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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
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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
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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
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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
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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
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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
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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
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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
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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
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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 !!
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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
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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!
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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
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