Current issues in clinical research and the development of new pharmaceuticals

As a normal part of the drug development process, U.S. pharmaceutical companies conduct many thousands of clinical trials each year. Only after a reasonable assurance of safety is made can the drug be given to patients who have the underlying medical condition that the drug is designed to treat. Patient welfare is assured by adhering to the Food and Drug Administration's interpretation of the “common rule”; if the data will be used to support a licensing application. 21 CFR Part 50 sets forth the regulations along with the principles of informed consent and the use of institutional review boards (IRBs) that assure patients’ rights are protected. Any potential conflict of interest on the part of a clinical investigator must be reported to the FDA. Pharmaceutical companies extensively monitor ongoing clinical trials for compliance with appropriate regulations. The recent revision of the Declaration of Helsinki governing placebo‐controlled clinical trials may adversely impact drug development     

Clinical trials integrity: a CRO perspective

When contract research organizations (CROs) were first formed, pharmaceutical companies outsourced to them only certain aspects of the conduct of their clinical trials. At first CROs were highly specialized entities, providing, for example, either biostatistical advice, clinical research associates who monitored investigational sites for regulatory compliance, or regulatory support. Gradually, full service CROs emerged, offering a full range of services for clinical trials, including the selection of investigators and investigational sites, assistance with patient recruitment, safety surveillance and reporting, site audits, and data management and biostatistics. This evolving relationship between CROs and the pharmaceutical and medical device industries has resulted in CROs assuming more and more of the regulatory and ethical risks and responsibilities inherent in the conduct of clinical trials. In this full service role, CROs, unlike sponsors, are not interested in the outcome of study, but like sponsors, are subject to heavy regulation by the federal government, must follow applicable state laws, must respect international guidelines, and are obliged to follow their own operating procedures. Moreover, they are judged by the industry on the basis of the scope and quality of services provided, including the degree of adherence to the research protocol, regulatory requirements, and timelines; the quality of the professional working relationships with investigators and institutions, both academic and community-based; and the validity of the data. Further, CROs are subject to comprehensive audits by sponsoring companies, FDA, and other regulatory authorities. For all these reasons, CROs are being tasked with strict vigilance of all stages of the clinical trial process to ensure that the laws, regulations, and industry standards designed for the protection of human subjects and data integrity are maintained.     

Clinical trials of drugs used off-label in neonates: ethical issues and alternative study designs

The use of drugs for indications unapproved by the Food and Drug Administration (FDA), often called "off label use, "is widespread in children, including neonates. The widespread off-label use of drugs in neonates presents ethical and safety challenges. Since the passage of the Best Pharmaceuticals for Children Act (BPCA) in 2002, both the FDA and National Institutes of Health (NIH) have taken initiatives to facilitate and encourage research to achieve the necessary labeling for drugs routinely used in infants and children. Federal regulations provide broad rules and guidance for the protection of human subjects in research. However, there are ethical issues that a physician may face when designing clinical trials of drugs in neonates that are routinely used off-label and widely believed to be beneficial. We attempt to describe these ethical challenges and provide recommendations, including alternative study designs, to resolve them in an ethical framework that takes into account the Belmont Report, the statement of the World Medical Association (WMA), and federal regulations.     

住宅小区物业管理的困境与相关法规的完善建议——基于自身经验和法律实践的考察

物业管理面临许多困境,有组织成立并运作业主大会、业主委员会实践经历的人对此有更深认识。在业主、物业公司、开发商(建设单位)及政府部门的利益和权能角力中,业主方最为势弱。除了政府相关部门、街道办和居委会等应当依法依职能给予业主更多支持和帮助外,更为重要的是,从法律设计上要大幅修正《物业管理条例》及相关的一系列法律法规:允许多种形式的物业管理模式存在;重新设计前期物业管理制度,要求开发商承担更多前期物业管理责任;明确业主大会和业主委员会法律地位,赋予其明确的民事主体地位;调整街道办、居民委员会等机构在物业管理中的职能。法规的修正要能让业主便于召开和运行业主大会及业主委员会,使广大业主能够更高效、便捷地实现自己物业管理自治权利和相关物权权利。     

Introduction: Accountability in Neuroethics

Pharmaceutical sponsored clinical trials, formerly conducted predominantly in the United States and Europe, have expanded to emerging regions, including the Middle East. Our study explores factors influencing clinical trial privacy and confidentiality in the United Arab Emirates. Factors including concept familiarity, informed consent compliance, data access, and preservation, were analyzed to assess current practices in the Arab world. As the UAE is an emerging region for clinical trials, there is a growing need for regulations related to data confidentiality and subject privacy. Informational and decisional privacy should be viewed within the realms of Arab culture and religious background.     

Investigators,industry, and the heuristic device: Ethics,patent law,and clinical innovation

There has been much discussion about the prevalence of scientific misconduct. Investigational drug trials and cancer clinical trials have been audited systematically in recent years. Review of the results of these audits indicates that misconduct is not uncommon: serious deficiencies have been identified in 11% of audits of drug trials by the United States Food and Drug Administration. The trend has been toward fewer of the most serious problems in the most recent years of the audit program, suggesting that it is having a deterrent effect. Still, many problems remain. A series of possible strategies for addressing them are critically assessed. The experience of this program of fers a model approach to evaluating potential misconduct in science against which programs in other agencies and other areas of science should be measured.     

Are antidepressant and antipsychotic drug trials registered? A cross-sectional analysis of registration and reporting of methodologic characteristics

Introduction: In 2005, the International Committee of Medical Journal Editors (ICMJE) proposed that all submitted trials in all 11 member journals must be prospectively registered in order to be considered for publication. Registering drug trials was meant to reduce the likelihood of selective reporting. The aim was to determine the proportion of antipsychotic and antidepressant trials that were registered.

Methods: We searched in Pubmed for all randomized controlled trials of any antidepressant or antipsychotic published between July and December 2014. The primary objective was to determine the proportion of trials that were registered. Secondary objectives included comparing the reporting of methodological details and positive study findings between registered and unregistered trials.

Results: Of the 67 studies identified, 58% were registered. 75% of the antipsychotic trials and 51% of the antidepressant trials were registered, respectively. Registered trials were more likely to report important methodological details associated with risk of bias in RCTs. There was no significant difference in trials reporting positive outcomes for the study intervention between registered and unregistered trials.

Conclusion: Approximately 60% of published antidepressant and antipsychotic drug trials during July to December 2014 were registered. Unregistered trials were less likely to report important methodological details.     

上海发展文化产业面临的挑战、机遇及对策

发展文化产业是社会主义文化建设的重要组成部分。上海发展文化产业面临着诸如思想观念上的差距、产业的规模化程度低、现代文化与现代科技结合度低等方面的挑战。鉴于此,各级领导者和从业人员都应尽快更新发展文化产业的观念;实施“走出去”战略,培育优质文化企业集团;建立健全文化产业法律法规,促进文化法制建设。根据已经具备的优势、自身特点和区域中的地位,上海应优先发展旅游业、传媒业、视觉产业、新闻出版与版权产业、会议展览业、创意产业等文化产业,培育文化支柱产业并整体提高文化产业的核心竞争力。     

The Roles Played by the Staff and Workers’ Representative Congress in the Formation of Work Regulations

Article 4 of the Labor Contract Law lays down the right of the Staff and Workers’ Representative Congress (SWRC) to deliberate on the formulation of (intra-enterprise) work regulations, but this has become a “soft” law in judicial practice. The judicial criteria for judging the validity of work regulations are in essence determined by the judge’s judgment on their reasonableness. As an important embodiment of Chinese politics, economics and culture, the transformation of the SWRC that accompanied the market economy has not negated its value as an indigenous traditional resource. The SWRC does not just enjoy deliberative rights in the formation of regulations, as clearly specified in constitutional law, but also has rights under the law in local legislation and practice. Hence the system of work regulations is neither a unilateral decision on the part of management nor a contract, but rather an autonomous norm developed through the SWRC mechanism. Given the mandatory nature of Article 4 of the Labor Contract Law, regulations will only be valid after they have gone through a democratic process. The further development of the theory of normative system formation should endow the SWRC with greater rights and integrate it smoothly with the collective contract system to standardize collective labor relations.     

Pharmacovigilance in Clinical Trials: Current Practice and Challenges

In view of the MENA increasing participation in multinational trials and the increasing number of national/regional trials, this article explores potential areas of pharmacovigilance, requiring reform and provides recommendations for building a robust safety reporting system. Regulatory silence on expedited reporting requirements creates confusion for local sites that are part of multinational trials. Not allowing waiver for serious adverse events that are protocol specified or are study endpoints, along with lack of emphasis on causality as reporting criteria, adds substantial burden of uninformative cases for regulatory review. Despite global focus on Development Safety Update Report, local regulators are not yet insistent on real-time update of a drug’s cumulative safety profile. Issues like reporting requirements for generic trials, pregnancy reporting and lenient timeline for death/life-threatening events need attention. Finally, the need to formulate an all-encompassing local pharmacovigilance guideline, in sync with global practice cannot be overemphasized.     

Clinical Trials of Drugs Used Off-Label in Neonates: Ethical Issues and Alternative Study Designs

The use of drugs for indications unapproved by the Food and Drug Administration (FDA), often called “off-label use,” is widespread in children, including neonates. The widespread off-label use of drugs in neonates presents ethical and safety challenges. Since the passage of the Best Pharmaceuticals for Children Act (BPCA) in 2002, both the FDA and National Institutes of Health (NIH) have taken initiatives to facilitate and encourage research to achieve the necessary labeling for drugs routinely used in infants and children. Federal regulations provide broad rules and guidance for the protection of human subjects in research. However, there are ethical issues that a physician may face when designing clinical trials of drugs in neonates that are routinely used off-label and widely believed to be beneficial. We attempt to describe these ethical challenges and provide recommendations, including alternative study designs, to resolve them in an ethical framework that takes into account the Belmont Report, the statement of the World Medical Association (WMA), and federal regulations.     

Developing a clinical trial governance framework for pharmaceutical industry-funded clinical trials

ABSTRACT

Rising concerns relating to pharmaceutical sponsor bias in the conduct of clinical trials have compelled the need to develop a clinical trial governance framework. This article describes the development of the Conflict of Interest in Research (COIR), a clinical trial governance framework. The COIR, consisting of three process phases (initiation, concurrent, and ongoing), developed following a needs assessment, using a four-stage methodology, and evaluated against the International Conference on Harmonization--Good Clinical Practice (ICH-GCP) guidelines. The Conflict of Interest Resolution algorithm, the backbone of COIR, enables constant surveillance to detect/resolve conflicts at all stages of the clinical trial life-cycle. COIR promotes interaction between the regulatory system and the sponsors, independent of individuals. COIR enables rapid detection of scientific and financial conflicts, to prevent subject harm and, to assure optimal funds utilization, the latter feature helped to reduce a significant burden for the ethics committee, as it lacks financial expertise. COIR is a semi-automated Oracle system, requires manpower, and is affected by human expertise and subjectivity. Complete automation to overcome this limitation will still need human expertise to scale changing trial regulations. Nevertheless, the COIR has won the distinction of the “most favored site” from pharmaceutical sponsors and is anticipated to be adopted by other clinical trial sites.     

我国社会慈善事业发展对策的思考

慈善事业作为我国社会保障体系的有机组成部分,是促进社会全面发展、构建社会主义和谐社会的一个战略选择。当前我国慈善事业发展中存在的问题主要表现在全社会尚未形成浓厚的慈善意识、慈善组织建设不够规范、组织自身能力建设不强、缺乏有效的管理与社会监督机制以及相关的法律法规不够健全。其相应的对策应是弘扬慈善文化、促进社会成员的普遍参与、加强慈善组织自身能力建设、完善社会激励机制以及健全政策法规制度。     

我国社会慈善事业发展对策的思考

慈善事业作为我国社会保障体系的有机组成部分,是促进社会全面发展、构建社会主义和谐社会的一个战略选择。当前我国慈善事业发展中存在的问题主要表现在全社会尚未形成浓厚的慈善意识、慈善组织建设不够规范、组织自身能力建设不强、缺乏有效的管理与社会监督机制以及相关的法律法规不够健全。其相应的对策应是弘扬慈善文化、促进社会成员的普遍参与、加强慈善组织自身能力建设、完善社会激励机制以及健全政策法规制度。     

Assessing commercial feasibility: a practical and ethical prerequisite for human clinical testing

This article proposes that an assessment of commercial feasibility should be integrated as a prerequisite for human clinical testing to improve the quality and relevance of materials being investigated, as an ethical aspect for human subject protection, and as a means of improving accountability where clinical development is funded on promises of successful translational research. A commercial feasibility analysis is not currently required to justify human clinical testing, but is assumed to have been conducted by industry participants, and use of public funds for clinical trials should be defensible in the same manner. Plant-made vaccines (PMVs) are offered in this discussion as a model for evaluating the relevance of commercial feasibility before human clinical testing. PMVs have been proposed as a potential solution for global health, based on a vision of immunizing the world against many infectious diseases. Such a vision depends on translating current knowledge in plant science and immunology into a potent vaccine that can be readily manufactured and distributed to those in need. But new biologics such as PMVs may fail to be manufactured due to financial or logistical reasons--particularly for orphan diseases without sufficient revenue incentive for industry investment--regardless of the effectiveness which might be demonstrated in human clinical testing. Moreover, all potential instruments of global health depend on translational agents well beyond the lab in order to reach those in need. A model compromising five criteria for commercial feasibility is suggested for inclusion by regulators and ethics review boards as part of the review process prior to approval of human clinical testing. Use of this model may help to facilitate safe and appropriate translational research and bring more immediate benefits to those in need.     

Letters to the editor

This article proposes that an assessment of commercial feasibility should be integrated as a prerequisite for human clinical testing to improve the quality and relevance of materials being investigated, as an ethical aspect for human subject protection, and as a means of improving accountability where clinical development is funded on promises of successful translational research. A commercial feasibility analysis is not currently required to justify human clinical testing, but is assumed to have been conducted by industry participants, and use of public funds for clinical trials should be defensible in the same manner. Plant-made vaccines (PMVs) are offered in this discussion as a model for evaluating the relevance of commercial feasibility before human clinical testing. PMVs have been proposed as a potential solution for global health, based on a vision of immunizing the world against many infectious diseases. Such a vision depends on translating current knowledge in plant science and immunology into a potent vaccine that can be readily manufactured and distributed to those in need. But new biologics such as PMVs may fail to be manufactured due to financial or logistical reasons—particularly for orphan diseases without sufficient revenue incentive for industry investment—regardless of the effectiveness which might be demonstrated in human clinical testing. Moreover, all potential instruments of global health depend on translational agents well beyond the lab in order to reach those in need. A model comprising five criteria for commercial feasibility is suggested for inclusion by regulators and ethics review boards as part of the review process prior to approval of human clinical testing. Use of this model may help to facilitate safe and appropriate translational research and bring more immediate benefits to those in need.     

比较法视域下西方国家刑事搜查证明标准考察——以完善我国刑事搜查证明标准为视角

伴随我国司法体制改革的逐步深入和社会主义法律体系的全面建构,《刑事诉讼法》的再修改势在必行,特别是随着刑事侦查理论的不断完善,被搜查人的人权保障日益受到学界的普遍关注,而作为《刑事诉讼法》重要内容之一的"刑事搜查证明标准"部分的规定却极不完善,相关司法解释对于被搜查人权利实现之救济机制亦存在诸多缺陷。且这些缺陷在《刑事诉讼法》再修改草案中并未得到实质性的改变。当前应借鉴西方国家刑事搜查证明标准的合理内核,从不断完善我国搜查行为的证明标准、被搜查人权利救济途径以及相关配套制度等方面着手,重构我国刑事搜查证明标准。     

Children as guinea pigs: historical perspective

Experimentation involving children is not a new phenomenon. Children have been used as research subjects in a diverse set of experiments, including the trials of new vaccines and sera, in efforts to understand normal pediatric anatomy and physiology and in the development of new drugs and procedures. Concern about child participants in research is also not a new development. For more than a century, critics of medical research have called attention to the fact that children and other vulnerable populations--pregnant women, prisoners, the mentally ill--have too often served as the unwitting and unwilling subjects of medical experiments. This paper looks at several early cases in which children participated, including the first trial of cowpox vaccine, the first human trial of rabies vaccine, and the first treatment of Listerian wound antisepsis. The history of concern for children, especially institutionalized children, in medical research is considered along with the development of regulations or guidelines, including the Declaration of Helsinki (1964).     

Conflict of Interest Policies and Industry Relationships of Guideline Development Group Members: A Cross-Sectional Study of Clinical Practice Guidelines for Depression

Because of increased attention to the issue of trustworthiness of clinical practice guidelines, it may be that both transparency and management of industry associations of guideline development groups (GDGs) have improved. The purpose of the present study was to assess a) the disclosure requirements of GDGs in a cross-section of guidelines for major depression; and, b) the extent and type of conflicts of panel members. Treatment guidelines for major depression were identified and searched for conflict of interest policies and disclosure statements. Multi-modal screens for undeclared conflicts were also conducted. Fourteen guidelines with a total of 172 panel members were included in the analysis. Eleven of the 14 guidelines (78%) had a stated conflict of interest policy or disclosure statement, although the policies varied widely. Most (57%) of the guidelines were developed by panels that had members with industry financial ties to drug companies that manufacture antidepressant medication. However, only a minority of total panel members (18%) had such conflicts of interest. Drug company speakers bureau participation was the most common type of conflict. Although some progress has been made, organizations that develop guidelines should continue to work toward greater transparency and minimization of financial conflicts of interest.