Clinical trials of drugs from the viewpoint of the Food and Drug Administration
J. Richard Crout, M.D.
Clinical trials are an essential feature of modem therapeutic research. No matter how much we know of structure-function relationships, no matter how extensively we study drugs in the test tube or in animals, the ultimate evaluation of safety, effectiveness, and therapeutic value must be conducted in those who need the drug, i.e., in patients who have, or are at risk of developing, a particular disease. The term clinical trial is the name we give to a disciplined, organized research study conducted in humans, which is intended to shed light on the drug as a therapeutic agent. A particularly important type of clinical trial is the controlled trial. Such trials include some mechanism for comparing the effect of the drug with another treatment or with no treatment. The purpose of this exercise (assuming the trial is properly designed, executed, and analyzed) is to permit the investigator to make a credible, probabilistic statement as to whether the findings in the drug-treated patients can be attributed to the drug. This scientific strength of the controlled clinical trial is, of course, the reason for its importance. Interestingly, the controlled trial is one of the few scientific techniques mandated by Congress, as a standard for the determination of safety and effectiveness in the Food, Drug and Cosmetic Act. I think it is fair to say that the principles of Reprint requests to: J. Richard Crout. M.D .. Director. Bureau of Drugs. Food and Drug Administration. Rockville. Md. 20852.
634
the design and analysis of controlled clinical trials are well known and widely accepted. Since the time of Eve and the serpent, man has known that appearances may deceive. Since the time of the voyage of Captain Cook, the essential elements of the design of a controlled trial have been understood. For several decades, statistical methods for analyzing all but the most complex clinical trials have been available. Clinical trials by the thousands have been conducted, and enormous gain in our knowledge and in human health has resulted. Why, then, do we need a workshop on clinical trials? If the principles are well known, what is the problem? In answer to these questions, I think we must acknowledge, regretfully, that all is not well. Something is happening, or perhaps many things are happening, that are unsettling to us all. The process seems not to be going as well as it might. We hear of the steadily increasing costs of clinical trials, with the implication that incremental costs are exceeding incremental gains in knowledge. We hear of investigators who cannot find patients because of overly stringent selection criteria in protocols for trial. We hear of sponsors who cannot find clinical investigators because the essential scientific discovery has already been made by someone else, often a European scientist. We hear of the increasing nonrelevance of drug trials to the practice of medicine, such lack of relevance deriving from too rigid pro-
Volume 18 Number 5, Part 2
Clinical trials of drugs-viewpoint of Food and Drug Administration
tocols, too narrow selection of patients, and unrealistic diagnosis criteria. We hear of prolonged review procedures and of studies dropped in quiet desperation, as the inertia of the system fails to yield even to enthusiasm. We hear of inadequate effort in developing new techniques for measuring drug effects as we cling to the "tried and true" in meeting regulatory requirements. We hear of serious gaps in our knowledge and yet of inadequate attempts to correct the problem. I refer particularly to studies of drugs in children, to trials of medically important drugs of limited commercial value, and to controlled trials of certain newly marketed drugs for specific important reasons. And, perhaps most importantly, we hear of increasing intellectual sterility, of dullness, of lack of challenge as a growing problem with controlled trials. We hear that the fundamental attraction of research-a sense of excitement over discovery-is in danger of being lost. In short, at the very time clinical trials are increasing in their sophistication and importance, we are being told that we are simply doing it more but enjoying it less. If these are some of our problems, what are the solutions? Again, a variety have been suggested. Some have suggested that we should abandon the controlled clinical trial as an appropriate scientific standard and rely instead in our judgments about drugs on the time-honored standard of the informed opinion of experts. Some have suggested that our current problems with clinical trials can be solved only by greater national commitment to the training and support of clinical pharmacologists and medical experts interested in therapeutics. Some have suggested that the current scene is not as sobering as I might have pictured it, and that all we need is greater judgment in interpreting the results of trials. One can, of course, only applaud a call for judgment, unless this call is really a plea for less-than-rigorous interpretation of results when it suits one's purpose. Some have suggested that current problems are caused by specific ogres who must be de-
635
molished. If only we could get rid of statisticians, or the FDA, or consumer groups, or Vice Presidents for Marketing, or congressional committees, then everything would be all right. Others have suggested the opposite: namely, that our problems stem not from the presence of ogres, but rather from the absence of good fairies. Thus, if we only had a National Institute for Drug Research, or department chairmen of medicine who cared about therapeutics, or a medical profession that cared about evidence, or no-fault insurance, or a Gilman proposal, then again everything else would be all right. Finally, some have recognized, and I count those here in this group, that there are no simple solutions. There is only a simple process for finding solutions, and that is for men and women of good will to sit down together, to identify problems, and then to work innovatively in search of answers. That is what this Workshop is for. The people at this Workshop are arranged into six panels, each dealing with an important aspect of drug research. Our purpose is to deal broadly with each topic. We should identify not only technical problems but also important issues in public policy-the financing of research, medical education, or what have youthat are worthy of attention. We should then pose solutions to the extent this is possible. The final report of this Workshop is intended to stimulate change where this is appropriate, just as it should reaffirm that which is good. Some examples of the questions I hope individual groups will address are as follows: What can be done to make drug research more attractive to university-based investigators and to universities as institutions? Is there really a medical need for normal volunteers in Phase I studies, or should more Phase I work be done in patients? For what specific purposes do we want a few patients studied well, and when do we want a large number studied less intensively; or can one generalize? Is our current emphasis on stringent criteria for patient selection realistic and proper? Again, are there some trials where this is important and others where it is less so?
636
Crout
Is the multiclinic trial really necessary or successful? Should we attempt to develop new techniques for data analysis or new statistical ground rules for pooling data that will obviate the need for such trials? What can we do to make Phase IV trials a practical reality? To what extent should the determination of blood levels of the drug become a routine part of drug trials, and what are the implications of measuring blood levels on dose titration and on classical approaches to blinding.
Clinical Pharmacology and Therapeutics
Many more such issues will be discussed before this Workshop is over. Dr. Gaffney has assembled a remarkable group of people heretalented, diverse in background, forthright enough to stimulate each other, but also publicspirited and comfortable enough as friends and colleagues to work together in common purpose. So let us bring new thought to the fundamental research tool of our discipline, the controlled clinical trial.
J. Richard Crout, M.D.
Clinical trials are an essential feature of modem therapeutic research. No matter how much we know of structure-function relationships, no matter how extensively we study drugs in the test tube or in animals, the ultimate evaluation of safety, effectiveness, and therapeutic value must be conducted in those who need the drug, i.e., in patients who have, or are at risk of developing, a particular disease. The term clinical trial is the name we give to a disciplined, organized research study conducted in humans, which is intended to shed light on the drug as a therapeutic agent. A particularly important type of clinical trial is the controlled trial. Such trials include some mechanism for comparing the effect of the drug with another treatment or with no treatment. The purpose of this exercise (assuming the trial is properly designed, executed, and analyzed) is to permit the investigator to make a credible, probabilistic statement as to whether the findings in the drug-treated patients can be attributed to the drug. This scientific strength of the controlled clinical trial is, of course, the reason for its importance. Interestingly, the controlled trial is one of the few scientific techniques mandated by Congress, as a standard for the determination of safety and effectiveness in the Food, Drug and Cosmetic Act. I think it is fair to say that the principles of Reprint requests to: J. Richard Crout. M.D .. Director. Bureau of Drugs. Food and Drug Administration. Rockville. Md. 20852.
634
the design and analysis of controlled clinical trials are well known and widely accepted. Since the time of Eve and the serpent, man has known that appearances may deceive. Since the time of the voyage of Captain Cook, the essential elements of the design of a controlled trial have been understood. For several decades, statistical methods for analyzing all but the most complex clinical trials have been available. Clinical trials by the thousands have been conducted, and enormous gain in our knowledge and in human health has resulted. Why, then, do we need a workshop on clinical trials? If the principles are well known, what is the problem? In answer to these questions, I think we must acknowledge, regretfully, that all is not well. Something is happening, or perhaps many things are happening, that are unsettling to us all. The process seems not to be going as well as it might. We hear of the steadily increasing costs of clinical trials, with the implication that incremental costs are exceeding incremental gains in knowledge. We hear of investigators who cannot find patients because of overly stringent selection criteria in protocols for trial. We hear of sponsors who cannot find clinical investigators because the essential scientific discovery has already been made by someone else, often a European scientist. We hear of the increasing nonrelevance of drug trials to the practice of medicine, such lack of relevance deriving from too rigid pro-
Volume 18 Number 5, Part 2
Clinical trials of drugs-viewpoint of Food and Drug Administration
tocols, too narrow selection of patients, and unrealistic diagnosis criteria. We hear of prolonged review procedures and of studies dropped in quiet desperation, as the inertia of the system fails to yield even to enthusiasm. We hear of inadequate effort in developing new techniques for measuring drug effects as we cling to the "tried and true" in meeting regulatory requirements. We hear of serious gaps in our knowledge and yet of inadequate attempts to correct the problem. I refer particularly to studies of drugs in children, to trials of medically important drugs of limited commercial value, and to controlled trials of certain newly marketed drugs for specific important reasons. And, perhaps most importantly, we hear of increasing intellectual sterility, of dullness, of lack of challenge as a growing problem with controlled trials. We hear that the fundamental attraction of research-a sense of excitement over discovery-is in danger of being lost. In short, at the very time clinical trials are increasing in their sophistication and importance, we are being told that we are simply doing it more but enjoying it less. If these are some of our problems, what are the solutions? Again, a variety have been suggested. Some have suggested that we should abandon the controlled clinical trial as an appropriate scientific standard and rely instead in our judgments about drugs on the time-honored standard of the informed opinion of experts. Some have suggested that our current problems with clinical trials can be solved only by greater national commitment to the training and support of clinical pharmacologists and medical experts interested in therapeutics. Some have suggested that the current scene is not as sobering as I might have pictured it, and that all we need is greater judgment in interpreting the results of trials. One can, of course, only applaud a call for judgment, unless this call is really a plea for less-than-rigorous interpretation of results when it suits one's purpose. Some have suggested that current problems are caused by specific ogres who must be de-
635
molished. If only we could get rid of statisticians, or the FDA, or consumer groups, or Vice Presidents for Marketing, or congressional committees, then everything would be all right. Others have suggested the opposite: namely, that our problems stem not from the presence of ogres, but rather from the absence of good fairies. Thus, if we only had a National Institute for Drug Research, or department chairmen of medicine who cared about therapeutics, or a medical profession that cared about evidence, or no-fault insurance, or a Gilman proposal, then again everything else would be all right. Finally, some have recognized, and I count those here in this group, that there are no simple solutions. There is only a simple process for finding solutions, and that is for men and women of good will to sit down together, to identify problems, and then to work innovatively in search of answers. That is what this Workshop is for. The people at this Workshop are arranged into six panels, each dealing with an important aspect of drug research. Our purpose is to deal broadly with each topic. We should identify not only technical problems but also important issues in public policy-the financing of research, medical education, or what have youthat are worthy of attention. We should then pose solutions to the extent this is possible. The final report of this Workshop is intended to stimulate change where this is appropriate, just as it should reaffirm that which is good. Some examples of the questions I hope individual groups will address are as follows: What can be done to make drug research more attractive to university-based investigators and to universities as institutions? Is there really a medical need for normal volunteers in Phase I studies, or should more Phase I work be done in patients? For what specific purposes do we want a few patients studied well, and when do we want a large number studied less intensively; or can one generalize? Is our current emphasis on stringent criteria for patient selection realistic and proper? Again, are there some trials where this is important and others where it is less so?
636
Crout
Is the multiclinic trial really necessary or successful? Should we attempt to develop new techniques for data analysis or new statistical ground rules for pooling data that will obviate the need for such trials? What can we do to make Phase IV trials a practical reality? To what extent should the determination of blood levels of the drug become a routine part of drug trials, and what are the implications of measuring blood levels on dose titration and on classical approaches to blinding.
Clinical Pharmacology and Therapeutics
Many more such issues will be discussed before this Workshop is over. Dr. Gaffney has assembled a remarkable group of people heretalented, diverse in background, forthright enough to stimulate each other, but also publicspirited and comfortable enough as friends and colleagues to work together in common purpose. So let us bring new thought to the fundamental research tool of our discipline, the controlled clinical trial.
