Table 2.

Recommendations for improving study procedures to increase retention, recruitment, and compliance for clinical trials

Finding	Impact	Recommendations
Information, communication, and education
1. Not all patients are fully informed about and appreciate study requirements at the time of enrollment.	Lower retention as a result of dropouts as true trial burden becomes apparent.	• Provide more time between provision of consent document and site-led consent process. • Use electronic study information/consent document, with definitions of words embedded and an audio functionality; a relatively simple tool such as this is likely to engage investigators and facilitate the consenting process. • Offer simplified paper informed consent form. • Provide guidance to sites on minimum understanding to be demonstrated by patients. • Provide options available before and during the study for patients to be fully informed according to their own learning styles.
2. Patients perceive a benefit from having up-to-date information about the latest science and treatment options for their disease.	Participation in a clinical trial is an opportunity to increase patient engagement by providing new data of interest to patients.	• Use study and site as a focal point for providing information with salience and relevance to patients about their disease. • Develop and/or provide materials to participating patients on the “state of the art” for SLE. • Provide access to materials designed to help patients feel empowered about managing their condition.
3. Patients are overwhelmed by the amount and complexity of information provided during screening and enrollment and display cognitive biases, including primacy, recency, self-relevance effects, and use of heuristic or rule-of-thumb strategies for decision making.	If patients do not consider how study participation will affect their lives, the reality of participation may lead them to feel dissatisfied, influencing, eg, PRO responses, or may lead patients to drop out.	• Reconfirm patient consent with different aspects of the study at intervals/milestones during the study to ensure ongoing comfort with the study. • Provide any patient materials, eg, study booklet/website, for as long a period as possible in advance of enrollment. • Provide simplified materials that are more accessible/easily digested. • Encourage involvement from family/friends where possible to allow the patients some leverage in dealing with a large amount of data.
4. Study booklet and website are valuable additions to the range of information on offer to the patients and are likely to be used by patients (not all). Some patients had issues with the font size and color and image sizes.	Study information well presented will allow patients to have a point of reference and a foundational understanding to support them throughout the study.	• Continue to refine the study booklet. • Consider reinstating notes pages in the study booklet, if it is possible to avoid an additional monitoring step. • Conduct readability assessments of the booklet with representative samples of patients. • Provide the booklet widely to patients who are considering enrollment/undergoing screening; consider lost booklets as a study advertising/awareness cost. • Provide the screening patients with static website access (booklet material), providing study booklet on randomization, if cost to provide booklets is an issue.
5. Patients want to know how their SLE experience compares with that of others and are interested in the study results, their own results, and the relative positioning of their response or disease progression relative to those of the study cohort.	Patients are engaged by information that helps them feel in control of their conditions, which includes tracking of performance.	• Proactively provide a comparative assessment of a patient’s conditions (investigators) (eg, compared with baseline, or with patients like them). • Provide educational material to patients on how lupus is assessed as part of the study (eg, explanations of SLEDAI, etc.). • Prior to the end of the study, estimate for both the sites and patients the time frame in which the patients can expect to be unblinded and receive the study results and their individual responses relative to those of the rest of the cohort. • Provide timely follow up with patients according to commitments made. • Provide materials in lay terms and with recommendations for disease management. • Establish a mechanism to inform study participants if the investigational product receives a marketing authorization or if development is discontinued.
6. Family and friends of patients are often nervous or not comfortable with patients taking part in a clinical trial.	Negative attitudes to clinical research limit recruitment and increase the probability of patient dropout.	• Seek to involve patients’ families where possible to ensure that concerns are allayed and that the positive aspects of trial participation are supported. • Develop materials that can be used by patients to educate friends and family on their disease status. • Encourage patients to be accompanied by family/friends for study visits and encourage site staff to engage positively with them. • Enlist the support of the patients’ social network as co-responsible for patients’ attendance (when possible). • Create an appropriate reward mechanism for supportive family/friends.
7. A taboo against discussion may exist in certain communities around a diagnosis of SLE, possibly because of a confusion of the term “autoimmune” with “immune deficiency.”	Unwillingness to communicate with family or others about their health status could limit patients’ willingness to be involved.	• Create awareness at sites that this possibility of a taboo exists and to be mindful of it. • Provide educational material to sites and patients. • Support discussions with family members (investigators or study coordinators).
8. Some patients are medically illiterate to the extent of not knowing what they are taking to manage their condition.	The meaning of access to standard of care may not be fully appreciated by patients.	• Investigators and coordinators should take care to explain to patients when participation in the study will give patients access to treatment options that may otherwise not be available to them.
9. A kidney biopsy is a painful and traumatic experience for some patients.	The requirement for the kidney biopsy could limit patient willingness to enroll.	• Educate investigators and site staff to clarify that the kidney biopsy is not a study procedure, but that it is a necessity of their diagnosis that they would have to undergo if entering the study or not.
Responsiveness to needs
1. Altruism is an important component of a decision to enroll in a clinical study.	Reinforcing a patient’s sense of doing something good and larger than oneself is likely to increase commitment and engagement with the study.	• Seek opportunities to recognize and speak authentically about the patients’ contribution to other sufferers and future generations.
2. The degree of disruption to patients’ lives due to study participation is very important to patients’ propensity to enroll and continue in the study.	The study may be difficult to recruit for if the visit duration and number of procedures per visit cannot be mitigated.	• Establish total time commitment of a study visit by sites, and communicate this as a commitment to patients and meet that expectation. • Consider if and how visits could be split without causing disruption to the data and to the study coordinator planning. • Provide guidance to sites on how to split a visit without triggering monitoring or data queries.
3. The degree of support of family and friends and fellow patients has an effect on the experience of clinical trial participation.	Enlisting allies in an endeavor to try to improve one’s health such as clinical trial participation is a powerful motivator.	• Encourage awareness and involvement of family members in patients’ participation. • Consider if and when responsibility can be given to family members to engage them in the patient’s well-being. • Provide material to the participant that will facilitate discussion with family members.
4. The completion of ePRO questionnaires is generally viewed as easy by the majority of patients; however, there are exceptions. Some patients find the exercise exhausting.	As the first item performed by patients at the study visit, ePRO potentially sets the tone for the study visit.	• Identify patients who are potentially uncomfortable with the questionnaire or the use of the ePRO device and provide them with the option of completing paper versions. • Consider allowing patients the option to complete paperwork at home, decoupled from study visits.
5. Some patients will have concerns associated with the need to undergo additional Pap smears.	For those patients with Pap smear concerns, this perception may limit their willingness to participate.	• Consider how to reduce the probability of required Pap smear by using the window of acceptability. • Ensure that Pap smears performed by patients’ usual obstetrician/gynecologist can be accepted. • Educate patients on the usual benefit of having this procedure, explaining that in a 16-month period they should probably have had a Pap smear in any case.
6. Providing the right type of support to study coordinators will give them the incentive to drive patients to a given study where a choice exists.	Study coordinators often have a choice of studies in which to place patients and will select the study in their own interest if there is no clear distinction for the patient. Equally, difficult or complex studies may under-recruit for the same reasons in the absence of competition.	• Conduct further research to identify the specific pain points of study coordinator and how these can specifically be mitigated. • Perform regular sampling of study coordinator experiences and feedback to the sponsor study team with a commitment to act on widely expressed concerns. • Promote and communicate any improvements made to the study to demonstrate that the study coordinators’ voices are being heard.
7. Visits are longer than optimal for patient population, and the ability to have flexibility around patients’ schedules is a minimum requirement.	Without the ability to reschedule, drop some visits, or avoid some assessments for reasonable cause, the patients will not feel in control and are likely to disengage initially emotionally and then physically by dropping out.	• See previous recommendations on split visits (finding 2 in “Responsiveness to needs” subsection). • Work with sites to establish an optimal visit flow structure to minimize patient time on site. • Proactively identify and communicate best practices for visit efficiency at sites. • Consider if key/specific sites will require additional resources and if these can be provided (eg, administrative support in advance of monitoring visits).
8. Monthly visits that require more than half a day to complete will effectively exclude patients who work.	A visit lasting more than half a day may require use of vacation time by patients. For others, it will result in loss of earnings.	• See previous recommendations for visit flexibility (finding 7 in “Responsiveness to needs” subsection). • Provide reimbursement for lost earnings to allow hourly wage workers to participate. • Early morning and late evening visits or visits that can be split over 2 days could be provided.
9. Child care is a concern for patients with children, particularly during summer months.	If options are not communicated upfront, patients with child care responsibilities may not enroll.	• Provide reimbursement for child care. • Provide temporary crèche facilities.
10. Transport to and from sites is a material concern for patients in lower socioeconomic groups.	Without a reliable form of transportation, certain patients will not be able to enroll and/or will have a high likelihood of missed visits or study dropout.	• Provide transportation or transportation reimbursement via the site. • Clearly communicate the availability of this option to patients.
11. Possibility that younger patients may be less inclined to manage their disease adequately.	If true, there may exist an untapped resource of poorly controlled patients who could benefit from trial participation. If this is not addressed, there is a possibility of an unrepresentative sample biased toward older patients.	• Recognize that younger patients may have different needs from an older cohort. • Develop patient materials targeted at a younger age group. • Use the “Lupus Ambassadors” concept to identify these younger patients for screening. • Create a subsection of any forum or community to address the younger cohort. • Encourage investigators to use the study as an educational tool for reaching the medically underserved in their community.
12. Lupus creates a sense of isolation in many patients who have a need for community. This is not necessarily a desire for a connection in real life, but may also be a requirement for virtual contact.	Creation of an online or real- life community for patients could provide a support structure for patients if and when the study becomes challenging.	• Encourage investigators to allow patients to engage with one another. • Allow proliferation of online communities if they arise spontaneously. • Create a study-specific online community for patients to interact with each other. • Leverage existing lupus communities online or in real life by directing patients toward them.
13. Community engagement is likely to be very important for the African-American population; peer and family approval seem to be more of a factor in decision making.	Opportunity to drive recruitment and retention by leveraging community effects.	• Identify existing lupus communities local to sites and engage with them. • Identify “SLE Ambassadors” active in the community who can help sites identify and overcome barriers to recruitment. • Use SLE community involvement to differentiate the study sponsor as a patient-focused partner in fighting SLE.
Access to care and coordination of care
1. Maintaining patient comfort during study visits is important to the patients’ experience of study participation.	Positive experiences during study visits are assumed to be linked to patients’ willingness to return to the clinic for follow up visits.	• Ensure that study coordinators are aware that discomfort during the study visit could affect retention. • Encourage specific actions to address patients’ individual difficulties, such as pain, fatigue, etc. • Consider and develop an action plan for how patients will be engaged for study visits that occur during a flare.
2. The completion of the Columbia Suicide Severity Rating Scale questionnaire is a negative experience for study participants.	Repeated questioning on suicidal ideation is likely to be uncomfortable for patients and could potentially create an unintended impression of risk.	• Explain to patients the reason for the assessment before administration. • Ensure that physicians administering the questionnaire have been trained in the use of the tool. • Consider if the tool needs to be used at every site visit. Consider if the tool can be used selectively, that is, not for patients with no relevant history.
3. Uninsured and underinsured patients are more comfortable with the probability of receiving placebo compared with insured patients.	This circumstance can result in preferential selection of patients of lower socioeconomic status and with associated lower health literacy and health status, with unknown effects on response rate.	• Ensure that the open-label extension option is clearly communicated at enrollment, when applicable. • Ensure that patients understand that they will receive standard of care whether they are given the placebo or not. Where applicable, indicate if this is a change to the individual patient’s regimen. • Highlight that participation in the study means that the patient’s SLE is more closely monitored than it would be otherwise without participation, and that the physician will always recommend the course of action in the best interest of the patients, regardless of study participation.
4. Large volumes of blood drawn are a concern to patients.	A large number of tubes to be filled is likely to overrepresent the perceived volume of blood to be taken, leading to patient discomfort.	• Use combined sample tubes for aliquoting offsite at analytical labs. • Use prelabeled tubes to allow the study coordinator to be more efficient. • Explain the total volume of blood drawn for a visit in terms that are familiar (eg, volume equivalent to two tablespoons, etc). • Avoid presenting the full lab kit to patients at the same time.
5. The administrative burden on site staff generated by “loose” lab kits that need to be created is excessive and likely to lead to errors. Prelabeled drug kits preassembled by visit are preferred.	Impact on study coordinator choice of study for which to recruit.	• See finding 4 in “Access to care and coordination” subsection.
6. Study coordinators request a direct line of communication with the decision maker for the sponsor to be able to quickly deal with “unique” patient situations as they arise.	Impact on study coordinator choice of study for which to recruit, and may avoid loss of potential recruits because of undue caution on part of study coordinator, as well as reduce dropout rate due to erroneous recruitment.	• Establish a list of decisions that can be made by the coordinator for repeated/common situations (when possible). • Maintain accessible, easily searchable decision log to support study coordinator’s decision making. • Use an international team to provide support during out-of-office hours, establishing a joint decision-making capability (when possible). • Ensure that areas where there is no need for discretion are made clear to the study coordinator. For areas where there is need for discretion, verify that there is no potential cost to the study coordinator for making a decision. • Establish a minimum turnaround time for response to study coordinator’s queries.
7. Any reduction in the administrative burden of site staff that can be applied has the potential to affect patient experience positively by creating additional capacity for the study coordinator to focus on the patient experience.	Potential positive impact on study coordinator’s choice of study for which to recruit. Such an improvement can result in better care from the study coordinator for patients in the study.	• Track study coordinator-identified pain points and address where possible. • Establish and maintain a study coordinator forum at which coordinators can share information. • Follow up on clinical research agency/monitoring issues if identified (clinical research agency quality was a high-sensitivity point for study coordinators).
8. The vital signs and blood draws section in the protocol (SLE and LN) is quite difficult to understand.	The complexity of this section can increase the potential for site error.	• Provide guidance with examples as to how this section can be interpreted. Reference minimum and expected numbers of vitals taken.
9. Some patients view study visits as an excuse to take time out from their lives.	This circumstance presents an opportunity to position trial participation as a resilience boosting, positive experience.	• Encourage patients to enjoy the break afforded by the study visit if they are so inclined. • Remind all patients of the visit duration in advance and provide, or encourage them to bring, books, magazines, music, or other diversions to use during the study visit. • Find out what the patients would be doing if not at the visit, and explore options to take care of that responsibility for them to enable study participation (eg, dry cleaning, dog walking).
10. The 24-hour urine sampling was not seen as practical by site staff, who expressed concerns for data quality linked to patient collection. Patients, however, did not express undue concerns.	24-hour urine collection represents a burden for site staff.	• Provide a robust mechanism for the collection and storage of 24-hour urine sampling from patients. • Consider if it can be collected directly from patients. • Provide suitable materials to minimize the burden on staff and the risk of unusable data (eg, carry bags, etc.).
Continuity and transition
1. Patients want feedback on the assessments they undergo in the course of the study and how they relate to their general health status and the progression (improvement or deterioration) of their SLE status.	Satisfying this informational need of patients will increase engagement; the possibility of greater insight into one’s health or condition could be a deciding factor in participation and retention.	• Investigators could provide a verbal or printed summary of the lab results to patients and the implications for their general health. • Investigators could schedule a “My Lupus” review with patients at intervals during the study. • Provide regular, eg, quarterly, readouts on study progress designed for participating patients.
2. Patients see the possibility of an open-label extension as a potential benefit.	This circumstance provides an opportunity to drive greater recruitment through a clearer message around the potential benefit to patients if they are responders.	• Ensure the open-label extension option is well understood prior to enrollment, as well as the implications. • Remind patients of the open-label extension option at intervals throughout the study to ensure the message is not lost.
3. The study coordinator may find the inclusion/exclusion criteria challenging when borderline scores would exclude a patient known to the investigator to be otherwise suitable for the study.	General observations about studies from staff feedback (examples provided included age, weight, and SLEDAI) suggest that the selection criteria may appear arbitrary to site staff, with a negative impact on attitude to the study if recruitment is difficult.	• Provide the summary rationale to study coordinators and investigators on the inclusion and exclusion criteria selected. • Seek out the opinion of study coordinators on potential recruitment challenges, and host a discussion about potential mitigation and options.
4. Simulation patients with experience of clinical trial participation and site staff are unhappy with the time it usually takes for them to be unblinded and to receive the study results.	A poor experience, or lack of follow up, is likely to devalue the patients’ participation in their mind and will reduce the likelihood of future cooperation, participation, or advocacy of the product or company.	• See finding 5 in “Information, communication, and education” subsection.

Abbreviations: ePRO, electronic patient-reported outcomes; LN, lupus nephritis; PRO, patient-reported outcomes; SLE, systemic lupus erythematosus; SLEDAI, SLE Disease Activity Index.