The investigator is responsible for obtaining free and well-informed consent from patients before their inclusion in a study. However, it is often both difficult and lengthy to obtain informed consent from patients (11,12). Explanations regarding trial methodology, especially the randomization, are often barely understood by the patients (13,14) and can result in refusal (15). It is our very personal point of view that this explanation has to be toned down in some patients or circumstances, or the investigator must be prepared to find appropriate and simple words to explain what is a placebo-
controlled, randomized, double-blind trial and why it is necessary. In contrast, the following information has to be given to patients: expected benefits (if any), possible risks and adverse events (those frequent and those rare but severe), constraints and discomforts (e.g. number of consultations, number of blood punctures, virological tests such as HIV, genetic test, description of painful or unpleasant tests, length of participation, etc.).
Guidelines do not resolve all the situations. Is the consent really free and well-informed, in patients who are old, hospitalized and confined to bed or suffer from cognitive deficiency (16), or those who live in residential homes and are dependent on the medical and nursing staff? In these borderline cases, the responsibility remains with the investigator to participate and include patients only in useful and well-conceived studies.
In emergency conditions, when it is impossible to ask a patient for consent, e.g. patient with acute thoracic pain or airflow obstruction, informed consent must be asked by proxy (if any), and the deferred informed consent of the patient must be confirmed afterwards (by which time the trial is often over) (17-19). Even strict guidelines allow for the inclusion of patients under such emergency conditions. It would otherwise have been impossible to prove the efficacy of early administration of throm-bolytics for acute myocardial infarction (20).
The explanation of placebo is difficult, with the risks of lack of understanding, and refusal. Many Phase III trials fail to obtain a written informed consent because of the placebo (21,22). We do not know how a patient's behaviour is modified by telling him that he has a 50% chance of receiving a placebo. The objective of a trial versus placebo is precisely to evaluate the true effect of the new treatment against a placebo in patients who are unaware of their treatment allocation. In order to help the investigators, the placebo could be presented as follows in oral and written information, without being unethical: "Substance with no direct effect, but susceptible to contribute to the improvement of the disease", "Half of patients will receive active treatment and the other half a treatment devoid of active substance", "You will receive either active treatment or a treatment without specific activity", "The objective of the study is to compare the effects of 2 treatments containing or not an active substance".
It is evident that patients are unlikely to understand all the information which is given to them by whatever means during consent consultations (14). Not only do the rather abstract terms of methodology (controlled trial, randomization, double-blind) raise problems of comprehension (13), but the recall of information about the risk/benefit ratio of treatment options and prognosis (e.g. in cancer) is also limited even in the short term (23,24). Informed consent based on verbal information alone is clearly not enough (23). Moreover, information letters need to be improved. A review of a sample of 101 clinical trial protocols approved in two Spanish university general hospitals showed that the written form of information provided to the patient had serious deficiencies, either in their formal readability or in the amount and quality of the information (25).
The optimal amount of information to be given to patients is debated. Montgomery and Sneyd (26) sent a postal questionnaire to 204 patients who had taken part in clinical trials. The conclusion was that increasing the amount and complexity of information does not alter patient satisfaction. A study tested the hypothesis that a simplified consent form would be less intimidating and more easily understood by individuals with low-to-marginal reading skills (183 adults). Nearly all participants thought that the simplified form was easier to read. However, the degree to which participants understood the forms was similar for the standard and the simplified consent forms, raising concerns about the adequacy of the design of written informed consent documents for such participants (27). Edwards et al. (28) reviewed research reports which provided data on methods of obtaining informed consent. Their results suggest that there is an optimal amount of information which enhances patient understanding and which might, in turn, reduce anxiety. But giving people more information and more time to reflect tends to be associated with a lower consent rate.
Efforts are currently being made to improve the effectiveness and quality of informed consent (29), e.g. development of a model consent document in cancer clinical trials with relevant and understandable information (30), implication of non-physician personnel in the informed consent process, such as nurses (31). Jimison et al. (32) adapted a structured multimedia informed consent system for clinical trials involving patients with potential cognitive impairment (depression, breast cancer, schizophrenia). Nevertheless, the provision of clear and accurate patient information is important, but this alone will not ensure consistent interpretation of concepts such as randomization (13). A high level of reading skill and comprehension is still necessary to understand and complete most consent forms that are required for participation in clinical research studies (27). And fully informed consent for all patients is an unobtainable ideal (14).
Whatever the difficulties, not to correctly inform a patient is not only unethical (33), it is the best way of increasing the risks of patients withdrawing or being lost to follow-up, which can be detrimental to the results of the trial. The simpler the protocol, the fewer the constraints and the more effective the drug, the easier it will be to obtain the informed consent.
Subjects must also be informed about their right to strict confidentiality of their data collected during a clinical trial, which can only be reviewed by investigators, sponsors or regulatory authorities. This is particularly true for the genetic information collected during clinical trials.
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