Table 2.

Selected examples^† of three levels of patients early engagement in research proposal development in the write-up of research proposal.

The anatomy of a research proposal	Guiding question(s)	Passive patient engagement - patient is a study participant	Tokenistic patient engagement - patient is an advisor	Authentic patient engagement - patient is a co-developer
Study title and tag line	In less than 15 words, what is this study about? What is the catchphrase or slogan that clarify the thought behind this study?	Pragmatic randomized trial of proton vs photon therapy for patients with nonmetastatic breast cancer: a radiotherapy comparative effectiveness consortium trial	Pragmatic clinical trial of proton vs photon therapy for patients with breast cancer	Comparing two types of radiation treatment for patients with breast cancer The RadComp study: a study at the heart of breast cancer treatment
Rationale for proposed research/context	What is the research area? What is known? What is the gap in knowledge? What is the critical need?	Nearly 3 million women are living with breast cancer in the USA. Radiotherapy plays a major role in the treatment of breast cancers. Radiotherapy carries increased risks of cardiovascular morbidity and mortality; survivors who receive radiotherapy have at least a twofold increased risk of cardiovascular death. Thus, success of cancer therapy has led to survivorship burden. Patients live longer but suffer from toxic consequences of treatment	Proton therapy, by reducing the volume of heart and lungs exposed to radiation in the treatment of breast cancer, has the potential to lessen the morbidity of radiation therapy compared with photon therapy, now the predominant radiation treatment in the USA. However, proton therapy is more expensive and has yet to be shown to improve health outcomes for patients with breast cancer	Patients we have engaged expressed the three rationales for this PCORI proposal: (1) the hope that proton therapy could lessen the burden of radiation-related toxicity; (2) the frustration that evidence describing the benefits and harms of proton therapy for breast cancer is lacking; and (3) the expectation that our study would examine heart problems, cancer control and quality of life
‘Big Picture’	What is the solution? What is the long-term goal and potential impact?	Radiotherapy is an important component of curative treatment for locally advanced breast involving lymph nodes within the axilla (the cavity in the underarm)	A broad range of stakeholders (patients, payers, providers, manufacturers, researchers and policy makers) have called for randomized trial level evidence on the clinical benefits and harms of proton therapy, a promising but expensive cancer treatment, for patients with breast cancer	With this study, we hope to better understand the best available technologies for breast cancer to help patients live a longer, healthier life
Specific Aims	What is your objective?	Assess the effectiveness of proton vs photon therapy in reducing major cardiovascular events, defined as myocardial infarction, coronary revascularization, hospitalization for heart failure, arrhythmia, or unstable angina or atherosclerotic heart disease or other cardiac death	Assess the effectiveness of proton vs photon therapy in improving patient-reported body image and function and other measures of HRQOL	“I don’t only want to know about dying from heart problems from the radiation. I want to know about the heart problems that I would have to live with and the impact on my quality of life after cancer treatment” - Breast Cancer Survivor, Mayo Clinic
	What is your hypothesis (expected outcome)?	We hypothesize that proton therapy, as part of multimodality curative treatment for locally advanced breast cancer, reduces major cardiovascular events, is noninferior in cancer control and improves HRQOL compared with photon therapy, the current standard treatment	We hypothesize that proton therapy, as part of multiple-regimen treatment for breast cancer, reduces cardiovascular events, can control cancer, and improves quality of life compared with photon therapy, the current standard treatment	It is possible that the new breast cancer therapy (proton therapy) can control cancer while reducing treatment side effects (particularly heart-related) and improving general well-being
	What will you do to test the hypothesis?	Build critical infrastructure to develop predictive models of the association between radiotherapy dose distributions and major cardiovascular events or quality of life after radiation treatment, which will help patients and physicians identify who benefits most from proton or photon therapy	Identify the impact of proton vs photon therapy on physical, mental and social HRQOL in breast cancer, which will be a major contribution to address a critical patient-centric evidence gap	Engage patients and other essential stakeholders in the design and conduct of large scale pragmatic clinical trials of a promising, but expensive, medical technology, a first-of-its-kind effort which will, irrespective of outcome, inform future efforts to conduct holistic, patient-centric, pragmatic comparative effectiveness research as part of a learning healthcare system. The RadComp study will be conducted at medical centers around the country to compare two types of standard care radiation therapy: PHoton Therapy (pronounced ‘fo-tahn’) and PRoton Therapy (pronounced ‘pro-tahn’) - to find out which type of radiation is best for treating breast cancer
Significance	What is the scientific premise? What is the importance of proposed research?	Interpreting the sparse evidence available is problematic because of the absence of trials of sufficient size and statistical power to assess key clinical outcomes, failure to adjust for known confounders, and substantial selection effects	Patients with breast cancer considering photon or proton therapy make treatment decisions in the context of extremely sparse comparative effectiveness evidence, and then may live for years with clinically burdensome treatment-related morbidity that affects their quality of life and engagement in activities of living. Our study results will be directly relevant to many thousands of patients who confront these difficult treatment decisions every day	“Of course I would want to know if proton therapy will improve the skin burn or my tiredness after radiation. But, I would be more motivated to participate in a big study if I knew we would learn whether proton therapy could avoid causing problems with my heart. That would help me weigh whether the long-term benefits of radiation outweigh the long-term side effects” - Breast Cancer Survivor, Rochester, MN
Innovation	Does your research employ novel methods? Is your hypothesis innovative? Does your research bring together novel expertise or resources?	While we hypothesize that the radiation dose characteristics of proton therapy translate into measurable clinical benefits for breast cancer, this has yet to be shown in a randomized study. The RadComp trials aim to address this evidence gap through real-world, patient-centered PRCTs for patients with locally advanced breast	Our goal is to generate new knowledge about how a promising, but expensive, cancer treatment (proton therapy) compares with its alternatives while ensuring that our approach reflects ‘real world’ clinical practice, identifies subgroups of patients that might benefit more from proton therapy, and helps patients and physicians apply our findings to their own lived experience	To increase enrollment and retention of eligible patients, we will use multifaceted innovative engagement and recruitment approaches and employ social networking techniques in collaboration with leading national breast cancer and patient advocacy organizations
Approach	What is the study design/strategy?	A total of 1716 breast cancer patients will be recruited at 22 centers within 48 months (3-month ramp up period, minimum 6 months of clinical follow-up, additional 3-month period for analysis)	The RadComp Coordinating Center, The PATIENTS Program, Executive Committee and Stakeholder Advisory Committee will work together to develop recruitment strategies	Reduced patient research visits and opened at more community sites. Patient partners will co-develop informed consent documents in a patient-friendly language. Partnerships with national advocacy partners and advocates will promote recruitment of participants through co-development of recruitment materials and outreach
	What are the study procedures/methods?	We anticipate patient contact via clinical visit, RadComp online portal, or by mail or telephone throughout the study period	Clinical research coordinators will facilitate patient-reported outcomes assessment as needed and clinician reported adverse events reporting in accordance with protocol procedures	We will conduct an extensive communications campaign with RadComp participants and consortium members which will include monthly news-briefs and quarterly newsletters and weekly posts to a selected online interface for quick digital information sharing and two way communication
	How are you going to analyze the data?	The primary HRQOL end points will be the BCTOS cosmesis and arm function scores for patients with breast cancer. […] After estimating the effect of the intervention on each end point, additional covariates will be evaluated to select those most related to selected end point. Likelihood ratio tests willbe used to assess the contribution of each variable across hierarchical models	The analyses and key research findings will be reported to the Stakeholder Advisory Committee to solicit their feedback and comments and allow our patient and stakeholder advisors to ask questions, provide feedback and fully comprehend the study findings	Focus groups will be conducted by The PATIENTS Program as part of the patient engagement process to address recruitment and retention and to seek guidance on how best to provide feedback to patients throughout the study. This information will inform an iterative process of refining talking points, providing feedback to RadComp centers and devising effective strategies to overcome identified barriers
	What is your dissemination strategy?	The research team anticipates at least three manuscript submissions and abstracts will be submitted to at least five national conferences and annual meetings, where we can present our study findings and recommendations	In the spirit of community-engaged research, we propose both scientific and lay publications, some co-developed with members of the project’s Stakeholder Advisory Committee, via peer-reviewed journals and online interfaces, such as the RadComp and advocacy partner websites	Planned activities include focus groups to provide real-time bidirectional learning on recruitment and retention, assistance with co-developing lay summaries and patient informational ‘give backs’ throughout the study, and identification of dissemination portals and outlets
	How are you going to address potential problems? What is the alternative strategy?	We recognize the potential for some patients to refuse their assigned treatment but expect cross-over to be minimal	Adherence data will be monitored carefully by the DSMB	Intensive patient engagement efforts aimed at robust informed consent will minimize treatment assignment refusal. Careful construction of study materials will present both therapies as viable, the US FDA-approved therapies; not representing one over another. The RadComp coordinating team is available by phone and email to address concerns

^†The examples in this table were adapted from the RadComp Study and are for illustrative purposes only; they may not necessarily reflect the exact language used in the original funded proposal.

BCTOS: Breast cancer treatment outcome scale; DSMB: Data and safety monitoring board; HRQOL: Health-related quality of life; PATIENTS: PATient-centered involvement in evaluating the effectiveness of treatments; PCORI: Patient-centered outcomes research institute; PRCTs: Pragmatic randomized clinical trials; RadComp: Radiation comparative effectiveness study.