171
Consensus Conference on the Methodology of Clinical Trials of "Nootropics", Munieh, June 1989 Report ofthe Consensus Committee
Introduction
Performing c1inical trials to assess new psychotropic drugs has become increasingly difficult over the past years. They have become a political and an ethical problem in many countries, and the c1inician carrying out studies is confronted with a number of c1inical, methodological, administrative, and legal problems. Therefore it was considered necessary and useful to organize Consensus Conferences on the Methodology of Clincical Trials in Europe. The first Consensus Conference on the Methodology of Clinical Trials, which took place in Zurich from March 10 - 12, 1988, was devoted to antidepressants, and the final report was published in "Pharmacopsychiatry" in January 1989. The second Consensus Conference on the Methodology of Clinical Trials took place in Munich from June 28 to 30,1989, and was devoted to drugs intended to improve attention, cognition, and memory in patients suffering from symptoms of dementia. This means it was devoted to drugs that in different European countries are called 'cognition enhancing agents', 'antidementia drugs', or 'nootropics' in the broad sense. In the developed countries the prolongation of life caused by modem medicine has increased the prevalence of dementing disorders to a considerable degree. While the prevalence of dementia of the Alzheimer type (DAn is about I % in the general population, it is about 4 % among those over 65. Until now the primary cause remains unknown, the deficits are not reversible, and the course of the illness is long and devastating. These disorders have therefore become a major focus of public health considerations. The conference focussed on the following points: terminology and c1assification of nootropic drugs, value of animal models and preclinical human studies, problems of design and patient characteristics, assessment instruments and statistical analysis, administrative regulations, and ethical problems.
The meeting was organized in a similar way to its prodecessor in Zurich. Each session was moderated by an expert. A rapporteur kept the minutes ofthe discussion following each paper. The speakers were asked not to concentrate their reviews on points where there is general agreement. On the contrary, they were asked to report on open questions, unsolved problems, adverse opinions, factors of dispute. After all the papers had been presented, a Consensus Committee, consisting of the Organizing Committee and the National Advisors, prepared a draft ofthe results and conclusions ofthe conference. These were presented to all participants, and were followed by a general discussion. After the meeting a revised report, incorporating the results of the discussion, was prepared and sent to all members of the Consensus Committee for correction. The names of the active participants are given in the appendix. Administrative Regulations and Existing Guidelines
In Europe, administrative regulations concerning the approval of cognition enhancing drugs differ greatly from country to country. In Germany or Italy, for instance, many nootropic drugs are marketed for a rather broad indication, while in the United Kingdom, for example, they playa limited role. The increased scientific interest in dementia (especially dementia of the Alzheimer type) over the past few years has been accompanied by various attempts to standardize methodology. For example, specific guidelines exist for the evaluation of drugs in the elderly neuropsychiatric patient (demented and nondemented) (Note I), for the clinical evaluation of cerebrocirculatory and metabolism improvers (Japan, 1987, unpublished), and for the evaluation of drugs in Alzheimer's disease (Medical Research Council, United Kingdom, 1989, unpublished), to mention only a few. A committee of the European College of Neuropsychopharmacology (ECNP) is currently working on the question of European standards for c1inical trials; a back-
Note 1: Pharmacopsychiat. 12(1981),81 - 82; 14(1981),150 - 154, 190 - 194,217 - 222. Pharmacopsychiatry23(1990) 171 - 175 © Georg Thieme Verlag Stuttgart· N ew York
Received: Accepted:
20.11.1989 24. 11. 1989
Downloaded by: University of Iowa Libraries. Copyrighted material.
L. Amaducci, J. Angst, P. Hech. O. Henkert, J. Hruinvels, R. R. Engel, C. G. Gott/ries, H. Hippius, R. Levy, O. Lingjaerde, J. J. L6pez-Ibor Jr., J. M Orgogozo, C. Pul/, H. Saletu, K. D. Stoll, H. Woggon
Pharmacopsychiatry 23 (1990)
ground document for EC guidelines on "dinical trials of drugs intended for the treatment of pathological intellectual deficits in the elderly" has been published, and in lune 1989 the advisory board of the Food and Drug Administration (FDA) held a conference on antidementia drugs, where protocol requirements for typical phase-three studies were discussed. Terminology and Oassification
A drug can be dassified from a pharmacological point ofview (according to the main efTects of a drug, e. g., "hypnotic"), or from a dinical point ofview (according to the syndromes or disorders treated best by a drug, e. g., "antidepressant"). In the announcement of the Consensus Conference the term 'nootropics' was used to describe in short "drugs intended to improve attention, cognition, and memory in patients sufTering from symptoms of dementia". Thus the term 'nootropic' was used in its broad dinical sense. During the conference it was stated that there are some countries where the term is only used in its narrow or strictly pharmacological sense. The conference did not succeed in its search for another word for the clinical dass of 'nootropic' drugs, though many terms were named or coined (examples: antihypoxidotics, antidementics, psychoenergizers, psychosynchronizers) and many paraphrases exist (examples: cognition enhancing drugs, cognition activators, drugs for impaired brain functions in old age (a term used by the German health authority), drugs intended to treat pathologic intellectual deficit in the elderly (the term used currently by the EC commission». There was consensus that drugs belonging to the clinical dass of 'nootropics' may be dassified into various pharmacological types (cerebral vasodilators, psychostimulants, nootropics in the strict sense, etc.) or neurochemical types (e. g., neurotransmitters, neuropeptides). As most of these types are not exdusive, a multifactorial pharmacological dassification scheme would probably serve better in the future. In describing the possible dinical efTects of a drug there might be a difTerence between the acute efTects of a drug (i. e., improving behavior) and its chronic efTects (i. e., preventing deterioration ofbehavior). Animal Models
For the development of new therapeutic agents, biological models are helpful. Unfortunately, appropriate animal models for the largest group of dementias do not exist. There is as ofyet no known animal disease comparable to Alzheimer's disease in humans. Most animal models used so far try to produce astate of memory and/or behavioral impairment that should be either prevented or reversed by nootropic drugs. Examples are brain lesions, electroconvulsive shock, genetic models, hypoxia, drug-induced deficit models (e. g., scopolamine, benzodiazepines), and the use of aged animals. Passive avoidance has been used as a routine screening tool to find antiamnesic activities of new substances. The data indicate a special antiamnesic activity for some nootropic drugs that is not shown for other drug dasses, but the data are far from being unequivocally dear, and their relevance to dinical problems remains questionable.
L. Amaducci et al.
Other, more complex models appear to address more specifically memory-related functions. Among these, there are the radial maze (short-term of working memory), the Morris water maze (Iong-term spatial memory), and various models of delayed response in rats and monkeys (immediate memory). All these tasks show dear deficits with aging which suggests some degree of validity. Most of them are, however, very time-consuming and, as a consequence, have not been used frequently for drug evaluation. The results obtained, particularly in aged monkeys, suggest that presently available nootropic drugs have only slight and inconsistent effects. Some ofthe more general problems in this area are: (a) current models describe only disturbances of memory. not of any other cognitive function; (b) in a11 models, evaluation is hampered by the fact that no reference compound exists; (c) the predictive value of currently used tests is not known. Studies with Human Volunteers
The usual goal for Phase-I studies is to study how weil new drugs are tolerated in man and to establish their pharmacokinetics. To predict dinical efficacy in the field of nootropic drugs there has been a tendency to extend the scope of Phase-I studies to indude experimental psychometric studies with healthy volunteers. As in animal experiments, this is only possible when valid models exist. Examples of models used in the past are: subjects studied under hypoxia or under mentally strainful conditions (e. g., under heavy mental work load), drug-induced memory deficits (e. g., scopolamine), the use ofhealthy e1derly subjects with memory deficits, or the study of subjects with vigilance impairments in the electroencephalogram (EEG). If the models are valid, nootropic drugs should either improve the deficits if given subsequently or prevent them if given previously. Deficits are measured either behaviorally (for instance, the number ofwords, recalled in a memory task) or by other variables reflecting brain functions (for instance, the delta/theta power in the EEG). The EEG studies are able to give a general indication of the cerebral activity of a drug, they are very sensitive to drug-induced vigilance changes, and they are able to indicate possible dose ranges. The behavioral studies have often been less sensitive in the past, but have a high validity ifthe studies have positive results for a drug (e. g., the scopolamine model with cholinergic drugs). It was nevertheless dearly spelled out during the discussion that the predictive validity of predinical models used with nootropics has been low in the past, and that it would be premature to stop the development of a theoretically useful drug because of negative results in studies with human volunteers. Patients
There should be general agreement that the interpretative value of a dinical trial depends on how weil the patient sampIe is defined. In the past, dinical trials with nootropics often have used heterogeneous groups of older patients sufTering to some degree from deficits in intellectual functioning. Within the last 10 years, scientific inquiries into
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172
Consensus Conference on the Methodology ofClinical Trials of "Nootropics"
problems of shifting baselines and that use wash-out periods long enough to exclude treatment-transfer effects. The recommended length of trials to prove nootropic efficacy in degenerative dementia is at least three months. For some subgroups of more acute organic mental syndromes, e. g., alcohol-induced organic mental disorder, trial duration may be shorter. However, since most of the disorders for which nootropic drugs are intended are chronic, trials should also be performed for at least six to 12 months. One should, however, bear in mind that a placebo-controlled study should not take longer than necessary to demonstrate the efficacy of a drug. The problem of dropouts is particularly important in trials with nootropics because of the high age of the patients. In long-term studies the drop-out rate can therefore become considerable and may invalidate the results. Every effort should be made to keep the drop-out rate low.
The se1ection of a patient for a nootropic drug trial is usually a gradual procedure: first, include patients with dementia as a syndrome (for instance according to OSM 111 R); second, exclude patients with possible secondary causes of dementia. It depends on the drug studied whether the selection of patients has to proceed further up to an etiologically homogeneous group; for instance, one with probable dementia of the Alzheimer type. Standard (computerized tomography, Cf) and advanced (magnetic resonance, MR) imaging techniques can play an important role in the selection of patients. In some cases it may also be of value to homogenize patient sampies according to target symptoms; for instance, to include only patients with a certain degree of memory deficit, or restless and agitated patients. For the purpose ofpatient selection, any combination of clinical, psychometric, and biological techniqul:s should be used that (a) improves the probability of collecting a homogeneous group of patients representing the syndrome or diagnosis that the drug is aimed for and (b) gives enough data to describe the patient sampie according to every clinically relevant criterion.
The adequate sampie size of a trial should be calculated on statistical grounds according to the acceptable limits of type land 11 errors, the definition of a clinically relevant difference, and an estimation of the variability of the outcome criterion. As in other conditions, multicenter trials are often the only way to achieve adequate numbers of patients. To reduce the error variance between centers, joint rater-training sessions before and during a multicenter trial are necessary. These training sessions should not only focus on the rating of psychopathologic symptoms, but should also cover global clinical judgment of the severity of a syndrome, clinical judgment of improvement, assessment of side-effects, and clinical diagnosis.
Besides the description of cognitive functions, it was feit that a thorough assessment of affective and emotional symptoms is necessary. These noncognitive factors may be essential for the clinical outcome, and may go unnoticed when focussing on cognitive symptoms only.
The establishment of the efficacy of a new drug is best (and most safely) demonstrated in a trial that is undisturbed by concomitant medication. Nevertheless one should bear in mind that, outside clinical trials, are nootropic drugs used with concomitant medication in most cases.
It was judged necessary to use a well-known rating or staging instrument that (a) can define cut-off points for the inclusion of a patient and (b) describes the severity of dementia within the study sampie. The reasons for this are twofold: (a) the reader ofthe report will know at which stage of the disorder the drug effect was observable; (b) the reader can evaluate possible floor or ceiling effects ofthe rating or test instruments used.
With most drugs, the use of a single ftxed dose or of multiple ftxed doses is recommended for a clinical trial. Some cholinergic drugs that are currently under trial have a very limited dose range that may vary from subject to subject. In these cases the use of a dose that has been individually specified in apretrial dose-finding phase may be appropriate.
Information on the recruitment procedure should be given. Patients in nursing hornes may be different from those recruited by press advertisements or from outpatient departments.
Researches planning clinical trials with nootropics fnd themselves in a conceptual dilemma. Generally, assessment is best done with measures that are objective and reliable. These demands are best fulfilled by tests or rating scales that document specific aspects of behavior. They are less weil fulfilled by global clinical ratings, which depend more on the individual observer. To the authors' current knowledge, however, the effectiveness of nootropics is more easily demonstrated by global clinical measures, thus leaving the researcher to choose between nonspecific but sensitive and specific but insensitive measures. Investigators sometimes try to solve the problem by using multiple outcome criteria. This is not always a good solution. When using multiple measures statistical alpha errors have to be adjusted with Bonferronitype procedures, thus making the measures even more insensitive.
Design ofTrials
A placebo-controlled parallel-group trial is judged by many experts to be the most preferable design to test the efficacy of a nootropic drug. Since there is still no reference drug, new drugs have to be evaluated against placebo. Crossover trials may be appropriate in some circumstances but their use must be limited to studies that are short enough to avoid
Note 2: Neurology 34 (1984) 939 - 944
173
CIinicaI and Psychometrie Assessment
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the classification of dementias have gained in insight and importance. Basic research has shown the existence of different pathophysiological mechanisms in different forms of dementia. In the light of these developments, it seems to be neoessary to classify patients according to the diagnostic standards set forth, for instance, by the Oiagnostic and Statistical Manual of the American Psychiatric Association (OSM III R), by the 10th edition of the International Classification of Oiseases (ICO-lO), or by the NINCOS-AOROA Criteria for Alzheimer's Oisease (Note 2).
Pharmacopsychiatry 23 (1990)
Pharmacopsychiatry 23 (1990) In the dementia syndrome, the assessment of stage has to be differentiated from the measurement of change. Instruments that are coarse enough to describe the degree of iIlness over a wide range of variation are usually not sensitive enough to describe small changes. The outcome of a trial may be measured at several levels, the most integrative (but possibly subjectively biased) of which is the c1inical global impression. Objective neurospychological tests are the most specific. In between are scales of intstrumental activities of daily living and psychopathologie rating scales. A1though it was not possible to reach a consensus on generally acceptable outcome criteria, it was agreed that they should not be based on measures of cognition alone. In addition to changes in cognition, changes in target symptom rating scores, daily life activities, everyday behavior, quality of life, and well-being of the patient should be carefully assessed. The usual outcome criteria aim to measure a reduction in impairment (e. g., ofmemory or vigilance). It may also be useful to measure the increase in compensatory mechanisms (adaptation, coping mechanisms, stress reduction). The ultimate goal must be to show that a drug produces clinically relevant changes. The value of self-rating instruments is very doubtful, since most patients will not be able to assess themselves reliably on instruction. For all measurement devices used in a trial with nootropics, normative data from healthy subjects of the same age should be available. It is often not possible to fulfil this requirement since many psychometrie tests are not standardized in this age range. A list of instruments often used in trials with A1zheimer patients is given together with the NINCDSADRDA criteria (Note 2). Biological Measures Some aspects of cerebral organisation are open to quantitative measurement. Structural measures include computerized tomography (CT), magnetic resonance imaging (MRI), and sonography, functional measures are regional cerebral blood flow (rCBF), single photon emission computerized tomography (SPECT), positron emission tomography (PET), EEG and evoked potentials, and magnetic resonance spectroscopy. There was general consensus that a brain er is a necessary diagnostic tool for the differential diagnosis betwenn DAT and multi-infarct dementia (MID). rCBF is also useful in this respect. Biological measures were considered less useful in the evaluation oftreatment success. This does not mean that they are not sensitive: on the contrary, computerized EEG techniques can lead to very sensitive measures of vigilance and may be useful in detecting even small drug-induced changes. In addition, they are objective, widely available, noninvasive, and comparatively cheap. Their problem is their relatively low correlation with behavioral and c1inical measures. They must therefore be considered useful research tools; while they may be valuable in studies aimed at generating new hypotheses, they are irrelevant for studies assessing the c1inical efficacy of a nootropic drug.
L. Amaducci et al.
Ethical Considerations Ethical principles are more complex in the face of psychiatrie disorders involving disturbed thinking. The very mental functions that the patient needs to decide whether to participate in a c1inical trial or not are usually affected by the ilIness. It is therefore c1ear that demented patients require special protection against unethical research. The following points were considered necessary: (a) investigations of nootropic drugs should follow the ethical guidelines as formulated in the Helsinki declaration of 1964 (modified in 1975); (b) trial protocols must be reviewed by a local ethical committee; (c) after accurate and usually written information, consent from the individual should be obtained. In some countries the agreement has to be signed by the patient, in others, documented oral consent in the presence of a witness is sufficient, while in others the form of consent is decided by the local ethical committee. The freedom to withdraw from the trial at any time should be c1early stated. It should especially be emphasized when the agreement is signed; (d) ifnecessary, the legally authorized guardian or the next-of-kin must consent to participation in the research project. In institutionalized patients the staff ofthe ward where the patient is cared for may be included in the ethical consideration of the study; (e) procedures that are part of routine c1inical investigation and those that are part of research should be c1early distinguished and spelt out to the patient and his guardian or next-of-kin; (f) the possible physical, mental, or social discomfort or risk involved in the research project should be c1early stated; (g) the ethical committee should decide on the scientific propriety ofthe trial. Conclusions In planning a consensus conference on "nootropics", the Organizing Committee was prepared to face more difficult problems than in the conference on antidepressants. The consensus reached at the meeting was accordingly more a consensus about the problems than about accepted methodology, and reflected the limits of current knowledge. Though the field has a long past, it only has a short history. The conference neverthe1ess he1ped to c1arify where "nootropics" are similar to other psychotropic drugs and where they are different. The current practice of c1inical trials with "nootropics" is very much shaped by experience with other psychotropic drugs. There are, however, specific needs for "nootropics": I) the syndromes aimed at are mostly chronic degenerative disorders. Treatment may either improve the condition or only maintain it and prevent its aggravation. In the latter case, trial duration must be much longer than in the first case; 2) there is no reference drug so far; 3) goals of therapy must be less ambitious than those with other c1asses of drugs. FutureConsensus Conferences The Organizing Committee plans to organize future consensus conferences on neuroleptics, anxiolytics, hypnotics, and relapse-preventing drugs. The next consensus conference will concentrate on neuroleptics and will take placeinZurichOctober 14-16, 1990.
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Consensus Conference on the Methodology ofClinical Trials of"Nootropics"
Psychiatrie University Hospital Nussbaumstraße 7 0-8000 München 2
List ofActive Participants ee ee ee ee
A
Amaducci Angst Bech Benkert Bobon Bruinvels Di/lier- Veillon Eagger Engel·· Gott/ries Herrmann Hippius· Israel Kanowski Köpcke Kozarewic Levy Lingjaerde L6pez-Ibor Orgogozo Phi/pot Porsolt Pull Riekkinen Saletu Spiegel Stefanis Stoll Woggon
F GB F L SF A eH G D eH
oe ee A S M R
Organizing eommittee eonsensus eommittee National Advisor Speaker Moderator Rapporteur
ee
oe
R S S
ee ee
oe A
ee
ee ee ee ee
S S S S S S S
R
oe
A A A A
M R M S S
ee ee
A A A
R S S
A ee ee
oe oe
R M
Three advisors, Prof. Bobon, Prof. P. Riekkinen, and Prof. e. Stefanis, were unfortunately unable to participate in the conference.
•
President of the Consensus Committee •• Local Organizer
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E
M M
A A A A
YU GB N
175
Prof Dr. R. R. Engel
Appendix
I eH DK D B NL eH GB D S D D F D D
Pharmacopsychiatry 23 (/990)
Consensus Conference on the Methodology of Clinical Trials of "Nootropics", Munieh, June 1989 Report ofthe Consensus Committee
Introduction
Performing c1inical trials to assess new psychotropic drugs has become increasingly difficult over the past years. They have become a political and an ethical problem in many countries, and the c1inician carrying out studies is confronted with a number of c1inical, methodological, administrative, and legal problems. Therefore it was considered necessary and useful to organize Consensus Conferences on the Methodology of Clincical Trials in Europe. The first Consensus Conference on the Methodology of Clinical Trials, which took place in Zurich from March 10 - 12, 1988, was devoted to antidepressants, and the final report was published in "Pharmacopsychiatry" in January 1989. The second Consensus Conference on the Methodology of Clinical Trials took place in Munich from June 28 to 30,1989, and was devoted to drugs intended to improve attention, cognition, and memory in patients suffering from symptoms of dementia. This means it was devoted to drugs that in different European countries are called 'cognition enhancing agents', 'antidementia drugs', or 'nootropics' in the broad sense. In the developed countries the prolongation of life caused by modem medicine has increased the prevalence of dementing disorders to a considerable degree. While the prevalence of dementia of the Alzheimer type (DAn is about I % in the general population, it is about 4 % among those over 65. Until now the primary cause remains unknown, the deficits are not reversible, and the course of the illness is long and devastating. These disorders have therefore become a major focus of public health considerations. The conference focussed on the following points: terminology and c1assification of nootropic drugs, value of animal models and preclinical human studies, problems of design and patient characteristics, assessment instruments and statistical analysis, administrative regulations, and ethical problems.
The meeting was organized in a similar way to its prodecessor in Zurich. Each session was moderated by an expert. A rapporteur kept the minutes ofthe discussion following each paper. The speakers were asked not to concentrate their reviews on points where there is general agreement. On the contrary, they were asked to report on open questions, unsolved problems, adverse opinions, factors of dispute. After all the papers had been presented, a Consensus Committee, consisting of the Organizing Committee and the National Advisors, prepared a draft ofthe results and conclusions ofthe conference. These were presented to all participants, and were followed by a general discussion. After the meeting a revised report, incorporating the results of the discussion, was prepared and sent to all members of the Consensus Committee for correction. The names of the active participants are given in the appendix. Administrative Regulations and Existing Guidelines
In Europe, administrative regulations concerning the approval of cognition enhancing drugs differ greatly from country to country. In Germany or Italy, for instance, many nootropic drugs are marketed for a rather broad indication, while in the United Kingdom, for example, they playa limited role. The increased scientific interest in dementia (especially dementia of the Alzheimer type) over the past few years has been accompanied by various attempts to standardize methodology. For example, specific guidelines exist for the evaluation of drugs in the elderly neuropsychiatric patient (demented and nondemented) (Note I), for the clinical evaluation of cerebrocirculatory and metabolism improvers (Japan, 1987, unpublished), and for the evaluation of drugs in Alzheimer's disease (Medical Research Council, United Kingdom, 1989, unpublished), to mention only a few. A committee of the European College of Neuropsychopharmacology (ECNP) is currently working on the question of European standards for c1inical trials; a back-
Note 1: Pharmacopsychiat. 12(1981),81 - 82; 14(1981),150 - 154, 190 - 194,217 - 222. Pharmacopsychiatry23(1990) 171 - 175 © Georg Thieme Verlag Stuttgart· N ew York
Received: Accepted:
20.11.1989 24. 11. 1989
Downloaded by: University of Iowa Libraries. Copyrighted material.
L. Amaducci, J. Angst, P. Hech. O. Henkert, J. Hruinvels, R. R. Engel, C. G. Gott/ries, H. Hippius, R. Levy, O. Lingjaerde, J. J. L6pez-Ibor Jr., J. M Orgogozo, C. Pul/, H. Saletu, K. D. Stoll, H. Woggon
Pharmacopsychiatry 23 (1990)
ground document for EC guidelines on "dinical trials of drugs intended for the treatment of pathological intellectual deficits in the elderly" has been published, and in lune 1989 the advisory board of the Food and Drug Administration (FDA) held a conference on antidementia drugs, where protocol requirements for typical phase-three studies were discussed. Terminology and Oassification
A drug can be dassified from a pharmacological point ofview (according to the main efTects of a drug, e. g., "hypnotic"), or from a dinical point ofview (according to the syndromes or disorders treated best by a drug, e. g., "antidepressant"). In the announcement of the Consensus Conference the term 'nootropics' was used to describe in short "drugs intended to improve attention, cognition, and memory in patients sufTering from symptoms of dementia". Thus the term 'nootropic' was used in its broad dinical sense. During the conference it was stated that there are some countries where the term is only used in its narrow or strictly pharmacological sense. The conference did not succeed in its search for another word for the clinical dass of 'nootropic' drugs, though many terms were named or coined (examples: antihypoxidotics, antidementics, psychoenergizers, psychosynchronizers) and many paraphrases exist (examples: cognition enhancing drugs, cognition activators, drugs for impaired brain functions in old age (a term used by the German health authority), drugs intended to treat pathologic intellectual deficit in the elderly (the term used currently by the EC commission». There was consensus that drugs belonging to the clinical dass of 'nootropics' may be dassified into various pharmacological types (cerebral vasodilators, psychostimulants, nootropics in the strict sense, etc.) or neurochemical types (e. g., neurotransmitters, neuropeptides). As most of these types are not exdusive, a multifactorial pharmacological dassification scheme would probably serve better in the future. In describing the possible dinical efTects of a drug there might be a difTerence between the acute efTects of a drug (i. e., improving behavior) and its chronic efTects (i. e., preventing deterioration ofbehavior). Animal Models
For the development of new therapeutic agents, biological models are helpful. Unfortunately, appropriate animal models for the largest group of dementias do not exist. There is as ofyet no known animal disease comparable to Alzheimer's disease in humans. Most animal models used so far try to produce astate of memory and/or behavioral impairment that should be either prevented or reversed by nootropic drugs. Examples are brain lesions, electroconvulsive shock, genetic models, hypoxia, drug-induced deficit models (e. g., scopolamine, benzodiazepines), and the use of aged animals. Passive avoidance has been used as a routine screening tool to find antiamnesic activities of new substances. The data indicate a special antiamnesic activity for some nootropic drugs that is not shown for other drug dasses, but the data are far from being unequivocally dear, and their relevance to dinical problems remains questionable.
L. Amaducci et al.
Other, more complex models appear to address more specifically memory-related functions. Among these, there are the radial maze (short-term of working memory), the Morris water maze (Iong-term spatial memory), and various models of delayed response in rats and monkeys (immediate memory). All these tasks show dear deficits with aging which suggests some degree of validity. Most of them are, however, very time-consuming and, as a consequence, have not been used frequently for drug evaluation. The results obtained, particularly in aged monkeys, suggest that presently available nootropic drugs have only slight and inconsistent effects. Some ofthe more general problems in this area are: (a) current models describe only disturbances of memory. not of any other cognitive function; (b) in a11 models, evaluation is hampered by the fact that no reference compound exists; (c) the predictive value of currently used tests is not known. Studies with Human Volunteers
The usual goal for Phase-I studies is to study how weil new drugs are tolerated in man and to establish their pharmacokinetics. To predict dinical efficacy in the field of nootropic drugs there has been a tendency to extend the scope of Phase-I studies to indude experimental psychometric studies with healthy volunteers. As in animal experiments, this is only possible when valid models exist. Examples of models used in the past are: subjects studied under hypoxia or under mentally strainful conditions (e. g., under heavy mental work load), drug-induced memory deficits (e. g., scopolamine), the use ofhealthy e1derly subjects with memory deficits, or the study of subjects with vigilance impairments in the electroencephalogram (EEG). If the models are valid, nootropic drugs should either improve the deficits if given subsequently or prevent them if given previously. Deficits are measured either behaviorally (for instance, the number ofwords, recalled in a memory task) or by other variables reflecting brain functions (for instance, the delta/theta power in the EEG). The EEG studies are able to give a general indication of the cerebral activity of a drug, they are very sensitive to drug-induced vigilance changes, and they are able to indicate possible dose ranges. The behavioral studies have often been less sensitive in the past, but have a high validity ifthe studies have positive results for a drug (e. g., the scopolamine model with cholinergic drugs). It was nevertheless dearly spelled out during the discussion that the predictive validity of predinical models used with nootropics has been low in the past, and that it would be premature to stop the development of a theoretically useful drug because of negative results in studies with human volunteers. Patients
There should be general agreement that the interpretative value of a dinical trial depends on how weil the patient sampIe is defined. In the past, dinical trials with nootropics often have used heterogeneous groups of older patients sufTering to some degree from deficits in intellectual functioning. Within the last 10 years, scientific inquiries into
Downloaded by: University of Iowa Libraries. Copyrighted material.
172
Consensus Conference on the Methodology ofClinical Trials of "Nootropics"
problems of shifting baselines and that use wash-out periods long enough to exclude treatment-transfer effects. The recommended length of trials to prove nootropic efficacy in degenerative dementia is at least three months. For some subgroups of more acute organic mental syndromes, e. g., alcohol-induced organic mental disorder, trial duration may be shorter. However, since most of the disorders for which nootropic drugs are intended are chronic, trials should also be performed for at least six to 12 months. One should, however, bear in mind that a placebo-controlled study should not take longer than necessary to demonstrate the efficacy of a drug. The problem of dropouts is particularly important in trials with nootropics because of the high age of the patients. In long-term studies the drop-out rate can therefore become considerable and may invalidate the results. Every effort should be made to keep the drop-out rate low.
The se1ection of a patient for a nootropic drug trial is usually a gradual procedure: first, include patients with dementia as a syndrome (for instance according to OSM 111 R); second, exclude patients with possible secondary causes of dementia. It depends on the drug studied whether the selection of patients has to proceed further up to an etiologically homogeneous group; for instance, one with probable dementia of the Alzheimer type. Standard (computerized tomography, Cf) and advanced (magnetic resonance, MR) imaging techniques can play an important role in the selection of patients. In some cases it may also be of value to homogenize patient sampies according to target symptoms; for instance, to include only patients with a certain degree of memory deficit, or restless and agitated patients. For the purpose ofpatient selection, any combination of clinical, psychometric, and biological techniqul:s should be used that (a) improves the probability of collecting a homogeneous group of patients representing the syndrome or diagnosis that the drug is aimed for and (b) gives enough data to describe the patient sampie according to every clinically relevant criterion.
The adequate sampie size of a trial should be calculated on statistical grounds according to the acceptable limits of type land 11 errors, the definition of a clinically relevant difference, and an estimation of the variability of the outcome criterion. As in other conditions, multicenter trials are often the only way to achieve adequate numbers of patients. To reduce the error variance between centers, joint rater-training sessions before and during a multicenter trial are necessary. These training sessions should not only focus on the rating of psychopathologic symptoms, but should also cover global clinical judgment of the severity of a syndrome, clinical judgment of improvement, assessment of side-effects, and clinical diagnosis.
Besides the description of cognitive functions, it was feit that a thorough assessment of affective and emotional symptoms is necessary. These noncognitive factors may be essential for the clinical outcome, and may go unnoticed when focussing on cognitive symptoms only.
The establishment of the efficacy of a new drug is best (and most safely) demonstrated in a trial that is undisturbed by concomitant medication. Nevertheless one should bear in mind that, outside clinical trials, are nootropic drugs used with concomitant medication in most cases.
It was judged necessary to use a well-known rating or staging instrument that (a) can define cut-off points for the inclusion of a patient and (b) describes the severity of dementia within the study sampie. The reasons for this are twofold: (a) the reader ofthe report will know at which stage of the disorder the drug effect was observable; (b) the reader can evaluate possible floor or ceiling effects ofthe rating or test instruments used.
With most drugs, the use of a single ftxed dose or of multiple ftxed doses is recommended for a clinical trial. Some cholinergic drugs that are currently under trial have a very limited dose range that may vary from subject to subject. In these cases the use of a dose that has been individually specified in apretrial dose-finding phase may be appropriate.
Information on the recruitment procedure should be given. Patients in nursing hornes may be different from those recruited by press advertisements or from outpatient departments.
Researches planning clinical trials with nootropics fnd themselves in a conceptual dilemma. Generally, assessment is best done with measures that are objective and reliable. These demands are best fulfilled by tests or rating scales that document specific aspects of behavior. They are less weil fulfilled by global clinical ratings, which depend more on the individual observer. To the authors' current knowledge, however, the effectiveness of nootropics is more easily demonstrated by global clinical measures, thus leaving the researcher to choose between nonspecific but sensitive and specific but insensitive measures. Investigators sometimes try to solve the problem by using multiple outcome criteria. This is not always a good solution. When using multiple measures statistical alpha errors have to be adjusted with Bonferronitype procedures, thus making the measures even more insensitive.
Design ofTrials
A placebo-controlled parallel-group trial is judged by many experts to be the most preferable design to test the efficacy of a nootropic drug. Since there is still no reference drug, new drugs have to be evaluated against placebo. Crossover trials may be appropriate in some circumstances but their use must be limited to studies that are short enough to avoid
Note 2: Neurology 34 (1984) 939 - 944
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CIinicaI and Psychometrie Assessment
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the classification of dementias have gained in insight and importance. Basic research has shown the existence of different pathophysiological mechanisms in different forms of dementia. In the light of these developments, it seems to be neoessary to classify patients according to the diagnostic standards set forth, for instance, by the Oiagnostic and Statistical Manual of the American Psychiatric Association (OSM III R), by the 10th edition of the International Classification of Oiseases (ICO-lO), or by the NINCOS-AOROA Criteria for Alzheimer's Oisease (Note 2).
Pharmacopsychiatry 23 (1990)
Pharmacopsychiatry 23 (1990) In the dementia syndrome, the assessment of stage has to be differentiated from the measurement of change. Instruments that are coarse enough to describe the degree of iIlness over a wide range of variation are usually not sensitive enough to describe small changes. The outcome of a trial may be measured at several levels, the most integrative (but possibly subjectively biased) of which is the c1inical global impression. Objective neurospychological tests are the most specific. In between are scales of intstrumental activities of daily living and psychopathologie rating scales. A1though it was not possible to reach a consensus on generally acceptable outcome criteria, it was agreed that they should not be based on measures of cognition alone. In addition to changes in cognition, changes in target symptom rating scores, daily life activities, everyday behavior, quality of life, and well-being of the patient should be carefully assessed. The usual outcome criteria aim to measure a reduction in impairment (e. g., ofmemory or vigilance). It may also be useful to measure the increase in compensatory mechanisms (adaptation, coping mechanisms, stress reduction). The ultimate goal must be to show that a drug produces clinically relevant changes. The value of self-rating instruments is very doubtful, since most patients will not be able to assess themselves reliably on instruction. For all measurement devices used in a trial with nootropics, normative data from healthy subjects of the same age should be available. It is often not possible to fulfil this requirement since many psychometrie tests are not standardized in this age range. A list of instruments often used in trials with A1zheimer patients is given together with the NINCDSADRDA criteria (Note 2). Biological Measures Some aspects of cerebral organisation are open to quantitative measurement. Structural measures include computerized tomography (CT), magnetic resonance imaging (MRI), and sonography, functional measures are regional cerebral blood flow (rCBF), single photon emission computerized tomography (SPECT), positron emission tomography (PET), EEG and evoked potentials, and magnetic resonance spectroscopy. There was general consensus that a brain er is a necessary diagnostic tool for the differential diagnosis betwenn DAT and multi-infarct dementia (MID). rCBF is also useful in this respect. Biological measures were considered less useful in the evaluation oftreatment success. This does not mean that they are not sensitive: on the contrary, computerized EEG techniques can lead to very sensitive measures of vigilance and may be useful in detecting even small drug-induced changes. In addition, they are objective, widely available, noninvasive, and comparatively cheap. Their problem is their relatively low correlation with behavioral and c1inical measures. They must therefore be considered useful research tools; while they may be valuable in studies aimed at generating new hypotheses, they are irrelevant for studies assessing the c1inical efficacy of a nootropic drug.
L. Amaducci et al.
Ethical Considerations Ethical principles are more complex in the face of psychiatrie disorders involving disturbed thinking. The very mental functions that the patient needs to decide whether to participate in a c1inical trial or not are usually affected by the ilIness. It is therefore c1ear that demented patients require special protection against unethical research. The following points were considered necessary: (a) investigations of nootropic drugs should follow the ethical guidelines as formulated in the Helsinki declaration of 1964 (modified in 1975); (b) trial protocols must be reviewed by a local ethical committee; (c) after accurate and usually written information, consent from the individual should be obtained. In some countries the agreement has to be signed by the patient, in others, documented oral consent in the presence of a witness is sufficient, while in others the form of consent is decided by the local ethical committee. The freedom to withdraw from the trial at any time should be c1early stated. It should especially be emphasized when the agreement is signed; (d) ifnecessary, the legally authorized guardian or the next-of-kin must consent to participation in the research project. In institutionalized patients the staff ofthe ward where the patient is cared for may be included in the ethical consideration of the study; (e) procedures that are part of routine c1inical investigation and those that are part of research should be c1early distinguished and spelt out to the patient and his guardian or next-of-kin; (f) the possible physical, mental, or social discomfort or risk involved in the research project should be c1early stated; (g) the ethical committee should decide on the scientific propriety ofthe trial. Conclusions In planning a consensus conference on "nootropics", the Organizing Committee was prepared to face more difficult problems than in the conference on antidepressants. The consensus reached at the meeting was accordingly more a consensus about the problems than about accepted methodology, and reflected the limits of current knowledge. Though the field has a long past, it only has a short history. The conference neverthe1ess he1ped to c1arify where "nootropics" are similar to other psychotropic drugs and where they are different. The current practice of c1inical trials with "nootropics" is very much shaped by experience with other psychotropic drugs. There are, however, specific needs for "nootropics": I) the syndromes aimed at are mostly chronic degenerative disorders. Treatment may either improve the condition or only maintain it and prevent its aggravation. In the latter case, trial duration must be much longer than in the first case; 2) there is no reference drug so far; 3) goals of therapy must be less ambitious than those with other c1asses of drugs. FutureConsensus Conferences The Organizing Committee plans to organize future consensus conferences on neuroleptics, anxiolytics, hypnotics, and relapse-preventing drugs. The next consensus conference will concentrate on neuroleptics and will take placeinZurichOctober 14-16, 1990.
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Consensus Conference on the Methodology ofClinical Trials of"Nootropics"
Psychiatrie University Hospital Nussbaumstraße 7 0-8000 München 2
List ofActive Participants ee ee ee ee
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Amaducci Angst Bech Benkert Bobon Bruinvels Di/lier- Veillon Eagger Engel·· Gott/ries Herrmann Hippius· Israel Kanowski Köpcke Kozarewic Levy Lingjaerde L6pez-Ibor Orgogozo Phi/pot Porsolt Pull Riekkinen Saletu Spiegel Stefanis Stoll Woggon
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Organizing eommittee eonsensus eommittee National Advisor Speaker Moderator Rapporteur
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Three advisors, Prof. Bobon, Prof. P. Riekkinen, and Prof. e. Stefanis, were unfortunately unable to participate in the conference.
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President of the Consensus Committee •• Local Organizer
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Prof Dr. R. R. Engel
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Pharmacopsychiatry 23 (/990)
