Proposal for Clinical Research Services



 Exhibit 10.2 
 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF

 DENOTED WITH “***” 
  
  
  
  

							
	

	 	

	 	A Proposal to Provide Clinical Research Services for:
	 	  
 Protocol: BUP-201
  
 *** Evaluation of the Efficacy, Safety, and Tolerability of BEMATM Buprenorphine
in the Treatment of Pain Associated with ***
  
 Prepared
for:
 David Blum, MD
 Vice President, Clinical Research
and Medical Affairs
 BioDelivery Sciences International
 801
Corporate Center Drive, Suite 210
 Raleigh, NC 27607

	 	 Tel:        919.582.9050
 Fax:        919.582.9051
 Email:    dblum@bdsinternational.com

	  	
	 	 Project No. ***
 09 February
2009
 Previous: ***
	  	
	 		  	 Prepared by:
 Pam Myrick

	 	Senior Associate II, Proposal Development
	 		  	


	 	BRUCE M. WAKEMAN
	 	Vice President
	 	U.S., Business Development

  

					
		  	Premier Research Group	  	TEL: 727.865.0803
		  	322 Monte Cristo Blvd	  	MOBILE: 727.244.9809
		  	Tierra Verde, FL 33715	  	EMAIL: bruce.wakeman@premier-research.com

  
  








 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Table of Contents 
  

									
	 •
	  	 EXECUTIVE SUMMARY
	  	1
			
	 •
	  	 PROJECT CONSIDERATIONS
	  	3
			
	 •
	  	 PROJECT RESPONSIBILITIES
	  	4
			
	 •
	  	 PROJECT OUTLINE
	  	5
			
	 •
	  	 PROJECT TIMELINE
	  	6
			
	 •
	  	 PROJECT TEAM DESIGN
	  	7
				
		  		  	 BDSI/Premier Research Project Team Organizational Chart
	  	8
		  		  	 Project Team Leadership
	  	9
			
	 •
	  	 PROJECT IMPLEMENTATION PLAN
	  	12
				
		  		  	 Project Plan Development
	  	12
		  		  	 Parallel Processing ApproachTM
	  	12
		  		  	 Start-up Activities
	  	12
		  		  	 Enrollment Plan
	  	13
		  		  	 Communication
	  	13
			
	 •
	  	 PRICE SUMMARY
	  	15
			
	 •
	  	 DETAILED COST ESTIMATE
	  	16
				
		  		  	 Notes on Pass-through Estimates
	  	19
		  		  	 I.
	  	 Travel Costs
	  	22
		  		  	 II.
	  	 Institutional Review Board (IRB) Fees
	  	22
		  		  	 III.
	  	 Shipping
	  	22
		  		  	 IV.
	  	 Miscellaneous
	  	22
			
	 •
	  	 CLINICAL RESEARCH CENTER INVESTIGATOR GRANT SUMMARY
	  	20
			
	 •
	  	 SERVICE DESCRIPTIONS
	  	21
				
		  		  	 2. Project Management
	  	26
		  		  	 3. Clinical Monitoring and Site Management
	  	27
		  		  	 4. Biostatistics
	  	31
		  		  	 5. Quality Assurance
	  	33
			
	 •
	  	 PAYMENT SCHEDULE
	  	39

  

 CONFIDENTIAL 
 This document is provided with the understanding that the copyright and the information contained herein remains the 
 property of Premier Research Group Limited. It shall be kept confidential and used only by the company or person to whom 
 it is
addressed, for no purpose other than assessing the merits of Premier Research Group Limited. 









 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Executive Summary 
 Premier Research Group Limited (“Premier Research”) is pleased to present this revised proposal in support of the BEMATM Buprenorphine program in patients with ***. In response to your request, we have prepared the
following proposal outlining our strategy to successfully conduct this study. We look forward to this opportunity to collaborate with the BDSI team and appreciate the study information you have provided. 
 We have attempted to accurately respond to your needs in the proposal text and cost estimate, and trust that the information in this document will be informative and
valuable as you determine your outsourcing needs. Where there are outstanding issues or answers yet unknown, Premier Research has made related assumptions. 
 In the pages that follow, we present compelling reasons why Premier Research is the best choice for this project. Those reasons include: 
 Premier Research is recognized as an industry leader in clinical research for acute and chronic pain, having managed more than 350 analgesia trials treating more than 90,000 patients. We have conducted some of the largest and most important
drug trials in pain in multi-center trials around the world and at our Research Centers in the United States. 
 Mr. Michael Kuss,
Vice President, Clinical Research Centers, in particular, is an expert in the field of analgesia research and as part of Premier Research’s commitment to quality assurance, is offered in a supervisory capacity at no charge to BDSI
throughout the course of the study. Mr. Kuss is familiar with many of the aspects involved in conducting successful pain studies and will offer his scientific guidance and therapeutic expertise on critical success factors crucial to the conduct
of this program. 
 Together with our operational experts, the senior leadership at Premier Research understands the challenges and nuances
involved in pain studies and will be available to support the project team as needed. Our experienced study team will provide more efficient program execution, including the ability to predict and overcome complex study issues in an expeditious
manner and complete this study within the timeline BDSI has requested. 
  

	•	 	 Experienced Staff Available to Meet Your Timelines 


 Our experienced study team will provide more efficient study execution, including the ability to predict and overcome complex study issues in an expeditious manner. We can provide a detailed staffing plan, including
team member credentials, which are unrivaled in the industry. 
  

	•	 	 Top-Down Commitment to Customer Satisfaction 


 We are small enough to provide appropriate levels of oversight to ensure that projects are conducted in a timely and efficient manner, but large enough to provide Sponsor with staffing and pricing considerations
appropriate to a long term relationship. 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


			
	Sponsor:	  	BioDelivery Sciences International
		
	Study Medication:	  	BEMATM Buprenorphine
		
	Protocol Number:	  	BUP-201
		
	Protocol Title:	  	*** Evaluation of the Efficacy, Safety, and Tolerability of BEMATM Buprenorphine in the Treatment of Pain Associated with ***
		
	Clinical Phase:	  	II
		
	Indication:	  	***
		
	Participating Regions:	  	North America
		
	Number of Subjects Enrolled/Complete:	  	***
		
	Number of Sites Participating:	  	***
		
	Premier Research Services Requested:	  	Clinical Trial Management, Biostatistics, Quality Assurance
		
	Total Estimated Investigator Grant:	  	$***
		
	Duration of CRO Services:	  	***
		
	Total Estimated Premier Research Fees:	  	$***

 We hope that the information in this document demonstrates our capabilities in this indication and conveys Premier
Research’s commitment to becoming a true partner with you in reaching and exceeding study goals. We enthusiastically anticipate the prospect of conducting this important program for BDSI and look forward to further discussions with you
regarding the information we have provided. 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Project Considerations 
 Premier Research understands the important role that we will play in the conduct of this study and looks forward to collaborating with BDSI to assure the study’s success. In preparing this proposal, we have sought input from our
in-house operations and medical specialists on the design, study timeline and other factors related to enrollment and investigator site selection. The following are issues that Premier Research has identified for your consideration and that we feel
are important to the successful completion of the program. The below comments are based on the original study synopsis date *** provided by BDSI to Premier Research. 
  

	 	•	 	 Premier Research would like to recommend a ***. 


  

	 	•	 	 We would also like to suggest the use of ***. If no *** are to be evaluated, we would recommend that *** also be used as the ***.



  

	 	•	 	 Premier Research would like to suggest the use of the ***. 


  


	 	•	 	 Premier Research would recommend the use of a modified BOCF imputation procedure instead of the currently proposed *** for the primary analysis.



 We welcome the opportunity to discuss further the issues associated with this trial and present our capabilities in person upon
BDSI’s request. Please see the following project responsibilities, outline, timeline, and budget summary for a complete list of assumptions and specifications that factored into our proposal. 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Project Responsibilities 
 *** 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Project Outline 
 *** 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Project Timeline 
  

					
	 Activity
	 	 Timeframe
	 	 Projected Dates


 *** 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Project Team Design 
 Premier Research will draw from our collection of qualified individuals to provide BDSI with a team that has the skills, knowledge, and relevant experience to successfully manage your clinical trial. We are organized into several separate
operational units; skill centers that perform the majority of the day-to-day client services: Clinical Trial Management, Medical Management, Data Operations, Biostatistics, Medical Writing, Regulatory Affairs, Quality Assurance and Information
Technology Client Services (our Interactive Voice Response systems). Each skill center provides the resources for the services required in drug development for their respective areas. 
 Project teams are the primary functional unit at Premier Research. A Project Manager, Clinical Manager, and Biometrics Project Manager generally comprise the leadership of the project team. With scientific guidance
provided by our therapeutic experts in Medical Affairs and senior level management and oversight provided on every project, we offer a strong focus on your needs – leading to a project team that is proactive, highly skilled and responsive.

 The Project Manager is ultimately responsible for overall strategy, planning and execution of the project, from start to finish. Experienced in the
indication and/or therapeutic area required, these team members provide the necessary scientific and operational oversight to ensure that our programs and projects stay on the critical path and that our clients receive timely and high quality
deliverables. 
 Another element that contributes to the success of the project team is the Biometrics Project Manager (BPM). Because study start up is a
very busy time with the initiation of activities in all disciplines, the benefits of a BPM joining the team maximize the attention to all details at the launch of a trial. The management responsibility of the study is then shared between the project
manager and the BPM. The Project Manager focuses on clinical, medical, safety, and regulatory activities while the BPM focuses on the IVRS, data management, biostatistics, and medical writing activities. This allows the Project Manager to spend more
time on external critical relationships and increase the time dedicated to the sites and the site staff allowing our team to build long term networks. The Project Manager remains responsible for the clinical study from beginning to end but has the
added resource of a BPM to assist in the management of the back end services. 
 Premier Research’s Parallel Processing Approach, combined with our
focused management strategy, ensures our clients the most efficient and cost-effective clinical trial. In addition, one key team member is assigned from each skill center and is responsible for the major set of tasks and deliverables provided by his
or her skill center. Each project team is completed by a number of contributors; individuals with backgrounds and expertise from their skill centers that are needed to satisfactorily execute the requirements of a given project. 
 The project team will exist for the duration of the project. However, the amount and continuity of time spent on the project will vary depending on the role of the
individual assigned to the project. The project team will receive support from the heads and line managers within the skill centers, along with senior management when needed. 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Premier Research believes that this team structure: 
  

	•	 	 Ensures the efficient use of each team member’s knowledge and experience, 


  

	•	 	 Ensures the focused management of each individual study, 


  

	•	 	 And provides overall guidance for all projects and programs, ensuring comprehensive project operations, team integration and seamless execution of the program.



 We have provided an organizational chart displaying the structure of this team, and we have also included biographical sketches of our
team leaders to demonstrate why BDSI can be assured that it will be working with a skilled and knowledgeable team. 
 BDSI/Premier Research
Project Team Organizational Chart 
 

 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Project Team Leadership 
 Michael Kuss, BS 
 Vice President, Clinical Research Center Administration 
 Mr. Michael Kuss has worked for Premier Research Group since 2001. He currently is the Vice President of the Clinical Research Centers. He previously served as the
Vice President of Medical Affairs in Analgesia and as the Executive Director, Clinical Trials Management for three years and worked as a Senior Director, Analgesia and Rheumatology, (SCIREX Corporation). From 1986 to 2001 he worked for Pharmacia
(formerly G.D. Searle) in various positions with the last being Director of Research and Development. Prior to G.D. Searle, Mr. Kuss worked as a Clinical Research Associate, (Abbott Laboratories), and as an Infectious Diseases Research
Technologist, (Good Samaritan Hospital and Wright State University SOM). 
 While at Premier Research Group, Mr. Kuss has worked primarily on projects
in the Analgesia and Rheumatology area. He is responsible for working with clients to help develop clinical development plans, write protocols, manage Premier study teams to conduct clinical trials and participate in the preparation of clinical
study reports. At Pharmacia, Mr. Kuss was responsible for clinical development of several COX-2 inhibitors (celecoxib, valdecoxib and parecoxib) and NSAIDs (oxaprozin, oxaprozin potassium and diclofenac/misoprostol) as part of the Arthritis and
Inflammation team. He also played an integral part in the development of lomefloxacin, a quinolone anti-infective. He is an author on many publications and posters in the areas of analgesia, rheumatology and infectious diseases. 
 Mr. Kuss graduated from Wright State University in Dayton, Ohio with a BS in Medical Technology. He received a certification in Medical Technology from the American
Society of Clinical Pathology. 
 Mr. Kuss is a member of the American Pain Society and Drug Information Association. He is a frequent presenter at
annual meetings of the American Pain Society and American College of Rheumatology annual meetings. He has presented at the DIA annual meeting and at several DIA sponsored symposia. 
 Clinical Executive Leadership 
 Stephen Daniels, DO 
 Executive Medical Director, Clinical Research Center Administration 
 Dr. Stephen Daniels is the Executive Director of the Research Centers, a position he has held for over five years. Dr. Daniels has served as principal investigator on numerous acute pain trials, including many in dental,
bunionectomy, knee arthroscopy and dysmenorrhea which involved oral, parenteral, and intranasal analgesics. 
 Prior to joining Premier Research,
Dr. Daniels spent two years as the Medical Director at Research for Health in Houston, TX and prior to that was Medical Director as RLC Healthcare. Dr. Daniels is a graduate of Texas Wesleyan College and Texas College of Osteopathic
Medicine where he received his D.O. 
 Over the past 5 years Dr. Daniels has authored or co-authored 12 publications in peer-reviewed medical journals
and provided medical oversight on all acute pain analgesic trials conducted within the Clinical Research Centers. 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Craig Dale, BBA 
 Executive Director, Clinical Trial Management 
 Mr. Dale has worked for Premier Research Group since 1998. He currently works as
Executive Director, Clinical Trial Management. Previous to that, he worked as a Senior Director, Clinical Trials Management (2005 - 2007), as a Project Director, General Medicine, (2001 - 2005) and as Senior Project Manager, General Medicine,
(1998-2001). He will be available to consult with the project team during these studies and will act as a liaison with BDSI as needed. Mr. Dale’s supervision is part of Premier Research’s commitment to quality assurance and is offered
at no charge to BDSI. 
 From 1990 to 1998, Mr. Dale worked for Pharmaceutical Product Development (PPD) in various positions with the last being Senior
Project Manager. While at Premier Research Group, Mr. Dale has worked primarily on projects in the General Medicine and Analgesia therapeutic areas including cardiovascular, gastroenterology and pain management. He is responsible for working
with clients to help develop clinical development plans, provide therapeutic expertise to internal and external clients, manage Premier study teams to conduct clinical trials and participate in the preparation of clinical study reports. 

Mr. Dale graduated from the University of Mississippi in Oxford, MS with a BBA in Marketing. He is a member of the American Pain Society and Drug Information
Association. 
 Project Manager 
 Daniel Solorio, BS

 Senior Project Manager, Clinical Research Centers 
 Mr. Solorio is responsible for overseeing the clinical operations of one or more multi-disciplinary project teams conducted in the clinical research centers. In this role, Mr. Solorio ensures that the project team has a common
understanding of project objectives, specifications, deliverables, timelines and tasks. 
 Mr. Solorio began his career in 1996, and has been with
Premier Research since 2000 focusing his experience in clinical site operations. Prior to becoming a Project Manager, Mr. Solorio worked two years as a Site Manager, one year as a Clinical Research Coordinator, and one year as a Supervisor for
Clinical Research Coordinators at the Clinical Research Center in Salt Lake City, UT. 
 Mr. Solorio received his B.A. in Communications from the
University of Utah. 
 Biometrics Project Management 
 Lisa Vickers, BA 
 Biometrics Project Manager 
 As a Biometrics Project Manager (BPM), Ms. Vickers is responsible for the overall project management of the data management, statistics and medical writing services. Ms. Vickers has worked on numerous Phase I to Phase IV projects
in oncology, CNS, cardiovascular, endocrinology, urology, women’s health, immunology, dermatology, and respiratory. 
 Lisa Vickers has been in the
Manager, Biometrics position with Premier Research Group since January 2006. Ms. Vickers was employed with PharmData Inc. as a Biometrics Project Manager from November 2003. Prior to that Ms. Vickers worked as both a Medical
Writer and Project Assistant at PharmData and held positions of increasing responsibility at WorldCom. 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Ms. Vickers obtained a Bachelor’s degree in Psychology and a Bachelor’s degree in Marketing from Miami
University in Oxford, OH. Ms. Vickers is a member of DIA and was a member of the American Medical Writers Association for 3 years, serving as Membership chair from 2002-2003. 
 An experienced BPM will be assigned to BDSI’s program upon finalization of the protocol. 
 Biostatistics

 James Johnson, PhD 
 Executive Director, Global
Biostatistics 
 Dr. James Johnson is the Executive Director, Global Biostatistics with overall responsibility for strategic and tactical management
for biostatistics, pharmacokinetics and biostatistical programming functions for the Premier Research. He is responsible for implementing best biostatistical and statistical programming practices, standard operating procedures, and a systems
approach integrated clinical/statistical critical thinking toward drug development and clinical trial design and analysis. 
 Dr. Johnson has
twenty-five years technical experience and leadership in Biostatistics, Clinical Trials Design and Analysis, Project Management, and International Regulatory Agency interaction. In addition Dr. Johnson provides biostatistical consulting
services in the areas of cardiology, oncology, dermatology, and infectious diseases. Dr. Johnson serves on data monitoring committees and is a sub-principal investigator for a long term cardiac imaging study. Dr. Johnson has also been the
lead biostatistician on five New Drug Applications, supported six additional ANDAs, and participated in many different international regulatory interactions (FDA, MHRA, EMEA, Health Canada, and Australian TGA) in his career. 
 Dr. Johnson holds a PhD degree from North Carolina State University, along with a Master’s degree from the College of William and Mary. He is an author of over
30 publications, abstracts, and professional meeting presentations. 
 An experienced Biostatistician will be assigned to BDSI’s program upon
finalization of the protocol and award of the program and will work under the direct supervision of Dr. Johnson to support this project. 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Project Implementation Plan 
 Project Plan Development 
 Premier Research believes that establishing a clear and agreed upon project plan between BDSI and Premier Research prior
to study start up activity is critical to the success of any collaboration. Working in concert, the leadership team for each study develops a study-specific project plan detailing project specific information and procedures to be used to carry out
the activities of the clinical team. The plan will include a description of the project team and any metrics used to assess performance. 
 In addition, the
project plan will determine appropriate communication channels, identify expectations, processes and responsibilities, and define study timelines, interim turnaround times, and critical path milestones for both Premier Research and BDSI. 

Parallel Processing ApproachTM 
 Premier Research has developed a
simple but highly effective strategy, the Parallel Processing ApproachTM (PPA), to ensure quality, speed and cost-effectiveness. We have tested, refined, and perfected this approach over a twelve year period on over 400 projects. Using the
Parallel Processing Approach, each biometrics discipline initiates and processes its part of the project as quickly as possible. As soon as the study protocol and CRF are finalized, the data management group begins the database design, the
statistical group begins the statistical analysis plan (SAP) and identification of feasibility checks and the medical writing group begins the shell report. As data arrives, it is cleaned and entered. Edit checks are run against new data and these
subsets of (blinded) data are used to test and validate the statistical analysis programs. The writers lay out the format of the report, including all tables, figures, and listings defined in the SAP, per FDA and ICH guidelines. 
 In short, all the critical processes and procedures are conducted simultaneously so that by the time the final CRF data is entered and validated, all the SAS
programming, the study report format, and table, graph, and analysis formats have been completed and agreed upon. Once the report is generated, an extensive ‘end-to-end’ review procedure is executed during which all data and results of the
study are quality controlled. Because extensive ‘pre-reviews’ have already been done and incorporated for style, format and content issues, the final review is extremely efficient and ensures a high quality product is delivered quickly.

 Start-up Activities 
  

	1.	Team Training and Meetings 

 The availability of a final
protocol and informed consent and assent templates at the beginning of the study will prevent unnecessary delays in supporting the sites with IRB submissions. Following the award of a project, the core project team, including the support of senior
clinical trial management staff and business development, hold a ‘hand-over’ meeting that serves as the first step in launching a clinical trial at Premier Research. Because departments within our company work closely together, the project
team is well informed and we will be prepared to act quickly to initiate the start of this study. 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Premier Research generally holds a project kick-off meeting with BDSI. SOP, therapeutic and study specific training
are tantamount to Premier Research’s practice of quality team performance, thus, this training is combined with the kick-off meeting and/or the Investigators’ Meeting. 
 Prior to conducting initiation visits, CRAs are provided with a study-specific agenda and associated presentation to ensure consistent dissemination of study information. CRAs will have been trained with regard to the
expectations for the following: query/issue resolution, site communication, project team communication, and routine visit report writing. 
  

	2.	Collection of Essential Documents and IRB Submission 

 At the
outset, several members of the Premier Research project team will be dedicated to the review and collection of regulatory documents from the investigative sites. The entire process will be closely managed and incorporate several means of
communication between Premier Research and the sites to reduce errors and expedite the receipt of accurate critical documents. 
 Key to the management of
regulatory submission is the tracking of IRB review meetings. This task is undertaken by the Premier Research clinical trial management team and tracked closely throughout the course of study start-up. Compared to local site IRB review periods that
can take two to three months (if not more at times), central IRBs that Premier Research has working experience with have an average review period of two to four weeks. Sites that can use Central IRBs will be key and the first to come on board with
initiation and enrollment, with the local sites showing enrollment a bit later in the course of the study. 
 Upon receipt of approval from the IRB, each
site will be contacted for an initiation visit. During these visits the CRA will instruct the site personnel in the technical aspects of the study, including conduct of the study protocol, CRF completion, study drug and related materials, and
adverse event reporting. 
 Enrollment Plan 
 Premier Research
places a strong focus on ensuring the sites are aware, at the qualification visit and re-confirmed during their initiation visit, of the enrollment expectations and the steps that may occur if the expectations are not met. These steps include
on-site monitoring visits with Investigator attendance required to discuss recruitment obstacles to the plan communicated at qualification and initiation visits, along with possible site closure if enrollment does not commence within the agreed upon
timeframe communicated during the qualification visit. While reviewing these expectations, Premier Research also has found it beneficial that the roles of the individuals who are responsible for subject recruitment be clearly defined, documented and
confirmed by the Principal Investigator. 
 Our approach is to institute frequent contact between site staff, the assigned CRA and the Project Management
team to ensure immediate identification of problems related to recruitment that may arise that were unanticipated. Ownership and accountability of recruitment and meeting the enrollment goals as expected is a joint effort with the sites and Premier
Research and as such, collaboration and constant reinforcement of the goals of the study is a key to success. 
 Communication 
 Strong communication is essential to a successful project and will be conducted according to the Project Plan. Communications may include but are not limited to overall
study status, outstanding and critical issues, patient enrollment and budget status. 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Communications will be conducted via telephone, fax, postal and electronic mail as needed. Teleconference calls will
be held as necessary, and as indicated below. 
 Primary Contacts 
 The Project Manager facilitates communication between BDSI and Premier Research; however, the Clinical Manager, as well as all team members, is available to communicate with the BDSI team as needed. 
 Sponsor Teleconferences 
 Teleconferences are held between the
Premier Research team and BDSI as noted in the table below. The day and time of these calls will be mutually decided upon by the Project Manager and BDSI. Participants are noted in the table below; however, the Executive Director, or any other
Premier Research team member would attend on an ‘as needed’ basis. Agendas are provided the day before the regularly scheduled call and minutes will be taken and provided to BDSI. BDSI is asked to review the minutes and approve for
finalization. 
 The following table is a general outline of our planned communication with BDSI as well as planned internal meetings with Premier Research
staff members. 
  

					
	 Meeting
	  	 Frequency
	  	 Premier Research Attendees

	Project Kick-off Meeting	  	One time	  	All key team management
			
	Training Meeting – often held in conjunction with the Kick-off	  	One meeting	  	See above
			
	Teleconferences with BDSI	  	Weekly	  	Project Manager, Clinical Manager, Biometrics Project Manager, additional team members as needed
			
	Teleconferences with Vendors	  	As needed	  	Project Manager, additional team members as needed
			
	Internal Project Management Teleconferences	  	Weekly	  	Project Manager, Clinical Manager, Biometrics Project Manager, Key team members as needed
			
	Internal Teleconferences with CRAs	  	Weekly	  	Project Manager (as needed), Clinical Manager, CRAs

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Price Summary 
 The following table presents a summarized cost estimate. Please see the Detailed Cost Estimate for a more detailed breakdown of costs. Please note that these costs are estimates only. The budget will be finalized upon award of the
project and provision of final project scope. Should the scope or size of the project increase or decrease, the estimates will be revised accordingly in writing and agreed upon by both parties. 
 If protocol design modifications change the scope of work to be provided, or if additional services are requested beyond the scope of this proposal, Premier Research
and BDSI will discuss and negotiate any appropriate revisions to the costs involved. 
 This budget estimate is valid for 90 days following the date
of this proposal. 
  

				
	 BioDelivery Sciences International, Inc.
 Protocol: BUP-201
	  	Estimated
Costs
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 ***
	  	 	***
	 Project Grand Total
	  	$	1,199,271

 NOTE: *** 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Detailed Cost Estimate 
 Please note that these costs are estimates only. The budget will be finalized upon award of the project and provision of final project scope. Should the scope or size of the project increase or decrease, the
estimates will be revised accordingly in writing and agreed upon by both parties. 
 If protocol design modifications change the scope of work to be
provided, or if additional services are requested beyond the scope of this proposal, Premier Research and BDSI will discuss and negotiate any appropriate revisions to the costs involved. 
 This budget estimate is valid for 90 days following the date of this proposal. 
  

			
	 BioDelivery Sciences International, Inc.
 Protocol: BUP-201
	  	Estimated
Costs
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


			
	 BioDelivery Sciences International, Inc.
 Protocol: BUP-201
	  	Estimated
Costs
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


			
	 BioDelivery Sciences International, Inc.
 Protocol: BUP-201
	  	Estimated
Costs
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
	 ***
	  	***
		
	 Project Grand Total
	  	$1,199,271

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Notes on Pass-through Estimates 
 Pass-through costs are estimated to provide a “total budget scenario” for your review. These costs are estimated given currently available information and historical averages. Every effort will be used to minimize these costs
and the final pass-through budget will be worked out with BDSI in advance of study start. 
 *** 
  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Clinical Research Center Investigator Grant Summary 
 PREMIER RESEARCH - INVESTIGATOR GRANT BUDGET 
 BioDelivery Sciences International, Inc. 
 *** 
  



			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Service Descriptions 
 The following are general descriptions of the services that Premier Research is offering to provide during the 
 course of this study. These descriptions are designed to be a summary of the concepts found in the Premier 
 Research
Standard Operating Procedures (SOPs) but are not an exact replica of these procedures. Unless 
 noted otherwise in this proposal,
Premier Research’s budget estimate is based upon the use of Premier 
 Research SOPs.* 
  

	 	1.1.	Protocol Development and Review 

  

	 	1.1.1.	BDSI will be responsible for delivery of a final protocol to Premier Research. 

  

	 	1.2.	eCRF Preparation 

  

	 	1.2.1.	eCRF Development 

  

	 	1.2.1.1.	BDSI will be responsible for development of the eCRF for this study. 

  

	 	1.3.	Subject Assessment Booklet Development and Review 

  

	 	1.3.1.	Subject Assessment Booklet Development 

  

	 	1.3.1.1.	Premier Research will not develop traditional patient diaries, but will develop an in-house assessment booklet to capture all of the patient pain assessment data. Premier Research
will provide BDSI with a draft of the in-house subject assessment booklet for approval for the study. 

  

	 	1.3.1.2.	Premier Research will prepare the subject assessment booklet in English. 

  

	 	1.3.1.3.	BDSI will be provided with a copy of the final approved subject assessment booklet. 

  

	 	1.3.2.	Subject Assessment Booklet Distribution 

  

	 	1.3.2.1.	Premier Research will determine site form needs and distribute diaries accordingly over the course of the study. 

  

	 	1.3.2.2.	Premier Research shall arrange for storage of diaries at an appropriate location. 

  

	 	1.4.	Study Materials Development 

  

	 	1.4.1.	Model Informed Consent Form (ICF) Development 

  

	 	1.4.1.1.	Premier Research will review the protocol, Investigators’ Brochures, etc. and discuss all study parameters with BDSI to fully understand the associated subject benefits and
risks. 

  

	 	1.4.1.2.	Premier Research will follow BDSI’s sample ICF, if provided. 

  

	*	Premier Research will carry out these services pursuant to the protocol; local, state, and federal regulations; and ICH/GCP guidelines. All study activities will be performed
according to Premier Research SOPs, unless otherwise noted. Premier Research will make available, upon request, its SOPs for BDSI review. It is Premier Research policy that copies of SOPs cannot be provided; however, BDSI may review the SOPs at any
Premier Research office. If BDSI requests activities to be performed according to its SOPs, budget modifications may be necessary. 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	1.4.1.3.	Premier Research will review the list of FDA-required ICF elements to ensure compliance. Premier Research will also review state ICF requirements to ensure compliance (e.g., State
of California, Bill of Rights). 

  

	 	1.4.1.4.	Premier Research will prepare a draft Model ICF to be circulated to the Premier Research Project Teams for internal review and comment. 

  

	 	1.4.1.5.	Premier Research can arrange for certified translation of the Model ICF, if necessary. 

  


	 	1.4.1.6.	Premier Research will incorporate Project Team comments, as appropriate, and provide the draft Model ICF (up to two drafts) for BDSI review. Any comments from BDSI will be
consolidated before being returned to Premier Research. 

  

	 	1.4.1.7.	Premier Research will incorporate BDSI’s consolidated comments and produce a final Model ICF for BDSI’s approval. 

  

	 	1.4.1.8.	Premier Research will make the approved Model ICF available to all investigative sites as a template to be used to generate their site-specific ICF. Premier Research will review the
site-specific ICF for each investigative site to ensure that it remains in compliance with FDA, state, and BDSI required ICF elements. 

  

	 	1.4.1.9.	Premier Research can arrange for certified translation of the site-specific ICFs, if necessary. 

  

	 	1.4.2.	Source Document Development 

  

	 	1.4.2.1.	Premier Research will develop a standard source document. This document will help to assure all required data points are appropriately captured per the protocol and it will help
expedite the CRF review process during monitoring visits. 

  

	 	1.4.3.	Clinical Plan Development 

  

	 	1.4.3.1.	The Premier Research Project Manager, in conjunction with the Premier Research Project Director, will develop a Clinical Plan. This document details project specific information and
the procedures to be used to carry out the activities and services provided by the clinical department. 

  

	 	1.4.4.	Regulatory Binder Setup 

  

	 	1.4.4.1.	Premier Research will set up for each Investigator a binder that will contain all relevant study documents. 

  

	 	1.4.4.2.	This binder should contain, but not be limited to, the following: 

  

	 	1.4.4.2.1.	Monitoring Sign-In Log, 

  

	 	1.4.4.2.2.	Randomization List/Emergency Envelopes (where applicable), 

  

	 	1.4.4.2.3.	Receipt/Retrieval documentation for drug/other study supplies, including eCRFs/diaries, 

  

	 	1.4.4.2.4.	Drug Accountability Forms (where applicable), 

  

	 	1.4.4.2.5.	Laboratory Certification and normal ranges (where applicable), 

  

	 	1.4.4.2.6.	Enrollment/Exclusion Log, 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	1.4.4.2.7.	Sample of Model ICF and site-specific ICF, 

  

	 	1.4.4.2.8.	Study Center Sample Signature Form, 

  

	 	1.4.4.2.9.	CVs for Investigator, Sub-Investigator, and other key personnel, 

  

	 	1.4.4.2.10.	Signed, original Protocol and all amendments, 

  

	 	1.4.4.2.11.	IRB/Ethics Committee approval(s), 

  

	 	1.4.4.2.12.	Essential documents (e.g., FDA-1572, submissions), 

  

	 	1.4.4.2.13.	Letter of indemnity (where applicable), 

  

	 	1.4.4.2.14.	National guidelines and legal information on clinical trials (where applicable), 

  

	 	1.4.4.2.15.	Investigators’ Brochure, 

  

	 	1.4.4.2.16.	Signed Confidentiality Agreement, 

  

	 	1.4.4.2.17.	Correspondence regarding the study, including written telephone contact forms, 

  

	 	1.4.4.2.18.	Instructions for eCRF/diary completion, 

  

	 	1.4.4.2.19.	Procedures for AE/SAE reporting and completed SAE report forms, 

  

	 	1.4.4.2.20.	Handling of clinical laboratory samples, 

  

	 	1.4.4.2.21.	The name of the appropriate Premier Research contact for specific issues (e.g., SAE reporting), and 

  

	 	1.4.4.2.22.	Instructions for ordering study supplies. 

  

	 	1.4.4.3.	Premier Research will distribute the final Regulatory Binder to the Investigators. 

  

	 	1.4.4.4.	Financial agreements, payment schedules, and correspondence regarding investigator payment will be maintained in a file separate from the Regulatory Binder.


  

	 	1.4.5.	Study File Setup 

  

	 	1.4.5.1.	Premier Research will set up and keep study documents in the Study File. 

  

	 	1.4.5.2.	This file shall contain, but not be limited to, the following documentation: 

  

	 	1.4.5.2.1.	All study-related correspondence, 

  

	 	1.4.5.2.2.	Serious Adverse Event reports, 

  

	 	1.4.5.2.3.	Receipt/Retrieval forms for drug and other study supplies, 

  

	 	1.4.5.2.4.	Meeting information, 

  

	 	1.4.5.2.5.	Client-approved study protocol and amendments, 

  

	 	1.4.5.2.6.	Sample eCRF and supplemental data forms will be provided in the investigator binder and will be used only as emergency back up if for any reason the system may become
non-operational, 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	1.4.5.2.7.	Sample subject instructions, Model ICF, and advertising, 

  

	 	1.4.5.2.8.	Investigators’ Brochure or Package Insert, 

  

	 	1.4.5.2.9.	Data Operations Guidelines, 

  

	 	1.4.5.2.10.	IRB/Ethics Committee approval(s), 

  

	 	1.4.5.2.11.	Regulatory approval(s), and 

  

	 	1.4.5.2.12.	Reports (interim/final). 

  

	 	1.4.6.	Translations 

  

	 	1.4.6.1.	Premier Research will not be responsible for any document translations. 

  

	 	1.4.7.	Statistical Analysis Plan (SAP) and TLG Shell Review 

  

	 	1.4.7.1.	The Project Manager will review the SAP prior to finalization. 

  

	 	1.5.	Investigator Identification and Recruitment 

  

	 	1.5.1.	Premier Research will utilize the Clinical Research Centers for this trial. 

  

	 	1.5.2.	Premier Research will review FDA’s Disqualified Investigators list, and FDA’s Monitoring Inspection Log to ensure that potential Investigators are qualified to conduct the
study. 

  

	 	1.5.3.	Premier Research will send to each Investigator (if appropriate) a Confidentiality Agreement, protocol/protocol synopsis, and Investigators’ Brochure. 


 

	 	1.5.4.	Premier Research will discuss briefly with each Investigator: 

  

	 	1.5.4.1.	Overview of BDSI, 

  

	 	1.5.4.2.	Study compound, 

  

	 	1.5.4.3.	Therapeutic area being studied, 

  

	 	1.5.4.4.	Study procedures/assessments, 

  

	 	1.5.4.5.	Number and availability of subjects to be recruited, 

  

	 	1.5.4.6.	Study duration, complexity, and the investigators’ clinical workload, 

  

	 	1.5.4.7.	Subject inclusion/exclusion requirements, and 

  

	 	1.5.4.8.	Study budget (i.e., investigator payments), if appropriate. 

  

	 	1.6.	Prestudy Site Reviews 

  

	 	1.6.1.	Premier Research will perform prestudy site reviews to: 

  

	 	1.6.1.1.	Discuss the study and impart obligations and responsibilities, 

  

	 	1.6.1.2.	Determine whether suitable subject population exists, 

  

	 	1.6.1.3.	Obtain pre-study documentation and essential documents when available, and 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	1.6.1.4.	Assess ability to begin the study in a timely fashion. 

  

	 	1.6.2.	Premier Research will not discuss BDSI’s company or drug name without confirming that the Investigator has signed a Confidentiality Agreement. 

  

	 	1.6.3.	Premier Research will follow up the prestudy review with the following tasks: 

  

	 	1.6.3.1.	Provide a summary of discussions, action items, requests for any outstanding documentation, etc. for suitable Investigators and 

  

	 	1.6.3.2.	Retrieve all confidential information from Investigators designated not suitable. 

  

	 	1.7.	Collection of Essential Documents 

  

	 	1.7.1.	Premier Research will be responsible for collecting essential documents from investigators selected for participation in this clinical trial, including the following:


  

	 	1.7.1.1.	A signed FDA Form 1572, 

  

	 	1.7.1.2.	A signed protocol signature page, if used, 

  

	 	1.7.1.3.	A current, signed CV for Principal Investigator and Sub-Investigators, 

  

	 	1.7.1.4.	An IRB Approval, 

  

	 	1.7.1.5.	An IRB-approved Informed Consent Form, 

  

	 	1.7.1.6.	The financial disclosure documents, 

  

	 	1.7.1.7.	A list of IRB members/Department of Health and Human Services Assurance Number, 

  

	 	1.7.1.8.	Laboratory certifications, and 

  

	 	1.7.1.9.	The normal ranges of laboratory tests or reference ranges for laboratory analyses. 

  

	 	1.7.2.	Premier Research will provide BDSI with all original essential documents after reviewing all essential documents for accuracy and completeness. 

  

	 	1.7.3.	BDSI will be responsible for filing these documents for the IND. 

  

	 	1.8.	Investigator Grant and Contract Negotiation 

  

	 	1.8.1.	Premier Research will set up a payment program based on the procedures outlined in the final protocol. Payments will be made on a prorated basis of work performed as set out in the
final contract. 

  

	 	1.8.2.	The grant amounts will cover all protocol procedures, institutional overheads, study coordinator fees, subject stipends, and advertising costs. Premier Research will execute final
contracts with each investigator and will process investigator payments based on the payment plan outlined in the negotiated clinical study agreements. 

  

	 	1.9.	Investigators’ Meeting 

  

	 	1.9.1.	Due to the minimal number of investigational sites and their recurring experience with this type of study, Premier Research has assumed that an Investigators’ Meeting is
unnecessary. 

  

	 	1.10.	Training 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	1.10.1.	Project Specific Training 

  

	 	1.10.1.1.	Premier Research will ensure that all appropriate project staff are adequately trained in all the clinical and administrative aspects of the study including the following:


  

	 	1.10.1.1.1.	Study protocol, 

  

	 	1.10.1.1.2.	Study plans and targets, 

  

	 	1.10.1.1.3.	Instructions to investigators, 

  

	 	1.10.1.1.4.	Study documents, and 

  

	 	1.10.1.1.5.	Clinical and administrative procedures, including consent waiver regulations. 

  

	 	1.11.	Vendor Selection and Consulting 

  

	 	1.11.1.	Institutional Review Board (IRB) Selection and Setup 

  

	 	1.11.1.1.	Premier Research will be available to assist the sites in obtaining the required IRB approvals. 

  

	 	1.11.1.2.	Premier Research will make the protocol, CRF, Diary, Investigators’ Brochure, and Model ICF available to the central IRB for review and comment, if necessary or requested by
BDSI. 

  

	 	1.11.1.3.	Premier Research will provide a copy of protocol amendments to investigators after the amendments are finalized with BDSI and appropriate regulatory agency approval.


  

	 	1.11.2.	Vendor Selection and Setup 

  

	 	1.11.3.	BDSI will identify the necessary vendors and set up vendors for study participation. 

  

	2.	Project Management 

  

	 	2.1.	Client Interaction 

  

	 	2.1.1.	Premier Research will communicate with BDSI management on a regular basis concerning the study and its progress. 

  

	 	2.1.2.	Client Teleconferences 

  

	 	2.1.2.1.	Premier Research assumes teleconferences between key project members and BDSI at the frequency indicated in the “Project Outline.” 

  

	 	2.1.3.	Ad Hoc Client Communications 

  

	 	2.1.3.1.	Premier Research anticipates that members of the project team will communicate informally with BDSI on a regular basis. 

  

	 	2.2.	Project Team Management 

  

	 	2.2.1.	Internal Project Team Meetings 

  

	 	2.2.1.1.	Appropriate members of the Premier Research project team will attend regular internal meetings as necessary. 

  

	 	2.2.1.2.	Premier Research will record major team meeting minutes for distribution. 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	2.2.2.	Internal Team Support 

  

	 	2.2.2.1.	The Premier Research team leader will perform the following general management functions for this study: 

  

	 	2.2.2.1.1.	Coordinate and manage the project team, including ad hoc training, resource management, mentoring, and support deemed necessary for the smooth execution of this project;


  

	 	2.2.2.1.2.	Manage project costs, schedules, and quality to ensure that study goals and objectives are achieved; 

  

	 	2.2.2.1.3.	Manage sub-contractors (i.e., external data sources, drug packaging/distribution, etc.) to ensure smooth interaction with other aspects of the study; 

  

	 	2.2.2.1.4.	Ensure invoices sent to BDSI are appropriate for work performed; and 

  

	 	2.2.2.1.5.	Ensure that work carried out is in accordance with Premier Research SOPs; ICH/GCP guidelines; and local, state, and federal regulations. 

  

	 	2.3.	Project Tracking 

  

	 	2.3.1.	Project Tracking and Status Reports 

  

	 	2.3.1.1.	This proposal is based on the tracking and compilation of the following information: site information (contact information for the Principal Investigator and Study Coordinator);
patient enrollment, visit, and disposition information (on a weekly basis); and grant payment information. Premier Research can track additional information to meet BDSI-specific study requirements; however, significant additions may incur
additional labor costs. 

  

	 	2.3.1.2.	Premier Research will provide a progress report on a monthly basis. The report will show the number of subjects enrolled in the study and the stage of each subject in the trial,
copies of correspondence generated in the previous month, copies of trip reports completed in the previous month, etc. The format for this report will be discussed with and approved in advance by BDSI. Premier Research can provide more frequent
progress reports to meet BDSI-specific study requirements; however, significant additions may incur additional labor costs. 

  

	3.	Clinical Monitoring and Site Management 

  

	 	3.1.	Initiation Visits 

  

	 	3.1.1.	Premier Research will provide investigators with an Investigators’ File prior to site initiation to ensure proper investigator file maintenance. 

  

	 	3.1.2.	Premier Research will maintain copies of all essential documents, unless specified otherwise by BDSI. Premier Research will maintain original correspondence and provide BDSI with
copies at the end of the study, unless specified otherwise by BDSI. 

  

	 	3.1.3.	Premier Research will perform initiation visits at each site according to Premier Research SOPs. During these visits, Premier Research will instruct the Investigator and the study
coordinator in the technical aspects of the study, including but not limited to: 

  

	 	3.1.3.1.	Conduct of the study protocol, 

  

	 	3.1.3.2.	Training on the eCRF data collection system, 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	3.1.3.3.	Specimen handling for laboratory evaluation and pharmacokinetic evaluation (if applicable), 

  

	 	3.1.3.4.	Inventory of the study drug and all related materials, and 

  

	 	3.1.3.5.	Adverse Event/Serious Adverse Event reporting. 

  

	 	3.1.4.	For each site visited, Premier Research will complete an initiation visit report according to Premier Research SOPs and make it available to BDSI within 15 business days of the
visit. 

  

	 	3.2.	Investigator Site Grant Administration 

  

	 	3.2.1.	Premier Research will administer all Investigator payments and account for them according to Generally Accepted Accounting Principles (GAAP). 

  

	 	3.2.2.	BDSI is expected to provide Premier Research with adequate funds to administer the Investigator payments. 

  

	 	3.3.	Study File Maintenance 

  

	 	3.3.1.	Premier Research will ensure all files in the Study Files are kept current, including updated essential documents and copies of all correspondence. 

  

	 	3.3.2.	Premier Research will also maintain, in the Study File, financial agreements, payment schedules, and correspondence regarding investigator payments. 

  

	 	3.3.3.	Protocol amendments may be required during the course of this trial. Premier Research will maintain copies of all protocol amendments in the Study File. In addition, copies of
amendments will be provided to each site for IRB submission and inclusion in the Investigator File. Premier Research standard labor estimate includes the administrative activities for up to two protocol amendments. 

  

	 	3.4.	Routine Monitoring Visits 

  

	 	3.4.1.	Premier Research shall conduct routine monitoring visits at each site at a frequency specified in the “Project Outline.” Trained Clinical Research Associates (CRAs) will
perform all monitoring. 

  

	 	3.4.2.	BDSI personnel are welcome to accompany Premier Research staff on any visit. 

  

	 	3.4.3.	For each visited conducted, Premier Research will complete a monitoring visit report according to Premier Research SOPs and make it available to BDSI according to the study-specific
monitoring plan. This report will include, but not be limited to: 

  

	 	3.4.3.1.	Subject accrual status report with the number of subjects entered, dropped, and completed; 

  

	 	3.4.3.2.	Issues related to subject accrual; 

  

	 	3.4.3.3.	Issues related to subject safety; 

  

	 	3.4.3.4.	eCRF/diary collection; 

  

	 	3.4.3.5.	Status of regulatory documents; 

  

	 	3.4.3.6.	Status of drug accountability; and 

  

	 	3.4.3.7.	ICH/GCP guidelines. 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	3.4.4.	A detailed follow-up letter will also be sent to the Investigator outlining the pertinent points from each visit and the agreed upon actions. 

  

	 	3.4.5.	One hundred percent (100%) Source Document Verification will be performed. 

  

	 	3.4.6.	Premier Research will consolidate and update the subject accrual status report on a regular basis as directed by BDSI. 

  

	 	3.4.7.	Premier Research will notify BDSI whenever accrual rates fail to attain the predicted rates. 

  

	 	3.4.8.	The CRAs (along with the Project Manager) will be responsible for: 

  

	 	3.4.8.1.	Routinely reviewing enrollment reports, 

  

	 	3.4.8.2.	Providing scheduled status updates, 

  

	 	3.4.8.3.	Writing and distributing newsletters to Investigators (if requested), 

  

	 	3.4.8.4.	Ensuring proper drug accountability, 

  

	 	3.4.8.5.	Reviewing site essential documents (collecting and transmitting to BDSI as needed), 

  

	 	3.4.8.6.	Managing protocol amendment submissions to the IRB(s), and 

  

	 	3.4.8.7.	Reporting Serious Adverse Events. 

  

	 	3.4.9.	The CRAs will ensure the study drug is secured and accountability records are accurate and updated. 

  

	 	3.4.10.	The CRAs will conduct a continuing review of the Investigators’ File for regulatory adherence. 

  

	 	3.5.	Interim Site Communications 

  

	 	3.5.1.	Premier Research CRAs will maintain ongoing communication with each site between monitoring visits to ensure close tracking of study progress. 

  

	 	3.5.2.	Substantive communications will be documented in telephone logs and memos. 

  

	 	3.5.3.	Copies of the telephone contact reports and memos will be distributed to specific Premier Research Team members and BDSI (as described above). 

  

	 	3.6.	SAE Administration 

  

	 	3.6.1.	Premier Research Clinical Trials Management will receive copies of completed SAE forms from Premier Research Medical Management. Premier Research Clinical Trials Management will
assist Premier Research Medical Management in retrieving requested follow-up information if requested and will receive completed follow-up SAE forms from Premier Research Medical Management. 

  

	 	3.6.2.	Premier Research Clinical Trials Management will track SAE information to ensure appropriate follow-up and distribution but is not responsible for detailed or specialized tracking
and reporting on SAE information. 

  

	 	3.6.3.	Premier Research Clinical Trials Management will receive IND Safety Reports from BDSI and provide them to the investigational sites. Premier Research will track IRB acknowledgement
of these IND Safety Reports. 

  

	 	3.7.	Response to QA Audits 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	3.7.1.	Premier Research will review each audit report and discuss findings with the auditor. 

  

	 	3.7.2.	The CRA will work with the Clinical Manager and the site to resolve any findings in the audit report. 

  

	 	3.7.3.	Responses will be provided to the auditor and included in the final audit report that is submitted to BDSI. 

  

	 	3.8.	Newsletters 

  

	 	3.8.1.	Premier Research will not provide newsletters for this study. 

  

	 	3.9.	Closeout Visits 

  

	 	3.9.1.	Premier Research CRAs will conduct closeout visits to each investigational site. 

  

	 	3.9.2.	Closeout visits will include the following tasks: 

  

	 	3.9.2.1.	Ensure that all CRF data and data queries (if applicable) has been entered into the data collection system, 

  

	 	3.9.2.2.	Review of the Investigators’ File for completeness and regulatory compliance, 

  

	 	3.9.2.3.	Management of final drug accountability and reconciliation, 

  

	 	3.9.2.4.	Discussion with study staff regarding continuing responsibilities, and 

  

	 	3.9.2.5.	Arrangement for record retention. 

  

	 	3.9.3.	Premier Research shall ensure that study documents including, but not limited to, the following are in order at the investigational site: 

  

	 	3.9.3.1.	Copies of the Signed IRB-Approved Informed Consent Forms and other documentation, 

  

	 	3.9.3.2.	Copies of FDA Form 1572 signed during the study, 

  

	 	3.9.3.3.	Laboratory Certification and Laboratory Reference Ranges, 

  

	 	3.9.3.4.	Copies of all CRFs/diaries and correction forms, 

  

	 	3.9.3.5.	Source Documents, 

  

	 	3.9.3.6.	Regulatory Binder, 

  

	 	3.9.3.7.	Copies of all communications (e.g., with BDSI, IRB, etc.), and 

  

	 	3.9.3.8.	Financial disclosure documents. 

  

	 	3.9.4.	Premier Research shall remove all appropriate study documentation, CRFs/diaries, drug supplies, etc. from each investigational site. 

  

	 	3.9.5.	After completing the closeout visit, Premier Research will complete a closeout visit report according to Premier Research SOPs and make it available to BDSI within 15 business days
of the visit. Following completion of the report, Premier Research will send a closeout letter to the Investigator outlining the pertinent points from the visit. 

  

	 	3.10.	IRB Maintenance and Closeout 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	3.10.1.	Premier Research will manage interactions with the IRB(s). 

  

	 	3.10.2.	If requested, Premier Research will provide the final protocol and any amendments, Investigators’ Brochure, Model ICF, and any background or educational materials required by
the IRB. 

  

	 	3.10.3.	Premier Research will work closely with each site to determine local IRB meeting schedules and requirements, if applicable. 

  

	 	3.11.	Vendor Services Maintenance and Closeout 

  

	 	3.11.1.	BDSI will manage the interactions with contracted vendors (e.g., central laboratories) to ensure the smooth execution of the project. 

  

	 	3.11.2.	BDSI will administer payments to vendors. 

  

	4.	Biostatistics 

  

	 	4.1.	Biostatistics Administration 

  

	 	4.1.1.	Meetings 

  

	 	4.1.1.1.	Biostatistics personnel will participate in the internal and external project team meetings as needed, as noted in the “Project Outline”, conducted by the Project Manager
to discuss issues and solutions surrounding the project. All key questions and decisions will be forwarded to BDSI. 

  

	 	4.1.2.	Data Management Plan Review 

  

	 	4.1.2.1.	Premier Research biostatistics personnel will participate in the review of the data management plan (DMP). All other services related to the DMP can be found in the “Data
Operations” section. 

  

	 	4.2.	Protocol and Case Report Form (CRF) Review 

  

	 	4.2.1.	Premier Research biostatistics personnel will participate in the review of the final Protocol and CRFs. 

  

	 	4.3.	Randomization 

  

	 	4.3.1.	Premier Research will develop the randomization schedule based upon information provided in the protocol and on other information provided by BDSI, e.g., block size.


  

	 	4.3.2.	Premier Research will provide BDSI with a “dummy” randomization schedule, showing the layout, format, and labeling of the treatment codes. Premier Research will implement
or respond to BDSI’s comments as appropriate. Once BDSI approves the dummy schedule, the actual schedule will be generated using a different random sequence. This proposal assumes one draft and one final version of the dummy schedule.


  

	 	4.3.3.	All processes will be done so that all parties involved with the study remain blinded (except where unblinding is necessary such as for pharmacy personnel preparing study
medication). Emergency unblinding, e.g., in case of a serious adverse event, will be done by the Premier Research head of Medical Safety, according to pertinent Premier Research SOPs. 

  

	 	4.3.4.	This proposal assumes that the Premier Research biostatistics department does not need to supply treatment codes in the form of individual study subject sealed envelopes. Rather,
the Premier Research biostatistics department will generate and confidentially deliver a separate list for each study site, or a single list for the entire study. 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	4.3.5.	Premier Research will create a randomized kit-mapping schedule for the packaging of study drug based on information provided in the protocol and from the sponsor and drug packager.


  

	 	4.3.6.	This proposal assumes that the kit map consists of a simple list matching kit numbers to treatments. 

  

	 	4.4.	Statistical Analysis Plan (SAP) 

  

	 	4.4.1.	Premier Research biostatistics personnel will develop the SAP, which will describe in detail the analysis populations, derived variables, and statistical methodology to be used for
the final analyses. The SAP will not include detailed analysis data set specifications or SAS programming code. 

  

	 	4.4.2.	The SAP will include “shells” (“mock-ups”) for tables, listings, and graphs. The number of shells assumed is indicated in the “Statistical
Specifications” section of the “Project Outline” above. 

  

	 	4.4.3.	The draft SAP will be provided to the appropriate BDSI personnel for review. 

  

	 	4.4.4.	Premier Research will implement or respond to BDSI’s comments as appropriate and then issue the final SAP. Once BDSI approves the final plan, preparation for programming and
analyses will begin. 

  

	 	4.4.5.	This proposal assumes one draft and one final version of the SAP. 

  

	 	4.5.	Interim Analysis Programming and Production 

  

	 	4.5.1.	No interim analyses will be performed during this study. 

  

	 	4.6.	Analysis Programming and Production 

  

	 	4.6.1.	Analysis Programming 

  

	 	4.6.1.1.	Premier Research biostatistics personnel will develop programs to create analysis data sets, which will include select derived variables required for the analyses.


  

	 	4.6.1.2.	Premier Research biostatistics personnel will develop programs for the tables, listings, and graphs (TLGs) specified in the SAP. The numbers of TLGs assumed is indicated in the
“Statistical Specifications” section of the “Project Outline” above. 

  

	 	4.6.1.3.	The programs for analysis data sets and TLGs will be checked according to Premier Research SOPs regarding quality control of statistical outputs. 

  

	 	4.6.2.	Analysis Production 

  

	 	4.6.2.1.	When the Premier Research biostatistics department has been provided with the locked database, written approval from BDSI to be unblinded, and the unblinded treatment codes,
preparation for production of the analyses will begin. 

  

	 	4.6.2.2.	Premier Research biostatistics personnel will review the data for changes in structure or values that might require changes in programming. 

  

	 	4.6.2.3.	Premier Research biostatistics personnel will execute the programs for the analysis data sets and TLGs, review the output, and make needed corrections and adaptations.


  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	4.6.2.4.	The quality control steps for the programs for the analysis data sets and TLGs will be updated according to Premier Research SOPs regarding quality control of statistical outputs.


  

	 	4.6.2.5.	Following these updates and reviews, the draft TLGs will be provided to the appropriate BDSI personnel for review. 

  

	 	4.6.2.6.	Premier Research will implement or respond to BDSI’s comments as appropriate. The reviews and quality control steps will be updated as necessary, after which Premier Research
will issue the final TLGs. 

  

	 	4.6.2.7.	This proposal assumes one draft and one final version of the TLGs. At BDSI’s request, the draft version may be divided into a small “top-line” set and a complete set,
with the top-line set to be provided earlier than the complete set. The timing of the delivery of the top-line set will depend on the number and complexity of the top-line TLGs. BDSI must specify the top-line set following finalization of the SAP,
prior to database lock. 

  

	 	4.6.2.8.	This proposal assumes that at most one hardcopy of each version (draft or final) of the TLGs will be provided to BDSI. If additional hardcopies are requested, additional labor,
production, and shipping expenses, if any, will be invoiced as a pass-through expense. The additional hardcopies may arrive after the initial copy. 

  

	 	4.7.	Statistical Writing 

  

	 	4.7.1.	Integrated Clinical/Statistical Report (ICSR) 

  

	 	4.7.1.1.	Premier Research biostatistics personnel will advise the Medical Writer regarding the statistical methods and results, including modifications or additions to the analyses (if any)
not specified in the SAP. 

  

	 	4.7.1.2.	Premier Research biostatistics personnel will review the ICSR paying particular attention to the descriptions of statistical methods and the interpretations of statistical results.


  

	 	4.8.	Submission of Programs to BDSI 

  

	 	4.8.1.	Premier Research does not typically provide its analysis data set and TLG programs to its clients. To date, Premier Research has not encountered any instances where a client has
needed the programs to successfully complete a project. If the FDA or another regulatory agency requests the programs, Premier Research will send the programs and appropriate documentation directly to the regulatory agency in a timely fashion.


  

	 	4.9.	Archiving 

  

	 	4.9.1.	Once BDSI signs the final report, Premier Research will archive all documentation, electronic files, and programs. Premier Research will provide to BDSI copies of all requested
documentation other than the programs used to generate analysis datasets, tables, listings, and figures. 

  

	5.	Quality Assurance 

  

	 	5.1.	The Premier Research Quality Assurance department will provide assurance to BDSI and Premier Research management that the study is being carried out in accordance with the protocol,
and Premier Research SOPs, local, state, and federal guidelines and regulations. 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  


	 	5.2.	Premier Research will audit the investigational sites (as indicated in “Project Outline”) to ensure documentation is complete and in compliance with Premier Research SOPs,
and is in conformity with the Study File. 

  

	 	5.3.	Premier Research will review the study protocol (amendments, if applicable), the CRF, and applicable Premier Research SOPs. 

  

	 	5.4.	Premier Research will check the Study File and Investigators’ Files for completeness and adherence to the relevant Premier Research SOPs, local, state, and federal guidelines
and regulations. 

  

	 	5.5.	Premier Research will confirm subject identification and IRB/Ethics Committee-approved informed consent documents. SAE reports (initial and final) will be checked for all subjects
against the source data. 

  

	 	5.6.	Auditors will conduct investigator site audits, independent or in conjunction with, BDSI’s QA/Regulatory Affairs Department. 

  

	 	5.7.	At the end of each audit, a report will be written within 20 working days of the audit and circulated to the Premier Research Project Manager. 

  

	 	5.8.	A meeting will be set up with the relevant Premier Research staff to discuss findings and agree on responsibilities and time frames for completing necessary actions.


  

	 	5.9.	Resolution of deficiencies will be documented on the final audit report. 

  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201
	  	












 CONFIDENTIAL TREATMENT REQUESTED 
 WITH RESPECT TO CERTAIN PORTIONS HEREOF 
 DENOTED WITH “***” 
  

 Payment Schedule 
 This proposal is incorporated into the Master Clinical Services Agreement between Premier Research International LLC and BioDelivery Sciences International as Exhibit 2. 
 *** 
 Invoices Address: 
 David Blum, MD 
 Vice President, Clinical Research and Medical Affairs

 BioDelivery Sciences International 
 801 Corporate Center
Drive, Suite 210 
 Raleigh, NC 27607 
  

					
	 Remittance Addresses:
	  		  	
	via Regular Mail:	  	via Overnight Mail:	  	via Wire:
	Premier Research International LLC	  	Image Remit	  	Bank: Commerce Bank
	P.O. Box 95000-2310	  	205 North Center Drive	  	Location: Philadelphia , PA
	Philadelphia, PA 19195-2310	  	North Brunswick, NJ 08902	  	Acct Name: Premier Research International LLC
		  	ATTN: P.O. Box 95000-2310	  	Acct #: 367139110
		  		  	ABA Routing #: 031201360
		  		  	BIC / Swift code: CBNAUS33

 ACCEPTED AND AGREED: 
  

									
	Premier Research International LLC	 		 	BioDelivery Sciences International
					
	BY:	 	 /s/ Dave Murcar
	 		 	BY:	 	 /s/ Mark Sirgo

		 	Dave Murcar	 		 		 	
		 	Director, Contract Development	 		 	TITLE:	 	President and CEO
					
	DATE:	 	 3/12/09
	 		 	DATE:	 	 3/13/09


  


			
	 Confidential
 4395 BioDelivery Sciences International
Proposal v3
 Protocol: BUP-201