Post‐trial obligations in the Declaration of Helsinki 2013: classification,reconstruction and interpretation

The general aim of this article is to give a critical interpretation of post‐trial obligations towards individual research participants in the Declaration of Helsinki 2013. Transitioning research participants to the appropriate health care when a research study ends is a global problem. The publication of a new version of the Declaration of Helsinki is a great opportunity to discuss it. In my view, the Declaration of Helsinki 2013 identifies at least two clearly different types of post‐trial obligations, specifically, access to care after research and access to information after research. The agents entitled to receive post‐trial access are the individual participants in research studies. The Declaration identifies the sponsors, researchers and host country governments as the main agents responsible for complying with the post‐trial obligations mentioned above. To justify this interpretation of post‐trial obligations, I first introduce a classification of post‐trial obligations and illustrate its application with examples from post‐trial ethics literature. I then make a brief reconstruction of the formulations of post‐trial obligations of the Declaration of Helsinki from 2000 to 2008 to correlate the changes with some of the most salient ethical arguments. Finally I advance a critical interpretation of the latest formulation of post‐trial obligations. I defend the view that paragraph 34 of ‘Post‐trial provisions’ is an improved formulation by comparison with earlier versions, especially for identifying responsible agents and abandoning ambiguous ‘fair benefit’ language. However, I criticize the disappearance of ‘access to other appropriate care’ present in the Declaration since 2004 and the narrow scope given to obligations of access to information after research.     

Ethical Considerations for Outcome‐adaptive Trial Designs: A Clinical Researcher's Perspective

In a typical comparative clinical trial the randomization scheme is fixed at the beginning of the study, and maintained throughout the course of the trial. A number of researchers have championed a randomized trial design referred to as ‘outcome‐adaptive randomization.’ In this type of trial, the likelihood of a patient being enrolled to a particular arm of the study increases or decreases as preliminary information becomes available suggesting that treatment may be superior or inferior. While the design merits of outcome‐adaptive trials have been debated, little attention has been paid to significant ethical concerns that arise in the conduct of such studies. These include loss of equipoise, lack of processes for adequate informed consent, and inequalities inherent in the research design which could lead to perceptions of injustice that may have negative implications for patients and the research enterprise. This article examines the ethical difficulties inherent in outcome‐adaptive trials.     

Putting placebo‐controlled trials in developing countries to the interpersonal justifiability test

This paper considers the ethics of placebo‐controlled trials in developing countries, where a treatment already exists but is not available due to the low local standard of care. Such trials would not be permitted in more developed nations where a higher standard of care is available. I argue that there are moral intuitions against such trials, but a further intuition that if the trials were aimed at producing treatment options for the developing world, that would be more permissible than if the trials were designed with the benefit of rich world people in mind. An approach based upon GA Cohen's work on interpersonal justifiability is suggested to allow us to explain these intuitions. Cohen's framework shows that these trials are ethically problematic because the inequality in healthcare provision between developing and developed nations that allows them to take place is at least partly the pharmaceutical corporations’ fault. Following Cohen's argument, this means the trials are non‐comprehensively justified. This allows for a more complete explanation of our intuitions than to consider such trials as cases of exploitation, because intuitions on the ethicacy of research can vary even when the exploitation relation remains the same. It is then established that there is good empirical evidence to believe that pharmaceutical corporations do fail the interpersonal justifiability test. The policy implications of this judgement are then considered, and it is suggested that the framework might be equally applicable to examining the permissibility of research conducted on vulnerable people within more developed nations.     

Not Fit for Purpose: The Ethical Guidelines of the Indian Council of Medical Research

In 2006, the Indian Council of Medical Research (ICMR) published its ‘Ethical guidelines for Biomedical Research on human participants’. The intention was to translate international ethical standards into locally and culturally appropriate norms and values to help biomedical researchers in India to conduct ethical research and thereby safeguard the interest of human subjects. Unfortunately, it is apparent that the guideline is not fit for purpose. In addition to problems with the structure and clarity of the guidelines, there are several serious omissions and contradictions in the recommendations. In this paper, we take a close look at the two key chapters and highlight some of the striking flaws in this important document. We conclude that ethics committees and national authorities should not lose sight of international ethical standards while incorporating local reality and cultural and social values, as focusing too much on the local context could compromise the safety of human subjects in biomedical research, particularly in India.     

Off‐Shoring Clinical Research: Exploitation and the Reciprocity Constraint

The last 20 years have seen a staggering growth in the practice of off‐shoring clinical research to low‐and middle‐income countries (LICs and MICs), a growth that has been matched by the neoliberal policies adopted by host countries towards attracting trials to their shores. A recurring concern in this context is the charge of exploitation, linked to various aspects of off‐shoring. In this paper, I examine Alan Wertheimer's approach and offer an alternative view of understanding exploitation in this context. I will suggest that the justification for the enterprise of research is largely dependent on its integration within a health system from which participants regularly benefit and I argue that an attention to a principle of reciprocity will enable us to better recognize and address exploitation in international research.     

Ethical Considerations in Clinical Trials: A Critique of the ICH‐GCP Guideline

This article examines issues relating to ethics decision‐making in clinical trials. The overriding concern is to ensure that the well being and the interests of human subjects are adequately safeguarded. In this respect, this article will embark on a critical analysis of the ICH‐GCP Guideline. The purpose of such an undertaking is to highlight areas of concern and the shortcomings of the existing ICH‐GCP Guideline. Particular emphasis is made on how ethics committees perform their duties and responsibilities in line with the principles outlined in the ICH‐GCP Guideline. This article will draw attention to the need for a new approach to addressing the weaknesses of the ICH‐GCP Guideline in its present form.     

Improving the Quality of Host Country Ethical Oversight of International Research: The Use of a Collaborative ‘Pre‐Review’ Mechanism for a Study of Fexinidazole for Human African Trypanosomiasis

Developing countries face numerous barriers to conducting effective and efficient ethics reviews of international collaborative research. In addition to potentially overlooking important scientific and ethical considerations, inadequate or insufficiently trained ethics committees may insist on unwarranted changes to protocols that can impair a study's scientific or ethical validity. Moreover, poorly functioning review systems can impose substantial delays on the commencement of research, which needlessly undermine the development of new interventions for urgent medical needs. In response to these concerns, the Drugs for Neglected Diseases Initiative (DNDi), an independent nonprofit organization founded by a coalition of public sector and international organizations, developed a mechanism to facilitate more effective and efficient host country ethics review for a study of the use of fexinidazole for the treatment of late stage African Trypanosomiasis (HAT). The project involved the implementation of a novel ‘pre‐review’ process of ethical oversight, conducted by an ad hoc committee of ethics committee representatives from African and European countries, in collaboration with internationally recognized scientific experts. This article examines the process and outcomes of this collaborative process.     

The Challenges of Research Informed Consent in Socio‐Economically Vulnerable Populations: A Viewpoint From the Democratic Republic of Congo

In medical research, the ethical principle of respect for persons is operationalized into the process of informed consent. The consent tools should be contextualized and adapted to the different socio‐cultural environment, especially when research crosses the traditional boundaries and reaches poor communities. We look at the challenges experienced in the malaria Quinact trial, conducted in the Democratic Republic of Congo, and describe some lessons learned, related to the definition of acceptable representative, the role of independent witness and the impact of socio‐economic vulnerability. To ensure children's protection, consent is required by the parents or, in their absence, by a legally mandated representative. In our setting, children's responsibility is often entrusted permanently or temporarily to relatives or friends without a tribunal mandate. Hence, a notion of ‘culturally acceptable representative’ under supervision of the local Ethics Committee may be more suitable. To ensure protection of illiterate subjects, an independent witness is required to confirm that the consent was freely given. However, in low‐literacy contexts, potential witnesses often don't have any previous relationship with patient and there may be power‐unbalance in their relationship, rather than genuine dialogue. In poor communities, trial participation may be seen as an opportunity to secure access to healthcare. Poverty may also lead to ‘competition’ to access the research‐related benefits, with a risk of disturbance at societal or household level. Adjusting consent procedures to sociocultural and socioeconomic realities is essential for fulfilling the underlying ethical principles. This requires a collaborative dialogue between researchers, regulators and ethics committees.     

Reciprocity‐Based Reasons for Benefiting Research Participants: Most Fail,the Most Plausible is Problematic

A common reason for giving research participants post‐trial access (PTA) to the trial intervention appeals to reciprocity, the principle, stated most generally, that if one person benefits a second, the second should reciprocate: benefit the first in return. Many authors consider it obvious that reciprocity supports PTA. Yet their reciprocity principles differ, with many authors apparently unaware of alternative versions. This article is the first to gather the range of reciprocity principles. It finds that: (1) most are false. (2) The most plausible principle, which is also problematic, applies only when participants experience significant net risks or burdens. (3) Seldom does reciprocity support PTA for participants or give researchers stronger reason to benefit participants than equally needy non‐participants. (4) Reciprocity fails to explain the common view that it is bad when participants in a successful trial have benefited from the trial intervention but lack PTA to it.     

A 6‐Month Randomized,Placebo‐Controlled,Dose‐Ranging Trial of Topiramate for Weight Loss in Obesity

Objective: To evaluate the efficacy and safety of topiramate (TPM) for weight loss in healthy obese subjects. Research Methods and Procedures: A randomized, double‐blind, placebo‐controlled, dose‐ranging trial was conducted. Three hundred eighty‐five subjects, 18 and 75 years of age, were randomized to receive either placebo or TPM at 64, 96, 192, or 384 mg daily. Dosing began at 16 mg once daily. In week 2, the dose was increased to 16 mg twice daily. Thereafter, the dose was raised every week by 32 mg/d (16 mg twice daily) until subjects reached their target dose. Twenty‐four weeks after beginning treatment, all subjects were tapered off treatment by a dose reduction of 50% per week. All participants received the same lifestyle program. Results: Mean percent weight loss from baseline to week 24 was ?2.6% in placebo‐treated patients vs. ?5.0%, ?4.8%, ?6.3%, and ?6.3% in the 64, 96, 192, and 384 mg/d TPM groups, respectively. Greater percentages of TPM‐treated patients lost at least 5% or 10% of body weight compared with placebo. The most frequent adverse events were related to the central or peripheral nervous system, including paresthesia, somnolence, and difficulty with memory, concentration, and attention. Most events were dose‐related, occurred early in treatment, and usually resolved spontaneously; only 21% receiving TPM withdrew due to adverse events compared with 11% on placebo. Discussion: TPM produced significantly greater weight loss than placebo at all doses.     

Geroscience‐guided repurposing of FDA‐approved drugs to target aging: A proposed process and prioritization

Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience‐guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA‐approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)‐like study involving such candidate gerotherapeutics.     

Six‐Month Treatment of Obesity with Sibutramine 15 mg; A Double‐Blind,Placebo‐Controlled Monocenter Clinical Trial in a Hispanic Population

Objective: To evaluate the safety and efficacy of sibutramine 15 mg by mouth once per day in obese patients over a period of 6 months. Research Methods and Procedures: A monocenter, double‐blind, placebo controlled, parallel, prospective clinical trial was carried out. Sixty‐nine male and female obese patients (body mass index [BMI] > 30 kg/m²) aged 16 to 65 years entered the trial. Results: 22 of 35 patients in the sibutramine group and 9 of 34 patients in the placebo group completed the trial. The high dropout rate in the sibutramine group was due to adverse events in 3 cases, lack of efficacy (as judged by patients) in 7, loss to follow‐up in 2, and an orthopedic device being worn in 1; in the placebo group the dropouts were ascribed to lack of efficacy (as judged by patients) in 17 cases and to loss to follow‐up in 8 cases. Using the method of last observation carried forward, the weight loss in the sibutramine group was 10.27 kg (95% confidence intervals [95% CI] 7.66; 13.07) and 1.26 kg (95% CI 0.3; 2.23) in the placebo group. The BMI loss was 4.17 kg/m² (95% CI 3.11; 5.22) in the sibutramine group and 0.53 kg/m² (95% CI 0.13; 0.92) in the placebo group. The waist circumference reduction was 12.51 cm (95% CI 9.25; 15.77) in the sibutramine group and 3.26 cm (95% CI 1.38; 5.14) in the control group (p < 0.05 by paired Student's t test for all the intragroup comparisons). Twenty‐three sibutramine patients had 34 adverse events, the most frequent adverse events in the sibutramine group were upper respiratory tract infections (n = 6) and constipation (n = 6); 16 placebo patients had 21 adverse events. Three sibutramine patients withdrew their informed consent when they had adverse events. Discussion: The results show that sibutramine induces significant loss of body weight and waist circumference. Cardiovascular function was not significantly affected by sibutramine. Sibutramine was well tolerated by most of the patients.     

Emergency Preservation and Resuscitation Trial: A Philosophical Justification for Non‐Voluntary Enrollment

In a current clinical trial for Emergency Preservation and Resuscitation (EPR), Dr. Samuel Tisherman of the University of Maryland aims to induce therapeutic hypothermia in order to ‘buy time’ for operating on victims of severe exsanguination. While recent publicity has framed this controversial procedure as ‘killing a patient to save his life’, the US Army and Acute Care Research appear to support the study on the grounds that such patients already face low chances of survival. Given that enrollment in the trial must be non‐voluntary, the study has received an exemption from federal standards for obtaining informed consent. How exactly, if at all, is non‐voluntary enrollment morally justifiable? In this essay, I appeal to the notable work of Hans Jonas in an effort to defend the EPR trial's use of non‐voluntary enrollment. It is often thought and, as I show, it may appear that Jonas has called for the end of experimental medical practice. Still, I derive from Jonas a principle of double‐effect upon which physicians may be seen as morally permitted to pursue innovations in emergency medicine but only as a byproduct of pursuing therapeutic success. With this position, I argue that the EPR trial can be granted a stronger philosophical justification than simply waiving the requirement of obtaining informed consent. The double‐effect justification would obtain, perhaps regardless of the success of such innovative procedures as therapeutic hypothermia.     

Reporting of informed consent, standard of care and post-trial obligations in global randomized intervention trials: a systematic survey of registered trials

Objective:  Ethical guidelines are designed to ensure benefits, protection and respect of participants in clinical research. Clinical trials must now be registered on open-access databases and provide details on ethical considerations. This systematic survey aimed to determine the extent to which recently registered clinical trials report the use of standard of care and post-trial obligations in trial registries, and whether trial characteristics vary according to setting.
Methods:  We selected global randomized trials registered on http://www.clinicaltrials.gov and http://www.controlled-trials.com . We searched for intervention trials of HIV/AIDS, malaria, and tuberculosis from 9 October 2004, the date of the most recent version of the Helsinki Declaration, to 10 April 2007.
Results:  We collected data from 312 trials. Fifty-eight percent (58%, 95% CI  =  53 to 64) of trial protocols report informed consent. Fifty-eight percent (58%, 95% CI  =  53 to 64) of trials report active controls. Almost no trials (1%, 95% CI  =  0.5 to 3) mention post-trial provisions. Most trials measure surrogate outcomes. Twenty percent (20%, 95% CI  =  16 to 25) of trials measure patient-important outcomes, such as death; and the odds that these outcomes are in a low income country are five times greater than for a developed country (odds ratio (OR) 5.03, 95% CI  =  2.70 to 9.35, p  = < 0.001). Pharmaceutical companies are involved in 28% (CI  =  23 to 33) of trials and measure surrogate outcomes more often than nonpharmaceutical companies (OR 2.45, 95% CI  =  1.18 to 5.09, p  =  0.31).
Conclusion:  We found a large discrepancy in the quality of reporting and approaches used in trials in developing settings compared to wealthier settings.     

Comparison of design strategies for a three‐arm clinical trial with time‐to‐event endpoint: Power,time‐to‐analysis,and operational aspects

To optimize resources, randomized clinical trials with multiple arms can be an attractive option to simultaneously test various treatment regimens in pharmaceutical drug development. The motivation for this work was the successful conduct and positive final outcome of a three‐arm randomized clinical trial primarily assessing whether obinutuzumab plus chlorambucil in patients with chronic lympocytic lymphoma and coexisting conditions is superior to chlorambucil alone based on a time‐to‐event endpoint. The inference strategy of this trial was based on a closed testing procedure. We compare this strategy to three potential alternatives to run a three‐arm clinical trial with a time‐to‐event endpoint. The primary goal is to quantify the differences between these strategies in terms of the time it takes until the first analysis and thus potential approval of a new drug, number of required events, and power. Operational aspects of implementing the various strategies are discussed. In conclusion, using a closed testing procedure results in the shortest time to the first analysis with a minimal loss in power. Therefore, closed testing procedures should be part of the statistician's standard clinical trials toolbox when planning multiarm clinical trials.     

Pesticide Risk Perceptions,Knowledge, and Attitudes of Operators,Workers, and Residents: A Review of the Literature

The literature on the risk perceptions, knowledge levels, and attitudes of operators, workers, and residents in relation to non-dietary exposure to agricultural pesticides is reviewed. No literature was identified in relation to bystander exposure. Research has primarily been conducted on participants in developing countries and migrant workers in the United States. For operators and workers, illiteracy, poverty, and a perception that exposure to pesticides is an inevitable part of their work results in limited adoption of safety precautions while using and storing pesticides. As a result, risk communication activities aimed at operator and workers need to take account of the wider socioeconomic and cultural conditions in which workers and operators are working and living. There is less research focused on residents’ and bystanders’ perceptions, attitudes, and behaviors. The lack of European data in general, and residents’ and bystanders’ data in particular, represents a knowledge gap that is pertinent to emerging EU legislation requiring residents’ and bystanders’ inclusion in pesticide risk assessment. This review provides a comprehensive overview that can assist policy-makers, and risk communicators in the development of targeted training and awareness-raising material for operators, workers, bystanders, and residents. Areas for future research are suggested.     

Factors Affecting the Delivery,Access, and Use of Interventions to Prevent Malaria in Pregnancy in Sub-Saharan Africa: A Systematic Review and Meta-Analysis

Background

Malaria in pregnancy has important consequences for mother and baby. Coverage with the World Health Organization–recommended prevention strategy for pregnant women in sub-Saharan Africa of intermittent preventive treatment in pregnancy (IPTp) and insecticide-treated nets (ITNs) is low. We conducted a systematic review to explore factors affecting delivery, access, and use of IPTp and ITNs among healthcare providers and women.

Methods and Results

We searched the Malaria in Pregnancy Library and Global Health Database from 1 January 1990 to 23 April 2013, without language restriction. Data extraction was performed by two investigators independently, and data was appraised for quality and content. Data on barriers and facilitators, and the effect of interventions, were explored using content analysis and narrative synthesis. We conducted a meta-analysis of determinants of IPTp and ITN uptake using random effects models, and performed subgroup analysis to evaluate consistency across interventions and study populations, countries, and enrolment sites. We did not perform a meta-ethnography of qualitative data.Ninety-eight articles were included, of which 20 were intervention studies. Key barriers to the provision of IPTp and ITNs were unclear policy and guidance on IPTp; general healthcare system issues, such as stockouts and user fees; health facility issues stemming from poor organisation, leading to poor quality of care; poor healthcare provider performance, including confusion over the timing of each IPTp dose; and women''s poor antenatal attendance, affecting IPTp uptake. Key determinants of IPTp coverage were education, knowledge about malaria/IPTp, socio-economic status, parity, and number and timing of antenatal clinic visits. Key determinants of ITN coverage were employment status, education, knowledge about malaria/ITNs, age, and marital status. Predictors showed regional variations.

Conclusions

Delivery of ITNs through antenatal clinics presents fewer problems than delivery of IPTp. Many obstacles to IPTp delivery are relatively simple barriers that could be resolved in the short term. Other barriers are more entrenched within the overall healthcare system or socio-economic/cultural contexts, and will require medium- to long-term strategies. Please see later in the article for the Editors'' Summary     

From protectionism to inclusion: A New Zealand perspective on health‐related research involving adults incapable of giving informed consent

The revision of the Council of International Organizations of Medical Sciences (CIOMS) International ethical guidelines for health‐related research (2016) heralds a paradigm shift from the ‘protectionist’ policies that emerged following historical research atrocities of the 20th century, towards a more nuanced and inclusive approach to research participation. Adopting this modified approach will enable countries to secure the benefits of research for individuals and for society as a whole, while at the same time minimizing the potential for exploitation and research‐related harms. This article considers the potential impact of Guideline 16 of the CIOMS 2016 from a New Zealand perspective, with respect to research involving adults with impaired capacity and who are incapable of giving informed consent. While the CIOMS 2016 apply a ‘minimal risk’ threshold to guide research involving adults who lack capacity to consent, New Zealand law currently adopts a ‘best interests’ standard which significantly restricts the scope of permissible research that may be performed in this context. This article argues that the CIOMS 2016 should influence change to New Zealand’s legal framework for ethical review of research. CIOMS 2016 provides useful guidance for the necessary standards and processes to enable the responsible and ethical inclusion of adults with impaired capacity in research.