Melamed et al of new drugs are randomized controlled trials which require research methods that often contradict accepted standards of treatment. Determination of dosage is in accordance with the re- search protocol, and may be influenced by additional agents including investigators, medical institutions, commercial and insurance companies [5]. An additional problem is that clinical trials often re- quire a washout period during which the patient receives no effective treatment. Types of studies A number of study designs can be used to prove treat- ment efficacy: placebo-controlled trials; active-drug com- parison trials, control group in comparison of dosages, his- torical control groups and control groups with no treatment [6]. The latter two designs are not considered valid for psy- chopharmacological studies. In placebo-controlled studies, or dosage comparisons, the goal is to emphasize superiority of the new drug, in any dosage, in comparison to placebo, or a lower dosage of the same drug. In a trial with a control group receiving active treatment – the aim is to prove superiority of the new drug over the ac- tive comparator. It is difficult to expect a new treatment to be better than a recognized standard therapy during the various stages of the study, therefore many investigators would pre- fer the situation where studies that plan to show equal value or non-inferiority would be considered valid. The research hypothesis that it is possible to differen- tiate between various treatments is called assay-sensitivity. This assumption is based on prior studies with active stan- dard treatments, but it should be noted that the instruments used for measurement in psychiatry are often based on ob- servation, self-report or interview and not on objective mea- sures. Some medications that are in use and considered ef- fective, have not always been proven as such in comparison to placebo. Thus, if we compare a new drug to these agents, we cannot scientifically prove that the new drug is effective, even if the trial reveals that it is of equal value to existing medications. A placebo arm in a clinical trial enables investigation of assay sensitivity. When there is no placebo arm in a trial, it may be necessary to increase the size of the study group to prove the postulation of non-inferiority, thus complicating performance of the study. In addition, in such a case more patients will be exposed to an experimental drug whose ef- ficacy has yet to be proven. Similarly, the smaller the gap, when comparing new and existing treatments, the larger the study sample needed in order for the difference to have sta- tistical significance. An additional experimental possibility which is used, for example in cardiology, is an add-on trial drug with a J Clin Med Res • 2009;1(3):132-136 placebo-control [7]. This method (placebo-controlled add- on) reduces the dilemma of administering placebo, since all participants receive active treatment. Informed Consent Due to the potential discordance between research and treatment, the patient must be aware that he/she is being treated in the framework of a research protocol and he/she must provide written informed consent. Since the compe- tency of schizophrenia patients to provide valid informed consent is questionable, stringent regulation is essential for the informed consent process involving this population. Thought disturbances and cognitive impairments char- acteristic of schizophrenia may give rise to concern regard- ing the ability of the patient to provide informed consent [8] especially patients with chronic illness [9]. In addition, the psychiatric patient who is hospitalized for long periods of time may more readily agree to partici- pate in clinical trials offered by his attending physician, be- cause of his/her dependency on the hospital. The Working Party on Research on the Mentally Inca- pacitated, London, discussed the issue [10] and determined that many people with mental impairment or disorders are able to consent to their inclusion in research provided care is taken to explain it to them. Patient’s competence should be evaluated using questionnaires designed especially for that purpose [11]. However, there are those who believe that pro- vision of informed consent neither protects the patient nor ensures an ethical basis for the study since the patient’s con- dition interferes with his/her ability to objectively weigh the various treatment options [12]. Placebo controlled trials in schizophrenia The need for new pharmacological treatments is based on the fact that some patients respond to currently avail- able antipsychotic agents with only partial improvement, especially in all aspects related to negative schizophrenia symptoms. The existing treatment for this disease is effec- tive mainly for positive symptoms and in delaying relapse of the disease in chronic patients. Moreover, the efficacy of antipsychotics in preserving cognitive functions has yet to be proven. In addition, the existing drugs, including second generation medications, have significant side-effects that may impair the health and quality of life of schizophrenia patients. In the formal sense there is no Gold Standard of care for negative symptoms, so it is necessary to engage in research that compares efficacy of the preparation to placebo [13]. In the United States, to gain Food and Drug Adminis- tration (FDA) approval, significant proof of the efficacy of the drug based on adequate controlled trials must be present- ed [14]. The majority of investigative new drug applications Articles © The authors, Journal compilation © J Clin Med Res and Elmer Press™, www.jocmr.org 133