Better Regulation of Industry-Sponsored Clinical Trials Is Long Overdue

Regulating clinical trials for testing new drugs is fraught with risk. Misregulation can slow development of innovative and useful new drugs, but in other ways misregulation can foster trials that are inefficient and unethical, driven by commercial rather than scientific ends, and that can harm patients. In this paper, we argue not for more but for better regulation, based on the goal of rapidly producing innovative and safe products that represent significant advances in medical care. Data on industry-funded, late-stage clinical trials demonstrate an urgent need for dramatic changes in how these trials are designed, conducted, and analyzed. On the one hand, current patent rules can dissuade development of innovative new products with smaller markets and press trial designers to create positive results too rapidly. But at the same time, numerous studies show that when the pharmaceutical industry sponsors clinical trials, the results are systematically biased in favor of the sponsor's product, often to the detriment of patients and the public. The reasons for this bias are both complex and unavoidable, and the ways in which clinical trial design, conduct, and reporting can be inappropriately influenced are so varied and nuanced, that efforts to manage this conflict of interest and prevent harms are inevitably unsuccessful. Instead, we conclude such conflict should be avoided and a strong firewall should exist between drug developers and the final stages of clinical testing in humans. All financial support for phase III clinical trials should pass through a public-private partnership organization — perhaps tied to a broader clinical effectiveness research enterprise — which would be charged with designing, funding, and monitoring late-stage human clinical trials of new pharmaceutical products.     

The path to cheaper and safer drugs: revamping the pharmaceutical industry in light of GlaxosmithKline's settlement.

The State of New York's ability to secure a settlement from GlaxoSmithKline in which they agreed to publish summaries of completed trials is a step in the right direction. It is likely that other pharmaceutical companies will follow suit and establish Clinical Trial Registers for their own drugs. In order to make such a transition positive, however, the government could consider further remedies, including mandating that pharmaceutical companies publicly disclose all premature terminations of clinical trials. If such a policy is not adopted, firms may have an incentive to withdraw funding for projects that are likely to produce negative results. In order to reduce pharmaceutical companies' ability to misrepresent the results of clinical trials, the FDA could begin rating drugs on the basis of their cost-effectiveness, efficacy and safety. Such a policy would have the effect of both improving patient outcomes and reducing the cost of pharmaceuticals.     

Ethical standards for clinical trials conducted in third countries: the new strategy of the European Medicines Agency

Clinical trials increasingly occur on a global scale as industry and government sponsors in wealthy countries move trials to low- and middle-income countries. The globalization of clinical research raises important questions about the economical and ethical aspects of clinical research and the translation of trial results to clinical practice: which ethical standards are applied? Are trials results accurate and valid, and can they be extrapolated to other settings? This article provides an overview of the strategy approved by the European Medicines Agency (EMA) to clarify ethical standards for clinical research conducted outside the European Economic Area (EEA) and included in Marketing Authorization Applications. Reference to the EMA Reflection paper is made.     

Making the World Health Organization work: a legal framework for universal access to the conditions for health.

Improving global health conditions has been one of the most important and difficult challenges for the world community. Despite concerted efforts by international organizations, like the World Health Organization, great disparities in health conditions remain between developed and developing countries, as well as within those countries. The World Health Organization has achieved some successes through its Health for All strategy; however, it can and should encourage member nations to enact national and international laws to protect and promote the health status of their populations. A comparison to the lawmaking efforts in other areas by international organizations indicates that WHO may have the authority and the means to institutionalize efforts to improve global health conditions.     

Are ethics promulgations self-defeating?

Alan Wertheimer argues that promulgating some ethical standards of international clinical research may be self-defeating: the intended purpose of these standards is to promote the interests of subjects and communities in LMICs, while the outcome of promulgation could be to undermine these very same interests. If enforced, such standards would increase the costs of performing beneficial research in LMICs, potentially diverting opportunities to participate in this research away from those who have no other access to the care participation allows. I argue that these standards are really intended as deontological constraints protecting subjects from being exploited by research sponsors. First, I show that Wertheimer begs the question against this deontological interpretation of ethics promulgations, rejecting it on non-deontological grounds. I go on to show that non-exploitation is an important goal on its own, sometimes independent from—and sometimes even outweighing—the goal of promoting the interests of subjects and communities in LMICs. I conclude by suggesting that those who criticize the promulgation of non-exploitation on the grounds that exploitative practices help those badly off might do best to reconsider the background assumption that sponsors in wealthier countries have no pre-existing obligation to promote the interests of the world''s poor.     

Conflict of interest in clinical research: direct payment to the investigators for finding human subjects and health information

The recent death of teenager Jesse Gelsinger in a drug therapy trial has drawn attention to how financial conflicts of interest may compromise patient protection. While research institutions throughout the world have instituted a variety of conflict of interest guidelines, the potential conflicts associated with investigators receiving direct payment from private companies for both the recruitment of patients and the running of clinical trials in pharmaceutical research remains a relatively unexplored area. Clinical researchers undoubtedly deserve to be reasonably compensated for their participation. But these incentive mechanisms also have the potential to create conflicts of interest--both real and perceived.     

Improving distribution of pharmaceuticals in developing countries: A case study of The Gambia project

Without sufficient sanitation, nutrition and primary health care infrastructures, developing nations must depend on pharmaceuticals as the principal defense against debilitating diseases such as malaria, schistosomiasis, river blindness, tetanus, and leprosy. Yet the distribution of pharmaceuticals within many developing countries is severely inadequate to meet the health care needs of large sectors of the population, particularly those persons living in rural areas. The result is that with 80% of the world's population, and an even greater share of the world's serious illnesses and disease, the Third World consumes only 20% of the global supply of pharmaceuticals. One of the major obstacles confronting individuals in developing countries that need pharmaceuticals is access — the drug delivery infrastructure is often inadequate. Problems exist in the entire range of drug management: Ordering, receipt, storage, distribution, and resupply. To help combat the problems, a unique collaboration began in 1981 at the initiation of several members of the Pharmaceutical Manufacturers Association (PMA), and Africare, a private voluntary organization, to improve the drug distribution and management system in The Gambia in Africa. The purpose of this article is to demonstrate the feasibility of transferring The Gambian model of cooperation between governments in developing countries, private voluntary organizations, and the international pharmaceutical industry to other Third World nations given different cultural, political and economic parameters. Last year, after observing how effectively The Gambia project had improved record keeping and management, the government of Sierra Leone invited Africare to help set up similar improvements in its drug distribution and inventory program. Although the multinational pharmaceutical corporations are often criticized by Third World governments for overpricing and dumping drugs, and excessive marketing schemes, The Gambia project demonstrates how the industry can work with health ministries to alleviate the problem of an inadequate supply and storage of pharmaceuticals particularly to poor, rural areas in Less Developed Countries.     

The scope of anthropological contributions to human rights investigations

This paper examines the participation of anthropologists in international human rights investigations between 1990 and 1999 by surveying four of the most active organizations, including the Argentine Forensic Anthropology Team, the Guatemalan Forensic Anthropology Foundation, Physicians for Human Rights and the U.N.-sponsored International Criminal Tribunal for the former Yugoslavia. The education level, sex, nationality and primary role of the anthropological members of each team are quantified, as are the types of projects in which they contributed. The results show that 134 anthropologists from 22 nations investigated nearly 1300 sites in 33 countries during the study period. While involvement is not limited to those with advanced degrees and few obstacles are placed before anthropologists who wish to participate, full-time service within these organizations is rare and those interested in a career in forensic anthropology and human rights should understand the employment limitations.     

Genetic Information and the Challenge to Privacy

Genetic screening and testing techniques provide a new and powerful diagnostic tool for the acquisition of predictive information. The potential value of such diagnostic techniques cannot be overstated. Genetic diagnostic tests pave the way for the development of gene therapy techniques which may provide remedies for diseases previously considered untreatable. There are clearly tremendous opportunities for improving the quality of life of those who suffer from genetic disorders as well as opportunities for biotechnology and pharmaceutical companies to swell their profits. A complex of pressures and tensions is currently developing around the use of genetic technology for therapeutic purposes in human beings. This paper considers only one element of this complex and dynamic situation, that of the regulatory climate surrounding the use of genetic screening in Europe. If, as many pharmaceutical companies concede, the key to the development of successful gene therapy products is the freedom to use genotyping and genetic screening without significant legal restriction, then the regulatory climate has a crucial significance for the future of this technology. It emerges, however, that there are other interests at stake apart from just those of the patients and the pharmaceutical companies. Insurance companies and employers are also highly interested in the acquisition and use of genetic information. There are arguments both for and against permitting such entities to use or request genetic testing and screening which shall be traversed in the body of the paper. However, the interest of insurance companies and employers in genetic information has stimulated a countercurrent of public pressure for restrictions on the use that can be made of genetic diagnostic information. In a number of countries, this pressure has generated enough concern to stimulate legislatures to seek to enact laws that curtail the use and acquisition of genetic information. This pattern has clearly emerged in the United States and there are strong indications that similar trends are developing in Europe. This article catalogues and critiques the laws and regulations currently affecting genetic screening and testing in Europe.     

Research with minors in Germany

The European GCP Directive has been implemented into German law in sect. 40 ff. AMG (German pharmaceutical law). Unlike the Directive, German pharmaceutical law basically differentiates between three constellations of clinical trials on minors: clinical trials on healthy minors, clinical trials on ill minors with an individual benefit for the individual participant, and clinical trials on ill minors without direct benefit for the individual participant, but with a so-called "group benefit". Particularly the latter possibility of conducting clinical trials on minors even if no individual benefit can be expected is not a matter of course in Germany since due to historical experiences a sceptical attitude towards clinical research on humans prevailed for a long time. German legislature has availed itself of the option granted by Article 3 of the GCP Directive to establish a higher level of protection of clinical trial subjects than the European level.     

论电影作者的法律确认——以我国《著作权法》第15、21条的修改为背景

在电影〔1〕作者的确认上,各国有浪漫主义与实用主义两种不同的立法理念。两种不同的立法理念使得各国在电影作者的确认上出现差异。有国家主张电影作者只能是自然人,有国家确信电影作者可以是法人或其他组织;有国家明确电影制片人的作者身份,有国家立法则否认制片人的电影作者身份。从我国的实际情况来看,我国立法应以创作作为基本原则来判定谁是电影作者,并从举证便捷与法律安全的角度出发,列明电影作者的基本名单。     

Revising the declaration of Helsinki: ethics vs economics or the fallacy of urgency

Constant vigilance is required to ensure that the rights of volunteers in clinical trials are protected, particularly in developing countries. In this presentation to the XIII International AIDS Conference (abstract ThOrE651), Dirceu B Greco, of the Federal University of Minas Gerais in Brazil, describes the debate that has raged over the proposed changes to the Declaration of Helsinki, particularly with respect to access to medical care for trial volunteers and to the use of placebos in the control arms of the trials. The presentation argues: (1) that all trial volunteers should have access to the best diagnostic, preventive, and therapeutic methods, regardless of the standard of care in the countries where the trials are taking place; (2) that large efficacy trials of vaccines and drugs should be done first in countries where the best diagnostic, preventive, and therapeutic methods are available; and (3) that the costs of providing care and prevention services should be considered an integral part of the cost of the trials. The presentation explains how a partnership between activists, scientists, ethicists, and medical associations was effective in resisting pressures to lower the ethical standards for clinic trials. The presentation concludes that the gains made by this partnership constitute an important step in the struggle to provide universal access to education and health.     

Sub-Saharan African randomised clinical trials into male circumcision and HIV transmission: methodological, ethical and legal concerns

In 2007, WHO/UNAIDS recommended male circumcision as an HIV-preventive measure based on three sub-Saharan African randomised clinical trials (RCTs) into female-to-male sexual transmission. A related RCT investigated male-to-female transmission. However, the trials were compromised by inadequate equipoise; selection bias; inadequate blinding; problematic randomisation; trials stopped early with exaggerated treatment effects; and not investigating non-sexual transmission. Several questions remain unanswered. Why were the trials carried out in countries where more intact men were HIV-positive than in those where more circumcised men were HIV-positive? Why were men sampled from specific ethnic subgroups? Why were so many participants lost to follow-up? Why did men in the male circumcision groups receive additional counselling on safe sex practices? While the absolute reduction in HIV transmission associated with male circumcision across the three female-to-male trials was only about 1.3%, relative reduction was reported as 60%, but, after correction for lead-time bias, averaged 49%. In the Kenyan trial, male circumcision appears to have been associated with four new incident infections. In the Ugandan male-to-female trial, there appears to have been a 61% relative increase in HIV infection among female partners of HIV-positive circumcised men. Since male circumcision diverts resources from known preventive measures and increases risk-taking behaviours, any long-term benefit in reducing HIV transmission remains uncertain.     

跨国公司人权责任的规制及其反思

在追究跨国公司的国际人权责任方面，目前主要有三种规制方式：国家对跨国公司的管制；来自非政府组织和其他国际组织的监督以及跨国公司的自律。但这些途径尚不足以成为跨国公司承担人权责任的有效保障．因而必须采取措施强化跨国公司国际人权责任的规制。     

Can the FDA improve oversight of foreign clinical trials?: Closing the information gap and moving towards a globalized regulatory scheme

Currently, pharmaceutical companies' utilization of foreign clinical trial data is a ubiquitous and indispensable aspect of gaining approval to market drugs in the United States. Cost benefits, a larger pool of ready volunteer subjects, and greater efficiency in clinical testing are some of the reasons for conducting clinical trials overseas. Despite these advantages, lack of proper oversight may have serious public health implications regarding the integrity of clinical research, ethical treatment of human subjects, and drug safety. Due to the expansive global nature of foreign clinical trials, there are concerns with the FDA's ability to monitor and regulate these trials. This article examines the FDA's oversight of foreign clinical trials and the agency's limitations regulating these trials. In addition to looking at steps the FDA is taking to address these limitations, the article examines other potential regulatory and cooperative actions that can be taken to effectively monitor foreign clinical trials and to ensure data integrity and patient safety.     

Just compensation: a no-fault proposal for research-related injuries

Biomedical research, no matter how well designed and ethically conducted, carries uncertainties and exposes participants to risk of injury. Research injuries can range from the relatively minor to those that result in hospitalization, permanent disability, or even death. Participants might also suffer a range of economic harms related to their injuries. Unlike the vast majority of developed countries, which have implemented no-fault compensation systems, the United States continues to rely on the tort system to compensate injured research participants—an approach that is no longer morally defensible. Despite decades of US advisory panels advocating for no-fault compensation, little progress has been made. Accordingly, this article proposes a novel and necessary no-fault compensation system, grounded in the ethical notion of compensatory justice. This first-of-its-kind concrete proposal aims to treat like cases alike, offer fair compensation, and disburse compensation with maximum efficiency and minimum administrative cost. It also harmonizes national and international approaches—an increasingly important goal as research becomes more globalized, multi-site trials grow in number, and institutions and sponsors in the United States move to single-IRB review.