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.     

Physicians' Understanding of Consent Requirements for Phase I Clinical Trials in Cognitively Impaired or Highly Vulnerable Patients

We investigated physicians' attitudes about entering patients who cannot give informed consent or who are of a vulnerable population into clinical trials. A survey instrument asked a nationwide sample of practicing physicians about whether ten hypothetical patients could be enrolled in a phase I clinical trials. The impact of demographic variables on the number of scenarios viewed as completely or somewhat acceptable was analyzed via student's T tests or analysis of variance (ANOVA) as applicable. All significant (p < 0.01) variables were entered into a multiple logistic regression model. Eighty-four percent of respondents indicated that at least one case scenario was acceptable. A majority of those who conduct clinical trials (62%), who had training in the ethics of clinical research (78%), and who sit on institutional review boards (IRBs) (83%) approved of at least one case scenario. Physicians approved of the entry of some patients who cannot give informed consent or who are of a vulnerable population into clinical trials. More effective education on the guidelines involving clinical research should be available to practicing physicians, residents, and medical students. There should also be assurance that physicians who conduct clinical trials or who sit on IRBs have the requisite knowledge about the ethics of clinical research.     

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.     

International research: Ethical imperialism or ethical pluralism? 1

Conflicts have arisen in international research when countries in which research is being carried out lack the ethical rules or mechanisms for review employed in the United States and Europe. It is objected that a requirement to adhere to regulations promulgated by the US government constitutes “ethical imperialism.”; But if researchers in some countries need not be bound by ethical standards widely accepted in the conduct of research, it could open the door to an ethical relativism allowing virtually any standard a country desires to accept. One example is the variations in informed consent, especially in countries that accord lesser importance to the individual than do the US and Europe. A recent controversy centered on a series of placebo‐controlled, HIV/AIDS trials sponsored by the United States and conducted in several developing countries. These trials could not ethically be carried out in the United States because a proven effective treatment exists. Attempts to avoid similar controversies in forthcoming HIV/AIDS vaccine trials have been initiated by the joint United Nations AIDS program, with a process of regional consultations in the countries where the research will be conducted.     

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.     

Scientific evidence and the judicial system

Research involving the vulnerable sick raises difficult challenges for investigators and Institutional Review Boards. Exactly who among the ill counts as vulnerable is a matter of judgement, and involves consideration of susceptibility to harm and capacity to provide free and informed consent. A balanced approach is required when protections are considered, and the benefits as well as the risks of research participation must be carefully weighed. A variety of protections for the vulnerable sick in research are available, including enrolling subjects in a study only with a strong justification, ensuring that consent is free and comprehending, and setting limits on the risk to which they may be asked to endure. Discussion of three contemporary controversies, placebo‐controlled trials in the psychiatric setting, phase I clinical trials and oncology patients, and emergency room research involving patients incapable of giving consent, highlights the little recognized prominence of risk‐benefit issues in the clinical studies in the vulnerable sick.     

Neurobiological research involving human subjects: Perspectives from the office for protection from research risks

Department of Health and Human Services (HHS) regulations at 45 CFR 46 require that all human subjects research supported by HHS be reviewed and approved by a local Institutional Review Board (IRB). Investigators may not involve human subjects in research without their informed consent, and additional safeguards are required when subjects are likely to be vulnerable to coercion or undue influence. Application of the regulations to neurobiological research is discussed.     

Ethics of research design

Discussions of ethical issues in research involving human subjects most usually provoke concerns about valid informed consent procedures. However, considering the recognized limitations of informed consent, arguably the way a study is designed is a more consequential concern for subject well‐being. This paper summarizes ethical issues in the design of clinical research, with reference to historic and current guidelines. Special attention is given to randomized clinical trials (RCTs) and psychiatric research.     

Research ethics and clinical trials: Fostering collaboration with research participants

Accountability in research is a concept that applies to researchers and study participants alike. Human subjects play an active part in the success or failure of a clinical trial by virtue of their understanding of a study's goals expectations of personal gain, and adherence to study design. Trials must be designed to address patient concerns, offer an improved consent process, and move beyond our narrow conception of “patient rights.”; Problems with protocol adherence may be reduced by conceptualizing clinical research as an endeavor with mutual accountability within a relational ethic.     

Is the trend to publish reviews and clinical trials related to the journal impact factor? Analysis in dentistry field

ABSTRACT

It is generally accepted that the Journal Impact Factor is a quality criterion. The objective was to determine the evolution along the period 2010–2016 of number of different types of papers, reviews and clinical trials, published by dental journals, as well as if they are related with the quartile occupied in the Journal Impact Factor 2017 ranking. To this end, ten journals per quartile belonging to the field Dentistry, Oral Surgery and Medicine in the 2017 Journal Citation Reports were randomly selected. For each journal and year, the total number of narrative reviews, systematic reviews (with and without meta-analysis), meta-analysis, clinical trials and randomized controlled trials were obtained from Pubmed. To achieve our goal, the slope of these variables over time was estimated using the least squares method, after which one-way analysis of variance of mean values was performed. In Dentistry, the journals of the top quartiles show a trend to publish increasing amounts of systematic reviews and meta-analysis, than the ones of the third and fourth quartile. On the other hand, globally, there was virtually no increase in narrative reviews, clinical trials and randomized controlled trial. Possible causes of this behavior are also discussed in this article.     

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.     

The Senior Outreach Program of Park Ridge Mental Health

Abstract

Availability and accessibility of mental health services for the elderly is woefully inadequate, failing to recognize the diversity of needs in the older adult population. Stigma, confusing and exclusionary insurance regulations and restrictive mental health center policies have both limited and discouraged treatment interventions. Through innovative case finding, programming and funding arrangements, the Senior Outreach program of Park Ridge Mental Health in Rochester, New York, has proven effective in identifying and providing outreach mental health services to elderly individuals. The program utilizes a human services agency model, yet operates within a large heath care system as part of a continuum of psycho-geriatric services.     

The therapeutic misconception,beneficence, and respect

In order to provide benefits to society, human medical trials must place subjects at risk of harm. This activity is thought to be justified in part by the consent of the subjects involved. But, studies have shown that most such consents are based on a therapeutic misconception (TM); the false belief of subjects that their researchers will act as their personal physicians (seeking their benefit and protecting them from harm), rather than placing them at risk of harm for the good of others. Toleration by researchers of the TM in their subjects is a form of “informational manipulation”; that renders consent procedures disrespectful to subject autonomy. Consent obtained from subjects who labor under a TM is neither voluntary nor informed; as long as they have not been disabused of the TM, the action they take in enrolling in a trial is not the one they intend nor is it autonomously chosen. Changes in consent procedures should be adopted to ensure that all subjects are aware inter alia that (a) the health interests of future patients (as well as the researchers’ and their sponsors’ financial interests) may be more important to researchers than the interest of a subject in his or her health, and (b) normal subjects neither understand nor believe this when told. Close attention to the response of prospective subjects to this information should allow for the exclusion of all but the truly altruistic. However, the result of conscientious implementation of such policies would likely be that human medical research could no longer be conducted on more than a minimal level.     

Punitive Damages in China: Evolution and Application

Abstract

The revised Law on the Protection of the Rights and Interests of Consumers (Consumer Protection Law), which sums up nearly twenty years of the evolution of Chinese punitive damages regulations, sets out a model system of punitive damages. These are in essence a special kind of penalty under a dual public-private legal system in which the punitive and deterrent functions of public law are realized through the mechanism of private law. Their application should be guided by the public law principle that the penalty should be proportionate to the offence. The question of whether the penalty is appropriate arises in the application of the two forms of punitive damages prescribed in the Consumer Protection Law—whether used separately or together, or in conjunction with or independently of fines or financial awards. The application of the new punitive damages regulations may overlap with the application of China’s Food Safety Law and Tort Liability Law.     

The role of research in drug policy in Hong Kong: highlighting life satisfaction from two longitudinal studies of drug abusers

ABSTRACT

This paper examines the role of research in the development of drug policy in Hong Kong. The upsurge of the prevalence of psychoactive drug abuse in young people since the mid-1990s had brought about a great demand for medical and social science research on psychoactive drugs and users. Among a large number of Beat Drugs Fund-funded projects, two longitudinal studies, conducted between 2000 and 2002 and between 2009 and 2011, respectively, were used to illustrate the possible contributions of research findings to treatment and rehabilitation services. The most salient finding present in both studies was the significant and negative relationship between life satisfaction and continuation of drug use. The finding suggested that subjective well-being should be incorporated into treatment programmes, and there is a need to provide post-treatment services to young rehabilitated psychoactive drug abusers in the form of life planning programmes and organisation of sustainable social activities in the community.     

Guinea Pigs on the payroll: The ethics of paying research subjects

Regulatory bodies and scholars have traditionally conceptualized biomedical research on healthy subjects in the same way as research on patients. Guidelines and regulations have portrayed payment to a healthy subject as a potential constraint, or “undue influence,”; on the subject's free consent. In this essay we suggest an alternative way of conceptualizing research on healthy subjects, which sees the basic issue not as one of undue influence but as one of justice. Healthy subjects generally enroll in research protocols not for humanitarian reasons but for the money they will receive. Many of these protocols are conducted by profit‐driven corporations. Yet current guidelines and regulations prohibit subjects from negotiating for fair payment for the risks, discomforts and inconveniences they undergo, and IRBs are not staffed adequately to monitor the subject's safety. We propose to remedy the situation by regulating payment to healthy subjects as a labor relation.     

The Importance of the Preservation of the Ethical Principle of Equipoise in the Design of Clinical Trials: Relative Impact of the Methodological Quality Domains on the Treatment Effect in Randomized Controlled Trials

Previous research has identified methodological problems in the design and conduct of randomized trials that could, if left unaddressed, lead to biased results. In this report we discuss one such problem, inadequate control intervention, and argue that it can be by far the most important design characteristic of randomized trials in overestimating the effect of new treatments. Current guidelines for the design and reporting of randomized trials, such as the Consolidated Standards of Reporting Trials (CONSORT) statement, do not address the choice of the comparator intervention. We argue that an adequate control intervention can be selected if people designing a trial explicitly take into consideration the ethical principle of equipoise, also known as "the uncertainty principle."     

All-In-One Motion

Abstract

In this essay, I recall a moment in my development as a clinician that serves as a marker, transforming my understanding of psychoanalytically informed clinical work from that of an intellectual encounter to one filled with the unconscious momentum, uncertainty, and rich symbolism that are intrinsic to therapeutic work.     

Pre-arrest drug use and associated risk factors among incarcerated offenders in China

ABSTRACT

Past research has consistently reported a higher rate of drug use before arrest among incarcerated inmates than that of the general population. However, there is a lack of either qualitative or quantitative research on this topic under the Chinese setting. Drawing upon survey data collected from 1,518 inmates in a Chinese province, this study attempts to fill in the research gap by assessing the connection between risk factors associated with pre-arrest use. Roughly a quarter of all inmates in the sample had the experience of drug use before arrest. Regression analysis suggested that impulsivity, volatile temper, and perceived prevalence of drug use in neighborhood were significantly related to drug use among inmates. Two control variables include offense type and stable job, were also found to be significant predictors of drug use. Implications for research and policy were highlighted in the end.     

The “Socialization of Elderly Hospitalization” in China: Development,Problems, and Solutions

ABSTRACT

Objectives to analyze the development of the elderly patients with chronic diseases and to make some suggestions for the elderly social hospitalization. Methods By using yearbook data and theoretical analyses, the paper respectively presents the problems and furthermore solutions of China's elderly services. Results The elderly patients with chronic illnesses have formed a new group, and the phenomenon of “socialization of elderly hospitalization” has become a major social risk. Discussions China needs to promote the idea of “long-term care” in elderly social security, establishing long-term care insurance and fostering a private, professional elderly service system.