Article

Ethical Considerations in Clinical Trials in Asia

Authors:
Article

Ethical Considerations in Clinical Trials in Asia

If you want to read the PDF, try requesting it from the authors.

Abstract

Clinical trials, by their very nature, are a kind of second choice involving uncertainty from the beginning. The inherent characteristics of clinical trials necessitate ethical considerations. Ethical analysis emphasizes the importance of medical indications, patient preferences, trial quality, and contextual features. Instances of clinical trial misconduct are usually due to insufficient analysis of medical indications, which ignore patient preferences and the way in which investigators assess clinical trial results. These problems are universal concerns. In the context of clinical trials, these are subjective needs in every society. For clinical trials conducted in Asia, ethics must consider the specific needs and benefits of Asian people.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the author.

ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Maternal-infant transmission is the primary means by which young children become infected with human immunodeficiency virus type 1 (HIV). We conducted a randomized, double-blind, placebo-controlled trial of the efficacy and safety of zidovudine in reducing the risk of maternal-infant HIV transmission. HIV-infected pregnant women (14 to 34 weeks' gestation) with CD4+ T-lymphocyte counts above 200 cells per cubic millimeter who had not received antiretroviral therapy during the current pregnancy were enrolled. The zidovudine regimen included antepartum zidovudine (100 mg orally five times daily), intrapartum zidovudine (2 mg per kilogram of body weight given intravenously over one hour, then 1 mg per kilogram per hour until delivery), and zidovudine for the newborn (2 mg per kilogram orally every six hours for six weeks). Infants with at least one positive HIV culture of peripheral-blood mononuclear cells were classified as HIV-infected. From April 1991 through December 20, 1993, the cutoff date for the first interim analysis of efficacy, 477 pregnant women were enrolled; during the study period, 409 gave birth to 415 live-born infants. HIV-infection status was known for 363 births (180 in the zidovudine group and 183 in the placebo group). Thirteen infants in the zidovudine group and 40 in the placebo group were HIV-infected. The proportions infected at 18 months, as estimated by the Kaplan-Meier method, were 8.3 percent (95 percent confidence interval, 3.9 to 12.8 percent) in the zidovudine group and 25.5 percent (95 percent confidence interval, 18.4 to 32.5 percent) in the placebo group. This corresponds to a 67.5 percent (95 percent confidence interval, 40.7 to 82.1 percent) relative reduction in the risk of HIV transmission (Z = 4.03, P = 0.00006). Minimal short-term toxic effects were observed. The level of hemoglobin at birth in the infants in the zidovudine group was significantly lower than that in the infants in the placebo group. By 12 weeks of age, hemoglobin values in the two groups were similar. In pregnant women with mildly symptomatic HIV disease and no prior treatment with antiretroviral drugs during the pregnancy, a regimen consisting of zidovudine given ante partum and intra partum to the mother and to the newborn for six weeks reduced the risk of maternal-infant HIV transmission by approximately two thirds.
Article
Full-text available
It was published almost 3 years ago that zidovudine administered orally to HIV-infected pregnant women, intravenously during labor, and later administered to newborn infants reduces the incidence of HIV infection in infants by two-thirds. This regimen, known as the ACTG 076 regimen and capable of saving the life of one of every seven infants born to HIV-infected women, subsequently became the standard of care in the US. However, the high cost of zidovudine and the ACTG 076 regimen impedes their use in developing countries. A regimen as effective but less expensive than ACTG 076 is therefore highly desirable in countries worldwide, but especially in developing countries. The authors oppose the use of placebo-controlled trials as unethical in the search for alternative antiretroviral drug regimens to prevent the perinatal transmission of HIV. 15 trials in developing countries are identified in which some or all of the participants are not being provided with antiretroviral drugs. Those studies violate recent guidelines designed specifically to address ethical issues regarding studies in developing countries. An urgent need exists to develop and adhere to a universally recognized code of ethics for medical research upon human subjects.
Article
Full-text available
To assess satisfaction of patients who participate in clinical trials requiring informed consent and to analyse factors determining patient satisfaction. The survey took place in 26 clinical trials at the University Hospital Maastricht (azM), The Netherlands. A personal interview and telephone questionnaire were used consecutively (n= 135; 135 out of 172=78.5% response rate) to measure patient's expectancies before starting the trial during the informed consent procedure and to evaluate aspects of trial participation. An additional control group of 34 patients was interviewed only by telephone (100% response). Satisfaction was assessed in two distinct ways: first, by measuring the patient's subjective evaluation of several aspects of trial participation; secondly, by comparing prior expectations and subsequent evaluations. Patient satisfaction was subdivided with respect to medical-technical, interpersonal and organizational aspects of trial participation. Changes in patient's health and illness perceptions were regarded as confounding factors in the relationship between satisfaction and its possible causes. Although patient satisfaction was quite high, dissatisfaction with aspects of trial participation became apparent when both prior expectations and subsequent evaluations were compared with each other. Prior expectations and general attitudes towards medical care and research before entering the trial have an impact on satisfaction with aspects of trial participation (10-20% explained variance). No linear relationship was found between perceived improvements in health and illness conditions and patient satisfaction with trial participation.
Article
Full-text available
The news media are an important source of information about new medical treatments, but there is concern that some coverage may be inaccurate and overly enthusiastic. We studied coverage by U.S. news media of the benefits and risks of three medications that are used to prevent major diseases. The medications were pravastatin, a cholesterol-lowering drug for the prevention of cardiovascular disease; alendronate, a bisphosphonate for the treatment and prevention of osteoporosis; and aspirin, which is used for the prevention of cardiovascular disease. We analyzed a systematic probability sample of 180 newspaper articles (60 for each drug) and 27 television reports that appeared between 1994 and 1998. Of the 207 stories, 83 (40 percent) did not report benefits quantitatively. Of the 124 that did, 103 (83 percent) reported relative benefits only, 3 (2 percent) absolute benefits only, and 18 (15 percent) both absolute and relative benefits. Of the 207 stories, 98 (47 percent) mentioned potential harm to patients, and only 63 (30 percent) mentioned costs. Of the 170 stories citing an expert or a scientific study, 85 (50 percent) cited at least one expert or study with a financial tie to a manufacturer of the drug that had been disclosed in the scientific literature. These ties were disclosed in only 33 (39 percent) of the 85 stories. News-media stories about medications may include inadequate or incomplete information about the benefits, risks, and costs of the drugs as well as the financial ties between study groups or experts and pharmaceutical manufacturers.
Article
Full-text available
Children with gastrointestinal infections caused by Escherichia coli O157:H7 are at risk for the hemolytic-uremic syndrome. Whether antibiotics alter this risk is unknown. We conducted a prospective cohort study of 71 children younger than 10 years of age who had diarrhea caused by E. coli O157:H7 to assess whether antibiotic treatment in these children affects the risk of the hemolytic-uremic syndrome and to assess the influence of confounding factors on this outcome. Estimates of relative risks were adjusted for possible confounding effects with the use of logistic-regression analysis. Among the 71 children, 9 (13 percent) received antibiotics and the hemolytic-uremic syndrome developed in 10 (14 percent). Five of these 10 children had received antibiotics. Factors significantly associated with the hemolytic-uremic syndrome were a higher initial white-cell count (relative risk, 1.3; 95 percent confidence interval, 1.1 to 1.5), evaluation with stool culture soon after the onset of illness (relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.8), and treatment with antibiotics (relative risk, 14.3; 95 percent confidence interval, 2.9 to 70.7). The clinical and laboratory characteristics of the 9 children who received antibiotics and the 62 who did not receive antibiotics were similar. In a multivariate analysis that was adjusted for the initial white-cell count and the day of illness on which stool was obtained for culture, antibiotic administration remained a risk factor for the development of the hemolytic uremic syndrome (relative risk, 17.3; 95 percent confidence interval, 2.2 to 137). Antibiotic treatment of children with E. coli O157:H7 infection increases the risk of the hemolytic-uremic syndrome.
Article
Full-text available
This article analyzes the development of the concept of informed consent in the context of the culture and economics of Japanese medicine, and locates that development within the framework of the nation's civil law system. Part II sketches the cultural foundations of medical paternalism in Japan; explores the economic incentives (many of them administratively directed) that have sustained physicians' traditional dominant roles; and describes the judiciary's hesitancy to challenge physicians' professional discretion. Part III delineates the forces testing the paternalist model: the undermining of the physicians' personal knowledge of their patients that accompanies the shift from neighborhood clinic to high-tech hospital medicine; the increasing sophistication of consumers of medical services, and their appetite for medical information; the rise of medical quality control issues, and patients' rights groups; and the influence of the movement for transparency, or openness in decisionmaking, in Japanese society as a whole. In particular, the article stresses the importance of two critical developments in focusing attention on informed consent: the debate over brain death and organ transplantation, and the enforcement by the Ministry of Health and Welfare of 'good clinical practice' rules governing clinical trials of investigational drugs.
Article
Effective, feasible interventions to prevent perinatal transmission of HIV-1 in developing nations are an urgent necessity. Scientific issues of concern include a need to identify other effective antiretroviral agents; to define the shortest effective course of therapy; to assess interventions other than antiretroviral agents; and to investigate interventions that may reduce HIV-1 transmission via breastfeeding. Sound scientific design is fundamental to all research studies. Ethical standards must guide such studies and include the necessity that the problem studied be a health priority in the host country; that the highest standard of care attainable in the country be assured to participants; that the health-care resources of the country not be harmed; that the informed consent of participants be obtained; and that a process of discussion ensure that a successful intervention will be considered for implementation. There are circumstances in which a no-antiretroviral comparison may be ethically justified.
Article
Objectives: We measured the pharmacokinetics and safety of zidovudine in pregnant women infected with human immunodeficiency virus and their offspring. Study design: Asymptomatic human immunodeficiency virus-infected women with uncomplicated singleton gestations (28 to 36 weeks) underwent parenteral and oral zidovudine treatment during pregnancy and labor. Maternal and neonatal drug levels were measured at delivery and sequentially for 48 hours. Infants were followed up for 18 months. Results: The total body clearance (26.3 ± 10.1 ml/min/kg), mean terminal elimination phase zidovudine half-life (1.3 ± 0.2 hours), and urinary zidovudine recovery were similar to values in nonpregnant adults. Essentially equivalent zidovudine levels in the mother and neonate at delivery implied little, if any, fetal zidovudine metabolism. The half-life of zidovudine in the neonates was tenfold that of the mother. No significant adverse effects were noted in the infant at birth or on follow-up. Conclusions: In both mothers and infants the drug appeared safe and well tolerated with no significant hematologic abnormalities.
Article
Background Many developing countries have not implemented the AIDS Clinical Trials Group 076 zidovudine regimen for prevention of perinatal HIV-1 transmission because of its complexity and cost. We investigated the safety and efficacy of short-course oral zidovudine administered during late pregnancy and labour. Methods In a randomised, double-blind, placebo-controlled trial, HIV-1-infected pregnant women at two Bangkok hospitals were randomly assigned placebo or one zidovudine 300 mg tablet twice daily from 36 weeks' gestation and every 3 h from onset of labour until delivery. Mothers were given infant formula and asked not to breastfeed. The main endpoint was babies' HIV-1-infection status, tested with HIV-1-DNA PCR at birth, 2 months, and 6 months. We measured maternal plasma viral concentrations by RNA PCR. Findings Between May, 1996, and December, 1997, 397 women were enrolled; 393 gave birth to 395 live-born babies. Median duration of antenatal treatment was 25 days, and median number of doses during labour was three. 99% of women took at least 90% of scheduled antenatal doses. Adverse events were similar in the study groups. Of 392 babies with at least one PCR test, 55 tested positive: 18 in the zidovudine group and 37 in the placebo group. The estimated transmission risks were 9·4% (95% CI 5·2–13·5) on zidovudine and 18·9% (13·2–24·2) on placebo (p=0·006; efficacy 50% [15·4–70·6]). Between enrolment and delivery, women in the zidovudine group had a mean decrease in viral load of 0·56 log. About 80% of the treatment effect was explained by lowered maternal viral concentrations at delivery. Interpretation A short course of twice-daily oral zidovudine was safe and well tolerated and, in the absence of breastfeeding, can lessen the risk for mother-to-child HIV-1 transmission by half. This regimen could prevent many HIV-1 infections during late pregnancy and labour in less-developed countries unable to implement the full 076 regimen.
Article
Data on surrogate end points such as blood pressure or body weight have often been used to support the approval of new pharmacologic treatments for cardiovascular risk factors. In small, short-term studies, a new drug reduces the level of a risk factor, and the changes in risk factor levels are interpreted as if the health benefits expected on the basis of those changes will necessarily follow. An editorial on the pharmacotherapy of obesity illustrates the argument1: in the context of discussing the association between appetite suppressant drugs and primary pulmonary hypertension,2 the editorialists used observational evidence on the association of body mass index with mortality and translated data on weight loss in a small, short-term trial of dexfenfluramine3 into an estimate of lives that could be saved by long-term drug therapy for obesity. The US Food and Drug Administration (FDA) approved dexfenfluramine on the basis of this same surrogate end point argument4: "the potential health benefits of anorectic drugs outweigh their risk when considered against the health hazards of obesity."5 When, after the drug was approved, the adverse effects were found to be greater than estimated on the basis of preapproval trials,6- 7 the drug was withdrawn. Is this an example of the drug-approval process working well, or does it point to a fundamental flaw in the way drugs are approved?
Article
This article has no abstract; the first 100 words appear below. Today, few young parents in the United States recognize the name Reye's syndrome or react strongly to it. A short time ago the response was far different. In the 1970s and 1980s, Reye's syndrome was feared by parents in a way that was reminiscent of the fear of poliomyelitis before the introduction of vaccine. Like polio, Reye's syndrome occurred mainly in children, in clusters of cases over limited periods and in limited geographic areas, generating headlines in local newspapers. Both could produce death or permanent disability. However, paralytic polio was easily recognized clinically and was associated with a specific virus. . . . Arnold S. Monto, M.D. University of Michigan School of Public Health, Ann Arbor, MI 48109
Article
This article reviews the federal regulations for emergency and acute resuscitation research in effect prior to October 1996, the historical issues that contributed to the development of these regulations, the controversies that arose surrounding the application of these regulations to emergency research circumstances, and the methods by which the regulations were changed. The new regulations introduced by the U.S. Food and Drug Administration (FDA) also are reviewed.
Article
Background Whether truth disclosure may harm patients may be critical for the promotion of truth disclosure in patients with cancer. We used the Functional Living Index-Cancer (FLIC) to study the influence of truth disclosure on quality of life (QOL) in cancer patients. Methods. Twenty-three truth-disclosed patients with cancer (TD group) and 21 truth-concealed patients (TC group) were asked to answer 22 FLIC questions at the outpatient clinic. Results were compared with those in 18 patients with irritable bowel syndrome (IBS group) and in 37 patients with other gastrointestinal diseases (OGD group). Results. Average FLIC scores were the same in the TD and IBS groups and in the TC and OGD groups. There were significant differences among the four groups for four FLIC items: Discouraged about life (P = 0.04), Uncomfortable today (P = 0.03), Pain disrupts activity, (P = 0.0003) and How much nausea (P = 0.04). The IBS group had the worst FLIC scores for the former three of these items. Truth disclosure influenced only one FLIC item, in that the TD group was more likely to think that their daily activities were disrupted by pain or discomfort than the TC group (P = 0.01). However, incurability of cancer worsened the score for ten FLIC items, among which incurability was independently associated with the deterioration of FLIC-QOL in terms of Family disruption (P = 0.03) and Cancer-related pain (P = 0.02). Conclusion. Incurability of cancer, not truth disclosure, negatively affects patients' QOL. Thus, if sufficient supportive care is provided particularly to patients with incurable cancer, the truth could be disclosed without fear of being cruel or harming patients.
Article
This letter notes that a 1993 randomized placebo-control trial conducted by Pape et al. demonstrated the efficacy of isoniazid in preventing tuberculosis in HIV-infected Haitians who had positive purified-protein-derivative tests. Given this result it is questionable whether a rationale exists for conducting additional trials such as that recently reported by Whalen. Additional placebo-controlled trials may be justified only to improve validity and generalizability. The potential threat to validity of underestimating the true effect in Papes study was underestimation of rather than inflation of the true effect. In addition there are no reasons to believe that Papes results were specific to Haiti. This negates the necessity to replicate Papes study to validate the findings.
Article
Japanese clinical trials have been drastically changing in response to the implementation of the International Conference on Harmonisation — Good Clinical Practice (ICH-GCP) guideline in 1997. The most important aim of the new guideline is to standardise the quality of clinical trials in the US, European Union and Japan, but it inevitably imposes substantial costs on investigators, sponsors and even patients in Japan. The study environment in Japan differs from that in the US in several ways: (i) historical lack of a formal requirement for informed consent; (ii) patients’ attitudes to clinical trials in terms of expectation of positive outcomes; (iii) the implications of universal health insurance for trial participation; (iv) the historical absence of on-site monitoring by the sponsor, with the attendant effects on study quality; and (v) the lack of adequate financial and personnel support for the conduct of trials. Implementation of the new GCP guideline will improve the ethical and scientific quality of trials conducted in Japan. It may also lead to an improved relationship between medical professionals and patients if the requirement for explicit informed consent in clinical trials leads to the provision of a similar level of patient information in routine care and changes the traditional paternalistic attitude of physicians to patients. The initial response of the Japanese ‘market’ for clinical trials to the implementation of the ICH-GCP guideline has been clinical trial price increases and a decrease in the number of study contracts. These changes can be explained by applying a simple demand-supply scheme. Whether clinical trials undertaken in Japan become more or less attractive to the industry in the long term will depend on other factors such as international regulations on the acceptability of foreign clinical trials and the reform of domestic healthcare policies.
Article
The current practice of requiring the informed consent of research subjects is relatively new. The emphasis on a person's right to accept or refuse participation in biomedical research stems directly from the atrocities committed by Nazi "scientists" — an extreme instance of ignoring the value of individual human beings allegedly in the pursuit of knowledge.1 2 3 Similar but less dramatic disrespect for the subjects of medical research was common just after the Second World War and reflected the paternalistic atmosphere that pervaded medical practice at that time.1 , 4 More recent examples of unethical research, which stimulated the development of the current theory . . .
Article
To determine whether the participants in a clinical trial had perceived adequate information about the trial according to the guidelines of the Declaration of Helsinki. About 18 months after the end of a gynaecological clinical trial the participants received a questionnaire by post, which focused on the quality of the information given to them before entering the trial. Neither researchers nor participants were aware in advance that the trial would become the subject of this follow up investigation. Eight different centres in Sweden. 43 women out of the 53 who completed the trial (mean (range) age 23 (16 to 35) years) returned the questionnaire. Adequacy of the information (based on requirements of the Declaration of Helsinki) to enable the following: understanding of the aims of the study; awareness of what participation meant; and awareness of the possibility of withdrawing from participation at any time. Motives for agreeing to participate, and a subjective evaluation of the given information were also recorded. All but one of the participants had been aware that they were taking part in a research project. Five women stated that they had not been aware that a second laparoscopy was performed only for research reasons. Seven women reported that they had not been aware of the meaning of participating in the project and 17 that they had had no information about the possibility of withdrawing from the study whenever they wanted. In the subjective rating 22 women considered the information given as good or very good. There was a systematic variation in the quality of the given information among the eight centres. Although all but one of the participants had been aware that they were taking part in a clinical trial, the quality of the information understood and recalled by participants varied, and in many cases clearly did not meet the guidelines of the Declaration of Helsinki. Variations among centres in participants' perception of information suggest that deficiencies in perception may be caused by informers rather than the participants.
Article
Zidovudine pharmacokinetics was determined in three human immunodeficiency virus type I-seropositive women receiving zidovudine (200 mg orally every 4 h) from 19 to 39 weeks ofpregnancy and postpartum. Zidovudine concentrations were measured using high-pressure liquid chromatography, and pharmacokinetic analyses were done using model-independent methods. For the pregnant versus postpartum periods, peak zidovudine levels (mean ± 1 SD) were 3.9 ± 1.7 µmol/l versus 4.3 ± 0.04 µmol/l (P = .56); elimination half-lives were 1.3 ± 0.6 versus 1.0 ± 0.3 h (P = .41); areas under the concentration curve were 4.5 ± 1.0 µmol/l × hand 6.8 ± 0.5 µmol/l × h (P = .02); apparent total body clearances were 2.5 ± 0.6/1h/kg and 1.7 ± 0.4 l/h/kg (P = .05); and apparent steady state volumes of distribution were 3.9 ± 1.0 1/kg and 2.6 ± 0.81/kg (P = .07), respectively. Umbilical cord serum levels ranged from 113%–127% of maternal levels. No persistent adverse effects of zidovudine therapy were seen in the three women or their babies.
Article
Patients who agree and those who refuse clinical trial entry may differ in attitudes towards decision control and the benefits associated with the trial arms. These differences, if they exist, have implications for the process of obtaining informed consent and for the generalization of the results of a clinical trial. This paper describes the development and initial application of methods designed to detect such differences. Developmental work involved creating an inventory of instruments designed to determine patients' attitudes towards participating in treatment decision making, permitting random selection of treatment, and undertaking the risks and benefits associated with the various treatments in a trial. Initial application involved modifying these instruments in terms of an actual chemotherapeutic trial for colonic adenocarcinoma, seeking responses to these measures from 60 non-eligible colorectal cancer patients, then determining whether those who would agree to trial entry differed systematically on these measures from those who indicated that they would refuse such a trial. Twenty-five of the respondents reported that, if faced with the actual decision, they would agree to trial entry: 35 would refuse. Refusers demanded more participation in decision making (Chi-square; P = 0.01) and a greater increment in treatment benefit (t-test; P = 0.0001). Twenty-two of the 35 refusers reported aversion to randomization as their primary reason for trial refusal. Since their particular content can be modified, these measures may be applicable to all clinical trials. They could be used to study the reasons patients accept or refuse trial entry and to determine if agreer-refuser attitude differences undermine the generalizability of a trials results.
Article
We measured the pharmacokinetics and safety of zidovudine in pregnant women infected with human immunodeficiency virus and their offspring. Asymptomatic human immunodeficiency virus-infected women with uncomplicated singleton gestations (28 to 36 weeks) underwent parenteral and oral zidovudine treatment during pregnancy and labor. Maternal and neonatal drug levels were measured at delivery and sequentially for 48 hours. Infants were followed up for 18 months. The total body clearance (26.3 +/- 10.1 ml/min/kg), mean terminal elimination phase zidovudine half-life (1.3 +/- 0.2 hours), and urinary zidovudine recovery were similar to values in nonpregnant adults. Essentially equivalent zidovudine levels in the mother and neonate at delivery implied little, if any, fetal zidovudine metabolism. The half-life of zidovudine in the neonates was tenfold that of the mother. No significant adverse effects were noted in the infant at birth or on follow-up. In both mothers and infants the drug appeared safe and well tolerated with no significant hematologic abnormalities.
Article
Not Available Bibtex entry for this abstract Preferred format for this abstract (see Preferences) Find Similar Abstracts: Use: Authors Title Return: Query Results Return items starting with number Query Form Database: Astronomy Physics arXiv e-prints
Article
Unlabelled: The following factors are relevant to the communication problems that exist in this country: 1. Cultural aspects: The impression is that patients here cope better with terminal illness at home than do patients elsewhere. The extended family, with its strong ties, and the strong Islamic faith that encourages its members to provide for parents and children in case of need mean that any input by health professionals is magnified by the family in the care of the patient. At first, it was uncertain if foreign health professionals would be accepted into Saudi homes (which are intensely private and protected for the family) for the purpose of caring for patients. This has proved unfounded. Hospitality is a very important part of Saudi society; nurses and doctors are welcomed and respected. Much of this success is due to the use of Saudi men as drivers and translators. These people provide 24-hour service, act as social workers assessing the needs of the family, and are the link between the patient and family, the nurse, and the doctor. 2. "CURE" OR "PALLIATION": The emphasis for cancer patients in Saudi Arabia is still on "curative treatment," even after any realistic hope of a cure is gone. The problem this causes is compounded by many patients being excluded from the decision-making process. Decisions made by the family may not always reflect the patient's wishes. Greater communication is needed to guide treatment decisions. 3. TRUTH-TELLING: Denying information of the patient's illness is probably more a historical than a cultural phenomenon. Similar attitudes prevailed until very recently in practically all other countries. In this very conservative country, people are committed to preserving Islamic culture in the face of Western technology. As medicine continues to demonstrate its effectiveness as well as its limitations, people will come to realize that the right of patients to know and understand their illness allows them to cope much better, and is compatible with the responsibility of the family to care for them. 4. WORK FORCE: The government employs 14,500 doctors, but only 12% are Saudi nationals. Nearly all the 33,000 nursing work force are expatriates. There is a constant turnover of expatriate staff. The commitment to continuing care with proper communication that is required for the whole of medicine is likely to be fully realized only when the majority of the workforce are Saudi nationals. 5. PRIMARY, SECONDARY, AND TERTIARY CARE SERVICES: The Kingdom is well served by a system of 174 public hospitals and numerous private clinics. However, for a patient with a chronic or terminal illness, continuing care, even in the community, tends to be provided by the hospital service; whereas the polyclinics and health centers seem to provide mainly crisis management. The aim should be to develop community care for chronic illness as part of the primary health care system. The impact of Western medicine on Saudi society has been dramatic and sudden, as evidenced by the high growth rate of the population. There is now widespread interest in matching the culture to the technology. Much of the drive to change the attitudes of both patients and health professionals comes from young Western-trained Saudi doctors, who are in the best position to merge the strengths of both cultures in this sensitive area.
Article
Meta-analyses are now widely used to provide evidence to support clinical strategies. However, large randomized, controlled trials are considered the gold standard in evaluating the efficacy of clinical interventions. We compared the results of large randomized, controlled trials (involving 1000 patients or more) that were published in four journals (the New England Journal of Medicine, the Lancet, the Annals of Internal Medicine, and the Journal of the American Medical Association) with the results of meta-analyses published earlier on the same topics. Regarding the principal and secondary outcomes, we judged whether the findings of the randomized trials agreed with those of the corresponding meta-analyses, and we determined whether the study results were positive (indicating that treatment improved the outcome) or negative (indicating that the outcome with treatment was the same or worse than without it) at the conventional level of statistical significance (P<0.05). We identified 12 large randomized, controlled trials and 19 meta-analyses addressing the same questions. For a total of 40 primary and secondary outcomes, agreement between the meta-analyses and the large clinical trials was only fair (kappa= 0.35; 95 percent confidence interval, 0.06 to 0.64). The positive predictive value of the meta-analyses was 68 percent, and the negative predictive value 67 percent. However, the difference in point estimates between the randomized trials and the meta-analyses was statistically significant for only 5 of the 40 comparisons (12 percent). Furthermore, in each case of disagreement a statistically significant effect of treatment was found by one method, whereas no statistically significant effect was found by the other. The outcomes of the 12 large randomized, controlled trials that we studied were not predicted accurately 35 percent of the time by the meta-analyses published previously on the same topics.
Article
We have argued for a revision of Freedman's concept of clinical equipoise to a broader sense of community that includes physicians and patients. Community equipoise is an essential condition for physicians and patients to answer these questions: Should there be a trial? If so, what kind? We have argued that community equipoise exists because of changes in the knowledge gap between physicians and patients and in the moral justification of medical decision-making. Finally, we have briefly examined the social aspect of medical knowledge to argue that it necessarily includes patients and their values. In effect, community equipoise is not so much an effort to change things, as to explain the way they are. We suggest that patients can participate at a number of points in the process of drug study design and approval: (1) study design with attention to criteria for eligibility, endpoints, and choice of methodology, (2) research review and approval with attention to enhancing community participation in IRB activities, and (3) interim evaluation of ongoing studies with attention to including patient and clinician values in the decisionmaking. Clinical trials are a tool. Like a gun or a bomb or the very drugs they test, they are powerful tools to achieve their ends. The issue is how to properly use such tools as randomization, placebo controls, endpoints, and eligibility. To the extent that community equipoise exists prior to a trial, it means that clinical researchers and patients have collectively addressed the risk and benefit trade-offs that govern the decision to start and to end a clinical trial. In this way, trials can be both valid and valued.
Article
Ethical challenges are posed by attempts to conduct clinical trials in developing countries. Such trials must seek interventions that could realistically benefit the population involved. An inadequate understanding of the complexity of such trials has led to unfair charges that developing country trials of interventions to prevent maternal-infant transmission of HIV are comparable with the infamous Tuskegee study where subjects were deprived of available treatment for syphilis. The system of ethical protection developed after the Tuskegee scandal called for respect for persons, beneficence, and justice in research trials. To apply these principles to research in developing countries requires the support and involvement of the host country as well as an understanding of how conditions in the host country may differ from conditions in the partner country and, thus, may require different types of clinical trials. The current debate hinges on the morality of using a placebo control when the AIDS Clinical Trials Group protocol 076 is being effectively used in other parts of the world. The 076 protocol, however, has not been proved effective in developing country settings, and its per person treatment cost exceeds that which can be assumed by developing countries. The most compelling response to criticisms of the placebo-control test designs is that it provides definitive answers to safety and effectiveness questions in the study setting. Debate on this issue is healthy but should be informed by adequate knowledge of local factors that influence research.
Article
This article reviews the federal regulations for emergency and acute resuscitation research in effect prior to October 1996, the historical issues that contributed to the development of these regulations, the controversies that arose surrounding the application of these regulations to emergency research circumstances, and the methods by which the regulations were changed. The new regulations introduced by the U.S. Food and Drug Administration (FDA) also are reviewed.
Article
Many developing countries have not implemented the AIDS Clinical Trials Group 076 zidovudine regimen for prevention of perinatal HIV-1 transmission because of its complexity and cost. We investigated the safety and efficacy of short-course oral zidovudine administered during late pregnancy and labour. In a randomised, double-blind, placebo-controlled trial, HIV-1-infected pregnant women at two Bangkok hospitals were randomly assigned placebo or one zidovudine 300 mg tablet twice daily from 36 weeks' gestation and every 3 h from onset of labour until delivery. Mothers were given infant formula and asked not to breastfeed. The main endpoint was babies' HIV-1-infection status, tested with HIV-1-DNA PCR at birth, 2 months, and 6 months. We measured maternal plasma viral concentrations by RNA PCR. Between May, 1996, and December, 1997, 397 women were randomised; 393 gave birth to 395 live-born babies. Median duration of antenatal treatment was 25 days, and median number of doses during labour was three. 99% of women took at least 90% of scheduled antenatal doses. Adverse events were similar in the study groups. Of 392 babies with at least one PCR test, 55 tested positive: 18 in the zidovudine group and 37 in the placebo group. The estimated transmission risks were 9.4% (95% CI 5.2-13.5) on zidovudine and 18.9% (13.2-24.2) on placebo (p=0.006; efficacy 50.1% [15.4-70.6]). Between enrolment and delivery, women in the zidovudine group had a mean decrease in viral load of 0.56 log. About 80% of the treatment effect was explained by lowered maternal viral concentrations at delivery. A short course of twice-daily oral zidovudine was safe and well tolerated and, in the absence of breastfeeding, can lessen the risk for mother-to-child HIV-1 transmission by half. This regimen could prevent many HIV-1 infections during late pregnancy and labour in less-developed countries unable to implement the full 076 regimen.
Article
Baseline data collected on each patient at randomisation in controlled clinical trials can be used to describe the population of patients, to assess comparability of treatment groups, to achieve balanced randomisation, to adjust treatment comparisons for prognostic factors, and to undertake subgroup analyses. We assessed the extent and quality of such practices in major clinical trial reports. A sample of 50 consecutive clinical-trial reports was obtained from four major medical journals during July to September, 1997. We tabulated the detailed information on uses of baseline data by use of a standard form. Most trials presented baseline comparability in a table. These tables were often unduly large, and about half the trials inappropriately used significance tests for baseline comparison. Methods of randomisation, including possible stratification, were often poorly described. There was little consistency over whether to use covariate adjustment and the criteria for selecting baseline factors for which to adjust were often unclear. Most trials emphasised the simple unadjusted results and covariate adjustment usually made negligible difference. Two-thirds of the reports presented subgroup findings, but mostly without appropriate statistical tests for interaction. Many reports put too much emphasis on subgroup analyses that commonly lacked statistical power. Clinical trials need a predefined statistical analysis plan for uses of baseline data, especially covariate-adjusted analyses and subgroup analyses. Investigators and journals need to adopt improved standards of statistical reporting, and exercise caution when drawing conclusions from subgroup findings.
Article
Background: African trypanosomiasis is a fatal disease caused by protozoan parasites of the species Trypanosoma brucei. The disease has reached epidemic dimensions in various countries of central Africa. Treatment of the second stage is long and complicated, and is hampered by severe adverse reactions to the first-line drug, melarsoprol. Despite these problems, melarsoprol is likely to remain the drug of choice for the next decade. We therefore did a randomised trial comparing the standard treatment schedule with a new, concise regimen. Methods: The safety and efficacy of the new schedule were assessed in patients presenting to a hospital in Kwanza Norte, Angola with sleeping sickness. The control group followed the 26-day standard Angolan schedule of three series of four daily injections of melarsoprol at doses increasing from 1.2 to 3.6 mg/kg within each series, with a 7-day interval between series. The new treatment schedule comprised 10 daily injections of 2.2 mg/kg. Primary outcomes assessed were elimination of parasites, deaths attributed to treatment, and rate of encephalopathy. Analysis was by intention to treat. Findings: Of 767 patients with second-stage disease, 500 were enrolled: 250 were assigned the standard schedule, and 250 the new schedule. 40 patients on the standard schedule and 47 on the new schedule had adverse events which resulted in treatment disruption or withdrawal. 50 patients on the standard regimen deviated or withdrew from treatment, compared with two on the new regimen. Parasitological cure 24 h after treatment was 100% in both groups; there were six deaths (all due to encephalopathy) 30 days after treatment in each group. The number of patients with encephalopathic syndromes was also the same in each group (14). Skin reactions were more common with the new treatment, but all could be resolved by additional medication or withdrawal of treatment. Interpretation: Considering the economic and practical advantages of the new 10-day schedule over the standard 26-day treatment schedule, and the similarity of treatment outcome, the new schedule is a useful alternative to the present standard, especially in epidemic situations and in locations with limited resources.
Article
Clinical practice is changing rapidly. New cardiovascular drugs, antiinflammatory drugs, cancer chemotherapy, and other pharmacologic weapons are being added to physicians' therapeutic armamentarium virtually daily. Most clinical studies that bring new drugs from bench to bedside are financed by pharmaceutical companies. Many of these drug trials are rigorously designed, employing the skills of outstanding clinical researchers at leading academic institutions. But academic medical centers are no longer the sole citadels of clinical research. The past 10 years have seen the spectacular growth of a new research model. Commercially oriented networks of contract-research organizations (CROs) and site-management organizations (SMOs) have altered . . .
Article
As we race toward the as yet unimagined scientific and medical triumphs of the 21st century, no one is more hopeful about the journey than I am. Nevertheless, moving ahead with cutting-edge research must not mean leaving behind well-established international standards for protecting human subjects in clinical trials. None of these principles is more important than the protection of research subjects by informed consent based on full disclosure of potential risks and benefits. I did not expect, or want, to complete my tenure as secretary of health and human services by raising questions about the safety of patients in clinical . . .
Bioethics and Secular Humanism: the Search for a Common Morality
  • H T Engelhardt
  • HT Engelhardt Jr
Engelhardt HT Jr. Bioethics and Secular Humanism: the Search for a Common Morality. London, SCM Press; 1991.
Law and Medical Ethics
  • Jk Mason
  • Mccall Smith
Mason JK, McCall Smith RA. Law and Medical Ethics. London, Butterworths; 1991.
Health policy report: uneasy alliance -clinical investigators and 18
  • T Bodenheimer
Bodenheimer T. Health policy report: uneasy alliance -clinical investigators and 18
Why Would Drug-Induced Tragedies not End? For the Safety of Drugs
  • R Hama
Hama R. Why Would Drug-Induced Tragedies not End? For the Safety of Drugs. Tokyo, Nihon-Hyoronsha; 1996. (in Japanese)
  • Zidovudine Collaborative
  • Working Group
Zidovudine Collaborative Working Group. Am. J. Obstet. Gynecol. 1993;168(5):1510-1516.
the pharmaceutical industry
the pharmaceutical industry. N. Engl. J. Med. 2000;342:1539-1544.
Task Force on Principles for Economic Analysis of Health Care Technology
  • Task Force on Principles for Economic Analysis of Health Care Technology
Perinatal HIV Intervention Research in Developing Countries Workshop Participants. Science, ethics, and the future of research into maternal infant transmission of HIV-1
  • Perinatal HIV Intervention Research in Developing Countries Workshop Participants