Attachment_4_-_Task_Order_1_Statement_of_Work.pdf

19-223-SOL-00023 - In Vitro and Non-Clinical Evaluation of Locally-Acting Topical Dermal and Ophthalmic Formulation Properties Attachment #4 – Statement of Work – Task Order 1

Project Title: Tear film thickness and menisci measurements on rabbit ocular surface after instillation of cyclosporine ophthalmic emulsion

1. Description of Work/Statement of Work

1.1. Background

Cyclosporine ophthalmic emulsion is a drug product approved by the FDA under the brand name Restasis®, which is indicated for the treatment of keratoconjunctivitis sicca (KCS), i.e. dry eye syndrome, with the strength of 0.05% (1). Regarding bioequivalence (BE) of this product, a pharmacokinetic (PK) study is not feasible due its plasma concentration levels that are below the lower limit of quantification (1, 2). The current product specific guidance (PSG) from the United States Food and Drug Administration (FDA) for cyclosporine ophthalmic emulsion recommends an in vitro or an in vivo option (3). For the in vitro option, an applicant is recommended to show qualitative (Q1) and quantitative (Q2) sameness, conduct a valid in vitro release rate test, show that six different physicochemical properties are similar, and to show similar drug distribution within the different phases of the formulation (3). These six properties include surface tension, osmolality, zeta potential, globule size distribution, pH, and viscosity profile as a function of applied shear (3). A randomized, double blind, parallel, placebo-controlled BE study is recommended for the in vivo option, where the subjects should be otherwise healthy subjects demonstrating a lack of tear production due to symptoms associated with KCS (3).

Though it is not required for the in vitro option, an enhanced understanding of how the physicochemical properties of interest affect in vivo absorption at the site(s) of action would be helpful for potentially widening acceptable limits of these properties as they relate to BE. A physiologically based pharmacokinetic (PBPK) model has been developed which uses a combination of physics-based and compartmental approaches to predict bioavailability of cyclosporine to the cornea and the conjunctiva in humans (4). The physics-based component of the modeling uses empirically derived tear film thickness and menisci measurement data to predict evaporation of the tear film (4). Also, drainage is estimated by using a physical model which is dependent on changes in viscosity that are tracked throughout the time course of the prediction (4). The transport of tear film fluid and drug concentration is tracked through five compartments which include the tear film, the upper and lower tear film menisci, and the upper and lower conjunctival sacs, where drug may be absorbed into either the cornea or conjunctiva, depending on which compartment is considered (4).

Since human cornea and conjunctiva tissue concentration measurements may not be feasibly obtained, it is not possible to compare bioavailability predictions from the previously described model with in vivo data. However, rabbit tissue concentration data is available (5) so it may be possible to compare model predictions based on a rabbit subject. This comparison is not currently possible though, due to the lack of tear film thickness and menisci measurements on a rabbit ocular surface after instillation of cyclosporine ophthalmic emulsion. For the model from Walenga et al. (4), the empirically derived human tear film thickness and menisci measurement data were collected by Wang et al. (6), who used optical coherence tomography (OCT) to measure the tear film after instillation of Refresh Liquigel, an artificial tear product with a similar viscosity to Restasis. A similar study using OCT with rabbits would allow for direct comparison of bioavailability predictions with tissue concentration data, and would also allow for clearance to be estimated based on this comparison. This comparison would allow for a more accurate extrapolation to humans.

1.2. Objectives

The objective is to measure the tear film thickness and menisci of a rabbit ocular surface after instillation of cyclosporine ophthalmic emulsion using OCT. This data will be useful for validation of a PBPK model which may be used to examine the influence of certain physicochemical properties on BE of cyclosporine ophthalmic emulsion. The results of the model may then be used to establish more precise limits on these physicochemical properties for the evaluation of BE.

1.3. Description of Work/Study Parameters

The following studies should be conducted for the purposes of this project:

1.3.1 Collect cyclosporine ophthalmic emulsion formulations from the Office of Testing and Research within the Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research at the FDA. These formulations may include those that are Q1/Q2 the same as the reference listed drug, and with different viscosity characteristics. Currently, it is expected that a minimum of five and up to ten different formulations will be supplied.

1.3.2 Obtain sufficient amount of the Allergan produced artificial tear product Refresh Liquigel

1.3.3 Similar to the rabbits used for Daull et al. (5), acquire approximately 20 adult pigmented rabbits in the weight range 2-2.9 kg.

1.3.4 Conduct pilot OCT experiments in a similar manner as Wang et al. (6) over a period of 3 days for five subjects. The formulations to be tested include the artificial tear product Refresh Liquigel ® (as a positive control) and water (as a negative control). Each day, baseline OCT images of one eye will be taken for two blinks. Then, the formulation of interest will be instilled in the eye and OCT images will be acquired at appropriate time points. For example, Wang et al.

(6) collected data 5, 20, 40, and 60 minutes after instillation. The process will be repeated for each eye twice, and with two total formulations this accounts for 8 experiments. Specific technical details of OCT image collection are available in Wang et al. (6). The purpose of the pilot study is to validate the experimental procedure and to identify key sources of variability and/or error.

1.3.5 Conduct OCT experiments in a similar manner as Wang et al. (6) over a period of 20 days for each subject. The formulations to be tested include the cyclosporine ophthalmic emulsion formulations obtained from the FDA, Restasis ®, the artificial tear product Refresh Liquigel ® (as a positive control), and water (as a negative control). Each day, baseline OCT images of one eye will be taken for two blinks. Then, the formulation of interest will be instilled in the eye and OCT images will be acquired at appropriate time points. For example, Wang et al. (6) collected data 5, 20, 40, and 60 minutes after instillation. The process will be repeated for each eye twice, and with between eight and thirteen total formulations (including the five to ten formulations from the FDA, Restasis ®, Refresh Liquigel ®, and water) this accounts for between 28 and 48 experiments. Specific technical details of OCT image collection are available in Wang et al. (6).

1.3.6 Post-process the data to measure tear film thickness, upper and lower tear film meniscus curvature, upper and lower tear film meniscus height, and upper and lower tear film meniscus cross sectional area, where these variables are to be used as defined in Wang et al. (6).

1.3.7 Generate a study report on the tear film measurement data.

1.3.8 Be responsible for animal acquisition, supplies, equipment, data collection, and computational software.

1.3.9 Adhere to all relevant FDA guidance documents including obtaining necessary IACUC approval.

1.4. Specific Tasks

Using the study parameters and objectives above as a guideline, the contractor shall perform the following tasks:

1.4.1 Kick-off Meeting – The Contractor shall participate in a Kick-off Meeting within 10 days of the award of this Task Order. The Contractor shall be responsible for preparing the meeting notes and providing a copy of those notes to the COR within 3 days after the meeting. The Kickoff Meeting shall cover, at a minimum:

• The objectives for the Task Order.

• A high-level overview and discussion of the execution plan,

• Introduction of the Federal Contracting Officer (CO) and Contracting Officer’s Representative (COR), as well as the key members of the Contractor’s team,

• A high-level overview and discussion of the transition plans,

• Questions and answers regarding the engagement.

1.4.2 Study Protocol and Implementation Plan – the Contractor shall develop and submit to the COR an FDA and IACUC approved study protocol and implementation plan. The study protocol and implementation plan shall include at a minimum:

• Specific Aims

• Significance

• Research Design and Methods

• Expertise

• Facilities and Other Resources

• Curriculum vitae of PI and key personnel, and if any, Co-PI(s) and collaborator(s)

• Letters of support from collaborators, if any

• Study timelines and diagrammatic representation of the proposed work flow

1.4.3 Analytical Method Validation Report - the Contractor shall develop and submit to the COR an FDA approved analytical method validation report. The study protocol and implementation plan shall include at a minimum:

• Experimental Method

• Deviations

• Results

• SOPs

The FDA’s guidance on “Bioanalytical Method Validation: Guidance for Industry” (May 2018) should be followed for reporting on bioanalytical method parameters.

1.4.4 Pilot Study – The Contractor shall conduct a Pilot Study implementing the protocol and plan developed under this task order. The Pilot Study shall include at a minimum:

• Synopsis

• Study Objectives

• Research Design and Methods

• Results

• Tables and Figures

• Individual Subject Data (if applicable)

• Conclusion

1.4.5 Bi-Annual Report – The Contractor shall prepare and submit to the COR Bi-annual reports every 6 months throughout the life of the Task Order. At a minimum, the Bi-annual report shall include the following:

• Study timeline and justifications for any delays

• Accomplishments/Milestones reached for each specific deliverable and/or activity for the reporting period of the contract

• General Progress on activities relating to the specific project plan from the contract submission

• Projected Timeline for uncompleted deliverable and/or activities based on Project Aim

• General Progress on Recruitment Activities

• Information on any additional studies completed during the reporting period

• Information on any pending issues/concerns that are impeding completion of contract deliverables and/or activities.

• Key Personnel Report

• Any Protocol Amendments and Deviation the study protocol.

• The most recent institutional review board (IRB) letter and RIHSC approval letter for the study.

• Any presentation or publication material during this period

• Study Coordinator Contact Information

1.4.6 Final Presentation – The Contractor shall provide a final presentation at the FDA prior to the expiration date of the contract. At a minimum, the final presentation shall address the following:

• Objective of the study

• Significance of the study

• Protocol Amendments and Deviation

• Final results of the study

• Conclusion

• Strengths of Study

• Limitations of Study

• Recommendations and Implications for Generic Drug Developments

1.4.7 Final Report – The Contractor shall prepare and submit to the COR a final report. At a minimum the final report shall cover the following:

Cover Page

• Contract Number and Project Title

• Project period Being Reported

• Contract Organization Name

• Author(s)

• Date of Submission

Final Report Content

• Background

• Study Aims

• Study Methods

• Study Results

• Interpretation of Study Results

• Conclusion

• Strengths of Study

• Limitations of Study

• Recommendations and Implications for Generic Drug Developments

• References

• List of Publications Posters and oral presentations (title and slides)

• Publications (reference list and articles)

• Appendices as appropriate

1.5. References

1. Rahman Z, Xu X, Katragadda U, Krishnaiah YSR, Yu L, Khan MA. Quality by design approach for understanding the critical quality attributes of cyclosporine ophthalmic emulsion. Mol Pharm.

2014;11(3):787-99.

2. Sall K, Stevenson OD, Mundorf T, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology.

2000;107(4):631-9.

3. Draft guidance on cyclosporine. Center for Drug Evaluation and Research; 2016.

4. Walenga R, Babiskin A, Absar M, Zhang X, Zhao L, Lionberger R. Modeling approach for assessing the impact of physicochemical properties on bioequivalence of cyclosporine ophthalmic emulsion. 2017 AAPS Annual Meeting and Exposition; San Diego, CA, USA. 2017.

5. Daull P, Lallemand F, Philips B, Lambert G, Buggage R, Garrigue J-S. Distribution of cyclosporine A in ocular tissues after topical administration of cyclosporine A cationic emulsions to pigmented rabbits. Cornea. 2013;32(3):345-54.

6. Wang J, Simmons P, Aquavella J, Vehige J, Palakuru J, Chung S, et al. Dynamic distribution of artificial tears on the ocular surface. Arch Ophthalmol. 2008;126(5):619-25.

2.0 MEETINGS

Meeting Meeting Date Kick off meeting Within 10 business days from date of award Conference calls with COR to discuss updates and monitoring progress

Monthly

Final Presentation at FDA Within 120 days of study completion

3.0 DELIVERABLES

Deliverable Due Date Submission of Study Protocol approved by COR and IACUC

120 calendar days after task order award.

Submission of COR approved Bioanalytical Method Validation Report

7 - 14 calendar days prior to initiating study protocol

Completion of Pilot Study Within 90 calendar days of submission of Study Protocol

Submission of Biannual Written Reports (number depending on study duration)

30 days following every subsequent 6 month anniversary of the task order award date

Final Report (written document) 120 calendar days after completing the study protocol

4.0. Place of Performance / Period of Performance

All work shall be performed at the Contractor’s Facility.

The period of performance is two years from award of task order.