Cross-Border Enrollment of Rare Disease Patients

Transcription

1 WHITE PAPER Cross-Border Enrollment of Rare Disease Patients Considerations for Planning & Conducting Global Rare Disease Clinical Trials Authors: AMY RAYMOND, PHD, PMP Clinical Scientist Scientific Affairs, Rare Diseases, PRA Health Sciences JOANNA SPRAGUE, BSC (HONS) Manager Global Regulatory Affairs, PRA Health Sciences VENKATA (SRAVAN) JAGGUMANTRI Clinical Scientist Scientific Affairs, Rare Diseases, PRA Health Sciences EXECUTIVE SUMMARY Clinical trials in rare diseases present unique challenges unseen in trials for more common conditions. Rare disease patient populations are inherently small, and prospective participants are widely dispersed. Likewise, the number of clinical research sites with such specialized experience is limited. These issues can be mitigated by enrolling patients who are not residents of the country in which the trial is being conducted. Cross-border enrollment can be key to enrolling and

2 retaining the required number of participants in a rare disease clinical trial. Thanks in part to Orphan Drug legislation approved in the US, Japan, Singapore, Australia, and the European Union, we have seen a recent increase in rare disease drug development activity. In addition to financial incentives supporting development of treatments for rare diseases, these previously intractable conditions are targeted by advancement in medicinal therapy such as gene therapy and somatic cell therapies. The aforementioned factors combine to create a regulatory maze that must be appropriately navigated. Understanding and complying with these regulatory considerations as part of patient logistics is critical to timely and successful study completion. INTRODUCTION In the US, a disease is defined as rare if it affects fewer than 200,000 people; in Europe, the criteria is fewer than 1 in There may be as many as 7000 rare diseases affecting 360 million people around the globe; only 5% of these have even 1 approved treatment. Many factors have combined to spur continued growth in the development of drugs to treat rare diseases, including government financial incentives, advocacy by patient populations, incremental progress in understanding individual rare diseases, and better technologies for precision therapeutics. Rare disease trials are inherently designed to include fewer patients, are often longer in duration, and more frequently terminated than trials in more common indications. 1 These challenges impact both sponsors and patients. A recent literature review revealed that recruitment and coordination of multinational patients and sites for rare disease clinical trials represents a major barrier to successful study completion. 2 Crossborder enrollment can provide a solution for some of these challenges. Cross-border enrollment is necessary when a patient enrolls in a clinical trial located at a site in a country other than their permanent residence. Rare disease studies are the most common application of cross-border enrollment. As the number of rare disease studies increases, the need for best practices for cross-border enrollment planning also grows. The majority of the centers that conduct clinical research in rare diseases are in the US and Europe, making these regions the primary focus of cross-border enrollment 1 Bell SA, Tudur Smith C. A comparison of clinical trials in rare versus non-rare diseases: an analysis of ClinicalTrials. gov. Orphanet J Rare Dis. 2014; 9: 170. doi: /s Rath A, Salamon V, Peixoto S, et al. A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome? Trials. 2017; 18(1): 556. doi: /s

3 planning. Crossing borders within Europe is complex but done frequently enough to be fairly commonplace. Transnational studies in Europe are supported by European Parliament Directive 2011/24/EU, which addresses patient rights in cross-border healthcare and notes a need for cooperation to address rare diseases. SITE SELECTION & PATIENT IDENTIFICATION In an ideal scenario, study sites are those at which patients are all pre-identified for study participation prior to the start of recruitment. This is not always possible with low-prevalence indications, even when including sites in several countries. Crossborder enrollment can expand access to eligible patients without requiring a site in each potential country. The recruitment process must ensure that, in addition to having research experience and sufficient patients, sites are willing and able to receive patients from other countries. Sites must have the staff, technology, and support infrastructure to manage the transfer of medical records and accommodate patients and families who are not fluent in the local language. In light of the scarcity of treatment options, rare disease patients are uniquely motivated to advance the standard of care. Many rare disease populations overcome low geographic density by building expansive virtual communities. It is very common for clinical trials to be discussed in these online forums. When a study is perceived as attractive and accessible, patients or caregivers may contact the sponsor or site directly. It is advisable that a study physician pre-qualify prospective patients before they embark on any study-related travel. This process must protect patient and data privacy at every step. Only minimal patient data, such as country of origin, language(s) spoken, and age (when relevant) should be collected. It is essential that all processes comply with the EU General Data Protection Regulation. ETHICS COMMITTEE REVIEW A global rare disease trial is most likely to achieve operational success if the team understands all applicable cross-border requirements, processes, and timelines and plans accordingly. It is challenging to backtrack and adjust these details when a study is already underway, and delays can easily jeopardize enrollment and timeline goals. Success depends on teams that are knowledgeable, flexible, and able to swiftly produce complete submission packages. WHITE PAPER - Cross-Border Enrollment of Rare Disease Patients 3

4 Just as not all sites embrace cross-border enrollment, some ethics committees object to the practice. Most, however, display compassion on ethical grounds and allow transnational patients to participate. Some regulatory authorities may also disallow transnational patient participation (for example, Argentina). Ethics committee review requirements and timelines vary widely. Some only require notification that patient materials have been translated (without issuing an acknowledgment of receipt), while others require review of all materials (at the next scheduled meeting) and allow the study to begin screening only upon formal approval. It is helpful for the sponsor to develop a template letter explaining exactly how patients will be recruited, the support they will receive, insurance details, and any planned poststudy support. TRANSNATIONAL LOGISTICS It is difficult and not necessarily advisable to prepare for all possible combinations of country of origin and country of research. It may be more prudent to identify the most promising cross-border routes based on experience, geography, and disease prevalence. Translating study materials based on the likelihood of transnational patient participation is a strategic decision that must be balanced against the cost and time to rapidly deploy translated study materials, if and when they are needed. Just as with any study, all patient-facing materials must be translated into the native language of the patient; this includes informed consent forms, patient appointment cards, patient diaries, questionnaires, and reimbursement guides. It is worth noting that translations must be approved for use in the country in which they are to be used. For example, a Russian translation of a Belgian informed consent form cannot be used for a Russian patient in any other country than Belgium. Some ECs have strict requirements regarding the certification of these translated documents and may wish to see the certificates of translation. While translations are a factor in all clinical trials, the timeline risks make planning a special consideration for cross-border studies. The sponsor must account for country-specific insurance requirements for every country under consideration, specifically whether patients will be covered under an existing policy, or if a second policy to cover travel is required. These complex calculations are time-consuming and should begin as soon as possible to limit timeline risk. WHITE PAPER - Cross-Border Enrollment of Rare Disease Patients 4

5 When a patient has been deemed viable for screening, a dedicated patient liaison will need to engage the patient and caregiver before travel is initiated. The patient liaison acts on behalf of the sponsor, provides information about the trial, and confirms the information provided by the pre-qualifying physician (including country of origin, languages spoken, and age). They also collect and report critical details necessary to making the decision to approve international travel, such as current condition, passport status, and fitness and willingness to travel and/or relocate. Personally identifiable data may not be recorded before patient consent is given; patients at this stage are referred to with codes (eg, Patient A). It is important to note that, in urgent cases, patients may travel before EC approval is obtained; assessing each country s definition of urgent is another risk management consideration. The patient liaison coordinates travel and accommodation for the patient, family, and caregiver. As part of this step, the patient liaison reviews any passport and visa requirements and ensures they are met. This includes ensuring that European patients have a European Health Insurance Card (EHIC) to cover any medical needs aside from the study visit, which is routine for anyone traveling within the coverage zone. The liaison accompanies the patient and family to the host country and remains for some or all of the relocation period. The liaison role includes ensuring that the patient is settled in the new location and can perform daily activities such as grocery shopping and using the local transportation network. The patient liaison also engages translators and makes other local arrangements for the study screening and treatment visits. If the study drug must be taken home during these inter-visit trips, the sponsor also must confirm in advance whether it can be shipped or transported, and define requirements and a process for ensuring proper delivery. Transnational Logistics in Pediatric Trials As roughly one-half of all rare disease patients are children, cross-border enrollment planning often includes consideration of the special factors that affect studies in pediatric patients. Transnational pediatrics studies involve considerations of a vulnerable population and recognition that the process involves the entire family. For example, are both parents able to travel and will the sponsor pay for both? How any siblings will be accommodated? Some patients may also wish to travel home between study visits. Depending on the duration of the temporary relocation, it is sometimes necessary for 1 parent to remain or return to the home country, or for parents to alternate traveling. While this return travel WHITE PAPER - Cross-Border Enrollment of Rare Disease Patients 5

6 increases cost and effort, it is an important consideration with respect to recruitment and increases families trust in the sponsor and engagement with the study. DOCUMENTATION OF CROSS-BORDER PROCESSES To proactively address the considerations discussed above, the sponsor should formulate a Cross-Border Recruitment Plan detailing processes and timelines. The plan should include eligibility checks to be performed before travel by any prospective patient. Eligibility checks include, for example, written documentation of sponsor and principal investigator approvals to advance a patient to travel approval. The plan should also outline instances that constitute exigent circumstances and define all mitigating factors. Formulating the Cross-Border Recruitment Plan during study start-up maximizes recruitment and enrollment and minimizes quality risks from making changes to an in-progress study. The Cross-Border Recruitment Plan should also address longer-term considerations, such as: Long-term strategy for patients (should they remain in the treatment country or return home between site visits), balanced against triggers for opening a site in a new country (eg, identifying previously unidentified patients in a particular country [assuming an expert center exists in that country], or the approval of a competing and exclusionary treatment in any of the countries in which the study is taking place) Use of mobile nursing or home healthcare for follow-up in patients country of residence as a valuable convenience for patients and a way to decrease study costs The plan for engaging the treating physician in the home country, including training on reporting serious adverse events, obtaining support, and sharing medical records A detailed procedure for medical treatment in the event of serious adverse events between visits A system to track and document patient status, translations, and the visit schedule (including anticipated and actual costs) Expectations for progress reporting from the patient liaison WHITE PAPER - Cross-Border Enrollment of Rare Disease Patients 6

7 CONCLUSION Global rare disease clinical trials require solutions to challenges not encountered in studies of non-rare indications. Masterful execution of international studies is the key to developing new treatments for the millions of rare disease patients with unmet medical needs. While we share a passionate drive to gather clinical evidence as quickly as possible, thoughtful consideration and thorough planning prior to site activation is the surest path to study success. Approximately 80% of rare diseases are genetic in origin. With an exponential rise in gene therapy drug development, much of which is focused on either oncology or rare diseases, we anticipate a proportional increase in the number of international trials. 3,4 By providing the means to deliver eligible and appropriate study participants into rare disease clinical trials, regardless of national boundaries, cross-border enrollment is a powerful tool for executing efficient and high-quality clinical studies and expediting development of rare disease treatments. ADDITIONAL RESOURCES Additional white papers on the specific challenges of rare disease clinical trials can be found on Multi-Stakeholder Collaborations Can Minimize Barriers & Drive Rare Disease Clinical Programs to Better Patient Outcomes Strategies for Accelerating Rare Disease Clinical Development The Patient Voice: Engaging Rare Disease Patients Improves Clinical Trial Enrollment & Retention 3 Hanna E, Rémuzat C, Auquier P, Toumi M. Gene therapies development: slow progress and promising prospect. J Mark Access Health Policy. 2016; 5(1): doi: / Gene & Cell Therapy It s Growing Potential to Disrupt Drug Research & Healthcare Delivery. Drug Development & Delivery Web site. Disrupt-1381.aspx. Published October 2, WHITE PAPER - Cross-Border Enrollment of Rare Disease Patients 7

8 CONTACT INFORMATION For further information or to discuss any aspect of PRA s services offered in the field of rare disease trials, please contact your PRA account director or the PRA employee below: Amy Raymond, PhD, PMP Clinical Scientist Scientific Affairs, Rare Diseases, PRA Health Sciences +1 (206) RaymondAmy@prahs.com World Headquarters 4130 ParkLake Avenue, Suite 400 Raleigh, North Carolina US Phone: +1 (919) Fax: +1 (919) PRAHEALTHSCIENCES APR2018 8

9 ABOUT PRAHEALTHSCIENCES PRA Health Sciences delivers innovative drug development solutions that improve patients lives. Our people are passionate about clinical research, working tirelessly to provide quality results for clients. We offer exceptional experience across all phases, therapeutic areas and a broad spectrum of solutions, ranging from full-service clinical development to our pioneering embedded model. With 15,000+ employees covering 85+ countries, we reinforce an impressive global presence with keen local insights. Our project teams apply their understanding of local regulations, standards of care and cultural customs to effectively align our approaches with each study s unique goals. At PRA, we love what do because we are making a difference in the lives of patients and their family members worldwide. Over the years, we have contributed to the development of 75+ drugs now available to countless patients. From our scientific and medical experts to therapeutically aligned project managers and monitors, we provide the commitment and expertise needed for today s complex studies. To learn more about PRA, please visit or us at prahealthsciences@prahs.com.

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