Rules Of Good Clinical Practice Research Articles

Prescriptions hors AMM supervisées de méthylphénidate dans le TDAH de l’adulte

ObjectiveOff-label prescription is a common practice in psychiatry, raising health and economic concerns. Collegial consultation could allow a framed prescription of treatments that are not authorized in specific indications. Attention Deficit Hyperactivity in adult populations (ADHD) is a striking example of a pathology where off-label prescription is frequent. First considered to be a childhood disorder, the awareness of this condition in adults is increasing, leading to the development of new clinical practices and treatments. However, the adult ADHD diagnosis and its management are still emerging in France despite a high prevalence. Treatment of adult ADHD relies on methylphenidate prescription, but the initiation of this drug is not authorized in adult populations. Methylphenidate is a central nervous system stimulant that is structurally close to amphetamine and acts as a norepinephrine and dopamine reuptake inhibitor. Due to these pharmacological properties, neuropsychiatric and cardiovascular side-effects could occur. Furthermore, its addictive potential has led France to classify it as a psychoactive drug, dispensed via secured prescription. The first prescription and the one-year follow-up are restricted to neurologists, paediatrics, psychiatrists and sleep disorders specialists at hospital. The objective of this article is to propose a multidisciplinary framework for the off-label prescription of methylphenidate in adult ADHD. MethodsThe Multidisciplinary Advice Consultation for Exceptional Addiction Treatments (Consultation d’Avis Multidisciplinaire de Traitements d’Exception en Addictologie CAMTEA) was first set up in Lille for the prescription of baclofen in alcohol dependence and was then extended to topiramate in binge eating disorder. This procedure has been adapted to the particularities of ADHD in adult populations, the differential diagnosis (bipolar disorder, depressive disorder, anxious disorder, personality disorder, substance use disorder) and the co-morbidities requiring a full psychiatric and neuropsychological assessment. Moreover, a particular attention has been paid to the monitoring of neuropsychiatric, cardiovascular and misuse risk because of the potential side-effects of methylphenidate. ResultsThe proposed prescription framework is structured into several specialized consultations. A first psychiatric evaluation aims to diagnose adult ADHD, using the French version of the Diagnostisch Interview Voor ADHD 2.0 questionnaire (DIVA 2.0), and to assess the quality of life impact with the Weiss Functional Inventory Rating Scale (WIFRS). It also searches for the presence of differential diagnosis or co-morbidities. The second appointment consists of a pharmacological evaluation that aims to search for contraindications and potential drug interaction. A neuropsychological evaluation based on standardized tests (Weschler Adulte Intelligence Scale [WAIS IV], Conner's Continuous Performance Test 3 [CPT] and the Minnesota Multiphasic Personnality Inventory [MMPI]) is also required to evaluate neurocognitive disabilities and personality features. Once the parameters of the different assessments have been collected, the synthesis is presented during a multidisciplinary meeting in order to assess the risk-benefit ratio for each patient. Several specialties are involved in this multidisciplinary meeting: psychiatry, addictology, general medicine, addictovigilance, pharmacovigilance and neuropsychology. One strategy among three possibilities can be decided: (1) contraindication to treatment with methylphenidate, (2) attention deficit disorder that does not require medication management, and (3) indication of treatment with methylphenidate with the choice of the pharmacological form (immediate or prolonged release). A biological check-up and an electrocardiogram are carried out systematically before any treatment. If the decision is made to initiate treatment, it is started at the lowest dosage and followed by a titration phase. A weekly follow-up is carried out during the titration phase in order to assess treatment efficacy and safety. After treatment stabilization, the general practitioner can carry out the renewal, and the patient will be reassessed within the framework of the multidisciplinary consultation every 3 months. ConclusionWhen an off-label prescription is being considered, it must comply with the basic rules of good clinical practice, and the benefit/risk ratio should be constantly reassessed. The proposed multidisciplinary framework, adapted to the characteristics of adult ADHD and the pharmacological properties of methylphenidate, appears to be an interesting strategy to meet the requirements of the good clinical practice. The complementary assessments carried out and the collegial framework allow enhancing the patient's follow-up and minimize the drug risk, particularly in the psychiatric, addictive and cardiovascular adverse events. Finally, this framework could also help the monitoring of other off-label treatments for ADHD, such as atomoxetine or guanfacine.

Transcorneal Electrical Stimulation for Patients With Retinitis Pigmentosa: A Prospective, Randomized, Sham-Controlled Follow-up Study Over 1 Year.

After promising results of an exploratory study, this study was designed to assess the safety and efficacy of transcorneal electrical stimulation (TES) over 1 year in patients with retinitis pigmentosa (RP). We included 52 RP patients in this prospective, randomized, partially-masked study which was done in accordance with rules of good clinical practice. Transcorneal electrical stimulation by Okustim was applied monocularly for 30 minutes per week for 52 consecutive weeks. Patients were assigned randomly to the groups: sham, 150%, or 200% of individual electrical phosphene threshold (EPT). Visual acuity (retroilluminated Snellen charts), visual field (VF; Octopus 900), electroretinography (ERG), rod and cone full-field stimulus threshold, EPTs and IOP were assessed. Primary outcome measures were VF area; secondary outcome measures were development of ERG parameters. The application of TES was tolerated well. Dry eye symptoms (31 of 52 patients) were registered as the main adverse event. Throughout the study period, the VF area showed only a trend for prevention of VF loss in the 200% group (P = 0.24). A significant improvement of light-adapted single flash b-wave was noted for the 200% (P < 0.0001) and 150% (P = 0.006) groups compared to the sham group. Tendencies of improved function were observed for scotopic b-wave amplitude for the 200% group (P = 0.097). Other examination methods did not reach statistical significance. The safety and acceptable tolerability of weekly TES self-administered by patients at home was confirmed over the course of 1 year. Objectively measured improvements in retinal function with ERG provide support for the potential benefits of TES for RP patients.

Engineering and ethical constraints

Written publications of scientific research are by necessity unambiguous and objective. Even the format of the manuscripts conforms to globally accepted standards. It is dry reading, devoid of subjectivity and emotion. Yet, among the hundreds of manuscripts received by the Editors of a scientific Journal like MBEC, some manuscripts are encountered that do evoke a subjective response. This editorial deals with the ethical boundaries of engineering research, encountered in one of those manuscripts. Pain research is an important field in Medicine. Many diseases cause pain. Many patients suffer from unbearable pain of unknown origin and require analgesics, such as opiates, or neurosurgery for its suppression. Therefore, non-invasive engineering solutions to quantify the severity of pain may appear useful. Of course, the careful scientific approach to such an application is that the method is validated and this requires comparison of the subjective pain to the objective measure of it. There are various ways to achieve this. One may be to ask a patient who is in pain to subject himself to the novel method before being treated (with the least possible delay of treatment guaranteed) and to compare the outcome to a person not in pain, or even to the same person after pain relief. Of course, this can only be done after obtaining full informed and written consent of the patients, after approval of the protocol by the Medical Ethical Committee, by adhering to Good Clinical Practice rules, and by conforming to the declaration of Helsinki. Alternative approaches to address the above research question are also possible and may involve application of unbearable pain to healthy ‘volunteers’. This is where we are treading unethical territory, because how can a normal person volunteer to undergo unbearable pain? How can a doctor induce unbearable pain in a subject that she would normally anaesthetize before the intervention? Is it ethical to withhold treatment for the prevention of pain? If a healthy subject tells (or shows) the doctor that the pain is unbearable why should we need a scientific quantification other than for the purpose of torture? All manuscripts submitted to MBEC dealing with human experimentation must state that the described work conforms to the rules mentioned above. For animal research similar regulations apply. But even if all ethical standards are met, one still needs to ask oneself whether the approach conforms to global and individual moral standards. History has taught us that in times of international conflict ethical standards are under duress. Horrible examples are the gruesome Nazi-experiments in the World War II concentration camps [1] and the horrendous Unit 731 experiments of Japan [3]. The question whether these data should be used or referred to is dealt with by David Bogod [2] and Kristine Moe [4]. Apart from this question, the engineering society has to be vigilant to prevent present or future transgressions of moral and ethical standards, particularly of work from countries in areas of conflict. One of us (H.V.) has commented on the Bill of Rights of Scientists and Engineers as defined by Henlee [5]. The last article of this Bill states: ‘At all times a [Scientist/Engineer] shall adhere to universal ethical and moral standards’. It is this universal and permanent duty of all scientific workers that we wish to underscore.

Enquête nationale sur la curiethérapie dans le cancer du sein : état des lieux et perspectives en 2009

Purpose To present the national survey patterns in France for breast cancer brachytherapy in 2009. Material and method A written questionnaire was sent to the academic and general hospitals and the anticancer centres. The different items were type of institution; breast cancer clinical trial participation; number of breast brachytherapy per year; its indications; material and dose rate used. Results Among the 76 sent questionnaires, 35 (46 %) answers were available: 9 % of academic hospitals and 50 % of cancer centres performed breast brachytherapy. The number of breast brachytherapy per year ranged between 300 and 350. The indications were boost (100 %), partial breast irradiation (20 %) and second conservative treatment for local recurrence (53 %). The implanted material consisted in needles (27 %) and plastic tubes (73 %). The dose rate was low (50 %), pulsed (25 %) and high (25 %). Conclusion Breast brachytherapy appears as a validated technique in case of boost but remains under investigation for partial breast irradiation and second conservative treatments. Good clinical practice rules as well as technical and dosimetric guidelines are needed. A cost-effective analysis of breast brachytherapy is warranted.

Developing Regulatory-compliant Electronic Case Report Forms for Clinical Trials: Experience with The Demand Trial

The use of electronic case report forms (CRF) to gather data in randomized clinical trials has grown to progressively replace paper-based forms. Computerized form designs must ensure the same data quality expected of paper CRF, by following Good Clinical Practice rules. Electronic data capture (EDC) tools must also comply with applicable statutory and regulatory requirements. Here the authors focus on the development of computerized systems for clinical trials implementing FDA and EU recommendations and regulations, and describe a laptop-based electronic CRF used in a randomized, multicenter clinical trial.

Résistance aux antiagrégants plaquettaires : le point de vue du cardiologue

The concept of resistance to aspirin and clopidogrel, initially described in the laboratory, has currently been reinforced with recent epidemiological clinical data. One of the elements of particular importance for the cardiologist is the possible participation of this resistance in the process of coronary stent thrombosis, a problem which appeared to be solved early in the 1990s with the introduction of thienopyridines. This complication has however become preoccupying again, particularly when occurring late, notably since the widespread use of biologically active coronary endoprostheses. Nevertheless, the debate continues concerning the usefulness of the biological definition of this concept since we still do not have correctly standardized coherent biological tools that can be used in the clinical setting to detect "resistant" patients. Since there is no real therapeutic strategy which should be applied in the event of resistance, there still is little interest in developing screening methods. But the cardiology community can learn from this concept. We should revisit the principles of revascularization within the framework of the rules of good clinical practice, without speculating about the possible therapeutic finality which might develop should such and such a phenomenon occur.

The Development of Ethical Review Practices in Eastern Europe and Central Asia

The countries of Eastern Europe and Central Asia are the heirs to Soviet history, public healthcare and education systems, values and research ethics. In healthcare and healthcare research, the disintegration of the Soviet Union and subsequent formation of independent states has been accompanied by the appearance of foreign pharmaceutical manufacturers, research companies and international multicentre projects in the medical markets of these countries. To fully participate in the international research environment, it was a necessity for the Eastern European and Central Asian countries to introduce the international rules of Good Clinical Practice (GCP) into medical research. It was also necessary to develop ethics review practices that adhered to international standards through the development of bioethics legislation, the organization of independent ethical committees at the national and local level and the training of physicians and research scientists in bioethics and GCP. These changes, along with the democratic transformation to post-Soviet political systems, began in the early 1990s and have enabled the formation of the current ethics review practices in the Eastern European and Central Asian countries. The shared history of countries in this region has made regional collaboration particularly effective and productive. This regional collaboration has lead to the formation of the Forum of Ethics Committees in the Confederation of Independent States (FECCIS), supported by the World Health Organization, and the Good Clinical Practice Alliance — Europe, which forms the organizational basis for such cooperation.

Safety and Efficay of BION Implant During Radiation Therapy

Objective To determine the safety and efficacy of BION implants during radiation therapy (XRT) of head and neck cancer (HNC). The implants were placed to treat complications of muscle disuse for swallowing. Methods Three patients who underwent surgery for HNC received BION implants. The study was conducted under rules of good clinical practice under an Investigational Device Exemption from the U.S. FDA and monitored by the University of Southern California IRB. The implant was placed 2–3 mm above and parallel to the hypoglossal nerve just proximal to the origin of the ansa cervicalis. Two patients started XRT 3–4 weeks after surgery. The third patient did not need XRT. Two sets of stimulation protocols are used: low (low frequency, supramaximal twitch) and high (strong, fused contractions - 20–30pps). Results No postoperative or implant specific complication was noted. During radiation therapy, the implants were stimulated. All patients tolerated stimulation without pain or discomfort. Visible contraction of base of the tongue muscles and muscles of laryngeal elevation was observed by using an external coil. All patients received high stimulation. The patients were provided with the coils and they continue to stimulate these muscles at home 3 times a day for a total of 1h/d. All patients maintained their oral feeding and weight during treatment of cancer. Conclusions BION is safe device to implant for stimulation of swallowing muscles. It effectively stimulate the hypoglossal and ansa cervicalis nerves. Robust contraction of swallowing muscles are visible during stimulation.

The controversial link between antidepressants and suicidality risks in adults: data from a naturalistic study on a large sample of in-patients with a major depressive episode

Some meta-analyses of randomized placebo-controlled trials on antidepressants conclude that there might be an increased risk for suicidal behaviour, especially in children and adolescents but also in adults. Placebo-controlled trials exclude patients with serious suicidality and might therefore underestimate the risk of respective adverse events. The change of suicidal ideation and the prevalence of suicides and non-fatal suicide attempts were therefore analysed in a large naturalistic prospective multicentre study of depressed in-patients. Additionally, specific risk factors for new emergence of suicidal ideation were investigated. The naturalistic prospective study was performed in 12 psychiatric hospitals of the German research network on depression and suicidality (seven psychiatric university hospitals and five district hospitals) in Germany. All patients (n=1014) were hospitalized and had to meet DSM-IV criteria for major depressive disorder. Six events were defined for the purposes of statistical analysis: 'emergence', 'extended emergence', 'improvement' and 'worsening of suicidal ideation', 'suicide attempts' and 'suicides'. Logistic regression analysis and classification and regression trees (CART) analyses were conducted to determine specific risk factors for new emergence of suicidal ideation. The mean HAMD total score decreased from 24.8 at baseline to 10 after 10 wk. An effect on suicidality was evident by week 2 in the sense of a decrease of the mean HAMD item-3 score. Emergence, worsening and improvement of suicidal ideation occurred in 3.2%, 14.74% and 90.79% of patients, respectively. A total of 10 suicide attempts and two suicides were reported. The rate of suicides (13.44/1000 patient-years) was rather low and comparable to the rate observed in randomized controlled antidepressant trials. Five risk factors for emergence of suicidal ideation were determined with two independent statistical methods: age (with higher risk at age <45 yr), treatment resistance, number of hospitalizations, presence of akathisia and comorbid personality disorder. Age <45 yr as one of five risk factors for the emergence of suicidal ideation is in line with the meta-analysis performed for the recent US Food & Drug Administration (FDA) memorandum; although the naturalistic study design does not permit definite conclusions to be made about certain compounds. The rate of suicides was comparable to that seen in randomized controlled trials, as were the rates of emergence and worsening of suicidal ideation, but more improvement was found. Thus, in-patient treatment in a psychiatric care setting, including daily assessments of suicidality by trained psychiatrists adhering to the rules of good clinical practice (e.g. use of specific co-medications, supportive psychotherapy and continuous medical attendance by nursing staff) might be beneficial.

Bioethical committees and data protection issues in Poland

In Poland there are only Regional Bioethical Committees. Unlike most EU countries Poland has no coordinating centre on bioethics for human research. However, the Ministry of Health and Welfare has established a Bioethics Appeals Committee.The functioning of the Bioethical Committees in Poland is regulated in detail by the Regulation of the Ministry of Health and Welfare of 1999. All regulations comply with important guidelines such as: the Helsinki Declaration, The Rules of Good Clinical Practice, EU Directives and legal regulations binding in Poland, mainly the Act of the Medical Doctor Profession and the Dentist Profession, as well as the Act of Pharmaceutical Law.In the framework of the Human Biomonitoring Programme, the application for bioethical evaluation will be submitted to the Bioethical Committee at the Nofer Institute of Occupational Medicine in Lodz.The data protection legislation in Poland according to the Act of the Protection of Personal Data of 29th of August 1997 with latest amendments fulfils EU regulations. The Act also contains detailed provisions regarding the duties of the Inspector General for Data Protection. The paper presents data on the activities of the Bureau of the Inspector General for Personal Data Protection in 2005, 2006 and 2007.

Briefpatienten - Die Geschichte der Konsiliarkorrespondenz - Einst weit verbreitete Praxis, erlebt sie heute eine gewisse Renaissance

Nowadays, a medical treatment without the personal meeting of the patient and the physician for the initial anamnesis and physical examination is regarded as offending the rules of good clinical practice. For the longest time, however, the epistolary consultation was a wide-spread and well-established practice. The patients' letters preserved in the correspondences of renowned physicians represent one of the main sources for medical historians who try to investigate in the feelings, thoughts and behaviour of patients of the early modern period. The paper discusses the rise and decline of the phenomena of consulting correspondence, analyses the advantages this praxis had both for the patients as for the physicians involved, and presents one example from the correspondence of the physician and surgeon Lorenz Heister (1683-1758).

Defibrillation testing at the time of implantation of cardioverter defibrillator in the clinical practice: a nation-wide survey

Despite an effective defibrillation testing (DT) is considered mandatory to be consistent with the rules of good clinical practice, some physicians are concerned about the risk of complications related to the induction test, and in real world clinical practice, several implant procedures are performed without any induction test. We conducted a systematic nation-wide retrospective survey in order to determine the DT rate and its complications. An ad hoc questionnaire was sent to all 343 Italian implanting centres and the data from the 229 (67%) centres that answered were analysed. During the year 2005, a total of 7857 patients underwent a first implantation of cardioverter defibrillator (ICD), 38% of which with cardiac resynchronization therapy (CRT). Of these, 2356 (30%) were implanted without any induction test. In 35 (15%) centres, the induction test was performed in < 25% of the patients, whereas in 136 (59%) centres, it was performed in > 75% of the patients. At multivariable analysis, performed in a subset of 1206 patients from 107 centres, CRT device (OR = 1.82) and primary prevention (OR = 1.47) were independent predictors of the decision to not perform DT. However, altogether, the clinical variables accounted only for 35% of the total variance, whereas the remaining 65% was probably unrelated to clinical factors. There was a total of 22 (0.4%) life-threatening complications as a consequence of the induction test: 4 deaths (0.07%), 8 cardiopulmonary arrests requiring resuscitation manoeuvres (0.15%), 6 cardiogenic shocks (0.11%), 3 strokes (0.05%), and 1 pulmonary embolism (0.02%). In real world practice, DT is not performed in a substantial number of patients, most of these in the absence of legitimate reasons. The clinical impact of DT vs. no DT remains unclear until the not negligible complication rate is compared against the long-term potential benefit.

Efficacy and tolerability of 0.2% brimonidine tartrate for the treatment of acute non-arteritic anterior ischemic optic neuropathy (NAION): a 3-month, double-masked, randomised, placebo-controlled trial

Neuroprotection may be an option in ischemic optic nerve disease. There have been promising reports about the neuroprotective ability of topical brimonidine in animal studies. Therefore, we tested whether 0.2% brimonidine tartrate could improve the outcome of patients with non-arteritic anterior ischemic optic neuropathy (NAION). The study was stopped after an interim analysis, having not proven its feasibility within practicable time frame. A 3-month, double-masked, placebo-controlled, randomised European multicenter trial conducted according to good clinical practice rules. Thirty-six patients (22 m, 14 f), older than 40 years with first eye involvement and typical signs of NAION were included in the study within the 1st week after visual loss (VA 0.05-1.0) and were randomized to treatment with either brimonidine 0.2% (Alphagan) or placebo. Visual acuity (VA, primary endpoint), visual field (VF, Humphrey 30-2 and Goldmann, quantified by a modified Esterman grid) and automated swinging flashlight test (SWIFT) were performed at baseline, 2 weeks, 4 weeks and 12 weeks after first visit. Primary analysis aimed at intention-to-treat group (ITT, n=29), secondary analysis to the per protocol population (PP, n=25). Tolerability and safety were tested in the safety group (n=36). A two-sample two-sided t-test was used for statistical analysis (alpha level at 0.05). VA did not show statistically significant difference by treatment. There were non-significant trends for better visual field results in the brimonidine group. Adverse events consisting of local irritation were observed six times in the verum and three times in the placebo group. No serious adverse events occurred. In contradiction to an open-labeled, retrospective study published by Fazzone et al., the results of this trial did not indicate any harmful effect of brimonidine in patients suffering from NAION. However, a statistically significant advantage for the patients receiving brimonidine tartrate could not be shown.

Nordic Myeloma Study Group, the first 15 years: scientific collaboration and improvement of patient care

The accomplishments of the Nordic Myeloma Study Group (NMSG) during its first 15 yr are briefly surveyed, together with a discussion of principles guiding the group's clinical trials and of problems that need to be addressed in coming years. The group has so far carried out 12 clinical trials, comprising more than 2500 patients, spanning from minor phase II to large randomised phase III trials. At the time of writing, two randomised trials are running (comparing two doses of i.v. pamidronate, and melphalan-prednisone (MP) vs. MP-thalidomide to elderly patients). The group has strived for a simple organisation with much responsibility delegated to regional coordinators (Denmark 3, Norway 5, Sweden 5). With regard to trial design, the group has considered it important that studies are based on sound scientific questions, are simple to handle for the participants, population based, investigator initiated, include quality of life and health resources assessment as end-points, and can be used as basis for diverse scientific spin-off projects. Like other clinical trial groups, NMSG faces a number of challenges in coming years. The financial situation for independent investigator-initiated trials is far from satisfactory, especially with regard to the resource-consuming implementation of more stringent good clinical practice rules and ethical committee demands. NMSG has also encountered increasing difficulties in recruiting patients to recent trials, partly because of problems related to participating physicians (lack of support, laborious paper work, insufficient credit for participation). Solutions to these problems have to be found if industry-independent clinical trial groups are to survive.

Implementing a randomized controlled trial with granulocyte colony-stimulating factor prophylaxis to improve the outcome of high-risk patients with colorectal cancer in the complex clinical setting of multiple surgical interventions

Abstract Background All large multicentre trials with immune modifiers in sepsis faded despite promising preclinical results. Several reasons for this have been discussed in the literature and include patient heterogeneity, different phases of pathophysiological state and trial errors. There are two additional and important points: the interaction of immune modifiers with the complex clinical management was not analysed preclinically and in multicentre trials the surgical management was not standardized. Methods Before implementing the clinical trial, the interaction of granulocyte colony-stimulating factor (G-CSF) with various surgical interventions was analysed in clinical modelling randomized trials (CMRTs) in rats, including different antibiotics, heparin, H1 and H2 antagonists, abdominal lavage, and management of preoperative and intraoperative bleeding. Good clinical practice rules were applied and the complexity of clinical reality was modelled in the CMRTs. In the clinical trial, high-risk patients (American Society of Anesthesiologists grades III and IV) with colorectal cancer were identified and randomized to the placebo and G-CSF groups (n = 40 per group). G-CSF prophylaxis (300 μg) was given subcutaneously 12 h before, and 12 and 36 h after operation. The three primary endpoints were health status measured with a modified McPeek index over 6 months, self-reported quality of life determined with the European Organization for the Research and Treatment of Cancer QLQ38 questionnaire and the true endpoint defined 6 months after operation. Results Implementation of the trial demonstrated that a high standardization of surgical management is not possible in multicentre trials since the surgical management of patients with colorectal cancer is heterogeneous and management of the most important complication, anastomotic leakage after colorectal surgery, is performed according to personal experience and is not based on high levels of evidence from clinical trials low evidence based medicine (EBM). For this reason the surgical management of patients in the trial should be defined, a centre-based clinical guideline for the management of anastomotic leakage applied and adherence to the guideline recorded. Conclusion Without CMRTs to analyse the interaction of immune modifiers in complex settings and defined clinical management of patients, no positive results will be obtained from such clinical trials.

Measurement of patient compliance and the interpretation of randomized clinical trials

The aim of this review is to demonstrate why the management of compliance, although not an explicit feature of the rules of Good Clinical Practice, is essential to the successful conduct of clinical trials and in correct interpretation of the results. Methods to measure compliance in randomized clinical trials are also described. The relevant literature was retrieved by a manual search of the Cumulated Index Medicus 1975-1989 and a MEDLINE computer search of publications in 1990 using the Medical Subject Headings "patient compliance" and "clinical trials". All retrieved articles are discussed. Research into patient compliance has stagnated because of the lack of a "gold" standard of measurement. Nevertheless, management of compliance at the different stages of clinical trials is necessary; at trial design, compliance should be taken into account in sample size calculations; during the conduct of a trial, compliance should be monitored in order to safeguard the power of the study; and in interpretation of trial results, compliance data are helpful both in order to avoid erroneous conclusions and to enrich the value of the data. Compliance should be measured in all limbs of randomized trials, including the placebo limb, without breaking trial blinding. A classification of compliance behaviour into six types (complier, partial complier, overuser, erratic user, partial dropout and dropout) is proposed, based on the changes in the risk-benefit ratio produced by non-compliance. The use of deuterium oxide, low dose phenobarbitone (2 mg per day), digoxin (2.2 micrograms per day) and the new electronic monitoring devices are suitable methods for measurement in clinical trials.