General study site selection and principal investigator engagement
Clinical study site management plays a pivotal role in the successful execution of clinical trials. With rare diseases, traditional site identification and recruitment approaches may not work efficiently. This section aims to provide an overview of the key considerations and best practices for effectively managing study sites in the context of rare disease therapies. By understanding the complexities of rare diseases, their limited patient populations, and the need for tailored strategies, you can optimize trial outcomes, enhance patient engagement, and contribute to the advancement of therapeutic options for these underserved populations.
Selecting appropriate study sites and establishing effective engagement with Principal Investigators (PIs) are critical for successful gene therapy trial execution. [3]
Study site selection
An established Center of Excellence Network can simplify the site selection process. Centers of Excellence are specialized programs within healthcare institutions which supply exceptionally high concentrations of expertise, experience, and related resources centered on a particular therapeutic area or disease field. If a network has not yet been established, we advise you to consider the following: [1].
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Patient population density
Carefully evaluating population density allows you to identify study sites that are better suited to achieve the recruitment and research objectives for your gene therapy clinical trials. This will help maximize recruitment potential, enhance representative population, ensure timely enrollment, improve access to healthcare services, and increase operational efficiency. You can utilize real-world data (RWD) to identify the variability in patient populations by location to tailor your site selection [4]. Potential sources for RWD include:
Epidemiological Studies
Disease Registries
Electronic Health Records
Claims Databases
Public Health Reports
Census Data
Work with CROs
Geographical accessibility
Geography plays a crucial role in patient participation and retention in clinical trials. Study sites that are geographically accessible to the target patient population may reduce the burden on participants in terms of travel time and expenses. This convenience can improve recruitment rates and help maintain participant engagement throughout the study duration. Having study sites in areas where the target population lives or often travel to may foster community engagement as residents and patient advocacy groups (PAGs) may have a greater sense of connection to nearby sites. [4]
Travel barriers can impact participant recruitment and retention, particularly for those with limited mobility or financial resources. They can hinder study population, compromising the generalizability of your findings. By selecting central locations, you can minimize travel challenges and encourage broader enrollment. PAGs and patient and family insights will help you anticipate the geographic challenges and develop proactive solutions for patients to participate in the study. Addressing travel barriers can enhance feasibility of your study and improve your resource allocations in the study operations.
If site selection presents challenges, you can also consider decentralized trials. Please refer to the Clinical trial design, planning, and execution section for more information on this.
Site capabilities
By considering site capabilities for rare disease research during study site selection, you can leverage existing expertise, access specialized facilities, foster collaborations, enhance patient support services, and navigate regulatory and ethical considerations effectively [4]. These factors contribute to the successful execution of clinical trials, enabling high-quality data collection, improved patient care, and advancements in rare disease research and treatment options. You can conduct site outreach through rare disease networks to identify sites with capabilities in your targeted rare disease.
Special accommodations
Participating trial sites may require special considerations to ensure smooth trial operations. Historical trial data (if prior studies have been performed in the indication) is a valuable tool to assessing what special accommodations may be required for your selected sites. These can include the following:
Training and education (e.g., logistics, cultural awareness, and rare disease training)
Site-specific infrastructure (e.g., storage requirements, patient disability accommodations)
Investigational product management (e.g., therapy delivery technology/mechanisms, route of administration, specialized devices, and equipment)
Patient support services (e.g., cultural awareness, childcare for participants, and concierge services)
If the clinical study will involve long stays at a distant site, it may also be helpful for you to be aware of how this may affect an individual or their family, and therefore also affect patient participation and retention in the study. Developing a patient support program will be crucial in this case, to ease this burden on the patients and their caregivers [4].
Principal investigator engagement
Within the dynamic landscape of gene therapy clinical trials, effective PI engagement plays a pivotal role in ensuring the success and integrity of your trial. One method you can use to ensure this process is seamless is to utilize vendors/Contract Research Organizations (CRO) who can provide this full-service offering for you. When selecting and engaging with PIs, there are certain things you can do to ensure that your trial goes smoothly. Key considerations include the following:
Specialized Expertise
It is important to engage skilled and motivated PIs who possess the necessary expertise and understanding of the unique challenges associated with rare diseases. They should have a deep understanding of the disease and the proposed therapy. As a sponsor, you can also identify and engage key opinion leaders (KOLs) who are renowned experts in your specific rare disease and AAV gene therapies. Their endorsement and involvement can significantly enhance the credibility and visibility of your trial.
Collaborative Approach
As a sponsor, you need to foster a collaborative relationship with your PIs. Involve the PIs in trial design, protocol development, and decision-making processes. We also recommend that you invite their input as they have valuable subject matter expertise that will also enhance their engagement and commitment to the trial.
Training and Education
It is essential that you provide comprehensive training and education to PIs regarding the specific gene therapy being used, including its mechanism of action, potential risks and benefits, administration techniques, and patient management strategies. This will ensure that they are well-prepared to handle the unique aspects of your AAV gene therapy.
Regular Communication
Maintain open lines of communication with your PIs throughout the trial, providing frequent updates on trial progress, regulatory changes, and any new information relevant to the study. Encourage the PIs to share any concerns or challenges they encounter and try to address them promptly.
Investigator Meetings
Organize regular investigator meetings or conferences where PIs can come together to discuss their experiences, share best practices, and learn from each other. These meetings also provide an opportunity to address common issues, refine study procedures, and build a sense of community among investigators.
Resource Support
Ensure that PIs have access to necessary resources, including adequate funding, study coordinators, research staff, and specialized equipment. This support will enable them to effectively carry out their responsibilities and streamline the trial operations.
Regulatory Compliance
Ensure that your PIs are well-informed about regulatory requirements and that they adhere to Good Clinical Practice (GCP) guidelines. Help them navigate the regulatory landscape, including ethics committee submissions, informed consent processes, and reporting of adverse events.
International sites and filings
The patient pool for rare disease clinical trials is often small and widely dispersed. Likewise, clinical sites with this specialized experience are rare. As a result, it may be beneficial to consider ex-US sites to meet your recruitment targets [2].
Investigators are responsible for complying with the applicable laws and regulations of the country in which the study is being conducted, regardless of whether the study is being conducted under an IND. It is recommended that you obtain signed, written statements from investigators acknowledging their commitment to comply with regional, national, or local laws and requirements. In addition, if a foreign clinical study is being conducted under an IND, the investigator must sign Form FDA 1572 (investigator statement) and ensure that the study is conducted in accordance with the investigator statement and all other applicable regulations under 21 CFR part 312. An exception to this requirement would be if you have requested, and FDA has granted, a waiver of the signature requirement. If a waiver is granted, you, together with the investigator, must ensure that the study is conducted in accordance with the terms of the waiver [2].
Some important things to note about foreign sites include the following [2]:
If a clinical study is conducted at a foreign site under an IND, all FDA IND regulations, including the requirement to obtain a signed 1572, must be met unless the sponsor requests and is granted a waiver that provides for specific exceptions.
In the case where a foreign investigator cannot or will not sign Form FDA 1572 (e.g., because regional, national, or local laws or regulations prohibit its signing), the sponsor may submit a request for a waiver of the 1572 signature requirement; alternatively, the site may operate as a non-IND site, in which case the study would be conducted as a non-IND study.
If a clinical study is conducted outside of the United States and the study is not under an IND, then the investigator need not sign a 1572.
If the study data from a non-IND site is to be submitted to support a marketing application (e.g., a new drug application (NDA)), the study at the non-IND site must be conducted in compliance with federal regulations.
For more information, consider referring to the FDA guidance Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions (fda.gov).
You may be faced with a situation where you would have to recruit outside the US and bring the study subjects to sites within the US. This is known as cross-border enrollment, and it can help reach recruitment targets for rare disease clinical trials. For such a scenario, refer to the following articles/whitepapers for more information: