Randomized Trial of Stepped Palliative Care Versus Early Integrated Palliative Care in Patients With Advanced Lung Cancer
Phase: NA
Conditions: Lung Cancer
Sponsor: Massachusetts General Hospital

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Randomized Trial of Stepped Palliative Care versus Early Integrated Palliative Care in Patients 
with Advanced Lung Cancer 
DF/HCC SOCIAL-BEHAVIORAL RESEARCH PROTOCOL 
 
 
Lead Site: 
Massachusetts General Hospital (Boston, MA) 
Participating Site(s): 
Duke Cancer Center (Durham, NC) 
University of Pennsylvania Abramson Cancer Center (Philadelphia, PA) 
 
 
Overall PI:  Jennifer Temel, MD – MGH 
Site Responsible PI: Thomas W. LeBlanc, MD, MA, MHS – Duke 
Site Responsible PI: Pallavi Kumar, MD – Penn 
 
 
 
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Section 1: Protocol Schema 
 
 
 
 
 
 

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Section 2: Body of Protocol 
 
Contents 
Section 1: Protocol Schema ............................................................................................................ 2 
Section 2: Body of Protocol ............................................................................................................ 3 
1.0. Introduction .......................................................................................................................... 6 
1.1. Overview .......................................................................................................................... 6 
1.2. Background and Rationale ............................................................................................... 6 
2.0. Objectives ............................................................................................................................ 8 
2.1. Primary Aim..................................................................................................................... 8 
2.2. Secondary Aims ............................................................................................................... 8 
3.0. Research Subject Selection .................................................................................................. 9 
3.1. Patient Eligibility Criteria ................................................................................................ 9 
4.0. Research Subject Entry ........................................................................................................ 9 
4.1. Patient Screening ............................................................................................................. 9 
4.2. Patient Recruitment ........................................................................................................ 10 
4.3. Informed Consent Process ............................................................................................. 10 
4.3.1. In-Person Informed Consent Process .......................................................................... 10 
4.3.2. Verbal Informed Consent Process .............................................................................. 10 
4.4. Baseline Completion and Registration........................................................................... 11 
5.0. Study Design and Methods ................................................................................................ 12 
5.1. Study Design .................................................................................................................. 12 
5.2. Selection of Instruments ................................................................................................ 12 
5.3. Description of Intervention ............................................................................................ 13 
5.4. Data Collection .............................................................................................................. 16 
5.5. Description of Study Processes ...................................................................................... 18 
5.6. Adverse Reactions and their Management .................................................................... 21 
6.0. Ethical and Legal Issues ..................................................................................................... 22 
6.1. Confidentiality ............................................................................................................... 22 
7.0. Statistical Analysis ............................................................................................................. 23 
7.1. Primary Endpoint ........................................................................................................... 23 
7.2. Secondary Endpoints ..................................................................................................... 23 
7.3. Exploratory Endpoints ................................................................................................... 23 
7.4. Sample Size and Power Calculation .............................................................................. 23 

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7.5. Analysis Plan ................................................................................................................. 24 
8.0. References .......................................................................................................................... 28 
9.0. Appendices .................................................................................................................... 32 
9.1. Suggested Template for Emailing Clinicians: Permission to Approach Patient.... 32 
9.2. Suggested Voicemail Script for Contacting Patients to Offer Enrollment ............. 32 
9.3. Suggested Template for Emailing Oncology Clinicians: Notification about Step 1 
Patients Following Enrollment .......................................................................................... 32 
9.4. Suggested Template for Emailing Oncology Clinicians: Notification about Step 1 
Patients on the Day of their First Oncology Appointment since Enrollment ................ 32 
9.5. Suggested Verbal Script for Questionnaire Administration .................................... 33 
9.6. Suggested Paper Cover Letter when Mailing the Baseline Questionnaire to 
Participants .......................................................................................................................... 33 
9.7. Suggested Paper Cover Letter when Mailing the Questionnaires to Participants 34 
9.8. Suggested Email Cover Letter when Emailing the Baseline Questionnaire to 
Prospective Participants ..................................................................................................... 34 
9.9. Suggested Email Cover Letter when Emailing the Questionnaires to Participants
............................................................................................................................................... 35 
9.10. Suggested Email Template when Sending Consent Form Copy to Participants via 
Email .................................................................................................................................... 35 
9.11. Suggested Email Template when Scheduling PC Visits with Participants via 
Email .................................................................................................................................... 35 
9.12. Data Safety Monitoring Plan .................................................................................... 36 
9.13. Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring 
Plan ....................................................................................................................................... 38 
1. 
INTRODUCTION ................................................................................................................ 40 
1.1 
Purpose ........................................................................................................................... 40 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions .......................................... 40 
2. 
GENERAL ROLES AND RESPONSIBILITIES ................................................................ 41 
2.1 
DF/HCC Sponsor ........................................................................................................... 41 
2.2 
Coordinating Center ....................................................................................................... 41 
2.3 
Participating Institution .................................................................................................. 42 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS................................. 42 
3.1 
Protocol Distribution ...................................................................................................... 42 
3.2 
Protocol Revisions and Closures .................................................................................... 43 
3.3 
Informed Consent Requirements .................................................................................... 43 
3.4 
IRB Documentation........................................................................................................ 43 

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3.5 
IRB Re-Approval ........................................................................................................... 44 
3.6 
Participant Confidentiality and Authorization Statement .............................................. 44 
3.7 
DF/HCC Multi-Center Protocol Registration Policy ..................................................... 44 
3.8 
DF/HCC Protocol Case Number .................................................................................... 45 
3.9 
Safety Assessments and Toxicity Monitoring ................................................................ 46 
3.10 
Data Management ....................................................................................................... 46 
4. 
MONITORING: QUALITY CONTROL ............................................................................. 47 
4.1 
Ongoing Monitoring of Protocol Compliance ............................................................... 47 
4.2 
Monitoring Reports ........................................................................................................ 47 
4.3 
Accrual Monitoring ........................................................................................................ 47 
5. 
AUDITING: QUALITY ASSURANCE .............................................................................. 48 
5.1 
DF/HCC Internal Audits ................................................................................................ 48 
5.2 
Audit Notifications ......................................................................................................... 48 
5.3 
Audit Reports ................................................................................................................. 48 
5.4 
Participating Institution Performance............................................................................. 48 
 
 
 

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1.0. Introduction 
1.1. Overview  
Early and longitudinal involvement of palliative care (PC) in the outpatient management 
of patients with advanced cancer improves patient-reported and end of life (EOL) care 
outcomes. While recommended by national organizations as the standard of care, this 
early integrated care model utilizes substantial PC resources, which has limited its 
dissemination across care settings. We seek to perform a multi-site randomized trial of 
stepped PC versus early integrated PC in patients with advanced lung cancer. By 
demonstrating the non-inferiority of a stepped PC model to early integrated PC, we seek 
to define a role for this more accessible, scalable and patient-centered approach to PC. 
 
1.2. Background and Rationale 
Early Integrated PC Improves Patient-Reported and End-of-Life Care Outcomes 
Over the past decade, a growing body of evidence has supported a new role for PC 
clinicians in the outpatient management of patients with advanced cancer.1-8 For example, 
Bakitas conducted a randomized trial comparing a telephone-administered PC psycho-
educational intervention with usual care in patients with newly diagnosed poor prognosis 
cancers, which demonstrated improvements in quality of life (QOL) and mood.2 In two 
additional trials, investigators evaluated in-person interventions administered by PC-
trained clinicians. Specifically, Zimmermann evaluated a four-month intervention 
involving monthly outpatient PC visits in patients with poor prognosis cancers, 
demonstrating improvements in QOL, symptom burden and satisfaction, compared with 
usual care.5 Similarly, in our trial of patients with newly diagnosed advanced non-small 
cell lung cancer (NSCLC), monthly visits with PC throughout the course of illness 
(“early integrated PC”) improved patient-reported QOL and depression, compared with 
usual care.6 Notably, this study also demonstrated improvements in the delivery of EOL 
care with early integrated PC including greater documentation of EOL care preferences, 
longer length of stay in hospice, and less chemotherapy administration near death.9 More 
recently, we completed a larger efficacy trial of the early integrated PC model in patients 
with advanced cancers, which confirmed prior findings and also demonstrated that the 
intervention led to an increase in patient-clinician communication about EOL care 
preferences.10 While both telephone-based and brief duration in-person PC interventions 
improve patient-reported outcomes, only early integrated PC enhances communication 
and decision-making about EOL care. 
 
Few Cancer Care Settings Can Deliver Guideline-Concordant Early Integrated PC 
Based largely on the data described above, in 2012 and 2016 the American Society of 
Clinical Oncology (ASCO) published Clinical Oncology Practice Guidelines 
recommending early PC for any patient with advanced cancer.11,12 Similarly, the Institute 
of Medicine and the National Comprehensive Cancer Network recommend consideration 
of early PC for patients with advanced cancers.13,14 By recognizing the value of PC in the 
care of patients with advanced cancer, these recommendations represent a significant 
advance in the field of oncology. However, few institutions have sufficient numbers of 
PC clinicians to provide care in accordance with these guidelines.15 Despite a recent 
growth in the number of PC clinicians, data suggest that the current workforce would 
need to be at least tripled to meet the growing demand for their services.16 Moreover, it is 

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unlikely that there will ever be a sufficient number of trained PC clinicians to see all 
patients with advanced cancer from the time of diagnosis and throughout the course of 
illness.17,18 Thus, we must develop and evaluate health care delivery models that increase 
access to care and efficient utilization of PC services. 
 
Stepped Care Increases Access with Limited Health Care Clinicians and Resources  
Stepped care was initially developed as a health care delivery model to increase access to 
and efficiency of psychological therapy due to limited numbers of trained mental health 
clinicians.19 In stepped care, all patients receive care for their condition, but with a 
minimum of required contact with the specialty trained clinician.20 More intensive 
treatment with the clinician is reserved for those who do not benefit sufficiently from the 
less intensive treatments. A key element of this model is that patients must be monitored 
systematically and “stepped up” to more intensive treatment if the minimal level of 
exposure to the clinician does not achieve sufficient health gain. Stepped care models 
have been shown to be effective in managing psychological illnesses such as depression, 
bulimia, and addiction as well as physical conditions including obesity, hypertension, and 
back pain.21-24 Moreover, studies support the use of stepped care models to address 
psychological distress in patients with cancer.25-27 When compared with proven strategies 
of more intensive specialist-delivered treatment, stepped care can achieve similar 
outcomes using fewer resources and at a lower cost.22,28,29 
 
Stepped Care as a Strategy to Deliver Accessible and Patient-Centered PC 
Stepped care is an appealing approach for PC delivery as it would enable all patients with 
advanced cancer to have some exposure to PC clinicians, thus representing guideline-
concordant care. Importantly, stepped care is patient-centered in tailoring the delivery of 
PC services to patients’ clinical needs. Such a patient-centered approach to integrating 
palliative and oncology care is quite timely as cancer therapies are becoming more 
personalized and effective with fewer side effects. For example, patients treated with 
targeted oral chemotherapies often remain on treatment for years and may see their 
oncologist only every few months.30,31 While these patients may have challenges with the 
physical and psychological burdens of their cancer, many are unlikely to require monthly 
visits with a specialized PC clinician.32,33 Thus, in the modern era of cancer therapeutics, 
a stepped care model, in which low intensity PC is delivered to all patients at clinically 
relevant points when they are likely to have symptoms or concerns about their cancer 
while reserving a higher level of PC involvement when patients’ health worsens, may be 
more accessible, efficient, and patient-centered. 
   
Lung Cancer is an Ideal Population in which to Study Patient-Centered PC  
The strongest evidence base supporting early integrated PC is among patients with 
advanced lung cancer, with two randomized trials demonstrating significant 
improvements in QOL, mood, and EOL care.6,34 However, treatment paradigms for 
patients with advanced lung cancer are changing rapidly.35 Approximately one-third of 
patients with metastatic lung cancer have gene mutations or fusions that predict responses 
to targeted oral therapies or express PDL1 and have tumor shrinkage with immune 
checkpoint inhibitors, both of which can portend a prognosis of several years.36-41 Despite 
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novel therapies and have a median survival of approximately one year.42 Moreover, these 
patients often experience a high symptom burden and poor QOL at diagnosis, which 
intensifies throughout their illness course.43 With the myriad of medical and psychosocial 
concerns that patients with advanced lung cancer experience, a one-size-fits-all approach 
to PC is unlikely to be optimal for this population. Rather, a PC delivery model 
personalized to each patient’s disease course and care needs represents a more patient-
centered approach for those with advanced lung cancer. 
 
Scientific Premise of the Project 
Early integrated PC has been shown to be an effective care model but is resource 
intensive, which has limited its dissemination in the outpatient oncology setting. 
Similarly, an insufficient number of trained clinicians has been a longstanding challenge 
in psychiatry, which led to the development of stepped care models to tailor treatment to 
the individual patient, ensure access to care, and increase efficiency. Although stepped 
care has not been specifically tested as a model for delivering PC, it has been used 
successfully in addressing the psychosocial needs of patients with cancer.25-27,44 In 
addition to increasing access to PC, a stepped care model is a more patient-centered 
approach by personalizing care to the patients’ illness trajectory and needs. Importantly, a 
limitation of prior research regarding stepped care models is the inclusion of usual care as 
the control arm in clinical trials. To ensure a stepped care intervention is as effective as 
more resource intensive standard of care interventions requires a non-inferiority study 
design.19 Thus, we propose to perform a multi-site randomized trial of stepped PC versus 
early integrated PC in patients with advanced lung cancer. By demonstrating the non-
inferiority of a stepped PC model to early integrated PC, we seek to define a role for this 
more accessible, scalable and patient-centered approach to PC. 
 
2.0. Objectives 
2.1. Primary Aim 
To determine whether stepped PC is non-inferior to early integrated PC in 
improving patients’ QOL at 24 weeks 
Hypothesis: Patients assigned to stepped PC will report QOL that is non-inferior 
to patients receiving early integrated PC at 24 weeks. 
 
2.2. Secondary Aims 
A. To assess whether stepped PC is non-inferior to early integrated PC with 
respect to patient-clinician communication about EOL care preferences and 
length of stay in hospice. 
Hypothesis: Stepped PC will be non-inferior to early integrated PC in the rate 
by which patients communicate their EOL care preferences to their clinicians 
and with respect to patients’ length of stay in hospice. 
 
B. To compare the superiority of stepped PC versus early integrated PC with 
respect to resource utilization. 
Hypothesis: Stepped PC will utilize fewer PC resources than early integrated 
PC. 
 

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3.0. Research Subject Selection  
We will recruit 510 patients with advanced lung cancer receiving their care at 
Massachusetts General Hospital, Duke Cancer Center, or University of Pennsylvania 
Abramson Cancer Center to participate in a multi-center, non-inferiority randomized trial 
of stepped PC versus early integrated PC. Patients will be randomized in 1:1 fashion and 
stratified by site (MGH vs. Duke vs. Penn) and underlying diagnosis (NSCLC vs. small 
cell lung cancer and mesothelioma). As patients with NSCLC have a significantly better 
prognosis than those with small cell lung cancer or mesothelioma, we will stratify by 
the underlying diagnosis to ensure adequate and balanced representation between the two 
study groups. 
 
3.1. Patient Eligibility Criteria 
Inclusion Criteria: 
The patient eligibility criteria will mirror those of our prior early PC studies in this 
patient population. 
1. 
Diagnosed with advanced NSCLC, small cell lung cancer, or mesothelioma, being 
treated with non-curative intent, and informed of advanced disease within the 
prior twelve weeks 
2. 
Eastern Cooperative Oncology Group (ECOG) Performance Status from 0 
(asymptomatic) to 2 (symptomatic and in bed <50% of the day) 
3. 
The ability to read and respond to questions in English or Spanish 
4. 
Primary cancer care at one of the three participating sites 
5. 
Age > 18 years 
 
Exclusion Criteria: 
Patients will be excluded if: 
1. 
They are already receiving outpatient PC or hospice services since diagnosis of 
advanced NSCLC, small cell lung cancer, or mesothelioma  
2. 
They have cognitive or psychiatric conditions as determined by the treating 
oncologist to prohibit study consent or participation  
 
4.0. Research Subject Entry 
4.1. Patient Screening 
At all three sites, the study staff will screen all patients presenting to the outpatient 
thoracic oncology clinic for study participation. By reviewing the electronic scheduling 
system and health record to determine cancer stage and treatment goals, the study staff 
will identify all patients with advanced lung cancer who are not being treated with 
curative intent. This determination will be made based upon stage of disease and the 
designated treatment goal in the chemotherapy treatment plan as some patients with 
locally advanced disease cannot be treated for cure and some patients with metastatic 
disease are treated with curative intent. We will complete a privacy waiver with our 
protocol submissions to the Institutional Review Board (IRB) to allow study staff to 
screen the thoracic oncology clinic schedules and identify patients for study participation. 
We will institute the same patient screening procedures in all three of the participating 
thoracic oncology clinics. 

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4.2. Patient Recruitment 
We will use the same recruitment and enrollment procedures used in our previous and 
ongoing trials.6,34 Prior to the study start, site investigators will meet with their respective 
thoracic oncology teams to review recruitment and enrollment procedures. Specifically, 
the study staff will send an email (see appendix) to the oncology clinicians to notify them 
when their patients appear to be eligible for study participation. If an oncology clinician 
reports that the patient is being treated with curative intent or otherwise does not meet 
eligibility criteria, study staff will document the reason.  
 
4.3. Informed Consent Process 
Either study staff or the oncology clinician can review the study details, offer study 
participation, and obtain informed consent in-person or verbally.  Both the written and 
the verbal consent forms describe all study procedures, information about potential risks 
and benefits of participation, and information regarding who they can contact for further 
questions. The forms also state that participation is voluntary, that participants can refuse 
to answer any questions, that they can withdraw from the study at any time, and that 
study participation is in no way related to their medical care. Study participants who do 
not provide consent will be asked the reason why they prefer to not participate in the 
study. 
 
4.3.1. In-Person Informed Consent Process 
Willing participants will be presented with a detailed, HIPAA-compliant consent form 
and given the opportunity to sign written informed consent either with the study staff or 
their oncology clinician.  
 
Patients who speak Spanish will have all study procedures and information regarding 
risks, benefits and study contacts explained to them verbally via the use of an interpreter 
or a Spanish-speaking study staff member as a first preference, or a family member as a 
second preference. Spanish speaking participants will be given the DF/HCC Spanish 
consent short form for signing, as well as a copy of the full English consent form for their 
own reference. The Spanish consent short form will be signed by the participant and by a 
witness. The witness will be either an interpreter, a Spanish-speaking study staff member 
or a family member. Spanish speaking participants will be provided with Spanish-version 
baseline demographic and study questionnaires.  
 
4.3.2. Verbal Informed Consent Process 
We are requesting a Waiver of Written Documentation of Consent. This study meets the 
requirements for a waiver as it is a Minimal Risk study and all study procedures can be 
communicated verbally. This Waiver will allow study staff to recruit participants 
remotely to address barriers to study enrollment including infrequent in-person visits, 
lack of space in clinic, and patients’ time constraints. All patients who provide verbal 
consent will receive an unsigned copy of the written informed consent.  
 
The study staff or an oncology clinician may contact eligible, English speaking patients 
to obtain verbal consent using the HIPAA-compliant verbal consent form. The verbal 

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consent process may be offered to patients via telephone or during a scheduled oncology 
video visit via institution-approved video technology. Verbal consent procedures will not 
apply to Spanish speaking patients. If the patient does not answer the phone, the clinician 
or study staff may leave a voicemail (see appendix 9.2 for suggested language for the 
voicemail).  
 
4.4. Baseline Completion and Registration 
Patients will be asked to complete baseline demographic and study questionnaires in-
person, over the phone, or via institution-approved video technology with a study staff 
member at the time of consent, or alternatively via email, telephone, institution-approved 
video, or mail within two weeks of signing consent. Once baseline measures are 
complete, patients will be registered for study randomization.  
 
If additional information about palliative care is requested by the patient, the study staff 
member or clinician may provide any of the following brochures about palliative care: an 
institutionally approved palliative care brochure produced by the site; the National 
Institute of Nursing Research brochure “Palliative Care: The Relief You Need When You 
Have a Serious Illness”; or the Center to Advance Palliative Care brochure “Palliative 
Care: What You Should Know”. These brochures are intended to provide additional 
information for potential study participants who are interested in learning more about 
palliative care.  
 
DF/HCC institutions will register eligible participants in the Clinical Trials Management 
System (CTMS) Oncore as required by DF/HCC SOP REGIST-101. Registration must 
occur prior to the initiation of protocol-specific procedures.  
 
For registration of patients from DF/HCC institutions, study staff will complete the 
protocol-specific eligibility checklist using the eligibility assessment documented in the 
participant’s medical record and/or research chart. Study staff will confirm that the 
participant meets all inclusion criteria as described in this protocol and the criteria on the 
eligibility checklist.  
 
Patients from other investigative sites will be entered on the study centrally by MGH 
study staff. Study staff from the participating institution will confirm eligibility criteria 
and fax or email the following documents to study staff at MGH: deidentified signed 
consent form/s, copy of baseline assessment, and a completed eligibility checklist. MGH 
study staff will follow DF/HCC Standard Operating Procedure for Human Subject 
Research Titled Subject Protocol Registration (SOP #: REGIST-101) and register the 
participant on the protocol. Once the patient has been registered, a member of the MGH 
study staff (independent from study staff who recruit, enroll and administer assessments 
to participants) will perform randomization procedures using a computer-generated 
randomization schema, stratified by study site. MGH study staff will fax or e-mail the 
information about randomization to the study staff at the participating site. MGH study 
staff may also call the study staff at the participating site to verbally confirm registration 
and randomization.  
 

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5.0. Study Design and Methods 
5.1. Study Design 
We will conduct a randomized trial of stepped PC versus early integrated PC in patients 
with advanced lung cancer. We have chosen three specific aims focused on 
demonstrating the non-inferiority of the more accessible and patient-centered stepped 
care model.  
 
5.2. Selection of Instruments 
We selected instruments based on our prior studies and the theoretical framework of our 
intervention, which seeks to improve patients’ QOL, illness understanding, use of 
adaptive coping strategies and ultimately communication and delivery of EOL care. 
Study staff will administer study assessments at baseline and multiple follow-up time 
points (with a +/- two-week window) to accommodate patient schedules (see Table 1). 
The selected self-report measures have strong psychometric properties and have been 
well validated in previous studies. All study measures are available in both English and 
Spanish, except the Self-Administered Comorbidity Questionnaire and the Prognosis and 
Treatment Perceptions Questionnaire, which were translated (forward and backward) into 
Spanish with a native Spanish speaking clinician. 
 
Measures: 
Demographic Questionnaire: Participants will self-report their gender, race/ethnicity, 
marital status, religion, education level, employment status, tobacco use, travel time and 
transportation mode to the cancer center, and health insurance co-payment charge.  
 
Self-Administered Comorbidity Questionnaire (SCQ): Medical comorbidity will be 
assessed at baseline with the Self-Administered Comorbidity Questionnaire.45 Patients 
will report on the presence of twelve comorbidities such as heart disease, lung disease, 
diabetes and arthritis. They will also have the option of reporting up to three further 
unlisted comorbidities and will be assigned a comorbidity score ranging from 0-45.  
 
Functional Assessment of Cancer Therapy-Lung (FACT-L): The FACT-L is a 35-item 
QOL tool that assesses physical, social/family, emotional, and functional well-being, as 
well as lung cancer specific symptoms over the past 7 days.46 We have used this measure 
in three prior PC trials in patients with lung cancer, demonstrating that early involvement 
of PC improves FACT-L scores.6,10  
 
EuroQol-5 Dimension (EQ-5D): The EQ-5D measures five dimensions of health 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with three 
levels of severity and self-rated health status on a 0-100 visual analog scale47,48 and is 
sensitive to QOL changes in patients with lung cancer.47,49 
 
Patient Health Questionnaire-9 (PHQ-9): The PHQ-9 is a nine-item measure that 
evaluates symptoms of major depressive disorder according to the criteria of the 
Diagnostic and Statistical Manual of Mental Disorders, which can be scored 
continuously or categorically.50 In our previous trials, early involvement of PC has 
improved PHQ-9 scores.6,10 

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Brief Cope: The Brief Cope is a 28-item questionnaire that assesses methods of coping 
(e.g., active, acceptance, denial) using a 4-point Likert scale ranging from 1 “a lot” to 4 
“never.”51 The psychometric properties of the Brief Cope have been demonstrated in 
studies of patients with serious illness and cancer.51,52 For our prior study, to minimize 
questionnaire burden, we solicited feedback from our research and PC teams about the 
coping strategies most likely to be influenced by our early PC intervention. We chose to 
exclude items such as self-distraction, substance use, and venting. We will limit our 
evaluation to eight coping strategies (16-items) deemed most relevant for the study (i.e., 
emotional support, positive reframing, active coping, acceptance, self-blame, denial, 
spiritual coping and behavioral disengagement). In our prior study, early involvement of 
PC increased use of active coping and decreased use of poor coping. We will administer 
16-items in the current trial. 
 
Support Service Utilization: At the 24-week primary endpoint, patients will be 
administered a single item assessing mental healthcare utilization since diagnosis. This 
item is designed to capture information which is routinely missing from the health record, 
as patients often either see mental health services external to the hospital, or access 
services which do not routinely document encounters in the electronic health record 
(EHR). 
 
Prognosis and Treatment Perceptions Questionnaire (PTPQ): The PTPQ is a tool that 
assesses patients’ illness understanding, communication about prognosis and goals of 
care, as well as discussions and preferences regarding EOL care.53 The PTPQ includes 
the item: “Have you discussed any particular wishes you have about the care you would 
want to receive if you were dying?” (Yes/No). This item has been previously used to 
assess EOL communication in patient with cancer.54  
 
5.3. Description of Intervention 
5.3.1. Stepped PC Arm 
Patients who have been randomized to the stepped PC arm will be scheduled for an initial 
visit with the PC clinician either in person or via secure video visit within four weeks of 
enrollment. During step 1, additional visits with the PC clinician will be scheduled at 
clinically relevant points in the patients’ illness. In our recent study, we observed that 
over 80% of clinic visits that the PC clinicians recorded as “significant interactions” 
occurred after patients’ cancer progressed or a recent hospitalization. Therefore, during 
step 1, patients will be scheduled to meet with the outpatient PC clinician either in person 
or via secure video visit within four weeks after a change in cancer treatment (including 
radiation), or within four weeks of discharge from an inpatient admission. ‘Change in 
treatment’ for this study is defined as: 
 
i. A change in cancer treatment due to either progression or toxicity 
ii. A discontinuation of cancer treatment 
 
Furthermore, if a step 1 patient is hospitalized within the first four weeks of enrollment, 
or if an inpatient admission occurs at any time, step 1 patients will default to the 

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procedure for hospitalizations and a PC appointment will be scheduled within four weeks 
of discharge. While hospitalized, step 1 patients may have inpatient PC appointments at 
the discretion of their oncology team, and such appointments will otherwise have no 
impact on study procedures.  
 
In our recent study, the early integrated PC intervention group had a median of seven PC 
visits per patient by week 24. Examining rates of cancer progression and hospitalizations 
from this study, we estimate that stepped care patients on step 1 of the intervention will 
have a median of three PC visits per patient by week 24, representing an approximate 
60% reduction in PC resource utilization. If a patient is unable to be scheduled in person 
or via secure video visit within four weeks of the change in treatment or hospitalization, 
the PC clinician will attempt to contact them by telephone within the four weeks, 
document the call in the EHR, and the visit will be scheduled as soon as possible. If 
patients miss any scheduled PC visits during step 1, and the visit cannot be rescheduled 
within four weeks of the change in treatment or hospitalization, the PC clinician will 
attempt to contact the patient by telephone within seven days from the missed visit, 
document the call in the EHR, and the visit will be rescheduled as soon as possible. If the 
patient is unable to be reached by phone, the PC clinician will document the attempted 
contact or voicemail in the EHR. If the PC clinician does not speak Spanish, visits for 
Spanish-speaking patients will be conducted with the assistance of an interpreter or 
family member. During step 1, PC clinicians will attempt to communicate with oncology 
regarding what occurred in each visit, either by phone, email, personalized electronic 
communication, or in person.  
 
Step 1 patients will complete the FACT-L every six weeks for a minimum of 12 months 
and up to 18 months from enrollment. FACT-L scores will be used to determine which 
step 1 patients need to step up to PC visits every four weeks. A 10-point change in the 
FACT-L is considered the upper range of a clinically meaningful difference and 
correlates with outcomes such as disease progression.55 Therefore, we will use a >10-
point decrease in the FACT-L from baseline at any follow-up time point to transition 
patients to step 2 of the intervention. In our recently completed trial of early integrated 
PC, 30% of patients receiving usual oncology care alone experienced a >10-point 
decrease in the FACT-L from baseline to week 12 with an additional 11% experiencing a 
>10-point decrease at week 24. For this trial, given that patients in step 1 will have 
intermittent visits with PC clinicians to help with symptoms and QOL, we anticipate that 
substantially fewer than 40% will have a >10-point decrease on the FACT-L by week 24, 
necessitating transition to step 2 of the intervention.  
 
Patients who transition to step 2 will then meet with the PC clinician either in person or 
via secure video visit at least every four weeks for the remainder of their illness and be 
seen by the inpatient PC team if they are hospitalized. If a patient is unable to be 
scheduled within four weeks from the last contact, the PC clinician will attempt to 
contact them by telephone (and document the call in the EHR) to maintain contact at least 
every four weeks. If patients miss a scheduled PC visit, and the visit cannot be 
rescheduled within four weeks of their previous contact, the PC clinician will attempt to 
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in the EHR. If the patient is unable to be reached by phone, the PC clinician will 
document the attempted contact or voicemail in the EHR. If the PC clinician does not 
speak Spanish, visits for Spanish-speaking patients will be conducted with the assistance 
of an interpreter or family member. For some short or weekend admissions or brief 
admissions for a planned medical procedure, it may not be feasible for PC to see the 
patient; if we are aware of a planned admission for a medical procedure or of a planned 
brief admission we will attempt to consult with the patient’s outpatient PC provider to see 
if it would be beneficial for them to see PC during the brief admission. 
 
A study staff member will score the FACT-L within 5 business days of receiving the 
surveys. Step 1 patients whose FACT-L scores are found to decrease by >10-points from 
baseline at any time during the study will be transitioned to Step 2 for the remainder of 
their illness. As outpatient PC is an available service at participating institutions, we will 
not deny patient or oncologist requests for additional PC visits for patients assigned to 
step 1. However, these visits will only be scheduled upon request and they will not 
trigger regularly scheduled visits every four weeks. In our prior study, only one-third of 
patients randomized to standard oncology care received a PC consultation based on 
request from the oncologist or the patient, with a median of 2 visits by 24 weeks. As step 
1 patients will have PC visits at clinically relevant points in their illness, we anticipate 
few requests for additional PC visits for patients on step 1 of the stepped care 
intervention. For patients who are still on step 1 at 18 months from enrollment, PC 
scheduling will be at the discretion of their PC and oncology teams. Patients on Step 2 
surviving greater than 18 months will be permitted to decrease the frequency of PC visits 
as per the discretion of their PC and oncology teams. Once patients are on hospice study 
visits will end, and further PC care will be per standard practice. 
 
5.3.2. Early Integrated PC Arm 
Patients assigned to early integrated PC will follow the identical study procedures used in 
our previous and ongoing trials.6,34 Specifically, patients will meet with the PC clinician 
either in person or via secure video visit within four weeks of enrollment and at least 
every four weeks throughout their course of illness. If a patient is unable to be scheduled 
in clinic within four weeks from the last contact, the PC clinician will attempt to contact 
them via telephone (and document the call in the EHR) to maintain contact at least every 
four weeks. If patients miss a scheduled PC visit, and the visit cannot be rescheduled 
within four weeks of their previous contact, the PC clinician will attempt to contact them 
by telephone within seven days from the missed visit and document the call in the EHR. 
If the patient is unable to be reached by phone, the PC clinician will document in the 
EHR that the PC team has attempted to contact the patient or they have left a voicemail 
asking for a return call if there are issues needing to be addressed. If the PC clinician does 
not speak Spanish, visits for Spanish-speaking patients will be conducted with the 
assistance of an interpreter or family member. The inpatient PC team will follow patients 
assigned to early integrated PC when they are hospitalized. For some short weekend 
admissions or brief admissions for a planned medical procedure it may not be feasible for 
PC to see the patient; if we are aware of a planned admission for a medical procedure we 
will consult with the patient’s outpatient PC provider to see if it would be beneficial for 
them to see PC during the brief admission. Patients on the early integrated PC arm 

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surviving greater than 18 months will be permitted to decrease the frequency of PC visits 
as per the discretion of their PC and oncology teams. Once patients are on hospice study 
visits will end, and further PC care will be per standard practice. 
 
5.3.3. Palliative Care Intervention Delivery 
While the study protocol details the frequency of contact with a PC clinician, a variety of 
uncontrollable factors may impact intervention delivery. Patient factors include a change 
in their cancer treatment schedule, cancellation of cancer treatment, or fatigue that 
prohibits participation in a visit. Clinician factors include clinic delays leading to missed 
patient appointments and insufficient staffing, especially due to meetings and vacations. 
To reduce patient and clinician burden, we will conduct PC visits either in-person or via 
an institution-approved secure video platform. If an in-person or video visit cannot be 
scheduled, PC visits may be conducted via telephone. We will document missed contacts 
as minor violations and institute a corrective action plan if more than 15% of all planned 
patient contact with PC does not take place per study protocol at a study site. 
 
5.4. Data Collection 
Table 1 depicts the assessments, measurements, and time points for the data collection. 
We will administer patient-reported measures for 48 weeks from enrollment. We selected 
a longer administration period in the current study as the median survival for patients 
with lung cancer is now approximately one year. The study assessment battery takes 
approximately 20 minutes to complete.  
 
Table 1. Summary of data collection instruments and time-points.   
 
 
 
 
5.4.1. Data from Electronic Health Record: 
Clinical information regarding tumor type (NSCLC, small cell lung cancer, and 
mesothelioma), current treatment regimen, date of diagnosis of incurable disease, 
*Step 1 patients will complete the FACT-L every 6 weeks for a minimum of 12 months and up to 18 
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previous diagnosis of early stage disease, tumor genotype, and ECOG Performance 
Status will be collected at baseline.  
 
Health care utilization data will be collected after death or at 12-months from the date the 
last patient enrolled on the study. We will collect data on: (1) outpatient and inpatient PC 
visits; (2) chemotherapy and radiation therapy administration; and (3) emergency 
department, hospital and intensive care unit admissions. EOL care measures will include 
referrals to and length of stay on hospice and location of death. 
 
5.4.2. PC Cost and Resource Utilization Data:  
To collect information on PC costs and resource utilization we will use the same data 
collection procedures as in our prior randomized trial of early integrated PC.56 
Specifically, we will collect data on the inpatient, and telephone PC encounters from the 
EHR and on number of outpatient, the duration of the PC visits from the Research 
Electronic Data Capture (REDCap) database. To collect outpatient and inpatient hospital 
costs, we will query Eclipsys Sunrise (EPSITM), which is the hospital cost accounting 
system used by all participating institutions and includes site specific software that 
provides Ambulatory Patient Classification (APC) codes for these encounters.57 Although 
we are unable to capture health care costs incurred at non-study institutions, patients 
receiving care at the participating sites most often utilize their institutions’ hospital. 
EPSITM has embedded reporting and analysis features that use the following data sources: 
budgeting and planning, cost accounting, patient financial and clinical analysis, and 
productivity. Actual total costs represent the total of direct costs (such as supplies, labor, 
laboratories, and procedures) and indirect costs (such as overhead and building 
management for the patient encounter). The data abstracted from EPSI TM represent the 
opportunity or resource use cost of care at the institution, rather than the amount charged 
to the patient’s insurance or the amount the hospital is reimbursed for patients’ care. We 
will utilize APC codes to normalize costs to those of the Center for Medicare and 
Medicaid Services (CMS). We will track medications prescribed in the EHR and 
determine their costs using standard methods.58 Chemotherapy drugs which are 
administered as part of a clinical trial will be assigned costs based on costs of similar 
FDA-approved medications. We will assign the cost of home and inpatient hospice days 
based on the CMS payment per day for the year of the patient’s hospice use. We will 
assess patient costs using survey data incorporated into our demographic questionnaire 
(travel time, transportation mode, co-payments), clinical data (number of clinic visits), 
and national wage data (value of patient time). All outpatient visits will incur 20% co-
insurance rate based on the Medicare Part B rate. We will also use Medicare Part A co-
insurance rates to estimate co-insurance costs for inpatient stays.  
 
5.4.3. Data on PC Visits: 
PC clinicians will report which domains they addressed during the study visit and the 
duration of the visit after each patient encounter, using REDCap. In our MGH trial, all 
PC clinicians completed REDCap entries after their clinical interactions for over 99% of 
their encounters.59 We will use the identical successful study procedures to ensure 
documentation of all PC clinical interactions in this trial. Specifically, prior to the study 
start all participating PC clinicians will be trained on the use of the REDCap survey and 

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the importance of entering this data. For each study patient encounter, the study staff will 
send a secure email with the patients’ name and a link to the REDCap system. PC 
clinicians will receive an email after the visit to remind them to complete the data entry. 
If the PC clinician does not complete the REDCap entry, they will continue to receive 
periodic reminders until the end of the 4-week window. We will not accept REDCap 
entries more than four weeks later than the appointment date. While we have trained 
study sites to complete these surveys after each patient encounter, it is not feasible for 
them to complete 100% of this documentation.  As such, we will not consider missed 
REDCap surveys from the PC clinicians to be protocol violations. 
 
5.4.4. Data Storage: 
All patient information and study source documents, including but not limited to signed 
informed consent forms, completed eligibility checklists, and participant questionnaires, 
will remain confidential and be scanned and stored on secure Partners computers and in 
REDCap. Since these records necessarily contain patient identifiers, only study staff will 
have access to them. Study staff will scan completed source documents, which may 
include identifiers such as participant names, upon their completion. Location, time, and 
date of the scanning of the document will be recorded. After the source document is 
scanned and the corresponding electronic document is confirmed to be legible, it will be 
collected and destroyed immediately. Study staff will destroy the original copy of the 
source document by following MGH procedures of destroying documents with Personal 
Health Information (PHI). Data abstracted from the EHR in Section 5.4.2 will be 
maintained in REDCap. REDCap is a free, secure, HIPAA-compliant web-based 
application hosted by the Partners HealthCare Research Computing, Enterprise Research 
Infrastructure & Services (ERIS) group. Vanderbilt University, with collaboration from a 
consortium of academic and non-profit institutional partners, has developed this software 
toolset and workflow methodology for electronic collection and management of research 
and clinical study data. Data collection projects rely on a study-specific data dictionary 
defined by members of the study staff with planning assistance from Harvard Catalyst 
and The Harvard Clinical and Translational Science Center EDC Support Staff. The 
iterative development and testing process results in a well-planned data collection 
strategy for individual studies. REDCap provides flexible features that can be used for a 
variety of research projects and provides an intuitive interface to enter data with real time 
validation (automated data type and range checks). The system offers easy data 
manipulation with audit trails, reports for monitoring and querying participant records, 
and an automated export mechanism to common statistical packages (SPSS, SAS, Stata, 
R/S-Plus). 
 
5.5. Description of Study Processes 
5.5.1. Instrument Administration 
A study staff member will administer study assessments at baseline and multiple follow-
up time points (see Table 1) within a +/- 2-week window to accommodate patient 
schedules. The assessment battery takes approximately 20 minutes to complete. Patients 
may complete assessments either in the clinic, online via REDCap email, on paper at 
home, via telephone, or via institution-approved video technology. As a first preference, 
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clinic. We will ask patients to provide their email address to allow us to email study 
measures using a secure electronic system when patients do not have a clinic appointment 
within the follow-up time points. For patients who opt out of using email, we will either 
send them paper copies of the survey or ask them to complete them verbally over the 
telephone or via institution-approved video technology. Surveys that are completed on 
paper at home will be labeled only with a case number and no identifying information; 
we will also add a note reminding participants to please not add their name or identifying 
information to the survey. We will provide a pre-paid, stamped envelope for participants 
who want to return questionnaires by mail.  
 
Spanish speaking participants will have the option of completing follow-up assessments 
in-person as a first preference, or otherwise via mail. Study staff who are fluent in 
Spanish may administer questionnaires via telephone or via institution-approved video 
technology. Spanish questionnaires will not be administered via email as this is not 
possible with REDCap.  
 
We will administer patient-reported measures for 48 weeks from enrollment. We selected 
a longer administration period in the current study as the median survival for patients 
with lung cancer is now approximately one year. The selected self-report measures have 
strong psychometric properties and have been well validated in previous studies. All 
study measures are available in both English and Spanish, except the Prognosis and 
Treatment Perceptions Questionnaire, which were translated (forward and backward) into 
Spanish with a native Spanish speaking clinician.  
 
5.5.2. PC Intervention Administration 
All participating PC clinicians will undergo training to ensure that the provision of PC 
services is consistent across study sites. Drs. Greer and Jackson developed a PC 
intervention guide based upon our prior studies that details the elements of PC in the 
outpatient care setting.60-62 The intervention guide outlines the domains that the PC 
clinicians will address at the initial visits (e.g., establishing a therapeutic relationship), 
visits throughout the disease course (e.g., symptom management and coping), and visits 
at the EOL (e.g., EOL care options), highlighting the essential elements and key points of 
each care domain.  The delivery of PC in both study arms will follow the intervention 
guide, with only the frequency and timing in which patients engage with PC differing by 
study arm. We also developed a series of training videos to illustrate the techniques 
included in the guide. Both the intervention guide and training videos are being used in 
our ongoing Alliance for Clinical Trials multi-site PC trial. Prior to the study start, all 
participating PC clinicians will watch the training videos. They will then attend a four-
hour training using video conferencing to review the intervention guide (the site PIs will 
complete this during their in-person or virtual training), led by the MGH study staff. They 
will also lead monthly supervision calls with the participating PC clinicians throughout 
the trial and ensure that new PC clinicians will receive training. Table 2 below 
summarizes the domains, elements, and key points of the PC intervention visits. 
Table 2. Palliative care visit summary 
Timing 
Domain 
Elements 
Key Points 

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5.5.3. Ensuring Fidelity of Study Design, Training, and Intervention 
We will take several steps to ensure the fidelity of our study design, training, and 
intervention delivery. Specifically, for the study design, we will utilize an evidence-based 
PC intervention guide, measure the number and duration of PC visits, and monitor the 
proportion of stepped care patients who transition to step 2 of the intervention. Also, we 
will employ rigorous training procedures for site PIs and study staff; use of video to 
illustrate delivery of the PC intervention; video-conferencing for training site PC 
clinicians and training for new PC clinicians; and monthly calls with the PC clinicians 
(led by Dr. Jackson) and the study staff (led by the MGH Project Manager). To ensure the 
Initial 
Visits 
Therapeutic   
Relationship 
• Introducing PC 
• Understanding the Patient and 
Caregiver Experience 
• Building Trust with the Patient 
and Caregiver 
• Develop a strong therapeutic relationship with patients and caregivers 
• Learn about the values, life goals, and experiences of patients and their 
caregivers both prior to and after the cancer diagnosis 
• Develop trust and credibility with patients and caregivers by providing 
reassurance and outlining parameters of communication 
All visits 
Patient  
Symptoms 
• Preparing for Symptoms 
• Assessing & Treating 
Symptoms 
• Coordinating Symptom 
Management with Oncology 
• Providing Referral for Symptom 
Management 
• Clarify the symptoms the patient will likely experience and offer reassurance 
about the methods for reporting and treating symptoms 
• At every visit, elicit existing and new symptom concerns 
• Maintain ongoing, effective communication with oncologists to define 
mutual collaboration and work within their preferred practice patterns  
• Emphasize team approach to care by referring to specialty care, mental 
health, alternative medicine, and spiritual support as needed 
Coping with   
Advanced  
Cancer 
• Reviewing & Validating Prior 
Coping Efforts 
• Discussing & Advocating for 
Different Methods of Coping 
• Supporting Caregiver Coping 
• Providing Referral for               
Additional Support 
• Recognize that patients and caregivers bring their own expertise in coping to 
the current circumstance based on prior experiences 
• Introduce strategies to help improve adjustment and meaning in life (e.g., 
behavioral, cognitive, and spiritual approaches; social support) 
• Bolster caregiver coping by assessing burden, enhancing their 
communication with patients, and recommending additional support 
• Involve other members of the team for patients and caregivers who may be 
experiencing severe distress (e.g., social work, psychology) 
Prognostic 
Awareness  
& Illness  
Understanding 
• Communicating with Oncology 
• Exploring Goals & Values 
• Assessing & Informing Patient 
Expectation of Prognosis  
• Conducting Separate 
Conversations with Caregivers  
• Consult with the oncologist to ensure the care team is consistent with their 
understanding of the patient’s prognosis 
• Assess patient’s hopes and expectations for treatment and future to clarify 
the patient’s level of prognostic awareness 
• Recognize that illness understanding often vacillates between more & less 
realistic expectations and work to improve prognostic awareness 
• Include both patients and caregivers in conversations about prognosis and 
illness understanding when possible 
Treatment 
Decision- 
making 
• Assessing Patient Values in 
Treatment Decision-Making 
• Discussing Treatment            
Considerations 
• Supporting Treatment Decisions 
• Elicit information from patients and caregivers regarding their decision-
making style, quality versus quantity of life concerns, and life goals 
• Provide support for patients and caregivers to understand the efficacy, and 
risks and benefits associated with cancer treatment 
• Clarify any misunderstanding about treatment, support patient decision-
making and freedom to change course 
Visits 
Near 
EOL 
EOL Care 
• Discussing EOL Care Options 
• Supporting Caregivers in EOL 
Care Coordination &               
Bereavement 
• Discuss/review selection of healthcare proxy, determination of resuscitation 
preferences, transition to hospice care, and location of death 
• Determine available resources for EOL care and whether it is appropriate for 
patients to receive care in the home or other settings; and provide resources 
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fidelity of intervention delivery, we will review PC documentation, and provide feedback 
to PC clinicians. As noted previously, the participating PC clinicians will complete an 
electronic survey after each clinical encounter to record the topics addressed during each 
visit. Two study staff will independently review the electronic surveys every 3 months to 
ensure intervention fidelity and conformity between sites in addressing the domains and 
topics as specified by the guide, allowing assessment of inter-rater agreement. Coder 
disagreement will be resolved via consensus discussion with Dr. Temel. Based on this 
review, Dr. Jackson will provide constructive feedback as needed to individual clinicians 
to confirm fidelity to the PC intervention. Trained study staff will also review PC notes in 
the health record to ensure adherence to the intervention guide content and provide 
feedback to clinicians at the site research meetings. 
 
5.5.4. Special Concerns 
Study staff at MGH, Duke, and Penn will all meet on a weekly basis to discuss any issues 
or concerns with study procedures. If it is decided that the protocol needs to be amended 
or modified, the lead site PI will make the necessary changes and submit an amendment 
to the DF/HCC IRB for approval. Once the amendment has been approved by the 
DF/HCC IRB, then the amendment will be submitted to the Duke IRB and the Penn IRB. 
 
5.6. Adverse Reactions and their Management 
5.6.1. Reporting Adverse or Unanticipated Events 
Identification of adverse events may come through notification from the study 
participant, caregiver, clinician, or from review of the EHR. In such circumstances, the 
PIs and investigative team will follow the following procedures: 
Serious Adverse Events: Given that this study is a PC intervention, we do not anticipate 
any study-related events meeting the FDA definition of a SAE (i.e., any fatal event, 
immediately life-threatening event, permanently or substantially disabling event, event 
requiring or prolonging inpatient hospitalization, or any congenital anomaly). This study 
population is comprised of individuals diagnosed with advanced lung cancer who 
frequently experience disease worsening, high rate of symptoms, and hospitalizations 
from the underlying disease and/or side effects of treatment. Therefore, as advanced lung 
cancer is a chronic-type terminal illness, regular fluctuations in cancer-related symptoms, 
disease worsening, hospitalizations, emergency department visits, and deaths are to be 
expected throughout the study, and we will not consider or report such events as SAEs in 
this trial. 
Non-Serious Adverse Events: The IRB will be provided with unblinded summaries of 
study related non-serious adverse events by treatment group at the continuing reviews. 
These reports will include types of events, severity, and treatment phase. To date, we 
have had very few non-serious events in our supportive care studies. 
 
5.6.2. Anticipated Reactions 
As this is a behavioral study, there are no ingested medications, and no biomedical 
procedures. It is unlikely that participants will be at any risk for physical harm as a result 
of study participation.   
 

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Participants may find some of the questions asked in the questionnaire to be emotionally 
upsetting and may experience some fatigue from the length of the assessment battery. As 
this is a study targeting symptoms that are debilitating and interfere with QOL, it is 
possible that some participants will experience depression. 
 
5.6.3. Reaction Management 
A detailed consent form will be signed by each participant following the explanations by 
the study staff or oncology clinician. The consent form will include all study procedures, 
information about potential risks and benefits of participation, and information regarding 
whom the participant can contact for further questions. It also will state that participation 
is voluntary, that participants can refuse to answer any question, that they can withdraw 
from the study at any time, and that study participation is in no way related to their 
medical care.  All study staff will complete the required human subjects training before 
working on any human subject aspects of the study.   
 
Should a participant exhibit or express distress, they will be reassured by the study staff 
that they need not answer any questions they find upsetting. They will also be reminded 
that study participation is voluntary. If participants remain distressed, both the PI and the 
primary oncology clinician will be notified. Should several participants express distress 
over an individual item, the study staff will review the questionnaire and contact the IRB 
to consider removing it from the study. 
 
If a participant reports severe distress or suicidal ideation during the study conduct, the 
study staff member has an obligation to inform the site PI and/or a member of the 
patient’s PC or oncology team. These clinicians will determine the need to involve 
psychiatry and take further action as deemed necessary. The study staff will review 
sensitive items regarding suicidal ideation within 120 hours (5 business days) of receipt 
of completed surveys and will report any suicidal ideation to the site PI and/or a member 
of the patient’s PC or oncology team promptly.  
 
6.0. Ethical and Legal Issues 
6.1. Confidentiality 
Patient data will be collected at each institution (MGH, Duke, and Penn) using REDCap. 
Each site will maintain their own separate list of patient names and study ID’s, which will 
be saved in secure electronic files. Participants will be identified on study 
forms by case number only to protect confidentiality. Identifiers such as name will only 
be used during the initial data retrieval process and can be destroyed once all data records 
have been obtained and data analysis has been completed as discussed previously. At the 
completion of the study, de-identified data files will be transferred from Duke and Penn 
to the MGH using a secure data transfer. 
 
Participants’ responses to survey questions will remain confidential unless there is active 
suicidal ideation confirmed by the study staff. Under these circumstances, as clearly 
stated in the patient consent form, the study staff member will inform the patient’s site PI 
and/or a member of the patient’s PC or oncology team. These clinicians will then 

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determine the need to involve social work, psychiatry and/or take further action as 
deemed necessary. 
 
7.0. Statistical Analysis 
7.1. Primary Endpoint 
To determine whether stepped PC is non-inferior to early integrated PC in improving 
patients’ QOL at 24 weeks. 
 
7.2. Secondary Endpoints 
7.2.1. To assess whether stepped PC is non-inferior to early integrated PC with 
respect to patient-clinician communication about EOL care preferences. 
7.2.2. To assess whether stepped PC is non-inferior to early integrated PC with 
respect to length of stay in hospice. 
7.2.3. To compare the superiority of stepped PC versus early integrated PC with 
respect to resource utilization. 
 
7.3. Exploratory Endpoints 
7.3.1. To compare the longitudinal patterns in QOL in patients assigned to stepped 
PC versus early integrated PC, as measured by repeated assessments of 
FACT-L. 
7.3.2. To compare the superiority of stepped PC versus early integrated PC with 
respect to cost-effectiveness. 
7.3.3. To compare coping strategies in patients assigned to stepped PC versus early 
integrated PC. 
7.3.4. To compare prognostic understanding in patients assigned to stepped PC 
versus early integrated PC. 
7.3.5. To compare depression in patients assigned to stepped PC versus early 
integrated PC. 
7.3.6. To compare health care utilization at the end of life (i.e., emergency 
department visits, hospitalizations, and chemotherapy administration) in 
patients assigned to stepped PC versus early integrated PC. 
 
7.4. Sample Size and Power Calculation  
The primary endpoint of the study is to establish that stepped PC is non-inferior to early 
integrated PC in the change in QOL, as measured by the FACT-L at week-24. Although 
the primary endpoints in our previous studies assessed the change in FACT-L from 
baseline to week-12, we chose to focus on QOL at 24 weeks as the life-expectancy of 
patients with advanced lung cancer has improved over the last few years. Thus, 
examining QOL at 12 weeks may overlook important differences between groups as the 
disease progresses. In our most recent trial of early integrated PC versus standard 
oncology care, we observed a 7.5-point difference in the FACT-L at week-24 favoring 
the integrated PC group. Thus, we chose a conservative non-inferiority margin of 4.5 
points, which is slightly less than 50% of the previously observed advantage with early 
integrated PC compared to oncology care alone. As a 6-point difference in FACT-L score 
is considered the lowest range of a clinically meaningful difference, our non-inferiority 
margin would not reach the threshold of clinically meaningful difference in QOL.55 With 

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188 patients per group, we will have >80% power to establish the non-inferiority of 
stepped PC compared to early integrated PC on the FACT-L with a one-sided alpha of 
0.05, and a non-inferiority margin of 4.5 points. We are currently observing 35% missing 
data across sites at 24 weeks, primarily due to progressive illness or death. Therefore, we 
increased our sample size to 255 per group to ensure we have adequate power to assess 
for non-inferiority of stepped PC. 
 
Our study also has adequate power to assess for non-inferiority of stepped PC compared 
to early integrated PC in EOL communication and hospice length-of-stay. With a sample 
size of 510, we will have >80% power, with a one-sided alpha of 0.05, to reject the 
hypothesis that patient-reported EOL communication with stepped PC would be 10% 
lower than early integrated PC, assuming that the rate of EOL communication in the early 
integrated PC group is 30% (based on our recent trial). With this sample size, we will 
also have ˃80% power to establish the non-inferiority of stepped PC compared to early 
integrated PC in hospice length-of-stay with a one-sided alpha of 0.05, and a non-
inferiority margin of 7 days. We were conservative with our power estimations by using 
the highest observed standard deviation for all outcomes from prior studies. 
 
Multiple testing: Testing of secondary outcomes will be one-sided for outcomes being 
tested for non-inferiority and two-sided for outcomes being tested for superiority. The 
Benjamini-Hochberg false discovery rate (FDR) control approach will be used to 
interpret results of significance tests of secondary outcomes with an FDR of 0.15. We 
selected an FDR of 0.15, which denotes the acceptable percentage of results that 
potentially represent false positives. Analyses of exploratory outcomes will not be 
adjusted for multiple comparisons, and presented results will emphasize estimates and 
confidence intervals. 
 
7.5. Analysis Plan  
The primary endpoint of the study is to establish that stepped PC is non-inferior to early 
integrated PC in QOL, as measured by the FACT-L at week-24. We will begin with 
descriptive and graphical summaries of the endpoints to evaluate whether the normality 
assumption is reasonable or if transformation is necessary. Based upon our prior study 
demonstrating statistical and clinically meaningful between group differences in the 
FACT-L at 24-weeks, the primary endpoint to compare patient FACT-L scores at week-
24 between the study groups using a linear regression model controlling for 
randomization stratification factors, baseline values, and demographic and clinical factors 
(as necessary for any imbalances in baseline variables). We will also use linear mixed 
models of the longitudinal data, allowing us to account for dependency among means 
over time and to control for demographic and clinical factors when examining change 
between groups in QOL across multiple time points. We will also compare the number of 
PC visits between the two groups to ensure that the stepped PC model led to a reduction 
in PC visits. 
 
We will compare depression (PHQ-9) and coping strategies (Brief Cope, including 
higher-order factors of the Brief Cope in our sample52: active coping & avoidant coping) 
at week-24 between groups using linear regression models controlling for randomization 

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stratification factors, baseline values and selected demographic and clinical factors. We 
will then evaluate linear mixed models of the longitudinal data, as described above, to 
examine changes in these outcomes between groups across multiple time points.  
 
To compare illness understanding as measured by the PTPQ between the two groups at 
week-24, we will analyze appropriate items using the appropriate model for the outcome 
of interest (e.g., linear regression or generalized linear models with an identity link 
function and binary response probability distribution) with adjustment for randomization 
stratification factors and any demographic and clinical factors that are imbalanced to 
assess differences between groups. 
 
We recently found that improvements in QOL and depression with PC are mediated 
through use of adaptive coping skills, and prior studies have shown that age, gender, and 
race can moderate the impact of PC in patients with cancer.63,64 Therefore, we will 
conduct bootstrapped tests of mediation to determine whether group differences in the 
FACT-L are mediated by improved coping or other potential mediators such as 
psychological distress. Additionally, we will explore potential moderators of the 
interventions to ensure generalizability and identify whether certain groups benefit more 
from one of the two PC models. We will create interaction terms for the linear regression 
and linear mixed models to examine whether differences in FACT-L are moderated by 
patient factors (e.g., age, gender, race, baseline distress), disease or treatment factors, or 
study site. 
 
The secondary aim of the study is to assess whether stepped PC is non-inferior to early 
integrated PC with respect to patient-clinician communication about EOL care 
preferences and length of stay in hospice. We will examine patient report of discussing 
EOL care preference with their clinicians using the following item: “Have you and your 
doctors discussed any particular wishes you have about the care you would want to 
receive if you were dying?” Although patients will complete this measure repeatedly 
during the course of the study, we will use the patient’s final assessment for this analysis. 
We will assess differences between study arms in the rate of patients reporting “yes” to 
this item using a one-sided alpha of 0.05 and a non-inferiority margin of 10%.  The 
difference in rates between study arms will be assessed using a generalized linear 
regression model specified with an identity link function and binomial response 
probability distribution with adjustment for the randomization stratification factors and 
any demographic and clinical variables that are imbalanced between groups.    
 
We will assess the non-inferiority of hospice length-of-stay between stepped PC and 
early integrated PC using linear regression model controlling for randomization 
stratification factors, as well as demographic and clinical factors that are imbalanced at 
baseline, with a one-sided alpha of 0.05 and a non-inferiority margin of 7 days. Although 
hospice length-of-stay is not normally distributed, based on a sample size of 510, the 
means would have a normal distribution (central limit theorem). We will also perform the 
Wilcoxon rank sum test to compare our results to those obtained with linear regression. 
We will also test whether differences in EOL outcomes are mediated by prognostic 

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awareness or moderated by patient factors (e.g., age, gender, race), disease or treatment 
factors, or study site as described in aim 1. 
 
We will also compare PC resource utilization and cost effectiveness of stepped PC versus 
early integrated PC. We will assess the superiority of stepped PC compared to early 
integrated PC with respect to PC resource utilization and cost. Total as well as category-
specific utilization and costs including PC, other outpatient care, emergency department 
use, inpatient care, and pharmaceuticals (chemotherapeutics and other pharmaceuticals 
evaluated separately) will be assessed to determine how resource use shifts for stepped 
versus early integrated PC. We will first compare the mean number of outpatient PC 
visits between the two groups using a linear regression model with adjustment for 
randomization stratification factors.. Although most utilization and cost outcomes are not 
normally distributed, based on a sample size of 510, the means would have a normal 
distribution (central limit theorem). We will also perform the Wilcoxon rank sum test to 
compare our results to those obtained with the linear regression model. 
  
We will assess the incremental cost-effectiveness of the early integrated PC arm relative 
to the stepped PC arm from the societal perspective using the average costs and quality 
adjusted life years (QALYs) accrued under each study arm and as follows: (Costearly 
integrated PC – Coststepped PC)/(QALYsearly integrated PC – QALYsstepped PC).65 A $50,000 per 
quality-adjusted life-year gained will be considered cost effective.66 Costs will include all 
direct health care costs and indirect (time) costs incurred by patients over their life spans 
while enrolled in the trial.67 The EQ-5D will be used to apply utility weights (quality 
adjustment) to patients’ life spans. Both costs and QALYs will be discounted at a rate of 
3%. Based on our prior trials, we expect that few patients will survive past the end of the 
study period.9 Cost and QALY data beyond the end of follow-up for those who are alive 
will be treated as missing data and estimated using multiple imputation methods. If we 
find that stepped care is non-inferior to early integrated PC in terms of both QALYs 
accrued and FACT-L scores, we will ignore QALY data and perform only a cost 
comparison between the study arms. We will use Monte Carlo methods using 10,000 
simulations to incorporate uncertainty in parameter estimates and develop confidence 
bounds on the estimated cost-effectiveness ratio or the cost difference. Following 
standard methods of economic evaluation as we have done in other studies, we will also 
perform parameter-specific sensitivity analyses in which individual parameters are varied 
singly and in combination, through plausible ranges to assess the relative impact different 
elements of the program have on overall cost-effectiveness.68,69 
 
7.5.1. Stratification Factors and Intervention Allocation Plan  
Patients will be randomized in 1:1 fashion and stratified by site (MGH vs. Duke vs. 
Penn) and underlying diagnosis (NSCLC vs. small cell lung cancer and mesothelioma). 
As patients with NSCLC have a significantly better prognosis than those with small cell 
lung cancer or mesothelioma, we will stratify by the underlying diagnosis to ensure 
adequate and balanced representation between the two study groups.   
 

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7.5.2. Stratification Factors and Their Impact on Design 
Stratification factors do not impact the design of the study but will be considered during 
data analysis to compare baseline statistics and outcomes based on initial eligibility 
criteria to participate in the study. Post-hoc comparisons between patients with 
NSCLC and those with small cell lung cancer and mesothelioma will determine if 
different outcomes existed between these two groups.  
 
7.5.3. Early Stopping Rules 
Not applicable. Participants will be included in the study as long as they continue seeking 
care at the study sites. Death or discontinuation of clinic visits are the only reasons for 
participants to not be included in the full intervention. 
 
7.5.4. Definition of and Allowance in Design for Unevaluable/Ineligible Participants 
No unevaluable and/or ineligible participants will be included in this study. 
 
7.5.5. Handling of Missing Data 
The analyses will initially focus on patients who completed the 24-week assessment to 
compare stepped PC with early integrated PC without imposing assumptions about 
missing data. We will also use the intention-to-treat principle with all randomized 
subjects, conducting sensitivity analyses to explore how various assumptions about 
missing data and differences between completers and non-completers affect the estimated 
outcomes. If data appear to be missing at random, we will employ multiple imputation 
methods. However, if we find that participants do not complete assessments due to 
progressive illness, suggesting missing data are not random, we will employ pattern 
mixture modeling or terminal decline joint modeling approach to address missing data. 
 
 
 
 

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Levy MH, Smith T, Alvarez-Perez A, et al. Palliative care, Version 1.2014. Featured 
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18. 
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Outpatient Palliative Care. J Palliat Med 2016;19:456-9. 
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Azizi M, Sapoval M, Gosse P, et al. Optimum and stepped care standardised 
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Kroenke K, Krebs EE, Wu J, Yu Z, Chumbler NR, Bair MJ. Telecare collaborative 
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Krebber AM, Jansen F, Witte BI, et al. Stepped care targeting psychological distress in 
head and neck cancer and lung cancer patients: a randomized, controlled trial. Ann Oncol 
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Jansen F, Krebber AM, Coupe VM, et al. Cost-Utility of Stepped Care Targeting 
Psychological Distress in Patients With Head and Neck or Lung Cancer. J Clin Oncol 
2017;35:314-24. 
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Singer S, Danker H, Briest S, et al. Effect of a structured psycho-oncological screening 
and treatment model on mental health in cancer patients (STEPPED CARE): study protocol for a 
cluster randomized controlled trial. Trials 2014;15:482. 
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Salloum A, Wang W, Robst J, et al. Stepped care versus standard trauma-focused 
cognitive behavioral therapy for young children. J Child Psychol Psychiatry 2016;57:614-22. 
29. 
Fokkenrood HJ, Scheltinga MR, Koelemay MJ, et al. Significant savings with a stepped 
care model for treatment of patients with intermittent claudication. Eur J Vasc Endovasc Surg 
2014;48:423-9. 
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Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus 
pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 
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Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced 
ALK-positive lung cancer. N Engl J Med 2013;368:2385-94. 
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Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in LUX-Lung 3: 
a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung 
adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3342-50. 
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PROFILE 1007: a randomized trial of crizotinib compared with chemotherapy in previously 
treated patients with ALK-positive advanced non-small-cell lung cancer. J Thorac Oncol 
2014;9:1625-33. 
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Temel J, El Jawahri A, Greer J, et al. Randomized Trial of Early Integrated Palliative and 
Oncology Care.  American Society of Clinical Oncology Annual Meeting; 2016. 
35. 
Hirsch FR, Suda K, Wiens J, Bunn PA, Jr. New and emerging targeted treatments in 
advanced non-small-cell lung cancer. Lancet 2016;388:1012-24. 

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lung cancers to select targeted drugs. JAMA 2014;311:1998-2006. 
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advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French 
Cooperative Thoracic Intergroup (IFCT). Lancet 2016;387:1415-26. 
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lung cancer. N Engl J Med 2015;372:2018-28. 
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Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39. 
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Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:123-35. 
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extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from 
KEYNOTE-028.  American Society of Clinical Oncology Annual Meeting; 2015. 
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non-small-cell lung cancer. N Engl J Med 2006;355:2542-50. 
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metastatic or locally recurrent lung cancer: a prospective study using the Lung Cancer Symptom 
Scale in a community hospital. J Palliat Med 2001;4:157-65. 
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psychological distress in follow-up care to identify head and neck cancer patients with untreated 
distress. Support Care Cancer 2016;24:2541-8. 
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Comorbidity Questionnaire: a new method to assess comorbidity for clinical and health services 
research. Arthritis Rheum 2003;49:156-63. 
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assess quality of life and meaningful symptom improvement in lung cancer. Semin Oncol 
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with advanced non-small-cell lung cancer: a prospective cross-sectional patient survey in a real-
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Health Policy 1990;16:199-208. 
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Carver CS. You want to measure coping but your protocol's too long: consider the brief 
COPE. Int J Behav Med 1997;4:92-100. 
52. 
Hagan TL, Fishbein JN, Nipp RD, et al. Coping in Patients With Incurable Lung and 
Gastrointestinal Cancers: A Validation Study of the Brief COPE. J Pain Symptom Manage 
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quality of life, and mood in patients with advanced cancer. Cancer 2014;120:278-85. 

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mental health, medical care near death, and caregiver bereavement adjustment. JAMA 
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Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire? Results from Eastern 
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Crit Care Med 2000;28:581-3. 
58. 
Hay JW, Smeeding J, Carroll NV, et al. Good research practices for measuring drug costs 
in cost effectiveness analyses: issues and recommendations: the ISPOR Drug Cost Task Force 
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Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness--the curious 
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Levy DE, Klinger EV, Linder JA, et al. Cost-Effectiveness of a Health System-Based 
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Celano CM, Healy B, Suarez L, et al. Cost-Effectiveness of a Collaborative Care 
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2016;19:185-91. 
 
 
 

32 
 
 
9.0. Appendices 
9.1. Suggested Template for Emailing Clinicians: Permission to Approach Patient 
 
Dear [MD/NP], 
 
We are screening patients for the randomized study of stepped palliative care versus early integrated 
palliative care in patients with advanced lung cancer. As a reminder, ALL study patients will receive 
longitudinal, concurrent care from a palliative care clinician but the timing in which the visits are 
scheduled will vary by study group. 
 
We plan to approach/contact [patient] [MRN] at one of their upcoming appointments to offer 
enrollment in this study. /We plan to contact [patient] [MRN] via telephone to offer enrollment in this 
study. 
 
Please respond to this email if you prefer to approach the patient for study participation yourself or if 
you prefer that we do not approach this patient (and please indicate the reason why). 
 
Thank you for your support, 
[Study Principal Investigator] 
 
9.2. Suggested Voicemail Script for Contacting Patients to Offer Enrollment 
 
Hello, my name is [study staff member] and I am contacting [patient] from [institution] on behalf of 
[oncologist] to offer participation in a research study. If you are interested in learning more about this 
opportunity, please contact our study staff at [staff phone number] at your convenience. Thank you for 
your time. 
 
9.3. Suggested Template for Emailing Oncology Clinicians: Notification about Step 1 Patients 
Following Enrollment 
 
Dear [MD/NP], 
 
Thank you for allowing me to meet with [patient] to introduce the Stepped Palliative Care study. After 
reviewing the details of the study and the consent form, [patient] signed consent and completed baseline 
measures. [Patient] will begin the study on Step 1 and will see palliative care at a reduced frequency 
following the initial visit. They will see palliative care again only following hospitalization or 
progression. Please plan to manage this patient’s prescriptions, since they will not see PC regularly. 
 
Thank you for your continued support of our study, 
[Study Staff Member] 
 
9.4. Suggested Template for Emailing Oncology Clinicians: Notification about Step 1 Patients on 
the Day of their First Oncology Appointment since Enrollment 
 
Good morning, 
 
You have an appointment with a Stepped Palliative Care [protocol number] study patient today.  
  

33 
 
 
[Last name, first name] (MRN) is on Step 1 of the study and [will see/is seeing] palliative care at a 
reduced frequency following the initial visit. They will see palliative care again only following 
hospitalization or progression. As a reminder, we will follow [patient name] closely and if their quality 
of life decreases, the palliative care visit frequency will increase to monthly. Please plan to manage this 
patient’s prescriptions, since they will not see palliative care regularly. 
 
Thank you for your continued support of our study, 
[Study Staff Member] 
 
9.5. Suggested Verbal Script for Questionnaire Administration 
 
Hello—is [name of patient] there? Hi, my name is [research coordinator’s name]; I work at the 
[institution name], and I am calling about the palliative care research study in which you are 
participating. Is now a good time to talk briefly? 
 
If yes →Move on to next section.  
If no → “Is there a better time at which I could call back?” 
 
As part of the study procedures, we would like to ask you to complete a questionnaire over the phone. 
Do you have about 15 minutes to complete it with me now? 
 
If yes →“Great, thank you.” Proceed to administering the questionnaire. 
If no → “Is there a better time at which I can call back so that we could complete the questionnaire 
together?”      
     
9.6. Suggested Paper Cover Letter when Mailing the Baseline Questionnaire to Participants  
 
Dear [name of patient], 
 
We are writing from [institution name] to see if you would be willing to take a questionnaire to 
complete your enrollment in the Stepped Palliative Care study that you discussed with our study staff 
[over the phone/at MGH] on [DATE]. The questionnaire should take about 15 minutes to complete. We 
have included a postage paid envelope for return of the questionnaire at no cost. If you prefer to do this 
electronically or by phone, please contact us at the phone number below. 
 
We greatly appreciate the time you have taken to participate in this study and for completing this 
questionnaire. Our study staff will contact you upon receipt of this questionnaire to confirm your 
enrollment and share the details about your first palliative care appointment.  
 
Thank you very much, 
[study staff name and contact information] 
 
Estimado/a [name of patient], 
 
Le estamos escribiendo de parte de [institution name] para ver si usted estaría dispuesto a tomar una 
encuesta y completar la registración en el estudio de cuidados paliativos que usted discutió con nuestro 
equipo de investigación por teléfono el [FECHA]. La encuesta debe tomar 15 minutos en 
completar.  Hemos incluido un sobre prepago para la devolución de la encuesta sin costo. Si usted 

34 
 
 
preferiría completarla electrónicamente o por el teléfono, por favor contáctenos al [número de 
teléfono]. 
 
Agradecemos mucho el tiempo que ha tomado para participar en este estudio y por completar esta 
encuesta. Nuestro equipo de investigación se comunicará con usted al recibir la encuesta para confirmar 
su registración y compartir los detalles de su primera cita con cuidados paliativos. 
 
Muchas gracias, 
[study staff name and contact information] 
 
9.7. Suggested Paper Cover Letter when Mailing the Questionnaires to Participants  
 
Dear [name of patient], 
 
We are writing from [institution name] to see if you would be willing to take a questionnaire that is 
part of the Stepped Palliative Care study that you are participating in with [oncology clinician name]. 
The questionnaire should take about 15 minutes to complete. We have included a postage paid envelope 
for return of the questionnaire at no cost. 
 
We greatly appreciate the time you have taken to participate in this study and for completing this 
questionnaire.   
 
Thanks very much, 
[study staff name and contact information] 
 
Distinguido [name of patient], 
Estamos escribiendo de [institution name] para ver si usted estaría dispuesto a tomar una encuesta que 
es parte del estudio de cuidados paliativos que estás participando en con [oncology clinician name]. La 
encuesta tomará 15 minutos para completar.  Hemos incluido un sobre de franqueo pagado para la 
devolución de la encuesta sin costo. 
 
Agradecemos mucho el tiempo que ha tomado para participar en este estudio y para completar esta 
encuesta. 
 
Muchas gracias, 
[study staff name and contact information] 
 
9.8. Suggested Email Cover Letter when Emailing the Baseline Questionnaire to Prospective 
Participants  
 
Dear [patient first name], 
 
I hope you are doing well. We are writing from [institution name] to see if you would be willing to take 
a questionnaire to complete your enrollment in the Stepped Palliative Care study that you discussed with 
our study staff on [DATE]. 
 
We are hoping that you can complete this questionnaire as a part of your participation. It would be great 
if you could try to complete it in the next few days. 

35 
 
 
 
Please feel free to reach out to me with any questions or concerns.  
 
Thank you, 
[Name and contact details of study staff member] 
 
9.9. Suggested Email Cover Letter when Emailing the Questionnaires to Participants  
 
Dear [patient first name], 
 
I hope you are doing well.  As a reminder, I am the research coordinator for the study you are enrolled in 
at [institution]. 
 
We are hoping that you can complete this questionnaire as a part of your participation.  It would be great 
if you could try to complete it in the next few days. 
 
Please feel free to reach out to me with any questions or concerns.  
 
Thanks, 
[Name and contact details of study staff member] 
 
9.10. Suggested Email Template when Sending Consent Form Copy to Participants via Email  
 
Dear [patient first name], 
 
I hope you are doing well. We are writing from MGH to share a copy of the consent form for the 
Stepped Palliative Care study that you discussed with our study staff on [MONTH + DAY, YEAR]. I 
will reach out shortly with a baseline questionnaire.  
 
Please feel free to reach out to me with any questions or concerns.  
 
Thank you,  
[Name and contact details of study staff member] 
 
9.11. Suggested Email Template when Scheduling PC Visits with Participants via Email  
 
Hi [patient first name], 
I hope you are doing well. As a reminder, I am the research coordinator for the study you are enrolled in 
at [institution]. I am reaching out to schedule a follow up appointment with [PC PROVIDER].  
Do you have any availability on [WEEKDAY, MONTH + DAY]? [PC PROVIDER] is available [at 
for any 30 minute session beginning at xx:yy-yy:xx./the following times:]  
Thank you so much,  
[Name and contact details of study staff member] 
 
 

36 
 
 
9.12. Data Safety Monitoring Plan 
 
The following procedures will be followed, in compliance with the Policy of the NCI for Data and Safety 
Monitoring of Clinical Trials. 
 
A. Responsibility for Data Safety and Monitoring 
As a supportive care efficacy trial with low risk to participants, the study will have a data safety 
monitoring plan and committee. Specifically, participation in this trial carries no risk of a Serious 
Adverse Event (SAE) and therefore the NCI does not require monitoring by a Data Safety Monitoring 
Board (DSMB).  Members of the MGH-based study staff (Temel, Greer, and Jackson) will serve as the 
data safety and monitoring committee (SMC). The study PI will be responsible for submitting necessary 
reports to the sponsor institutional regulatory board, as well as the NCI.  The study PI will collaborate 
with the two site-PIs to submit reports to their institutional regulatory board. 
 
B. Procedures for Monitoring Safety, Minimizing Research-Associated Risk, & Protecting 
Confidentiality.  
The SMC will meet weekly in person to review randomization data, as well as adverse events, across 
all three study sites. These adverse events are tracked for IRB submission as well. Per our IRB, study 
related adverse events are reported in real time, and study unrelated adverse events are reported with 
the continuing review. Safety information for this study will be reviewed by the SMC in an unblinded 
manner. A statistical penalty will not be assessed for the ongoing unblinded review of safety by the 
committee. Unblinded data will not be released to the investigators unless necessary for safety 
reasons. 
a. Protocol Fidelity and Investigator Compliance. To ensure protocol fidelity and investigator 
compliance, the SMC will audit and review a random selection of 5 participant cases from each 
study site each year. This process will include a review of study procedures for conforming with 
informed consent requirements and investigative team compliance with all study activities, as 
outlined in the protocol.  
b. Minimizing Research-Related Risks. The study PI/project manager will oversee weekly 
meetings with the participating institutions’ research staff members to discuss study operations 
and ensure consistent and safe implementation of study procedures, address problems or 
challenges with study procedures, and review general training issues. During this meeting, the 
study PI/project manager will review study procedures and address issues related to participant 
recruitment and enrollment, and data collection, management and analysis.  The study 
PI/project manager will also provide continuous training to address any issues with study 
operations and ensure ongoing review of the protocol and assessment procedures. The PI will 
review and address any participant risks and human subject issues. In addition, to ensure 
appropriate implementation of the study intervention and guard against any risk to participants, 
the primary and site PIs (i.e., Drs. Temel, Kumar, and Kamal) will ensure a rigorous training and 
supervision process for the study staff.  
c. Protection of Participant Confidentiality. Confidentiality will be assured by study procedures to 
ensure that participants will be identified on all study materials only by participant number, visit 
number, and date of visit. By recording the study data in this manner, the information can be 
considered 'de-identified,' and therefore compliant with the Standards for Privacy of Individually 
Identifiable Health Information ("Privacy Rule") of the Health Insurance Portability Act of 1996 
("HIPAA"). All study research staff will be trained in standard procedures to ensure that no 
participant names are directly associated with any data forms, but rather use designated ID 
codes to protect participant confidentiality. The study staff will present reports to the SMC on 
any breach to participant confidentiality, reasons for the breach, and a proposed plan for 
corrective action. 
d. Ensuring Data Validity and Security. The study PI had coordinated research initiatives over the 
past ten years that have established procedures and technologies for data collection, 
management, and security. Dr. Temel will oversee that aspect of the study, and the study staff 

37 
 
 
will have operational responsibility for data collection, de-identification, and management. 
Specifically, the study staff will develop a study specific data management protocol and 
standard operating procedures for the creation and testing of all study forms, data collection, 
quality control, and data extraction. We will provide ongoing oversight of data management 
throughout the study, and will be responsible for generating reports and datasets for quality 
control and data analysis. All data management activities will utilize REDCap, a software toolset 
and workflow methodology for electronic collection and management of research and clinical 
trial data. REDCap (Research Electronic Data Capture) data collection projects rely on a 
thorough study-specific data dictionary defined in an iterative self-documenting process by all 
members of the study staff with planning assistance from Partners HealthCare Research 
Computing, Enterprise Research Infrastructure & Services (ERIS) group. REDCap provides 
secure, HIPAA compliant, web-based applications with an intuitive interface for users to enter 
data and have real time validation rules (with automated data type and range checks) at the 
time of entry. 
e. Monitoring of Data Quality by the SMC. The SMC will review data quality and completeness 
from each of the participating sites twice yearly. They will review the progress of participant 
intake and retention; summary reports describing participant adherence with visits and 
evaluations as described in the protocol; and a summary of the completeness and quality of key 
data elements needed to characterize participants, their protocol adherence, and their primary 
and secondary outcomes. These reports will be used to evaluate the capacity of the data 
capture and processing to support scientifically valid analyses. For ease of understanding, 
reports will be done graphically, similarly to the CONSORT diagrams. 
 
A. Procedures for Review and Reporting of Adverse Events and Unanticipated Problems. 
Identification of adverse events may come through notification from the study participant, clinician, or 
from review of the electronic health record. In such circumstances, the PIs and investigative team will 
follow the following procedures: 
a. Serious Adverse Events. Given that this study is a randomized trial comparing two delivery 
modalities of an evidence-based supportive care intervention, we do not anticipate any study-
related events meeting the FDA definition of a SAE (i.e., any fatal event, immediately life-
threatening event, permanently or substantially disabling event, event requiring or prolonging 
inpatient hospitalization, or any congenital anomaly). The proposed study population is 
comprised of individuals diagnosed with advanced lung cancer who frequently experience 
disease worsening, high rate of symptoms, and hospitalizations from the underlying disease 
and/or side effects of treatment. Therefore, as advanced lung cancer is a chronic-type terminal 
illness, regular fluctuations in cancer-related symptoms, disease worsening, hospitalizations, 
emergency department visits, and deaths are to be expected throughout the study, and we will 
not consider or report such events as SAEs in this trial. 
b. Non-Serious Adverse Events. At yearly intervals during the course of the study and then again 
at its completion, the SMC will review unblinded summaries of the numbers and rates of non-
serious adverse events by treatment group. To date, the majority of non-serious adverse events 
in our prior supportive care studies have been due to patient discomfort with the study 
questionnaires. 
c. Other Safety-Related Reports. At yearly intervals throughout the course of the study, the SMC 
will also review unblinded summary reports of treatment retention and reasons for dropout, by 
treatment group.  
d. Study Stopping Rules. If at any time during the course of the study, the SMC judges that risk to 
participants outweighs the potential benefits, the SMC shall have the discretion and 
responsibility to recommend that the study be terminated. We do not, however, have a pre-
specified stopping rule given the low risk of this behavioral study to participants. 
 
B. Multisite Study Data Safety and Monitoring. 

38 
 
 
The procedures for data safety monitoring and reporting will be the same for the three participating 
study sites. Throughout the course of the study, the primary PI will have monthly meetings with the site 
PIs to ensure consistent implementation of procedures for data safety monitoring and reporting. The 
SMC will review reports that include all relevant data stratified by study site. 
 
C. External Factors That May Impact Safety of Participants or Ethics of the Study. 
The PI will conduct a literature review every six months to ensure that no new developments have 
emerged that may affect the study or participants.  
 
D. Advance Plans for Interim and/or Futility Analyses.  
This study will not include interim and/or futility analyses. 
 
E. Timely Reporting to the NCI. 
The PI will report to the NCI within 7 days of occurrence of any unanticipated problems or unexpected 
adverse events that may be related to the study protocol; IRB-approved revisions to the study protocol 
that indicate a change in risk for participants; a summary of recommendations made by the SMC and 
the action plan for response; or notice of any actions taken by the IRB or regulatory bodies regarding 
the research and any responses to those actions. 
 
9.13. Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION 
40 
1.1 
Purpose 
40 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 40 
2. 
GENERAL ROLES AND RESPONSIBILITIES 
41 
2.1 
DF/HCC Sponsor 
41 
2.2 
Coordinating Center 41 
2.3 
Participating Institution 
42 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
42 
3.1 
Protocol Distribution 42 
3.2 
Protocol Revisions and Closures 
43 
3.3 
Informed Consent Requirements 
43 
3.4 
IRB Documentation 43 
3.5 
IRB Re-Approval 
44 
3.6 
Participant Confidentiality and Authorization Statement 
44 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 44 
3.8 
DF/HCC Protocol Case Number 
45 
3.9 
Safety Assessments and Toxicity Monitoring 
46 
3.10 
Data Management 
46 
4. 
MONITORING: QUALITY CONTROL 
47 
4.1 
Ongoing Monitoring of Protocol Compliance 
47 

39 
 
 
4.2 
Monitoring Reports 
47 
4.3 
Accrual Monitoring 47 
5. 
AUDITING: QUALITY ASSURANCE 
48 
5.1 
DF/HCC Internal Audits 
48 
5.2 
Audit Notifications 
48 
5.3 
Audit Reports 48 
5.4 
Participating Institution Performance 48 
 
 
 

40 
 
 
1. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The DF/HCC 
DSMP serves as a reference for any sites external to DF/HCC that are participating in a DF/HCC clinical 
trial.  
 
1.1 
Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center protocol 
will comply with Federal Regulations, Health Insurance Portability and Accountability Act (HIPAA) 
requirements and applicable DF/HCC Standard Operating Procedures.        
 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one or more outside institutions are 
collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the sponsor. 
DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-Farber 
Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center 
(BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital (BWH) responsible for the 
coordination, development, submission, and approval of a protocol as well as its subsequent amendments 
per the DFCI IRB and applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), 
Office of Biotechnology Activities (OBA) etc.).  The Lead Institution is typically the home of the DF/HCC 
Sponsor. The Lead Institution also typically serves as the Coordinating Center for the DF/HCC Multi-
Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol who takes responsibility 
for initiation, management and conduct of the protocol at all research locations. In applicable protocols, 
the DF/HCC Sponsor will serve as the single liaison with any regulatory agencies. The DF/HCC Sponsor 
has ultimate authority over the protocol and is responsible for the conduct of the study at DF/HCC and all 
Participating Institutions. 
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium that is 
collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  The Participating 
Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and responsibility for the 
overall conduct of the study. 
    
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research Organization 
(CRO), etc) that provides administrative support to the DF/HCC Sponsor in order that he/she may fulfill 
the responsibilities outlined in the protocol document and DSMP, and as specified in applicable regulatory 
guidelines (i.e. CTEP Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center 
for the DF/HCC Multi-Center Protocol.  
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high-quality 
standards are used for data collection and the ongoing management of clinical trials, auditing, and data and 
safety monitoring. ODQ also coordinates quality assurance efforts related to multi-center clinical research. 

41 
 
 
 
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within DF/HCC responsible 
for providing a comprehensive data management platform for managing clinical trial data. 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities:  
 
2.1 
DF/HCC Sponsor 
 
The DF/HCC Sponsor, Jennifer Temel, will accept responsibility for all aspects of conducting a DF/HCC 
Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments.  
• Ensure that the investigators, study staff members, and Participating Institutions are qualified and 
appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study staff member receives adequate protocol 
training (and/or a Site Initiation Visit prior to enrolling participants) and throughout trial’s 
conduct as needed. 
• Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS). 
• Maintain documentation of Adverse Event (AE) reports and deviations/violation submitted by 
Participating Institutions and provide to the DF/HCC Sponsor for timely review and submission to 
the DFCI IRB, as necessary.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (i.e. NIH) 
reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by anyone other than 
the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior to extending 
the protocol to that site. 
• Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements.  
 
2.2 
Coordinating Center  
 
The general responsibilities of the Coordinating Center, which will synonymous with the DF/HCC sponsor 
for this protocol, may include but are not limited to: 
• Assist in protocol development.  
• Maintain NIH correspondence, as applicable. 
• Distribute protocol and informed consent document updates to Participating Institutions as needed. 

42 
 
 
• Oversee the data collection process from Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements that they will 
be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or remote monitoring.  
• Maintain Regulatory documents of all Participating Institutions which includes but is not limited 
to the following: local IRB approvals/notifications from all Participating Institutions, 
confirmation of Federal wide Assurances (FWAs) for all sites,  all SAE submissions, Screening 
Logs for all sites, IRB approved consents for all sites 
• Conduct regular communications with all Participating Institutions (conference calls, emails, etc) 
and maintain documentation all relevant communications. 
 
2.3 
Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations and DF/HCC 
requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not limited to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial as required 
(i.e., teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research related 
activities.  
• Submit AE reports to local IRB per institutional requirements and to the Coordinating Center, in 
accordance with DF/HCC requirements.  
• Submit protocol deviations and violations to local IRB per institutional requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at the conclusion 
of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring queries or audit 
findings. 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
The following section will clarify DF/HCC Requirements and further detail the expectations for participating 
in a DF/HCC Multi-Center protocol.  
 
3.1 
Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent 
amended protocols to all Participating Institutions.    
 

43 
 
 
3.2 
Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its IRB of these 
revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written notification of 
protocol revisions regarding non life-threatening events from the Coordinating Center. Non-life-
threatening protocol revisions must be IRB approved and implemented within 90 days from receipt 
of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive immediate notification 
from the Coordinating Center concerning protocol revisions required to protect lives with follow-
up by fax, mail, e-mail, etc.  Life-threatening protocol revisions will be implemented immediately 
followed by IRB request for approval. 
 
• Protocol closures and temporary holds: Participating Institutions will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and holds will be 
effective immediately.  In addition, the Coordinating Center, will update the Participating 
Institutions on an ongoing basis about protocol accrual data so that they will be aware of imminent 
protocol closures. 
 
3.3 
Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the informed consent for 
Participating Institutions. The Participating Institution consent form must follow the consent template as 
closely as possible and should adhere to specifications outlined in the DF/HCC Guidance Document on 
Model Consent Language for PI-Initiated Multi-Center Protocols.  This document will be provided 
separately to each Participating Institution upon request. 
 
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior to 
submission to their local IRB. The approved consent form must also be submitted to the Coordinating 
Center after approval by the local IRB for all consent versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician members of the 
study staff who will be obtaining consent and signing the consent form for therapeutic protocols. 
Participating institutions must follow the DF/HCC requirement that only attending physicians obtain 
informed consent and re-consent for all interventional drug, biologic, or device research.   
 
3.4 
IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB.  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB.  
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 

44 
 
 
 
3.5 
IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to continue research 
activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received from the 
Participating Institution on or before the anniversary of the previous approval date.   
 
 
3.6 
Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information known as the 
Health Insurance Portability and Accountability Act (HIPAA). Any information, related to the physical or 
mental health of an individual is called Protected Health Information (PHI). HIPAA outlines how and under 
what circumstances PHI can be used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course of a study, 
the study participant must sign an authorization statement.  This authorization statement may or may not 
be separate from the informed consent document.  The Coordinating Center, with the approval from the 
DFCI IRB\, will provide a consent template, with information regarding authorization for the disclosure of 
protected health information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. 
However, because of the nature of these trials, certain protected health information must be collected. 
DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather than limited data 
sets with data use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly confidential. 
Whenever reasonably feasible, any participant specific reports (i.e., Pathology Reports, MRI Reports, 
Operative Reports, etc.) submitted to the Coordinating Center should be de-identified. It is recommended 
that the assigned protocol case number (as described below) be used for all participant specific documents. 
Participant initials may be included or retained for cross verification of identification.  
 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
 
3.7.1  Participant Registration and Randomization  
To register a participant, the following documents should be completed by the Participating Institution 
and e-mailed to the Lead Institution [mghsteppc@partners.org]: 
 
• Signed de-identified informed consent document 
• HIPAA authorization form (if separate from the informed consent document) 
• Completed Eligibility Checklist 
 
The Lead Institution will review the submitted documents in order to verify eligibility and consent. To 
complete the registration process, the Lead Institution will: 

45 
 
 
• Register the participant on the study with the DF/HCC Clinical Trial Management System (CTMS). 
• Upon receiving confirmation of registration, the Coordinating Center will inform the Participating 
Institution and provide the study specific participant case number, and, if applicable, assigned 
treatment and/or dose level.  
 
Protocol-specific interventions may not begin without confirmation from the Coordinating 
Center that the participant has been registered.  
 
Randomization can only occur during normal business hours, Monday through Friday from 8:00 AM to 
5:00 PM Eastern Standard Time. 
 
3.7.2  Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before the initiation of protocol-specific 
interventions. Protocol-specific interventions may not be initiated until the Participating Institution receives 
confirmation of the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and 
DFCI IRB must be notified of any violations to this policy. 
 
3.7.3  Eligibility Exceptions 
 
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be permitted. 
All Participating Institutions are required to fully comply with this requirement. The process for requesting 
an eligibility exception is defined below. 
 
3.8 
DF/HCC Protocol Case Number 
 
At the time of registration, the following identifiers are required for all subjects: initials, date of birth, 
gender, race and ethnicity. Once eligibility has been established and the participant successfully registered, 
the participant is assigned a unique protocol case number.  Participating Institutions should submit all de-
identified subsequent communication and documents to the Lead Institution, using this case number to 
identify the subject.   
 
3.8.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to ensure that 
researchers do not initiate changes in approved research without IRB review and approval, except when 
necessary to eliminate apparent immediate hazards to the participant. DF/HCC requires all departures 
from the defined procedures set forth in the IRB approved protocol to be reported to the DF/HCC Sponsor, 
who in turn is responsible for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to describe 
departures from a protocol. All Participating Institutions must adhere to these requirements for reporting 
to the DF/HCC Sponsor and will follow their institutional policy for reporting to their local IRB. 
 
3.8.2  Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved protocol 
which is prospectively approved prior to its implementation. 
 

46 
 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
  
 
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB prior to its 
initiation or implementation.   
 
3.8.3  Reporting Procedures 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the medical record 
and/or regulatory documents to describe all protocol exceptions, deviations and violations. The DF/HCC 
Sponsor will also be responsible for ensuring that all protocol violations/deviations are promptly reported 
per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. The 
Participating Institution must submit the deviation request to the Coordinating Center who will then submit 
the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation is submitted to the 
Participating Institution IRB, per institutional policy. A copy of the Participating Institution’s IRB report 
and determination will be forwarded to the Coordinating Center within 10 business days after the original 
submission.  The deviation may not be implemented without all required approvals. 
 
All protocol violations must be sent to the DF/HCC sponsor in a timely manner. The Coordinating Center 
will provide training for the requirements for the reporting of violations.  Subsequently, the Participating 
Institution’s IRB violation/deviation report will be submitted to the DFCI IRB for review per DFCI IRB 
reporting guidelines.  
 
3.9 
Safety Assessments and Toxicity Monitoring 
 
The study staff at all participating institutions are responsible for protecting the safety, rights and well-
being of study participants. Recording and reporting of adverse events that occur during the course of a 
study help ensure the continuing safety of study participants.  
 
 
3.9.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed in protocol 
section 5.6. As a supportive care trial entailing scheduled interactions with a palliative care clinician, this 
trial is of low risk to study participants. Specifically, participation in this trial carries no risk of a Serious 
Adverse Event (SAE).   
 
 
 
 
 
Participating Institutions must report the AEs to the DF/HCC Sponsor and the Coordinating Center 
following the DFCI IRB Adverse Event Reporting Policy.  
 
The DF/HCC Sponsor will maintain documentation of all Participating Institution Adverse Event reports 
and be responsible for communicating to all participating investigators, any observations reportable under 
the DFCI IRB Reporting Requirements.  Participating Institutions will review and submit to their IRB 
according to their institutional policies and procedures 
3.10 
Data Management 
The DF/HCC Sponsor will develop case report forms (CRF/eCRFs), for use with the protocol.  These forms 
are designed to collect data for each study.  
   

47 
 
 
3.10.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. If study forms are received 
with missing or questionable data, the submitting institution will receive a written or electronic query from 
the DF/HCC Office of Data Quality, Coordinating Center, or designee.  
 
Responses to all queries should be completed and submitted within 14 calendar days.   
 
Responses may be returned on the written query or on an amended paper case report form, or in the case 
of electronic queries, within the electronic data capture (eDC) system. In the case of a written query for 
data submitted on a paper case report form, the query must be attached to the specific data being re-
submitted in response.   
 
If study forms are not submitted on schedule, the Participating Institution will periodically receive a 
Missing Form Report from the Coordinating Center noting the missing forms.  
 
 
4. MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance and data 
accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides quality 
control oversight for the protocol. 
 
4.1 
Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions may be required to submit participant source documents to the Coordinating 
Center for monitoring. Participating Institution may also be subject to on-site monitoring conducted by the 
Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating 
Institutions are complying with regulatory and protocol requirements, data quality, and participant safety. 
Monitoring practices may include but are not limited to source data verification, and review and analysis 
of eligibility requirements, informed consent procedures, adverse events and all associated documentation, 
review of study drug administration/treatment, regulatory files, protocol departures reporting, pharmacy 
records, response assessments, and data management.  
 
Participating institutions will participate in monthly conference calls to review the study progress and 
address any challenges with the study conduct The Coordinating Center will also send monthly emails to 
the Participating Sites to update them on the study progress. 
 
4.2 
Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The DF/HCC 
Sponsor may increase the monitoring activities at Participating Institutions that are unable to comply with 
the protocol, DF/HCC Sponsor requirements or federal and local regulations.  
 
4.3 
Accrual Monitoring 
 

48 
 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual requirements 
for each participating institution. Accrual will be monitored for each participating institution by the 
DF/HCC Sponsor or designee. Sites that are not meeting their accrual expectations may be subject to 
termination.  All Participating Institutions agreed to enroll a minimum of 160 patients per year. 
 
 
5. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance and involves the systematic and independent examination of all 
trial related activities and documents.  Audits determine if evaluated activities were appropriately 
conducted and whether data was generated, recorded and analyzed, and accurately reported per the 
protocol, applicable Standard Operating Procedures (SOPs), and the Code of Federal Regulations (CFR). 
 
5.1 
DF/HCC Internal Audits 
  
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). Typically, 
approximately 3-4 participants would be audited at the site over a 2-day period. If violations which impact 
participant safety or the integrity of the study are found, more participant records may be audited.  
 
5.2 
Audit Notifications 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all external audits or 
inspections that involve this protocol. All institutions will forward a copy of final audit and/or re-audit 
reports and corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after the 
audit date.  
 
5.3 
Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. The 
Coordinating Center, must forward any reports to the DF/HCC ODQ per DF/HCC policy for review by the 
DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee would forward the 
final audit report and corrective action plan to the DFCI IRB as applicable. 
 
5.4 
Participating Institution Performance 
 
The DF/HCC Sponsor, Coordinating Center, and the DFCI IRB are charged with considering the totality 
of an institution’s performance in considering institutional participation in the protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of timely and 
accurate data, adherence to protocol requirements, and compliance with state and federal regulations, may 
be recommended for a six-month probation period. Such institutions must respond with a corrective action 
plan and must demonstrate during the probation period that deficiencies have been corrected, as evidenced 
by the improved performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. A DF/HCC 
Sponsor and/or the DFCI IRB may terminate a site’s participation if it is determined that a site is not 
fulfilling its responsibilities as described above.