Pharmaceutical trials in general practice: the first 100 protocols. An audit by the clinical research ethics committee of the Royal College of General Practitioners.

OBJECTIVE: To assess the outcome of 100 general practice based, multicentre research projects submitted to the ethics committee of the Royal College of General Practitioners by pharmaceutical companies or their agents between 1984 and 1989. DESIGN: Analysis of consecutive submitted protocols for stated objectives, study design, and outcomes; detailed review of committee minutes and correspondence in relation to amendment and approval; assessment of final reports submitted at conclusion of studies. SUBJECTS: 82 finally approved protocols, embracing 34,523 proposed trial subjects and 1195 proposed general practice investigators. MAIN OUTCOME MEASURES: Success at enrolling subjects and investigators; commencement and completion data; validity of final report''s assessment of efficacy, safety, tolerability, and acceptability; and method of use and dissemination of findings. RESULTS: 18 studies were not approved and 45 had to be amended. Randomised controlled trials comprised 46 of the original submissions. Remuneration considerations, inadequate information or consent sheets, pregnancy safety, the need to discontinue existing therapy, and suboptimal scientific content were major reasons for rejecting studies or asking for amendments. Of the 82 approved studies 8 were not started. Shortfalls of investigators (of 39%) and trial subjects (of 37%) and an overall 23% withdrawal rate were responsible for a significant incidence of inconclusive results. Within the six year follow up interval, only 19 of the studies had been formally published. CONCLUSIONS: This audit identified substantial ethical concerns in the process of approving multicentre general practice pharmaceutical research.     

Equipoise,design bias,and randomized controlled trials: the elusive ethics of new drug development

The concept of 'equipoise', or the 'uncertainty principle', has been represented as a central ethical principle, and holds that a subject may be enrolled in a randomized controlled trial (RCT) only if there is true uncertainty about which of the trial arms is most likely to benefit the patient. We sought to estimate the frequency with which equipoise conditions were met in industry-sponsored RCTs in rheumatology, to explore the reasons for any deviations from equipoise, to examine the concept of 'design bias', and to consider alternative ethical formulations that might improve subject safety and autonomy. We studied abstracts accepted for the 2001 American College of Rheumatology meetings that reported RCTs, acknowledged industry sponsorship, and had clinical end-points (n = 45), and examined the proportion of studies that favored the registration or marketing of the sponsor's drug. In every trial (45/45) results were favorable to the sponsor, indicating that results could have been predicted in advance solely by knowledge of sponsorship (P < 0.0001). Equipoise clearly was being systematically violated. Publication bias appeared to be an incomplete explanation for this dramatic result; this bias occurs after a study is completed. Rather, we hypothesize that 'design bias', in which extensive preliminary data are used to design studies with a high likelihood of being positive, is the major cause of the asymmetric results. Design 'bias' occurs before the trial is begun and is inconsistent with the equipoise principle. However, design bias increases scientific efficiency, decreases drug development costs, and limits the number of subjects required, probably reducing aggregate risks to participants. Conceptual and ethical issues were found with the equipoise principle, which encourages performance of negative studies; ignores patient values, patient autonomy, and social benefits; is applied at a conceptually inappropriate decision point (after randomization rather than before); and is in conflict with the Belmont, Nuremberg, and other sets of ethical principles, as well as with US Food and Drug Administration procedures. We propose a principle of 'positive expected outcomes', which informs the assessment that a trial is ethical, together with a restatement of the priority of personal autonomy.     

Choosing the programme for an international congress.

The method of selecting abstracts for an international congress at which only 15% of submitted papers could be accepted entailed a panel of 12 assessors using their specialised knowledge, but presentation of the abstract was also important is selection. There was only a limited agreement between assessors in arranging abstracts in order of merit, so that a single assessor would be unacceptable. Use of the full panel to grade all abstracts was very expensive, but it could be replaced, without unacceptable injustice, by dividing the work randomly among groups of three selectors.     

Stereotaxic cytology of brain tumors. Review of an eight-year experience

The cytologic diagnosis of 312 stereotaxic samplings performed on 292 patients suspected of having a brain tumor over an eight-year period was reviewed. At different depths of the stereotaxic track, biopsy specimens were secured for cytologic and histologic observations. Smears for cytology were stained both by the May-Grünwald-Giemsa and the Papanicolaou methods since each of them disclosed information complementary to the other. Cytology and histology were in good agreement in 87.5% of the cases. Analysis of the data revealed a cytologic sensitivity of 88.8% and a specificity of 81.9%. The main difficulty encountered was differentiating between nonspecific glial hyperplasia and low-grade astrocytoma. To a lesser degree, differentiating metastases from glioblastoma sometimes was a problem. Stress is laid on the reliability of this type of cytology, its great help when sectioning of unfit specimens makes histologic evaluation hazardous, and its obvious importance when craniotomy is not desirable but a precise pathologic diagnosis is necessary for therapeutic decision. The stereotaxic procedure is briefly reviewed, and the main cytologic findings for the principal lesions encountered are illustrated and discussed.     

Injuries from antipersonnel mines: the experience of the International Committee of the Red Cross.

OBJECTIVE--To describe and quantify patterns of injury from antipersonnel mines in terms of distribution of injury, drain on surgical resources, and residual disability. DESIGN--Retrospective analysis. SETTING--Two hospitals for patients injured in war. SUBJECTS--757 patients with injuries from antipersonnel mines. MAIN OUTCOME MEASURES--Distribution and number of injuries; number of blood transfusions; number of operations; disability. RESULTS--Pattern 1 injury results from standing on a buried mine. These patients usually sustain traumatic amputation of the foot or leg; they use most surgical time and blood and invariably require surgical amputation of one or both lower limbs. Pattern 2 injury is a more random collection of penetrating injuries caused by multiple fragments from a mine triggered near the victim. The lower limb is injured but there is less chance of traumatic amputation or subsequent surgical amputation. Injuries to the head, neck, chest, or abdomen are common. Pattern 3 injury results from handling a mine: the victim sustains severe upper limb injuries with associated face injuries. Eye injuries are common in all groups. CONCLUSIONS--Patients who survive standing on a buried mine have greatest disability. Non-combatants are at risk from these weapons; in developing countries their social and economic prospects after recovery from amputation are poor.     

Human immunodeficiency virus and drug misuse: the Edinburgh experience.

During 1985 many drug abusers who lived in Edinburgh were found to be infected with the human immunodeficiency virus (HIV). As a result an alternative counselling and screening clinic for testing for antibodies to HIV was established for use by drug abusers. Four hundred and forty one patients were counselled in the first year, and over 60% were either drug abusers or their sexual contacts. One hundred and fourteen (26%) patients were positive for HIV antibody, and 100 (88%) of these were current or former drug abusers. The HIV seropositivity rate in drug abusers was 52% but was only 7% in their sexual contacts. Services were provided for these people as well as counselling before and after the test. The cost of this counselling service for the first year was 27,000 pounds or 61.22 pounds per patient. The unexpected mobility of 23% of the Edinburgh drug abusers, particularly to other areas of Britain, suggests that similar services need to be set up elsewhere.     

Ethical and legal dilemmas arising during predictive testing for adult-onset disease: the experience of Huntington disease.

The goal of predictive testing is to modify the risk for currently healthy individuals to develop a genetic disease in the future. Such testing using polymorphic DNA markers has had major application in Huntington disease. The Canadian Collaborative Study of Predictive Testing for Huntington Disease has been guided by major principles of medical ethics, including autonomy, beneficence, confidentiality, and justice. Numerous ethical and legal dilemmas have arisen in this program, challenging these principles and occasionally casting them into conflict. The present report describes these dilemmas and offers our approach to resolving them. These issues will have relevance to predictive-testing programs for other adult-onset disorders.     

Parasitism of arbuscular mycorrhizal fungi: reviewing the evidence.

In order to understand the functioning of mycorrhizal fungi in ecosystems it is necessary to consider the full suite of possible biotic interactions in the soil. While a number of such interactions have recently been shown to be crucially important, parasitism is a highly neglected feature in the ecology of arbuscular mycorrhizal fungi (AMF). A number of studies have classified some interactions between populations of bacteria and fungi with AMF as parasitism, generating discussion about its consequences at both 'parasite' and host population levels. This paper reviews these various publications, and based on a set of criteria that are necessary to demonstrate parasitism, it was concluded that parasitism has not been conclusively shown to exist in AMF, even though some data are highly suggestive of such a relationship. The difficulties in gathering data supportive of parasitism were discussed, and hypotheses for defense were offered. This paper concludes by presenting potential consequences of AMF parasitism at the population/community levels and by discussing applied aspects.     

Clinical trials of the treatment of breast cancer in Britain and Ireland. Report by co-ordinating committee.

Thirteen trials of systemic chemotherapy in early breast cancer were identified and protocols obtained. The differences in the latter prevented a true comparison of the results. In setting up any trial it is important to define the primary objectives and to include a statistician from the start. Only truly random allocation of patients is acceptable, while treatment programmes must be fully monitored. Other important aspects include review of the results by an independent member of the trial committee and keeping full, but simple, case records. Though any trial must be designed by a committee and not a single investigator, the individual clinician remains responsible for the patients under his care. To launch a controlled randomised trial without full preparation and guaranteed resources is in the best interests of neither patients nor doctors.     

Review. The neurobiology of pathological gambling and drug addiction: an overview and new findings

Gambling is a prevalent recreational behaviour. Approximately 5% of adults have been estimated to experience problems with gambling. The most severe form of gambling, pathological gambling (PG), is recognized as a mental health condition. Two alternate non-mutually exclusive conceptualizations of PG have considered it as an obsessive-compulsive spectrum disorder and a 'behavioural' addiction. The most appropriate conceptualization of PG has important theoretical and practical implications. Data suggest a closer relationship between PG and substance use disorders than exists between PG and obsessive-compulsive disorder. This paper will review data on the neurobiology of PG, consider its conceptualization as a behavioural addiction, discuss impulsivity as an underlying construct, and present new brain imaging findings investigating the neural correlates of craving states in PG as compared to those in cocaine dependence. Implications for prevention and treatment strategies will be discussed.