Declaration of Helsinki: ethical norm in pursuit of common global goals.

The World Medical Association's Declaration of Helsinki is in the process of being revised. The following amendments are recommended to be incorporated in pursuit of the common goal of promoting health for all. 1. Data-driven research that facilitates broad informed consent and dynamic consent, assuring participant's rights, and the sharing of individual participant data (IPD) and research results to promote open science and generate social value. 2. Risk minimisation in a placebo-controlled study and post-trial access to the best-proven interventions for all who need them. 3. A future-oriented research framework for co-creation with all the relevant stakeholders.

Radiological protection in human research ethics using a case study: toward update of the ICRP Publication 62.

The benefits of biomedical research involving humans are well recognised, along with the need for conformity to international standards of science and ethics. When human research involves radiation imaging procedures or radiotherapy, an extra level of expert review should be provided from the point of view of radiological protection. The relevant publication of the International Commission for Radiological Protection (ICRP) is now three decades old and is currently undergoing an update. This paper aims to provoke discussions on how the risks of radiation dose and the benefits of research should be assessed, using a case study of diagnostic radiology involving volunteers for whom there is no direct benefit. Further, the paper provides the current understanding of key concepts being considered for review and revision-such as the dose constraint and the novel research methods on the horizon, including radiation biology and epidemiology. The analysis revisits the perspectives described in the ICRP Publication 62, and considers the recent progress in both radiological protection ethics and medical research ethics.

Utilization of genetic information for medicines development and equitable benefit sharing.

Advances in genomic research have significantly enhanced modern drug development. However, equitable benefit sharing of the results of scientific advancement has not always been achieved. This paper shows how molecular biology has modified medicines development while also leaving open significant challenges for benefit sharing. Presented here is a conceptual modeling describing the processes in genetic-related medicines development and how these are related to specific ethical considerations. The focus is on three important areas: 1) population genetics and the need for discrimination prevention; 2) pharmacogenomics and the need for inclusive governance; and 3) global health to be achieved in open science frameworks. Benefit sharing is taken as the ethical value that underlies all these aspects. The implementation of benefit sharing requires a value shift in which the outcomes of health science are not viewed simply as trade commodities but also as a "global public good". This approach should lead to genetic science to contribute to promoting the fundamental human right to health to all members of the global community.

The ethical responsibility to continue investigational treatments of research participants in situation of armed conflicts, economic sanctions or natural catastrophes.

This paper discusses the effects of armed conflict, economic sanctions, and natural catastrophes on ongoing clinical trials. We suggest that • stopping the accrual of new patients in clinical trials under such extreme conditions is acceptable. • research participants already receiving trial medication in such disruptive situations are to be considered highly vulnerable due to their medical dependency for ongoing treatment according to the approved clinical study protocol. • based on the present experience in Ukraine and Russia, we conclude that finishing ongoing trial treatments according to approved or amended protocols should be considered to be an ethical obligation of trial sponsors irrespective whether trial disruption is due to war, economic sanctions, or natural catastrophes. • it is important to devote more attention to the ethical challenges raised by such fundamentally disruptive situations to clinical trials generally in any region of the world.

Linking the Declarations of Helsinki and of Taipei: Critical Challenges of Future-Oriented Research Ethics.

Expansion of data-driven research in the 21st century has posed challenges in the evolution of the international agreed framework of research ethics. The World Medical Association (WMA)'s Declaration of Helsinki (DoH) has provided ethical principles for medical research involving humans since 1964, with the last update in 2013. To complement the DoH, WMA issued the Declaration of Taipei (DoT) in 2016 to provide additional principles for health databases and biobanks. However, the ethical principles for secondary use of data or material obtained in research remain unclear. With such a perspective, the Working Group on Ethics (WGE) of the International Federation of Associations of Pharmaceutical Physicians and Pharmaceutical Medicine (IFAPP) suggests a closer scientific linkage in the DoH to the (Declaration of Taipei) DoT focusing specifically on areas that will facilitate data-driven research, and to further strengthen the protection of research participants.

Corrigendum: Linking the Declarations of Helsinki and of Taipei: Critical Challenges of Future-Oriented Research Ethics.

[This corrects the article DOI: 10.3389/fphar.2020.579714.].

Development and Use of Gene Therapy Orphan Drugs-Ethical Needs for a Broader Cooperation Between the Pharmaceutical Industry and Society.

Gene therapy orphan medicinal products constitute a unique group of new drugs which in case of hereditary diseases are usually administered only once at an early age, in the hope to provide sufficient gene product to last for the entire life of the patients. The combination of an exceptionally large single payment and the life-long clinical follow-up needed for understanding the long-term benefits and safety of gene therapy, represent new types of scientific, financial, social and ethical challenges for the pharmaceutical industry, regulators and society. With special consideration of the uniqueness and importance of gene therapy, the authors propose a three points plan for a close cooperation between the pharmaceutical industry and society to develop orphan gene therapy. (1) In fully transparent health technology negotiations a close and long-lasting, contractually fixed cooperation should be established between the manufacturers and local health-care stakeholders for sharing the medical and scientific benefits, the financial risks as well as the burdens of the post-authorization clinical and regulatory development. (2) The parties should agree on a fair, locally affordable drug price without the usually very high premium price calculated to compensate for the low number of patients. In case of high manufacturing costs, the companies should offer prolonged, 15-20 years long payment by installment with risk-sharing, especially considering that the late outcome of the treatment is unknown. Society should assist scientifically and financially organizing a specific patient registry, treatment in specialized hospitals and adequate long-term follow-up of patients, the coordinated management of financial transactions related to the risk sharing program. (3) The post-authorization treatment and prolonged observation of additional new cases coordinated by society should provide real world data needed for the modern complex regulatory evaluation of gene therapy products by the competent authorities. We assume that fair sharing of the benefits and risks as well as a well-organized cooperation of society with the industry in collecting real world evidence might result in better drug evaluation and improved accessibility due to lower prices. The outlined concept might support gene therapy more efficiently than the presently requested outstandingly high prices.

The Shared Ethical Responsibility of Medically and Non-medically Qualified Experts in Human Drug Development Teams.

The complexity of developing and applying increasingly sophisticated new medicinal products has led to the participation of many non-medically qualified scientists in multi-disciplinary non-clinical and clinical drug development teams world-wide. In this introductory paper to the "IFAPP International Ethics Framework for Pharmaceutical Physicians and Medicines Development Scientists" it is argued that all members of such multidisciplinary teams must share the scientific and ethical responsibilities since they all influence directly or indirectly both the outcome of the various phases of the medicines development projects and the safety of the research subjects involved. The participating medical practitioner retains the overriding responsibility and the final decision to stop a trial if the well-being of the research subjects is seriously endangered. All the team members should follow the main ethical principles governing human research, the respect for autonomy, justice, beneficence and non-maleficence. Nevertheless, the weighing of these principles might be different under various conditions according to the specialty of the members.

Core ethical values of radiological protection applied to Fukushima case: reflecting common morality and cultural diversities.

The International Commission on Radiological Protection (ICRP) has established Task Group 94 (TG94) to develop a publication to clarify the ethical foundations of the radiological protection system it recommends. This TG identified four core ethical values which structure the system: beneficence and non-maleficence, prudence, justice, and dignity. Since the ICRP is an international organization, its recommendations and guidance should be globally applicable and acceptable. Therefore, first this paper presents the basic principles of the ICRP radiological protection system and its core ethical values, along with a reflection on the variation of these values in Western and Eastern cultural traditions. Secondly, this paper reflects upon how these values can be applied in difficult ethical dilemmas as in the case of the emergency and post-accident phases of a nuclear power plant accident, using the Fukushima case to illustrate the challenges at stake. We found that the core ethical values underlying the ICRP system of radiological protection seem to be quite common throughout the world, although there are some variations among various cultural contexts. Especially we found that 'prudence' would call for somewhat different implementation in each cultural context, balancing and integrating sometime conflicting values, but always with objectives to achieve the well-being of people, which is itself the ultimate aim of the radiological protection system.

[Conflict of Interest Guidelines of the Japanese Society of Psychiatry and Neurology: Current Status and Considerations in the Area of Psychiatry].

In 2011, the Japanese Society of Psychiatry and Neurology released the Guidelines on Conflict of Interest(COI) in Clinical Research and detailed regulations. According to the Guidelines, the COI Committee has been engaged in COI management for a one-year trial period. The members of the Society have to disclose their COIs at the time of presentations, manuscript submissions, and publications; the board and committees members have to disclose their COIs to the President of the Society; and the President reports these COI disclosures to the COI Committee. In this article, we provide a summary of this year's COI disclosures: among the 455 board and committees members, 297 were without COIs (68.5%); 98 (excluding the following two problematic cases) disclosed COIs (23.1%, excluding the following two cases); two cases were discussed regarding whether or not they were problematic (0.44%); 11 (2.4%) cases have not yet been reviewed because of a delay in disclosure; and 25 cases have yet to be disclosed (5.5%). Responding to serious COI-related affairs in other disease areas, public interest in the COI ssue has been increasing. Additionally, the Japanese Pharaceutical Manufacturers Association (JPMA) implemented Transparency Guidelines, and companies are disclosing their payments for lectures or manuscript fees to individual researchers. We should foster a deeper understanding of the concept of COI and discuss COI management in society more extensively.

[Regulatory Framework for Approval of PET Drug in Korea: A Survey Report].

OBJECTIVES: To identify regulatory framework for approval of PET drugs in Korea. METHOD: Interview and literature survey. RESULTS: In Korea Good Manufacturing Practice (GMP) regulation specific to radiopharmaceuticals, including PET (Positron Emission Tomography) drugs, under the Pharmaceutical Affairs Act was issued in August 2014, to be enforced on July 1, 2015, and its guidance was issued in December 2014. The new facilities to be established after July 1 of 2015 have to be compatible with this new regulation and already established facilities have two years grace period until June 30 of 2017. During this period, the regulatory authority will inspect all of the production sites which hold or submit approvals of radiopharmaceuticals. As of September 2015 in Korea, there are 7 commercial companies and 15 hospitals and institutes, which have approvals of PET drugs mainly FDG, and these companies and/or hospitals can supply PET drugs outside institutions. In this article we introduce the Korean regulations of development and approval of radiopharmaceuticals. CONCLUSION: The Korean regulatory authorization policy for radiopharmaceuticals are to some extent similar to the policy which the U.S. regulators set as the new regulations of PET drug. It is expected that the situations of production sites in Korea are to be improved through actual discussions among regulators and PET community through the process of actual inspection.

[Implementation of Guidelines on Conflict of Interest in Clinical Research of the Japanese Society of Psychiatry and Neurology: actual status and future perspectives].

In May 2011, the Japanese Society of Psychiatry and Neurology released their Guidelines on Conflict of Interest (COI) in Clinical Research and detailed regulations. These guidelines cover clinical research, although each committee of the society may have a policy to cover basic research as well as clinical research. The COI Committee implemented the guidelines, including a one-year trial period. According to the guidelines, members of the society have to disclose their COIs at the time of presentations, manuscript submissions, and publications; the board and committees members have to submit their COIs to the president of the society. During the trial period, the latter was limited to the four committees involved in the development of the guidelines: Conflict of Interest; Pharmaceutical Affairs; Research Ethics; and Editorial Committees. The COI Committee reviewed the COIs submitted by the board and committee members. The COI Committee found that, among the 382 board and committee members, 298 were without COI; 31 COIs were regarded by one committee member as not necessary to be circulated to all the attending members (total of these 2 categories: 329, 87%); 31 COIs (8%) were regarded as necessary to be circulated; and 18 cases (4.7%) were problematic: not submitted or explicit rejection of submission. Considering the seriousness of scientific misconduct by a researcher in another disease area who resigned his professorship and is now under investigation, we should further discuss the implementation of our COI guidelines.

High rate of awarding compensation for claims of injuries related to clinical trials by pharmaceutical companies in Japan: a questionnaire survey.

INTRODUCTION: International norms and ethical standards have suggested that compensation for research-related injury should be provided to injured research volunteers. However, statistical data of incidence of compensation claims and the rate of awarding them have been rarely reported. METHOD: Questionnaire surveys were sent to pharmaceutical companies and medical institutions, focusing on industry-initiated clinical trials aiming at new drug applications (NDAs) on patient volunteers in Japan. RESULTS: With the answers from pharmaceutical companies, the incidence of compensation was 0.8%, including 0.06% of monetary compensation. Of the cases of compensation claims, 99% were awarded. In turn, with the answers from medical institutions, the incidence of compensation was 0.6%, including 0.4% of serious but not death cases, and 0.04% of death cases. Furthermore, most claims for compensation were initiated by medical institutions, rather than by the patients. On the other hand, with the answers from clinical trial volunteers, 3% of respondents received compensations. These compensated cases were 25% of the injuries which cannot be ruled out from the scope of compensation. CONCLUSION: Our study results demonstrated that Japanese pharmaceutical companies have provided a high rate of compensation for clinical trial-related injuries despite the possibility of overestimation. In the era of global clinical development, our study indicates the importance of further surveys to find each country's compensation policy by determining how it is being implemented based on a survey of the actual status of compensation coming from statistical data.

Ethical, legal, and social implications (ELSI) of microdose clinical trials.

A "microdose clinical trial" (microdosing) is one kind of early phase exploratory clinical trial, administering the compound at doses estimated to have no pharmacological or toxicological effects, aimed at screening candidates for further clinical development. This article's objective is to clarify the ethical, legal, and social implications (ELSI) of such an exploratory minimum-risk human trial. The definition and non-clinical study requirements for microdosing have been harmonized among the European Union (EU), United States (US), and Japan. Being conducted according to these regulations, microdosing seems to be ethically well justified in terms of respect for persons, beneficence, justice, human dignity, and animal welfare. Three big projects have been demonstrating the predictability of therapeutic dose pharmacokinetics from microdosing. The article offers suggestions as how microdosing can become a more useful and socially accepted strategy.

[The revised Japanese pharmaceutical law and research ethics: risk-benefit assessment of fetal stem cell research].

The Japanese Pharmaceutical Law was revised at the end of July 2002. The important features of this revision are the postmarketing safety scheme, especially for biological products, and reconstruction of the legislation for effective pharmaceutical development. This is based on the national policy to foster life sciences such as genetic research and regenerative medicine for both healthcare improvement and industrial promotion. Such research requires study participants who donate human tissue including abandoned embryos or aborted fetuses, which may touch the human dignity. In particular, fetal stem cell research appears to have unpredictable risks not only to women who undergo abortions but also to societal epistemology. The authors conducted risk-benefit assessment of fetal stem cell research, reviewing the scientific, ethical, legal, and social aspects, including a case study of critical appraisal on a report of the double-blind, sham surgery-controlled trial of implantation of fetal tissues in patients with Parkinson's disease conducted in the USA. It is concluded that risk-benefit assessment with a wide, profound perspective is necessary for advanced biotechnology. Some types of research should not be assessed based only on such utilitarian viewpoints as risk and benefit. Conscientious reflection is necessary to reach a public consensus on which types of human material can be utilized as research or pharmaceutical resources.