Call for More Effective Regulation of Clinical Trials with Advanced Therapy Medicinal Products Consisting of or Containing Genetically Modified Organisms in the European Union.

Advanced therapy medicinal products (ATMPs), such as gene therapies that consist of or contain genetically modified organisms (GMOs) need to comply with the European Union (EU) GMO legislation, as implemented in each EU Member State, before a clinical trial can commence. Complying with GMO requirements is complex, varies significantly across EU Member States and is leading to delays to clinical trials with ATMPs. Such delays and varying implementation of the GMO legislation makes the EU less attractive as a region to conduct clinical trials with investigational gene therapies. This is detrimental to EU patients, since their timely access to these transformative potentially curative medicines is delayed. Despite recent initiatives coordinated by the European Commission (EC) to facilitate and reduce discrepancies across the EU regarding the application of the GMO requirements, it remains particularly difficult to conduct multicenter clinical trials with ATMPs containing or consisting of GMOs involving several EU Member States. The recent decision for the EC to temporarily derogate potential coronavirus disease 2019 treatments and vaccines from some provisions of the GMO requirements was made on the basis of a clear recognition of such complexities and resulting delays to clinical development. The Alliance for Regenerative Medicine, the European Federation of Pharmaceutical Industries and Associations, and the European Association for Bioindustries call upon the EC, together with national competent authorities, to exempt ATMPs containing or consisting of GMOs from the GMO legislation. Such a simplification will eliminate the delays currently reported to occur when submitting environmental risk assessments and GMO applications to the national competent authorities. An exemption from GMO requirements will make the EU a more attractive region for clinical development of gene therapies and could accelerate European patients' access to these potentially life-saving medicines. Maintaining a system for GMO assessment that is different across countries may also prevent ATMPs from realizing the full benefits of a harmonized clinical trial approval process under the Clinical Trials Regulation. The undersigned organizations to this publication urge the EC to use its right of initiative to put forward a legislative proposal to exempt ATMPs in clinical development from the EU GMO legislation, within the timeframe proposed in the 2020 EU Pharmaceutical Strategy (by 2022). Implementation of a GMO exemption scheme before the end of the transition period for the Clinical Trial Regulation (the end of 2023) is important to avoid new Clinical Trial Application submissions for ATMPs under the Clinical Trial Regulation having to conduct the whole GMO assessment process in parallel. It is considered that ATMPs pose negligible risk to the environment. Such ATMPs include the following: human somatic cells modified ex vivo; recombinant virus-based vectors, including those containing genome editing nucleic acid sequences (which may also be delivered nonvirally); and bacterial vectors. Outside of controlled storage conditions, gene therapies cannot survive for any appreciable length of time. Upon clinical administration, any recombinant gene therapy viral vector particles that do not enter host cells are diluted within the body and if excreted are in such low multiplicity to no longer be viable or considered infectious to persons, animals, or living organisms within the environment. Any nucleic acids released into the environment are rapidly degraded.

Regulatory and operational challenges in conducting Asian International Academic Trial for expanding the indications of cancer drugs.

There are many differences between Asian regions in terms of the regulatory requirements and operational procedures in conducting international academic clinical trials for the approval of new drugs. The National Cancer Center Hospital in Japan has launched an international investigator-initiated registration-directed trial (IIRDT) in Japan, Korea, Taiwan, and Singapore, aiming at obtaining pharmaceutical approval in participating regions. Differences in regulatory and operational procedures were identified while coordinating the trial. In Japan, regulatory authority reviews should be performed after approval by institutional review boards for IIRDT, whereas in other regions these can be done in parallel. There were disparities in Good Manufacturing Practice-related documents between regions. Several differences were found regarding investigational product (IP) management, specifically concerning labeling, import/export procedures, and customs clearance costs. On the other hand, safety reporting procedures were relatively well-harmonized in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH-E2A). Regions also differed in per-patient costs, due to varying regulations for academic registration-directed trials. In conclusion, the observed differences among Asian regions should be harmonized to facilitate international academic trials in Asia and thus resolve unmet patient needs worldwide. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? International clinical trials have become common because they make it possible to accrue patients faster and obtain new drug approval in wider areas. However, pharmaceutical regulatory differences hinder the efficient conduct of international clinical trials, especially in academia. WHAT QUESTION DID THIS STUDY ADDRESS? We conducted an academic international clinical trial on new drug applications in four Asian countries and clarified pharmaceutical regulatory differences and operational difficulties. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study identified differences between countries in terms of regulatory affairs, institutional review board (IRB) review processes, investigational new drug (IND) dossiers, investigational product (IP) management procedures, and clinical trial costs, while safety reporting procedures were relatively harmonized. Japan utilizes investigator-initiated registration-directed trials, an advanced regulatory system for new drug application by academia, but the other countries do not. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Harmonization of pharmaceutical regulations and trial initiation procedures, and regulatory reform of clinical trial costs are important to accelerate academic international clinical trials for new drug applications.

Challenges of international oncology trial collaboration-a call to action.

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.

Ethical approval for multicenter cohort studies on drug exposure during pregnancy: A survey among members of the European Network of Teratology Information Services (ENTIS).

The European Network of Teratology Information Services (ENTIS) is in a privileged position to perform independent post-marketing surveillance of drugs in pregnancy. The aim of this survey was to describe the legal requirements and procedures involved in obtaining ethical approval for collaborative cohort studies. We sent a survey questionnaire to all 28 Teratology Information Services (TIS), of which 25 (89%) in 18 countries completed our questionnaire. For 15 TIS, specific research ethical approval was mandatory. The review process was estimated to last from 2 up to 16 weeks. Procedures for patients' information and consent were oral (12), written (5) or both (3). Five TIS had no requirement to inform patients and seek consent. Since data on drug exposure during pregnancy are scarce, ENTIS research efforts should be further encouraged, and procedures optimized so that legitimate ethical and legal requirements do not translate into deterrent administrative constraints and costs.

A checklist for clinical trials in rare disease: obstacles and anticipatory actions-lessons learned from the FOR-DMD trial.

BACKGROUND: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. METHOD: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. RESULTS: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. CONCLUSION: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

Financial management of large, multi-center trials in a challenging funding milieu.

BACKGROUND: Randomized clinical trials that have public health implications but no or low potential for commercial gain are predominantly funded by governmental (e.g., National Institutes of Health (NIH)) and not-for-profit organizations. Our objective was to develop an alternative clinical trial site funding model for judicious allocation of declining public research funds. METHODS: In the Vitamin D and Type 2 Diabetes (D2d) study, an NIH-supported, large clinical trial testing the effect of vitamin D supplementation on incident diabetes in 2423 participants at high risk for diabetes, a hybrid financial management model for supporting collaborating clinical sites was developed and applied. The funding model employed two reimbursement components: Core (for study start-up and partial efforts throughout the study, ~40% of the total site budget), invoiced by sites, and Performance-Based Payments (for successful enrollment of participants and completion of follow-up visits, ~60% of the total site budget), automatically issued to the sites by the Coordinating Center based on actual recruitment and visits conducted. Underperforming sites transitioned to Performance-Based Payments only. RESULTS: Recruitment occurred from October 2013 through December 2016, requiring one additional year than the 2-year projection. Median enrollment at each site was 88 participants (range 29-318; 20 to 205% of the site target). At the end of year 1, study-wide recruitment was at 12% of the target (vs. 50% projected) and 12% of the total grant award was invested. The model constantly evaluated sites' needs and re-allocated resources to meet the study enrollment goal. If D2d had issued cost reimbursement subaward agreements and sites invoiced for their entire budget, 83% of the award would have been spent for all study activities over the first 4 years of the trial compared to 65% of the award spent (US$26M) under the hybrid model used by D2d. CONCLUSIONS: It is feasible to foster a hybrid financial management approach to steward limited available public funds for research in a dynamic and consistent way that does not compromise the trial's scientific integrity and ensures conservation of funds to complete recruitment and continue to follow up participants.

Barriers to the conduct of randomised clinical trials within all disease areas.

BACKGROUND: Randomised clinical trials are key to advancing medical knowledge and to enhancing patient care, but major barriers to their conduct exist. The present paper presents some of these barriers. METHODS: We performed systematic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. RESULTS: The following barriers to randomised clinical trials were identified: inadequate knowledge of clinical research and trial methodology; lack of funding; excessive monitoring; restrictive privacy law and lack of transparency; complex regulatory requirements; and inadequate infrastructures. There is a need for more pragmatic randomised clinical trials conducted with low risks of systematic and random errors, and multinational cooperation is essential. CONCLUSIONS: The present paper presents major barriers to randomised clinical trials. It also underlines the value of using a pan-European-distributed infrastructure to help investigators overcome barriers for multi-country trials in any disease area.

[Principles of the EU Clinical Trials Regulation No 536/2014 : What will change?] / Grundzüge der EU-Verordnung 536/2014 : Was wird sich ändern?

The new Regulation (EU) No. 536/2014 for clinical trials of medicinal products for human use will replace the still valid European Directive 2001/20/EC in the future. The new regulation aims to further harmonise authorisation and reporting procedures for clinical trials and introduces of a joint European assessment for multinational clinical trials in the EU. Despite the joint assessment administered by a reporting member state, each member state continues to authorise clinical trial applications nationally. In the future, applications and any communication will be submitted paperlessly via a new electronic EU portal, which is still being developed. The regulation provides detailed information on the implementation of multinational clinical trials. In particular, the complex processing procedures and shorter time limits are to be stressed in comparison to the previously valid regulations. This is a major challenge for all stakeholders, but on the other hand it should contribute to the future role of the EU in the development of innovative medicines.

[Implementation status of Regulation EU 536/2014 in the member states]. / Vorbereitungsstand zur EU Verordnung 536/2014 in den Mitgliedstaaten.

The upcoming Regulation EU 536/2014 for clinical trials of medicinal products for human use requires multinational cooperation in the assessment of clinical trial applications by the member states concerned as well as one single decision per member state concerned, supported by the new EU Portal and database system. The implementation makes national reorganisation of the processes necessary, especially coordination and cooperation between the national competent authorities and the ethics committees, necessary.A brief overview of implementation status with regard to national law adaptations, (re-) organisation, information technology systems as well as national or multinational pilot projects in 7 of 28 member states is given.Within these member states some national laws have been adapted already, while others will be soon. The national reorganisation covers mostly administrative organisation and coordination especially within the ethics committees. Overall, it is foreseen that a reduced number of ethics committees will be involved in the approval of clinical trials on medicinal products within the member states.Most of the seven member states expect that in addition to the new EU Portal/database system a national IT system for national cooperation and interaction will be necessary. Therefore, an interface within the EU system for national systems is essential.In order to test the new processes some member states are running national pilot projects or are planning them. In addition, almost all participate in the voluntary multinational assessment of clinical trials on medicinal products, which had existed since 2009, a few also in cooperation with their ethics committees.The member states are confident that all national processes will be in place when the EU regulation becomes applicable.

Challenges to complete and useful data sharing.

Data sharing from clinical trials is one way of promoting fair and transparent conduct of clinical trials. It would maximise the use of data and permit the exploration of additional hypotheses. On the other hand, the quality of secondary analyses cannot always be ascertained, and it may be unfair to investigators who have expended resources to collect data to bear the additional burden of sharing. As the discussion on the best modalities of sharing data evolves, some of the practical issues that may arise need to be addressed. In this paper, we discuss issues which impede the use of data even when sharing should be possible: (1) multicentre studies requiring consent from all the investigators in each centre; (2) remote access platforms with software limitations and Internet requirements; (3) on-site data analysis when data cannot be moved; (4) governing bodies for data generated in one jurisdiction and analysed in another; (5) using programmatic data collected as part of routine care; (6) data collected in multiple languages; (7) poor data quality. We believe these issues apply to all primary data and cause undue difficulties in conducting analysis even when there is some willingness to share. They can be avoided by anticipating the possibility of sharing any clinical data and pre-emptively removing or addressing restrictions that limit complete sharing. These issues should be part of the data sharing discussion.

Research ethics committees in the regulation of clinical research: comparison of Finland to England, Canada, and the United States.

BACKGROUND: The aim of this paper is to compare common features and variation in the work of research ethics committees (RECs) in Finland to three other countries - England, Canada, the United States of America (USA) - in the late 2000s. METHODS: Several approaches and data sources were used, including semi- or unstructured interviews of experts, documents, previous reports, presentations in meetings and observations. A theoretical framework was created and data from various sources synthesized. RESULTS: In Finland, RECs were regulated by a medical research law, whereas in the other countries many related laws and rules guided RECs; drug trials had specific additional rules. In England and the USA, there was a REC control body. In all countries, members were voluntary and included lay-persons, and payment arrangements varied. Patient protection was the main ethics criteria, but other criteria (research advancement, availability of results, payments, detailed fulfilment of legislation) varied. In all countries, RECs had been given administrative duties. Variations by country included the mandate, practical arrangements, handling of multi-site research, explicitness of proportionate handlings, judging scientific quality, time-limits for decisions, following of projects, role in institute protection, handling conflicts of interests, handling of projects without informed consent, and quality assurance research. The division of work between REC members and secretariats varied in checking of formalities. In England, quality assurance of REC work was thorough, fairly thorough in the USA, and not performed in Finland. CONCLUSIONS: The work of RECs in the four countries varied notably. Various deficiencies in the system require action, for which international comparison can provide useful insights.

Navigating the maze of requirements for obtaining approval of non-interventional studies (NIS) in the European Union.

OBJECTIVE: The purpose of this article is to give an overview of the complexities and unexpected regulatory requirements for obtaining approval of multinational and multicentre non-interventional studies (NIS) in the European Union (EU). METHODS: The websites of national competent authorities (CAs), ethics committees (ECs) and data protection (DP) authorities were consulted to find regulations and guidance information related to the authorisation of NIS in various member states of the EU. RESULTS: Many additional hurdles, neither disclosed nor clear in the various regulations/guidances for NIS, were identified. Although approval from the CA is not needed for NIS, in many countries request of CA opinion is nevertheless recommended, prior to submission to the EC, to obtain confirmation that the planned NIS does not fall in the interventional trial category. Clinical trial insurance was required in some countries. In countries like Belgium and Italy, the multicentre NIS required the approval from a central EC and local ECs as a single central EC opinion was not considered sufficient. The EC document requirements for submission and the fees were extremely variable among all member states. Additional approvals from data protection authorities and insurance companies were required in some countries. CONCLUSIONS: The process of obtaining approval for multicentre and multinational NIS is time consuming due to lack of transparency and the different regulatory requirements among member states. The EU pharmacovigilance legislation and clinical trial regulation No 536/2014 is a step forward in providing a regulatory framework for PASS (post-authorisation safety studies) and low intervention clinical trials, but since regulation No 536/2014 excludes NIS, it will be difficult to enforce harmonization of requirements for approval of NIS among member states.

Regulatory challenges associated with conducting multicountry clinical trials in resource-limited settings.

International public health and infectious diseases research has expanded to become a global enterprise transcending national and continental borders in organized networks addressing high-impact diseases. In conducting multicountry clinical trials, sponsors and investigators have to ensure that they meet regulatory requirements in all countries in which the clinical trials will be conducted. Some of these requirements include review and approval by national drug regulatory authorities and recognized research ethics committees. A limiting factor to the efficient conduct of multicountry clinical trials is the regulatory environment in each collaborating country, with significant differences determined by various factors including the laws and the procedures used in each country. The long regulatory processes in resource-limited countries may hinder the efficient implementation of multisite clinical trials, delaying research important to the health of populations in these countries and costing millions of dollars a year.

Managing personal health information in distributed research network environments.

BACKGROUND: Studying rare outcomes, new interventions and diverse populations often requires collaborations across multiple health research partners. However, transferring healthcare research data from one institution to another can increase the risk of data privacy and security breaches. METHODS: A working group of multi-site research programmers evaluated the need for tools to support data security and data privacy. The group determined that data privacy support tools should: 1) allow for a range of allowable Protected Health Information (PHI); 2) clearly identify what type of data should be protected under the Health Insurance Portability and Accountability Act (HIPAA); and 3) help analysts identify which protected health information data elements are allowable in a given project and how they should be protected during data transfer. Based on these requirements we developed two performance support tools to support data programmers and site analysts in exchanging research data. RESULTS: The first tool, a workplan template, guides the lead programmer through effectively communicating the details of multi-site programming, including how to run the program, what output the program will create, and whether the output is expected to contain protected health information. The second performance support tool is a checklist that site analysts can use to ensure that multi-site program output conforms to expectations and does not contain protected health information beyond what is allowed under the multi-site research agreements. CONCLUSIONS: Together the two tools create a formal multi-site programming workflow designed to reduce the chance of accidental PHI disclosure.

Regulatory challenges in the review of data from global clinical trials: the PMDA perspective.

Regulatory agencies face challenges in reviewing data from global clinical trials (GCTs) in the era of globalization of drug development. One major challenge is consideration of ethnic factors in evaluating GCT data so as to extrapolate foreign population data to one's own national population. Here, we present the Pharmaceuticals and Medical Devices Agency (PMDA) perspective in reviewing GCT data in new drug applications (NDAs) and discuss future challenges for new drug approval.

New EU regulation on clinical trials: the impact on ethics and safeguards for participants.

The European Commission has proposed a new regulation to replace the current clinical trials directive. The proposed regulation aims at accelerating the application procedure and simplifying and harmonising the administrative requirements for multi-centre trials across the European Union. One striking feature of the proposed regulation is a two-tiered assessment, one at the central level, to be carried out by a reference member state, binding on all concerned member states; and one at the national level, where the ethics aspects will be assessed. Second, the proposal no longer requires the approval of the clinical trial application by a separate ethics committee. Third, it introduces the concept of "low intervention" trials that will undergo a "light" approval procedure. The proposed regulation may stimulate clinical trials that yield substantial public health benefits. However, it is a step back in terms of protection of the rights and safety of trial participants. It undermines current frameworks for ethical review by not requiring the involvement of an ethics committee, and by insufficiently integrating the Declaration of Helsinki into assessment procedures at the national and European levels. The introduction of the riskbased approach needs more preparation as there is no consensus yet on key issues, such as how to define risk, and who is going to define it.

[Focus on academic multicenter trials: impact of the German drug law on hematological/oncological therapy optimization trials]. / Akademische multizentrische Studien im Fokus: Auswirkungen der Arzneimittelgesetzgebung auf Therapieoptimierungsstudien in der Hämatologie/Onkologie.

BACKGROUND: The purpose of this study was to evaluate the effect of legal regulations for clinical trials on study centers participating in investigator-initiated trials (IITs) in the field of hematology/oncology. METHOD: Questionnaires were sent out to the heads of hematology-oncology study centers. RESULTS: Medical units participating in IITs have a good infrastructure and extensive experience in clinical trials. Depending on indication, a high proportion of patients have been treated in studies with the purpose to improve outcome. However, 35% of the responders will reduce their participation in IITs in the future due to a lack of financial support for staff involved in the extensive organizational tasks. CONCLUSIONS: The widely recognized research field in therapy optimization trials in hematology and oncology in Germany is at risk. This will have negative effects on the patients as highly sophisticated protocols will no longer be initiated in several study centers, resulting in the loss of valuable data for the improvement of patient therapy and outcome. To stop this development, legislators as well as regulatory authorities and health insurances need to make the necessary changes in the legal framework.