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.

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.

Evolution of the Development of Core Competencies in Pharmaceutical Medicine and Their Potential Use in Education and Training.

The evolution of postgraduate vocational education and training in pharmaceutical medicine is described alongside the growth of this scientific-medical discipline and profession for the development of new medicines. Over the past 50 years, whilst the training of competent professionals for their work has been paramount, this has paralleled the need to engage with the rapid and complex changes in R&D technologies, patient and healthcare system needs, and the ethical and regulatory obligations applied to the development of medicines throughout their lifecycle. The move from unstructured training to formal programs with syllabus, curricula and assessments for certification, has been accompanied by educational changes to outcomes-based, learner-centered, competency-based programs. The evolution of education and training along with the development of the set of 57 core competencies for professional practitioners in pharmaceutical medicine are described within the competence framework of seven domains: discovery of medicines and early development; clinical development and clinical trials; medicines regulation; drug safety and surveillance; ethics and subject protection; healthcare marketplace; communication and management. The application of the core competencies in a harmonized, international platform of education and training in medicines development at the undergraduate, postgraduate and continuing professional development levels would invigorate the potential for having a competent workforce with the intent to provide faster access to better and appropriate medicines for patients worldwide.

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.

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.].

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.

Fostering Competence in Medicines Development: The IFAPP Perspective.

IFAPP (International Federation of Associations of Pharmaceutical Physicians and Pharmaceutical Medicine) is a nonprofit organization with the mission to promote Pharmaceutical Medicine & Medicines Development (PM&MD) by enhancing the competencies and maintaining high research ethical standards of Pharmaceutical Physicians and other professionals involved in medicines development worldwide, leading to the availability and appropriate use of medicines for the benefit of patients and society. About 30 national professional associations related to PM&MD, involving 7000 professionals, are affiliated to IFAPP. Medicines development has traditionally been a challenging enterprise, with high risk, high investment, and potentially high returns in the lengthy and complex process of identifying a new chemical entity as a candidate for development and possibly succeeding in bringing it as a pharmaceutical product to the market. However, the emergence of genomics, translational research, biomarkers, and precision medicine pose challenges going forward involving allocation of resources, price, market access, and cost-effectiveness as opposed to the traditional concepts of "efficacy" and "safety." Education and Continuing Professional Development (CPD) are a major focus of IFAPP. The International Conference on Pharmaceutical Medicine (ICPM) is the largest event for our organization; ICPM is held every 2 or 3 years and is aimed to provide the state of the art in key areas for our discipline and profession. The paper is a reflection on the role of competency-based education and training for Pharmaceutical Physicians and medicines development scientists, as was discussed during the recent ICPM 2016 held in Sao Paulo, Brazil on April 18-19, with the support of the Brazilian Association of Pharmaceutical Medicine, and gathered around 200 representatives from the pharmaceutical, clinical research and regulatory arenas from all over the world,.

Earlier identification of risks: cumulative probability analysis of time to safety alerts for therapeutic monoclonal antibodies.

OBJECTIVE: Previous analysis of US FDA Medwatch safety alerts for monoclonal antibody therapeutics demonstrated that premarketing clinical trials can predict more than half of safety concerns. We expanded this analysis to assess whether the predictable alerts are detected sooner than the unpredictable alerts. METHODS: Times to alert were compared using Mann-Whitney test, Kolmogorov-Smirnov test, and using curves displaying cumulative frequencies of alerts over time. RESULTS: Until December 31, 2013 inclusive, 76 Medwatch alerts for therapeutic monoclonal antibodies were reported: 43 predictable vs. 33 unpredictable. Predictable alerts were reported at a median (IQR) of 41 (19-77) months after approval vs. 53 (23-73) months for the unpredictable alerts. The mean (SE) was 52.07 (6.69) months and 55.91 (7.06) months for the predictable and unpredictable, respectively. Although the difference of 12 months between medians of time to alert was observed, the difference was not demonstrated as significant. Cumulative frequency curves show that predictable alerts were detected sooner until month 73 after approval, when ~ 80% of alerts were detected. Immunological reactions (such as infusion reactions, anaphylaxis, and reactions due to antibodies) were identified early; all 12 such alerts were released before the curves of cumulative frequencies cross at month 73. On the other hand, reactions occurring after the curves cross are predominantly late-occurring cancers and opportunistic infections. CONCLUSIONS: The results imply that focus on predictable reactions defined as potential risks may play a role in early detection of important safety concerns.

Education and training for medicines development, regulation, and clinical research in emerging countries.

The aim of this satellite workshop held at the 17th World Congress of Basic and Clinical Pharmacology (WCP2014) was to discuss the needs, optimal methods and practical approaches for extending education and teaching of medicines development, regulation, and clinical research to Low and Middle Income Countries (LMICs). It was generally agreed that, for efficiently treating the rapidly growing number of patients suffering from non-communicable diseases, modern drug therapy has to become available more widely and with a shorter time lag in these countries. To achieve this goal many additional experts working in medicines development, regulation, and clinical research have to be trained in parallel. The competence-oriented educational programs designed within the framework of the European Innovative Medicine Initiative-PharmaTrain (IMI-PhT) project were developed with the purpose to cover these interconnected fields. In addition, the programs can be easily adapted to the various local needs, primarily due to their modular architecture and well defined learning outcomes. Furthermore, the program is accompanied by stringent quality assurance standards which are essential for providing internationally accepted certificates. Effective cooperation between international and local experts and organizations, the involvement of the industry, health care centers and governments is essential for successful education. The initiative should also support the development of professional networks able to manage complex health care strategies. In addition it should help establish cooperation between neighboring countries for jointly managing clinical trials, as well as complex regulatory and ethical issues.

Corrigendum: Core competencies for pharmaceutical physicians and drug development scientists.

[This corrects the article on p. 105 in vol. 4, PMID: 23986704.].

A European approach to clinical investigator training.

A better education and training of clinical investigators and their teams is one of the factors that could foster the development of clinical research in Europe, a key objective of the Innovative Medicines Initiative (IMI). PharmaTrain (an IMI programme on training in medicines development), and European Clinical Research Infrastructures Network (ECRIN) have joined forces to address this issue. An advisory group composed of representatives of universities, pharmaceutical companies and other organisations met four times between June 2011 and July 2012. This resulted in a position paper proposing a strategy to improve and harmonize clinical investigator training in Europe, and including a detailed syllabus and list of learning outcomes. Major recommendations are the establishment of minimal and mutually recognized certification requirement for investigators throughout the EU and the creation of a European platform to provide a suitable course and examination infrastructure.

Core competencies for pharmaceutical physicians and drug development scientists.

Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine), are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes (LO) of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain LO anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide.

[Clinical pharmacology aspects of development and application of biosimilar antibodies]. / Követo, biohasonló ellenanyagok fejlesztésének és alkalmazásának klinikai farmakológiai szempontjai.

Due to the microheterogeneity of the macromolecules produced in biological systems, only the high degree of similarity but not the structural identity of the follow-on biological active agents can be proven. In case of monoclonal antibodies (mAbs) the proof of similarity is much more difficult due to the large molecular weight, complicated structure and complex biological effects of the IgG molecule. The identity of the amino acid sequence is the basic requirement of biosimilarity. Smaller changes in the carbohydrate side chains attached to the protein molecule can be accepted if they do not cause significant functional changes. On the other hand, the alteration of some carbohydrate side chain(s) located at strategically important sites might significantly influence the biological properties of the mAbs. Besides the antigen binding the pharmacological effects of the antibodies depend on several other effector functions related to the Fc fragment such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and phagocytosis. Hence several biological functions must be measured and evaluated in their totality for stating the degree of biosimilarity. According to the concordant strict requirements of the European Medicines Agency (EMA) and the American Food and Drug Administration (FDA), the proof of similar efficacy and safety must be based on the results obtained in the most sensitive and suitable in vitro and in vivo experimental designs. The fundamental proofs are provided by the comparison of the pharmacokinetic and pharmacodynamic measurements, as well as the similarity of the dose-effect relationships. These observations are complemented by the comparative clinical therapeutic trials which eventually support the similar therapeutic use of the follow-on medicinal products in the clinical practice. The final judgement of biosimilarity is a case-by-case decision based on the joint evaluation of all the data available.

[Influence of the Nuremberg physicians' trials--beginning a new era in the ethical judging of human experiments]. / A nürnbergi orvosper korszakváltó befolyása a humán kísérletek etikai megítélésére.

This short historical review attempts to shed light on the tortuous road on which society moved toward the general acceptance of the idea of experimenting on human beings. Unfortunately people had to realize that under antihuman or lenient political leadership, some physicians might apply their knowledge against their fellow beings, or might endanger them while pursuing their scientific goals. For this reason, it became necessary to codify the ethical requirements of medical experiments. This was done first by the Prussian government in 1900. The historical significance of the Nuremberg physicians' trials is that, by recognizing the enormous scientific importance of human experiments, they led to the formulation of general ethical principles governing human studies, which became known as the Nuremberg Code. Broad, international regulations were developed as the consequence of the trial. Unfortunately human experiments performed on prison inmates were judged at the trial as ethically acceptable, provided an informed consent was signed. Misusing this possibility many unethical experiments were done primarily in the US after the war. The great indignation due to ethical misconduct in prison trials and the highly unethical Tuskegee experiments performed on black Americans' suffering from syphilis, led much later to the organization of independent ethics committees. Through these committees, society exercises supervision of human trials. However, in case of severely ill patients the physician might be left alone to make a quick, and ethically correct, decision corresponding to the situation. In the final analysis the safety and ethical protection of research subjects remain the joint responsibility of society and of the experimenting physicians.