# Presentation: 351041

## Regulatory Perspective of Exposure-Response (E-R) in OTC Drug Development

- Abimbola Adebowale Ph.D.
- Office of Clinical Pharmacology and Biopharmaceutics
- Center for Drug Evaluation and Research
- Food and Drug Administration

## Disclaimer

- 	The opinions expressed during this presentation are those of the speaker, and do not necessarily represent those of the Food and Drug Administration.

## Objectives

- Review the purpose of E-R information and discuss its use in OTC drug development
- Discuss the benefits of integrating E-R information into the design of studies during the OTC drug development process and,
- Discuss the benefits of examining the drug and drug class to assess E-R relationships for more effective problem solving in the OTC drug development process

## Presentation Outline

- Background
- Definitions of exposure and response
- Related E-R guidance documents
- Utility of E-R information in OTC drug development
- Examples illustrating the benefits of utilizing E-R information in various OTC drug development scenarios
- Overall summary

## Background: Exposure and Response Definitions

- ‘Exposure’ (E) refers to
- Dose
- Blood Concentration
- Single or Integrated
-  ‘Response’ (R) refers to
- Biomarker
- Surrogate Endpoint
- Clinical Endpoint

## Background (continued): Definitions of Response Measurements

| Response measurements | Definition | Example (s) |
| --- | --- | --- |
| Biomarker | A physical sign or laboratory measurement that occurs in association with a pathological process, and has putative diagnostic and/or prognostic utility | Gastric acid
Fasting blood glucose |
| Surrogate Endpoint | A biomarker that is intended to serve as a substitute for a clinically meaningful endpoint, and is expected to predict the effect of a therapeutic intervention | Intragastric pH
Blood Pressure |
| Clinical Endpoint | A clinically meaningful measure of how a patient feels, functions or survives | Pain Relief
Heartburn Relief |

*Lesko LJ and Atkinson A, 2001*

## Background (continued): Related E-R Guidances

**2003 FDA Guidance**
- Exposure-Response Relationships: Study Design, Data Analysis and Regulatory Applications
- Provides recommendation on the use of E-R information in the development of drugs e.g. optimal dose selection
**1998 FDA Guidance**
- Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products
- http://www.fda.gov/cder/guidance/index.htm

## How is E-R information utilized in OTC drug development ?

## Utilization of E-R in OTC Submissions

**70 approved Rx  to OTC switches**
**Different indication**
**Different dose, and dosing regimen**
**New dosage forms **
**18 approved for new uses**
**New indication for OTC active ingredient**
**New active ingredient for OTC indication**
**New population-pediatrics**

*CDER 2003 Report to the Nation*

- ~ 18 % had E-R studies

## For New Indications

- Rx active ingredient for self-diagnosable OTC Indication, e.g. Rx=GERD, OTC = heartburn relief
- OTC active ingredient for new indication e.g. aspirin for pain of migraine
- New active ingredient for an OTC indication

## For New Indications (Continued)

**E-R information can **
- Provide Proof of Concept
- Support optimal dose selection for Phase III efficacy and safety trials
- Support selection of appropriate OTC dosage form
- Support interpretation of clinical relevance of any observed differences in exposure due to e.g. drug-drug interactions, food-drug interactions and herbal-drug interactions

## Different Dose and Dosing Regimen

- Different dose (usually lower) and/or dosing regimen
- E.g. NSAIDs, Antihistamines
**E-R information can**
- Support the new dose strength or dosing regimen where there are observed differences in exposure without the need for an additional clinical efficacy trial

## New Formulation, Salt or Dosage Form

- Effectiveness is usually assessed on the basis of bioequivalence (BE) or comparative bioavailability (BA) studies
**E-R information can**
- Support the effectiveness of a new formulation, salt or dosage form where there are observed differences in exposure, without the need to reformulate the product or repeat the BE study

## New Drug Delivery System

- For example, modified release (MR) dosage form
- Exposure profiles of MR dosage forms are usually different from that of immediate release (IR) dosage forms
**E-R information can**
- Support the approval of the new drug delivery system on the basis of PK data linking the MR formulation to the IR formulation together with E-R information, to extrapolate the IR data to the MR dosage form.

## A Clinical Pharmacology Paradigm for a New Formulation, Salt, Dosage Form and Delivery System

**Are Exposure Profiles of the New Product Different **
**from the Approved Drug Products**

**PK Data**
**Safety Studies**

**Well-Understood PK/PD Relationship?**

**Adequate and Well-Controlled Efficacy **
**and Safety Studies**
**Supportive PK Data**

**PK Data and**
**PK/PD Relationship**
**Safety Studies**

**No**

**Yes**

**No**

**Yes**

**Yes**

## New Target Populations

- Previously approved drug product in a new target population
- e.g. loratadine for seasonal allergic rhinitis for pediatrics
**E-R information can be used to **
- Support use by bridging the efficacy data in the adult population to the pediatric population without additional controlled efficacy studies in the pediatric population

## Pediatric Algorithm illustrating the integration of E-R relationships to establish labeled doses

- Reasonable to assume (pediatrics vs adults)
-  similar disease progression?
-  similar response to intervention?

- Conduct PK studies
- Conduct safety/efficacy trials

**NO**

- Reasonable to assume similar
- concentration-response (C-R)
- in pediatrics and adults?

- Is there a PD measurement that
- can be used to predict
- efficacy?

- Conduct PK studies to achieve
- levels similar to adults
- Conduct safety trials

- Conduct PK/PD studies to get C-R for PD measurement
- Conduct PK studies to achieve target concentrations based on C-R
- Conduct safety trials

**YES TO BOTH**

**NO**

**YES**

**NO**

**YES**

## Applying E-R to Optimize Use of OTC Drugs in Subpopulations

- Greater access, greater concern for the effect of  intrinsic (e.g. age, gender, and race) and extrinsic (drug-drug interaction, effect of food/diet, and alcohol) factors
- Necessitates well-characterized E-R relationships

## Dose Selection, Labeling and Study Design

- In the pediatric population E-R information can be used to support pediatric dose
- E-R information can be used to support labeling in other special populations e.g. renal and hepatic impairment, and in drug-drug interactions
- E-R information should be used to support the design of actual use studies

## Labeling

- An example of a renal and hepatic label warning for an OTC drug product
**Warnings: **
**Ask a doctor before use if you have **liver or kidney disease. **Your doctor should determine if you need a different dose.**
**Directions: **
- adults and children 6 years and over 1 tablet daily; **consumers with liver or kidney disease ask a doctor**

## 	
	Examples Illustrating the Benefits of Utilizing E-R in Various OTC Drug Development Scenarios

**	**Examples Illustrating the Benefits of Utilizing E-R in Various OTC Drug Development Scenarios

## Facilitating Optimal Dose Selection for a Different Dosage Form

**Development Program**
- PK Characterization, Comparative Bioavailability Study, Single Clinical Efficacy and Safety Study
**Results**
- Higher strength was more effective, but exposure was 25% higher than the approved product
- Options to address safety issues were to conduct large safety trial or provide E-R data
- Based on Agency recommendations, Company provided published dose-response information for safety endpoints

## Facilitating Optimal Dose Selection for a Different Dosage Form

**Agency Decision**: The provided E-R information coupled with the safety data from this product and existing products was adequate to support the approval of this product
**Benefit:** The company did not have to conduct  a large safety trial.

## Facilitating the Development of a New Salt and Dosage Form

**Development program **
- Clinical efficacy and safety studies, PK/PD, DDI, Comparative BA
**Results**
- OTC capsules were not BE to the Rx tablets
- Exposure (AUC and Cmax) was 15% and 30% lower for the capsule relative to the tablet
- However evaluation of E-R indicated that lower exposure does not translate to a difference in response for efficacy

## Facilitating the Development of a New Salt and Dosage Form

**Agency Decision**: The provided E-R data coupled with the previous clinical efficacy and safety data was adequate to support the approval of this product
**Benefit:** The company did not have to reformulate the product or conduct additional studies

## Overall Summary

- E-R information can be used to support OTC drug development and regulatory decision making.
- The utilization of E-R information can accelerate drug development programs and minimize uncertainty in regulatory decision making.

## Overall Summary

- Integration of E-R information into OTC drug development should be encouraged within industry and by regulatory agencies.
- Exploring E-R relationships by drug class should also be encouraged.

## Acknowledgement

- John Lazor, Pharm.D.
- Arzu Selen, Ph.D.
- Dennis Bashaw, Pharm.D.
- David Hilfiker, MSc.
- Elaine Abraham, RPh.
- Michelle Jackson, Ph.D.