1. Preclinical Animal Studies for Cardiovascular Devices Victoria Hampshire, VMD Division of Cardiovascular Devices US Food and Drug Association White, Oak, MD June 24, 2010 vahampshire@fda.hhs.gov 301-796-6375

2. Objectives of Todays Interaction Explain the purpose of the preclinical submission and how FDA generally utilizes this information Explain how to organize the preclinical submission Explain the level of detail that is important in the submissions Will discuss examples where appropriate

3. General Principals or Assumptions in Todays Discussion: Applicants should follow GLP for all animal studies that will be submitted to the Agency; even if the applicant is from a non-GLP facility. We will discuss how this can be achieved. Applicants should select animal models that are generally accepted for the study of the device type. That is there should be a reasonable amount of scientific evidence that the animal model has utility for the study of the product; understanding that there are limitations in all animal models to attaining a perfect simulation of the human anatomy or disease state. FDAs primary purpose in asking for an animal study for a particular device is to demonstrate sufficient safety (we define this as reliably demonstrated to be reasonably safe given the totality of the information). A secondary objective for the FDA is efficacy although sometimes the performance of a particular device is intricately linked to its safety i.e.: circulatory support products.

4. Key assumptions (continued) The in-vivo setting generally provides FDA with an initial assessment of how the device interacts within a biologic system and also how the biologic system may affect the device (structural durability and corrosion for example.) Scientists should observe the best practices of refinement, reduction, and replacement and all other current standards of humane veterinary care and use, including the use of validated alternatives if they or exist or if you should choose to demonstrate any.

5. Elements of the Preclinical Animal Test Submission A rationale for the selection of the model The study assurances (USDA, NIH, AAALAC, GLP if applicable) Each study should be associated by a test protocol and each test protocol should have a final report prepared by the PI. For each test protocol/report: –An introduction and background –The purpose and objectives of each test protocol –The study schedule –The methods and procedures utilized in the study –The characterization of the test articles and test systems –The in-vivo study results –Any applicable ex-vivo test article characterization –Any ex-vivo tissue characterization –The relevant study conclusions, including any limitations imparted by the choice of animal model and any amendments and deviations from the original test plan

6. Organization Tabular overview of all studies performed Executive Summary of all studies including time line, rationale, etc –Individual study reports and data

7. Detailed Preclinical Animal Studies Report Organization Table of Contents Executive Summary; usually contains all helpful background information such as rationale, assurances, objectives, etc. Individual Test Reports and Protocols including all methods (surgery, anesthesia, imaging, program of written veterinary care and use (pre, post operative monitoring) Signed Individual contributing Scientist reports with relevant appendices –Principle Investigator Report –Attending Veterinary Report Summary of Mortality and Morbidity Individual health records and laboratory work –GLP Compliance Statement or report including inspection dates Please include discussion related to how bias was controlled (21 CFR Part 58.35) Please include the qualifications of the inspector and the method that the QA inspector utilized to determine that all animals reported were all animals studied (how did they determine that there was no data selection) –Gross pathology report and accompanying images. –Histopathology report and accompanying images We will go over Records/Reports and Submission to the FDA however ideally in addition to any computerized and hard records, this information can be stored in PDF for submission to FDA. Large files such as Cine images or histopathology images can be stored and submitted on CD-Rom

8. Level 1: the Executive Summary: Summarize the type of studies, numbers of animals, groupings (controls, experimental s) and time points of observation State why did you picked the particular animal model's) State what were the strengths and limitations that you faced? State the anatomic similarities and differences (include cardiac orientation in the chest, atria, ventricles, intra-atrial and intraventricular structures such as valves, trabeculae, papillary muscles, arterial and venous take off and supply, conduction system, and collaterals (see suggested references) What are the dimensions of each of the chambers and vessels you put your device in or passed the device through studied and key landmarks of each and how is this ratio similar or different than you expect in the humans. If the device was inserted as a catheter, where was it inserted, tracked and landed. If it was a permanent implant surgically placed, what was the approach to the surgical site, was it placed under direct or indirect visualization and how does this method of delivery or placement of the device differ from what you propose to do in the human? What were the key performance and safety objectives? Did the study meet the objectives and why? If there was mortality or morbidity, to what did you contribute it and why and why should the agency accept it as reasonable demonstration of safety?

9. Rationale and objectives for the selection See decision Flowchart State which of the elements of the risk analysis or failure modes and effects is being addressed in the animal model and why it was selected. If there are limitations to the animal model such that risks of the device are best addressed by bench or cadaver testing, these relationships should be described. You should also describe any inherent challenges to the test system such as:

10. Sample challenges to an animal test system: Similarities and differences between the human and particular test animal metabolism of drugs that represent standard of care or ancillary care for the type of device (example might be dual antiplatelet handling) The size (diameter/length) of the device and delivery systems as compared to the same characteristics and relationships of this fit in humans. The location of device insertion and tracking pathway similarities/differences or perhaps the surgical approach in the animal vs. the human.

11. Introduction/Rationale/challenges and similarities of test system to human continued. Tortuosity of the vascular bed of interest and why any size limitations exist as barriers (excluding cost) to obtaining the most size- appropriate model. If the device is intended for use in or near the heart such as a prosthetic heart valve, the selection of the profile and diameter of the device and the distance to key cardiac or great vessels (coronary ostia, mitral valve, brachycephalic trunk, etc)

12. Study Assurances USDA PHS AAALAC GLP Other (NIH has ARAC for example)

13. Executive Summary, Continued: B. What is the in-vivo test history? Describe all animal use. pilotfeasibility pivotal

14. Level 2 discussion each protocol/report Animal Use, continued –Recommend a tabular overview including columns for study groupings, number and type animal, date of initiation and date of completion and key findings. If there were multiple design iterations to the device, state which one was used for each study –State whether the study was feasibility or pivotal. –State whether the study overlapped or occurred sequentially to simulated use on the bench and what design iteration of the device was used. –State whether the study was non-GLP or GLP. If it was non-GLP, what was the scientific reason and how did the methods differ from GLP (see 21 CFR Part 58) and why did this not impact study outcome? – State whether you utilized a dedicated animal protocol or an umbrella protocol. –If this is a non-GLP study, state who the IACUC coordinator is. We recommend that minimally for the pivotal studies, you have a dedicated IACUC protocol

15. Two general types of studies submitted: Performance/Handling Studies –Usually a pre-established set of performance criteria for surgical or interventional handling (Ease of instructions, preparation, insertion, tracking, deliverabilty, visibility under fluoro, deployment, withdrawal, withdrawal through a stent, etc.) –Usually two different users who utilize the objective scoring criteria Device Safety: hemodynamics, physiologic, pathologic outcomes at serial time points, device structural durability, migration, perforation, etc. Note: Most studies can incorporate the performance/handling studies atop or on the front end of the chronic studies. Note: The performance and handling studies may often be key to developing user instructions (later labeling).

16. Test Methods Describe Presurgical methods for receipt, quarantine, housing, baseline examination, including who made the observations and how they were qualified and including the records they utilized. Describe the program of veterinary care: who examines the animals, how do they document findings, who makes the diagnoses, etc. What is the frequency and intensity of monitoring? Describe gross and histologic tissue methods, personnel and qualifications Describe imaging methods, personnel and qualifications.

17. Final Study Report: Quality Assurance Who is the QA, what are their qualifications? If they do not have an advanced degree, how do they determine the qualifications and methods of individuals that do have advanced degrees? What are the methods QA utilizes to determine that all animals reports are all studied? Especially so if you are using umbrella protocols.

18. Lessons learned Simulated use on the bench whenever possible; finish as many engineering studies as possible. If you have to re-engineer the device, FDA will ask for new animals studies. Make sure you support the animal as closely as possible to the human setting Angiographically pre-screen Monitor for and treat Arrythmias Monitor and control infections and bleeding Biggest reasons for failed study: infection, Arrythmias, poor technical proficiency, void of engineering/bench testing to show any structural deformities and lack of pilot and feasibility testing The model was not good to begin with in which case the level of evidence of negativity will need to be produced and it will need to be persuasive if you believe there is no good alternative. (example; covered vs. uncovered stent valve)