Interview: Beyond industry sponsors: supporting patients and centers through trial design
The company wants to 'bring unparalleled industry expertize' to provide the right solutions so those working with cell or gene therapies can advance their solutions and accelerate patient access so they can access the therapies that could change their ilves. OSP wanted to find out a little more about how their work elevates clinical trials.
OSP: Could you explain what elements of design help set up a clinical trial for success?
The clinical study protocol details study background, rationale, product information, required data collection and study processes to support answering the research questions. As the overarching site-facing document, the protocol must convey scientific endpoint requirements and processes in non-technical content so that centers can translate and operationalize. Best practices on how a protocol can be designed include the following:
- Consider establishing a scientific advisory board to consult on the aims and statistical design of the proposed study. Ideally, this committee convenes prior to formal protocol development to guide study design up-front for center acceptance and post-study for practice implementation.
- Include only critical eligibility criteria to both generate the largest pool of subjects to participate and to allow results to be as generalizable as possible.
- Design the subject visit schedule to align to standard-of-care. This approach reduces the burden on both the site to create specific clinical trial process and the subject who can avoid extra trips and assessments.
- Ensure the protocol does not collect extraneous data that requires effort to collect and analyze but is then not utilized. Taking this step reduces the study budget and labor burden.
- Invite a broad set of stakeholders to review the protocol to understand impacts from all angles. Beyond core protocol team members, valuable voices include those of the patient or advocates, center PIs, research coordinators and laboratory partners.
OSP: How exactly do you assess and mitigate risk when designing a clinical trial?
Risk mitigation is ideally centered within the protocol development process. Many sponsor organizations and CROs require completion of risk sections in the protocol and project management plan templates. Key study stakeholders must not only own operational area content, but they must also identify risks and propose mitigation solutions for holistic quality oversight. For example, the quality function assesses regulatory strategy to craft an audit schedule to prepare for potential inspections. In the same manner, each operational area should review the study design, assess risk and implement controls, e.g., medical/safety/statistics for appropriate stopping rules; project management for low enrollment, data management and safety for critical forms collections, operations for product availability, etc. Key to this step is ensuring knowledgeable personnel own risk mitigation. The sooner risk identification occurs, the sooner plans can be implemented for mitigation, ultimately leading to a trial run more safely and efficiently.
OSP: There are going to be some current barriers for sites to participate in clinical trials and how do you mitigate them?
Primary site barriers to participation on clinical trials include constraints associated with budget, personnel and available patient populations.
For myriad reasons, site budgets may be insufficient to cover research costs. Studies funded through grant mechanisms are often stretched thin, and invited sites may need to determine feasibility of subsidizing portions of their own efforts for the good of the research question. For industry funded studies, many sponsors undertake a fair market value assessment to understand true site costs associated with data collection; however, the budget may not encompass nuances or the breadth of a research activity at a specific institution. For example, a sponsor may estimate labor hours for a research coordinator to enter initial data into the study database but may not budget for effort associated with resolving queries or responding to adverse-event related questions. To mitigate the risk of a site declining participation due to budget reasons, sponsor organization should up-front attempt to fairly address the entire elements of study costs. Sponsors must also be receptive to negotiation when sites perform their own calculations and provide strong justification for increases in costs.
Additionally, resourcing and retention struggles within hospital clinical trial offices are well-documented as a barrier for site participation or delayed start-up. Sites may decline participation simply because they do not have the staff to accommodate the trial. When assessing sites for participation, sponsors should include a strong rationale document for the trial to help it pass through committee approvals. Next, sponsors should be cognizant of a study’s impact and try to reduce anticipated time and effort from site staff.
Lastly, centers may want to participate on a trial but either do not have the patient population to attract trial opportunities or are already committed to other trials that directly compete. While academic referral centers are highly desired for sponsor organizations, collaborating with smaller institutions offers benefits such as a diverse patient pool, committed research staff and opportunities to influence practice at the community level. Sponsors can also explore whether a smaller site could be a satellite site to a larger institution.
OSP: What about for patients, are there current barriers that they face in order to participate and if so, how are they negotiated?
While many patients theoretically understand benefits of clinical trial participation, they may decline involvement due to lack of transparency or lack of trust in the medical community. Patients also encounter financial, cultural and logistical barriers that prevent initial and ongoing participation.
The first formal trial contract for a patient is via the informed consent process. The Informed Consent Form (ICF) conveys trial background, risks/benefits and the patient’s expected experience. Because informed consent is a process, not a document, providers must deliver the content in a manner consumable to the individual patient. Beyond being written in language below 7th grade reading level in the patient’s primary language, consider other tactics such as adding visuals and videos. Patients also give feedback that reading the ICF is exhausting so consider structuring the document with a high-level summary at the beginning with key information. Providers must shoulder the responsibility to ensure the patient is comfortable by arming themselves with data to answer key questions (perhaps via a checklist to confirm patient comprehension).
Other barriers patients experience include financial, logistical and lack of support. These barriers can be mitigated by compensating patients for travel expenses beyond standard-of-care and for time spent answering patient-reported outcomes questionnaires. Organizing transport may also incentive a patient to participate. Centers (perhaps via sponsor reimbursement) can consider including patient advocates to offer a personalized support structure. Lastly, researchers should close the loop on the trial by ensuring patients receive the results of the research study so they can understand how they have impacted the scientific question.
OSP: What sponsor-led processes do you think sites find most helpful when implementing new clinical trials?
Clinical research sites are busy, and the key to implementing a new clinical trial quickly is to make the site’s job easier. Sponsors can do this by offering solutions that streamline sites’ activities without overly disrupting standard site processes. Therefore, the sponsor should provide options sites can adapt to fit their needs. For example, a sponsor may decide to provide sites with an electronic investigator site file (eISF) platform for regulatory documents. While this is a great option for sites that do not have an existing eISF option, if a site already utilizes a different eISF platform, it would be inefficient to adopt the sponsor’s full platform. In this scenario, the sponsor should provide two options: a full eISF option for those sites that do not have an existing solution and partial access option to download study documents and templates for those sites with an existing solution. These options ensure all sites have access to study documents but do not disrupt processes that are already working.
Another example of a sponsor-led process that requires options is protocol training. Ideally, all site personnel would be present at the site initiation visit and be fully engaged during protocol training. In reality, site staff are pulled away for other obligations, and training may need to be conducted at different times. The sponsor can provide training options including eLearning, recordings with assessments or other high-quality training methods for site personnel that are unable to attend in-person training. This allows site staff to train at times convenient for them and better allows them to retain information.
OSP: How can the voice of the patient be incorporated into clinical trials?
The voice of the patient is essential in clinical trial design to ensure the patient perspective is considered during the development of new treatments. Patient engagement should be an ongoing process throughout the entire clinical trial journey. One way Sponsors can incorporate this perspective is to establish patient and caregiver advisory boards. These boards provide valuable insights that allow sponsors to understand the patient experience and make more patient-centered decisions. Through the advisory board, patients and caregivers can actively engage in the planning, design and conduct of clinical trials. The boards can also review patient recruitment materials and trial processes to ensure they are patient friendly.
Another way to ensure the patient voice is represented is to incorporate patient-reported outcome measures in the clinical trial design. Traditional clinical trial outcomes often focus on biomedical markers or disease-specific endpoints. Patient Reported Outcomes (PROs) are data about a patient’s health condition collected directly from the patient. Studies recognize the value or measuring PROs, as they are the most accurate measure of the patient’s experience with disease and treatment and can actually be predictors of disease activity.
By incorporating patient-reported outcomes, sponsors can assess the impact of new treatments on patients’ quality of life, symptoms and other factors important to them.
OSP: How do you think clinical trial participation can be made easier for patients?
Recruiting and retaining a diverse range of participants is one of the biggest factors in a clinical trial’s success and currently one of the biggest challenges in the clinical trial industry. Making participating in clinical trials easier for patients is crucial to support recruitment and retention activities. Some patient-centered strategies include the following:
- Clear and Accessible Informed Consent Process: The informed consent process should be patient-friendly and clearly explain the trial purpose, procedures, potential risks and benefits, and alternatives in language understandable to all patients regardless of background. The consent forms could include diagrams and images to assist patient understanding. Electronic consent forms and online enrollment platforms can are also great tools for a clear and accessible consent process. Electronic consent can be more convenient for patients to provide their consent, include videos to explain the study or research in general, and can be used to assess patient understanding.
- Patient-Centric Trial Design: Trials should be designed with patient convenience in mind. During protocol development, Sponsors should collaborate with clinical staff at sites to understand standard of care procedures and design the protocol-required assessments to align with the standard of care. This ensures patients do not need to do extra visits or assessments. Protocols should also allow flexibility to accommodate differences in standard of care procedures across multiple sites. Additionally, Protocols should minimize the number and duration of study visits and consider remote monitoring or telemedicine options when appropriate.
- Patient Support and Education: Sponsors and sites can collaborate to provide support and education to patients throughout the trial by offering educational materials and resources to help patients understand the trial processes and their role in research.
- Trial Result Dissemination: After clinical trial results are available, Sponsors should develop summaries explaining study results in lay terms and provide these summaries to participants. Taking the time to share trial results makes patients feel appreciated and that their trial participation contributed to greater scientific knowledge.
OSP: What is the best way to support a research center throughout the conduct of a study?
The best way to support a research center (site) is to treat them as a trusted partner and provide excellent customer service. To accomplish this, study teams should create real connections, develop a communication strategy and constantly search for ways to reduce site effort.
Sponsor or CRO personnel should focus on creating real connections with site staff. This can be accomplished by approaching site staff with empathy and assuming positive intent. If a site pushes back against a sponsor requirement, the site management team should approach the resistance with curiosity rather than frustration. Additionally, study monitors should be knowledgeable about the therapeutic area. Site clinical staff are more likely to trust the monitor and cooperate with requests if monitors speak the same language as clinical staff and don’t ask unnecessary questions.
Sponsors should also have a high-quality, realistic communication strategy. The Sponsor and site should work together to establish communication expectations up-front and commit to honest and clear communication throughout the study. Sponsors should make an effort to understand the site timelines and give the site space between deadlines. Too-frequent communications can be frustrating and make the site less willing to respond to requests.
Finally, Sponsors should find ways to reduce site effort. During protocol design, Sponsors should collaborate with sites to develop a well-designed study protocol that aligns with the site’s standard processes and is feasible for sites to operationalize. As stated in question 5, sponsors can also offer options to streamline processes without hindering established site processes that work well.
OSP: How do you make sure the right data are being collected on a trial?
Collecting the right data for a trial is integral to ensuring the study objectives are met and the results of the trial are meaningful. To do this, study teams should employ strategies during protocol and CRF development. First, study teams can review prior trials, manuscripts and clinicaltrial.gov summaries to understand what data collected were important for primary and secondary analyses. This can assist the study team with designing CRFs with meaningful data collection techniques that exclude extraneous data. Study teams should also design the trial protocol and CRFs with the end-goal in mind. Prior to finalizing the protocol and study case report forms (CRFs), study teams consider the publication and regulatory strategy and tailor the data to those strategies. While designing the study case report forms (CRFs), the study team should map the trial’s primary and secondary endpoints to data fields on the CRFs to ensure all required data are captured.
Additionally, if the protocol includes multiple data sources such as an Electronic Data Capture (EDC), PRO measures, or outcomes registry data, the study team should define which source will inform which endpoint. If the multiple sources include duplicate data, identify a source of truth hierarchy. For example, if the CRFs and PROs both capture race and ethnicity, a study team may decide race and ethnicity is more reliable from the PRO data since it is patient reported. In this case, the PRO data would be the source of truth unless the data were missing. Finally, when testing the study database during the build process, data management should engage clinical teams to write realistic clinical scenarios to test the CRFs and ensure that the CRFs are designed to capture data correctly.
OSP: How do you design a clinical trial to be accessible and attractive to a diverse set of patients?
The FDA has recently issued draft guidance acknowledging the need for clinical study enrollment to reflect the diversity of the country’s population. To accomplish this goal, a variety of recruitment strategies should be considered and documented, when applicable in a Race and Ethnicity Diversity Plan. Beyond ensuring eligibility criteria are not specifically restrictive to certain patient populations, how patients are approached should be considered. Consider methods that identify people that are not yet patients. Social media can be a viable method, keeping in mind the demographics of the patient population you are seeking and targeting specific social media platforms that have a greater likelihood of reaching specific age groups for example. Perhaps the recruitment material can be posted in a language in addition to English. The study contact information telephone number and/or study inbox could be staffed with a bilingual research staff person.
Besides centrally recruiting patients to trials, a critical step for study teams is to select centers with known ethnically diverse patient populations. This question of known population must be asked on site selection questionnaires or mined from publicly available datasets. Following selection, site enrollment should be tracked against initial projections so study teams can assess if there is a particular aspect of the trial that is causing patients to decline participation.
Once patients are identified in acknowledgment of the need to foster trust between providers and ethnically diverse patients, providers should explain during the consenting process why trial diversity is important and provide data on prior treatments or studies delineated by participant diversity. The patients will then have information to understand how a treatment may affect them personally. Ethnically diverse patients have also given positive feedback for being consented to a trial by a physician of their own ethnicity.
Lastly, consider whether a full or partial decentralized clinical trial model can be utilized as this could attract patients that have little flexibility for multi-hour clinic visits. In a decentralized model, some or all of the trial-related activities occur at locations other than traditional clinical trial sites. Be flexible for when and how study assessments can be completed by allowing wide study visit windows. Have research site and staff available for visits and/or assessments before or after business hours or on weekends. Allow surveys to be mailed or completed on a smartphone. Consider the type of assessments that are being proposed in the study. The more invasive the test or the more preparation it takes (e.g., fasting), the less attractive the study is to any potential subjects.
