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Report on the Third Consensus Conference on the Methodology of Clinical Trials with Antipsychotic Drugs J. Angst, P. Bech, D. Bobon, R. Engel, H Hippius, G. J. Janzen, Y. Lecrubier, O. Lingjaerde, H-J. Möller, St. Montgomery, M Paes de Sousa, A. Rossi, B. Saletu, G. Sedvall, C. Stefanis, K.-D. StolI, B. Waggon

General Remarks

Introduction

Each session was moderated by an expert and a rapporteur kept the minutes of the discussion. One or two speakers gave papers on current problems of practical methodological consequences, in order to encourage discussion among the participants. The rapporteurs made a written summary of each discussion and presented this report to the Consensus Committee, who prepared a draft with the resulting recommendations. This draft was presented to all participants in the final session of the conference and was discussed in detail. Based on this discussion, a revised draft was prepared and sent to all participants (n = 123) after the conference for additional remarks and corrections. The names of the members of the Organizing Committee, the Consensus Committee, advisors, moderators, speakers and rapporte urs are given in the Appendix (n = 23). Further Consensus Conferences The fourth Consensus Conference will concentrate on anxiolytics and will take place in Munich, October 27-29, 1991.

Pharmacopsychiat. 24 (1991) 149-152 © Georg Thieme Verlag Stuttgart· New York

The purpose of the conference was a scientific one and was not limited to recommendations for clinical trials for the registration of new drugs. This conference could not deal with the entire field of the use of antipsychotic drugs, but was restricted to schizophrenia. When planning studies, ethical considerations are important. One can distinguish normative from individual ethics. Both should be taken into account, but individual ethics prevail. Studies with new drugs, and especially with placebo, should be performed under the best treatment conditions, for instance with enough statT to guarantee good care. The approval of the ethical committee and the fully informed consent ofthe patients are always required. The diagnosis should be registered and documented using internationally accepted diagnostic systems. A rating scale score only is insufficient and is not equivalent to a diagnosis. It was recommended that to allow retrospective c1assification of subjects with regard to research diagnostic criteria, a diagnostic symptom checklist should be used. Moreover, inclusion and exclusion criteria, as well as information on the number of patients "screened" to obtain the patients included, must be specified to gain an impression as to whether the sampie is representative, and hence how far the results can be generalized. The quality of the process of collecting (assessment and documentation) clinical data determines the value of a c1inical trial to a great extent. For measuring drug effects, the investigators should always use the best available rating scales for the question that is being studied (positive symptoms, negative symptoms, social adjustment) and, in addition, global assessment scales (CGI, GAS, etc.). The quality of rating scales varies, items with the character of single symptom entities being preferable to items with the character of syndromes or heterogeneous groups of symptoms derived from factor analyses (e.g. BPRS). For the assessment of side effects it is important to register somatic symptoms at baseline. In addition to the use of rating scales, standardized interviews and psychological tests can be used. The results of the trial should include not only rating score changes, but in addition, the percentage of patients who improved at different levels, for example the proportion of patients with a 50 % improvement on a scale. Furthermore, the percentage of responders and non-responders should be

Received: Accepted:

19.7.1991 29.7.1991

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The performance of c1inical trials on new psychotropic drugs has become increasingly difficult during the past 10 years. Therefore, in 1987 a small group of experts formed a committee to organize Consensus Conferences on the Methodology of Clinical Trials in Europe, including members of the Association for Methodology and Documentation in Psychiatry (AMDP), the Collegium Internationale Psychiatriae Scalarum (CIPS) and the Psychiatric Hospitals of the Universities of Munich and Zurich. The first two conferences were dedicated to the methodology of c1inical trials of antidepressants (Angst et al., 1988) and of nootropic drugs (Amaducci et al., 1990). The third conference focused on the methodology of clinical trials of antipsychotic drugs and took place in Zurich, October 14-16, 1990. For this conference the patronage was extended to include the European College of Neuropsychopharrnacology (ENCP). Experts from 14 European countries advised us concerning special topics and the selection of participants.

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Pharmacopsychiat. 24 (1991) given. In general, all important terms used for study designs should be defined by operational criteria, for instance, efficacy; relapse; low versus high dose; negative or positive symptoms. Antipsychotic Efficacy

The first topic discussed was the proof of antipsychotic efficacy. From a statistical point of view the following can be summarized: Under the usual assumptions of a given significance level (a or 2 a = 0.05) the power of a statistical test (80 or 90%), the sample size is dependent on the expected difTerence between the treatments which are compared, and the standard deviation of the measurement. Therefore, one way to reduce the necessary number of patients in a trial is to use a sensitive measurement with a low amount of "noise". Any improvement to reduce variance in the measurement device (for instance by intensive and continuous rater training before and during a trial) can also mean an enhancement of the power of the study. This is true for studies against placebo and studies against a reference drug. In studies against placebo usually the expected difTerence between the two treatments is much larger than it is in studies comparing two active compounds. The power calculation is a balance between the lowering (reduction) of risk for a false negative result, increasing the sensitivity to small, but clinically relevant difTerences, and keeping the sample size within reasonable bounds. The restriction for further statistical considerations are: parallel groups (between group comparisons); and fixed sample sizes (ratio I: I). In trials with more than two groups, a different sample size is sometimes used. In trials based on sequential analysis, the sample size depends on the observed pairwise difTerence between the treatments. However, this procedure is problematic, because it is always difficult to find two comparable patients who can be treated at about the same time, and partly because only one outcome measure can be taken into account. The pharmacological effects of placebo and a new investigational drug may be different, but this is no proof of antipsychotic efficacy. Therefore, the so-called threearm study design, comparing investigational and standard drug and placebo in the same study, is desirable because it demonstrates both pharmacological efficacy and yields a measure of the efficacy of the experimental treatment compared to existing treatment. In designs where the investigational drug is compared to placebo, the problem to be tested is whether the two treatments differ. In designs where the investigational drug is compared to a standard drug (active control), usually the hypothesis of equivalence or at least equivalence is tested. The comparison of low, medium and high dose ranges is a variant of testing hypothesis of difTerence with a possible regression analysis approach. Controlled therapeutic studies in schizophrenia involve several restrictions: patients included in controlled studies are less severely ill than those who are excluded. The drOJHlut rates are often high and should be considered in the statistical analysis. A flXed dosage design is desirable, but sometimes clinically difficult to maintain. Placebo-controlled studies are not easy to perform. The

blindness of a study can be compromised by different side effect profIles of the two compounds being compared. No consensus was reached on the usefulness of rating the blindness of a study. Such a rating can create problems and may interfere with the purpose of the study. In essence, the studies have to be blind and every effort to maintain the blindness should be made. In multiple dose designs it is difficult to meet the individual optimal dose for some patients. The control of interrater reliability during a trial is important and in multicenter trials it is mandatory. The optimal duration of a short-term trial is 4 to 8 weeks. Since samples treated at different times are not always comparable, historical comparisons cannot be used for proving antipsychotic efficacy, but they can yield important hints for evolving hypotheses. Open Clinical Trials The value of open pilot trials was discussed extensively during the plenary session. No consensus was reached as to whether they should be considered mandatory and performed as open-eye studies by experienced psychiatrists using a study protocol and a case report form. They cannot supply proof of efficacy, but they do give the information needed for planning double-blind studies. The overall objectives of early open clinical studies are (I) to guess the safety of the administered new substance in patients, to describe the most common side effects or adverse effects, to identify idiosyncratic effects, (2) to identify target symptoms or syndromes and discover new actions, (3) to observe the time-eourse of major psychopathological changes to determine the rating days of the double-blind studies, (4) to estimate the therapeutic dose range. In general, open clinical trials serve to generate hypotheses that have to be tested by double-blind studies. Open clinical trials must be planned and carried out as carefully as double-blind studies to increase the validity of the results. Sampling

The main purpose of the sampling procedure is to achieve a representative sample of the patient population in question. A high homogeneity of the sample maximizes the power of the comparative study by lowering the variance, and has the advantage of well-defined results. On the other hand, it has the disadvantage of difficult recruitment of patients and restricted generalizability. The practical solution may be to make a careful selection of some well-defmed and well-described inclusion criteria. The sampling criteria depend on the purpose of the study. The sampling procedure must always be described in detail. The sampling is highly dependent on the type of study carried out, e. g. one can distinguish the following types of studies: short-term efficacy, short-term relapse studies, long-term consolidation studies, long-term substitution studies, long-term dose reduction, long-term low dose maintenance (in flXed or flexible doses) and intermittent medication. When planning such a trial, eight sets of criteria may be considered: (I) sociodemographic variables, (2) course of the disease, (3) diagnostic

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One has to distinguish between acute treatment (that is four to eight weeks), medium-term trials (two to six months) and long-term trials (six months to 24 months). The length of the trials is dependent on the type of the study. Placebo-controlled trials should be as short as possible, acute studies for instance four weeks, long-term studies one year. SampIe attrition can lead to serious methodological problems. Drop-outs and early withdrawals should be carefully defined in advance and can be used as dependent variables for the comparison of different substances. Placebo

The placebo-controlled parallel group trial is judged by the majority of experts to be the design of choice to test the efficacy of an antipsychotic drug. Moreover placebo-controlled studies can give an estimation of the extent of changes due to spontaneous remission and non-specific factors as weil as a measure of the magnitude of specific pharmacological effects. They have a high efficiency concerning the required number of patients and time needed. It is difficult to establish equivalent efficacy to a reference antipsychotic unless rather large numbers are inc1uded. In order to obtain the maximal benefit of placebo-controlled trials to establish efficacy of antipsychotic drugs, the patients in these trials should as much as possible be the type of patients usually treated i. e. "ordinary schizophrenic patients" and not non-responders or those suffering from strong side effects. Patients with special risks (suicidal, violent) should be excluded. Thus, the smallest number of patients is exposed to the "risk" of being treated with a new drug or placebo. Special patients should be studied, but preferably after having established efficacy in "normal" patients. Alternative designs to the parallel group study have rarely been used up to now. They suffer from drawbacks (carry-over effect, interaction). Sequential analysis offers the possibility to reduce the number of patients given placebo. Dosage

In the development of new substances doseresponse and dose-side effect relationships should be investigated as early as possible, because they are important prerequisites for other investigations. Failure to observe dose-response relationships can produce misleading results. It is important to establish the "active dose range" by finding the ineffective as weil as the toxic dose range. In phase I, in normal volunteers single doses and stepwise increasing doses can be tested open or doubleblind. PET studies and EEG studies can give important information on receptor binding and central action and may help to determine equipotent dosages of comparable drugs. Such

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studies in volunteers also yield important pharmacokinetic and pharmacodynamic information. In phase 11, dose finding studies should preferably start with open trials. A stepwise forced titration study is recommended to a flexible dose design in order to determine the highest tolerated dose. In a second step, doubleblind studies, with for instance three fixed doses plus placebo, should be carried out. Controlled trials with flexible doses for testing the optimal range are also recommended. Fixed dose designs have the advantage of being standardized, easy to perform, but with the disadvantage that some patients may be underdosed or overdosed leading to a decrease of efficacy and increase of drop-out rates. In cases of intolerance, a lowering of dose is preferable to a withdrawal from the trial. A flXed dose design can answer the question of how the drugs compare in standard doses and a flexible dose design may answer the question of how the drugs compare in optimal doses. It has the advantage of being clinically realistic, but the disadvantage ofbeing harder to evaluate, to perform, and again, under- and overdosing may occur. A better compromise than to study flexible doses and then flXate them in the last part of the study probably is to perform a 3-4 week flXed dose study and then go flexible, reducing the doses in patients with side effects (too high dose?) and increasing it in patients with a partial response (too low?). Moreover, it should be specified that doses should not be changed more often than once a week to prevent that doses are changed before having had a chance to come to effect. To optimize treatment in individual patients, non-overlapping dose ranges instead of flXed doses were proposed. Analysis of actual dosing within these ranges may help to establish the most effective dose (range). In phase 111 extensive double-blind studies have to be carried out. Many experts recommend flXed doses for these kind of studies, others recommend flexible doses. Loog-Term Trials

Long-term studies last for 6 to 24 months. They should be carried out either as double-blind or open trials. Frequent visits can improve compliance, a minimum of one per month is required. Patients included in the study should usually have experienced more than one episode. Patients with first-episode schizophrenia should be studied, but not in the same long-term trials as the other patients; at least they should be analysed separate1y as a subgroup. In cases of long-term trials the short-term efficacy should usuaIIy be proven in advance. Random plasma sampling in order to control compliance is recommendable. Any concomitant therapy has to be standardized and documented in detail. Other antipsychotic drugs should not be permitted. Criteria for stabilization, prodromal signs and relapse have to be defined in advance. For the assessment of changes, different types of psychopathological rating scales are again necessary, including global assessment and social adjustment, or quality of life. The expected attrition rate should be taken into account for power calculation. Survival analysis would be applied for relapses. Usually a relapse includes the reappearance ofpositive symptoms. Negative symptoms could be considered too.

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subgroups, (4) inclusion criteria (for instance minimum scores on rating scales), (5) treatments received and previous response, (6) evolution criteria, (7) social adjustment inc1uding quality of life and (8) availability of patients over the whole time period of the trial.

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Maintenance treatment is difficult to distinguish from prophylaxis. The latter refers to subjects with remission of acute symptoms over a defined period of time. Again, some experts recommend placebo controls for longterm trials. Negative Symptoms Negative symptoms have been neglected in schizophrenia research until recent years and are recommended as a priority area for the near future. They can occur during the acute phase and in the chronic stage of the illness. Negative symptoms often co-occur with positive symptoms. The study design should include not only measures of nega-

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tive symptoms but also of positive symptoms, depression, extrapyrarnidal side efTects and psycho-organic symptoms because they tend to correlate with each other. Cognitive and psychophysiological tests are not only useful in patients with negative symptoms but in all subtypes of schizophrenia. In patients with predominance of negative symptoms a placebo-

Report on the third consensus conference on the methodology of clinical trials with antipsychotic drugs.

149 Report on the Third Consensus Conference on the Methodology of Clinical Trials with Antipsychotic Drugs J. Angst, P. Bech, D. Bobon, R. Engel, H...
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