October 6, 2022 PAO-09-022-CL-07
The ultimate goal of clinical research is to develop new treatments that will benefit patients. To do that effectively, trials must reach more patients and be representative of demographic diversity. At present, the ability to participate in clinical studies depends largely on which country a person lives in, which skews the study populations away from true representation. DCTs provide a means for resolving this issue and provide equal opportunities to everyone within Europe, which will ensure that study populations are accurately reflective of the intended patient populations.
Access to life-saving drugs is a global need. Clinical research must be conducted in the Americas, Europe, and Asia–Pacific. Europe presents unique trial opportunities but also complex logistical factors to consider, as there are numerous countries within and outside the European Union (EU), all representing different national regulations, languages, costs, hospital operations, standards of care, and cultures.
Therefore, running successful trials in each European country requires a clinical research organization (CRO) with a true understanding of local demographics and costs. As an example of knowledge needed on a local level, Denmark is one of the smaller countries in Europe. While only a small number of clinical trials are held in Denmark, the number of trials per capita is high.
There have been fewer decentralized trials run in Europe than in the United States. This difference is a reflection, in part, of the fundamental difference between European countries’ universal healthcare systems and the privatized healthcare system of the United States, in addition to the complexity of the mosaic of national regulations across Europe. Additionally, European patients are largely treated at government-funded hospitals, while American patients mostly visit physicians located in private clinics, many of which are dedicated to clinical research and are linked into large networks that support clinical research of all types, including more traditional centralized and modern decentralized studies.
As a result, most technology companies driving the movement toward DCTs through the development of novel digital tools are based in the United States. Consequently, every U.S.-based company seeking to conduct DCTs in Europe must be fully prepared to support trial sites located on other continents. They must understand that deployment of these new solutions is typically easier in the country in which they were developed, owing to the large size of Europe, the need for extensive translation, and the need to develop products that meet the regulatory, data privacy, and data transfer standards of multiple EU countries. As such, sponsors conducting effective DCTs in Europe depend even more on service providers that understand the regulations, the available technologies and can make the optimal recommendations.
Overall, the existing European trial landscape, even for traditional clinical trials, does not make participation in clinical studies easy for patients or conducting those studies easy for drug developers. However, while clinical research in Europe in general would benefit greatly from initiatives to achieve greater harmonization, those challenges can be overcome with the right support from an organization that understands the nuances of regulations and attitudes across the continent.
Deployment of these new solutions is typically easier in the country in which they were developed, owing to the large size of Europe, the need for extensive translation, and the need to develop products that meet the regulatory, data privacy, and data transfer standards of multiple EU countries.
Many U.S.-based companies benefit from experienced support in navigating Europe’s regulatory requirements for DCTs, since Europe’s healthcare legislation differs from country to country. Even among EU member states, the European Medicines Agency (EMA) only provides guidance, and legislation is implemented at the national level. Each of the 27 member states has interpreted these guidelines individually, leading to disparate regulations. More specifically, Denmark and Sweden have national guidances that directly support DCTs, while many other countries do not.
In addition to the differing regulatory requirements among EU countries, the EMA does not provide a central dashboard on its website providing information about which countries allow DCT solutions, such as eConsent or direct-to-patient home healthcare. As a result, there is a lack of visibility and transparency with respect to DCTs, and pharma companies are left to learn the specifics of each country’s regulations on their own — but in this area where the EMA has not yet offered a unified resource, we see ample opportunity to provide a centralized point of access to help understand EU regulations.
As we gain knowledge and experience we continue to develop PPD’s RegView system, our detailed regulatory “heat map” and extensive database providing information relevant to DCTs. Since regulations are constantly evolving, we continually update and evolve this heat map and associated database in near real time to provide the most accurate information. Furthermore, in EU, the national ethics committees are free to change their interpretations from submission to submission. Therefore, in order to strategize and provide the right level of study detail for trials planned in a specific EU country, let alone multiple countries, pharma companies and CROs benefit from staying informed on regulatory updates through resources like RegView.
In Northern Europe, where technology has become a significant component of daily life and been implemented within hospitals, DCTs are more welcome and are already being adopted as part of the standard of care. In Eastern Europe, however, there is more hesitancy to implement some of the DCT elements, possible due to a lower level of trust in electronic monitoring and in-home nurse visits. Essentially, adoption of DCTs depends on the experience and familiarity with — and cultural acceptance of — the relevant technologies and home healthcare.
Obtaining consent for participation in traditional trials is well accepted and a part of the standard of care. Electronic consent (eConsent) is newer but is experiencing a reasonably high rate of uptake. The focus across Europe is on ensuring patient safety and bringing value to patients.
Although most countries in Europe, apart from Germany and the Netherlands, allow eConsent, there are instances where national ethics committees may hesitate to approve usage, despite it being allowed within the country. Generally, this occurs when, after looking at the entire trial design from the patient perspective, the committee does not determine that eConsent adds value. Additionally, access to the technology at the specific government-funded hospital involved in the study and culture can also play a role.
Understanding the nature of that hesitation and the cultural context can play a critical role in making a compelling case for approval, as can past experience overcoming similar hurdles. Additionally, it is essential to ensure that the value add is clearly communicated to all stakeholders and to confirm that the hospital has access to the relevant technology during site selection. Support from a CRO fluent in these discussions can make all the difference.
Government-funded hospitals in Europe are generally accustomed to working with primary nurses who continue to see patients at home after they are discharged for follow-up and home treatment. In a clinical research program, the principal investigator (PI) maintains responsibility and oversight for the patient’s research, treatment, and safety. However, the home healthcare professionals deployed to perform remote visits on behalf of the PI are not actually employees of the PI — the PI did not hire those nurses, and in some cases did not even have the opportunity to determine if those nurses were acceptable –– which complicates oversight issues.
As a result, there has been some concern from PIs in Europe around home healthcare. Part of the issue can stem from concerns related to liability insurance and how the PI maintains oversight, although the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice guidelines (ICH-GCP) enable the investigator to delegate trial-related duties, even those that are significant, to appropriately qualified individuals or parties under their supervision (i.e., home healthcare providers).
There can also be differences in the acceptance level for home healthcare between countries on the basis of the indication involved. For some therapeutic areas, there may be more confidence in using a home healthcare provider in some countries than in others. Additionally, in some countries, there are differences in what assessments a nurse can perform in a remote setting.
At PPD, part of Thermo Fisher Scientific, we have tackled the concerns around PI oversight by establishing a process that supports PI preferences. We work with home healthcare providers within this process and recommend that protocols clearly outline trial-related tasks that may also be performed at the trial participant’s home; flexible protocols are key to deploying DCT solutions.
Remote visits that are facilitated by a fit-for-purpose telehealth app are typically referred to as “televisits” in the clinical trial setting. As is the case with eConsent and home health visits, televists have historically been much less common in Europe than in the United States. Most EU countries have nothing stipulated in their national guidances or regulations regarding televisits. As a result, submitting trial designs that include televisits can be a trial-and-error exercise. Based on our past experience, it is our recommendation to work with a partner that has regulatory experience and understands the nuances of each region.
The use of telehealth technology has increased recently due to the COVID-19 pandemic, not just in clinical research but also by general practitioners and hospitals. It is therefore one of the digital aspects that will likely be easier to implement going forward, especially because there are no PI oversight concerns, as is the case with home healthcare.
Many countries allow some level of remote monitoring but also still require CRAs to maintain a certain level of physical contact with the site. Determining how best to leverage remote monitoring in international DCTs requires support from an organization with a full understanding of the landscape.
The use of remote monitoring and direct-to-patient delivery of medicines also varies from country to country. In some countries, it also may vary from hospital to hospital, as not all hospitals have electronic medical records (EMRs) or use a mix of paper and electronic records. That by itself makes it challenging to perform remote source data verification (SDV) and source data review (SDR). Some countries do not allow remote monitoring and oversight at all and require onsite visits by clinical research associates (CRAs). Many countries allow some level of remote monitoring but also still require CRAs to maintain a certain level of physical contact with the site. Determining how best to leverage remote monitoring in international DCTs requires support from an organization with a full understanding of the landscape.
While digital tools and decentralized trial elements ultimately streamline and simplify clinical research, incorporating these tools — especially for the first time — into already complex study designs can add to the complexity. Even though the various digital modules within the U.S./English digital platform are built first, their construction must take into consideration all of the locations of the trial sites. Once the U.S./English version has been finalized, the European versions can be created. Each of these versions, including each of the individual digital modules, must be translated and validated in the native languages of the European countries involved.
Because DCT technology is patient-facing, each language version of the study-specific software build must also be part of the clinical trial application process. All of the translated country packages must be included in the overall central submission package, and all patient-facing materials (e.g., DCT platforms, eConsent, televisit layout, home healthcare) must be reviewed and approved by each country’s ethics committee. It is therefore essential to factor the translation time into the trial design timeline. With the new centralized submission process in EU, the Clinical Trials Information System (CTIS) presents a single entry point for clinical trial sponsors to submit, which is beneficial but requires additional planning when adding DCT technology with patient-facing components, as the screenshots all need to be readily available and included in the submission package. To some extent, therefore, start-up timelines may need to be extended for European clinical trials.
Vendors of digital tools used in European DCT trial designs must also be registered in a new centralized system referred to as the Organization Management System (OMS) launched by EMA to support regulatory activities throughout EU. This registration does not occur at the study level but is required before their products can be used. Trials that include tools developed by vendors that have not yet registered must therefore allow time for this registration process, as well as the trial design review process.
To meet these requirements, it is important to take time during the protocol development stage to really understand which countries should be included in the study and determine whether there is ample time during the start-up phase to create all of the versions needed to meet the requirements of those countries. Even if the start-up time is increased, the enrollment time may be reduced by using digital tools, and the trial may benefit from both easier access to and more participation by more diverse patient groups and higher retention rates.
To meet these requirements, it is important to take time during the protocol development stage to really understand which countries should be included in the study and determine whether there is ample time during the start-up phase to create all of the versions needed to meet the requirements of those countries.
There is an expectation that the potentially longer start-up times will eventually be reduced as familiarity with new digital tools in the clinical research setting increases, and technology vendors’ multi-tenant DCT platforms will have more translated standards over time, ultimately reducing translation needs. With DCTs being a fairly recent phenomenon, there is much still to be learned about implementing multiple digital and decentralized solutions simultaneously. Currently, not all digital tools are embedded effectively and thus are not well-connected. Home healthcare data, for instance, often involves notes handwritten by home healthcare nurses that need to be transcribed by sites for data entry to electronic data capture, which creates an added burden for the site. As DCTs mature in Europe and globally, stakeholders across the industry are striving to improve interoperability and align these digital tools and data acquisition solutions, so challenges of this nature should be resolved soon.
In addition, there are different technologies, capabilities, and approaches in different systems, resulting in the use of multiple different technologies at the site level. That also creates extra work, which is only compounded if the site is involved in multiple DCTs. Within PPD, there is an additional focus on site burden during DCT strategy development, where dedicated DCT consultants not only map out the patient and data journeys but also assess what strategies are truly needed to elevate the patient trial experience and how these may involve different technologies and solutions and, where possible, to ensure that most are tied in through one DCT platform or through an application planning interface (API) to reduce the site burden.
As these issues are discovered and evaluated, solutions will be developed to address them. Greater integration of digital tools and better approaches to generating, collecting, and managing data will have a positive impact. On the front end, greater understanding and clarity regarding what data must be submitted will also help increase the efficiency of the trial design process.
Harmonization of DCT regulations across EU countries and between the EU and the United States would also go a long way toward simplifying DCTs in Europe. Pharma companies and CROs have all been advocating for harmonized guidances from the EMA that would result in similar regulations for each member state. The Accelerating Clinical Trials (ACT) initiative seeks to transform the EU clinical research environment in support of medical innovation and better patient outcomes.
The EMA is working with the U.S. Food and Drug Administration (FDA) on a harmonized approach to drug approval and other regulations. During the COVID-19 pandemic, the two agencies aligned on clinical trial guidances, including the addition of home healthcare, eConsent, and direct-to-patient services. PPD is hopeful that this alignment will remain and grow and that the EMA will continue to work to stay aligned with the FDA regarding DCTs.
While harmonized guidances remain the key challenge to implementing DCTs in Europe, PPD continues to work through various industry networks and organizations to provide input to the EMA and to encourage progress on this front.
To best support clients running European DCTs, PPD has established teams for each EU country that include country heads and feasibility, start-up groups, and clinical teams. The team members work closely with the local medicines agencies and ethics committees to stay abreast of ongoing developments that can impact trial design. They also have close interactions with representatives of client companies with offices or affiliates in their respective countries. Having ears, eyes, and boots on the ground ensures that we understand what is happening within each European country.
The information gathered by each country team is widely shared internally to provide optimal customer guidance. The clinical operations and project delivery teams have access to this intelligence, and our regulatory group stays up to date. In addition, the digital and decentralized solutions group is linked in with the regulatory group and therefore has access to all the relevant information needed to ensure that digital and decentralized strategies put forward meet the requirements of each country. This collaboration is also what enables us to create our regulatory heat map for DCTs for every country around the world.
The PPD RegView heat map and database for Europe is updated every other day with red, green, and amber indicating the level of regulatory acceptance of key digital and decentralized requirements per country. Using the heat map during strategy development, for instance, it is possible to know the limitations for eConsent and why they exist, as well as which countries do not have any limitations.
Information learned from our clients and vendors of digital decentralized solutions during the trial design process and throughout the submission process is also fed back into the same intelligence loop. All of that intelligence is combined at the study level to create sound, coherent, and flexible trial strategies that meet the individual requirements of the countries where the trials will take place.
While conducting DCTs in Europe involves meeting a range of differing requirements from individual countries, we would like to see more trials conducted in European countries. The complexity of DCTs can largely be attributed to the fact that the technology used to support these studies has more touchpoints with than a traditional study. The greater involvement of patients attracts greater interest and desire for control by the ethics committees in each country. Of course, the more digital and decentralized solutions that are included, the more patient-facing yet complex a trial becomes.
In the past, material targeted for patients primarily consisted of informed consent documents. A few trials required the provision of limited training materials to patients. There is much more patient-facing material needed for DCTs. The complexities associated with European DCTs, therefore, are not only due to the differences in regulations from country to country but derive from the need to interact with patients in their own languages and to take their local cultures into account.
While the complexity of conducting DCTs in Europe is greater than what many U.S.-based companies are accustomed to domestically, the benefits for the patient are measurable. In addition, drug developers gain access to more patients from more diverse backgrounds and are better able to develop products that will be effective for all patients. With the right knowledge, resources, and support, the still largely untapped potential of the younger European DCT landscape can offer vital new data and opportunities to bring new therapeutics to market.
Kamilla Posselt is a Senior Director in the Digital & Decentralized Solutions consultancy, innovation, and strategy group. Her role is focused on driving DCT initiatives as well as providing consultancy to help sponsors realize the potential of decentralized trials by developing strategies and trial designs focused on reducing patient burden and enhancing trial participation. Kamilla has more than 22+ years in experience working within clinical research mainly for Top 5 CROs and in early days for clinical research sites. She has been engaged in various roles within DCT, clinical operations, as well as in strategic partnerships and alliance management, leading the development of operational strategy and framework solutions between CRO and several Top 50 Pharma clients. She has a proven ability to lead, develop and achieve successful operational business delivery and growth. She is passionate about streamlining and simplifying clinical research and identifying bespoke strategies and solutions that will suit patients, sites, study teams and bring benefits to clients.