# Presentation: 853613

## FDA Oncology : A Partner in Innovation

- Ramzi Dagher, MD
- DODP/CDER/FDA

## Outline

- Exploratory (Screening) IND
- Regular and Accelerated Approval
- Endpoints Efforts
- VGDS
- FDA/EMEA interactions

## Exploratory IND

- Draft guidance issued April 2005
- Consistent with the FDA Critical Path initiative
- Discusses preclinical requirements for *very* early Phase 1 studies
- Limited human exposure
- Limited dosing (e.g., 7 days)
- No therapeutic intent
- Covers drugs and biologics

## Goals of  Nonclinical IND Studies

- Traditional Phase 1 approach
- Select lead compound from promising candidates
- Conduct basic safety tests in 2 species
- Identify starting dose
- Identify organ toxicities and reversibility
- Estimate a safety margin
- Guide dosing regimens and escalation schemes

##  Goals of Draft Exploratory IND

- Provide for an understanding of mechanism of action and treatment of disease
- Provide pk information
- Aid in selection of lead candidate drug from promising candidate compounds
- Explore biodistribution with imaging technologies
- Not intended to supplant a traditional IND

## Draft Exploratory IND Guidance

- Clinical information
- Chemistry, Manufacturing and Controls information
- Safety program designs

## Basis for NDA Approval

- Demonstration of efficacy with acceptable safety in adequate and well-controlled studie_***s***_
- Ability to generate product labeling that
- Defines an appropriate patient population for treatment with the drug
- Provides adequate information to enable safe and effective use of the drug

**Notes:**
The requirement to demonstrate safety and efficacy before drugs are marketed stems from two Congressional actions. The safety requirement comes from the Federal Food and Drug and Cosmetic Act of 1938. The efficacy requirement stems from a 1962 amendment. The FDA has interpreted the 1962 amendment to require in most cases at least two trials for drug approval and to require claims to represent clinical benefit.

For drug and indication to receive approval sufficient information must be available to define an appropriate patient population for drug use and enable safe and effective use.The product label represents a licensing agreement between the sponsor and the Federal government. Marketing and advertising claims are derived from the product label. 

## Regular Approval

- Demonstrate clinical benefit
- Endpoints in oncology
- survival
- DFS in adjuvant setting
- symptom benefit
- durable remission in leukemias
- Johnson JR et al JCO 21:1404-1411, 2003
- Williams G et al J Biopharm Statistics 14:5-21, 2004

## Accelerated Approval (subpart H)

- serious/life-threatening disease
- surrogate *reasonably likely* to predict clinical benefit
- advantage over available therapy
- studies to confirm clinical benefit

## Oncology Experience

- Single-arm trials measuring objective response rate in advanced or refractory patients (e.g. imatinib)
- Randomized trials in few cases (e.g. oxaliplatin)
- Dagher et al JNCI 96:1500-1509, 2004

## AA update

- As of June 1, 2005
- 22 drugs approved for 26 oncology indications
- 9 converted to regular approval
- ODAC  03, planning for 05

## AA Conversions

- Confirmatory trial(s) usually ongoing or multiple trials planned/ongoing at time of AA
- population
- similar/identical 4/9
- less refractory 5/9

## Model for AA and Confirmation of Benefit

## AA and Confirmation of Benefit in Same Trial 

- same population for AA and regular approval
- assures completion of confirmatory study
- randomization allows
- comparison to available therapy
- placebo or add-on
- evaluation of toxicity profile

## Guidance for Industry 

- Clinical Trial Endpoints for Approval of Cancer Drugs and Biologics
- posted 4/1/05
- www.fda.gov/cder/guidance/6592dft.htm
- www.fda.gov/ohrms/dockets/default.htm
- plan subsequent disease-specific documents

## Endpoints Efforts

- Workshop
- discussion of endpoints in different stages of disease
- involve academia, industry, patient advocacy
- ODAC
- focused on issues raised at workshop
- discussion and voting when appropriate

## Endpoints Efforts to date

- Workshops
- NSCLC
- Colon
- Prostate
- leukemias / lymphomas
- ODAC
- NSCLC , colon, prostate

## Endpoints : Future Efforts

- Brain tumors
- Ovarian cancer
- Breast cancer

## Voluntary Genomic Data Submission (VGDS)

- For knowledge-building
- Information not used in regulatory process
- Information kept confidential
- Format flexible

**Notes:**
-So the concept of voluntary gemonic data submission, or VGDS, is that FDA and drug sponsors will experiment with submission and review of genonic data.  This process will benefit both parties as we prepare for future submissions where genomic data will be a key factor in drug approval.  Industry will learn how to submit data and interact with FDA in this new area, and FDA will develop the capability to evaluate data across submissions with the potential for discovering concepts, facts, or methods that will benefit the public health.
-Another purpose of this guidance is to dispel fear that FDA will use exploratory pharmacogenomic data for regulatory purposes in an inappropriate manner.  We have heard such fears, and we certainly don’t want investigators to be inhibited from doing important experiments because of fear that data will be requested and fear that this will lead to an inappropriate regulatory action based on exploratory data.
-For information that FDA and the sponsor consider to be exploratory, given the current state of scientific knowledge, FDA will agree to use the information only for non-regulatory purposes.  Information from individual applications will be held in the same strict confidence that FDA is accustomed to providing for proprietary information for the many drug applications it has reviewed in INDs, NDAs, and BLAs for decades.  
-And, the FDA will work with sponsors to find a format for data submission that will not be burdensome.

## Known 		Known valid 

- Test system with established performance characteristics
- established framework to elucidate significance

- Test system with established performance characteristics
*widespread agreement* in medical/scientific community about significance of test results

## Submission of PG Data to an IND

**1.  Used for decision making in clinical trial         or in a preclinical safety study**
**2.  Used by sponsor to support arguments on safety, efficacy, dosing or pharmacology**
**3.  Is a **_***known valid biomarker***_

**Notes:**
Here is the algorithm for pharmacogenomic data generated under an IND during drug development. The regulations require that data which is used for decision making in clinical trial or in a preclinical safety study or data used by sponsor to support arguments on safety, efficacy, dosing or pharmacology should be submitted to the IND with full data submission.  
-Other data which is relevant, but will not be used in this manner, would be submitted in abbreviated reports.  This guidance has defined the critical threshold for determining whether such data is submitted for formal regulatory review to be whether the data represent a known valid biomarker.  
-If none of these thresholds are met, then according to this draft guidance, data is considered to  be exploratory and would be suitable for submision under VGDS.

## Submission of PG Data to an NDA or BLA

**1.  Intended to be used in the drug label or to****support drug approval**
**2.  Is a **_***known valid biomarker***_
**3.  Is a **_***probable valid biomarker***_

**Notes:**
The algorithm for data submission at the time of submission of a marketing application such as an NDA or BLA is different because these regulations state that the sponsor must submit reports on all experiments with the drug.  So the guidance interprets this to mean that any information on a valid biomarker needs to be submitted in some for, at least an abbreviated report, and that information used to support drug approval or drug labeling should have a full data submission.  All other exploratory information would be encouraged for submission under VGDS.  

## FDA/EMEA interactions

- Annual Regulators Meeting at ASCO
- Panel discussions
- Teleconferences
- Joint publications when appropriate