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Going Global? Points to Consider When Planning International Trials

Going Global?  Points to Consider When Planning International Trials

There are numerous reasons for conducting clinical trials outside the U.S. For example, if the disease studied is predominant or endemic in particular geographical regions; or the potential enrollment from the U.S. population is insufficient for the trial to be completed in a reasonable length of time. Regardless of the reason, trials conducted in non-U.S. countries, sometimes known in the Contract Research Organization (CRO) industry as Rest-of-World (ROW), must take into consideration several factors that may pose greater challenges than for trials limited to the U.S. This article offers practical advice based on TRI’s experience with global trials for managing country assessment and site selection, regulatory matters, safety reporting, clinical supplies, laboratory management, and most importantly, communication.

 

Feasibility Assessment and Site Selection


The first step in country selection and site identification is to conduct feasibility studies, which aim to collect disease prevalence, regulatory submission, reporting requirements, and other pertinent data. It is important to avoid including or eliminating a country without conducting due diligence. In addition, in-country resources should be engaged who are knowledgeable or capable of obtaining information on the patient population of interest, regulatory timelines, additional cost drivers, and any country-specific obstacles that may render it impractical to conduct the trial.

 

Nothing should be assumed in regards to facilities and equipment, especially if conducting studies in resource-limited regions or trial sites. Both country and site selection need to address these by carefully comparing the protocol requirements against site capabilities. Once a feasibility study confirms the decision to include a country, site assessment visits can provide additional details. However, there are additional barriers to understanding due to language and culture. The local site monitor must accurately transmit all required information to and from the site staff, asking detailed questions on processes and staffing, and visually verifying any needed equipment. Attendance by a Sponsor representative can enhance the attention and time provided to the Monitor during the assessment visit, especially in countries with formal class hierarchies. This is also true during study conduct (as discussed later under Communication).

 

Regulatory Strategy


The paths to regulatory approval for conducting a trial vary from country to country. In Europe (EU), a central application may be made to the European Medicines Agency (EMA) to conduct trials with a novel drug for which the Sponsor eventually will seek marketing authorization in the 28 EMA member states (note: status of the UK is currently uncertain). Submission to the EMA includes applying for a European Clinical Trials Database (EudraCT) registration number, comparable to the Food and Drug Administration (FDA) Investigational New Drug (IND) number. However, this does not replace the role of national regulatory bodies or ‘national competent authorities’ which also are involved in trial oversight.

 

In other regions, as well, each country has a path to clinical trial approval involving reviews by a national health authority and ethics committees (ECs). Clinical trial insurance must also be obtained, with the requirements differing by country. Submission to a national authority may occur before, after, or in parallel with EC submissions. Central ECs may be involved in addition to, or instead of, local committees. Regulatory approval can take 12-18 months (e.g., Brazil, China), and may require multiple/duplicate submissions as opposed to the EMA’s centralized procedure. Often, an in-country authorized representative must be contracted to prepare and submit the application dossier, and receive and reply to regulatory comments. Local agents with special expertise in navigating the regulatory maze should be qualified to prepare a complete and adequate submission package. Ideally, they anticipate any likely questions, and advise on any special protocol or informed consent language to be included. Such agents obtain document translations, receive and transmit authority or EC feedback, and assist with sponsor responses. However, their ability to accurately interpret the feedback and advise on responses can vary. The better ones are sufficiently experienced to recommend optimal strategies for achieving obstacle-free reviews and timely approvals. Ultimately, it is the Sponsor’s responsibility to remain engaged; and it is not unusual for additional resources to be called upon for assistance with regulatory communications and strategic advice.

 

Not all countries have the same trial concerns; the Sponsor can expect a variety of responses, depending on the particulars of the trial. For example, there may be questions on methods of obtaining informed consent or the age limits for eligibility. In recent years, there have been issues with collection of certain demographic data such as date of birth and race, and the Sponsor needs to adapt accordingly.

 

Something to consider if multiple translations (and back translations) are needed is the wordiness and length of the major study documents such as the protocol, informed consent, and investigators brochure. In these, there is a tendency to write overly complicated and lengthy sentences. This practice in verbosity is unnecessary and leads to unclear translations. It is important to consider there is a cost for every translated word.

 

A Regulatory Management Plan should include details of each country’s regulatory authority entity, address, and contacts; contents of the dossier; process for submission; review and approval timelines, and translation requirements. If the Sponsor selects all the countries for participation at the beginning of the trial, the one with the longest approval time should be the earliest for initiating a submission.

 

Safety Reporting


For IND trials in the U.S., adverse reactions that are serious, unexpected, and suspected to be related to study drug are reported to the FDA. In the EU, Suspected Unexpected Serious Adverse Reactions (SUSARs) are reported to the EudraVigilance (European Union Drug Regulating Authorities Pharmacovigilance) data processing network and management system. A Sponsor is required first to register in this system before safety reports may be submitted. In addition, the Sponsor appoints a Qualified Person (QP) Responsible for Pharmacovigilance, residing in the E.U. and usually medically qualified, who is responsible for ensuring that the company meets its legal obligations for safety monitoring. This role is especially critical if the drug obtains marketing authorization.

 

While the FDA has moved towards more streamlined reporting of serious adverse events (SAEs), other countries often have additional requirements. These may include reporting both AEs and SAEs; monthly SAE or SUSAR line listings in addition to individual (single event) safety reports; submitting both placebo- and active-treatment arm SUSARs, or only active-treatment arm SUSARs. This last requirement entails setting up a regulatory specialist “unblinded” to study treatment to handle such reporting, while keeping the remainder of the safety team “blinded.” A detailed Safety Reporting Plan should summarize the requirements and process by country, and ensure sufficient staff is assigned to comply with all country requirements.

 

Clinical Supplies and Laboratory Testing


Investigational drugs and devices are typically manufactured, packaged, and stored in a central location, then exported to the countries of use. Per EU directive since 2001, a QP must certify that each batch of manufactured drug meets relevant requirements for release and use in a clinical trial. The QP usually is a licensed pharmacist, biologist, or chemist with pharmaceutical manufacturing experience, and has been certified per the appropriate examinations.

 

Depending on the import requirements per country, it may be feasible to trigger resupply shipments just prior to site needs. However, if a lengthy inspection and entry process is anticipated, then either the sites must store extra supplies ahead of time or, for when supplying multiple sites within a country, it may be more efficient to set up an in-country depot. Country depots also handle the occasional atypical regulatory aspects of return and destruction. One such example, is a requirement to store all returned used drug packages (bottles, vials, etc.) throughout the trial until the study is entirely completed and closed, a situation which most sites do not have space to accommodate.

 

Drug expiry also requires special attention. In the U.S., investigational drugs are not required to be labeled with an expiration date, as long as stability studies support their ongoing use (and the data are reported to the IND). In most other countries, however, drug must be labeled with an actual expiration date. As stability reports are produced which support extension of expiry dating, the drug may be relabeled on site. Some sites or countries require the pharmacist to do this; others permit the Site Monitor to relabel. Either way, operational planning is needed to ensure study conduct and treatment of subjects are not interrupted by this activity, including anticipating any pharmacy fees associated with the extra service.

 

Non-drug/device supplies (e.g., recruitment materials, study binders, temperature monitors) are often more efficiently prepared or procured in-country. Some countries control their import nearly as strictly as investigational drugs and devices, so this may be the only means of provision. However, there should be a method to ensure consistency and quality of documents across all countries.

 

If a trial calls for central laboratory testing of research samples, it is important to determine whether a country allows export of samples and under what conditions. While most countries permit this, some (e.g. China) do not, and require an in-country laboratory to perform the testing. It may be easier to remove the country from the testing requirement, especially if the anticipated patient accrual is not a high proportion of the overall enrollment.

 

Communication


A large multinational trial may involve multiple CROs, with regional and in-country managers; clinical supply vendors; central services for laboratory, radiology, and randomization; central readers; regulatory or other consultants; as well as a Data and Safety Monitoring Committee and an Advisory Board. It is critical to ensure that everyone is working from the same road map. Prior to, or during the start-up period, task and regional managers should provide input on risk assessments for the Risk Management Plan, and timelines for the Project Plan. A robust formalized Communications Plan details staff roles and functions, expectations for scheduled meetings and teleconferences, types and frequencies of metrics reporting within the team and to the Sponsor, and escalation paths. It is especially important to clarify which party is or is not accountable for every aspect of the trial, as with multiple parties involved and potentially overlapping responsibilities, there is a strong possibility of tasks ‘falling between the cracks’ and being overlooked.Communication section: If the budget permits, periodic in-person meetings between the Project Director and geographically dispersed Task/Functional Managers, and with key study partners, are quite beneficial to establish and maintain good relations.

 

Investigator Meetings should be tailored to the regions participating in the trial. Though it may be ideal to gather all sites together in a single meeting, this may be impractical for some trials. Site staff may find it easier to obtain visas for travel to one country rather than another. Multiple languages usually are involved. Smaller regional meetings can be more effective than one massive gathering, by limiting translations to one or two languages, and customizing training for the staff in attendance. Regional meetings may also be necessary if countries enter the trial in a staggered manner due to differing regulatory approval timelines. Use of an expert meeting planner is strongly recommended, especially one experienced with visa issues. Meetings in Western Europe generally can be held in English, while those in Latin America and Asia likely require translation services. It is also very important to ensure consistency of the materials used for training.

 

As in any trial, the Site Monitor is the local ‘face’ of the Sponsor, but when great distances separate Sponsor and sites, investigators may feel less motivated and invested in the trial’s success. This is especially true if there is a long enrollment or follow-up period, and more so if enrollment is challenging. It cannot be emphasized enough the importance of occasional Sponsor visits to sites: to boost enrollment by motivating, clarifying eligibility criteria, and identifying obstacles; to ensure consistency in trial conduct by observing Monitoring visits; and to maintain relationships with the Principal Investigator (PIs). The willingness of a Sponsor to travel to sites is usually greatly appreciated, and helps build loyalty for the trial, the drug, and potential future programs.

 

Conclusion


Successful strategies for global trials are not very different from those applied to any trial, but with several key additions and enhancements needed, primarily in the areas of Planning and Communications. The well-prepared study team is more likely to succeed in handling the anticipated and unanticipated challenges that invariably occur. As in all trials, expect the unexpected in global trials, just more so.

 



About the Author

 

Ms. Neta R. Nelson, MPH, is an Associate Director of Clinical Operations and Project Management, with over 30 years’ experience in biomedical and clinical research. She has managed clinical trials in the U.S. and internationally for pharmaceutical companies and CROs. Please visit www.tech-res.com for more information about TRI's services.


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