# Presentation: 672990

## OTC 101

- David Hilfiker
- Chief, Project Management Staff
- Division of Over the Counter Drug Products
- FDA

- May 11, 2005

## Presentation Outline

- Just the Basics
- NDAs
- Monographs
- NDA vs. Monographs Comparison
- The Quiz
- Q&A

- May 11, 2005

## Just the BasicsMarketing Options

- Two Regulatory Systems
- New Drug Applications
- OTC Drug Monographs
- General OTC Drug Lifecycle

- Rx NDA

- OTC NDA

- OTC Drug Monograph

- May 11, 2005

## Marketing under an NDA

- May 11, 2005

## Just the BasicsMarketing under an NDA

- Requires a pre-approved application
- May require clinical studies
- May require a user fee under PDUFA
- Post-approval NDA maintenance
- Individual license to market
- May provide marketing exclusivity
- Mandated FDA review timeline

- May 11, 2005

## Just the BasicsWhere to Begin for an NDA

- An IND (Investigational New Drug) for trials in human subjects
- Typical “milestone” development meetings with FDA
- Pre-IND
- End of Phase 2
- Pre-NDA

- May 11, 2005

## Just the BasicsNDA references

- _For the pre-IND Meeting_:
- 	Guidance entitled “Formal Meetings With Sponsors and Applicants for PDUFA Products”
- _For the NDA review process_:
- 	Guidance entitled “Good Review Management Principles for PDUFA Products”
- _For IND requirements_:  21 CFR 312
- _For NDA requirements_:  21 CFR 314

- May 11, 2005

## Marketing under an OTC Drug Monograph

- May 11, 2005

## Just the BasicsWhy did we create monographs?

- 1962 Amendments to FDCA
- Drug Efficacy Study Implementation (DESI)
- 420 drugs of low toxicity deferred
- Developed monographs by therapeutic class (rather than individual product review) for efficiency

- May 11, 2005

## Just the BasicsWhat are OTC Drug Monographs?

- The Quick Start Guide to pharmaceutical marketing
- Required Conditions that are Generally Recognized As Safe and Effective (GRASE)
- NDA regulations (Part 314) do not apply

- May 11, 2005

## Just the BasicsRequired Conditions

- Active Ingredients
- Dosage Forms
- Dose or Concentration
- Required Labeling
- Packaging and/or Testing Requirements (in some cases)

- May 11, 2005

## Just the BasicsWhat Labeling is Required?

- Uses
- Warnings
- Directions
- Professional Labeling
- (healthcare provider instruction)

- May 11, 2005

## Just the BasicsHow is a Monograph Established?

- See 21 CFR 330
- Three Step Rulemaking Process

- Advanced Notice of Proposed Rulemaking
- (ANPR)

- Proposed Rule
- Tentative Final Monograph (TFM)

- Final Rule
- Final Monograph

- May 11, 2005

## Category I: GRASE
Category II: not GRASE
Category III: cannot determine if safe and effective; more data needed

- Category II: not GRASE
- Category III: cannot determine if safe and effective; more data needed

- Just the BasicsHow is a Monograph Established?

**Notes:**
First, the Advisory review panel.  This is a group of experts on a particular therapeutic category.  The panel is charged with determining which active ingredients and combinations of active ingredients are safe and effective for the appropriate indications of a particular therapeutic category.   The panel categories each active ingredient or combination in one of three category.  Category I active ingredients and combinations are those that are generally recognized as safe and effective, or GRASE.  Category II active ingredients and combinations, on the other hand, are those that for which data has been submitted but that the panel did not find to be safe and effective.  The last category is category III.  This category represents active ingredients and combination for which there was not enough data submitted to make a determination as Category I or II.  More data must be submitted for these active ingredients before a determination can be made as to whether they are GRASE.

## Category I: GRASE
Category II: not GRASE
Category III: undetermined

- Category II: not GRASE
- Category III: undetermined

- Just the BasicsHow is a Monograph Established?

**Notes:**
The conclusions of the panel, known as the Panel Report, are included in the ANPR.  The ANPR is published in the Federal Register to notify the public of the agency’s intent to create an OTC drug monograph.  By including the Panel report, the ANPR also provides a list of each active ingredient and combination reviewed for a particular OTC drug monograph as well as the status of each as either Category I, II, or III. 

## Just the BasicsHow is a Monograph Established?

**Comments**

- Just the BasicsHow is a Monograph Established?

**Notes:**
The ANPR allows a 90-day comment period in which any interested party can submit information regarding the OTC drug monograph to the agency.  The agency reviews these comments and incorporates them with the panel report to develop a TFM.  Again, the TFM is published in the Federal Register.  The TFM contains a discussion of the submitted comments and panel report.  And, most importantly, the TFM established a proposed OTC drug monograph.  This is FDA’s preliminary position regarding the safety & effectiveness of particular active ingredients as well as acceptable labeling and final formulation testing.

## Just the BasicsHow is a Monograph Established?

**Comments**

**Data**

- Just the BasicsHow is a Monograph Established?

**Notes:**
Similar to the ANPR, the TFM includes a 90-day comment period, but it also includes a 12-month period for submission of data.  The agency then reviews all of the comments and data submitted and amends the proposed OTC drug monograph as appropriate.  The amended OTC drug monograph is then published in the Federal Register in the form of a FM.  The FM is similar to the TFM in that it includes a discussion of submitted comments and data as well as an OTC drug monograph.  Although the name “FM” signifies that this the agency final version of an OTC drug monograph and that this is the last step in the drug review, as I will explain in a few minutes, the FM can be amended.  It is also important to point out that, unlike the TFM, the FM has an effective date.  The FM is incoporated in the CFR and drug manufacturers must comply with it by the effective date. 

## Just the BasicsCan I Add to the Monographs?

- Citizen Petition, IF
-  Product was marketed prior to 1975
- Time and Extent Application (TEA) under 21 CFR 330.14, IF
-  Product marketed OTC outside of U.S.
-  Product marketed OTC inside U.S. after 1975
- Both are preliminary to a Proposed Rule

- May 11, 2005

## NDA vs. Monographs

- May 11, 2005

## Just the BasicsHow are NDAs and Monographs Different?

| NDA | Monograph |
| --- | --- |
| Pre-approval Required | Pre-approval Not Required |
| Clinical studies and user fees may be necessary | Clinical studies not necessary and no user fees |
| Approved labeling is unique to your drug | Labeling is the same for all similar drugs |
| Possible marketing exclusivity | No marketing exclusivity |
| Approved NDA is your license to market | Final monograph is open to anyone |

## Just the BasicsHow are NDAs and Monographs the Same?

- Standards for safety and efficacy
- Manufacturing and GMP inspections
- Labeling under 21 CFR 201.66
- Advertising regulation

- May 11, 2005

## Just the BasicsEnsuring Safety and Efficacy without a Prescription

- Patient safety in an unsupervised setting
- Self-diagnose?
- Self-manage?
- Self-help?
- Label Comprehension Studies
- Actual Use Studies
- U.S. and worldwide adverse event data

- May 11, 2005

## Just the BasicsOTC Drug Labeling

- “Drug Facts” format
- Standard format for labeling of OTC drugs that consumers become accustomed to
- “Nutrition Facts” for foods and “Supplement Facts” for dietary supplements
- 21 CFR 201.66
- Final Rule: 64 FR 13254 (March 17, 1999)

- May 11, 2005

## Just the BasicsOTC Drug Advertising

- Federal Trade Commission regulates advertising
- FDA regulates labeling
- 	_FDCA definition (201.m)_
- 		Includes all labels, as well as other 	written, printed, or graphic matter 	accompanying the product

- May 11, 2005

## QUIZ!!!

- May 11, 2005

## Question 1

- I use OTC drugs:
- Every day
- Every week
- Occasionally
- Never

**Answer:  (a)  WE HOPE**

- May 11, 2005

## Question 2

- 	I am a newcomer to FDA regulation of OTC drugs.  Where do I begin?

- Answer:
-  Under “Other Regulatory Information”
-  See “Frequently Asked Questions”

- May 11, 2005

## Question 3

- 	I want to market my product as a cosmetic.  Can I do that?

- Answer:
- 1.  Under Industry Information
- 2.  See “Is It a Drug, a Cosmetic, or Both”

- May 11, 2005

## Question 4

- 	I have a competitor making claims that are not supported by the monograph or an approved NDA.  Can I make the same claims?

- Answer:  NO.
- Contact CDER Office of Compliance.
- Robert Eshelman, 301-827-8981.

- May 11, 2005

## Question 5

- 	I want to market a 2% aluminum hydroxide gel for poison ivy.  What do I have to do?

- Answer:  Is it allowed under a monograph?
-  Ingredient listing
-  Milestone listing for FR date
-  Categorical listing to look up publication
-  CFR for allowed concentrations and uses
-  Registration and Listing

- May 11, 2005

## Question 6

- 	I want to market a 150 mg docusate sodium laxative product.  What do I have to do?

- Answer:  Is this allowed in the monograph?
-  Ingredient listing
-  Compliance Policy Guide (CPG 450.200)
-  Dose?
-  Milestone listing (for publication date)
-  Categorical listing (for publication link)
-  Look in publication

- May 11, 2005

## Question 7

- 	I want to market ipecac as an expectorant.  What do I have to do?

- Answer:  Is it allowed in the monograph?
-  Ingredient Listing
-  NDA or citizen petition

- May 11, 2005

## Question 8

- 	I was asleep for most of this.  Am I in trouble?
- 	Answer:

- Yes you are.

- Contact us
- Main phone:  301-827-2222
- My phone:  301-827-2265
- Email:  hilfikerd@cder.fda.gov

- May 11, 2005

## Coming up next...

- The Basics of Chemistry, Manufacturing and Control
- Ram Randad, Chemist, Division of Chemistry, CDER Office of Generic Drugs

- May 11, 2005

**Notes:**
Ram Randad is the Review Chemist for the U.S. Food and Drug Administration, Office of Generic Drugs, Rockville, MD. In this position, he reviews Chemistry Manufacturing Control information of the ANDA. He has a Ph.D. Degree in Chemistry from the University Of Poona, India in 1985. He did his post doctoral studies at the Purdue University, West Lafayette, Indiana.  He worked in a various research positions for National Cancer Institute, Tibotec, and Neogenissis before starting his FDA career in 2001.  He has published 28 research papers and has 14 patents.