Are Drug Companies Living Up to Their Human Rights Responsibilities? The Merck Perspective

BACKGROUND TO THE DEBATE: The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.     

Are Drug Companies Living Up to Their Human Rights Responsibilities? The Perspective of the Former United Nations Special Rapporteur (2002-2008)

BACKGROUND TO THE DEBATE: The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.     

Are Human Peripheral Nerves Sensitive to X-Ray Imaging?

Diagnostic imaging techniques play an important role in assessing the exact location, cause, and extent of a nerve lesion, thus allowing clinicians to diagnose and manage more effectively a variety of pathological conditions, such as entrapment syndromes, traumatic injuries, and space-occupying lesions. Ultrasound and nuclear magnetic resonance imaging are becoming useful methods for this purpose, but they still lack spatial resolution. In this regard, recent phase contrast x-ray imaging experiments of peripheral nerve allowed the visualization of each nerve fiber surrounded by its myelin sheath as clearly as optical microscopy. In the present study, we attempted to produce high-resolution x-ray phase contrast images of a human sciatic nerve by using synchrotron radiation propagation-based imaging. The images showed high contrast and high spatial resolution, allowing clear identification of each fascicle structure and surrounding connective tissue. The outstanding result is the detection of such structures by phase contrast x-ray tomography of a thick human sciatic nerve section. This may further enable the identification of diverse pathological patterns, such as Wallerian degeneration, hypertrophic neuropathy, inflammatory infiltration, leprosy neuropathy and amyloid deposits. To the best of our knowledge, this is the first successful phase contrast x-ray imaging experiment of a human peripheral nerve sample. Our long-term goal is to develop peripheral nerve imaging methods that could supersede biopsy procedures.     

What Is Needed to Eradicate Lymphatic Filariasis? A Model-Based Assessment on the Impact of Scaling Up Mass Drug Administration Programs

Background

Lymphatic filariasis (LF) is a neglected tropical disease for which more than a billion people in 73 countries are thought to be at-risk. At a global level, the efforts against LF are designed as an elimination program. However, current efforts appear to aim for elimination in some but not all endemic areas. With the 2020 goal of elimination looming, we set out to develop plausible scale-up scenarios to reach global elimination and eradication. We predict the duration of mass drug administration (MDA) necessary to reach local elimination for a variety of transmission archetypes using an existing model of LF transmission, estimate the number of treatments required for each scenario, and consider implications of rapid scale-up.

Methodology

We have defined four scenarios that differ in their geographic coverage and rate of scale-up. For each scenario, country-specific simulations and calculations were performed that took into account the pre-intervention transmission intensity, the different vector genera, drug regimen, achieved level of population coverage, previous progress toward elimination, and potential programmatic delays due to mapping, operations, and administration.

Principal Findings

Our results indicate that eliminating LF by 2020 is unlikely. If MDA programs are drastically scaled up and expanded, the final round of MDA for LF eradication could be delivered in 2028 after 4,159 million treatments. However, if the current rate of scale-up is maintained, the final round of MDA to eradicate LF may not occur until 2050.

Conclusions/Significance

Rapid scale-up of MDA will decrease the amount of time and treatments required to reach LF eradication. It may also propel the program towards success, as the risk of failure is likely to increase with extended program duration.     

Guidelines for Guidelines: Are They Up to the Task? A Comparative Assessment of Clinical Practice Guideline Development Handbooks

Objectives

We conducted a comparative review of clinical practice guideline development handbooks. We aimed to identify the main guideline development tasks, assign weights to the importance of each task using expert opinions and identify the handbooks that provided a comprehensive coverage of the tasks.

Methods

We systematically searched and included handbooks published (in English language) by national, international or professional bodies responsible for evidenced-based guideline development. We reviewed the handbooks to identify the main guideline development tasks and scored each handbook for each task from 0 (the handbook did not mention the task) to 2 (the task suitably addressed and explained), and calculated a weighted score for each handbook. The tasks included in over 75% of the handbooks were considered as ‘necessary’ tasks.

Result

Nineteen guideline development handbooks and twenty seven main tasks were identified. The guideline handbooks’ weighted scores ranged from 100 to 220. Four handbooks scored over 80% of the maximum possible score, developed by the National Institute for Health and Clinical Excellence, Swiss Centre for International Health, Scottish Intercollegiate Guidelines Network and World Health Organization. Necessary tasks were: selecting the guideline topic, determining the guideline scope, identifying relevant existing guidelines, involving the consumers, forming guideline development group,, developing clinical questions, systematic search for evidence, selecting relevant evidence, appraising identifies research evidence, making group decision, grading available evidence, creating recommendations, final stakeholder consultation, guideline implementation strategies, updating recommendations and correcting potential errors.

Discussion

Adequate details for evidence based development of guidelines were still lacking from many handbooks. The tasks relevant to ethical issues and piloting were missing in most handbooks. The findings help decision makers in identifying the necessary tasks for guideline development, provide an updated comparative list of guideline development handbooks, and provide a checklist to assess the comprehensiveness of guideline development processes.     

Are Female Starlings Able to Recognize the Scent of Their Offspring?

Background

Although there is growing evidence that birds may have individual chemical profiles that can function in several social contexts, offspring recognition based on olfactory cues has never been explored. This ability should be more likely evolved in colonial birds and/or species suffering brood parasitism, in which the risk of being engaged in costly misdirected parental care is high.

Methodology/Principal Findings

We performed a choice experiment to examine whether females of the spotless starling, Sturnus unicolor, a species that is colonial, and where a fraction of the population is exposed to intraspecific brood parasitism, can discriminate between the scent of their offspring and that of unrelated nestlings. We also explored whether the development of the uropygial gland secretion may play a role in such olfactory discrimination by performing the choice experiments to females rearing nestlings of two different ages, that is, without and with developed uropygial glands. Results showed that female starlings did not preferentially choose the scent of their offspring, independently of whether the gland of nestlings was developed or not.

Conclusions/Significance

Our results suggest that female starlings do not have or do not show the ability to distinguish their offspring based on olfaction, at least up to 12–14 days of nestling age. Further research is needed to examine whether odour-based discrimination may function when fledgling starlings leave the nest and the risk of costly misidentification is likely to increase.     

Measuring Nepotism through Shared Last Names: Are We Really Moving from Opinions to Facts?

Nepotistic practices are detrimental for academia. An analysis of shared last names among academics was recently proposed to measure the diffusion of nepotism, the results of which have had a huge resonance. This method was thus proposed to orient the decisions of policy makers concerning cuts and funding. Because of the social relevance of this issue, the validity of this method must be assessed. Thus, we compared results from an analysis of Italian and United Kingdom academic last names, and of Italian last and given names. The results strongly suggest that the analysis of shared last names is not a measure of nepotism, as it is largely affected by social capital, professional networking and demographic effects, whose contribution is difficult to assess. Thus, the analysis of shared last names is not useful for guiding research policy.     

Are Eating Occasions and Their Energy Content Related to Child Overweight and Socioeconomic Status?

The objectives of this study were: (i) to assess the relationships between childhood overweight (OW) and four eating behaviors: daily eating frequency, and the relative contribution of breakfast, main meals (lunch and dinner), and snacks to total daily energy intake (EI); (ii) to explore whether these eating behaviors are involved in the negative association between socioeconomic status (SES) and OW. A representative sample of French children aged 3-11 years (n = 748) was taken from the 1998-1999 cross-sectional French INCA1 (Enquête Individuelle et Nationale sur les Consommations Alimentaires) food consumption survey. Food intake was reported in a 7-day food record, and SES, physical activity, sedentary behavior (SED), weight, and height were reported by answering face-to-face questionnaires. After adjusting for EI, physical activity, and SED, OW was positively associated with the contribution of the main meals to EI (P = 0.03), not significantly associated with the contribution of breakfast to EI, and inversely correlated to the number of eating episodes (P = 0.009) and to the contribution of snacking episodes to EI (P = 0.007). Our data suggest that a combination of more frequent intake occasions and lower contribution of the main meals to total daily EI is associated with a smaller risk of OW in children. However, eating frequency was the only eating behavior that played a slight mediation role (contributing approximately 8%) in the inverse relationship between SES and OW.     

Moving Focus from Weight to Health. What Are the Components Used in Interventions to Improve Cardiovascular Health in Children?

Introduction

Obesity in childhood impacts on many areas of the child’s current and future health, including their cardiovascular health. To date many attempts have been made to design interventions to tackle excess childhood weight but with limited success. We aimed to establish the components common to interventions in children that improve cardiovascular health parameters.

Methods

We searched the following databases: EMBASE 1974-week 3 November 2014, Ovid Medline 1946 Present, and PsychINFO 1967-Present for studies reporting interventions in healthy young people under the age of 18. Included interventions had to contain an education component and have been carried out in a community, school, or clinical setting. Papers had to report on at least one of the pre-specified CVD risk parameters and at least one non-biological outcome from knowledge, attitudes or behaviours.

Results

We retrieved 2451 papers, from which 12 studies (18 papers) of 3046 participants were included. From the selected papers we identified four component themes; Health Behaviours, Self-Concept, Practical and Cognitive Tools, and Intervention Characteristics. The subcomponents that made up these themes were fairly consistent across the studies analysed although the studies varied in their duration, settings and children with which they were carried out. Nine of the studies were able to bring about positive change in at least one biological and one non-biological aspect of child cardiovascular health.

Conclusion

The component themes identified here were common to intervention studies that had success in improving parameters of cardiovascular health. We suggest that the focus of childhood health interventions be moved from weight onto cardiovascular health parameters and that future interventions use the lessons learned by their predecessors to incorporate those components that are associated with successful interventions.     

Should an Institution That Has Commercial Rights in a New Drug or Device Be Allowed to Evaluate the Technology?

BACKGROUND TO THE DEBATE: In the United States, the passage of the Bayh-Dole Act in 1980 encouraged universities to license inventions for commercial development. Although this financial incentive can stimulate academic researchers to discover new drugs and devices, there is concern that the possibility of monetary reward could distort investigators' objectivity.     

Are Pharmaceuticals with Evolutionary Conserved Molecular Drug Targets More Potent to Cause Toxic Effects in Non-Target Organisms?

The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L⁻¹, respectively) followed by promethazine (1.6 and 0.18 mg L⁻¹, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L⁻¹, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals.     

Does Gender Moderate Factors Associated with Whether Spouses Are the Sole Providers of IADL Care to Their Partners?

We explored whether gender moderated the influence of other factors on solo spousal caregiving. The subsample (N = 452) from the AHEAD study included elderly care recipients (CRs) receiving IADL assistance and their spouses. Logistic regression modeled the likelihood of solo spousal IADL care. Gender moderation was tested by product terms between CRs' gender and measures of partners' health, potential helpers, and sociodemographic characteristics. As numbers of CRs' IADLs and couples' proximate daughters increased, wives less often received care solely from their husbands, but husbands' receipt of care from their wives was unaffected. Age differences between spouses and CRs affected solo spousal caregiving to wives and husbands in opposite ways. Regardless of gender, CRs' number of ADL limitations and spouses with IADL or ADL limitations reduced the likelihood of solo spouse care. Identifying circumstances influencing solo spouse caregiving differently among couples with frail wives and husbands facilitates gender sensitive services.     

Are Dogs Able to Communicate with Their Owners about a Desirable Food in a Referential and Intentional Way?

The ability of dogs to use human communicative signals has been exhaustively studied. However, few studies have focused on the production of communicative signals by dogs. The current study investigated if dogs are able to communicate by using directional signals towards some desirable object in the environment and also if they show an apparent intention to manipulate their owner’s behavior in order to receive it. Some operational criteria were used to investigate referential and intentional communication: the signal should be influenced by the audience and by the recipient’s direction of visual attention; the sender should display gaze alternations between the recipient and the object and attention-getting behaviors, and, finally, the sender should persist and elaborate the communication when attempts to manipulate the recipient failed. Aiming to investigate these criteria in dogs, 29 subjects were tested using an experimental set up in which they could see a desirable but unreachable food and they needed the cooperation of their owners in order to receive it. This study found evidence of all operational criteria, especially for gaze alternation between the owner and the food, which suggested that some dogs’ communicative behaviors could be functionally referential and intentional. Nevertheless, similar to other studies about social cognition in animals, it is not possible to distinguish if the dog’s behaviors are based on simple mechanisms or on a theory of mind about their owners.     

Do Dogs (Canis lupus familiaris) Make Counterproductive Choices Because They Are Sensitive to Human Ostensive Cues?

Dogs appear to be sensitive to human ostensive communicative cues in a variety of situations, however there is still a measure of controversy as to the way in which these cues influence human-dog interactions. There is evidence for instance that dogs can be led into making evaluation errors in a quantity discrimination task, for example losing their preference for a larger food quantity if a human shows a preference for a smaller one, yet there is, so far, no explanation for this phenomenon. Using a modified version of this task, in the current study we investigated whether non-social, social or communicative cues (alone or in combination) cause dogs to go against their preference for the larger food quantity. Results show that dogs' evaluation errors are indeed caused by a social bias, but, somewhat contrary to previous studies, they highlight the potent effect of stimulus enhancement (handling the target) in influencing the dogs' response. A mild influence on the dog's behaviour was found only when different ostensive cues (and no handling of the target) were used in combination, suggesting their cumulative effect. The discussion addresses possible motives for discrepancies with previous studies suggesting that both the intentionality and the directionality of the action may be important in causing dogs' social biases.     

Birth Origin Differentially Affects Depressive-Like Behaviours: Are Captive-Born Cynomolgus Monkeys More Vulnerable to Depression than Their Wild-Born Counterparts?

Background

Adverse early-life experience might lead to the expression of abnormal behaviours in animals and the predisposition to psychiatric disorder (e.g. major depressive disorder) in Humans. Common breeding processes employ weaning and housing conditions different from what happens in the wild.

Methods

The present study, therefore, investigated whether birth origin impacts the possible existence of spontaneous atypical/abnormal behaviours displayed by 40 captive-born and 40 wild-born socially-housed cynomolgus macaques in farming conditions using an unbiased ethological scan-sampling analysis followed by multifactorial correspondence and hierarchical clustering analyses.

Results

We identified 10 distinct profiles (groups A to J) that significantly differed on several behaviours, body postures, body orientations, distances between individuals and locations in the cage. Data suggest that 4 captive-born and 1 wild-born animals (groups G and J) present depressive-like symptoms, unnatural early life events thereby increasing the risk of developing pathological symptoms. General differences were also highlighted between the captive- and wild-born populations, implying the expression of differential coping mechanisms in response to the same captive environment.

Conclusions

Birth origin thus impacts the development of atypical ethologically-defined behavioural profiles, reminiscent of certain depressive-like symptoms. The use of unbiased behavioural observations might allow the identification of animal models of human mental/behavioural disorders and their most appropriate control groups.