# Presentation: 929206

## Innovative Systems for Delivery of Drugs and BiologicsDrug-Eluting Stents Current Approach to Review

- Ashley B. Boam, MSBE
- Division of Cardiovascular Devices
- Office of Device Evaluation
- Center for Devices and Radiological Health

## What is a Drug-Eluting Stent (DES)?

- DHHS/FDA/CDRH

***Example:*****  ****Cordis’ Cypher****TM Sirolimus-Eluting Coronary Stent**

- Stent Platform & Delivery System
- Carrier(s)
- Drug

_***Components***_

## DES and the Regulatory Process

- Stent Platform & Delivery System
**[CRDH Review]**

- Pharmacologic
- Agent (‘Drug’)
**[CDER Review]**

- Carrier (*e.g.*, Polymer)
**[CDRH Review]**

**Drug**
**Eluting**
**Stent**

- DHHS/FDA/CDRH

***Three Component System***

**Notes:**

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## Overview of Review “Challenges” for DES

- Regulatory jurisdiction
- Inspectional authority & site readiness
- Disparity in statutory & regulatory 	requirements between CDRH & CDER
- Appropriate leveraging of information from 	INDs, NDAs, DMFs, MAFs, etc.
- Appropriate pre-clinical testing & clinical trial design
- Post-market studies and surveillance

## Regulatory Jurisdiction

- Combination Products (21 CFR Part 3)
- CDRH lead center with CDER consultation
- 	http://www.fda.gov/oc/combination/updates.html
- Divisions involved include...
- Cardiovascular Devices (ODE/CDRH)
- Cardio-Renal Drug Products (OND/CDER)
- New Drug Chemistry I (OPS/CDER)
- Pharmaceutical Evaluation I (OCP/CDER)
- Mechanics & Materials (OST/CDRH)
- Submissions: IDEs & PMAs

- DHHS/FDA/CDRH

**Notes:**

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## Regulatory Review Team for DES

- CDRH + CDER = SUCCESS

***Expertise required...***

**Mechanical Performance**
**& Testing Regimes**

**Chemistry **
**[Drug Substance & Carrier(s)]**

**Manufacturing**

**Animal Experimentation **
**& Evaluation**

**Clinical Trial Design **
**& Methodology**

**Pharmacokinetics / **
**Pharmacodynamics**

- DHHS/FDA/CDRH

## Inspectional Authority and Site Readiness

- Inspections conducted by CDRH with CDER/ONDC participation
- Validations should be complete prior to inspection
- Subsequent manufacturing changes may require reinspection

## Approval of Devices, Drugs & Biologics

| CDRH | CDER | CBER |
| --- | --- | --- |
| Approval to begin Clinical Evaluation |  |  |
| IDE
Investigational Device Exemption | IND
Investigational New Drug | IND
Investigational New Drug |
| Permission to begin Marketing |  |  |
| PMA
(Class III Devices) | NDA
New Drug Application | BLA
Biologic License Application |
| Permission to Market a Modified Product |  |  |
| PMA Supplement | NDA or Efficacy/Manufacturing Supplement (for approved drug) | New License Application, Efficacy or Manufacturing Supplement |
| Other Pathways to Marketing |  |  |
| 510(k)
PreMarket Clearance | ANDA
Abbreviated NDA | N/A |
|  | Generic drug bioequivalent to approved drug |  |

**Notes:**

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## Comparison of Device & Drug Development

- DHHS/FDA/CDRH

| Developmental Feature | Device | Drug |
| --- | --- | --- |
| 
Rate of technology change | 
Fast | 
Slow |
| Ease of in vitro assessment | High | Low |
| Reimbursement during clinical trials | Frequent | Rare |
| Influence of MD technique on results | High | Low |
| Ability to visualize performance after use | High  | Low |
| Definition of “Orphan” (# of patients) | 4,000 | 200,000 |
| # of full scale studies usually required | 1 | 2 |
| # of regulatory classes | 3 | 1
 |

**Notes:**

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## Information to Support DES Applications

- * **Refer to CDER Guidance**, “Content & Format of INDs for Phase 1
-       Studies of Drugs...”; www.fda.gov/cder/guidance/phase1.pdf

- * **Refer to CDRH Guidance**, “...Interventional Cardiology Devices:
-       ...Intravascular Stents”; www.fda.gov/cdrh/ode/846.pdf

- DHHS/FDA/CDRH

|   
Drug ± Carrier(s) | Stent Platform * |  |
| --- | --- | --- |
|  | Approved | Unapproved |
| Approved | 1 | 2 |
| Unstudied * | 3 | 4 |

**Notes:**

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## Approved vs. UnstudiedDrug Substances

- Potential Sources for Safety Data (Phase 1 IND)
- Approved drug – NDA
- Drug under IND investigation
- “Unstudied” – New Molecular Entity (NME)
- Analog of Approved Drug is an NME
- Necessary Categories of Safety Information
- Chemistry, Manufacturing & Controls (CMC)
- Systemic Pre-clinical Pharmacology/Toxicity
- Systemic Clinical Exposure
- Potentially Influences Clinical Trial Design

## Preclinical Testing Objectives

- Characterization of finished, sterilized product to be studied is essential
- Coating/drug loading characteristics – drug and carrier content, uniformity, abrasion resistance (if coating), particulate
*In vitro*/ *in vivo* elution
- Methods and initial specifications for stability testing
- Adequate animal studies needed to assess safety prior to human studies

- DHHS/FDA/CDRH

## Common Preclinical Testing Deficiencies

- Inadequate Stent Platform Testing
- Fatigue and corrosion testing
- Inadequate Analysis of Surface Modifications
- Coating integrity/durability
- Drug content/uniformity
- Incomplete *In vitro* Pharmacokinetics
- Methodology and IVIVC, if possible
- CMC Issues Inadequately Addressed
- Stability/shelf life

## Common Animal Study Deficiencies

- Inadequate Reports to Assess Safety
- Lack evaluation of _doses intended for __clinical evaluation_ &/or _overdosage_ at appropriate time points
- Lack evaluation of serial sections of myocardium
- Lack description of arterial histopathology
- Lack necropsy reports   					(especially important for unexpected deaths)

- DHHS/FDA/CDRH

## Clinical Evaluation of DES

- Reasonable Assurance of _Safety_ and _Effectiveness_
- Clinical Study Needs to Be Designed for Both Objectives
- Usual Standard of Evidence is RCT
- Study Endpoints for Coronary DES
- Primary – Clinically Meaningful
- Use of surrogate and/or co-primary endpoints?
- Non-inferiority trial - appropriate delta
- Use of Independent Core Labs, CEC & Active 	DSMB

- DHHS/FDA/CDRH

## DES Post-Market

- TPLC is critical for DES!
- 5 year follow-up of all patient cohorts (feasibility, pivotal, any supportive)
- Additional data collection post-market to gain further understanding of rates of drug-related adverse events
- Approval for new indications, new study populations through IDE
- Adverse events are reported through MDR
- reports to CDRH, data shared with CDER

**Notes:**
1000 patient trials large for devices, small for drugs

## Questions?  Talk to us!

- Coronary DES
- Ashley Boam, Branch Chief (_[aab@cdrh.fda.gov](mailto:aab@cdrh.fda.gov)__)_
- Joni Foy, Ph.D., Lead Reviewer (_[jrf@cdrh.fda.gov](mailto:jrf@cdrh.fda.gov)__) _
- Peripheral DES
- Elisa Harvey, DVM, Branch Chief (_[edh@cdrh.fda.gov](mailto:edh@cdrh.fda.gov)__)_
- Jennifer Goode, Lead Reviewer (_[jlg@cdrh.fda.gov](mailto:jlg@cdrh.fda.gov)__) _