The use of placebo control groups in the assessment of psychiatric drugs: an historical context.

The reliable evaluation of treatments intended for the management of psychiatric illness would not be possible without the use of placebo. Other types of control groups can provide useful information, but none are capable of adducing a finding as compelling and unambiguously interpretable as a statistically significant drug-placebo difference. Its epistemological advantage notwithstanding, the ethicality of employing a placebo control group has been increasingly challenged in recent years. Many who object to the use of placebo on ethical grounds assume, incorrectly, that there are fungible alternatives to the use of placebo in the assessment of psychotropic drugs. This essay attempts to explain, within an historical context, not only why placebo is irreplaceable, but why it is often so difficult to communicate its advantages to those unfamiliar with the epistemological aims and methods of controlled clinical trials.

Threats to the validity of clinical trials employing enrichment strategies for sample selection.

Subject selection and exclusion criteria employed in typical clinical effectiveness trials of investigational new drugs have two fundamental aims: (1) to ensure that patients entering a study are truly suffering from the condition the drug is intended to treat and (2) to maximize the likelihood that the study will detect an effect of the drug if, in fact, one exists. Typical protocol selection criteria not only specify exacting procedures for establishing and documenting the diagnosis of those recruited for a study but also seek to increase, relative to the prevalence in the general population, the proportion of individuals in the sample likely to respond to pharmacological treatment. Because it is ordinarily impossible to learn prior to extensive clinical experience with a new drug which, if any, patient characteristics reliably predict a consistent treatment response, strategies for sample "enrichment" typically operate by excluding patients (for example, those with very advanced and/or complicated illness, those with serious concomitant illness, those at the extremes of age, those with very mild illness, and so forth) in whom a dependable response to treatment seems unlikely on logical and/or generic grounds. Some studies use positive strategies for sample "enrichment." In studies evaluating drugs intended to treat recurrent episodes of psychiatric illnesses, many protocols recommend selective recruitment of patients with a history of meaningful positive responses to antipsychotic treatment during prior episodes. Sample selection procedures of these kinds impose limits on the generalizability of a study's results (i.e., external validity), but the use of nonrandom patient samples is ordinarily held to have no effect on the internal validity of the results. In short, studies employing highly selected patient samples are, despite their limited external validity, regularly accepted as valid sources of evidence bearing on a drug's effectiveness. There are exceptions, however; this paper describes one in which the use of a seemingly innocuous sample enrichment maneuver proved highly damaging to the ultimate credibility of an important multicenter trial. In particular, exposure to an experimental treatment during an open qualification phase may invalidate drug-placebo comparisons made during a later randomized, blinded, controlled phase. Our review of the trial also reveals that the enrichment maneuver employed probably failed to accomplish its intended aims, selecting patients whose improvements on the outcome variable may be as reasonably ascribed to chance as to drug effect. This is all the more surprising because the method of sample enrichment employed has much in common with those long recommended in the clinical trial literature.

Slowing the progression of Alzheimer disease: methodologic issues.

The evidence to support a claim that a new drug will slow the progression of Alzheimer disease (AD) must derive from epistemologically valid research methods. Although agency regulations do not specify the magnitude of an effect that a drug must possess to be granted a claim as a treatment for AD, the evidence to support any claim must be adduced in adequate and well-controlled clinical investigations and must meet the standard of "substantial evidence." Because a claim presented in drug product labeling may not be false or misleading in any particular, a distinction must be made between treatments that provide a "symptomatic" benefit and those that alter the course of dementia. Examples of some of the difficulties likely to be encountered by sponsors seeking to develop evidence to support a claim that a new drug slows the progression of dementia are presented. A suggestion is made for a clinical trial design, designated as the "randomized start design," that may be useful in such a question. Why this design might overcome many of the difficulties, both practical and ethical, present in the "discontinuation" design, the design ordinarily proposed to assess a drug's effect on disease progression, is discussed.

Protocols to demonstrate slowing of Alzheimer disease progression. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. The Disease Progression Sub-Group.

Two suggested clinical trial designs for assessing progression of Alzheimer disease are the randomized withdrawal design and the randomized start design. The most promising of these, the randomized start design, has the potential to demonstrate a delay in progression, but there remain problematic design, ethical, and statistical issues to be solved before the protocol can be used in a clinical trial. The development of biological markers of the disease process using neuroimaging or other measures also may provide a robust method of measuring disease progression and demonstrating the biological effect of a drug on the disease process.

Observations and suggestions on antidementia drug development.

Recent advances in the theoretical neurosciences have suggested a number of novel strategies that might be applied to prevent and/or retard the progression of Alzheimer disease. Whether or not these interventions will succeed cannot be determined on theoretical grounds, however; the value of each new stratagem must be evaluated in patients with Alzheimer disease. How best to conduct clinical studies of disease-modifying treatments remains a controversial subject. The author reviews and compares two clinical trial designs that may prove useful in assessing whether or not a putative treatment actually modifies the course of dementia.

Speed of onset.

Speed of onset can be an important attribute of drug product performance. In studies employing appropriate designs and outcome measures, it is theoretically possible to make internally valid comparisons of the distribution of onset times associated with the use of two or more drug products. The external validity of such estimates is still potentially arguable. Steps that may be taken to enhance the likelihood that the results of such comparative studies will be accepted as valid bases for comparative claims are discussed.

Is there an alternative to the randomized controlled trial?

The advantages of the concurrently randomized controlled trial as a device to assess the efficacy of drugs intended for use in the field of psychiatry are reviewed. The importance of "assay sensitivity" is discussed and illustrations of errors that can arise when inferences about efficacy are based upon comparisons that find no difference between experimental and standard treatments are presented. These illustrations are derived from data collected in two different pre-marketing commercial drug development programs. Also discussed is the argument that controlled trials are inappropriate devices to test drug efficacy because of their alleged lack of sensitivity to drug effects.

British Association for Psychopharmacology Max Hamilton Memorial Lecture Quantitative estimates of drug effects in psychopharmacology: what we measure and what we do not.

This paper is an edited version of the Max Hamilton Memorial Lecture that was delivered at the annual meeting of the British Association for Psychopharmacology in Cambridge in July 1989. In tribute to Professor Hamilton's pioneering efforts in the field, the lecture focuses on several aspects of the measurement process in psychopharmacology. The role of enumeration in the classification of psychopathology is reviewed and its importance illustrated with an example drawn from the literature. Attention is given to the fundamental link between agreements within the field about the nature and qualities of clinical phenomena and the field's ability to construct and use multi-item rating scales to measure meaningful changes in the intensity of psychopathology. The importance of global assessment as a validation procedure is emphasized and selected hazards to reliable inference are examined.

Hazards of inference: the active control investigation.

A finding of no significant difference in seizure incidence and/or severity among groups of epileptic patients prospectively randomized to treatment with either a standard or experimental antiepileptic drug is often advanced as compelling proof of the latter's anticonvulsant efficacy. Regrettably, the finding of no difference does not, on its own at least, support such a conclusion. A finding of no difference between treatments has numerous explanations that have nothing whatsoever to do with the pharmacological actions of the experimental drug. To be clear, it is possible to argue that a pharmacological effect is the most plausible explanation for a finding of no difference in an active control study, but this argument is only supportable if it is based on additional information gathered from sources external to the study. In most circumstances, the essential external evidence is not available, and the interpretation of the null difference as a positive result turns entirely upon the truth or falsity of the sanguine assumptions made. There is a risk in inferring efficacy from the seemingly consistent results of a series of active control studies that fail to find differences. Despite the long-recognized deficiencies in the active control study design, it remains popular.

Activities of chlorinated ethane and ethylene compounds in the Salmonella/rat microsome mutagenesis and rat hepatocyte/DNA repair assays under vapor phase exposure conditions.

Three chlorinated ethane and ethylene solvent products were examined for their genotoxicity in the Salmonella/microsome mutagenesis and hepatocyte primary culture DNA repair assays using vapor phase exposures. The positive control in this study, monochloroethylene (vinyl chloride), induced reversion mutation of Salmonella tester strains TA100 and TA1535 with enhancement by an exogenous activation system and elicited unscheduled DNA synthesis in rat hepatocytes in culture. Exposures to 1,1,1-trichloroethane (methyl chloroform) or 1,1,2-trichloroethylene samples which contained stabilizers resulted in increased recovery of revertant colonies of Salmonella at concentrations causing greater than 96% cell killing. However, these stabilized materials did not induce DNA repair and low-stabilized trichloroethylene did not induce reversion mutation or DNA repair. Exposure of Salmonella tester strains and hepatocytes to highly toxic vapor concentrations of technical grade 1,1,2,2-tetrochloroethylene, low-stabilized and stabilized, increased reversion mutation and elicited DNA repair. Tetrachloroethylene of high purity was not genotoxic. With all of these test products, the presence of an Aroclor-induced rat liver subcellular enzyme preparation in the mutagenesis assay did not have any effect on the results. These observations suggest that stabilizers or unknown impurities normally present at low concentrations in these products are responsible for the positive responses observed at the high exposure concentrations achievable under in vitro test conditions.