# Presentation: 149105

## Sandra L. Kweder, M.D.
FDA, Office of  Drug Evaluation IV
December 2000

**Sandra L. Kweder, M.D**.
**FDA, Office of  Drug Evaluation IV**
**December 2000**

**Labeling Products for Use in Pregnancy: Moving Forward**

## Objectives for Today 

**1. ****	****Labeling drugs for use in pregnancy**
**2.****	****	****Development of a new label model**
**3.  ****	****Related initiatives**
**4. ****	****Critical role of clinical pharmacology**

## Labeling 101

**Product label is a legal document - tool**
**Vetted source of information;**
**Widely available**
**Basis for marketing approval/promotion**
**Source is basis for many others**
**FDA does not conduct the research **

## Label Guides Use of Product

**Indications shown to be effective**
**Description of safety profile**
**Dosing and administration**
**Including altered physiologic states **
**Use in special populations**
**Gender; children; elderly; ethnic minorities**
**Pregnancy**

## I.  Pregnancy Section of Label

**First addressed in regulations in 1979**
**To assist physicians prescribing for pregnant women**
**Inadvertent/retrospective issues not addressed**
**Simplified risk/benefit information**
**Letter categories A, B, C, D and X**
**Pregnancy is a special population; NOT an indication**

## Experience Applying Categories

**Most products have only animal data**
**Nature of animal studies**
**Positive findings (Category C)**
**Uncertain predictive value**
**Rarely changed or updated**
**“****Warning” perceived as optimal**

## Greatest ChallengeArea of medicine where the most certainty is desired, but there is the least data.

_**Greatest Challenge**_**Area of medicine where the most certainty is desired, but there is the least data****.**

## II.  Pregnancy Labeling Taskforce

_**Three Major Tasks**_
**1.  Examine current regulations **
**2.  Recommend changes**
**3.  Consider bigger picture of related needs**

## Task A:  Examine Current Regulations:Part 15 Public Hearing

**September 1997:**
***Is it relied on by practicing providers?***
***Is it useful? How?***
***What is good and bad about it?***
***If, overall, it is not informative or excessively problematic, what can be done to improve it?***

## Current System: Positive Aspects

**Information **_**is**_** relied upon by practitioners**
**Simplicity is attractive**
**Condense down to single, ordered letters**
**Clinician doesn’t have to interpret complex data**
**Familiar**

## Current System: Sample Criticisms

**Overly simplistic (many examples)**
**Fosters passive approach to complex**
**Does not facilitate clinical decision-making**
**Data poorly described**
**Updates are rare -  no teeth in regs**

## 
	The current system is uninformative.  Descriptive text would be much more useful.

- 	**The current system is uninformative.  Descriptive text would be much more useful.**
**	**

**       “****Take Home Message”**

## II.  Developing a New Model

**Goals**
**Provide practical, useful information**
**Clearly state risk assessment and its basis**
**Data to meet variety of user needs**
**Process**
**Multidisciplinary consensus**
**Seek public input along the way**

## Model Label Format

**Clinical Considerations**
***What clinicians need to consider to link RA to practical application***
**Risk Assessment**
***Incorporate human & animal data and clearly states relevant factors considered***
**Discussion of Data**
***Brief, but convey body of science***

## December 2000Where are we now?

**Draft version nearly complete**
**Advisory Committee review**
**Focus testing (clinician)**
**Standard risk assessment language**
**Updating through other regulatory mechanisms is near**
**Beginning the internal cultural shift**

## Why Does it Take Years?

**Scientifically challenging**
**New regulations are intentionally slow**
**More is needed than label model **
**Must raise expectations for data quality and quantity**
**Many obstacles to developing the science that this so sorely needed**

## III. Broader Needs of Pregnancy Labeling

**Data**

**Expertise**

**Communicate**

## 1.  FDA Expertise

**Science **
***Assessing Human Pregnancy Outcome Data***** **** www.FDA.gov/CDER/guidances**
***Integrated approach to review of reproductive toxicology data***** **
**Pregnancy labeling advisory committee**
**Outside experts**

## 2.  Improving Data: Safety  

**Safety: new reporting regulation **
**Pregnant women are a special population **
**More and better prospective data**
**Shift focus from finding toxicity to describing margins of risk **
**Guidance Document for Industry 6/99: *****“Establishing Pregnancy Registries”***

## Safety Data in the Future

**One drug per registry is not efficient. **
**Centralized, coordinated approach**
**government agencies; industry; NGOs**
**CDC/FDA Workshop Nov 2000**
**We can do better; we must**

## 3.  Data: Lactation

**Labels should facilitate clinical decisions**
**Consideration of risks and benefits**
**Clinical pharmacology**
**Better use of data available**
** ****Product labels not informative**
**Sharp contrast with Healthy People 2010; AAP**

## FDA and Lactation

**Joint meeting: Pregnancy Labeling and Pediatrics Advisory Committees**
**September 2000**
**Guidance under development**
**“****How to” conduct studies to assess presence and extent of drugs in breast milk**
**New labeling rule will apply same format to lactation as for pregnancy**

## 4.  Data: Clinical Pharmacology

**Once treatment is decided, right dose is essential**
**Every patient should not be an “N of 1” **
**Few drug labels include PK or dose data**
**Consequence**
**Clinician Rx “lowest dose”**

## Pregnancy Changes Physiology and Alters Drug PK

**Expansion of plasma volume**
**Increase cardiac output**
**Changes in regional blood flow**
**Changes in enymatic activity**
**Increase in GFR**
**Altered GI**
**Decrease in Albumin**

## Contrast of Altered Physiologies 

**FDA guidances for assessing changes in pharmacokinetics and dosing**
**Renal impairment (1998)**
**Hepatic impairment (1999)**
**Children (1998)**
**No current guidance or recommendations for pregnancy**
**Scientific attention to this area has been limited**

## FDA and Pregnancy PK/PDCurrent Status

**New safety regulation increase label updates**
**New literature will come to attention**
**NICHD Workshop, Sept 2000****	**
**Am Society of Clin Pharm Therapeutics, March 2001**
**Scientific Development**
**New guidance being considered **

## Where We Need To Go: Collaboration and Facilitation

**Clinical needs are great **
**More scientific development**
**Essential to meeting clinical needs**
**Clinical pharmacology is part of evidence based medicine**
**Effective programs must bridge clinical disciplines and build partnerships**

## Collaboration (continued)

**Confront perceived barriers**
**Reproductive health versus  women’s health**
**Research conduct**
**Funding**

##  Summary

**Steady progress in multiple facets of pregnancy labeling**
**Increasing emphasis on enhancing sound clinical management**
**Models for data collection**
**Thinking beyond standard**
**PK/PD**
**Collaboration is essential**
**Public deserves our collective best**