Michael Sigmund

"Move to EU to avoid Brexit costs, firms told.” This was the news in UK a couple of weeks after the signing of the Trade and Commerce Agreement, as reported by 

 The recommendation, directed at all companies of the United Kingdom that export to the European Union (EU), also applies to sponsors of pan-European clinical trials located outside of the new EU27—such as the United States.

Whether it be the location of the legal representative, the submissions of applications to responsible regulatory agencies, the pharmacovigilance duties to assure the safety of medicines, or the delivery of Investigational Medicinal Products (IMP) to clinical sites: after Brexit, new procedures must be set in place to address all these aspects. There is plenty of guidance information available. Both the European Medicines Agency (EMA) and the British Medicines and Healthcare products Regulatory Agency (MHRA) are continuously publishing and updating relevant information.

 In this article, we summarize the most important changes for sponsors located outside of the EU27 that wish to conduct clinical trials of medicinal products in the EU27 and the UK. A visualization of these changes can be found in Figure 1 below.

Starting with the location of the sponsor or legal representative of an EU clinical trial: US pharmaceutical companies have traditionally looked to the United Kingdom for competent and capable partners to conduct clinical trials in Europe owing to the ease of communication that the shared language brings. Unfortunately, solely UK-based CROs can no longer conduct clinical trials in the EU on behalf of sponsors from the US or other non-European locations. EU law demands that the sponsor or legal representative be established in the EU.

In contrast, EU sponsors or CRO partners based in the EU can conduct a clinical trial for medicinal products in both the EU and the UK. In 2019, in its Human Medicines (Amendment etc.) (EU Exit) Regulations,

 the UK introduced an approved countries list that defines where a clinical trial sponsor or their legal representative may be established to be allowed to conduct a clinical trial for medicinal products in the UK. This list initially includes all EU and European Economic Area (EEA) countries and will be reviewed at least every three years by the British government.

Acting as legal representatives for non-EU sponsors—whether from the UK or other parts of the world—CROs must be legally integrated in the EU to be able to conduct clinical trials there. UK-based CROs must establish a presence in the EU if they do not want to be left out.

Over the lifecycle of a clinical trial, various submissions such as initial applications, substantial amendments, or end of trial notifications must be made. Sponsors or CRO partners of clinical trials for medicines in the EU27 and UK are responsible for these submissions. They can no longer solely use the EU portals—currently still the Common European Submission Portal (CESP) and, from January 31, 2022, onward, the Clinical Trials Information System (CTIS). Instead, they must use the MHRA gateway, as the MHRA is now the standalone medicines and medical devices regulator for the UK.

Similarly, the EU/EEA and the UK are now separate regulatory entities with regards to drug safety. Thus, parallel reporting through the appropriate channels in the EU (EudraVigilance gateway) and UK (MHRA gateway) is necessary.

Accordingly, marketing authorization holders have increased responsibilities in terms of assuring the ongoing safety of marketed products in both regulatory systems. They are required to keep two pharmacovigilance system master files (PSMF) up to date. And although the UK allows the qualified person for pharmacovigilance (QPPV) to be located in the EU or EEA, it is still necessary to define a national contact person for pharmacovigilance in the UK.

CROs representing sponsors in clinical trials taking place in both the EU and the UK, therefore, have a higher workload, as an additional regulatory agency must be addressed.

Time and costs for IMP logistics between EU and UK

An important issue for sponsors is how to ensure continued and unrestricted supply of IMPs to the clinical trial sites. Sponsors of EU and UK clinical trials that import IMPs into Great Britain from outside the UK must reassess their study supply chains after Brexit. They are required to create assurance systems to control whether the IMPs have been duly certified by a qualified person (QP), before release of the IMPs to trial sites. The UK will continue to recognize QP Certification of IMPs from countries on an approved list, which currently includes all EU and EEA countries. As for the abovementioned list of accepted countries for the sponsor’s location, this list of approved countries will also be subject to review at least every three years, introducing a new level of uncertainty in the long-term planning of clinical trials.

For the export of IMPs from Great Britain to the EU, on the other hand, sponsors must organize a new importer and batch releaser, plus a new QP declaration. The only workaround for this is to have the IMP manufactured in Northern Ireland and then ship it to the EU, as it is then not considered an imported IMP under the Northern Ireland Protocol.

This issue will be for CROs coordinating the logistics of the IMP supply to deal with. The simplest scenarios are those in which the IMP is manufactured, packaged, and distributed either in the EU or the UK alone. Sponsors wishing to ship IMPs between the EU27, and the UK should factor in the longer timeframes and additional organizational issues at the very beginning of planning the clinical trial.

Small parenthesis: business as usual for data protection

At the end of June 2021, the European Commission determined that the UK provides an adequate level of data protection and formally adopted adequacy decisions for the UK under the General Data Protection Regulation (GDPR). These allow for the continued unrestricted personal data flow from the EU to the UK. Personal data flows in the opposite direction also remain unaltered, as the British government has similarly decided not to impose additional safeguards. With regard to data protection issues, no adaptation is required by sponsors or CROs after Brexit, regardless of whether they are UK or EU-based.

CTIS simplifies submissions, but not in the UK

As early as in 2014, the EU members adopted the clinical trials regulation (Regulation (EU) No 536/2014), which provides for the central submission of study applications and of documents for European studies. Since the end of 2014, a clinical trial application for multinational studies in the EU can be submitted in accordance with the Voluntary Harmonized Procedure (VHP). In a single submission, a sponsor can simultaneously submit a clinical trial application to the competent authorities in all participating member states of the European Union. But the VHP is only an intermediate solution for a centralized submissions system. On January 31, 2022, the new EU-hosted portal, Clinical Trials Information System (CTIS), will go live. The EMA website states that “CTIS will become the single-entry point for clinical trial application submission, authorization and supervision in the EU, and in the European Economic Area (EEA) countries Iceland, Liechtenstein and Norway.” Through CTIS, sponsors and/or their CRO partners will be able to apply for clinical trial authorization in up to 30 EEA countries with one single application. The same requirements and deadlines will apply to all EU member countries, resulting in a harmonized electronic submission and assessment process for clinical trials conducted in multiple member states. With CTIS, information sharing will be ensured and decision-making processes between and within member states will be expedited. The activation of the new portal will allow Clinical Trials Regulation (Regulation (EU) No 536/2014) to come fully into force at the beginning of 2022—thereby making it easier for trials to be conducted in the EU across multiple member states and making the EU much more attractive for sponsors worldwide. As submissions in the UK will have to be carried out separately via the MHRA, they will not benefit from the simplifications provided by the new CTIS system.

In summary, the workload to conduct an international trial taking place in the UK and EU has become heavier. Whereas Brexit has increased the complexity of conducting pan-European clinical trials including the UK, in the EU the Clinical Trials Regulation will make it easier for trials to be conducted across multiple EU member states.

As every clinical project is different, sponsors must carefully select the right European countries in order to bring the clinical trial to successful completion. This success depends on many aspects, including not only the availability of patients in the respective countries but also the availability of dedicated investigators and the treatment praxis.

 The UK is still an important player from a health economics point of view. Nonetheless, sponsors will not automatically include the UK in their clinical program planning and will always evaluate whether the extra effort involved is worth it.

Additionally, regardless of a certain level of economic integration assured by the EU-UK Trade and Cooperation Agreement concluded in late December 2020, insecurities about a stable British partnership remain that may also affect clinical research. Sponsors and CROs should keep a watchful eye over future legislative changes in the United Kingdom. One thing is certain: Planning and successfully performing clinical trials in the EU and UK involves higher costs and more work after Brexit. Sponsors from the US and other non-European countries should take this into account at the earliest possible time point when planning their clinical program for the EU.

Article (British government officials advise companies to expand to EU.)

https://www.theguardian.com/politics/2021/jan/23/brexit-hit-firms-advised-government-officials-set-up-shop-in-eu

https://www.ema.europa.eu/en/about-us/brexit-uk-withdrawal-eu/brexit-related-guidance-companies

The Human Medicines (Amendment etc.) (EU Exit) Regulations 2019, SI 2019/775

Interview with Lars Behrend from 21.07.2021 by P. Ledesma, Sofpromed, 

https://www.sofpromed.com/sss-cro-for-clinical-trials-in-germany/

Chief Executive Office, Founder; all with SSS International Clinical Research

Articles

Higher costs headline list of new challenges faced by CROs and sponsors.

Consequences of Brexit for Clinical Trials in Europe

	In 2014 the German Federal Association of Contract Research Organizations (Bundesverband Medizinischer Auftragsinstitute, BVMA), supported by the European Clinical Research Organization Federation (EUCROF), conducted a survey among Clinical Research Associates (CRAs) in Europe to get a picture about their experience and assessment of risk-based monitoring (RBM) processes [

]. Two years later, in 2016, the survey was repeated in order to find out, how knowledge and practical experience with RBM have changed over that time period. This article compares the results of this second survey with replies from 2014 and analyzes the progress of RBM implementation.

	Both surveys included 21 questions from the areas working efficiency and site contact as well as data quality and patient safety. Although some questions were slightly modified in the 2016 survey for better clarity, answers and results of both surveys are well comparable. The 2016 questionnaire was performed as an internet-based online survey from August to October 2016 and was answered by 231 CRAs, whereas the 2014 survey had been distributed via email and replies from 180 CRAs had been collected from August 2014 until January 2015.

	This article shows the results of several selected questions and compares the answers given in 2014 to the responses in 2016. The total number of respondents of a survey question is labeled as “N” whereas “n” indicates the number of respondents for each answer option. Percentages for the proportion of “n” within “N” are shown as well. As not every CRA answered each survey question, the total number of respondents (N) may vary between questions.

	Table 1 gives an overview about the work experience of participating CRAs. In 2014 as well as in 2016, respondents were monitoring mainly in Germany and more than half of the respondents had three or more years of experience as a CRA (71%, n=128, N=180 in 2014; 58%, n=134, N=230 in 2016).

	In both surveys, the vast majority of responding CRAs were familiar with the term RBM (74%, n=134, N=180 in 2014; 79%, n=181, N=229 in 2016) and about 40% of the respondents had already monitored studies using RBM (hereafter labeled as “RBM-experienced” CRAs). The percentage of RBM-experienced CRAs increased slightly from 36% in 2014 to 41% in 2016 (n=65, N=180 in 2014; n=94, N=231 in 2016). However, the 2016 survey revealed that 37% (n=34) of the RBM-experienced CRAs had monitored only 1 study with RBM so far, 55% (n=51) had monitored two - five studies, and only 9% (n=8) had monitored six or more studies using RBM (N=93; data not shown; question in the 2016 survey only).

	Among all respondents only the CRAs with RBM experience were asked to answer the RBM-specific survey questions concerning working efficiency and site contact as well as data quality and patient safety.

	There was no clear opinion whether RBM facilitates the work of a CRA, neither in 2014 nor in 2016, but overall only half of the CRAs experience the RBM model as a supportive tool. In 2014, 57% (n=35) of the RBM-experienced CRAs (N=61) stated that RBM facilitates their work, whereas in 2016 46% of CRAs (n=42, N=91) assessed RBM to ease a CRA’s activities. The following citations are representative replies from the 2016 survey that illustrate the CRAs' perception:

		“Despite RBM, complete patient source data have to be reviewed to have the overview and see the critical points (hidden SAEs etc.)”

		“If SAEs occurred all data have to be verified; it is even hard to understand a context if not all data are reviewed! It is more time consuming to check what is allowed to be verified rather than verifying all data of the subject!”

	Moreover, survey answers of both years indicate that cooperation with sites has become more difficult with the implementation of RBM. In 2014, more than half (55%, n=34) of the RBM-experienced CRAs (N=62) reported that RBM makes the communication and cooperation with sites “

 The 2016 survey confirmed this result, with 48% (n=39, N=82) stating that working with sites in RBM studies is “

. Only 13% of RBM-experienced CRAs (2014: n=8; 2016: n=11) say it is “

 with RBM and about one third think that RBM has “

 on communication and cooperation with the sites (32%, n=20 in 2014; 39%, n=32 in 2016).

	Figure 1 shows persisting skepticism regarding data quality in RBM studies-even slightly higher in the 2016 survey. In 2014, the majority (73%, n=43) of RBM-experienced CRAs (N=59) did not believe that RBM improves data quality. This number in fact increased in 2016, with 81% (n=66) of RBM-experienced CRAs (N=82) doubting that RBM improves data quality.

	Still, there is concern that (S)AEs and protocol deviations might be overlooked when applying RBM. In 2014, about 59% (n=37, N=63) of the RBM-experienced CRAs argued that (S)AEs might be overlooked with reduced source data verification (SDV) in comparison to traditional on-site SDV and this number was even higher in 2016 (64%, n=54, N=85).

	Furthermore, about 60% of respondents of both surveys are concerned that important protocol violations can easily be overlooked when applying RBM (61%, n=39, N=64 in 2014; 58%, n=48, N=83 in 2016).

	Figure 1: Data Quality and Patient Safety with RBM

	Figure 2 illustrates the skepticism of CRAs regarding the quality of site performance in RBM studies. In 2014, 61% of CRAs (n=105, N=173) assumed that only up to 20% of the sites would deliver good study data quality without any on-site monitoring and the 2016 survey revealed the same picture (62%, n=121, N=195). The following selected citations of individual survey responses are representative for the CRAs' opinion:

	• “The Investigators are motivated by the CRAs presence at the site […].”

	• “RBM needs very well trained site personnel which need less control by the monitor.”

	The results of the 2016 survey indicate that CRAs' experience and satisfaction with RBM have not changed much over the last two years. In 2016, there is still uncertainty and limited practical experience with RBM among the responding CRAs. The survey performed in 2016 reveals a persisting preference to traditional monitoring and skepticism about the ability to maintain high data quality with RBM. Regular contact to the sites including on-site visits is rated as very important, especially with regard to the motivation of site staff. For many respondents, quality of data is still linked to the extent of monitoring and SDV.

	The focus and the way clinical monitoring is performed as well as responsibilities of the CRA will change with new RBM technologies and regulatory requirements. However, CRAs will remain the most important “connector” between sites and sponsor. Therefore, the CRAs will play a key role in successful implementation of the new monitoring processes. RBM will only be a promising approach and gain more acceptance among CRAs if we do not impose the new procedures to the CRAs, but listen to them and include their input. Moreover, the challenges emerging from new RBM-specific tasks demand thorough training, both for CRAs and site staff. Despite the potential which centralized monitoring, analytical data or trend analyses offer for a risk-based quality approach, the human factor and the CRAs' perspective and experience remain invaluable.

	We would like to give special thanks to the participating CRAs and to the BVMA member CRO proinnovera GmbH, especially Nicole Baeumer, PhD, and Kathrin Weber, PhD, who contributed significantly to the creation of this manuscript.

	1. Litterscheid, S., et al. "RBM Experiences Among European CRA," 

	Risk-based monitoring, RBM, centralized monitoring, CRA, survey, acceptance, data quality, site performance

Christine Künzl, PhD, is Head of Medical Writing, CRO proinnovera GmbH Germany;

Yvonne Rollinger, PhD, is Managing Director, OmniComm Europe GmbH;

Michael Sigmund, DVM, is Chief Executive Officer, SSS International Clinical Research GmbH;

Veronika Kunert is Chief Operating Officer, CRO proinnovera GmbH Germany;

Burkhard Breuer, PhD, is Chief Executive Officer, CRO proinnovera GmbH Germany 

An RBM survey conducted in 2014 was repeated in 2016 in order to find out, how knowledge and practical experience with RBM have changed over that time period.

Michael Sigmund

Articles

Consequences of Brexit for Clinical Trials in Europe

RBM—An Update of Experiences Among European CRAs