Designing Clinical Trials in Neonatology—International Trials


  • 1.

    Assessing therapeutic safety and efficacy of a drug/device or technology requires carefully designed trials that are sufficiently powered to detect differences in outcomes.

  • 2.

    International trials can help reduce the time required for the study and improve generalizability of the findings.

  • 3.

    Variations in regulations for clinical trials between jurisdictions can significantly prolong the time required to conduct the trial.

  • 4.

    Anticipating challenges by obtaining local expertise and buy-in from collaborators are keys to the success of international trials.


In the past decades, the development and the study of drugs, technology, and interventions has moved from national and regionally centered activities to a global collaborative effort. This shift has occurred in all areas of medicine, including neonatology. Assessing therapeutic safety and efficacy of a drug/device or technology requires carefully designed trials that are sufficiently powered to detect differences in outcomes. This can be a particular challenge when studying interventions for a rare genetic disease, when the disease prevalence is relatively low (such as neonatal hypoxic ischemic encephalopathy), or when outcomes are rare. To complete a trial in a timely matter and recruit sufficient patients in a shorter time frame, multicenter, international trials have increased in the past 2 decades.

Although international trials enhance external validity of the findings, there are several issues that need to be considered before embarking on such trials. These include variations in population demographics, racial and ethnic variation in propensity for complications, genetic differences between populations, and country-specific variations in health services organization. , Moreover, variations in care practice between countries can be a significant issue when it comes to evaluating therapeutic interventions, because differences in co-interventions could be extremely challenging. The desire to enhance the generalizability of a trial’s findings and the need for larger sample sizes recruited over short periods of time have led to an increase in international collaborations. An international trial is a clinical trial that is conducted in two or more countries and uses a common study protocol. International trials can be completed faster and more efficiently than even a multicenter trial in a single country. International trials can also contribute to our knowledge base from a global health perspective when certain types of trials are conducted in countries that would not otherwise have access to a specific intervention or health program. Whether an international trial involves low- or high-income countries, it requires careful consideration and planning. This chapter focuses on specific opportunities and challenges that arise when conducting research in more than one country and how to address them ( Fig. 99.1 ).

Fig. 99.1

Framework for the Design of International Clinical Trials in Neonatology .

Building a Shared Vision of the Purpose of the Study

Careful planning of the trial is the most crucial initial step. Establishing a common understanding with potential collaborators about the health impacts of the disease and how the intervention can potentially improve a process or outcome or the health of participants is an essential first step to obtain buy-in to move forward. During the planning phase, careful attention must be paid to having clearly predefined study objectives that address a primary scientific question, the selection of appropriate subjects, the ability of the study design to appropriately address the research question, and having measurable and clinically important outcomes.

Once the need for a trial has been established, designing the trial is the next opportunity to have co-investigators actively contribute and continue to build engagement. This inherently leads to changes in the various design elements of the study, but this should be viewed as a unique opportunity to consolidate buy-in and participation of site investigators. Multicenter trial planning can be complex due to organizational differences between units. Mapping out how an intervention will be implemented in each unit is critical to troubleshoot and anticipate hurdles. International trials have added complexity due to between-country variations in roles of healthcare professionals, standards of care, cultural practices, and regulations that may impact the implementation of the protocol. Having local experts in trial design in each country can provide anticipatory guidance.

During the study design, the selection of participating sites will usually depend on disease prevalence at the institute, local expertise, availability of research infrastructure including administrative staff and clinical staff, a track record of implementing similar trials, and the willingness of the center to participate. Practical aspects of such organization include a meeting of potential site investigators either face to face or via use of technologies (video/teleconferencing). During these meetings, the principal investigator(s) should explicitly list the time and resources required to participate to help potential sites assess their capacity to enroll.

How to Encourage Local Buy-in and Participation

Early involvement of all stakeholders in the study design and during each and every step of the preparation is the most important consideration. To achieve effective engagement, establishing effective communications is key. Successful communication strategies include regular tele/videoconferences, in-person meetings if possible, and regular electronic communications by e-mail or newsletters. , The essence of success will include incorporation of views from all stakeholders to the extent possible and feasible. Supporting and creating an environment for open dialogue will lead to development of a culture that values and encourages critical thinking about the quality of the trial. For the sites that are passive participants, actively seeking feedback would uncover some issues that would best be addressed in advance.

Regulatory and Ethical Considerations

It is relatively easy to conduct a single-center trial, from the perspectives of ethical and regulatory oversight. However, when a trial extends to either multiple centers within one jurisdiction or country or internationally within multiple jurisdictions and regulatory organizations, the complexity increases immensely. A majority of countries have their own agencies for oversight and regulations and guidelines for conducting clinical trials (e.g., the U.S. Food and Drug Administration, Health Canada, the European Medicines Agency, the UK Medicines and Healthcare Products Regulatory Agency, etc.). Regulations for the conduct of clinical trials refer to the rules and requirements for ethical and safe conduct of clinical trials.

To conduct clinical trials, investigators must obtain approval from an ethical board, also known as an institutional review board, research and ethics board, independent ethics committee, or ethical review board. Ethics boards are meant to apply ethical and regulatory frameworks that aim to minimize risks, have an optimal risk-benefit ratio, ensure informed consent is obtained, ensure that patients are recruited and compensated fairly, protect privacy, and ensure a methodologically rigorous approach. , Three basic ethical principles guide ethics boards: respect for participants, beneficence, and justice. The ethics board is usually composed of a multidisciplinary panel of scientific peers, researchers, experts in bioethics and law, and representatives of the lay community. Typically, in the United States, a trial’s coordinating center will obtain ethical board approval for the trial, and each participating center will need to obtain approval from their local ethical board before recruitment can start in their center. This process can vary based on the country.

Individual institutional ethics board review is based on the regulatory framework applied in the institution’s jurisdiction. Some countries have attempted to harmonize these regulations to minimize variations. For example, in Europe, trials have to adhere to the European Union Clinical Trials Directive and European Union Good Clinical Practice Directive. However, interpretation and applications of these directives can vary. Several different aspects of regulations need to be considered in international trials, such as the ethics board review process, regulations regarding the intervention, data sharing, data monitoring, contracts, and consent for participants.

Ethics Board Review Process

Despite similar frameworks and guiding ethical principles, each country, health region, and institution may have different ethics board requirements. This can mean having a single ethics board application for a single region or country or having to apply to the ethics board of each institution. For example, a single ethics board review is required for nationwide clinical trials in the United Kingdom, France, and Australia, whereas individual institution review is required in countries such as Canada and the United States.

There are currently efforts to streamline the approach in the United States with the proposed revisions to the Common Rule, which is the regulation that guides federally supported human research in the United States. Although the European Union Clinical Trials Regulation includes provisions for low-risk intervention trials and cluster randomized trials, the International Council for Harmonization of Good Clinical Practice guideline does not currently address these issues. , In Canada, attempts are underway to allow one ethics board to be the board of record; review from that ethics board will be acceptable to other ethics boards within the jurisdiction and would require only an administrative review. However, these are still local/regional initiatives, and national harmonization is lacking.

The variations in the ethics board review process can significantly affect the time required to obtain ethics board approval. For example, in a recent multicenter study in Canada involving 16 sites, the ethics board approval took a median time of 42 days (range, 4–443 days). The investigators reported that the main issues raised by the ethics boards were different interpretations of privacy rules and language of the consent.

Sufficient time must be allocated for the ethics board applications, considering the process will vary based on institutions despite being in the same country and operating under the same regulations. Variability in local requirements may include variations in assessment of the project itself, assessment of the level of risk of participation, privacy concerns, and the assessment of local resource availability to perform the research. , Strategies to mitigate delays include having collaborators with expertise in running clinical trials in each jurisdiction involved and consulting the ethics board at the time of trial design. It is often helpful to submit previous correspondence with the ethics board that has already granted approval along with a new ethics application for the same trial to another ethics board.

Regulations Affecting the Intervention Itself

Generally, an intervention being studied can be drug/device/technology. This may involve a new indication for an existing drug or a completely new molecule being tested. For a device or technology, it also could be a refined use for a different indication or a completely new technology. Based on the nature of the intervention being studied, regulations that apply will vary from one country to another.

When the intervention is a drug or device, a separate approval from each country’s drug or medical device regulating agency is required, even for investigational purposes. Investigators must ensure that the drug/device can be studied in the participating country. The regulations regarding certain products vary between countries; an intervention that may be allowed to be tested in human studies in one country may not be permitted by another country at all. Clarification and proper documentation are necessary initial steps before embarking on a trial. Instances of inability to test specific modes of ventilation on new or existing ventilators have arisen when a specific ventilator was not approved or used in certain countries.

Data Sharing and Data Transfer Agreements

Once investigators have obtained ethics board approval from individual sites, the next step will be to finalize data sharing agreements between the data-receiving site and the data-transferring site. These agreements/contracts need to be signed between the coordinating site and each participating site. In a majority of cases, these contracts are initiated by the host site, which will receive the data. Legal support services are involved on either side, and they ensure that privacy, confidentiality, and security of data are taken care of by the receiving sites. Each jurisdiction may have different interpretations and concerns for privacy and confidentiality. For example, some institutions will not allow sharing of the exact date/time of birth of patients, whereas others will allow it with specific security measures. This step could be time consuming, laborious, and frustrating for clinical investigators who would like to initiate the trial and start recruitment. Personal experience indicates that at times, this step alone could take a few months if the study involves multiple centers. We recently spent 20 months to finalize a data-sharing agreement between Canada, Australia, and France for a retrospective study. For example, dealing with different health data protection regimes across European states could lead to challenges in accessing and sharing health data within Europe. It is hoped that implementation of the General Data Protection and Regulation framework will help with alignment of regulatory requirements.

Investigators should preemptively think about primary and secondary use of data and the possibility that they may want access to data beyond the initial approval or contract period. It may be even more beneficial if the consent obtained from participants allows for secondary use of data if such approach is allowed by local ethics boards. The drafting of these agreements and what is included in consent is becoming increasingly more important because there is now a move toward public data sharing from studies/trials. Many journals are now asking for data repository statements and data access arrangements. These issues should be carefully considered prior to initiation of international studies.

Data and Safety Monitoring Board

During the trial design, investigators need to determine whether the trial will require a data and safety monitoring board. A data and safety monitoring board is a group of independent individuals, external to the trial, who are experts in relevant areas. They review the accumulated data from the trial on a regular basis and advise the sponsor about the continued safety of trial participants, the continued validity of the trial, and the continued scientific merit of the trial. The need for a data and safety monitoring board for a trial will vary based on the type of intervention, size of the trial, potential risks for participants, and outcome measures. Several funding agencies such as the National Institutes of Health have developed guidelines on how to run data and safety monitoring boards (available at ). ,

In the context of an international trial with a data and safety monitoring board, it is important to make sure the data upload is done in a timely fashion. Strategies to improve timeliness include using a web-based system to allow to real-time data entry, monitoring of data quality, and continuous reporting and tracking of the study progress. Another consideration for a data and safety monitoring board in international studies is the potential need to translate data and safety monitoring board reports and communications with each ethics board.

Differences in Healthcare Systems and Insurance Structures

One increasingly recognized aspect of participation in trials is the insurance coverage of participants. Individual patient insurance coverage can affect their inclusion in a trial. Consequently, a country’s healthcare insurance policy (universal vs. private) and the organization of its healthcare system (private vs. public hospitals) need to be considered prior to site enrollment.

Additionally, there are variations in insurance requirements and coverage for conducting research between countries. Clinical trials liability insurance that provides coverage for investigators in the event of harm caused to participants and subsequent compensation is often required. Increasingly, trials are asked to obtain insurance from private companies to ensure that if participants incur any unintended or previously unknown harm due to participation in trials, they are covered to receive appropriate medical care. A clinical trials liability insurance policy ensures that the investigators are adequately covered in case of harm incurred by patients. In general, clinical trials liability insurance is required for trials using medications/devices in humans and may be required for other clinical interventions. Additional loss or damage incurred by a drug/device developer may require a commercial general liability insurance policy.

Financial Contracts

Participating sites are often compensated for patient enrollment, trial participation, and data collection. Typically, the coordinating center oversees the contracts with each participating site. This can be complex and time-consuming and can only be initiated after ethics approvals are obtained. Furthermore, contracts may need to be translated to another language. Investigators at the coordinating center should meet as early as possible with their grant and contracts office to review the contracting process and estimated timeline. Potential issues between countries include translation of contracts, currency, and indirect cost recovery.

Payment mechanisms can vary between trials. Compensation may be awarded per patient, as a lump-sum pay-for-participation for each site, or as compensation for each step, such as the research and ethics board (REB) application, study initiation, etc. Payment per patient enrolled tends to encourage sites to recruit more patients compared with a lump-sum site payment for participation. Payments per patient enrolled rewards sites that recruit more patients by creating a financial incentive to recruit. However, payments per patient enrolled can be more complex to negotiate with the contracts office and requires tracking of patient enrollment, tracking of data transfer, and constant communication between the coordinating site and each site investigator. Strategies to simplify the process include having the coordinating site prepare the invoice template for each local site at predefined times in the year (annually or biannually). Additional considerations need to be given on the mode of payments (wire transfer vs. check) and the currency used. Paper checks can be costly to send and may not even be accepted in different countries. Financial arrangement is an important step for the smooth conduct of a trial to ensure that sites are compensated adequately, to build site enthusiasm, and to keep the overall budget in control.

Informed Consent

Informed consent is an essential component of recognizing patient autonomy and respect for a person’s right to make decisions about their participation in a clinical trial. Neonatal research is made complex because it requires proxy consent. Although requirements for consent can be cumbersome and create challenges when studies address interventions done emergently, information required is generally similar between jurisdictions and relates to the information required for families to make properly informed decisions (level of risk, description of the intervention, and other therapeutic options). Some study designs, such as those assessing interventions in the delivery room, may require waived consent or deferred consent. Criteria for waived and deferred consent may vary according to the institution. Regardless of the method used to obtain consent, researchers should strive to be transparent with patients and families by providing information on the ongoing study and should return a summary of the results to the community and to individual participants.

Patient Reimbursement and Compensation

Variations exist between countries as to how patients/legal representatives can be reimbursed for their participation in clinical research. For example, some countries have regulations that prohibit incentives for parents/legal guardians in pediatrics trials whereas others allow it. , Additional considerations should be given when compensation is offered to families in vulnerable settings or in developing countries. Investigators should be attentive to the sums of money and value of nonmonetary incentives used, which may seem coercive for patients living in a low-income setting.

Language and Translation of Documents

Although most investigators may speak a common language, some ethics boards and contracts offices may not accept documents such as the study protocol and contracts in English, depending on the country’s official communication language. Time and funding must be allocated to translating these documents when required. Obtaining information on local ethics board communication language and requirements during the study design from local site investigators can help plan for these tasks. Additional considerations need to be given to translation of patient information pamphlets and patient consent forms, because these may introduce recruitment bias. For example, although English may be an official language in a country, there may be cultural minorities that exclusively speak another language, which would exclude them from participating in the study and would lead to selection bias. Anticipating the need to translate patient forms with site investigators during the design of the consent forms will reduce unnecessary delays at the time of ethics board approval.

Strategies to Navigate Regulatory Issues

The overall regulatory process needs to be overseen and followed by the coordinating center. Some departments or agencies may approve the substitution of another country’s regulations governing protection of human subjects if they are at least equivalent to those of the other country. Several agencies already have arrangements to recognize their regulation process as comparable, such as the US Food and Drug Administration and Health Canada. Exemptions from such drug regulations typically involve research on clinical practice, educational practices, quality improvement trials, survey procedures, interviews, etc. Mapping out the application process at the time of trial design is an essential part of reducing the time required for the application process.

Contract research organizations are companies that provide support to investigators and/or sponsors in the form of research services outsourced on a contract basis. They offer comprehensive services for all aspects of the study, including applying to ethics boards, obtaining contracts, patient recruitment, and data collection. They range from large, international, full-service organizations to small, specialized groups. Local contract research organizations can facilitate navigating local regulations in a timely fashion but will add to the financial burden of the trial.

Guidelines for the Conduct of International Clinical Trials

There are three generic international guidelines for conducting clinical trials in human subjects.

  • 1.

    The World Health Organization (WHO) guidelines for good clinical practice for trials on pharmaceutical products

  • 2.

    The International Ethical Guidelines for Biomedical Research Involving Human Subjects, by the Council for International Organizations of Medical Sciences

  • 3.

    The International Council for (formerly Conference on) Harmonization of Good Clinical Practice Guidelines

The WHO guidelines concern all WHO member states but do not supersede local regulations. Each country may have adopted, modified, or developed their own specific guidelines. Consequently, during the trial design, it is relevant to identify which countries will participate and which guidelines will apply. As previously mentioned, even if a single guideline is followed within a country, interpretation may vary according to the institution. The Council of International Organizations of Medical Sciences is an international nongovernment organization with official relations with the WHO. Their guidelines focus on the ethical principles that guide medical research in low-resource countries and take into consideration the cultural and socioeconomic context and local laws. The International Council for Harmonization of Good Clinical Practice Guidelines is a joint collaborative with expertise from Europe, Japan, Canada, Australia, and the United States and partners from the pharmaceutical industry. Today, the International Council for Harmonization of Good Clinical Practice Guidelines has been implemented in most jurisdictions and is reasonably similar. The guidelines were originally intended for trials using pharmaceutical interventions but are now used beyond their original scope.

Each country has some specific regulations that may need to be addressed, but the main objective of the International Council for Harmonization of Good Clinical Practice Guidelines is to harmonize the application process and reduce delays. Table 99.1 provides a list of relevant websites for additional guidelines. A limitation of many of these guidelines is that they were not specifically developed for research in neonatology and may not include considerations for rare disease, deferred consent, or consent by a legal guardian.

Sep 9, 2023 | Posted by in PEDIATRICS | Comments Off on Designing Clinical Trials in Neonatology—International Trials

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