Clinical Utility Study of a Low-Cost Hand-Held Breast Scanner
Phase: NA
Conditions: Breast Cancer
Sponsor: University of Pennsylvania

PEF Evaluation 
 
page 1 
UPCC 24114 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
Clinical Utility Study of a Low-Cost Hand-Held Breast Scanner  
 
 
Regulatory Sponsor: 
Ari D. Brooks, MD 
Department of Surgery 
University of Pennsylvania Health System 
800 Walnut Street  
Philadelphia, PA 19107 
(215) 829-8461 
Funding Source: 
UE Lifesciences, Inc. 
3711 Market St, Suite 800 
Philadelphia, PA 19104 
(631) 980-8340 
Sub-Investigators 
Brian Englander, MD 
Department of Radiology 
Pennsylvania Hospital 
800 Spruce Street 
Philadelphia, 19106 
(215) 829-6079 
 
 
 
 
 
NCT02597452 
 
 
 
 
 
 
 
 
Initial version: 12/09/2014 

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Table of Contents 
 
1 
INTRODUCTION .................................................................................................................................. 3 
1.1 
BACKGROUND ................................................................................................................................ 3 
1.2 
INVESTIGATIONAL DEVICE ............................................................. ERROR! BOOKMARK NOT DEFINED. 
1.3 
FEASIBILITY TESTING ...................................................................................................................... 5 
1.4 
CLINICAL DATA TO DATE................................................................................................................. 6 
1.5 
RISK/BENEFITS .............................................................................................................................. 6 
2 
STUDY OBJECTIVES ......................................................................................................................... 7 
3 
STUDY DESIGN ................................................................................................................................... 7 
3.1 
GENERAL DESIGN .......................................................................................................................... 7 
3.2 
STUDY ENDPOINTS......................................................................................................................... 7 
4 
SUBJECT SELECTION ....................................................................................................................... 7 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 7 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 7 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 8 
5 
STUDY PROCEDURES ....................................................................................................................... 8 
6 
STATISTICAL PLAN ......................................................................................................................... 11 
6.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 11 
6.2 
STATISTICAL METHODS ................................................................................................................ 11 
7 
SAFETY AND ADVERSE EVENTS ................................................................................................... 12 
7.1 
DEFINITIONS ................................................................................................................................ 12 
7.2 
RECORDING OF ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS ................................. 12 
7.2.1 
Investigator reporting: Notifying the IRB ............................................................................... 13 
7.2.2 
Investigator reporting: Notifying the Abramson Cancer Center DSMC ................................. 13 
7.3 
MEDICAL MONITORING ................................................................................................................. 14 
8 
DATA HANDLING AND RECORD KEEPING ................................................................................... 14 
8.1 
CONFIDENTIALITY ......................................................................................................................... 14 
8.2 
MAINTAINING RECORDS ….……………………………………………………………………………..14 
8.3          SOURCE DOCUMENTS ................................................................................................................... 15 
9 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 15 
9.1 
STUDY MONITORING PLAN ............................................................................................................ 15 
9.2 
AUDITING AND INSPECTING ........................................................................................................... 15 
10 
STUDY FINANCES ............................................................................................................................ 15 
10.1 
FUNDING SOURCE ........................................................................................................................ 15 
10.2 
CONFLICT OF INTEREST ................................................................................................................ 15 
10.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 15 
11 
REFERENCES ................................................................................................................................... 16 
 
 
 

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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (International Conference on 
Harmonization ICHE6), the Code of Federal Regulations Title 21 parts 803 and 812, and other 
applicable government regulations and Institutional research policies and procedures.  
1.1 Background 
Breast cancer is a leading cause of cancer related deaths amongst women in Pennsylvania as 
well as in the US. Early detection improves the survival rate, makes treatment less costly and 
lowers the overall burden of the disease. Of note, Breast cancer (BC) is the most common 
cancer in women worldwide, disproportionately affecting low- and middle-income countries 
(LMICs): 
• Today, 52.6% of new breast cancer cases occur in LMICs, and this is expected to grow to 
70% by year 2020.i 
• Two-thirds of the estimated 15,000,000 healthy-life years lost annually to breast cancer 
globally are from LMICs.ii 
• 5-year survival is 40-60% in most LMICs as compared to 80-90% in High Income Countries 
(HICs).iii 
Lack of secondary prevention programs (population based screening) and enhanced 
treatment, are the two major differentiating factors for poorer breast cancer outcomes in LMICs. 
Tumors detected as a result of routine screening tend to be smaller, well differentiated and less 
likely to have regional lymph- node involvement, making treatment more effective and survival 
more likely.iv,v,vi Smaller, earlier-stage tumors are amenable to better, less costly treatment 
options. The National Cancer Institute-supported Cancer Intervention and Surveillance and 
Modeling Network (CISNET) suggests that 28–65% (median 46%) of the observed decrease in 
BC mortality in USA can be attributed to screening, with the remainder attributed to adjuvant 
treatment. 
1.2 Challenges with secondary prevention and early diagnosis of breast cancer in LMICs 
In HICs, screening mammography and clinical breast exam (CBE) are the standards of 
care for BC screening and detection. Their efficacy, cost-effectiveness and effect on survival and 
mortality of BC have been well documented. However, availability and/or use of these 
modalities remain limited in LMICs. 
Organized screening mammography is expensive, resource intensive, requires stringent 
quality assurance and a large, well-trained workforce of technicians and radiologists. The cost 
per year of life saved ranges between Int.$3,468 and Int.$16,000,vii viii which is beyond the health 
spending capabilities of most LMICs. In terms of human resources, most LMICs simply do not 
have the radiology expertise capacity required for an effective mammographic screening 
program. India, for example, has 10% the number of radiologists of the U.S. but almost 4 times 
the population.ix Clinically, mammograms are limited in women with dense breasts, which 
includes most women under 50 years of age. Culturally, in LMICs there are reservations about 
radiation based, sometimes painful mammogram tests.x So even when mammography is 
available, it is often not utilized; Mexico’s Ministry of Health reports that only 25% of the 
installed mammography units are in use.xi 
CBE. The World Health Organization and the Breast Health Global Initiative recognize 
CBE as a cost-effective measure to screen for BC in LMICs. In a study in Indonesia, CBE 
performed nearly as well as single-view mammography.xii In an IARC-supported, cluster-

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randomized controlled study in India, CBE has been shown to enable the detection of early-stage 
breast cancers.xiii It is known however that the efficacy of CBE may be substantially lower (28-
36%) in practice than is reported in clinical trials.xiv Physical exams in community health 
practice are often less systematic and poorer quality than in many organized clinical trials.xv So 
the true contribution of CBE to BC detection in healthy women, and to improved survival in BC 
patients, has come under question, resulting in recent calls to standardize and lower the 
subjectivity of CBE administration and reporting.xvi 
1.3 Health worker led “earlier detection”  
The American Joint Committee on Cancer (AJCC) staging system indicates prognosis 
based on the size of the tumor at detection viz. stage of breast cancer. Identifying tumors at 
earlier stages (down-staging) can improve survival, assuming high-quality treatment is 
accessible. In the U.S., approximately 40 million women receive mammograms annually and 
roughly 232,000 new cases are identified; vast majority are detected at stage Tis and T1 with a 5-
year survival of 100%. In the context of LMICs, where up to two-thirds of breast cancer cases 
present at late stages, systematic down-staging is required, such that majority of the cases would 
be identified at Stage II or earlier, where survival can be 93% or better (again, assuming 
treatment is available). 
In LMICs, health workers, nurses and midwives represent the most affordable resource to 
bridge the accessibility gap due to the lack of secondary prevention programs like in HICs. What 
is needed is a low-cost, user-friendly technology that can be used by health workers with 
minimal training to administer standardized breast exams without any special infrastructure with 
the goal to down-stage breast cancer to at least Stage II. The low-cost technology must perform 
with better detection sensitivity than CBE (higher than 50%) and equally high specificity as CBE 
(94%) to accurately and effectively identify breast lumps in need of further diagnostic follow-up 
(diagnostic ultrasound, breast biopsy) without clogging the under-resourced infrastructure with 
false positives due to typical benign breast features (tissue variability, lumpiness and nodularity). 
Contrast in elastic stiffness between normal and abnormal breast tissue has long been 
recognized (Harris '94). Breast cancers are known to be stiffer than normal breast tissues. Major 
medical device manufacturers are exploring different sensing mechanisms like Ultrasound 
Elastography and MRI, which use tissue stiffness to differentiate between malignant and non-
malignant tissue.  
1.4 Investigational Device 
 
The Piezoelectric Finger (PEF, Fig1), invented by Dr. Wan 
Shih and Dr. Wei-Heng Shih at Drexel University is a novel, 
quantitative and low-cost elastic modulus (E) sensor that can 
measure tissue compression by simple electrical means. PEF’s 
ability to apply a force and measure the displacement 
electrically, all within the finger, makes for an ideal 
“electronic palpation” sensor for in vivo breast tissue imaging. 
Detection of abnormal breast tissues (e.g., carcinoma in situ, 
intra-ductal carcinoma, lobular carcinoma, etc.), and benign 
growths (e.g., fibrocystic lesions, hyperplasia, and 
calcifications) can be achieved by performing an E scan. The 
size and depth of the abnormal breast tissue can also be 
calculated using adjacent fingers.  
Figure 1 

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The current PEFS system (Product Name: Intelligent Breast Exam™ or iBE™, Fig. 2) 
consists of a hand-held compression probe containing a 4 x 4 array of PEFS, a custom built 
electronics board and a tablet.  iBE communicates wirelessly with a mobile device to display 
the findings in real-time, to store and share the data digitally and to easily compare the results 
with past records. iBE has the potential to ‘optimize’ CBE by improving on its overall 
effectiveness to detect Stage I and IIa breast cancers with minimally trained health workers. 
iBE will also ‘standardize’ breast exams by assisting every health worker to administer and 
record breast exams objectively, consistently and with the ability to share the results easily 
using the mobile device app.  
 
   
The device will be stored in Dr. Brooks’ office at 800 Walnut Street, 20th floor, Philadelphia, PA, 
19107. 
 
1.5 Feasibility Testing 
1.5.1 Proof-of-Concept:  
Early testing was performed using tissue models as part of the development of the proof-of-
concept device. This testing included characterization of the device, establishing its ability to 
distinguish smooth and rough surface characteristics of benign and malignant tumors, and 
determining its depth limit ex vivo and in vivo. I  
1.5.2 Ex-Vivo Tissue Testing:  
We conducted testing on 71 ex vivo breast tissue samples under an IRB-approved protocol and 
compared PEF results with the pathology reports. Of the 71 cases, there were 33 cases of 
invasive cancer (32 cases of invasive ductal carcinoma and 1 case of invasive lobular 
carcinoma), 9 cases of ductal carcinoma in situ (DCIS), and 19 cases of benign conditions 
including fibrocystic, hyperplasia, calcifications, fibroadenoma, papilloma, and glandular tissues. 
The E values at the malignancies were 3-5 times those of areas of the normal breast tissues 
regardless of patients’ ages.  
 

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1.6 Clinical Data to Date 
 
In Vivo Testing: Forty in vivo evaluations of the 1x4 PEF-compression probe were conducted by 
Dr. Ari Brooks at his Hahnemann Hospital outpatient office under an IRB-approved protocol. 
These evaluations were performed for device development, not clinical utility. The probe was 
tested with various pushing depth, i.e., at 2 mm, 4 mm, or 6 mm pushing depths to assess the 
effect of different pushing depth on the measured elastic modulus map. The results showed that 
different pushing depths did not alter the tissue elastic map, in terms of the lesion location and 
size. The PEF measurements were compared to patients’ mammography reports. All tests were 
blinded. 
 
A total of 40 patients were enrolled and 46 lesions were confirmed by imaging or pathology. 
PEF reported 55 lesions, with 9 false positives and 2 true positives not originally found on 
imaging or palpation. The overall sensitivity of the PEF test was 40/46 or 87%. In women 40 
years or younger the overall sensitivity was 19/19 or 100%. In women who had a lesion visible 
on mammography, PEF had a sensitivity of 83% (24/29). Of these, in women aged 40 or 
younger, PEF identified all 7 mammographically visible lesions, including 2 malignant lesions. 
When compared with ultrasound, PEF correctly identified 87% (34/39) in this group. Of these, in 
women aged 40 or younger, PEF identified 100% (19/19) of all ultrasound visible lesions. 
  
UPenn Clinical Pilot Study 
A total of 44 patients were enrolled in this prospective signal processing/algorithm development 
trial.  Patients presenting to the Pennsylvania Hospital Women’s Imaging Center for breast 
diagnostic services including ultrasound and/or diagnostic mammogram and/or needle biopsy 
were recruited for an iBE exam prior to biopsy.  The final production prototype device was used 
for all studies.  
 
The demographic result of the patient population is 59% Caucasian 34% African Americans, 2% 
Asian, and 4.5% unknown with an average age of 41 with one male having participated in the 
study.  The patient population is comprised of those who needed breast diagnostic services of the 
44 patients 50% were determined to be BIRADs 2, and the other 50% were BIRADs 3 or 4, zero 
patients were categorized BIRADs 1 or 5.  17 subjects of underwent a biopsy.  
1.7 Risk/Benefits 
The piezoelectric finger (PEF) is a battery powered, electrically insulated device and poses very 
little risk of electric shock to subjects. The maximum voltage is 5V and the maximum current is 
1 mA, both of which are safe to humans. The PEF presses gently on the breast causing negligible 
discomfort, similar to an ultrasound exam. The subject may feel the contact of the polycarbonate 
holder without discomfort, and once the polycarbonate holder is in position, the PEFS will 
compress a maximum of 35 microns, which the subject will not be able to feel. In conclusion, 
PEFS will pose minimal risk to subjects with negligible discomfort. 
 
This study will provide no direct benefit to subjects and there may or may not be any direct 
benefit to society. In the future, possible benefits to others include the ability for patients, for 
whom mammography is less effective or not available, to be screened for cancer. 
 

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2 Study Objectives 
The company that has licensed the technology has received funding to develop a low-cost, 
reliable, and commercially viable device for screening individuals who don’t have access to the 
benefits of mammographic screening. This device is called the iBE (see Section 1.2). 
 
The goal of this research project is to measure the accuracy of the iBE device for detection of 
clinically relevant findings in the breast.  This study would establish a validated sensitivity and 
specificity for breast lesion detection using the results of current mammography based breast 
screening. These results are needed in preparation for an international trial of the device in Low-
Middle Income Countries. This research project will have no impact on clinical decision making. 
3 Study Design 
3.1 General Design 
Determination of the accuracy of iBE for the detection of clinically relevant breast lesions will 
be performed by means of a prospective study.  Subjects may participate during a previously 
scheduled visit to the women’s imaging center. All women presenting to the imaging center, 
including screening, diagnostic or interventional procedures, will be eligible for participation. A 
subset of patients will undergo dual examinations by different trained individuals with the results 
compared for inter-rater reliability.  
 
The estimated date for the investigators to complete this study (complete primary analyses) is 
approximately 2 years from study activation.  
3.2 Study Endpoints 
• To determine the sensitivity and specificity of iBE exams for the detection of 
clinically relevant breast lesions (defined as BIRADs 3-5 on imaging, and/or 
malignant on biopsy). 
• To determine inter-rater reliability in the iBE production prototype. 
 
4 Subject Selection  
4.1 Inclusion Criteria 
• 18 years of age and older 
• Women and men with symptomatic breast lump (either by palpation or 
imaging) OR 
• Asymptomatic women presenting to the imaging center for a screening 
mammogram. 
• Signed Informed Consent 
4.2 Exclusion Criteria 
• Patients under 18 years of age 
• Patients who previously participated in this study and are returning 
to the Women’s Imaging Center for follow-up diagnostic tests 

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4.3 Subject Recruitment and Screening 
Subjects will be offered participation in the study during their visit to the Women’s Imaging 
Center by the PIs, Dr. Ari Brooks, Dr. Brian Englander, and/or their designee. This study may 
recruit up to 1000 subjects. Patient’s will be eligible for study participation if they have a 
scheduled visit for the Women’s Imaging Center and have not previously participated in this 
study.  The reason for the patient’s visit, screening or diagnostic, will not affect their eligibility.  
Diagnostic visits are included as it is necessary to ensure the accuracy of the iBE device’s ability 
to detect BIRADs 3-5.  The iBE device was created to use as a screening tool to detect clinically 
relevant breast lesions, defined here as BIRADs 3-5, with the purpose of giving patients proper 
follow-up recommendations without causing unnecessary anxiety of  avoidable diagnostic tests.   
 
5 Study Procedures 
 
Participants will be recruited from the Women’s Imaging Center who are scheduled to undergo 
screening or diagnostic imaging including biopsies.  Subjects will have the study explained to 
them and given the consent form to review early in their imaging center visit. After the subjects 
have had time to review the consent, the PI or designee will answer all questions. If she/he 
agrees and signs the consent form, they will receive a signed copy to take home with them.  All 
subjects must meet the inclusion and exclusion criteria. Consent will be obtained prior to any 
study-related activities.  
 
The iBE evaluation will be performed by a trained individual who is blinded to the outcome of 
the radiology studies at the time the iBE is performed.  The trained individual will be a 
healthcare worker with minimum education (or equivalence) to a licensed practical nurse (LPN) 
or an ultrasound tech.  This is the target education level for the intended iBE operators.  The 
selected healthcare worker will be trained by Dr. Ari Brooks, MD to administer the iBE and 
clinical breast exams.  The trainee will follow Dr. Brooks during clinic hours for 1-2 days and 
trained for clinical breast exams, similar training to a medical student.  The iBE training will 
mostly be software and instrument training by the leading iBE user in the United States, Dr. 
Brooks. A minimum of two healthcare workers will be trained.    
 
Subjects will be scanned with the iBE device administered by the trained individual while in a 
supine position without breast immobilization similar to ultrasound testing.  A bilateral iBE 
exam will be performed on the entire breast as well as a bilateral Clinical Breast Exam (CBE) the 
findings will be documented on the case report forms and the device tablet concurrently.  
 
If the patient is selected to participate in the inter-rater reliability portion of the study, the subject 
will undergo both the iBE and the clinical breast exams twice performed by two different 
separately trained individuals sequentially during the same visit.  The trained individuals will 
have their own case report forms and tablets that integrate to the iBE to prevent results sharing 
and bias.  The selection for the inter-rater reliability portion of the study will be decided by the 
day of the week.  The second trained individual will be present one a day week and that day all 
the patients will be asked to participate in the dual exam inter-rater reliability portion of the 
study.   
 

9 
 
These data are recorded and processed by an automated software algorithm and the results are 
displayed topographically on a “breast-map” with red areas showing positive findings and green 
areas showing negative findings.  All the recorded data are collected on the tablet without 
HIPAA identifying variables. The tablet will assign a four digit subject number incrementally 
increasing for each subject prior to the iBE scan and this number will be recorded on the case 
report form.  Results of the test will be reported to the patient as well as the radiology 
technologist and radiologist. The iBE evaluation may add between 10 and 30 minutes to the 
clinic visit.  The iBE evaluation will be done prior to the patient’s original scheduled imaging 
visit. After the completion of the imaging visit the radiologist will evaluate the images and the 
iBE report.  If there are areas identified on the iBE that are not resolved by the scheduled 
mammogram an ultrasound will be performed in the area of concern (if not already scheduled).   
 
The current pathway of breast lesion detection can be modified in this protocol in order to 
ascertain the accuracy of the iBE device illustrated in Scheme 1 below.  The current pathway of 
breast lesion screening and detection begins with a screening mammogram or a diagnostic 
mammogram/ultrasound.  If nothing is detected by mammogram or ultrasound then the pathway 
is complete and a follow-up recommendation is given.  However, if something suspicious is 
detected by the initial mammogram then additional imaging is requested such as an ultrasound.  
If the additional ultrasound reveals something suspicious a biopsy maybe recommended for 
confirmation or if a benign finding is revealed a follow-up recommendation is be given.  The 
addition of iBE screening will only modify the current pathway if the iBE exam returns a 
positive result when the initial mammogram provides a negative result.  If this occurs a study 
provided ultrasound will be recommended and the ultrasound’s results will be used to verify the 
iBE positive result.  If the ultrasound invalidates the iBE positive result, it will be deemed a false 
positive and the diagnostic tests are complete.  However, if the ultrasound confirms the iBE’s 
result Dr. Brooks and the radiologist will discuss if further diagnostic intervention (i.e. biopsy) is 
required.   Data on the final disposition of the imaging, any biopsies and any follow up imaging 
to 18 months after participation will be recorded in the database. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

10 
 
 
Scheme 1: Current Algorithm with Integrated Study Pathway 
 
 
 
 
 
 
Quantitative Data 
Quantitative data from the test will be documented and analyzed for accuracy metrics.  
 
The iBE device collects only compression measurements and stores these data on the mobile 
device. Compression data are recorded for our records and a copy is available to UELS via 
Dropbox, which is backed up online and offsite. 
 
We know the data are captured accurately because a unique file gets created at the end of every 
scan in a specific folder inside the DELL tablet. The app gives the user a notification that the 
data were saved properly to the tablet at the end of each scan. 
 
The data sent to the UELS database are identical to those on the tablet, as they are synced 
between the folder inside the tablet and Dropbox. This ensures that an exact copy of the files 
created at the site are sent to UELS. These files use a unique ID entered by the user and have no 
identifiable patient information. 
 
No identifiable data are collected or stored by the iBE software.  iBE data are stored at UELS on 
an encrypted database.  All data that are transmitted are de-identified and sent directly to the 
database from the device.  Each study performed on the device has a unique number. The unique 

11 
 
study numbers are entered into the database at Penn and associated with a subject number. The 
results of the clinical breast exam are recorded on the touch screen in a similar heat map fashion. 
 
Other data associated with each subject number includes age, bra size, BMI, and breast lesion 
location. In symptomatic individuals, imaging results, final diagnosis, type of lesion, imaging 
and pathology data will be collected on a separate CRF and entered in the Penn database.  
 
The data listed above as well as identifiable demographic data will be entered into a REDCap 
database that is only accessible to the research team. The original signed consent documents and 
CRFs are kept in a locked office at 800 Walnut Street, 20th floor.  
 
6 Statistical Plan-Paul’s expertise 
6.1 Sample Size Determination 
Based on a study of BIRADS grading of a mammography registry, 80% of all screening 
mammograms are BIRADS 1 and 2. The incidence of malignancy should be 1-2% of all 
screening mammograms.  The screening center performs 11,000 screening mammograms a year 
plus over 3000 biopsies.  About 600 breast cancers are diagnosed yearly. Since symptomatic 
individuals scheduled to undergo diagnostic imaging or biopsy are eligible to participate this will 
enrich the population categorized to BIRADs 3-5.  Using a sample size of 1000 subjects provides 
80% power.   
6.2 Statistical Methods 
Data will be analyzed using contingency table methods, estimating the sensitivity and specificity 
of the device to correctly assign subjects to BIRADS 1, 2 versus BIRADS 3, 4, 5 categories.  
Sensitivity is calculated from contingency table counts as TP/(TP+FN), and specificity is 
calculated as TN/(TN+FP), (and will be log transformed) with variances obtained using the delta 
method.  Both sensitivity and specificity measures are expected to be high, given great 
performance in preliminary data (0.95 and 0.92 respectively).  We will use a non-inferiority 
approach, attempting to demonstrate that in the clinical setting, iBE matches our preliminary 
values, and we will test them against null hypothesis values (Non inferiority boundaries) that are 
5% below our preliminary data using the z-score for the log-transformed measure. 
 
 
Mammogram BIRADS 1,2 
Mammogram BIRADS 3,4,5 
or biopsy positive (same 
breast and same quadrant) 
iBE negative 
True Negative (TN) 
False Negative (FN) 
iBE positive 
False Positive  (FP) 
True Positive (TP) 
 
And to CBE as a primary comparison 
 
CBE negative 
CBE positive 
iBE negative 
True Negative 
False Negative 
iBE positive 
False Positive 
True Positive 
 
 
 
 

12 
 
7 Safety and Adverse Events 
Due to the nature of this device and our experience thus far, adverse effects are not anticipated, 
however, the investigator will follow the processes below should an event occur. 
7.1 Definitions 
 
Adverse Device Effect (ADE) 
All adverse events will be graded using NCI Common Terminology Criteria for Adverse Events 
(CTCAE) v4.0. For the purposes of this study, an adverse device event (ADE) will be defined as 
any untoward medical occurrence following exposure to the PEFS device regardless of 
expectedness or attribution.  
 
Unanticipated Adverse Device Effect (UADE) 
An unanticipated device effect is any serious adverse effect on health or safety, or any life-
threatening problem or death caused by or associated with a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan, or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
 
Serious injury 
Any injury that is any one of the following:  
• Life-threatening 
• Results in permanent impairment of a body function or permanent damage to body 
structure 
• Necessitates medical or surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure 
 
7.2 Recording of ADEs 
All events experienced by subjects or identified by the investigator that qualify as an ADE or 
UADE will be recorded in the medical records. The clinical course of each event should be 
followed until resolution, stabilization, or until it has been determined that study participation is 
not the cause. Serious ADEs (SADEs) that are still ongoing at the end of the study period must 
be followed up to determine the final outcome.  
 
The minimum initial information to be captured in the subject’s source document concerning the 
ADE includes:  
 
• Study identifier 
• Subject number 
• A description of the event 
• Date of onset 
• CTCAE Grade 
• Investigator assessment of the attribution to 
PEFS 
• Investigator assessment of the 
expectedness of the event 
• Current status 
• Whether the event is serious and reason for 
classification as serious 

13 
 
7.2 Reporting of ADEs and Unanticipated Problems 
 
7.2.1 Investigator reporting: Notifying the IRB 
 
Unanticipated Problems Involving Risk to Subjects or Others 
In alignment with 21 CFR 312, investigators are required to promptly report unanticipated 
problems, including suspected adverse reactions and adverse reactions, to the IRB. An event is 
considered a “suspected adverse reaction” when there is reasonable possibility that the 
drug/investigational product caused the adverse event. For these reporting purposes, reasonable 
possibility means there is evidence to suggest a causal relationship between the investigational 
device and the event. For University of Pennsylvania IRB reporting, this means an event 
should be considered probably or definitely related to the research procedures. 
The IRB requires investigators to submit reports within 10 working days (with one exception) of 
events that meet the definition of an unanticipated problem involving risks to subjects or others. 
Exception: If the adverse event involved a death and indicates that participants or others are at 
increased risk of harm, investigators are required to submit a report to the IRB within 3 days.  
 
7.2.2 Investigator reporting: Notifying the Abramson Cancer Center Data and Safety 
Monitoring Committee (DSMC) 
On-Site subjects (this includes any subjects enrolled at other sites on an in-house study) 
1. All grade 3 or higher events (ADE or SADE) within 5 business days of knowledge  
2. All unexpected deaths within 24 hours of knowledge 
3. All other deaths within 30 days of knowledge. Deaths of subjects off-study for greater 
than 30 days from the last study treatment/intervention are not reportable with the 
following exceptions: 
a) 
Deaths on in-house gene or cellular therapies 
b) 
Deaths on in-house studies utilizing on-campus manufacturing of the study 
agent(s) or components of the study agent(s) 
c) 
Deaths on first-in-human studies 
All events meeting the DSMC reporting requirements must be entered into the mandatory Velos 
AE/SAE form.  
Every effort will be made to report an event as a diagnosis, not as a list of symptoms. Symptoms 
that led to the diagnosis should be included in the event description, but should not be the actual 
event. 

14 
 
7.3 Exceptions and Deviations 
 
Exception 
A one-time intentional action or process that departs from the IRB- and CTSRMC-approved 
study protocol, intended for one occurrence. If the action disrupts the study progress, such that 
the study design or outcome (endpoints) may be compromised, or the action compromises the 
safety and welfare of study subjects, advance documented IRB and DSMC approval is required. 
 
Deviation 
A one-time, unintentional action or process that departs from the IRB- and CTSRMC-approved 
study protocol, involving one incident and identified retrospectively, after the event occurred. If 
the impact on the protocol disrupts the study design, may affect the outcome (endpoints), or 
compromises the safety and welfare of the subjects, the deviation must be reported to the DSMC 
within 5 business days. The PI will document his assessment of the impact of the event on safety 
and/or study outcome integrity in a memo to file for each deviation. 
 
7.3 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his site. 
This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above. Medical monitoring will include a regular assessment of the number and 
type of ADEs.  
8 Data Handling and Record Keeping 
8.1 Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI  
 
Subjects may withdraw permission to use and share their health information at any time and for 
any reason. Even if subjects withdraw permission, we may still use their information that was 
collected before their request if that information is necessary to the study.  
 
8.2 Maintaining Records 
 
Regulations require investigators to maintain all data/records for a period of 2 years after the date 
the investigation is completed or terminated or the records are no longer required to support a 
premarket approval (PMA), whichever date is later. Since the data/records from this pilot study 
will be needed to support a PMA for the clinical utility study, data/records for this study will be 
maintained for 2 years from the clinical utility PMA. 

15 
 
8.3 Source Documents 
 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents.  
9 Study Monitoring, Auditing, and Inspecting 
9.1 Study Monitoring Plan 
 
Safety and study quality will be monitored on an ongoing basis by the PI and the study team per 
the study-specific Abramson Cancer Center (ACC) monitoring plan submitted with this study 
protocol. The Principal Investigator will review all data for accuracy. Safety data will be 
collected at the time of the procedure. The PI or designee will review the study charts to evaluate 
events at each subject interaction to ensure the grade, relationship to the study device, 
expectedness and the course of action for each subject is documented.  
9.2  Auditing and Inspecting 
 
This protocol will be audited as a moderate risk study by the ACC Department of Compliance 
and Monitoring in accordance with the National Cancer Institute-approved Institutional Data and 
Safety Monitoring Plan. The investigator will permit study-related monitoring, audits, and 
inspections by the IRB, the sponsor, government regulatory bodies, and University compliance 
and quality assurance groups of all study-related documents (e.g., source documents, regulatory 
documents, data collection instruments, study data, etc.). Participation as an investigator in this 
study implies acceptance of potential inspection by government regulatory authorities and 
applicable University compliance and quality assurance offices. 
  
10 Study Finances 
10.1 Funding Source 
 
UE Lifesciences, Inc. 
10.2 Conflict of Interest 
 
There are no conflicts of interest.  
10.3 Subject Stipends or Payments 
 
Subjects will receive a $10 cash card for participation in the study to compensate them for their 
time. 
 

16 
 
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