies that presage future developments in the industry. However, like most of the rest of the book this discussion suffers from a lack of tables and graphics, and a paucity of references. Following this initial introduction the book is divided into sections covering development of drugs for congestive heart failure (CHF), antihypertensive therapy, antiarrhythmic therapy, antilipid therapy, and anti-ischemic therapy. The section on CHF therapy was presented by Drs. Jeffrey Borer and John Somberg with a chapter on CHF trial design by Dr. Raymond Lipicky of the Cardio-Renal Division of the Food and Drug Administration (FDA). Dr. Borer provides insight into the challenges faced by pharmaceutical companies in developing new agents for CHF given the need to show efficacy against standard treatment. Although the chapter is poorly organized, Table 1 does summarize strategies for the development of new CHF drugs. Dr. Lipicky discusses the problems with developing CHF drugs in regards to effect on symptomatic relief and survival. He points out the difficulty in determining appropriate outcomes to measure, e.g., exercise tolerance, quality of life, symptoms, morbidity and mortality. He states that for re-hospitalization the clearest endpoint is “all-cause” hospitalizations, which removes any ambiguity. In the chapter on angiotensin-converting enzyme inhibitors (ACE-I), the authors provide a summary of the major trials conducted in this field. The authors state that the pharmacologic and clinical effects on the different ACE-I vary, and thus “it precludes one from generalizing the mortality effects among ACE-I.” Although this may be true, the authors fail to mention that there Controlled Clinical Trials 21:140–143 (2000) Elsevier Science Inc. 2000 655 Avenue of the Americas, New York, NY 10010
0197-2456/00/$–see front matter
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was a meta-analysis [1] that suggested there was a “class effect” of ACE-I on mortality. Finally, the majority of the discussion was spent on intravenous formulation for CHF when, from a pharmaceutical perspective, the design of clinical trials for approval of an oral formulation are more challenging and of greater interest. The section on development of antihypertensive therapy begins with Dr. Lipicky justifying the use of blood pressure lowering as a surrogate for clinical efficacy, citing the “. . . many placebo controlled clinical trials that measured morbidity and mortality and involved many different specific drugs, dosing regimens and combination therapies over many pharmacological classes . . .” as the basis for this surrogate. References for these studies would have been useful given the lack of morbidity and mortality data for several currently approved antihypertensive agents. Dr. Lipicky then outlines a very streamlined development program for antihypertensive therapy. His presentation is logical and well organized. He recommends foregoing the traditional phases of drug development and sketches the designs of two trials, which would be sufficient for establishing efficacy and dosing. He stresses that approximately 2000 patients should be studied in randomized controls trials to adequately characterize the safety profile of a new chemical entity. Furthermore, the development program should no longer focus on whether the drug has a greater antihypertensive effect than placebo but rather address the following issues: dose response and how it might be affected by other medication, age, sex, and race; time-action relationships; pharmacodynamics; pharmacokinetics; and the relationship of the severity of hypertension to the response to the drug. He concludes with a discussion of two ongoing agency efforts. One is to address concerns over the use of shortterm placebo controlled trials in antihypertensive programs. The other is to investigate, among other things, the magnitude of placebo effect observed in ambulatory blood pressure monitoring (ABPM). Dr. Borer’s presentation of safety issues surrounding the use of calcium channel blockers summarizes the current controversy. He begins with a discussion of the pitfalls encountered with observational studies and meta-analysis. He then presents the results of a number of studies for each of the classes of calcium channel blocking agents. Owing to the differing patient populations, diseases, and durations of action of the drugs used in the studies discussed, it is difficult to follow Dr. Borer’s conclusions. Fortunately, these are summarized at the conclusion of the chapter, although the strength of these conclusions is questionable. As with the rest of the text, references would have been helpful. The section on antihypertensive drug development concludes with a panel discussion moderated by Dr. Borer. This rapidly turns into a debate over the definition and treatment of hypertensive emergencies and urgencies. There ensues a discussion of the feasibility of designing a hypertensive urgency study and the resulting labeling. Given the scope of the preceding chapters, this topic seemed overemphasized and out of place. Further labeling discussions include whether a mortality/morbidity benefit was established, categorizing drugs according to their metabolism, and whether ABPM data could serve as a basis for approval. On the whole, the discussions focus too much on the debate over obtaining labeling for treatment of severe hypertension, whereas further
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discussion regarding the implementation of the antihypertensive development plan outlined by Dr. Lipicky would have benefitted a wider audience. The section on antilipid therapy was presented by Dr. David Orloff of the Metabolic and Endocrine Drug Products division of the FDA. Dr. Orloff’s formal presentation provides a review of the major recent statin trials. There are two tables supplied that have minimal information. The remainder of the chapter reviews some of the side effect and safety issues with statin therapy. Toward the end he raises the issue of whether there is a class effect with all statin agents but does not go into any discussion of the implications of this for competitive drug development. At the conclusion of his presentation he comments on the difficulty of studying new statins and other lipid-lowering therapies but provides no insights for future trial development, deferring to the panel discussion. This is disappointing given that the intent of the book is to cover protocol design and methodology. The review of cardiovascular drug development and trial methodology presented by Dr. Lipicky is a standout, with an excellent description of the development of anti-anginal agents. In particular, he emphasizes the importance of demonstrating increases in exercise duration and explains that evaluation of symptom relief is a soft endpoint. He points out the need for placebo-controlled studies and indicates that mortality is a non-issue because these are not trials of acute coronary syndromes. Unfortunately, there is no discussion of the development of agents for treatment of acute coronary syndromes; this would have been a timely topic. Dr. Fredd provides a discussion on antiplatelet therapy including fibrinogen receptor (GPIIb/IIIa) antagonists and adenosine diphosphate (ADP) receptor antagonists. However the coverage of acute coronary syndrome trial design methodology as well as coronary interventional trial methodology is almost nonexistent. There is also a brief discussion of “putative placebo” trial design. However, this was not explained in any satisfactory detail. Following the chapters on antilipid, anti-ischemic, and antiplatelet therapy there is the panel discussion. One would think that the panel discussion would start off addressing issues presented by the panel participants in their formal presentations. Instead there is an extensive discussion of the potential importance of silent ischemia in designing trials for treatment of symptomatic angina. This is an interesting discussion but appears out of place given the earlier topics covered. A discussion of thrombolytic agents and placebo controls follows. Finally issues of equivalence and “putative placebo” methodologies are covered. However, these important issues are given only minimal discussion, which does not help improve the readers’ understanding of these vital areas of trial design. Furthermore, there is minimal global perspective, not surprising because all but one of the panel participants is a U.S. investigator or a member of the FDA. Although the concept of the book is intriguing, overall the coverage of trial design and methodology is erratic and poorly organized. It would have been more effective to edit the panel discussions to follow each chapter, with the panel discussions addressing the issues raised in the formal presentations. In addition, the paucity of tables, graphics, and references makes for tedious reading. Finally, it should be noted that the participants do not represent a global perspective. For example, in addition to the two authors there are four
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panel members from the U.S. FDA but only one member from the Medicines Control Agency of the United Kingdom. In the introduction the authors add the disclaimer that this book was not intended to be an encyclopedic review of cardiovascular drug development. Unfortunately, except for a few highlights, the book does not live up to its promise of giving even an overview of cardiovascular drug development. REFERENCE 1. Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:1450–1456.
Paul R. Eisenberg, M.D., M.P.H. Medical Director, Cardiovascular Therapeutic Area and Rekha Garg, M.D., Matthew D. Rotelli, Ph.D., Kenneth J. Winters, M.D. Lilly Research Laboratories Indianapolis, Indiana PII S0197-2456(99)00055-0
0197-2456/00/$–see front matter
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was a meta-analysis [1] that suggested there was a “class effect” of ACE-I on mortality. Finally, the majority of the discussion was spent on intravenous formulation for CHF when, from a pharmaceutical perspective, the design of clinical trials for approval of an oral formulation are more challenging and of greater interest. The section on development of antihypertensive therapy begins with Dr. Lipicky justifying the use of blood pressure lowering as a surrogate for clinical efficacy, citing the “. . . many placebo controlled clinical trials that measured morbidity and mortality and involved many different specific drugs, dosing regimens and combination therapies over many pharmacological classes . . .” as the basis for this surrogate. References for these studies would have been useful given the lack of morbidity and mortality data for several currently approved antihypertensive agents. Dr. Lipicky then outlines a very streamlined development program for antihypertensive therapy. His presentation is logical and well organized. He recommends foregoing the traditional phases of drug development and sketches the designs of two trials, which would be sufficient for establishing efficacy and dosing. He stresses that approximately 2000 patients should be studied in randomized controls trials to adequately characterize the safety profile of a new chemical entity. Furthermore, the development program should no longer focus on whether the drug has a greater antihypertensive effect than placebo but rather address the following issues: dose response and how it might be affected by other medication, age, sex, and race; time-action relationships; pharmacodynamics; pharmacokinetics; and the relationship of the severity of hypertension to the response to the drug. He concludes with a discussion of two ongoing agency efforts. One is to address concerns over the use of shortterm placebo controlled trials in antihypertensive programs. The other is to investigate, among other things, the magnitude of placebo effect observed in ambulatory blood pressure monitoring (ABPM). Dr. Borer’s presentation of safety issues surrounding the use of calcium channel blockers summarizes the current controversy. He begins with a discussion of the pitfalls encountered with observational studies and meta-analysis. He then presents the results of a number of studies for each of the classes of calcium channel blocking agents. Owing to the differing patient populations, diseases, and durations of action of the drugs used in the studies discussed, it is difficult to follow Dr. Borer’s conclusions. Fortunately, these are summarized at the conclusion of the chapter, although the strength of these conclusions is questionable. As with the rest of the text, references would have been helpful. The section on antihypertensive drug development concludes with a panel discussion moderated by Dr. Borer. This rapidly turns into a debate over the definition and treatment of hypertensive emergencies and urgencies. There ensues a discussion of the feasibility of designing a hypertensive urgency study and the resulting labeling. Given the scope of the preceding chapters, this topic seemed overemphasized and out of place. Further labeling discussions include whether a mortality/morbidity benefit was established, categorizing drugs according to their metabolism, and whether ABPM data could serve as a basis for approval. On the whole, the discussions focus too much on the debate over obtaining labeling for treatment of severe hypertension, whereas further
142
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discussion regarding the implementation of the antihypertensive development plan outlined by Dr. Lipicky would have benefitted a wider audience. The section on antilipid therapy was presented by Dr. David Orloff of the Metabolic and Endocrine Drug Products division of the FDA. Dr. Orloff’s formal presentation provides a review of the major recent statin trials. There are two tables supplied that have minimal information. The remainder of the chapter reviews some of the side effect and safety issues with statin therapy. Toward the end he raises the issue of whether there is a class effect with all statin agents but does not go into any discussion of the implications of this for competitive drug development. At the conclusion of his presentation he comments on the difficulty of studying new statins and other lipid-lowering therapies but provides no insights for future trial development, deferring to the panel discussion. This is disappointing given that the intent of the book is to cover protocol design and methodology. The review of cardiovascular drug development and trial methodology presented by Dr. Lipicky is a standout, with an excellent description of the development of anti-anginal agents. In particular, he emphasizes the importance of demonstrating increases in exercise duration and explains that evaluation of symptom relief is a soft endpoint. He points out the need for placebo-controlled studies and indicates that mortality is a non-issue because these are not trials of acute coronary syndromes. Unfortunately, there is no discussion of the development of agents for treatment of acute coronary syndromes; this would have been a timely topic. Dr. Fredd provides a discussion on antiplatelet therapy including fibrinogen receptor (GPIIb/IIIa) antagonists and adenosine diphosphate (ADP) receptor antagonists. However the coverage of acute coronary syndrome trial design methodology as well as coronary interventional trial methodology is almost nonexistent. There is also a brief discussion of “putative placebo” trial design. However, this was not explained in any satisfactory detail. Following the chapters on antilipid, anti-ischemic, and antiplatelet therapy there is the panel discussion. One would think that the panel discussion would start off addressing issues presented by the panel participants in their formal presentations. Instead there is an extensive discussion of the potential importance of silent ischemia in designing trials for treatment of symptomatic angina. This is an interesting discussion but appears out of place given the earlier topics covered. A discussion of thrombolytic agents and placebo controls follows. Finally issues of equivalence and “putative placebo” methodologies are covered. However, these important issues are given only minimal discussion, which does not help improve the readers’ understanding of these vital areas of trial design. Furthermore, there is minimal global perspective, not surprising because all but one of the panel participants is a U.S. investigator or a member of the FDA. Although the concept of the book is intriguing, overall the coverage of trial design and methodology is erratic and poorly organized. It would have been more effective to edit the panel discussions to follow each chapter, with the panel discussions addressing the issues raised in the formal presentations. In addition, the paucity of tables, graphics, and references makes for tedious reading. Finally, it should be noted that the participants do not represent a global perspective. For example, in addition to the two authors there are four
Book Review
143
panel members from the U.S. FDA but only one member from the Medicines Control Agency of the United Kingdom. In the introduction the authors add the disclaimer that this book was not intended to be an encyclopedic review of cardiovascular drug development. Unfortunately, except for a few highlights, the book does not live up to its promise of giving even an overview of cardiovascular drug development. REFERENCE 1. Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:1450–1456.
Paul R. Eisenberg, M.D., M.P.H. Medical Director, Cardiovascular Therapeutic Area and Rekha Garg, M.D., Matthew D. Rotelli, Ph.D., Kenneth J. Winters, M.D. Lilly Research Laboratories Indianapolis, Indiana PII S0197-2456(99)00055-0