Ethics approval
The study described here was approved by the University of Alabama at Birmingham (UAB) Institutional Review Board (IRB-300005305), with UAB serving as the single IRB (sIRB) of record. In accordance with the SMART (Streamlined, Multisite, Accelerated Resources for Trials) IRB reliance model, participating sites ceded review to the UAB IRB as the Reviewing IRB under the Master Common Reciprocal IRB Authorization Agreement.
Study design, setting, and population
A hybrid type 1 effectiveness-implementation design will be used to test the effectiveness of the HPV PROTECT healthcare provider-directed intervention in improving HPV vaccine uptake in childhood cancer survivors, and to evaluate implementation outcomes (Fig. 2). This study will be conducted at six participating sites (The University of Alabama at Birmingham/Children’s of Alabama, Emory University/Children’s Healthcare of Atlanta, Baylor College of Medicine/Texas Children’s Hospital, Oregon Health & Science University/Doernbecher Children’s Hospital, Atrium Health Wake Forest Baptist, and the University of Minnesota/M Health Fairview Masonic Children’s Hospital). Each of these sites have active pediatric oncology outpatient clinics that provide ongoing care for young cancer survivors 9–17 years of age and at least 1 year off-therapy, and each clinic has existing access to their state vaccine registry via their electronic medical record (EMR) system. Sites were chosen to be representative of pediatric oncology practices of varying characteristics including varied geographic location, size, and patient populations, and were especially enriched for sites serving populations in areas of lowest HPV vaccine uptake (i.e., U.S. southern states) [49, 50]. None of these sites have a standardized (quality improvement) program in place to address HPV vaccine initiation in cancer survivors. Each site has an identified Intervention Champion, who will be responsible for all aspects of the study at their site, including overseeing data collection, engaging and training providers in the targeted pediatric oncology clinics, identifying context-specific resources, assuring availability and context-appropriateness of intervention resources, providing ongoing group peer feedback/coaching sessions to providers, overseeing interface with clinic support staff in carrying out all aspects of the intervention, and assuring intervention fidelity. Each participating site has agreed to operationalize HPV PROTECT as a quality improvement (QI) initiative; therefore, all providers caring for cancer survivors will be expected to complete the training sessions, and will be given access to all intervention components at the time of intervention implementation. Healthcare providers at the participating sites will be invited, but not required, to participate in the research aspects of the project.
HPV PROTECT intervention components
Provider communication training
This training session, presented to clinicians at each site by the Intervention Champion, is based on the Announcement Approach Training framework [17, 20, 32]. Content of the program is tailored to the pediatric oncology provider caring for young cancer survivors, and includes survivor-specific information, such as timing of vaccination post-therapy, and number of doses needed to complete the vaccine series [7]. Thus, this training is designed to increase provider knowledge of survivor-specific HPV vaccine issues and to enhance provider skills in recommending HPV vaccine to young cancer survivors and their parents.
Assessment and peer feedback/coaching
This training session, presented to clinicians at each site by the Intervention Champion, includes review of specific evidence related to risk of HPV-related cancers in childhood cancer survivors, the low vaccine uptake among survivors, and the specific HPV vaccination rates among 9–17-year-old cancer survivors at the site (using Vaccine Report Card data). The Intervention Champion will also describe the HPV PROTECT intervention components and resources, identify the site’s goal for improving HPV vaccine initiation rates for survivors, and highlight the techniques and tools that will be employed toward meeting the goal [20,21,22, 31].
Provider toolkit
This toolkit will be introduced by the Intervention Champion and made available to clinicians at each site during the Intervention Year. The Provider Toolkit includes practice-focused resources designed to facilitate HPV vaccine uptake in the pediatric oncology setting [22, 26], as follows: i) Vaccine Action Plan for providers to complete with parents, tailored to local context. For example, the Vaccine Action Plan will include details regarding where the survivor can initiate and/or complete the vaccine series, if not feasible in the pediatric oncology setting (e.g., PCP office, health department, pharmacy) based on local context and site-specific practices; ii) Provider Recommendation Note Cards, which summarize key messages for recommending the HPV vaccine to survivors, as presented in the communication training session; iii) Survivor Vaccine Fact Sheets, which highlight pediatric oncology-specific information regarding the HPV vaccine for survivors; iv) Standardized templates for oncologist-PCP communication, regarding the vaccination plan; v) Standardized templates for oncologist-parent communication regarding the agreed-upon plan for vaccination, for inclusion in clinic discharge paperwork; vi) EMR Documentation Template, for documenting discussion of the HPV vaccine recommendation and plan for vaccine receipt in the EMR; and vii) HPV PROTECT Intervention Website, which provides access to intervention resources and video-recordings of training sessions for providers at participating sites. All HPV PROTECT components are designed to be accessible via this web-based platform. All participating study sites will have access to the HPV PROTECT website, with controlled release concurrent with the intervention year.
Adaptation of the intervention to local context
Intervention Champions will be given the opportunity to adapt components of the Provider Toolkit (e.g., Vaccine Action Plan; Recommendation Videos), in order to add salient information that may be necessary for survivors to procure the vaccine locally, as well as to adapt training videos to feature local influential providers.
Intervention fidelity
To assure intervention fidelity, all components of the intervention will be standardized and manualized prior to delivery. The site Intervention Champions will undergo intensive intervention-specific training (including a 2-day intensive training group program followed by individual meetings) led by the study PIs and co-investigators with intervention-related expertise, beginning two to three months prior to intervention implementation at their sites. This train-the-trainer approach includes review of all aspects of the intervention, use of the intervention manual, training in skill sets relevant to leading the intervention and supporting providers at their sites, and assistance in adapting intervention materials to local context. The site Intervention Champions will be responsible for monitoring all aspects of fidelity at their sites and for completion of a fidelity checklist. Toolkit resources will be tailored to site-specific local context as specified in the intervention manual; however, all training sessions for healthcare providers, including those adapted for local context, will remain scripted, regardless of the individual delivering the messaging. Thus, training sessions delivered by the site Intervention Champions, will incorporate standardized scripts and presentation materials, and will be observed by the study Principal Investigators (PIs) for fidelity. Intervention Champions will monitor provider participation in intervention training sessions and ongoing use of intervention components (including Toolkit resources) at their sites, and will track participation in peer feedback meetings. Site Intervention Champions and study PIs will meet at least quarterly to address any issues or challenges that may arise.
Participants
Healthcare providers
Healthcare providers are the main target for this implementation trial, and the provider-directed intervention occurs at the clinic level; thus, the research component of the trial focuses on the providers. Eligible providers will be invited to participate in the research study in order to assess their knowledge and current practices related to the HPV vaccine in young cancer survivors, and to understand provider perspectives regarding the feasibility, acceptability and appropriateness of the HPV PROTECT intervention components, and provider adherence (fidelity) to each of the intervention components.
Childhood cancer survivors
The population of interest for measurement of HPV vaccine initiation and completion rates is defined as: Childhood cancer survivors, who are 9 to 17 years of age and at least 1-year following completion of cancer therapy, and are returning to one of the targeted pediatric oncology clinics for follow-up care.
Recruitment
Healthcare providers
Potential participants for this study will be identified using rosters of eligible healthcare providers, and their associated email addresses, at participating sites (compiled by the site Intervention Champions). Each site Intervention Champion will send all eligible healthcare providers at their site an email introducing the study coordinating center and describing study procedures, including risks and benefits of participation. The study coordinating center will then send each eligible healthcare provider an invitation to participate in the study.
Childhood cancer survivors
Childhood cancer survivor vaccine initiation and completion rates will be measured as part of each site’s QI initiative to increase HPV vaccination rates. No patient/parent recruitment will be conducted by the sites, since patients/parents will be only indirectly involved in the research through the calculation of clinic-level vaccination rates, and a full Health Information Portability and Accountability (HIPAA) waiver is in place. All patient-level data collected for this study will be completely de-identified (removal of the 18 protected health information [PHI] identifiers), prior to submission to the study coordinating center.
Inclusion and exclusion criteria
Healthcare providers
Inclusion: Healthcare providers (physicians, advanced practice providers) in the targeted pediatric oncology clinics at the participating sites: i) caring for childhood cancer survivors; ii) licensed to order vaccines; iii) willing to complete surveys and/or interviews. Exclusion: Meets eligibility criteria but unwilling to provide informed consent for study participation.
Childhood cancer survivors
Inclusion: Childhood cancer survivors who are 9–17 years of age, ≥ 1 year following completion of cancer therapy, receive follow-up care (in person or via telehealth) in a targeted pediatric oncology clinic at a participating site, and reside in the state where the clinic is located. Exclusion: State vaccine registry data not available for the survivor.
Informed consent
Healthcare providers
Healthcare providers who provide care to patients in the targeted population will receive a study email from the coordinating center with an information sheet, along with a link to the online survey. The IRB has authorized waiver of consent documentation; thus, completion of the survey will imply consent. An item on the survey will ask the healthcare provider if they wish to participate in study interviews. Those indicating interest in interview participation will be contacted by the study Clinical Research Assistant (CRA) at the study coordinating center via email or telephone. Verbal consent will be obtained prior to interview initiation.
Childhood cancer survivors
There will be no interaction between the study team and cancer survivors. Study involvement includes abstraction of existing clinical information only.
Approach
Effectiveness trial
The HPV PROTECT intervention will be implemented as standard of care (quality improvement), and will be evaluated across the six participating sites using a cluster-randomized stepped-wedge design. During the first year of the trial, all six participating sites will be assigned to the baseline (control) condition in which they will proceed with usual care and measure HPV vaccination rates of the targeted population (cancer survivors 9–17 years of age and ≥ 1 year following completion of therapy) using state vaccine registry data accessible via EMRs. In Year 2, three of the sites will implement HPV PROTECT while the remaining three sites will continue with usual care. In Year 3, the remaining three sites will implement HPV PROTECT, and sustainability of the intervention will be evaluated for the three sites that implemented HPV PROTECT in Year 2. In Year 4, sustainability (i.e., ongoing improvement in vaccine initiation rates) of the HPV PROTECT intervention will be evaluated across all six sites. Measurement of HPV vaccination rates using state vaccine registry data accessible via EMRs will continue across the entire 4-year period of the trial.
Implementation trial
To inform future dissemination of the intervention, we will use a mixed methods approach to estimate change in healthcare provider HPV vaccine-related knowledge and practice; evaluate healthcare provider perspectives regarding intervention feasibility, acceptability, and appropriateness in the pediatric oncology setting; and evaluate provider adherence (fidelity) to intervention components.
All of the targeted pediatric oncology healthcare providers at each clinic will be invited to complete electronically-administered surveys, yearly for four years, via Research Electronic Data Capture (REDCap®) [51], a secure password-protected, web-based research database, regarding their HPV vaccine-related knowledge, current HPV vaccine-related practices (e.g., provision of vaccine recommendations to parents/patients), their evaluation of the HPV PROTECT intervention components, and their sociodemographic information (e.g., age, sex, education, role, years of experience). Healthcare providers who complete surveys will be asked to indicate if they would like to participate in qualitative interviews in the survey year during which the participant’s site is implementing the HPV PROTECT intervention. Healthcare providers who indicate interest in interview participation will be invited to participate in telephone or secure web-based interviews regarding feasibility and acceptability of the intervention components and barriers/facilitators to implementation of the intervention. Interviews will be recorded and transcribed by the coordinating center CRA. Personal identifiers will be removed from the data by the CRA following data collection. Results will be reported in aggregate without personal identifiers.
Randomization
In this stepped-wedge cluster-randomized design, randomization will occur at the site level, with three sites randomized to begin the intervention in Year 2, and three sites randomized to begin the intervention in Year 3 (Fig. 3). There is no difference in the intervention between the two groups other than the intervention start date. The study’s stepped-wedge design incorporates a control period for all participating sites during Year 1, allowing for collection of baseline vaccination rates, thus avoiding historical comparisons. Before the beginning of Year 2, sites will be randomized according to the stepped-wedge design. The sites assigned to the control condition in Year 2 (sites A, B, C) will be assigned to the intervention in Year 3, and the Year 2 intervention sites (sites D, E, F) will be moved to the post-intervention (sustainability) condition for Year 3. All sites will be assigned to the post-intervention (sustainability) condition for Year 4. The stepped wedge design will allow comparison of the primary outcome (HPV vaccine initiation rate; i.e., proportion of survivors in targeted population who have received ≥ 1 HPV vaccine dose, as of the last day of each study year) across groups (control vs. intervention), while allowing each site to serve as its own pre-intervention control, and using the control observations in Years 1 (all sites) and 2 (sites A, B, C) to estimate secular trends. Sustainability will be assessed in the post-implementation period, i.e., in Years 3 (sites D, E, F) and 4 (all sites) (Fig. 4).
Measures
Healthcare provider data
Participating healthcare providers will complete the following:
Healthcare Provider Electronic Survey. The healthcare provider survey will be completed electronically via REDCap® yearly for 4 years in Years 1–4; estimated completion time is 15 min per year. The survey will ascertain the following data: Sociodemographics (age, sex, race/ethnicity, education); Clinical characteristics (provider license type [MD, NP, PA]; role [attending, staff, trainee], years of experience in current role, average number of survivors seen per week); provider HPV vaccine-related knowledge/practices (knowledge regarding HPV vaccine, familiarity with strategies to increase vaccine uptake, recall [or prior knowledge] of key messages in the training program, current practices related to the HPV vaccine (e.g., method used to assess survivor vaccination status, frequency and quality of recommendation for HPV vaccine, strategies used to promote HPV vaccination); and intervention evaluation (objective rating of feasibility, acceptability, appropriateness of the intervention in the pediatric oncology setting and provider fidelity to intervention components [e.g., vaccine recommendations, educational materials]).
Healthcare Provider Qualitative Interview. Semi-structured qualitative interviews will be conducted with those healthcare providers who opt-in to this portion of the study. The interviews will occur once, during the year that the healthcare provider’s site initiates the intervention; estimated interview duration is 30 min. Providers will be asked about their perceptions of the feasibility (perceived potential for success), acceptability (perceived need), and appropriateness (perceived fit) of the intervention to the pediatric oncology setting, and their adherence (fidelity) to intervention components (e.g., delivery of recommendations, developing and communicating vaccine action plans to parents and PCPs). Interviews will be conducted during the second half of Year 2 (sites D, E, F) and Year 3 (Sites A, B, C) via telephone or secure web-based platform by an interviewer from the coordinating center trained in qualitative interview techniques. An Interview Guide will be used and interviews will be recorded and transcribed verbatim.
Patient-level data
The intervention occurs at the clinic level, and medical record and vaccine registry data for the cancer survivor population will be accessed by the site CRA under a HIPAA waiver as part of each site’s QI initiative. The site CRA will abstract the following data elements from the medical record for each survivor added to the study roster: Diagnosis category (leukemia, lymphoma, solid tumor, central nervous system [CNS] tumor); age at diagnosis, time from diagnosis, and time off-therapy at cohort entry; history of hematopoietic cell transplant (yes/no; if yes: type, number, age); history of Chimeric Antigen Receptor (CAR)-T cell therapy (yes/no: If yes: number, age); sex; and race/ethnicity. The CRA will abstract the following additional visit-specific data elements from the survivor’s medical record for the initial clinic visit and for each subsequent clinic visit occurring during the study period: Age at visit, study year and week of visit, provider type (physician, advanced practice provider), study identification number of healthcare provider(s) providing care at clinic visit, visit type (in-person, telehealth), and insurance type.
Upon adding each survivor to the study roster, the CRA will access the state vaccine registry and abstract all HPV vaccine dose(s) and associated date(s) of administration occurring prior to the date of the survivor’s cohort entry visit. At least yearly throughout the data collection period (Years 1–4), the CRA will access the state vaccine registry and abstract any additional HPV vaccine dose(s) and associated date(s) of administration occurring since the most recent data abstraction. Additionally, dose(s) and date(s) of additional vaccines recommended for adolescents (i.e., meningococcal, Tdap, influenza and COVID-19), will be abstracted by the CRAs at the same timepoints, for use as co-variates in the analysis, as it is important to understand whether uptake of the HPV vaccine differs from uptake of the other recommended adolescent vaccines [52]. All data will be completely de-identified prior to submission to the study coordinating center; survivors with visits in more than one year will be linked so that multiple observations per survivor can be addressed in the analysis. Coded roster data (with no elements of personal health information [PHI]) will be submitted weekly by participating sites to the study coordinating center via the study’s REDCap® study database. Data quality will be monitored in real-time by the site CRAs for each individual site and by the CRA at the study coordinating center for the overall study, using the study Standardized Operating Procedures, which include detailed instructions for data collection, verification, and cleaning. Additionally, range checks for key variables, and warnings to prevent missing data, are built into the REDCap® study database.
Outcomes
Primary outcome
Change in survivor HPV vaccine initiation rates one year following intervention implementation, measured using state vaccine registry data accessed via the EMR at each participating site as part of the QI project associated with this research. The primary outcome will be measured as of the final day of the intervention year (Year 2 for sites DEF, Year 3 for sites ABC).
Secondary outcomes
Healthcare provider knowledge and current practices related to the HPV vaccine, measured by survey (yearly in Years 1–4). Provider perspectives regarding feasibility/acceptability and appropriateness of the intervention in the pediatric oncology setting, and provider adherence (fidelity) to intervention components, measured by survey (yearly in Years 1–4), and interview (once during intervention year [Year 2 or Year 3]).
Exploratory outcomes
Change in survivor HPV vaccine series completion rates, and ongoing HPV vaccine initiation rates in years subsequent to implementation of the intervention (sustainability), measured using state vaccine registry data accessed via the EMR at each participating site as part of the QI project associated with this research. The exploratory outcomes will be measured as of the final day of each relevant study year.
Analytic plan
Effectiveness trial
Unless otherwise noted, all statistical tests will be two-sided. The main hypothesis of the intervention’s effect will be tested using a mixed effects logistic regression model including a random intercept for each site. The base model for HPV vaccine initiation for participant i at site j during year y without covariates will be:
$$\mathrm{log}\left({Odds}_{initiation,i,j,y}\right)={\beta }_{0}+{\beta }_{1}\bullet {year}_{j,y}+{\beta }_{2}\bullet {x}_{intervention,j,y}+{b}_{j}$$
where \({year}_{i,j}\) indicates the study-year of the visit, and \({x}_{intervention,j,y}\) equals 0 if site j has not been exposed to the intervention by \({year}_{j,y}\), and equals 1 if it has, and \({b}_{j}\) is the random intercept for site j. The primary hypothesis will be tested by the significance of the coefficient \({\beta }_{2}\) in the model, which will capture the initial year of active intervention. Exploratory aims include testing whether the intervention results in increased rates of series completion and whether there is a sustained intervention effect in increasing HPV vaccine initiation. The analysis for series completion will parallel the analysis for initiation, with the exception that the analytic cohort for each year will be limited to those who had not completed the series prior to their index clinic visit for that year. Sustained effects will be tested using a similar model augmented by specific coefficients for duration of time in the intervention arm:
$$\mathrm{log}\left({Odds}_{initiation,i,j,y}\right)={\beta }_{0}+{\beta }_{1}\bullet {year}_{j,y}+{\beta }_{2}\bullet {x}_{intevention,j,y}+{\beta }_{3}\bullet {x}_{2int,j,y}+{\beta }_{4}\bullet {x}_{3int,j,y}+{b}_{j}$$
In this model, \({\beta }_{1}\) will continue to account for a constant secular trend, while \({\beta }_{3}\) will allow for an additional effect in the 2nd year of intervention and \({\beta }_{4}\) will similarly allow for an additional incremental effect in the third year. Thus, the log odds of initiation for a participant at site j in year 4 for a site in the third year of intervention will be estimated as \({\beta }_{0}+{\beta }_{1}\bullet 4+{\beta }_{2}+{\beta }_{3}+{\beta }_{4}\) + \({b}_{j}\). While hypothesis testing will be included in the exploratory aims, the focus will be on reporting estimated rates of outcomes and intervention effects with confidence intervals. For each outcome, secondary analyses will include patient age at visit, sex, insurance type, and race/ethnicity as covariates to improve the precision of estimates and provide an estimated standardized prevalence. We will also evaluate the impact of clinic level factors on vaccination initiation rates (e.g., clinic volume, provider characteristics, practice size, geographic location, and baseline initiation rates) as fixed effects. We will also report the HPV vaccine initiation rate among survivors who were vaccine-naïve at cohort entry (i.e., incidence of vaccine initiation). Last, we will perform subgroup analyses stratified by relevant biological variables (i.e., age at visit, sex, and race/ethnicity groups). For survivors who complete > 1 clinic visit/study year, the number and timing of subsequent clinic visits during the study period will be included as covariates in secondary analyses. Patients who develop a relapse or subsequent malignancy requiring active cancer treatment at any time during the study period will be removed from the data set as of the date of diagnosis of the relapse or subsequent malignancy. Parallel analyses will further consider providers as random effects within sites, adding a random intercept for each provider. Given the potential complexity of correlation structures and nesting, the main hypothesis tests will also be reported using permutation testing. As an example, for permutation testing the main effect based on coefficient \({\beta }_{2}\), for multiple (> 1000) iterations, participants will be randomly assigned to sites and the models fit to develop an empirical distribution for estimates of \({\beta }_{2}\) under the null hypothesis of not different. The p-value of \({\beta }_{2}\) (with genuine assignments) will be estimated from distribution of coefficients estimated from the permutations.
Sample Size and Power. Based on a combination of our prior work [6], secular trends since publishing that work, and general population data regarding state-specific vaccination rates [53], pre-intervention prevalence rates of vaccine-initiated patients at the 6 sites are estimated to be 0.404, 0.496, 0.462, 0.473, 0.415, and 0.488, for an average prevalence rate of 0.456, with a stable baseline incidence initiation of 0.025 (or 2.5 absolute percentage points) [6, 53]. For evaluating the intervention, we expect to have approximately 1273 patients with clinic visits per year with site-specific numbers estimated as 227, 215, 135, 104, 403, and 189. Power was estimated using simulations making conservative assumptions about the number of available appointments, and rates of increase. From simulations, we have > 80% power to detect increased rates of initiation resulting in average prevalence after year 2 (1st year of intervention) of 48.2% for the control practices vs. 57.0% for the intervention practices, an absolute difference of 8.7%, which is less than the 10% difference we expect to observe. In terms of the logistic regression model, this equates to a 6% relative increase per year in rates of incident initiation (for a secular trend with an absolute increase of 2.5%) in the control group and a 24.3% relative increase in the intervention group. Subgroup analyses: For a subgroup of half our sample (e.g., stratifying by sex, age at visit, or race/ethnicity) we have 80% power to detect a difference in rates of 49% vs. 61%.
Implementation trial
Quantitative analysis. Descriptive statistics (e.g., frequency, percentage mean, standard deviation [SD], median, range) will be used to summarize quantitative measures. Scores for Provider HPV Vaccine-related Knowledge/Practices will be modeled at the provider level using mixed models similarly to the methods for the Effectiveness Trial, to properly account for repeated observations and within-practice clustering, but with a continuous rather than binary outcome. Model-based predictions with confidence intervals will be reported over time and by intervention exposure, and will be displayed graphically. We expect to be underpowered for formal hypothesis testing, but model-based effect estimates for HPV-related Knowledge and Practices will be reported. Sample Size and Power. We recognize that we may not have sufficient power to test objective measures of provider HPV vaccine-related knowledge and practices, or objective ratings of the intervention; as such, the Implementation Trial is a secondary aim, and the provider knowledge/practices portion of the analysis will be exploratory.
Qualitative analysis. We will code interview transcripts and analyze them using content analysis. Two investigators will evaluate each transcript using line-by-line open coding to develop a preliminary codebook of emerging themes. We will use the preliminary codebook to guide additional analyses, and will develop a robust codebook as additional transcripts are analyzed. We will use team discussions to arrive at a consensus regarding final coding, aggregate the codes, and categorize them to identify major themes. Data saturation will occur when no new themes emerge. Qualitative software (e.g., NVivo) will be used for analysis.
Mixed methods: Integration of data. Results from the quantitative and qualitative analyses will be integrated through comparison to generate metainferences regarding the feasibility/acceptability of the intervention. The analysis will be weighted toward the qualitative strand [54]. The mixed analysis will expand our understanding of providers’ experiences implementing the intervention.
Data management and safety monitoring plan
Participation in the research aspects (i.e., surveys and interviews) of this clinical trial are optional for healthcare providers. Intervention Champions will not have access to identifiable provider data and will not know which healthcare providers from their site choose to participate or not participate in the research aspects of the study. Nevertheless, it is possible that some healthcare providers who do not wish to participate in the research aspects of the study may perceive pressure to do so and may believe that not participating would be viewed negatively by their peers or superiors. Therefore, a data safety monitoring plan will be implemented to monitor for Unanticipated Problems related to research participation. The study PIs, and the Intervention Champions at each site, will be responsible for monitoring protocol conduct across all participating sites and reporting any deviations or unanticipated problems related to the protocol intervention and/or research procedures performed during this study to the study sIRB (UAB-IRB). Reports of unanticipated problems will include a description of the circumstances surrounding the unanticipated problem and the PI assessment of its impact on the study’s overall risk–benefit ratio. If an unanticipated problem appears to significantly affect the study’s risk–benefit ratio, an urgent review of the unanticipated problem will be made to determine whether immediate action is required. Based on the frequency and severity of unanticipated problems, the study PIs may deem it necessary to suspend or terminate the trial. When appropriate, the study PIs may recommend that unanticipated problems be reported to federal agencies.
