1. Steps to a Successful DES Development Program Jonette Foy, PhD Division of Cardiovascular Devices Center for Devices & Radiological Health Office of Device Evaluation Food & Drug Administration FDA Regulatory Pathways Workshop at CRT May 6, 2004

2. Challenges with DES  Initial safety data & source(s) of safety data on drug substance Studied vs. unstudied drugs (NMEs, which includes analogs of approved drugs)  Adequate nonclinical evaluation  Animal studies crucial to support safety of clinical study  Test methodologies – early development  Designing clinical trials  Pre- and post-market balance (TPLC) Bottom line…Appropriate Interaction can be Beneficial !! DHHS/FDA

3. Potential for Informal Collaboration  Sponsors may request an informal meeting at many different times throughout DES lifecycle In early product development After bench & early animal data generated, but before clinical trial Between feasibility & pivotal clinical studies Mid clinical trial (if issues have arisen – change in protocol, design, etc.) Pre-marketing submission During review of marketing submission (to seek clarification on questions)  Can be by phone, electronic, or face-to-face Interaction meant to serve as avenue for timely feedback… Typically to answer critical questions DHHS/FDA

4. Suggested Early Interactions  Request an informal meeting early in development for high-level discussion Stent platform, carrier (if applicable) & drug substance should be selected Dose/dose density, full characterization not necessary  FDA can provide guidance on: Development of safety data if not already available Planned studies for dose-response/dose selection  If referencing an IND/NDA/DMF, a good relationship with your business partner is crucial  Consider inviting a representative to your early meetings with FDA DHHS/FDA

5. DES are Combination Products  DES are NOT simply devices  Cannot only evaluate drug & device components separately due to synergistic effects  Pharmaceutical agent should have benefit to offset additional risk to patient  Must establish safety & effectiveness of the finished product DHHS/FDA Stent Platform & Delivery System [CRDH Review] Pharmacologic Agent (‘Drug’) [CDER Review] Carrier (e.g., Polymer) [CDRH & CDER Review] Drug Eluting Stent

6. Adequate Nonclinical Evaluation  Characterization of finished, sterilized product to be studied is essential Coating/drug loading characteristics – drug & carrier content, uniformity, abrasion resistance (if coating), particulate, corrosion For degradable coatings, time course & mechanism of coating breakdown critical; fate of degradants In vitro / in vivo elution characteristics Methods & initial specifications for stability testing  Adequate animal studies needed to assess safety prior to human studies Evaluate doses 1X, 3-10X intended dose plus overlapping stents Follow-up minimum of 6 months, may be longer depending on DES design, elution and/or coating degradation (if applicable) characteristics DHHS/FDA

7. Engineering Testing (Bare) Balloon RBP Stent diameter vs. inflation pressure (compliance) Balloon fatigue Balloon inflation/deflation times Crossing profile Catheter bond strength Stent securement Balloon deflatability & withdrawal Radial (hoop) strength Stent recoil Stent uniformity MRI & radiopacity Percent free area/dimensional verification Kink & crush resistance Accelerated fatigue testing/ FEA Material analysis Mechanical Properties Corrosion STENT & DELIVERY SYSTEM STENT INTEGRITYSPECIFICATION CONFORMANCE * Refer to CDRH Guidance, “…Interventional Cardiology Devices: …Intravascular Stents”; www.fda.gov/cdrh/ode/846.pdf DHHS/FDA

8. Some Additional Testing (DES)^ Chemical composition Impurities/degradation products Total content of active & inactives Elution rate & methodology * Pharmacokinetics Residual solvents & leachants Stability ** Biocompatibility Sterilization Manufacturing Drug content Dose density Uniformity of drug distribution Coating durability (adhesion, expansion, fatigue, etc.) Particulate analysis (USP ) FINISHED PRODUCTCOATING/ CARRIER (e.g., polymer) DHHS/FDA * For elution, submit development test data to support robustness & adequacy of proposed method ** For stability, ICH guidelines should be followed & take into consideration drug & carrier stability ^ List is not all-inclusive

9. Potential Interactions for Nonclinical Issues  Interact with engineers, chemists, pathologists – request review of nonclinical protocols prior to beginning these studies Mechanical testing/coating integrity Animal testing  Interact with chemists Stability protocol Establishing specifications for impurities, etc.  Interact with biopharmaceutists & chemists on PK Discernable in vitro elution methodology Measurement of in vivo PK Potential for in vitro / in vivo correlation (IVIVC) DHHS/FDA

10. Suggested Interactions for Clinical  Specific clinical trial design issues discussed by subsequent FDA speakers  Discussion of clinical development plan Dose/dose density should be selected Pre-clinical safety data in place Characterization of important aspects of finished DES (e.g., time course for drug elution or degradation of coating, if applicable) Animal studies can be ongoing  Even if initial clinical experience will be OUS, FDA input can be crucial to ensure collecting most useable information DHHS/FDA Strongly recommend discussing clinical plans with FDA prior to conducting any human studies !!

11. Organization of Submission  Complete description of DES to be studied or commercialized with any & all modifications from DES tested non-clinically or clinically  Submission of “Master Table”  Chemistry, Manufacturing & Controls (CMC) section  All non-clinical testing (e.g., engineering, animal, PK, etc.)  Clinical trial data (US & OUS)  Inclusion of appropriate data, protocols, etc. for verification  Searchable CD-Roms, in addition to sufficient number of paper copies Submission of complete, high-quality applications at IDE & PMA stages facilitates timely review DHHS/FDA

12. Summary & Conclusions  DES are complex combination products requiring knowledge of both device & drug development paradigms  Utilize internal company resources (coronary programs should speak with peripheral programs…FDA does)  Establish good working relationship(s) with drug &/or carrier manufacturer  We will work with you to design a successful DES development program, but you have to ask !!  Realize that with more interaction, need to plan ahead to schedule meetings DHHS/FDA The good news…FDA’s door is open!

13. Questions? Contact Us  Ashley Boam, MSBE, Branch Chief, ICDB aab@cdrh.fda.gov (301) 443-8243  Jonette Foy, PhD, Team leader for Coronary DES jrf@cdrh.fda.gov (301) 443-8243  Jennifer Goode, Team leader for Peripheral DES jlg@cdrh.fda.gov (301) 443-8517  Neal Muni, MD, MSPH, Medical Officer nim@cdrh.fda.gov (301) 443-8609