Public Speaker Characteristics at Meetings of the Dermatologic and Ophthalmic Drug Advisory Committee and the Ophthalmic Devices Panel.

PURPOSE: We investigated meetings of the Dermatologic and Ophthalmic Drug Advisory Committee (DODAC) and the Ophthalmic Devices Panel (ODP) of the Food and Drug Administration (FDA) to determine whether a relationship exists between receipt of industry payments by speakers of the Open Public Hearing (OPH) portion and the nature of their recommendations regarding treatment approval. DESIGN: Cross-sectional study. METHODS: We reviewed publicly available transcripts of all DODAC and ODP meetings from February 2009 to December 2019. For each meeting, information about each public speaker including presence of conflict of interest (COI) and whether their testimony regarding the drug or device was positive, negative, or neutral toward treatment approval was extracted in a blinded fashion using a pilot-tested Google Form. RESULTS: Of the 86 speakers, 66 (76.7%) included a COI disclosure statement and 41 (47.7%) disclosed a COI. Regarding classification of the speakers' testimonies, 70 (81.4%) of 86 were positive, 9 (10.5%) of 86 were negative, and 7 (8.1%) of 86 were neutral. Each one of the 41 speakers with a COI gave a positive testimony. Speakers who disclosed a COI were significantly more likely to give a positive testimony than speakers who did not (P < .001). CONCLUSION: We recommend the DODAC and ODP require full disclosure of COI information and introduce stricter policies to manage COIs, allowing the committee to fully understand the context of the public speakers' comments, including the possible influence of COI on these comments.

Are We Ready to Abandon Placebo in Randomised Clinical Trials for Inflammatory Bowel Disease? Pros and Cons.

The role of placebo in clinical trials for drug development in inflammatory bowel disease [IBD] was the topic of a panel discussion held during the 10th Congress of the European Crohn's and Colitis Organisation [ECCO], in Barcelona, Spain, in 2015. Panellists discussed a number of issues around placebo-controlled trials in IBD, noting issues such as difficulties with recruitment, leading to less then representative patient populations in clinical studies. It was noted that, whereas the easiest answer may be to drop placebo, it is much more complicated than that. The relevance of placebo is affected by a number of factors, including the phase of the trial, as well as the nature of the drug. In most cases where placebo has been left out in drug development, it has been for trials involving a new formulation, a new dosing schedule, or a biosimilar, for example. The panel agreed that placebo-controlled trials are of particular importance early in the development programme, perhaps not so much in phase III, although placebo is important for monitoring safety. The current trial paradigm, in which patients remain on a plethora of, likely ineffective and toxic, background medication, was also questioned. The applicability of placebo in the paediatric population was also discussed. The overall consensus from this panel discussion was that placebo is still necessary in clinical trials in inflammatory bowel disease, but there remain questions as to how and when placebo should be used.

Preclinical assessment of abuse liability of biologics: In defense of current regulatory control policies.

Current regulatory policies of both the US Food and Drug Administration and Drug Enforcement Administration do not delineate automatic exceptions for biologics with respect to preclinical assessments for abuse liability of all new entities. As defined in current guidance documents and drug control policies, an exception may be given upon thorough review of available data, therapeutic target and in consultation with the Controlled Substances Staff within the Center for Drug Evaluation and Research of the FDA, but a blanket exception for all biological entities is not currently available. We review the abuse liability testing of four known biologics with definitive positive abuse liability signals in the three core abuse liability assays, self-administration, drug discrimination, and dependence potential described in the FDA draft guidance document. Interestingly, while all four examplars have positive abuse liability signals in all three assays, two of these biologics are controlled under the Comprehensive Drug Abuse and Control Act (CSA, 1970) and the other two are not currently controlled. Admittedly, these four biologics are small molecule entities. However, there is no reference to "molecular size" in the legally-binding statutory definition of biologics under the FD&C act or in the Controlled Substances Act. Neither of these drug control policy mandates have a bifurcated control status in which to make exceptions based solely on molecular size. With the current pharmaceutical focus on new technologies, such as "Trojan Horses", targeting the active transport of large molecule entities directly into the CNS, an argument to automatically exempt new molecular entities solely on molecular size is untenable. We argue that for the safety and health of general public the current regulatory control status be maintained until definitive criteria for exceptions can be identified and amended to both the FD&CA and CSA, if warranted.

Clinical trials of medicines in neonates: the influence of ethical and practical issues on design and conduct.

In the past, there has been a perception that ethical and practical problems limit the opportunities for research in neonates. This perception is no longer appropriate. It is now clear that research about the medicines used in neonates is an ethical requirement. It is possible to conduct high quality research in neonates if the research team adapt to the characteristics of this population. Good practice involves respecting the specific needs of newborn babies and their families by adopting relevant approaches to study design, recruitment, pharmacokinetic studies and safety assessment. Neonatal units have a unique culture that requires careful development in a research setting. Clinical investigators need to recognize the clinical and ethical imperative to conduct rigorous research. Industry needs to engage with neonatal networks early in the process of drug development, preferably before contacting regulatory agencies. Follow-up over 3-5 years is essential for the evaluation of medicines in neonates and explicit funding for this is required for the assessment of the benefit and risk of treatments given to sick newborn babies. The views of parents must be central to the development of studies and the research agenda. Ethical and practical problems are no longer barriers to research in neonates. The current challenges are to disseminate good practice and maximize capacity in order to meet the need for research among newborn babies.

Clinical trials in children.

Safety and efficacy data on many medicines used in children are surprisingly scarce. As a result children are sometimes given ineffective medicines or medicines with unknown harmful side effects. Better and more relevant clinical trials in children are needed to increase our knowledge of the effects of medicines and to prevent the delayed or non-use of beneficial therapies. Clinical trials provide reliable evidence of treatment effects by rigorous controlled testing of interventions on human subjects. Paediatric trials are more challenging to conduct than trials in adults because of the paucity of funding, uniqueness of children and particular ethical concerns. Although current regulations and initiatives are improving the scope, quantity and quality of trials in children, there are still deficiencies that need to be addressed to accelerate radically equitable access to evidence-based therapies in children.

[Reduction of animal experiments in experimental drug testing]. / Reduktion von Tierversuchen in der experimentellen Arzneimittelprüfung.

In order to ensure the quality of biomedical products, an experimental test for every single manufactured batch is required for many products. Especially in vaccine testing, animal experiments are traditionally used for this purpose. For example, efficacy is often determined via challenge experiments in laboratory animals. Safety tests of vaccine batches are also mostly performed using laboratory animals. However, many animal experiments have clear inherent disadvantages (low accuracy, questionable transferability to humans, unclear significance). Furthermore, for ethical reasons and animal welfare aspects animal experiments are also seen very critical by the public. Therefore, there is a strong trend towards replacing animal experiments with methods in which no animals are used ("replacement"). If a replacement is not possible, the required animal experiments should be improved in order to minimize the number of animals necessary ("reduction") and to reduce pain and suffering caused by the experiment to a minimum ("refinement"). This "3R concept" is meanwhile firmly established in legislature. In recent years many mandatory animal experiments have been replaced by alternative in vitro methods or improved according to the 3R principles; numerous alternative methods are currently under development. Nevertheless, the process from the development of a new method to its legal implementation takes a long time. Therefore, supplementary regulatory measures to facilitate validation and acceptance of new alternative methods could contribute to a faster and more consequent implementation of the 3R concept in the testing of biomedical products.

Performance enhancement, elite athletes and anti doping governance: comparing human guinea pigs in pharmaceutical research and professional sports.

In light of the World Anti Doping Agency's 2013 Code Revision process, we critically explore the applicability of two of three criteria used to determine whether a method or substance should be considered for their Prohibited List, namely its (potential) performance enhancing effects and its (potential) risk to the health of the athlete. To do so, we compare two communities of human guinea pigs: (i) individuals who make a living out of serial participation in Phase 1 pharmacology trials; and (ii) elite athletes who engage in what is effectively 'unregulated clinical research' by using untested prohibited or non-prohibited performance enhancing substances and methods, alone or in combination. Our comparison sheds light on norms of research ethics that these practices exacerbate with respect to the concepts of multiplicity, visibility, and consistency. We argue for the need to establish a proper governance framework to increase the accountability of these unregulated research practices in order to protect the human guinea pigs in elite sports contexts, and to establish reasonable grounds for the performance enhancing effects, and the risks to the health of the athlete, of the methods and substances that might justify their inclusion on the Prohibited List.

Innovations in monitoring of adverse drug reactions: the role of a technical advisor.

Adverse drug reactions (ADRs) have ethical implications. These include assessment of the risk-benefit ratio and re-administering informed consent based on the new ADRs identified. The Indian Council of Medical Research ethical guidelines mandate the scrutiny of ADR; and the standard operating procedures of the ethics committee of the authors' medical school endorse this line. However, institutional review board members are often hardpressed for time and are unable to analyse all the reported ADRs as thoroughly as required. This calls for a dedicated system for the scrutiny of ADRs. This paper seeks to share the experience of development and implementation of a review mechanism for ADR monitoring. The authors report an innovation in ADR monitoring by appointing a technical advisor on ADR (TA-ADR). During routine assessment, an unusual occurrence of ADRs was noticed from internal and external sites which were related to the study drug, which in turn resulted in the trial being put on hold. This system is being reported here for possible adoption by others.

Pharmaceutical knowledge governance: a human rights perspective.

Industry control over the production and distribution of pharmaceutical safety and efficacy data has become a serious public health and health care funding concern. Various recent scandals, several involving the use of flawed representations of scientific data in the most influential medical journals, highlight the urgency of enhancing pharmaceutical knowledge governance. This paper analyzes why this is a human rights concern and what difference a human rights analysis can make. The paper first identifies the challenges associated with the current knowledge deficit. It then discusses, based on an analysis of case law, how various human rights associated interests can be invoked to support the claim that states have an obligation to actively contribute to independent knowledge governance, for example through ensuring clinical trials transparency. The paper further discusses a conceptual use of human rights, as a methodology which requires a comprehensive analysis of the different interwoven historical, economic, cultural, and social factors that contribute to the problem. Such an analysis reveals that historically grown drug regulations have, in fact, contributed directly to industry control over pharmaceutical knowledge production. This type of finding should inform needed reforms of drug regulation. The paper ends with a recommendation for a comprehensive global response to the problem of pharmaceutical knowledge governance.

International collaborative trials, placebo controls and The Declaration of Helsinki: need for clarification in paragraph 32.

Inequities in socio-economic and healthcare systems between developed and developing countries have been thrown into sharp relief by globalisation. At the same time, pharmaceutical companies have started conducting clinical trials in developing countries in order to reduce their costs substantially. Together, these two developments create ethical challenges for sponsors and researchers of these trials. One such challenge is that of placebo-controlled trials (PCTs). In this paper we analyse Paragraph 32 of the Declaration of Helsinki referring to PCTs, identifying ambiguities in the wording, and then examine three arguments presented by sponsors of PCTs in developing countries, in defence of such trials. These arguments are: (i) a placebo control provides a definitive answer, and is therefore methodologically superior; (ii) placebo-controlled trials are ethical because they serve the principle of utility, and (iii) interpreting the "best current proven intervention" as the local standard of care allows PCTs to be conducted, if the local standard of care is "no treatment". We argue that PCTs are not methodologically superior; nor are they ethically defensible. Other trial designs conforming to the ethics of research are feasible; the reason for conducting PCTs is expediency. We further propose that, given the global applicability of the Declaration of Helsinki, it is imperative to remove the ambiguities in Paragraph 32. In the context of collaborative trials, when a treatment exists, conducting PCTs is ethically unacceptable, irrespective of the geographic location of the trial. Universal standards ought to be applied universally.

[Pharmacoepidemiolgy: regulatory basis, methodological approaches and scope]. / La pharmacoépidémiologie: bases réglementaires, approches méthodologiques et champ d'application.

Pharmacoepidemiology is a discipline that studies the use of drugs and evaluation of their beneficial or adverse effects on large populations. It requires compliance with laws and maintaining a regulatory approach in order to ensure confidentiality and protection of personal data. It also requires good knowledge of drugs and diseases and the use of the different available data sources. Pharmacoepidemiology incorporates epidemiological methods (cohort, case-control and cross-sectional studies) where the exposure is drug intake. These methods must be applied at the conception of the pharmacoepidemiological study in order to minimize the effect of bias hich can lead to false conclusions. This paper reviews the regulatory basis, methodological approaches and scope of pharmacoepidemiology.

Exploitations and their complications: the necessity of identifying the multiple forms of exploitation in pharmaceutical trials.

Human subject trials of pharmaceuticals in low and middle income countries (LMICs) have been associated with the moral wrong of exploitation on two grounds. First, these trials may include a placebo control arm even when proven treatments for a condition are in use in other (usually wealthier) parts of the world. Second, the trial researchers or sponsors may fail to make a successful treatment developed through the trial available to either the trial participants or the host community following the trial. Many commentators have argued that a single form of exploitation takes place during human subject research in LMICs. These commentators do not, however, agree as to what kind of moral wrong exploitation is or when exploitation is morally impermissible. In this paper, I have two primary goals. First, I will argue for a taxonomy of exploitation that identifies three distinct forms of exploitation. While each of these forms of exploitation has its critics, I will argue that they can each be developed into plausible accounts of exploitation tied to different vulnerabilities and different forms of wrongdoing. Second, I will argue that each of these forms of exploitation can coexist in single situations, including human subject trials of pharmaceuticals. This lesson is important, since different forms of exploitation in a single relationship can influence, among other things, whether the relationship is morally permissible.

Institutionalisation of Bulgarian ethics committees: history and current status.

This paper provides an overview of the institutionalisation of the ethics review process in Bulgaria in accordance with the worldwide trend in establishment of ethics committees. Historical and current politico-legal changes influencing the work of ethics committees are analysed. The paper focuses on ethics committees which review biomedical research involving humans, with an emphasis on their composition, functions, training of members, and decision-making processes. Recent positive changes addressing insufficient training of ethics committees'members are highlighted. Recommendations are made for enhancement of the ethics review process and improved transparency.