# Presentation: 129028

## Biomarker Imaging in Drug Development&Licensed Products

**George Mills, M.D.**
**Director**
**Division of Medical Imaging & Radiopharmaceutical Drug Products**
**CDER/FDA**
**May 6, 2005**

## < Imaging Biomarkers >

**the Intent **
**To Improve & Speed Drug Development**

**www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf**

- < **Imaging ****Biomarkers** >

## Topics

**Separate Imaging Biomarker IND **
**Four Classes of Biomarker Development **
**Image Archive**
**Applied Biodistribution Imaging for Portfolio Assessment**

## Separate Imaging Biomarker IND?

## Separate IND for Biomarker?
   				 or
Develop within investigational agent IND?

**   ****	****	****	****	**** ****or**
**Develop within investigational agent IND?**

## Critical Path Development

**FDA biomarker database development**
**“****Biomarkers studied” **_**but unavailable**_** **
**Investigational biomarker**** **
**studied within the therapeutic IND**
**“****locked inside” - closed therapeutic IND**

##  - “Missed Opportunities” Costs -

**If biomarker is “closed” **
**No potential **
**To recover development costs **
**To improve “IP”**

## - Potential Opportunities -

**If biomarker is “open” in separate IND**
**Biomarker is available by “Letter of cross-reference”**
**Protects “IP”**
**Potential for **
**  ****Cost recovery **
**  ****Further drug development**
**  ****Additional intellectual property**

## Four Classes of Biomarker Development 

## “All biomarkers are not created equal, and we need to develop the vocabulary about where they are on this progress of qualification.”Janet WoodcockTHE PINK SHEET, 18-April-2005

## Defining Imaging Biomarker Classes Based on Four Stages of Development from the Regulatory Perspective

## 1. In-Development Pre-Biomarker Class

**Phase 1 trials ongoing, promising development**
**To be establish during Phase 1**
**Safety profile**
**Reproducibility & precision in assessment**
**Targeting**
**Imaging technique**

## 2.  Biomarker Class

**Biomarker - Phase 1 trials established**
**Safety profile**
**Reproducibility & precision **
**Targeting**
**Imaging technique**
**Unanswered question:**
**Is there “value added” for the biomarker?**

## 3.  Surrogate Biomarker Class

_**Qualified**_** biomarker **_**for use in drug development**_
**	****“****Appropriate” combination of supporting documentation,**
**	****	**** ****medical literature, clinical trials development**
**	****Reproducible, defined biomarker assessment for**
**Drug development**
**Clinical safety**
**Clinical efficacy**
**Established “value added” for drug development**

## Clinical Diagnostic Surrogate Biomarker Class

_**Integrated**_** into an **_**approved/licensed**_** therapeutic regimen**
**“**_**Validated**_** Gatekeeper”**
**Safety**
**Efficacy**
**“****Assessed **
**	****	****to assure/improve safety and/or efficacy!”**

## Image Archive

## 
Effective archives of biomarker imaging results
Retain images for future re-review
Retrieval of images – single trial – multiple trials 
Reanalyze images & digital data
Relate images to effective outcome assessments

**Effective archives of biomarker imaging results**
**Retain images for future re-review**
**Retrieval of images – single trial – multiple trials **
**Reanalyze images & digital data**
**Relate images to effective outcome assessments**

## What is an “Appropriate” Combination of Supporting Documentation,Medical Literature, and Clinical Trials?

## Questions: Who will use the biomarker result? and For what assessment?

## Medical literature
Preclinical development
Phase 1 clinical trials
Phase 2 clinical trials 

**Preclinical development**
**Phase 1 clinical trials**
**Phase 2 clinical trials **

**  **_**Qualified**_** biomarker for **_**Industry**_** decision making**
**-**
**to separate the “promising” from the “not so promising”**

## Medical literature
Preclinical development
Phase 1 clinical trials
Phase 2 clinical trials
Phase 3 clinical trials
FDA Advisory Committees

**Preclinical development**
**Phase 1 clinical trials**
**Phase 2 clinical trials**
**Phase 3 clinical trials**
**FDA Advisory Committees**

_**Qualified**_** biomarker for **_**FDA**_** decision making**
**-**
_**Safety & Efficacy**_

## Defining Biomarker Utility

## Biomarker Utility  “Value Added” Descriptions

**Diagnosis of disease – Yes/No**
**Potential to respond to therapeutic intervention**
**Response to therapeutic intervention**
**Severity of disease – Staging – Continuous scale**
**Progression of disease – Rate of change**
**Prognosis – Future rate of change**

## Radiolabeled Diagnostic BiomarkerImaging Model  

## Imaging radiolabeled pharmacokinetic studies 
Whole body imaging - multi-time points
			 Organ biodistribution 
      Radiation dosimetry 

**Whole body imaging - multi-time points**
**	****	****	**** ****Organ biodistribution **
**      ****Radiation dosimetry **
**	****	****	**

## Whole Body Biodistribution Imaging

**Time Point 1 (baseline)**

**Time Point **
**2**

**Time Point **
**3**

## Approved safety imaging surrogates
Adjacent organs at risk for radiation injury 
Altered biodistribution = immune response

**Adjacent organs at risk for radiation injury **
**Altered biodistribution = immune response**

- Established Imaging Safety Biomarker Model

- Radiation Dosimetry

## Slide 28

## Slide 29

## Tumor/lesion Therapeutic targeting

## Whole Body Biodistribution Imaging

**Time Point 1**

**Time Point **
**2**

**Time Point **
**3**

**Abdominal SPECT**

**Abdominal CT**

## Comparative Biomarker Whole Body Imaging

Four implementation issues

** **
**Four implementation issues**

## Issue 

1. Selection of multiple imaging time points
Baseline - 30 minutes – 60 minutes – 90 minutes
Baseline - 24 hrs – 48 hrs – 72 hrs – 96 hrs

**1. Selection of multiple imaging time points**
**Baseline - 30 minutes – 60 minutes – 90 minutes**
**Baseline - 24 hrs – 48 hrs – 72 hrs – 96 hrs**

## Issue

2.  Radiolabel selection
PET: C-11, F-18, I-124 
Gamma emitters: I-123, In-111, I-131

**2.  Radiolabel selection**
**PET****: C-11, F-18, I-124 **
**Gamma emitters****: I-123, In-111, I-131**

## Gamma Emitters

| Label | 1⁄2 Life | Production Method | In Vitro Stability | In Vivo Stability | Availability | Pharmacist Needed for Dose Prep at Clinical Site? | Chelate Required? | Other Considerations? |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| I-123 | 0.55d | Cyclotron | De-Iodination and Oxidation | De-Iodination | Limited & NaI Precursor or Dose Prep for Use | Central Dose Prep & Dose Delivered for Use | No | I-1  Salt Precursors for Substitution Reactions or I2 Precursor for Iodogen Reactions |
| In-111 | 2.8d | Cyclotron | Hydrolysis | Metal  Ion Exchanged via Transferrin | Several Suppliers for InCl3    | Yes  | Yes, Cross-Coupled to Drug via Linker for Stabilizing 
In-111 | Weak Organic Acid Buffer Used for In-111 to Avoid Hydrolysis |
| I-131 | 8.05d | Reactor
(Accompanied by Beta Emissions) | De-Iodination and Oxidation | De-Iodination | Several Suppliers for NaI Precursor or Dose Prep for Use | Central Dose Prep & Dose Delivered for Use | No  | I-1  Salt Precursors for Substitution Reactions or I2 Precursor for Iodogen Reactions |

**Gamma Emitters**
**Available for Radiolabeling Drugs and Biologics to Prepare Imaging-Biomarkers****	**

## Positron Emitters

| Label | 1⁄2 Life | Production Method | In Vitro Stability | In Vivo Stability | Availability | Pharmacist Needed for Dose Prep at Clinical Site? | Chelate Required? | Other Requirements? |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| C-11 | 20.5m | Cyclotron | Use ASAP | De-Methylation | Limited & Dose  Prep Immediate Use | Central Dose Prep & Delivered for Use | No | C-11 Methyl Iodide, Hydrogen  Cyanide or Other Precursors |
| F-18 | 109.8m | Cyclotron | Use ASAP | De-Fluorination | Limited & Dose  Prep Immediate Use | Central Dose Prep & Delivered for Use | No | F-18  Salt Precursors for Substitution Reactions |
| I-124 | 4.17d | Cyclotron Only 25%  PET | De-Iodination and Oxidation | De--Iodination | Dose Prep for Use; but  NaI Precursor Maybe Ordered Single Supplier | Central Dose Prep & Delivered for Use | No | I-1  Salt Precursors for Substitution Reactions or I2 Precursor for Iodogen Reactions |

**Positron Emitters**
**Available for Radiolabeling Drugs and Biologics to Prepare Imaging-Biomarkers**** *****	***

## Issue
3.  Radiolabeling technique selection
   Non-destructive to drug candidates
   In-vivo stability of the radiolabel

**3.  Radiolabeling technique selection**
**   ****Non-destructive to drug candidates**
**   ****In-vivo stability of the radiolabel**

## Issue
Imaging technique
PET
Gamma
Whole body 
Selected regional

**Imaging technique**
**PET**
**Gamma**
**Whole body **
**Selected regional**

## Biomarker Imaging in Drug Development&Licensed Products

**George Mills, M.D.     **
**301-827-6314**
**millsg@CDER.FDA.GOV**

## Slide 40

##  Exploratory IND

##  - “Exploratory IND” -

**Facilitates “first in human” imaging IND trials**
**Reduces initial entry pharmtox requirements**
**Limited human exposure to drug/biologic **
**“****Diagnostic dose” - no therapeutic intent**

## Facilitates applied Whole body Imaging 
Confirmation of pre-clinical assessment
PK, biodistribution, organ targeting and clearance
Demonstration of potential efficacy targeting

**Confirmation of pre-clinical assessment**
**PK, biodistribution, organ targeting and clearance**
**Demonstration of potential efficacy targeting**

## Facilitates rapid portfolio assessment
Earlier separation: 
		“Promising < > Not so Promising” 
Comparative whole body imaging

**Earlier separation: **
**	****	****“****Promising < > Not so Promising” **
**Comparative whole body imaging**

## Facilitates reduction in costs and development time
Promising drug/biologic imaging agents
	      Complete pharmtox 
			with the completion of initial Phase 1 study

Non-promising drug/biologic imaging agents
Limit/close clinical development early
Reduces pharmtox costs & development time

_**Promising**_** drug/biologic imaging agents**
**	****      ****Complete pharmtox **
**	****	****	****with the completion of initial Phase 1 study**
_**Non-promising**_** drug/biologic imaging agents**
**Limit/close clinical development early**
**Reduces pharmtox costs & development time**

## Imaging Whole Body Biomarker ModelApplied to Drug Development

## Applied Research Development

**Whole Body Biodistribution Imaging**
**For Portfolio Assessment**

## Current, known imaging technique, 
whole body biodistribution imaging, 
applied to known drug development issue

Pre-clinical -> clinical portfolio selection 

**whole body biodistribution imaging, **
**applied to known drug development issue**
**Pre-clinical -> clinical portfolio selection **

## Opportunities

Enriched early drug/biologic candidate selection 

Reduce allocation of development time and resources to “not so promising candidates”

**  **
**Enriched early drug/biologic candidate selection **
**Reduce allocation of development time and resources to “not so promising candidates”**

## 

Technique
Radiolabel the competing candidates 
Perform comparative whole body biomarker imaging

Utility
Confirmation of pre-clinical findings
Phase 0 -> Phase 1 – First in human experience
Identify the “promising” and “the not so promising”

**Technique**
**Radiolabel the competing candidates **
**Perform comparative whole body biomarker imaging**
**Utility**
**Confirmation of pre-clinical findings**
**Phase 0 -> Phase 1 – First in human experience**
**Identify the “promising” and “the not so promising”**
**	**

##  Comparative biomarker whole body imaging
	Assessments
	 Efficacy selection potential
Tumor targeting
Abscess localization

Safety selection potential
Non-target/unexpected organ localization
			 Kidney, liver, gastrointestinal tract	
Routes of clearance

**	****Assessments**
**	**** ****Efficacy selection potential**
**Tumor targeting**
**Abscess localization**
**Safety selection potential**
**Non-target/unexpected organ localization**
**	****	****	**** ****Kidney, liver, gastrointestinal tract****	**
**Routes of clearance**

## Expected imaging drug/tumor = 
			Potential efficacy? 
Unexpected drug/organ localization = 
		Potential safety concern? 

**	****	****	****Potential **_**efficacy**_**?**_** **_
_**Unexpected**_** drug/organ localization =**** **
**	****	****Potential **_**safety concern**_**? **

- Drug development questions: