# Presentation: 007644

## Concept of “No regulatory impact” for Data Submissions

- Janet Woodcock, M.D.
- Director, Center for Drug Evaluation and Research
- June 10, 2003

## Translation of innovative science to bedside medicine

## Issue:

- New science of pharmacogenomics (and increasingly, proteomics) applied extensively in drug development
- Potential to revolutionize process
- Most of the data not seen by regulatory agencies, partly out of concern for how it will be used
- Need an approach that will enable free exchange of information, help advance the science & technology & aid in the timely development of appropriate regulatory policies

## Background

- VARIABILITY IN HUMAN RESPONSE TO DRUGS:  A major barrier to effective therapeutics

## Variable Effectiveness

- For many drugs (leaving aside antibiotics, antivirals,  etc)...
- Size of treatment effect from randomized trials is < 10% of outcome measure
- Many conclude that effect is “small” or that “drug doesn’t work”

## Mean

**Mean**
**Response**

**Placebo**

**Drug**

## Number

**Number**
**of**
**subjects**

**Drug**

**Placebo**

**Response**

## Variability in Drug Toxicity

- Drug vs placebo:  each drug has consistent pattern of side effects over placebo rate.
- Observed with common as well as rare events
- Some attributable to known pharmacologic effects; others “idiosyncratic”
- Current medical approach is at the level of organ function, or is observational

## There is an Inherited (Genetic) Component to Variability in Drug Response

- Pharmacogenomics (PG):  Application of genome-wide RNA or DNA analysis to study differences in drug actions
- Pharmacogenetics :  Study of genetic basis for interindividual PK differences

## Efficacy Response:  Three Types of Genetic Variables Contribute

- Genetic diversity of disease pathogenesis:
- What disease?
- Variable drug metabolism:
- What dose?
- Genetically based pharmacodynamic effects:
- What subgroup?

## Drug Toxicity: Genetic Contributions to Variability

- Genetically based interacting state:
- predisposition to synergistic toxic effect
- Differences in drug metabolism:
- overdose
- “Toxicodynamic” interactions:
- vulnerable subgroup

## How Important are these Differences?

- How much of the variability will be explained by genetic differences?

## At the Level of the Individual, a Genetic Difference may:

_*Determine*_  drug response
- Enzyme deficiency disease
_*Highly influence*_  drug response
- Polymorphic drug metabolizing enzymes

## Individual Drug Response

- However, many responses will be---
- Emergent Property of multiple gene product interactions with each other and with environmental factors
- Many individual genetic differences - or even patterns of differences - may have a small  effect on drug response

## Oltvai and Barabasi, Science, 298,

- Oltvai and Barabasi, _Science_, 298,
-        25 Oct 02.

## Current Drug Development

- Satisfactory determination of efficacy--but on a population basis
- Determination of drug toxicity is observational--based on animal and then human exposures
- Carcinogenic and reproductive toxicity potential based on *in vitro * and animal studies

## Potential Uses of PG in Drug Development

- Improve candidate drug selection
- Develop new sets of biomarkers for toxic responses in animals and humans-- eventually minimize animal studies
- Predict who will respond to a drug
- Predict who will have serious side effects
- Rationalize drug dosing

## Potential Impact of PG on Drug Development

- Move from current empirical process to     mechanism-based process, hypothesis driven
- Lower cost, faster process resulting in more effective, less toxic drugs for smaller population

##  Drug Regulation and Pharmacogenomics

- How can this new technology be smoothly integrated into the drug regulatory process?

## Legal requirements:  FD &C Act

- Safety:  evaluate reports of “all methods reasonably applicable to show whether or not such drug is safe for use under the conditions...in the proposed labeling”
- Effectiveness:  “adequate and well controlled trials” to show that “the drug will have the effect it purports to have under the conditions of use”

## IND Submission requirements:  21 CFR 312.23(a) (8)

- Pharmacology and toxicology information “on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations”

## NDA Submission requirements:  21 CFR 314.50

-   Nonclinical studies.  d (2) (I):  submit “studies that are pertinent to possible adverse effects”
- Clinical d (5) (iv):  submit “data or information relevant to an evaluation of the safety and effectiveness of the drug product”

## Issues  to Resolve

- When/how to use developing PG information in regulatory decisions?
- When is the information “reasonably applicable”, “pertinent”, or “relevant”  to safety?”
- Under what circumstances is submission to FDA needed?

## Plan	

- FDA to establish policies on PG data
- What types of data required/not required to be submitted
- What types of data appropriate for /not appropriate for regulatory decision - making

## Submission Requirement?  (working proposal)

- Based on interpretation of regulations cited above
- Any data actually used in protocol decision-making in people needs to be submitted
- Sponsor may submit data to bolster claim or scientific position
- For most results, submission NOT required

## Submission of Data                      

- If submission not required, how will FDA develop a  knowledge base about the field?
- We will request voluntary submission of results--these results will not be used in regulatory decision making

## When will FDA use the data for regulatory decision-making? (working proposal)

- FDA will apply a threshold determination to required data
- Data submitting voluntarily (for information purposes) will not be used in decision making
- Data submitted by sponsor to make a case will be evaluated

## Threshold:  Valid Biomarker

- When the meaning of a genetic test is well understood and of known predictive value, results from testing animals or patients should be submitted to FDA
- Research or exploratory tests are not suitable for making decisions on safety or efficacy of a drug

## Public Input 

- FDA will develop threshold and policies using public and transparent process with advisory committee oversight

## Plan  (working proposal)

- Publish Guidance for Industry
- Decision tree for submission requirements
- Decision tree for use in regulatory decision making
- FDA would establish Interdisciplinary PG Review Group (IPGRG)
- Centralized review of information
- Ongoing policy development

## Plan

- FDA is also actively working with the private sector on standardization issues
- FDA will issue guidance on format of submission and data

## Examples:  Toxicology Studies (working proposal)

- Required submisison:  No current example
- Voluntary submission:  We are interested
- Explain an animal toxicity finding:  up to sponsor

## Example:  Toxicology (working proposal)

- Q:  What if a study shows increased expression of a (proto)oncogene after drug exposure
- A:  Many common drugs have elicited this finding in toxicity studies

## Example:  Clinical Pharmacology Studies  (working proposal)

- Genotyping/phenotyping trial subjects for CYP450 isoenzyme polymorphism
- Value and meaning of information is well known and relevant to:
- assessing outliers in PK studies
- evaluating toxicity
- Should be submittted to FDA

## Screening Patients to Correlate Adverse Event  (working prop)

- Does genomic data gathered on patients during trial need to be submitted to FDA ?
- A:  No
- If analysis indicates a potential correlation with an adverse event, how would this finding be interpreted by FDA?
- A:  As a potential biomarker, would need more evaluation in additional trials and diverse populations

## Summary

- Pharmacogenomics holds great promise for drug development and rational therapeutics
- Use of these techniques is increasing
- Free and open exchange of results between industry and FDA is needed to ensure appropriate development of regulatory policies

## Summary

- Concerns about how data will be used by regulators has stifled exchange
- FDA will develop clear policies on use of pharmacogenomic data in regulatory decision-making
- We all look forward to the advances in medicine and health that these techniques will bring