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In confirmatory clinical trials, the prespecification of the primary analysis model is a universally accepted scientific principle to allow strict control of the type I error. Consequently, both the ICH E9 guideline and the European Medicines Agency (EMA) guideline on missing data in confirmatory clinical trials require that the primary analysis model is defined unambiguously. This requirement applies to mixed models for longitudinal data handling missing data implicitly. To evaluate the compliance with the EMA guideline, we evaluated the model specifications in those clinical study protocols from development phases II and III submitted between 2015 and 2018 to the Ethics Committee at Hannover Medical School under the German Medicinal Products Act, which planned to use a mixed model for longitudinal data in the confirmatory testing strategy. Overall, 39 trials from different types of sponsors and a wide range of therapeutic areas were evaluated. While nearly all protocols specify the fixed and random effects of the analysis model (95%), only 77% give the structure of the covariance matrix used for modeling the repeated measurements. Moreover, the testing method (36%), the estimation method (28%), the computation method (3%), and the fallback strategy (18%) are given by less than half the study protocols. Subgroup analyses indicate that these findings are universal and not specific to clinical trial phases or size of company. Altogether, our results show that guideline compliance is to various degrees poor and consequently, strict type I error rate control at the intended level is not guaranteed., (© 2019 The Authors Pharmaceutical Statistics Published by John Wiley & Sons Ltd.)

Although EU inspectors and clinical assessors are mandated to identify and act upon ethical issues, regulators lack guidance on how this can be done. Hence, we propose a four-step regulatory approach on ethically relevant GCP violation findings. The first step is identification of the ethical issue. Next is analysis [i.e., identifying the gravity (intensity or severity) and the magnitude (amount and duration) of the ethics violation as well as the responsible person(s) or entity or entities]. The third step is evaluation, (i.e., the process of deliberating to determine the significance of the ethics violation, with the intention of identifying the most reasonable sanction and/or corrective or reparative action). Last is decision-making or the process of choosing and implementing a regulatory course of action., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The objective of the study was to describe the characteristics of the Clinical Trials (CT) supervised by the Institute of Health Technology Assessment and Research carried out in EsSalud between 2015 and 2018 and the main observations of the supervisions completed. A descriptive study of 82 supervised clinical trials was conducted between 2015 and 2018. Most of the clinical trials were phase III studies (81.7%); the most frequent route of administration of the study products was oral (47.6%), and most were sponsored by the pharmaceutical industry (96.3%). The most frequent observations were those related to the study contract (83.8%), overhead payment (57.3%), and the lack of regulatory documents (47.6%). These findings allow the identification of opportunities for improvement in research regulation and management.

The legislation of Italy and the European Union requires a shift in terms of the organisation and national regulation of ethics committees and clinical trials. More generally, this affects the entire sphere of biomedical research. The first part of this contribution provides a brief review of the history of ethics committees in Italy. We then discuss the current situation and formulate proposals. There is a vital need for rules that promote efficiency of ethics committees, to guarantee that Italy's position remains competitive and attractive within the European Union.

International collaboration in oncology trials has the potential to enhance clinical trial activity by expediting the recruitment of large patient populations, testing treatments in diverse populations and facilitating the study of rare tumours or specific molecular subtypes. However, a number of challenges continue to hinder the efficient and productive conduct of both commercial and non-commercial international clinical trials. These challenges include complex and burdensome regulatory requirements, the high cost of conducting trials, and logistical challenges associated with ethics review, drug supply and biospecimen collection and management. We propose solutions to promote oncology trial collaboration, such as regulatory reform, harmonisation of trial initiation and management processes and greater recognition and funding of academic (non-commercial) clinical trials. It is only through coordinated effort and leadership from researchers, regulators and those responsible for health systems that the full potential of international trial collaboration can be realised.

Recombinant technology has revolutionised the way novel vaccines are developed and manufactured. The possibility to genetically modify micro-organisms to bring immunogenic material (antigens/epitopes) to the human (or animal) immune system to provoke an immune response, provides new hope to producing prophylactic vaccines against HIV, malaria and tuberculosis and emerging diseases. Regulatory requirements associated with the development of genetically-modified organism (GMO)-containing vaccines in Europe add an additional burden to the clinical trial application procedure and to the preparation and initiation of a clinical trial of such vaccines. Moreover, the GMO regulatory framework is complex and only partially harmonised across Europe, which may hamper multi-country clinical trials with GMO-containing vaccines. This paper provides an overview of clinical trial applications with GMO-containing vaccines in Europe and reviews the regulatory framework in countries where GMO-containing vaccine clinical trial authorisation (CTA) applications were submitted between 2004 and 2017., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Patient engagement in health care has been an emerging priority in the global effort and move toward the consideration of patients as experts of their own conditions. However, the input of pediatric patients and their families have not been consistently requested nor regarded as valuable when deriving protocols for, as well as assessing the outcomes of, pediatric clinical trials. Extending this mutual collaboration further upstream is important, especially in the area of pediatric drug development where the lack of formalized trials for children and adolescents result in the increased use of off-label prescribing and risk of adverse effects. While recent changes to European and North American legislation contributed to the inclusion of children and youth in pediatric drug development, the lack of systematic guidelines and methodologies in literature serve as barriers for practical application. When combined with the work of external pediatric advocacy and patient advisory groups, the hope is that pediatric patient voices can be brought forward for the future. This article brings together international experts to review current best practices, progress from regulatory agencies, as well as global advocacy efforts to involve patients and families in the pursuit of drug development processes that value the voice of children and youth.

This report describes changes to cell therapy research and clinical practice in China as a result of guidelines from the central government finalized at the end of 2017. The tables list Chinese authorities and regulations on human cells for medical research over the years 1993-2018. Under the new regulations, cell therapy products (CTPs) are treated like drugs, in alignment with policy in the USA and European Union. At civil institutions in China, there are now two pathways for human clinical trials: research versus pharmaceutical development. At the end of 2018, trials of CTPs were only authorized at 114 approved hospitals. It is hoped that the new policies will help CTPs developed in China gain acceptance by health regulators in the west.

Importance: The US Food and Drug Administration (FDA) created the exception from informed consent (EFIC) pathway in 1996 to allow some emergency trials to enroll patients without informed consent. To protect individual autonomy and preserve public trust, the FDA requires that EFIC trial investigators consult with community members before a trial may begin., Objectives: To analyze data from surveys conducted as part of community consultation ahead of EFIC trials and assess levels of public approval., Data Sources: All trials granted an EFIC must submit documentation of compliance with EFIC regulations to a publicly available docket at the FDA. Submissions between November 1, 1996, and October 23, 2017, were reviewed., Study Selection: Trials with survey data were included., Data Extraction and Synthesis: Data were extracted between January 2018 and June 2018 and were analyzed between June 2018 and August 2018. The quality and validity of data were assessed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A random-effects metaregression was used to assess the association of demographic characteristics with EFIC approval., Main Outcomes and Measures: The primary study outcome was EFIC approval., Results: The FDA docket contained 15 958 pages of material with survey data for 42 448 individuals submitted by 27 trials. Public approval of EFIC varied by question type, with more people willing to approve initiation of EFIC trials in their community (86.5%) than personal enrollment (73.0%), enrollment of a family member (68.6%), or the principle of enrollment without consent (58.4%) (P < .001 for all comparisons). In the United States, African American individuals made up 29.3% of those enrolled in EFIC trials that reported data on race (5064 of 17 302) but only 16.7% of those surveyed as part of community consultation. In the United States and Canada, men made up 42.9% of the surveyed population but 65.6% of those eventually enrolled in EFIC trials (29 961 of 45 694). Groups surveyed with higher proportions of African American and male respondents had lower rates of EFIC approval., Conclusions and Relevance: Public approval of EFIC trials varied by question type and by the respondents' reported race and sex. The demographic characteristics of those surveyed did not match the demographic characteristics of EFIC enrollees. The FDA could strengthen community consultation by standardizing survey instruments and reporting, requiring broader inclusion of African American and male respondents, clarifying the function of surveys in the development and modification of trial protocols, and building more public consensus around the acceptable use of EFIC.

Introduction : There is a broad global acknowledgment that the timely and effective communication of clinical trial results is not only essential to the development, diagnosis, and treatment of medical conditions but also meets an ethical obligation to inform patients and the public. Areas covered : At this time, less than 2% of all clinical trials completed or terminated within the past three years returned plain language summaries to study volunteers. This estimate is far below our forecast made 10 years ago when we evaluated a pilot effort to demonstrate a feasible and efficient process for communicating summary results to patients. At that time, we anticipated that research sponsors would embrace the obligation and in so doing would improve their relationship with and trust among their study volunteers and patient communities. This article discusses why adoption remains low and suggests that the absence of clear regulatory requirements and their enforcement are the primary cause. Expert opinion : The authors anticipate that the regulatory environment will tighten and that public, patient and patient advocate appetite and expectation for the disclosure of clinical trial results summaries in plain language will intensify during the next 18 months. These pressures will compel research sponsors to accelerate adoption.

Gene-editing techniques have progressed rapidly in the past 5 years. There are already ongoing human somatic gene-editing clinical trials for multiple diseases. And there has been one purported scenario of human germline gene editing in late 2018. In this paper, we will review the current state of the technology, discuss the ethical and social issues that surround the various forms of gene editing, as well as review emerging stakeholder data from professionals, the 'general public' and individuals and families dealing with genetic diseases potentially treatable by gene editing.

Testing novel drugs on fellow human beings is fraught with potential ethical concerns; however, developing drugs to treat the wide spectrum of human diseases and disorders is a moral imperative. How do we best navigate the balance between protecting the individual vs. the greater good? Global government regulatory bodies are accountable for ensuring that medical experiments on human subjects are appropriately justified and subject to close oversight. In this article, we focus on two major global health authorities, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and the path to legally treating humans with new investigational products., (© 2019 Denali Therapeutics Inc. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Regulatory inspection of clinical trial is necessary in order for (1) assessing compliance with statutory requirements and regulatory requirement governing the conduct of clinical trials and (2) verifying the accuracy and reliability of clinical trial data submitted to regulatory agencies such as the United States Food and Drug Administration (FDA) in support of research or marketing applications. This article provides an overview of clinical inspection process and issues that are commonly encountered during the conduct of clinical trials. In addition, a couple of sampling plans for clinical inspection of relatively large trials are proposed. The proposed statistical process for clinical inspection that will achieve a desired degree of inspection accuracy and reliability is useful when the resources of inspectors are limited. The proposed 2-stage sampling plan can be applied to clinical inspection for multicenter and/or multinational multicenter clinical trials.

The regulatory framework of clinical research is necessary to ensure the protection of participants and to define the actors and their responsibilities. Although main principles have been set up in 1947 with the Nuremberg Code, this regulatory framework is relatively recent in Europe: development of national regulations in the years 1980-1990, first European Directive regarding clinical trials in 2001. In France, as 2006 was marked by the implementation of this first "Clinical trials Directive", the end of the year 2016 and the following months were marked by the enforcement of the Jardé law (previously modified in order to reinforce the regulatory requirements following the death of an healthy volunteer in a clinical trial). As clinical researches involve processing of personal data, the entry into force, on 25 May 2018, of the General Data Protection Regulation (GDPR) had also consequences on their implementation. Finally, regarding clinical trials on drugs, the "Clinical trials Regulation" repealing the Directive, voted in 2014, should come into force in the coming months., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

At the turn of the century, the pharmaceutical industry began a transition toward a focus on oncology, rare diseases, and other areas of high unmet need that required a new, more complex approach to drug development. For many of these disease states and novel approaches to therapy, traditional approaches to clinical trial design fall short, and a number of innovative trial designs have emerged. In light of these changes, regulators across the globe are implementing new programs to provide regular development program support, facilitate accelerated access, use real-world data, and use digital tools to improve patients' lives. Emerging market regulators are also focusing on simplifying their regulatory pathways via regional harmonization schemes with varying levels of ambition. These changes in the external environment imply that biopharma regulatory teams need to adapt and evolve, leveraging digital tools, data, and analytics, and positioning themselves as strategic advisors during development., (© 2019 The Boston Consulting Group. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Efficacy trials, designed to gain regulatory marketing approval, evaluate drugs in optimally selected patients under advantageous conditions for relatively short time periods. Effectiveness trials, designed to evaluate use in usual practice, assess treatments among more typical patients in real-world conditions with longer follow-up periods. In "efficacy-to-effectiveness (E2E) trials," if the initial efficacy trial component is positive, the trial seamlessly transitions to an effectiveness trial component to efficiently yield both types of evidence. Yet more time could be saved by simultaneously addressing efficacy and effectiveness in an "efficacy and effectiveness too (EE2) trial." Additionally, hybrids of the E2E and EE2 approaches with differing degrees of overlap of the two components could allow flexibility for specific drug development needs. In planning EE2 trials, each stakeholder's current and future needs, incentives, and perspective must be considered. Although challenging, the ultimate benefits to stakeholders, the health system, and the public should justify this effort., (© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The number of global clinical trials including Japan is increasing but still much lower than those including the USA and Europe. The regulatory requirements for clinical trials have been harmonized among Japan, USA, and Europe, and the quality of clinical trials is kept high in these regions. Xofluza (baloxavir marboxil) for influenza approved in Japan under the SAKIGAKE Designation System is a good example of clinical trials including Japan. To include Japan in more global clinical trials, stakeholders should work more collaboratively, and increase the perception that clinical trials can be conducted appropriately and efficiently in Japan. Further measures for better management of clinical trials should also be developed. These would ultimately lead to improved benefits for patients with timely access to new drugs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Within the EU, regulators are obliged to take ethical issues into consideration during marketing authorization deliberation. The goal of this manuscript is to identify what kinds of ethical issues regulators encounter during marketing authorization application deliberations, and the incidence of these ethical issues., Methods: This study used an EMA-provided Excel file that contains all the GCP non-compliance findings from all inspection reports from 2008-2012. There were 112 medicinal products and a total of 288 clinical trial sites. There were a total of 4014 GCP non-compliance findings. The findings that were ethically relevant were extracted using NVivo 10.0 and categories for the ethically relevant findings (ERFs) were created. Note was taken of the incidence of ERFs for each category and the inspectors' gradings of these findings were extracted. This study also looked at the mean and the maximum number of ERFs per grading per medicinal product application, as well as the number of medicinal products with at least one ERF and those with at least major ERFs., Results: With multiple coding, there were 1685 ERFs. ERFs were present in almost all of the medicinal products (97.3%). The majority of ERFs were graded as major. At least major ERFs were present in almost all medicinal products with ERFs. The categories with the highest number of ERFs were protocol issues, patient safety, and professionalism issues. In terms of the density of combined critical and major findings, monitoring and oversight, protocol issues, and respect for persons top the list. This study also showed that, on average, there were 7.54 major and 2.95 critical ERFs per medicinal product application, although ERFs can increase to 30 major and 12 critical., Conclusion: Regulators regularly encounter ERFs that at least "might adversely affect the rights, safety or well-being of the subjects". It remains to be explored how regulators respond to these ethical issues.

In 2009, members of the ophthalmic research community held a joint meeting with members of the Food and Drug Administration (FDA) and the National Eye Institute (NEI) to define and describe the types of patient-focused drug development (PFDD) tools used in ophthalmology. Since then numerous reports have been published which indicate that many of the questionnaires used for patient-reported outcomes (PROs) in ophthalmic clinical development lack rigor and reliability according to modern methods. In 2017, the FDA began development of a series of four methodological guidances for sponsors of clinical trials on the significance of PFDD. The new guidances delineate the FDA's thinking and commitments under the Prescription Drug User Fee Act to implement a more structured approach to the assessment of risks and benefits in clinical trials. In these guidances, the FDA provides steps that drug and device manufacturers should follow, not only to obtain, but also to develop reliable and validated tools that measure patients' experience in clinical trials. Subsequent efforts have resulted in the development and validation of PROs specifically for ophthalmology. The purpose of this paper is to assesses the PROs currently used in ophthalmology and to provide practical strategies for incorporating them into clinical trials.

In a context of perpetual evolution of treatments, access to therapeutic innovation is a major challenge for patients and the various players involved in the procedures of access to medicines. The revolutions in genomic and personalized medicine, artificial intelligence and biotechnology will transform the medicine of tomorrow and the organization of our health system. It is therefore fundamental that France prepares for these changes and supports the development of its companies in these new areas. The recent "Conseil stratégique des industries de santé" launched by Matignon makes it possible to propose a regulatory arsenal conducive to the implementation and diffusion of therapeutic innovations. In this workshop, we present a number of proposals, our approach having remained pragmatic with a permanent concern to be effective in the short term for the patients and to simplify the procedures as much as possible. This was achieved thanks to the participation in this workshop of most of the players involved (industrial companies, "Agence nationale de sécurité du médicament et des produits de santé", "Haute Autorité de santé", "Institut national du cancer", "Les entreprises du médicament", hospitals, "Observatoire du médicament, des dispositifs médicaux et de l'innovation thérapeutique"…). The main proposals tend to favor the implementation of clinical trials on our territory, especially the early phases, a wider access to innovations by favoring early access programs and setting up a process called "autorisation temporaire d'utilisation d'extension" (ATUext) that make it possible to prescribe a medicinal product even if the latter has a marketing authorisation in another indication. In addition, we propose a conditional reimbursement that will be available based on preliminary data but will require re-evaluation based on consolidated data from clinical trials and/or real-life data. Finally, in order to better carry out these assessments, with a view to access or care, we propose the establishment of partnership agreements with health agencies/hospitals in order to encourage the emergence of field experts, in order to prioritize an ascending expertise closer to patients' needs and to real life., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: While the development and evaluation of clinical ethics services in Norway has been recognized internationally, the country's research ethics infrastructure at times may have been less well developed. In 2016, media interest in the controversial nature of some health services research and pilot studies highlighted gaps in the system with certain types of research having no clear mechanisms through which they may be given due independent consideration. It is not clear that new legislation, implemented in 2017, will address this problem. We explore relevant law, committee scope, and the function of the system. We show that 1) Norwegian law provides for ethics assessment for all forms of health research; 2) regional RECs in Norway might not have always enforced this provision, considering some interventional health services research to be outside their remit; and 3) Norwegian law does not explicity provide for local/university RECs, meaning that, in practice, there may be no readily accessible mechanisms for the assessment of research that is excluded by regional RECs. This may include health services research, pilot studies, and undergraduate research. New 2017 legislation has no effect on this specifically but focuses on institutions regulating researcher activity. This may place researchers in the difficult situation of on one hand, needing to hold to recognized ethical standards, while on the other, not readily having access to independent committee scrutiny to facilitate consistent operation with these standards., Conclusion: To support researchers in Norway and to protect the public, it may be necessary either to widen the regional RECs' remit or to make legislative alterations that permit and do not discourage the existence of local RECs.

The increasing amount of clinical research conducted outside the "traditional" countries raises questions about the benefits of hosting offshored clinical research. The extent to which trials contribute to the scientific knowledge base and, in particular, whether there are differences between different types of trials remain open questions. By examining a change in clinical trial regulations in India, a country often viewed as a first-choice offshoring location, we study how the relaxation of clinical trial regulations affects the number and the type of clinical trials as well as the domestic scientific knowledge base. Based on trial data from ClinicalTrials.gov and data on associated publication activities, our empirical analysis suggests that, despite an initial increase in the number of clinical trials, relaxing clinical trial regulations has a limited impact on the domestic scientific knowledge base. More specifically, the number of Indian researchers involved in the production of trial-related scientific knowledge remains modest. Furthermore, the potential to learn from the additional trials appears to be limited: the influx of phase 3 trials-mainly sponsored by Western-pharmaceutical firms-is accompanied by a lower likelihood that the trial results will be used in Indian researchers' subsequent research activities when compared to phase 3 trials with preceding phase 2 trials, as was required before the regulatory change. Overall, our results contradict expectations that relaxing the regulatory requirements for conducting late-stage clinical trials is an appropriate means of supporting the development of the domestic scientific knowledge base., Competing Interests: The authors have declared that no competing interests exist.

Clinical trials in emergency situations present unique challenges, because they involve enrolling individuals who lack capacity to consent in the context of acute illness or injury. The US Department of Health and Human Services and Food and Drug Administration regulations allowing an Exception from Informed Consent (EFIC) in these circumstances contain requirements for community consultation, public disclosure and restrictions on study risks and benefits. In this paper, we analyse an issue raised in the regulations that has received little attention or analysis but is ethically complex. This challenge is when to solicit and honour objections to EFIC trial enrolment, including from non-legally appointed representatives. We address novel questions involving whose objections should be honoured, what level of understanding is necessary for objections to be considered valid and how hard investigators should work to offer an opportunity to object. We present a set of criteria that provide conceptual and practical guidance. We argue that objections should be honoured if they undermine one of the key assumptions that allows for the permissibility of EFIC trials: that individuals would likely not object to enrolment based on their values or preferences. We then clarify the practical implications of this approach through examination of three cases of refusal in an EFIC study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Within the evidentiary hierarchy of experimental inquiry, randomized trials are the gold standard. Oncology patients enter clinical studies with diverse lifestyles, treatment pathways, host tissue environments, and competing comorbidities. Randomization attempts to balance prognostic characteristics among study arms, thereby enabling statistical inference of 'average benefit' and attribution to the studied therapies. In contrast, interpretations of uncontrolled trials require additional scrutiny to attempt to place the findings in the context of external evidence. Counter-factual reasoning and speculation across trials may be obscured by the disproportionate enrollment of prognostic subpopulations which may be unknown from publications of trial reports. Recent modifications to the regulatory environment (Food and Drug Administration Safety and Innovation Act) have elevated the importance of non-comparative trials. Moreover, the emergence of recent innovations in precision medicine have yielded trial designs that partition potentially heterogeneous subpopulations into 'statistically exchangeable' cohorts by histologies, or genetic alterations, further elevating the importance of single-cohort analyses. As patient cohorts become ever more refined into smaller targeted subsets, consumers of reports of uncontrolled trials should be further empowered with improvements in reporting practices that better describe the enrolled prognostic subpopulations and importantly their association with study end points. This article demonstrates the issue with a sensitivity analysis of the findings reported in a recent trial that was devised to evaluate the preliminary clinical efficacy of vemurafenib in BRAF V600 mutation-positive nonmelanoma cancers.

In the context of regenerative medicine and cellular therapies, the treatment under study often targets a less common disease or condition for which recruitment of a large number of research participants at any given site is challenging, if not impossible. One way to overcome this challenge is with a multi-centre clinical trial. This manuscript first aims to briefly outline the existing ethical, legal and social implications as well as the regulatory frameworks associated with multi-centre regenerative medicine clinical trials. Second, it considers the regulatory limitations and barriers surrounding the initiation of such trials in Canada, the USA and Europe. Third, it concludes with a set of recommendations for facilitating multi-centre clinical trials, at both national and international levels.

Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht.

Competing Interests: Die Autorin ist Mitarbeiterin der Bayer AG im Bereich Pädiatrische Entwicklung und Mitglied der Projektleitung „conect4children“.

In the last few decades, genomic manipulation has made significant progress as a result of the development of recombinant DNA technologies; however, more often than not, these techniques have been costly and labor intensive. In contrast, recently developed next-generation sequencing (NGS) technologies have provided a cheaper, faster, and easier process to study genomics. In particular, an NGS technique emerged from bacterial CRISPR-associated protein-9 nuclease (Cas9) as a revolutionary method to modify, regulate, or mark specific genomic sequences on virtually any organism. A later adaptation of this bacterial defense mechanism that successfully and permanently edits dysfunctional genes and corrects missing proteins has resulted in a new era for disease genetic engineering. Clinical trials using this technique are already being performed, and the applicability of CRISPR-Cas9 techniques is actively being investigated using in vivo studies. However, the concept of genome correction poses great concerns from a regulatory perspective, especially in terms of security, so principles for the regulation of these methodologies are being established. We delved into CRISPR-Cas9 from its natural and ortholog origins to its engineered variants and behaviors to present its notable and diverse applications in the fields of biotechnology and human therapeutics.

Competing Interests: Der Autor gibt an, dass kein Interessenkonflikt besteht.

Background: Although children have historically been excluded from clinical trials (CTs), many require medicines tested and approved in CTs, forcing health care providers to treat their pediatric patients based on extrapolated data. Unfortunately, traditional randomized CTs can be slow and resource-intensive, and they often require multi-center collaboration. However, an adaptive design (AD) framework for CTs could be used to increase the efficiency of pediatric CTs by incorporating prospectively planned modifications to CT methods without undermining the integrity or validity of the study. There are many possible adaptations, but each will have ethical, logistical, and statistical implications. It remains unclear which adaptations (or combinations thereof) will lead to real-world improvements in pediatric CT efficiency. This study will identify, evaluate, and synthesize the various regulatory, ethical, logistical, and statistical considerations and emerging issues of AD in CTs that could be used to evaluate the use of drugs in children., Methods/design: Following the development of a peer-reviewed search strategy, a systematic review on AD in CTs will be conducted. Data on regulatory, ethical, logistic, and statistical considerations as well as population and trial design characteristics will be synthesized. A mixed-methods study including surveys and focus groups with regulators, research ethics board members, biostatisticians, clinicians, and scientists, as well as representatives from patient groups and the public will evaluate the opportunities and challenges in applying AD in trials enrolling children and propose recommendations on best practices., Discussion: This study will deliver practical recommendations on the use of AD in pediatric CTs. Collaboration and consultation with national and global partners will ensure that our results meet the needs of researchers, regulators, and patients, both locally and globally, and that they remain current and relevant by engaging a wide variety of stakeholders. Overall, this research will enrich the knowledge base regarding if, how, and when AD can be used to answer research questions with fewer resources while still meeting the highest ethical standards and regulatory requirements for CTs. In turn, this will result in increased high-quality clinical research needed by health care providers so they have access to appropriate, population-specific evidence regarding the safe and effective use of medicines in children.

Rising concerns relating to pharmaceutical sponsor bias in the conduct of clinical trials have compelled the need to develop a clinical trial governance framework. This article describes the development of the Conflict of Interest in Research (COIR), a clinical trial governance framework. The COIR, consisting of three process phases (initiation, concurrent, and ongoing), developed following a needs assessment, using a four-stage methodology, and evaluated against the International Conference on Harmonization--Good Clinical Practice (ICH-GCP) guidelines. The Conflict of Interest Resolution algorithm, the backbone of COIR, enables constant surveillance to detect/resolve conflicts at all stages of the clinical trial life-cycle. COIR promotes interaction between the regulatory system and the sponsors, independent of individuals. COIR enables rapid detection of scientific and financial conflicts, to prevent subject harm and, to assure optimal funds utilization, the latter feature helped to reduce a significant burden for the ethics committee, as it lacks financial expertise. COIR is a semi-automated Oracle system, requires manpower, and is affected by human expertise and subjectivity. Complete automation to overcome this limitation will still need human expertise to scale changing trial regulations. Nevertheless, the COIR has won the distinction of the "most favored site" from pharmaceutical sponsors and is anticipated to be adopted by other clinical trial sites.

Background: Due to the acuity and time-sensitive needs of their clinical condition, patients presenting with certain emergent pathologies may lack capacity to provide meaningful prospective informed consent to participate in clinical research. For these reasons, these populations have often been excluded from research investigations. To mitigate this, regulations allowing exception from informed consent (EFIC; 21 CFR 50.24) or waiver of informed consent (WIC; 45 CFR 46.101) were developed in 1996. The purpose of this study was to identify trends in the utilization of EFIC and WIC in emergency research. We also sought to describe the disclosure of necessary prestudy regulatory requirements and justification for the use of EFIC/WIC as reported in completed EFIC/WIC clinical trials., Methods: This study is a review of 20 years of published trials using EFIC or WIC as the primary method of patient consent. Studies were identified using a MEDLINE search; ClinicalTrials.gov; queries to emergency and resuscitation researchers, research directors, department chairs, and principal investigators of acute care research networks; clinical review papers; and a query of the Federal Drug Administration (FDA) docket. All eligible studies were reviewed by three investigators and study data of interest were abstracted. Data are presented descriptively., Results: We identified 45 potentially eligible studies; 11 were ongoing (with no data yet available), four were completed (with no publications or data available), and two did not use EFIC or WIC. Of the remaining 28 studies, 24 (86%) used EFIC and four used WIC. The most common pathologies under study were cardiac arrest (10), hemorrhagic shock (six), and traumatic brain injury (five). Completion of the prestudy regulatory requirements was reported as follows: FDA investigational new drug/investigational device exemption application (for FDA regulated studies; 14, 50%), community consultation (13, 46%), public disclosure (10, 36%), and opt-out procedures if requested by the institutional review board (seven, 25%). The justification of the need for the use of EFIC or WIC in the reported clinical trial, as defined as mention of at least one of the eight established criteria, was described in the text of 13 (46%) publications., Conclusions: Since their implementation in 1996, the EFIC/WIC regulations have allowed progress in research aimed at determining optimal care for devastating life-threatening conditions. However, consistent and rigorous report of regulatory prestudy requirements and justification of the use of EFIC/WIC is lacking in clinical trial publications or on websites such as ClinicalTrials.gov. Since research without consent is an ethically sensitive issue and not widely understood, better justification of its needs within the presentation of the research itself may educate the general medical community and also reduce concerns about whether or not the regulations are being properly applied., (© 2018 by the Society for Academic Emergency Medicine.)

Background: The US Food and Drug Administration (FDA) ensures that clinical trials meet regulatory and ethical standards through inspections of researchers, also known as clinical investigators. Inspections with significant regulatory/ethical violations may result in regulatory actions, such as a warning letter or a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE). Objectives included the standardization of regulatory violation themes cited by the FDA for novel analysis of published regulatory actions rate issued by study intervention type, violation theme by intervention type, and violation theme variation between regulatory action type., Methods: Cross-sectional analysis of regulatory actions from October 1, 2006, to September 30, 2015, for inspections of researchers. For each FDA regulatory action, the main measure was the Code of Federal Regulations cited coded into a violation theme. Data were paired with FDA's published researcher inspection metrics to perform fiscal year analysis., Results: The FDA conducted 6375 domestic inspections of researchers in 2007 to 2015: 360 had significant regulatory violations, and 194 received published regulatory actions. Since 2007, rates of significant deviations have decreased. Medical device researchers had higher rates of warning letter issuance than did biologic product researchers. In contrast, medical device researchers had lower rates of NIDPOE issuance as compared to rates of biologic or pharmaceutical researchers. Lack of researcher supervision and submission of false information were cited more frequently for NIDPOEs., Conclusions: Researcher compliance has significantly improved as evidenced by medical device researchers having the lowest rate of the most significant noncompliance. Disqualification is more likely to occur when researchers fail to supervise the trial or false information is submitted.

Cognitive function is an important end point of treatments in dementia clinical trials. Measuring cognitive function by standardized tests, however, is biased toward highly constrained environments (such as hospitals) in selected samples. Patient-powered real-world evidence using information and communication technology devices, including environmental and wearable sensors, may help to overcome these limitations. This position paper describes current and novel information and communication technology devices and algorithms to monitor behavior and function in people with prodromal and manifest stages of dementia continuously, and discusses clinical, technological, ethical, regulatory, and user-centered requirements for collecting real-world evidence in future randomized controlled trials. Challenges of data safety, quality, and privacy and regulatory requirements need to be addressed by future smart sensor technologies. When these requirements are satisfied, these technologies will provide access to truly user relevant outcomes and broader cohorts of participants than currently sampled in clinical trials., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)