Prostate Cancer Screening in Men With Germline BRCA2 Mutations
Conditions: Prostate Cancer
Sponsor: Yale University

Page 1 of 24 
YALE UNIVERSITY 
 HUMAN INVESTIGATION COMMITTEE 
Application to Involve Human Subjects in Biomedical Research 
100 FR1 (2013-1) 
 
 
SECTION I: ADMINISTRATIVE INFORMATION 
Title of Research Project:  
Prostate Cancer Screening in Men with Germline BRCA2 mutations 
Principal Investigator: 
Preston C. Sprenkle 
Yale Academic Appointment: 
Assistant Professor 
Department: Urology 
Campus Address:  
Department of Urology, Fitkin Memorial Pavilion Suite 315b, PO Box 208058 
Campus Phone: 
203-785-2815 
Fax: 
203-785-4043 
Pager: 
475-201-5778 
E-mail:  
preston.sprenkle@yale.edu 
Protocol Correspondent Name & Address (if different than PI): 
 Cayce Nawaf 
Campus Phone: 203-785-2815 
Fax: 203-
785-4043 
E-mail: cayce.nawaf@yale.edu 
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable): 
Campus Phone: 
Fax: 
E-mail: 
Business Manager: 
Campus Phone : 
Fax : 
E-mail: 
Investigator Interests: 
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)           
 NA 
Yale Academic Appointment: 
Campus Address: 
Campus Phone: 
Fax: 
Pager: 
E-mail: 
DATE STAMPED-RECEIVED 
PROTOCOL NUMBER 
Please refer to the HIC website for application 
instructions and information required to complete 
this application.  The Instructions are available at 
http://www.yale.edu/hrpp/forms-
templates/biomedical.html  
Submit the original application and one (1) copy 
of all materials including relevant sections of the 
grant which funds this project (if applicable) to 
the HIC.   
HIC OFFICE USE ONLY 
Final Protocol  3/29/2019

Page 2 of 24 
 
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research.  
See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI  
  Yes  
■  No  
 
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol? 
  Yes  
■  No  
 
 
 
If yes to either question above, list names of the investigator or responsible person: 
 
 
 
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as con-investigators on a protocol with a 
Yale University Principal Investigator must also have a current financial disclosure form on file 
with the University’s Conflict of Interest Office. If this has not been done, the individual(s) 
should follow this link to the COI Office Website to complete the form:  
http://www.yale.edu/coi/   
 
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol. 
 
SECTION II: GENERAL INFORMATION 
 
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply: 
  
a. Internal Location[s] of the Study: 
 Magnetic Resonance Research Center  
 
 Yale University PET Center 
     (MR-TAC)    
 
 
 
 
 YCCI/Church Street Research Unit (CSRU) 
 Yale Cancer Center/Clinical Trials Office (CTO)    
 YCCI/Hospital Research Unit (HRU) 

Page 3 of 24 
 
 Yale Cancer Center/Smilow 
 
 
 YCCI/Keck Laboratories 
 Yale-New Haven Hospital  
 
 
 Yale-New Haven Hospital—Saint Raphael Campus 
 Cancer Data Repository/Tumor Registry 
 Specify Other Yale Location: 
 
 
 
 
 
b. External Location[s]: 
 APT Foundation, Inc. 
 
 
 
 Haskins Laboratories 
 Connecticut Mental Health Center 
 
 John B. Pierce Laboratory, Inc. 
 Clinical Neuroscience Research Unit (CNRU) 
Veterans Affairs Hospital, West Haven 
 
 Other Locations, Specify:  
 
 
 International Research Site  
(Specify location(s)): 
 
 
c. Additional Required Documents (check all that apply): 
 N/A 
*YCCI-Scientific and Safety Committee (YCCI-SSC)  
Approval Date:  
*Pediatric Protocol Review Committee (PPRC) 
 
Approval Date:  
*YCC Protocol Review Committee (YRC-PRC) 
 
Approval Date: 
 
*Dept. of Veterans Affairs, West Haven VA HSS 
 
Approval Date:  
*Radioactive Drug Research Committee (RDRC) 
 
Approval Date:  
 YNHH-Radiation Safety Committee (YNHH-RSC) 
 
Approval Date:  
 Magnetic Resonance Research Center PRC (MRRC-PRC) 
Approval Date:  
 YSM/YNHH Cancer Data Repository (CaDR)  
 
Approval Date:  
 Dept. of Lab Medicine request for services or specimens form 
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found at 
 http://radiology.yale.edu/research/ClinTrials.aspx) 
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements. 
 
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities.  
 
Ongoing 
 
3. Research Type/Phase: (Check all that apply) 
a. Study Type 
   
 Single Center Study 
   
 Multi-Center Study 
Does the Yale PI serve as the PI of the multi-site study? Yes 
 
No 
 
  
 Coordinating Center/Data Management 
  
 Other:  
 
 
b. Study Phase 
 N/A 
    
 Pilot  
 Phase I 
 Phase II 
 Phase III 
 Phase IV 
    
 Other (Specify)  

Page 4 of 24 
 
 
 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found  in the instructions section 4c: 
 Clinical Research: Patient-Oriented 
   
 
 Clinical Research: Outcomes and  
 Clinical Research: Epidemiologic and Behavioral  
                 Health Services 
 Translational Research #1 (“Bench-to-Bedside”)      
 Interdisciplinary Research 
 Translational Research #2 (“Bedside-to-Community”)  
 Community-Based Research 
 
 
5.   Is this study a clinical trial? Yes 
 
No 
 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events” 
  
If yes, where is it registered? 
  
 
Clinical Trials.gov registry 
 
  
 
Other (Specify)  
 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE. 
 
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used. 
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx or 
 contact YCCI at 203.785.3482) 
 
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)?  
Yes 
 No
 
 
 
7. Will this study have a billable service? A Billable Service is defined as a service or procedure 
that will be ordered, performed or result in charging in EPIC for individuals who are enrolled in 
a clinical research study, regardless if the charge is intended to be paid by the subject/their 
insurance or the research study. 
 
Yes 
 No
 
If you answered "yes", this study will need to be set up in OnCore Support 
http://medicine.yale.edu/ymg/systems/ppm/index.aspx  
 

Page 5 of 24 
 
8. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes XX No ___  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III. 
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform? - Yes 
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure? - No 
  
c. Will a novel approach using existing equipment be applied? - No 
  
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol. 
 
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING 
 
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply. 
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).   
 
 
PI  
Title of Grant 
Name of Funding Source  
Funding 
Funding Mechanism 
 
Sprenkle 
 
 
Internal 
  Federal 
  State 
  Non Profit 
  Industry 
  Other For 
Profit  
  Other 
 
Grant-M#            
Contract#  
Contract Pending 
  Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify: 
 
 
 
 
 
  Federal 
  State 
  Non Profit 
  Industry 
  Other For 
Profit  
  Other 
 
Grant-M#            
Contract#  
Contract Pending 
  Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify: 
 

Page 6 of 24 
 
 
 
 
 
  Federal 
  State 
  Non Profit 
  Industry 
  Other For 
Profit  
  Other 
 
Grant-M#            
Contract#  
Contract Pending 
  Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify:  
 
 
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors.  
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided. 
 
Send IRB Review Fee Invoice To: 
 
Name: 
 
Company: 
Address: 
  
2. Research Team:  List all members of the research team. Indicate under the affiliation column whether 
the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty or staff 
from a collaborating institution, or are not formally affiliated with any institution. ALL members of 
the research team MUST complete Human Subject Protection Training (HSPT) and Health 
Insurance Portability and Accountability Act (HIPAA) Training before they may be listed on the 
protocol.  See NOTE below. 
 
NOTE: The HIC will remove from the protocol any personnel who have not completed required training. 
A personnel protocol amendment will need to be submitted when training is completed. 
 
 
 
Name 
Affiliation: Yale/Other Institution 
(Identify) 
 
Net ID 
Principal 
Investigator  
Preston C. Sprenkle 
Yale University, Dept of Urology 
PS577 
Co-
Investigator(s) 
Brian Shuch 
Yale University, Dept of Urology 
bms53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kamyar Ghabili Amirkhiz 
Yale University, Dept of Urology 
Kga25 
 
 
Jamil Syed 
Yale Urology 
Js3569 
Study 
Personnel 
Marta Boeke 
Yale University, Dept of Urology 
Mb273 
 
 
Cayce Nawaf 
Yale, Department of Urology 
Cbn8 

Page 7 of 24 
 
SECTION IV: 
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR 
AGREEMENT 
 
 
 
 
 
 
 
 
 
 
 
 
As the principal investigator of this research project, I certify that: 
 The information provided in this application is complete and accurate. 
 I assume full responsibility for the protection of human subjects and the proper conduct of the 
      research. 
 Subject safety will be of paramount concern, and every effort will be made to protect subjects’ 
      rights and welfare. 
 The research will be performed according to ethical principles and in compliance with all federal, 
      state and local laws, as well as institutional regulations and policies regarding the protection of   
      human subjects. 
 All members of the research team will be kept apprised of research goals. 
 I will obtain approval for this research study and any subsequent revisions prior to my initiating the 
      study or any change and I will obtain continuing approval of this study prior to the expiration date      
      of any approval period. 
 I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
      participants. 
 I am in compliance with the requirements set by the University and qualify to serve as the 
      principal investigator of this project or have acquired the appropriate approval from the  
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at 
      Yale-New Haven Hospital, or have a faculty advisor. 
 I will identify a qualified successor should I cease my role as principal investigator and facilitate a 
smooth transfer of investigator responsibilities. 
 
__Preston C. Sprenkle___ 
 
 
 
 
 
 
 
 
 
 
  
PI Name (PRINT) and Signature 
 
 
 
 
Date 

Page 8 of 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Department Chair’s Assurance Statement 
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a 
sponsoring company, patents, licensure) associated with this research project? 
 Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
 No 
 
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project? 
Yes (provide a description of that interest in a separate letter addressed to the HIC) 
No 
 
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately. 
 
   ____________________________  
 
 
 
 
 
 
   Chair Name (PRINT) and Signature   
     
 
 
 Date 
 
   _________________________________ 
   Department 
 
 
 

Page 9 of 24 
 
 
YNHH Human Subjects Protection Administrator Assurance Statement 
Required when the study is conducted solely at YNHH by YNHH health care providers. 
 
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that: 
 I have read a copy of the protocol and approve it being conducted at YNHH. 
 I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest. 
 The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project. 
 
  ______________________________________ 
 
 
 
 
 
 
 
 
    YNHH HSPA Name (PRINT) and Signature         
 
 
Date 
 
 
 
 
For HIC Use Only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date Approved  
 
 
 
Human Investigation Committee Signature 
 
This protocol is valid through ______________________________________________ 
 
 
 
SECTION V: RESEARCH PLAN 
 
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.  
Specific Aims: 
1.Determine the incidence of prostate cancer in men with the BRCa2 gene mutation as an 
independent indicator for prostate cancer screening. 
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data. 
 
Prostate cancer remains the most commonly diagnosed malignancy among men with an 
estimated 230,000 incident cases annually in the U.S.  Emphasis has been placed on 
overtreatment, but prostate cancer remains the most lethal malignancy for men.  Genetic 
factors, like a family history of prostate cancer, are associated with a higher risk of developing 
the disease, but a connection with more aggressive disease is controversial.  Recently, the 
BRCA mutation, commonly known for its role in breast and ovarian cancer, has been identified 
as risk factor for prostate cancer in men that may also confer a risk of developing more 
aggressive prostate cancer at a younger age. While several retrospective studies of men with 
prostate cancer suggest that BRCA2 mutation carriers are at significantly higher risk of 
developing prostate cancer at an earlier age and more advanced stage, [1-4] prospective data is 
lacking. Concern about whether this mutation confers more advanced disease and worse 
survival may contribute to significant anxiety in some men.  A man in England with a BRCA2 
mutation, for example, was so worried about his possible risk of prostate cancer that he had a 

Page 10 of 24 
 
prophylactic surgical removal of his prostate[5].  This example clearly illustrates the key 
knowledge gaps that exist about the actual risk of prostate cancer among BRCA2 mutation 
carriers. 
 
We have established a multidisciplinary group of radiation oncologists, urologists, geneticists 
and engineers that is uniquely positioned to address this knowledge gap about the importance 
of the BRCA mutation and risk of prostate cancer.  Our group has developed the Yale School of 
Medicine Fusion Prostate Biopsy Program. This program uses cutting-edge multiparametric 
magnetic resonance imaging (MRI) to identify previously invisible lesions in the prostate. The 
office-based Artemis platform (Eigen, Grass Valley CA) then “fuses” these images with 3D 
ultrasound to achieve more precise and accurate prostate biopsies, allowing for better clinical 
staging with a single biopsy.  The Yale Fusion Prostate Biopsy Program has dramatically 
improved prostate cancer detection to more than 60%, almost twice that of the current standard 
of care.  Through the Yale Cancer Center Genetic Counseling program, which provides genetic 
counseling and testing to people at increased risk for hereditary cancer, we have an established 
cohort of families with known genetic mutations including BRCA2.  
 
Our study, by combining the Fusion Prostate Biopsy Program and the Genetic Counseling 
program to perform highly sensitive prostate biopsies in a population of BRCA2 mutation 
carriers, is a novel approach to accurately determine the risk of prostate cancer, adverse 
pathologic features and abnormal MRI findings among BRCA2 mutation carriers. While it is 
beyond the scope of this pilot grant, we believe that early identification of men with higher risk 
disease should allow for more rapid treatment and a higher likelihood of cure.  We hypothesize 
that the BRCA-2 mutation is associated with a higher risk of prostate cancer incidence, worse 
grade, and abnormal MRI findings compared to patients without this mutation.  To address 
these important questions, our specific aims are:  
 
1. To prospectively determine the incidence of prostate cancer in BRCA2 mutation carriers. 
 
 
 
2. To investigate different characteristics of MRI-detected prostate lesions.   
 
 
 
 
3. To compare pathologic and clinical findings to clinically matched controls using the same 
sensitive MRI-based biopsy technique. 
4.  
Localized prostate cancer is treatable and often curable while metastatic disease is not, hence 
prostate cancer screening is performed to identify patients at an earlier stage. Early detection 
of prostate cancer in this group of younger men at high-risk population may allow for 
identification while at a lower stage and grade, potentially increasing the number of patients 
able to receive treatment with curative intent. 
 
All previous studies in the literature have evaluated the incidence of BRCA2 mutation 
carriers in a population of patients already diagnosed with prostate cancer.  The incidence of 
prostate cancer in men with a BRCA2 mutation, however, has not been previously described. 
 
3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and include 
any flowcharts of visits specifying their individual times and lengths. Describe the setting in 
which the research will take place. 

Page 11 of 24 
 
 
This is a cohort screening study to prospectively identify the incidence of prostate cancer in a 
population of BRCA2 carriers.  All men identified to have a BRCA2 mutation as part of the 
Yale Cancer Genetic Counseling Program will be approached and offered participation in the 
study via our program newsletter, BRCA listserv, Facebook page and a targeted mailing.  We 
will also contact all female BRCA2 carriers and ask them to invite their male relatives known 
to carry BRCA2 mutations into this study through the same means.  For patients who test 
positive for a BRCA2 mutation after this study has opened, we will discuss this study with 
them at result disclosure and include it as part of their summary letter. 
Potential participants will meet with a urologic oncologist to discuss the risks and benefits of 
prostate cancer screening including individual risks and benefits of PSA testing, prostate 
examination, pelvic MRI, prostate biopsy, and a prostate cancer diagnosis..   
Standard of care screening at the Yale Cancer Center for men with a normal prostate cancer 
risk consists of a PSA test and prostate physical examination beginning at age 50 years and if 
either is abnormal an MRI of the prostate followed by Fusion-targeted biopsy of the prostate 
is performed (Figures 1 and 2).  Men with genetic risk factors such as African American or 
Caribbean heritage, a positive family history of prostate cancer, or a BRCA2 mutation, are 
counseled about their increased risk of prostate cancer and that prostate cancer screening 
(PSA and prostate exam then MRI and prostate biopsy if indicated) should begin at age 40yr 
but is available to them at any age. 
Study participants will be identified because of their BRCA2 mutation that places them at 
increased risk for developing prostate cancer.  Because this is a pre-selected high-risk 
population, and our goal is to establish the incidence of cancer and association of risk factors 
with developing disease, all men ≥30 years of age, able to give informed consent, and with 
at least a 5-10 year life expectancy will have PSA testing, prostate examination, Pelvic MRI, 
and Artemis fusion prostate biopsy (Figures 1 and 2).   
Men identified to have prostate cancer will be treated according to current standards of care. 
Treatment for prostate cancer at the Yale Cancer Center is largely based on clinical risk; 
options include, but are not limited to, active surveillance for appropriate men with low risk 
disease, treatment with curative intent for men with localized intermediate and high risk 
prostate cancer, and systemic therapy for men with metastatic disease. 
  
 
Figure 1. Instrument set up at Yale to perform precision 
imaging-guided biopsy. The prototype device of Artemis 
3D biopsy tracking system. Instrument set up at Yale from 
Eigen (510K approved). 
 
Figure 2. Precision image-guided biopsy. A+B) Identification of 
suspicious regions in two MRI sequences C) overlay of MR contoured 
region on realtime US view D+E) two planes of view of the 3D model 
generated by US and MR segmentation F) matching whole mount 
histology slide following prostatectomy. 

Page 12 of 24 
 
Typical clinical workflow for an Artemis MR-US fusion biopsy includes a pre-procedure 
MRI followed by a 12-core transrectal-ultrasound (TRUS) guided biopsy (Figure 1,2). The 
ultrasound transducer is fixed with a needle guide, and the biopsy needle is then guided to 
specific regions in the prostate gland for systematic sampling of the gland. If any areas 
suspicious for cancer (labeled regions of interest (ROIs)) are identified in the MRI, they are 
outlined using specialized software, and the target is visible on the Artemis device. Targeted 
biopsies will be taken from each ROI to rule out cancer in these suspicious areas. 
 
 

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Page 14 of 24 
 
 
 
4. Genetic Testing    N/A 
 
 
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study. 
 
Men ≥30 years of age with known BRCA2 mutation and able to give informed consent.   
 
6.  Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement. 
 
 Children 
 
 
 Healthy  
 
Fetal material, placenta, or dead fetus 
 Non-English Speaking 
 Prisoners  
 Economically disadvantaged persons 
 Decisionally Impaired 
 Employees  
 Pregnant women and/or fetuses 
 Yale Students  
 
Females of childbearing potential 
 
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects? 
 Yes  
 No (If yes, see Instructions section VII #4 for further 
requirements) 
 
 
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion? 
All men ≥30 years of age with at least a ten-year life expectancy, a known BRCA2 mutation, 
ability to have an MRI, and able to give informed consent will be approached to participate 
in the study.  If a man has received or is currently receiving treatment for prostate cancer he 
will be excluded from the study. 
 
 
8. How will eligibility be determined, and by whom?  
Yale genetic counselors will determine initial eligibility from the BRCA2 registry to confirm 
the presence of a BRCA2 mutation.  Trained physicians will determine clinical eligibility 
based on medical history. 
 
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research.  
Risks of prostate biopsy include: infection, rectal bleeding, blood in urine or semen, 
prostatitis, urosepsis, urinary retention, and potential difficulty with urination.  
Magnetic resonance (MR) is a technique that uses magnetism and radio waves, not x-
rays, to take pictures and measure chemicals of various parts of the body.  The United States 
Food and Drug Administration (FDA) has set guidelines for magnet strength and exposure to 
radio waves, and we carefully observe those guidelines.   

Page 15 of 24 
 
Patients will be watched closely throughout the MR study.  Some people may feel 
uncomfortable or anxious.  If this happens to you, you may ask to stop the study at any time 
and we will take you out of the MR scanner.  On rare occasions, some people might feel 
dizzy, get an upset stomach, have a metallic taste or feel tingling sensations or muscle 
twitches.  These sensations usually go away quickly but please tell the research staff if you 
have them.   
There are some risks with an MR study for certain people.  If someone has a pacemaker 
or some metal objects inside their body, they may not be in this study because the strong 
magnets in the MR scanner might harm them.  Another risk is a metallic object flying 
through the air toward the magnet and hitting the participant.  To reduce this risk we require 
that all people involved with the study remove all metal from their clothing and all metal 
objects from their pockets.  Nothing metal can be brought into the magnet room at any time.  
Also, once the participant is in the magnet, the door to the room will be closed so that no one 
from outside accidentally goes near the magnet. 
 
 
 
 
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized. 
Risks will be minimized using standard of care methods to limit prostate biopsy-related 
patient discomfort and the risk of infection through administration of local anesthetic and 
peri-procedure antibiotics, respectively. 
FDA guidelines for MRI safety are strictly adhered to. 
 
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24. 
a. What is the investigator’s assessment of the overall risk level for subjects participating in 
this study?  
 
- Moderate risk: participants will be offered the standard of care fusion targeted 
prostate biopsy that is performed at Yale and offered to other patients at risk for 
prostate cancer.  Some participants, however, would not have received a biopsy if not 
participating in the study. 
 
1. Personnel responsible for the safety review and its frequency: 
 
The principal investigator will be responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews at the specified frequency which must be 
conducted at a minimum of every 6 months (including when reapproval of the protocol is 
sought).  During the review process, the principal investigator (monitor) will evaluate 
whether the study should continue unchanged, require modification/amendment, or close 
to enrollment. Either the principal investigator, the IRB or the Yale Cancer Center Data 
and Safety Monitoring Committee (DSMC) have the authority to stop or suspend the 
study or require modifications. 
 

Page 16 of 24 
 
2. The risks associated with the current study are deemed moderate for the following 
reasons: (choose those that apply) 
 
1. We do not view the risks associated with the prostate biopsy as minimal given the 
alternative is no biopsy. 
2. Given the now established safety and validity of the current biopsy procedure in our 
prior work, we do not view the proposed studies as high risk. 
 
Although we have assessed the proposed study as one of moderate risk, the potential 
exists for anticipated and/or unanticipated adverse events, serious or otherwise, to occur 
since it is not possible to predict with certainty the absolute risk in any given individual 
or in advance of first-hand experience with the proposed study methods. Therefore, we 
provide a plan for monitoring the data and safety of the proposed study as follows: 
 
     3. Attribution of Adverse Events: 
Adverse events will be monitored for each subject participating in the study and 
attributed to   the study procedures / design by the principal investigator Preston Sprenkle 
according to the following categories: 
 
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). 
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s). 
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s). 
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s). 
e.) Unrelated: Adverse event is clearly not related to investigational 
procedures(s)/agent(s). 
 
     4. Plan for Grading Adverse Events: 
 
The following scale will be used in grading the severity of adverse events noted during 
the study: 
 
1. Mild adverse event 
2. Moderate adverse event 
3. Severe  
 
     5. Plan for Determining Seriousness of Adverse Events: 
 
     Serious Adverse Events: 
In addition to grading the adverse event, the PI will determine whether the adverse event 
meets the criteria for a Serious Adverse Event (SAE).  An adverse event is considered 
serious if it: 
 
1. is life-threatening OR 
2. results in in-patient hospitalization or prolongation of existing hospitalization OR 
3. results in persistent or significant disability or incapacity OR 

Page 17 of 24 
 
4. results in death OR 
5. based upon appropriate medical judgment, may jeopardize the subject’s health and 
may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition, OR 
6. adversely affects the risk/benefit ratio of the study 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event.  Similarly, an adverse event may be graded as moderate but still meet the criteria for 
an SAE.  It is important for the PI to consider the grade of the event as well as its 
“seriousness” when determining whether reporting to the IRB is necessary. 
 
6. Plan for reporting Reportable Adverse Events and other unanticipated problems 
involving risks to subjects or others to the IRB 
 
The principal investigator will report the following types of events to the IRB: a) adverse 
events that are serious or life-threatening AND unanticipated (or anticipated but occurring 
with a greater frequency than expected) AND possibly, probably or definitely related to the 
drug/device/intervention; and b) other unanticipated problems involving risks to subjects or 
others. 
 
These adverse events or unanticipated problems involving risks to subjects or others will be 
reported to the IRB in accordance with IRB Policy 710, using the appropriate forms found on 
the website. 
 
 
7. Plan for reporting adverse events to co-investigators on the study, as appropriate the 
protocol’s research monitor(s), e.g Yale Cancer Center Data and Safety Monitoring 
Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study sponsors, funding 
and regulatory agencies, and regulatory and decision-making bodies. 
 
For the current study, the following individuals, funding, and/or regulatory agencies will be 
notified (choose those that apply): 
 
X All Co-Investigators listed on the protocol. 
 
X Yale Cancer Center Data and Safety Monitoring Committee (DSMC) 
□ National Institutes of Health 
□ Food and Drug Administration (Physician-Sponsored IND #_______) 
□ Medical Research Foundation (Grant______) 
 
The principal investigator Preston Sprenkle will conduct a review of all adverse events upon 
completion of every study subject. The principal investigator will evaluate the frequency and 

Page 18 of 24 
 
severity of the adverse events and determine if modifications to the protocol or consent form 
are required. 
 
d. For multi-site studies for which the Yale PI serves as the lead investigator: N/A 
 
12. Statistical Considerations: Describe the statistical analyses that support the study design.  
This is a screening study to establish the incidence of prostate cancer in a high-risk 
population since it is not currently known.  There is an estimated 4.6-23 fold increased risk of 
prostate cancer, especially in men < 58 years of age with a BRCA2 mutation. Typically, 
prostate cancer detection in normal risk men correlates directly with age and ranges between 
0.01 and 6.5% for men in their 30s-60s (CDC website). Given these parameters, we plan 
initial evaluation of 100 men. 
 
 
 
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND 
DEVICES 
 
N/A  
 
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES  
1. 
Targeted Enrollment: Give the number of subjects: 
a.  targeted for enrollment at Yale for this protocol__100 
b.    If this is a multi-site study, give the total number of subjects targeted across all 
sites___  
 
2. 
Indicate recruitment methods below.  Attach copies of any recruitment materials that will 
be used. 
 
 Flyers 
 
 
 
 
 Internet/Web Postings 
 
 
 Radio 
 Posters  
 
 
 
 Mass E-mail Solicitation  
 
 Telephone 
 Letter 
 
 
 
  
 Departmental/Center Website 
 
 Television 
 Medical Record Review  
 
 Departmental/Center Research Boards 
 Newspaper 
 Departmental/Center Newsletters 
 Web-Based Clinical Trial Registries 
 
  YCCI Recruitment database 
 
 Clinicaltrials.gov Registry (do not send materials to HIC) 
 Other (describe): 
 
3. 
 Recruitment Procedures:  
a. Describe how potential subjects will be identified. 
i. Potential subjects will be identified through the Yale Cancer Genetic 
Counseling Program. 
ii. For patients who test positive for a BRCA2 mutation after this study has 
opened, we will discuss this study with them at result disclosure and include it 
as part of their summary letter 
b. Describe how potential subjects are contacted.  

Page 19 of 24 
 
i. Potential subjects with a known BRCA2 mutation will be approached and 
offered participation in the study via our program newsletter, BRCA listserv, 
Facebook page and a targeted mailing.  We will also contact all female BRCA2 
carriers and ask them to invite their male relatives known to carry BRCA2 
mutations into this study through the same means.   
ii. For patients who test positive for a BRCA2 mutation after this study has 
opened, we will discuss this study with them at result disclosure and include it 
as part of their summary letter 
c. Who is recruiting potential subjects?  
i. Trained genetic counselors will be recruiting possible subjects. 
 
 
4. 
Screening Procedures 
a. Will email or telephone correspondence be used to screen potential subjects for eligibility 
prior to the potential subject coming to the research office? 
 Yes  
 No 
b. If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process.  
 
HEALTH INFORMATION TO BE COLLECTED: 
 
 
HIPAA identifiers:  
 Names  
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits 
contains more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 
20,000 or fewer people is changed to 000.  
  Telephone numbers 
 Fax numbers  
 E-mail addresses 
 Social Security numbers  
 Medical record numbers 
 Health plan beneficiary numbers  
 Account numbers  
  All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older  
 Certificate/license numbers  
 Vehicle identifiers and serial numbers, including license plate numbers  
 Device identifiers and serial numbers  
 Web Universal Resource Locators (URLs)  
 Internet Protocol (IP) address numbers  
 Biometric identifiers, including finger and voice prints  
 Full face photographic images and any comparable images  
 Any other unique identifying numbers, characteristics, or codes  
 
 
5. 
Assessment of Current Health Provider Relationship for HIPAA Consideration: 
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?  

Page 20 of 24 
 
 Yes, all subjects 
 Yes, some of the subjects 
 No 
 
If yes, describe the nature of this relationship. 
Dr. Sprenkle could potentially see some of these patients while they are undergoing their 
standard of care prostate cancer treatment. 
 
 
 
6. 
Request for waiver of HIPAA authorization:  (When requesting a waiver of HIPAA 
Authorization for either the entire study, or for recruitment purposes only.  Note: if you are collecting 
PHI as part of a phone or email screen, you must request a HIPAA waiver for recruitment purposes.) 
 
Choose one: For entire study: ______ For recruitment purposes only: ______ 
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data; 
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data; 
 
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB. 
 
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer. 
 
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided: 
 
  
 Compound Consent and Authorization form 
 
  
 HIPAA Research Authorization Form 
 
 
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent.  
Preston Sprenkle 
 
 
 

Page 21 of 24 
 
9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making.  
Prior to screening for prostate cancer patients will have an office visit as part of standard clinical 
care to discuss the risks and benefits of prostate cancer screening. During this visit, if they are 
interested in being screened for prostate cancer and meet eligibility criteria the study will be 
described and if patients are interested in participating they will be provided a study information 
sheet and asked to sign consent. Only patients that can provide written informed consent will be 
enrolled in this study, and if there is any doubt subjects will not be enrolled. Information sheets 
will also be available to patients as part of the Yale Cancer Genetic Counseling Program. 
 
 
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed.  
 
Preston Sprenkle, after explaining the research plan orally, and after providing time for subjects 
to review written information from an informational flyer, will ask open-ended questions to 
gauge subject comprehension and capacity to provide informed consent. Questions will include: 
“Can you tell me what happens if you agree to take part in this study?” and “What should you do 
if you no longer want to take part in the study?” 
 
 
 
11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects.  
 
An adult consent form will be provided, and is attached.  
 
 
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent materials must 
be submitted for approval prior to use.  
 
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.   
 
 Not Requesting a consent waiver  
 
 Requesting a waiver of signed consent 
       
 Requesting a full waiver of consent 
    
 
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6) 
 Requesting a waiver of signed consent for Recruitment/Screening only  

Page 22 of 24 
 
If requesting a waiver of signed consent, please address the following: 
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
 
 
 
 
OR 
 
c. Does the research activity pose greater than minimal risk?  
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity   
 No  
AND 
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No 
 
 Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.) 
 
  
If requesting a waiver of signed consent, please address the following: 
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
 
 
 
 
OR 
 
c. Does the research pose greater than minimal risk? 
 Yes If you answered yes, stop. A 
waiver cannot be granted.    
 No  
AND 
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No 
 
  
 B. Full waiver of consent: (No consent from subjects will be obtained for the activity.)  
 Requesting a waiver of consent for Recruitment/Screening only  
a. Does the research activity pose greater than minimal risk to subjects?   
 Yes  If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity  
 No 
 
  
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No 
 
  
c. Why would the research be impracticable to conduct without the waiver?  
 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?  
 
 
 Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.) 

Page 23 of 24 
 
 
  
 
If requesting a full waiver of consent, please address the following: 
 
 
  
a. Does the research pose greater than minimal risk to subjects?   
 Yes  If you answered yes, stop. A waiver cannot be granted.   
 No 
 
  
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No 
 
  
c. Why would the research be impracticable to conduct without the waiver?  
 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?  
 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS 
 
    Confidentiality & Security of Data: 
a. What protected health information (medical information along with the HIPAA 
identifiers) about subjects will be collected and used for the research?   
b. Subject Name, date of birth, and Medical Record number as well as clinical imaging, 
pathologic and staging information will be collected.     
        
c. How will the research data be collected, recorded and stored?  
All research data will be collected as part of the medical record and stored in a secure ITS 
managed database (FMS Med). Only co-investigators will be able to collect, record and access 
this workstation, and no collaborators on this study will have access to PHI. 
d.  
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard    
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other 
d.    What methods and procedures will be used to safeguard the confidentiality and security of     
the identifiable study data and the storage media indicated above during and after the 
subject’s participation in the study? 
The data will be stored on and ITS managed secure database in the medical school, 
accessible only by co-investigators 
Do all portable devices contain encryption software? 
 Yes   
 No 
         If no, see http://hipaa.yale.edu/guidance/policy.html 
  
e. What will be done with the data when the research is completed? Are there plans to 
destroy     the identifiable data? If yes, describe how, by whom and when identifiers will 
be destroyed. If no, describe how the data and/or identifiers will be secured. 
All identifies will be secured in an encrypted database. 
f. Who will have access to the protected health information (such as the research sponsor, 
the  investigator, the research staff, all research monitors, FDA, Yale Cancer Center 
Data and Safety Monitoring Committee (DSMC), SSC, etc.)? (please distinguish 
between PHI and de-identified data) . 
PHI will be accessible by co-investigators only, collaborators will not have access 
g.   If appropriate, has a Certificate of Confidentiality been obtained? N/A 
h.   Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -

Page 24 of 24 
 
incidents of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to 
be reported.  N/A 
 
SECTION IX: POTENTIAL BENEFITS 
 
 
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.)  
 
Prostate cancer could potentially be discovered at an earlier and more localized stage allowing 
for greater chance of cure with treatment. 
 
 
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS 
 
1.     Alternatives: What other alternatives are available to the study subjects outside of the research? 
There is no current alternative.  Patients may request to be screened for prostate cancer with 
standard of care management 
 
2.  
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation.  – no payment for participation 
 
3. 
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.   - No cost to participate, all research will be performed 
as part of standard prostate cancer screening.  
 
4. 
In Case of Injury:  
 
If a patient is injured while on study, he should seek treatment and contact the study doctor as 
soon as he is able. Yale School of Medicine and Yale-New Haven Hospital do not provide funds 
for the treatment of research-related injury. If the patient is injured as a result of participation in 
this study, treatment will be provided. He or his insurance carrier will be expected to pay the 
costs of this treatment. No additional financial compensation for injury or lost wages is available.