# Presentation: 875942

## REGULATORY OPPORTUNITIES & CHALLENGES OF IMAGING AS A DRUG DEVELOPMENT TOOL

- George Mills, M.D., M.B.A.
- Director
- Division of Medical Imaging & Radiopharmaceutical Drug Products
- CDER/FDA
- May 5, 2005

## FDA Critical Path Initiative

## FDA Critical Path Initiative

- Imaging is a key technology for assessing, accelerating the development of, and guiding the use of new therapeutic options
- The Agency believes that synergy between current drug development programs and current imaging techniques can be created for drug development to work in a more cost effective manner

## An initiative to describe and delineate

-  the processes to identify imaging biomarkers
-  the qualification process for imaging surrogates

## FDA Critical Path Initiative

- “Gap analysis”
- Available data on imaging biomarkers
- Current imaging specifications and standards for imaging biomarkers
- The regulatory & technology challenges to qualify imaging biomarkers as surrogates

## FDA Critical Path Initiative

- “Trials analyses”
-  Imaging biomarkers - available & studied - in clinical trials with active agents
-  The available data for promising biomarkers that may qualify as surrogates
-  Mechanisms to conduct further studies

## FDA Critical Path Initiative

- Two mechanisms to enable further studies
-  Promote stakeholders’ collaborations:
- 	FDA, NCI, drug and biologic developers, the medical imaging industry, & payors
- Promote integration of Biomarker evaluations with ongoing trials or with clinical care to reduce the development expenses of promising biomarkers

## Opportunities & Challenges

**Vocabulary, lexicon **
**Exploratory IND draft guidance**
**Synergies for Drug Development: **
**	****	****Exploratory IND, Imaging & NMEs **
**Standardization Imaging procedures**
**Imaging archives**

## Vocabulary/Lexicon

## “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

## Four Stages of Biomarker Development 

- Regulatory Development Perspective

## 1. In-Development Pre-Biomarker

- Phase 1 trials - ongoing, promising development
- Yet to be establish in Phase 1
- Reproducibility & precision in assessment
- Targeting
- Imaging technique
- Safety profile

-   Developing “Proof of Concept”
-   Establishing technical performance

## 2.  Imaging “Biomarker” Class

- Phase 1 trial - established
- Reproducibility & precision
- Targeting
- Imaging technique
- Safety profile
- Unanswered question:
- Does the biomarker have true “value added” for drug development?

## 3.  “Surrogate” Imaging Biomarker Class

- _Qualified_ biomarker _for use in drug development_
- “Value added” established
- Drug development
- Clinical safety
- Clinical efficacy
-  “Appropriate” combination
- 	supporting documentation, medical literature, clinical trials development

## 3.  “Surrogate” Imaging Biomarker

- Radiation Dosimetry

## Licensed Imaging Surrogate Biomarker

- _Required integration_
- 	into a _licensed_ therapeutic regimen
- “_Validated_ Gatekeeper”
- Safety
- or
- Efficacy
- “Must be assessed
- to assure/improve safety and/or efficacy!”

## Licensed Imaging Surrogate Biomarker

- Whole Body Biodistribution Imaging
- Bexxar & Zevalin

## What is the “Appropriate” Combination of Supporting Documentation,Medical Literature, and Clinical Trials to “Qualify” a Biomarker?

## Two Questions: 1.  Who will use the biomarker result? 2.  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

- _Industry_ decision making
- Qualified biomarker for drug development to separate
- 	the “promising” from the “not so promising”

## Precedents

Sharp’s criteria for rheumatoid arthritis

RECIST criteria for oncology

Chesson’s criteria for oncology

- Sharp’s criteria for rheumatoid arthritis
- RECIST criteria for oncology
- Chesson’s criteria for oncology

- _FDA_ licensure decisions
- Qualified imaging biomarker surrogates

## Opportunities and Challenges

- Exploratory IND Draft Guidance
- &
- Current Biomarker Imaging Techniques
- &
- Drug Development Needs for NMEs

## Exploratory IND Draft GuidanceApril 2005

##  Exploratory IND Draft Guidance

- Facilitates “first in human” imaging IND trials
- Reduces initial entry pharmtox requirements
- “Diagnostic dose” - no therapeutic intent
- “Proof of concept” development trials for new imaging agents & “imaging biomarkers”

##  Synergy “FIH” Biomarker Imaging Trials& Early Drug Development Needs for NMEs

## Exploratory IND facilitates

Early “FIH” diagnostic imaging biodistribution studies

Early “FIH” drug/biologics development seeks to confirm promising preclinical findings for NMEs in early trials in human subjects
Targeting
Organ localization
Routes of clearance

Combination
Radiolabel promising NME candidates -> 

		“FIH” biodistribution images for these NMEs

- Early “FIH” diagnostic imaging biodistribution studies
- Early “FIH” drug/biologics development seeks to confirm promising preclinical findings for NMEs in early trials in human subjects
- Targeting
- Organ localization
- Routes of clearance
- Combination
- Radiolabel promising NME candidates ->
- 		“FIH” biodistribution images for these NMEs

## Exploratory IND facilitates

“First in human” NMEs biodistribution imaging trials  

Confirmation of pre-clinical assessments
	Tumor targeting, PK, biodistribution, normal organ targeting & routes/rates of clearance

- “First in human” NMEs biodistribution imaging trials
- Confirmation of pre-clinical assessments
- 	Tumor targeting, PK, biodistribution, normal organ targeting & routes/rates of clearance

## “FIH” NMEs biodistribution trials findings

Efficacy – selection/localization to target
Tumor targeting
Abscess localization

Safety selection 

Non-target/unexpected organ localization
		Kidney, liver, gastrointestinal tract
Routes/rates of clearance

Exploratory IND “FIH” whole body imaging

	Initial “Proof of concept” for promising NMEs

- Efficacy – selection/localization to target
- Tumor targeting
- Abscess localization
- Safety selection
- Non-target/unexpected organ localization
- 		Kidney, liver, gastrointestinal tract
- Routes/rates of clearance
- Exploratory IND “FIH” whole body imaging
- 	Initial “Proof of concept” for promising NMEs

## “FIH” NMEs Whole Body Imaging

- “Real-World” Available Techniques

## 
PK - Select multiple imaging time points  

Baseline - 30 min – 60 min – 90 min

Baseline - 24 hrs – 48 hrs – 72 hrs – 96 hrs

- PK - Select multiple imaging time points
- Baseline - 30 min – 60 min – 90 min
- Baseline - 24 hrs – 48 hrs – 72 hrs – 96 hrs

## 
Select radiolabel: stability & clearance rate

PET: C-11, F-18, I-124 

Gamma emitters: I-123, In-111, I-131

- Select radiolabel: stability & clearance rate
- PET: C-11, F-18, I-124
- Gamma emitters: I-123, In-111, I-131

## Radiolabeling technique

   Non-destructive to NMEs

   In-vivo stability of the radiolabel

-    Non-destructive to NMEs
-    In-vivo stability of the radiolabel

## Whole Body Biodistribution Imaging

**Time Point 1**

**Time Point **
**2**

**Time Point **
**3**

**Abdominal SPECT**

**Abdominal CT**

## NMEs Portfolio Analysis

- “FIH” Whole Body Imaging

## 

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

- Portfolio Analysis

## Reductions in NMEs’ development time & costs 

“Promising” NMEs – whole body biodistribution

	    Complete pharmtox 
		with the completion of initial Phase 1 study

“Not-so-promising” NMEs

Limit/close early - clinical development
	Reduce pharmtox costs 
	Reduce development time/costs

- _“__Promising”_ NMEs – whole body biodistribution
- 	    Complete pharmtox
- 		with the completion of initial Phase 1 study
- _“__Not-so-promising”_ NMEs
- Limit/close early - clinical development
- 	Reduce pharmtox costs
- 	Reduce development time/costs

-  Exploratory IND

## Expected imaging of drug -> tumor = 
			Potential efficacy? 

Unexpected drug -> organ localization = 
		Potential safety concern? 

- 			Potential _efficacy_?_ _
- _Unexpected_ drug -> organ localization =
- 		Potential _safety concern_?

- Challenge = New knowledge
- Relate the “imaging signals” to long term drug development

## Standardize Imaging Techniques

- Precision - Precision - Precision

## Multi-center trial design = Variations in imaging

Hardware & Software algoritms

Standardize imaging techniques across multi-centers 
Cross-consistency - within & across imaging systems

Don’t assume – assess!
Phase 1/2 - discover & adjust for these differences

- Hardware & Software algoritms
- Standardize imaging techniques across multi-centers
- Cross-consistency - within & across imaging systems
- Don’t assume – assess!
- Phase 1/2 - discover & adjust for these differences

## “Precision is the goal”

Implement the same, detailed imaging acquisition protocols at all clinical sites

Optimize image processing & reconstruction software
Avoid manual techniques as possible
Select & develop semi-automated -> automated
Reduce human interactions

“Established” vs. “cutting edge”

At all costs avoid “practice of medicine”

- Implement the same, detailed imaging acquisition protocols at all clinical sites
- Optimize image processing & reconstruction software
- Avoid manual techniques as possible
- Select & develop semi-automated -> automated
- Reduce human interactions
- “Established” vs. “cutting edge”
- _At all costs avoid_ “practice of medicine”

## Clinical Site Imaging Protocol/Manual

- “HOW-TO” Imaging Manual
- _for_ _Radiologists_ & _X-Ray Technologists_
**Text & Images **
**Description** & **requirements**
- Imaging procedure with special positioning
- Equipment with setup
- Radiographic output – Film and/or Digital
- Archive

## Onsite Training & Monitoring

**Necessary steps**
- Prepare/Train/Monitor the clinical imaging sites
- Imaging procedures – Onsite manual
- Acquisition of required clinical history
- Case Report Form
- Imaging archive

## “HOW-TO” Imaging Manual 

5. Imaging archive database documentation 

Archive of imaging at the clinical sites
Transfer of imaging for the Independent Review 
Archive of imaging at the independent review site

Tracking record for all steps
Document deviations

**5.**** Imaging archive database documentation **
- Archive of imaging at the clinical sites
- Transfer of imaging for the Independent Review
- Archive of imaging at the independent review site
**Tracking record for all steps**
**Document deviations**

## Imaging Archives

- Opportunity for Imaging in Drug Development

## Enter large volumes of raw digital imaging data 
Retain the raw imaging digital data without loss 
Enable 
Current & future reconstruction processing
Re-review with results logged to database
Developed with relational databases
Imaging data
Subject and study demographics 
Associate multiple interpretations
Associate multiple study populations

Standardized CRFs

- Retain the raw imaging digital data without loss
- Enable
- Current & future reconstruction processing
- Re-review with results logged to database
- Developed with relational databases
- Imaging data
- Subject and study demographics
- Associate multiple interpretations
- Associate multiple study populations
- Standardized CRFs

- Imaging Archives

## Opportunities & Challenges

**Vocabulary, lexicon development**
**Exploratory IND draft guidance**
**Synergies in Development: **
**	****	****Exploratory IND, Imaging & NMEs **
**Standardization Imaging procedures**
**Imaging archives**

## FDA Critical Path Initiative

- Imaging is a key technology for assessing, accelerating the development of, and guiding the use of new therapeutic options
- The Agency believe that synergy between current drug development programs and current imaging techniques can and will be created for drug development to work in a more cost effective manner

## 		       Thank you!

- 		       Thank you!

- George Mills, M.D.
- _[millsg@CDER.FDA.GOV](mailto:millsg@CDER.FDA.GOV)_
- 301-827-6314

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