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PubMed2001

After Helsinki: unresolved issues in international research.

Following a long process of revision, a new version of the Declaration of Helsinki was approved by the World Medical Association in 2000. Two provisions of the Declaration address ongoing international controversies regarding research sponsored by industrialized countries and conducted in developing countries. Despite the issuance of the final version of the Declaration, opponents remain locked in debate. Moreover, the Declaration remained silent on other prominent controversies concerning international research. An analysis of these current controversies reveals reasons why they are not likely to be readily resolved, despite apparent agreement by opponents on overarching ethical principles.

Clinical Trials as Topic↗
PubMed2005

Ethical concerns regarding guidelines for the conduct of clinical research on children.

In this article we examine ethical aspects of the involvement of children in clinical research, specifically those who are incapable of giving informed consent to participate. The topic is, of course, not a new one in medical ethics but there are some tensions in current guidelines that, in our view, need to be made explicit and which need to be responded to by the relevant official bodies. In particular, we focus on tensions between the World Medical Association Declaration of Helsinki, and the guidance offered by the British Medical Association, the Royal College of Paediatrics and Child Health (formerly the British Paediatric Association), and the Council for International Organizations of Medical Sciences. We conclude with a call for these organisations to make their guidance explicit in relation to the World Medical Association Declaration.

Child↗
PubMed2002

The use of placebo-controlled and non-inferiority trials for the evaluation of new drugs in the treatment of postmenopausal osteoporosis.

Registration of new agents for the treatment of postmenopausal osteoporosis has been based over the past few years on placebo-controlled phase III trials with the incidence of patients with new vertebral/nonvertebral fractures as the most usual primary endpoint. The use of a placebo in diseases where an active treatment is available has been a matter of debate following the update of the Declaration of Helsinki by the World Medical Association which questioned this trial design. Current regulatory recommendations within the European Union suggest that placebo-controlled trials are still the best option when assessing the efficacy and safety of new drugs intended for the treatment of postmenopausal osteoporosis. This suggestion seems to be in apparent contradiction with the current content of the Declaration of Helsinki. This paper addresses the ethics and feasibility of placebo-controlled trials in the treatment of postmenopausal osteoporosis, in the light of available therapeutic options, and discusses possible alternative approaches in those patients where placebo treatment could be deemed to be unethical. It is concluded that placebo-controlled trials remain the most efficient design to establish the efficacy and safety of a new agent for the treatment of postmenopausal osteoporosis. Such trials are feasible and ethically acceptable in patients with osteoporosis but without prevalent vertebral fractures. Conversely, in patients with prevalent vertebral fractures, placebo-controlled trials are ethically questionable and non-inferiority trials are more appropriate. A relative margin of non-inferiority of 20-30% is suggested, to be discussed on a case by case basis.

Aged↗
PubMed2004

Ethical issues in research on control of the HIV/AIDS epidemic: report from a workshop of the world federation of scientists, Erice, Sicily, Italy, 22-24 August 2003.

In research on control of the HIV/AIDS epidemic there are many ethical issues to be considered. The problem of personal autonomy versus the interest of society to prevent the spread of the disease in various settings makes it difficult to follow the regulations of the Declaration of Helsinki in all respects. This is particularly clear in the evaluation of trials aimed at preventing mother-to-child transmission of HIV. The interest of the child does not always conform to the policy of avoiding stigmatization of the mother. Programmes for the implementation of antiretroviral therapy and vaccine trials may differ in countries with different mean incomes of the inhabitants, and are also influenced by local patterns. For this reason, the Declaration of Helsinki should be changed in such a way that it conforms with the ways in which it may be possible to combat such a disastrous epidemic as that caused by HIV.

Developing Countries↗
PubMed1994

Moral reasoning in biomedical research protocols.

An analysis was performed of the ethics section in 134 biomedical research protocols submitted for review to a Danish Research Ethical Committee (REC) in 1990. The statements made in the ethics sections were identified and classified. It was found that 20% of the protocols lack an ethics section despite a specific requirement for such a section in the Helsinki-II declaration and the guidelines issued by the REC. The ethics sections have a median length of 6 lines of text and contain a median of 3 ethically relevant statements, thereby comprising 1.13% of the total research protocol. An analysis of the statements made show that 32% are purely formal and 30% are concerned with the area of information, consent and voluntariness. The remaining 38% are spread over a wide range of considerations. It is hypothesized that this relatively meager result reflects the researchers perception of the research review procedure as a mostly formal procedure.

Clinical Protocols↗
PubMed2000

Some recent developments in the international guidelines on the ethics of research involving human subjects.

We are in a period of reconsideration and revision of international ethical guidelines for the conduct of biomedical research involving human subjects. The proximate cause of much of this activity is the recent controversy over the ethics of the use of a placebo control in the clinical trials of the short-duration regimen of zidovudine for prevention of perinatal transmission of HIV infection, trials that were carried out in several so-called technologically developing countries. Critics of these trials claimed that they were in violation of Article II.3 of the Declaration of Helsinki, which states: "In any medical study, every patient--including those of a control group, if any--should be assured of the best proven diagnostic and therapeutic method. This does not exclude the use of inert placebo in studies where no proven diagnostic or therapeutic method exists." The critics claimed that since the "best proven ... method" is the 076 regimen, this is what must be provided to members of the control groups. Failure to do so, they asserted, was a serious breach of ethics. In response to this allegation, several major international and national agencies convened multidisciplinary groups to consider the ethics of multinational clinical research. The first thing they realized was that Article II.3 was in error in that it did not reflect contemporary ethical thinking. Moreover, it was routinely violated in research conducted in developed as well as in developing countries. What replaces this standard? The 1993 CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects include several criteria for justification of research carried out in developing countries. Most importantly, the research must be responsive to the health needs and priorities of the host country. They also require that any therapeutic products developed in such research must be made "reasonably available" to residents of the host country. A new standard is emerging for selecting therapies to be administered to participants in multinational clinical trials and for use as the control "treatment" in such trials. It is called the "highest attainable and sustainable" therapeutic method. Application of this standard differs from application of the "best proven method" standard in that it permits the evaluation of new therapies that are responsive to the health needs and priorities of resource-poor countries. It has long been recognized that the Declaration of Helsinki is a flawed document in that it relies on the illogical distinction between therapeutic and nontherapeutic research. This distinction has been removed from the most recent draft revisions of the Helsinki and the CIOMS documents.

Acquired Immunodeficiency Syndrome↗
PubMed1999

The protection of the person in medical research in Germany.

Because of its history Germany has many rules concerning the protection of persons in medical research. In fact Germany was the first state to issue a directive regulating medical experimentation with human beings in the year 1900. The ten principles of Nuremberg originated out of the medical case. Germany adheres to the Revised Declaration of Helsinki of the World Medical Association and will probably sign the European convention on biomedicine. The pharmaceutical act contains elaborate provisions for the protection of the patient or proband, e.g. informed consent, risk-benefit ratio, no experimentation on prisoners, approval of a local ethics committee. Moreover in pharmaceutical trials there has to be third party accident insurance for the experimental subject. There is no strict liability for medical experimentation, but the standard of care is high. In general the German law seems to be adequate for the protection of experimental subjects.

Confidentiality↗
PubMedDate not supplied

Is it ethical to use placebos in osteoporosis trials?

The use of placebo control groups (e.g., subjects using calcium and vitamin D) in osteoporosis trials with subjects at high risk for fracture has been systematically questioned by institutional review boards (IRBs). Regulatory agencies, on the other hand, continue to not only recommend but also require that placebo-controlled trials be presented for the registration of new drugs for osteoporosis treatment. The Declaration of Helsinki and its updates have upheld the principle that protection of research subjects' rights is of primary concern. Nevertheless, even the Declaration keeps clearly opening the possibility of using placebo-control designs if it is justified for "compelling and scientifically sound methodological reasons." The use of intermediary endpoints or surrogates to establish the efficacy or safety of new medications in the management of osteoporosis is currently considered scientifically insufficient. This concept has led regulatory agencies, such as the Food and Drug Administration in the United States and the European Medicines Agency in the European Union, to require "fragility fracture reduction" as the primary endpoint in clinical trials for the registration of new drugs. Superiority or noninferiority trials are alternatives to placebo-controlled designs. However, factors such as sample size, cost, and statistical limitations render these models impractical for the registration of new medications for osteoporosis. We recommend collaboration among regulatory agencies, IRBs, scientists, and ethicists on the design of clinical trials for the registration of new medications for reduction of fracture risk. Delay in developing mutually acceptable models may impair scientific development in the field and possibly deprive patients of potentially beneficial treatments.

Calcium, Dietary↗
PubMed2002

Patients' perceptions of information provided in clinical trials.

BACKGROUND: According to the Declaration of Helsinki, patients who take part in a clinical trial must be adequately informed about the trial's aims, methods, expected benefits, and potential risks. The declaration does not, however, elaborate on what "adequately informed" might amount to, in practice. Medical researchers and Local Research Ethics Committees attempt to ensure that the information which potential participants are given is pitched at an appropriate level, but few studies have considered whether the patients who take part in such trials feel they have been given adequate information, or whether they feel able to understand that information. OBJECTIVES: To explore trial participants' views (i) on the amount of information provided, and (ii) of their own understanding of that information. DESIGN: Structured interviews of patients participating in clinical trials for the treatment of chronic medical condition. FINDINGS: Patients generally felt they were given an appropriate amount of information, and that they were able to understand all or most of it. They felt they were given adequate time to ask questions before agreeing to take part. In comparison with treatment given out with the research setting, patients generally felt they received more information when participating in a clinical trial. CONCLUSIONS: Researchers sometimes complain that patients are given too much information during clinical trials, and have limited understanding of that information. The present study shows that this perception is not necessarily shared by patients. More research is needed in this area, particularly to gauge whether patient understanding is indeed accurate.

Adult↗
PubMed2000

Bioethics. Helsinki's new clinical rules: fewer placebos, more disclosure.

After 3 years of intense debate, medical researchers and ethicists have agreed on international standards that would dramatically tighten the rules for clinical research and put new limitations on the risks to which patients may be exposed. Meeting in Edinburgh, U.K., on 7 October, the general assembly of the World Medical Association voted to approve a revised version of the 1964 Declaration of Helsinki, the cornerstone of clinical research ethics, that reduces ambiguity in existing guidelines and could force changes in the design of future drug trials.

Bioethics↗
PubMedDate not supplied

[Placebo in clinical research--a continual compromise between ethical requirements and scientific rigor].

The use of placebo in clinical trials has been the object of continuous controversy. If effective treatment is not available, then the comparison of a new treatment versus placebo is the only sound and ethical approach. If effective treatment exists and its withdrawal can cause severe or irreversible harm or severe suffering, the use of placebo is forbidden. In all other instances, the scientific community has been divided into two extreme positions: the placebo orthodoxy considers the use of placebo as the only scientifically and hence ethically valid approach; and the active-control orthodoxy denies the use of placebo and recommends the comparison between active treatments. The latter has been supported by the Declaration of Helsinki that, until the Edinburgh 2000 Version, denied the use of placebo whenever effective treatment existed. This position has been the object of recent, strong criticism by ethicists and international Institutions, to the point that in October 2001 the World Medical Association decided to review paragraph 29 of the Declaration. The new version of the Declaration admits the use of placebo, even in the presence of effective treatment, when there are scientifically sound methodological reasons or when the patients receiving placebo are not exposed to any additional risk of serious or irreversible harm. The problem now is that the sudden opening of the World Medical Association may be interpreted as an encouragement to use placebo. Thus, it is necessary to define a new area for a scientifically motivated, but not unscrupulous use of placebo.

Ethics, Clinical↗
PubMed1998

[The structure of meta-ethical reasoning and "paradigmatic instability" of medicine].

Meta-ethics is such a philosophical discipline that it analyses meaning and logical status of moral conceptions and arguments. Its scope of interest is focused on such problems, among others, as to what extent are moral values the intrinsic part of our reality and, on the other hand, to what extent are they merely the expression or certain conventions, emotions or directives. Codes of medical ethics and other legal acts concerning ethical commitments, both domestic and international (as, for example, Declaration of Helsinki), are based on a certain hidden meta-ethical presumption that morality is a human creation, and thus it belongs to a certain so-called "social realm". As such, medical ethics undergoes continuous transformations with regard to technological progress, which creates new moral challenges. This frequently leads to conflicts between moral, legal and praxiological norms under the absence of consensual conformity of utilitarian and deontological ways of moral reasoning. It may be useful for medical ethics to differentiate between axiological and thetic norms that are present in codes of medical ethics and in various international bioethical declarations and conventions.

Ethics, Medical↗
PubMed2003

Design and analysis of non-inferiority mortality trials in oncology.

The recent revision of the Declaration of Helsinki and the existence of many new therapies that affect survival or serious morbidity, and that therefore cannot be denied patients, have generated increased interest in active-control trials, particularly those intended to show equivalence or non-inferiority to the active-control. A non-inferiority hypothesis has historically been formulated in terms of a fixed margin. This margin was historically designed to exclude a 'clinically meaningful difference', but has become recognized that the margin must also be no larger than the assured effect of the control in the new study. Depending on how this 'assured effect' is determined or estimated, the selected margin may be very small, leading to very large sample sizes, especially when there is an added requirement that a loss of some specified fraction of the assured effect must be ruled out. In cases where it is appropriate, this paper proposes non-inferiority analyses that do not involve a fixed margin, but can be described as a two confidence interval procedure that compares the 95 per cent two-sided CI for the difference between the treatment and the control to a confidence interval for the control effect (based on a meta-analysis of historical data comparing the control to placebo) that is chosen to preserve a study-wide type I error rate of about 0.025 (similar to the usual standard for a superiority trial) for testing for retention of a prespecified fraction of the control effect. The approach assumes that the estimate of the historical active-control effect size is applicable in the current study. If there is reason to believe that this effect size is diminished (for example, improved concomitant therapies) the estimate of this historical effect could be reduced appropriately. The statistical methodology for testing this non-inferiority hypothesis is developed for a hazard ratio (rather than an absolute difference between treatments, because a hazard ratio seems likely to be less population dependent than the absolute difference). In the case of oncology, the hazard ratio is the usual way of comparing treatments with respect to time to event (time to progression or survival) endpoints. The proportional hazards assumption is regarded as reasonable (approximately holding). The testing procedures proposed are conditionally equivalent to two confidence interval procedures that relax the conservatism of two 95 per cent confidence interval testing procedures and preserve the type I error rate at a one-sided 0.025 level. An application of this methodology to Xeloda, a recently approved drug for the treatment of metastatic colorectal cancers, is illustrated. Other methodologies are also described and assessed - including a point estimate procedure, a Bayesian procedure and two delta-method confidence interval procedures. Published in 2003 by John Wiley & Sons, Ltd.

Antimetabolites, Antineoplastic↗