# Presentation: 927428

## Pediatric Initiatives

- Leanne CusumanoRegulatory Policy
- CDER (HFD-7)301-594-2041pdit@cder.fda.gov

- FDA

## The Problem

**Approximately 3/4 of prescription drugs have inadequate pediatric use information.**** **
**	****Gilman:  Clinical Pharmacokinetics   1992**
**	****	****	****	**

## Pediatric Regulations & Legislation

**December 1994**
**Pediatric Labeling Regulation**
**November 1997**
**Pediatric Exclusivity**
**December 1998**
**Pediatric Studies Requirement**

## 1994 Pediatric Rule

**Applies to drugs and biologics**
**A pediatric indication may, in some cases, be based on adult efficacy data if**
**course of the disease is similar**
**product’s effects are similar**
**additional pediatric data is provided**
**dosing**
**pk**
**safety**
**21 CFR 201.57(f)(9)**

## PEDIATRIC EXCLUSIVITY

- 21 U.S.C. 355a - Section 505A
- Guidance for Industry
- MaPP
- www.fda.gov/cder/pediatric

## Effect of Pediatric Exclusivity

- attaches to exclusivity or patent life of the active moiety as EXCLUSIVITY extension
- adds 6 months of exclusivity
- possible delay of generic approvals
- once submitted, maximum of 90 days
- six month period runs during delay

## Applications to Which Pediatric Exclusivity Applies

- Applications
- containing the active moiety
- held by the same sponsor
- Unapproved applications upon approval
- Later-filed NDAs & Supplements
- data earned prior ped. ex and
- essential to approval of later-filed NDA or supp.

## Moieties in Multiple Products

- Monotherapy
- montherapy exclusivities
- monotherapy patents
- Combination Therapy
- combination protections
- each montherapy’s protections

## Can you earn more than one 6-month period of pediatric exclusivity?

- Response to the Written Request is a supplement for a new use.
- A new use is a use that is not included in the approved labeling of an approved drug, including a new pediatric population.
- The supplement qualifies for 3-year Waxman-Hatch exclusivity
- The 6-month period of pediatric exclusivity attaches *only *to the 3-year exclusivity.

## The Statute:  Section 505A

- New Drug Applications (505A(a))
- Already Approved Applications (505A(c))

## Qualifying for Pediatric Exclusivity Under the Statute

- conducted in accordance with Written Request, AND
- conducted in accordance with
- written agreement or
- commonly accepted scientific principles,
- AND
- reported in accordance with FDA filing requirements

## List of Approved Drugs (505A(b))

- “Approved” means
- approved active moiety for
- an approved adult indication that occurs in the pediatric population
-  - otherwise unapproved
- Published May 20, 1998, updated at least annually
- No action REQUIRED
- Non-priority v. Priority

## “Priority” Section of the List

- significant improvement compared to marketed products; or,
- widely used, as measured by at least 50,000 prescription mentions per year; or,
- additional therapeutic or diagnostic options are needed.

## Obtaining Pediatric Exclusivity

- Proposed Pediatric Study Request
- FDA Written Request
- Written Agreement or commonly accepted scientific principles
- Submitted in accordance with FDA’s requirements for filing
- Acceptance
- 60 days v. 90 days

## Written Requests

**FDA asseses what studies are needed to produce a health benefit in the pediatric population.**
**Recommend sponsors provide a proposed pediatric study request as a first step. **
**Written Request may or may not reflect some or all elements in the sponsor’s proposal.**
**FDA can issue a Written Request without  a sponsor’s request.**** **

## Relationship to Regulations

- Pediatric Rule
- Required Studies
- Completeness, Timeliness, and Other Requirements

## Sunset

*FDA can issue a Written Request for a drug (active moiety) after January 1, 2002, only if:*
- an application for the drug is submitted on or before January 1, 2002; and
- the drug was in commercial distribution on November 21, 1997; and
- the drug is on the List on January 1, 2002; and
- FDA finds that there is
- continuing need for information and
- the drug may provide health benefits

## Sunset

*Studies submitted on or after January 1, 2002, can earn pediatric exclusivity if:*
- the studies are submitted in response to a Written Request issued on or before January 1, 2002, and
- the Written Request is for a drug (active moiety) for which an application was submitted on or before January 1, 2002.
*FDA cannot issue a Written Request for a drug (active moiety) after January 1, 2002, if the first application for the drug is submitted after January 1, 2002.*

## Report to Congress

- Due January 1, 2001
- Must address:
- effectiveness in obtaining pediatric information
- adequacy of incentive
- economic impact
- suggestions for modification

## Actions as of 9/1/99

- 95 Written Requests
- 31 Incomplete Responses
- 1 PPSR Withdrawal
- 15 Amended Written Requests
**PPSRs RECEIVED = 155**
**TOTAL ACTIONS = 143**
**PPSRs PENDING = 37**
**PPSRs > 4 months = 7**

## Pediatric Exclusivity Grants as of 9/1/99

**Approved Moieties:****	****5**
- Abacavir (Glaxo Wellcome, Inc.)
- Ibuprofen
- McNeil Consumer Products
- Whitehall-Robbins Healthcare
- Midazolam Hydrochloride (Hoffmann-La Roche)
- Propofol (Zeneca Pharmaceuticals)
- Ranitidine Hydrochloride (Glaxo Wellcome, Inc.
**Unapproved Moieties:  3**
**Pending Review:****	****2**

## Resources on Pediatric Exclusivity

- The Statute:  21 U.S.C. 355a
- The Guidance:  *Guidance for Industry:  Qualifying for Pediatric Exclusivity *
- The MaPP:  *Review Management:  Process for Handling Pediatric Exclusivity*
- www.fda.gov/cder/pediatric

## Key Elements

- FDAMA
- Voluntary
- Incentive
- Pediatric Rule
- Mandatory
- Fills the gaps

## 1998 Final Rule

- Requires pediatric assessment of
- safety
- effectiveness
- Unless waived or deferred
- Covers
- drug product and
- indication
- under review

## Applications Covered by Rule

- New Drugs
- New Chemical Entities (NCE)
- New Indications (except Orphan indications)
- New Dosage Forms
- New Dosing Regimens
- New Routes of Administration
- Marketed Drugs meeting certain criteria

## Marketed Drugs

- Meaningful therapeutic benefit and absence of labeling poses a  risk
**or**
- Substantial use and absence of labeling poses a risk

## Meaningful Therapeutic Benefit

- a significant improvement in
- treatment
- diagnosis
- prevention
- of a disease, compared to
- marketed products
- adequately labeled for that use
- in the relevant pediatric population
- the drug is in a class of drugs or for an indication for which there is a need for additional therapeutic options

## Substantial Number of Pediatric Patients 	

- 50,000 pediatric patients with the disease for which the drug or biological product is indicated
- Estimated based on physician mentions per year
- Not codified
- FDA may modify it, after consulting with the Pediatric Advisory Subcommittee.

## What is a Pediatric Assessment?

- Data adequate to assess the safety and effectiveness of a drug product
- for the claimed indications
- in all relevant pediatric subpopulations, and
- Data adequate to support dosing and administration
- for each pediatric subpopulation
- for which the drug is safe and effective.

## Deferral Criteria

- Deferral may be of some or all assessments until a specific time after approval if:
- drug is ready for approval in adults before ongoing studies in pediatric patients are complete
- pediatric studies should be delayed until additional safety or effectiveness data have been collected
- other reasons

## To Request Deferral

- Applicant must
- certify the grounds for delaying pediatric studies,
- describe the planned or ongoing studies,
- show that the studies are being or will be conducted with due diligence and at the earliest possible time
- 21 CFR 314.55(b)

## To Request Waiver

- Certify with supporting information and documentation:
- studies are impossible or highly impractical, or
- evidence strongly suggests the product would be ineffective or unsafe, or
- reasonable attempts to produce a pediatric formulation have failed, or
- (1) no meaningful therapeutic benefit, &
-     (2) not likely to be used in a substantial number of patients, &
-     (3) absence of adequate labeling could not pose significant risks

## Scope of Waiver

- FDA will grant a full or partial waiver if the agency finds a reasonable basis to conclude that one or more of the grounds for waiver have been met.
- If not possible to develop a pediatric formulation, the waiver will cover only those pediatric age groups requiring that formulation.
- If evidence that the product would be ineffective or unsafe in pediatric populations, this information will be included in the product's labeling.
- (21 C.F.R. § 314.55(c)).

## Final Rule Implementation Dates

- After April 1, 1999, NDA at approval must have:
- pediatric assessment OR
- waiver OR
- deferral.
- After December 2, 2000, FDA can require pediatric assessments unless waived or deferred.

## Implementation and Comparison

**Pediatric Exclusivity & the Pediatric Rule**

## Rule Compared to Ped. Ex.

- Studies are required
- Evaluate the need for pediatric information on only the drug product and indication currently being reviewed or to be submitted

- Studies are voluntary
- Evaluate the need for pediatric information on the active moiety
- Incentive only exists when there is patent or exclusivity protection

## Rule Compared to Ped. Ex.

- Meaningful therapeutic benefit or substantial use
- Studies not required for orphan indications

- Additional information that may produce a health benefit in the pediatric population
- Incentive attaches to existing orphan exclusivity

## Rule Compared to Ped. Ex.

- December 2, 2000, before FDA can require studies to be submitted
- No Sunset date

- As of November 21, 1997, FDA could request studies
- Sunsets January 1, 2002

## Implementation of Pediatric Initiatives

- Pediatric drug development will become routine part of FDA’s activities
- End of Phase 2 meeting,
- Phase 1 for life-threatening diseases
- Pre-NDA meeting
- Review status of pediatric studies

## Pediatric Rule & the Approval Letter

- At time of approval, approval letter will state:
- need for pediatric studies,
- deferral date, if deferred
- waiver, if waived
- need to evaluate potential for pediatric exclusivity

## Pediatric Advisory Subcommittee

- 	1.	Provide annual oversight of the implementation of the 	Rule
- 	2.	Discuss ethical issues raised by clinical trials in 		pediatric patients
- 	3.	Review trial design and data analysis
- 	4.	Review need for additional therapeutic options
- 	5.	Recommend specific marketed drugs and biological 	products that should be studied in pediatric patients
- 	6.	Provide oversight on progress of studies

## Pediatric Subcommittee Meetings

- April 23, 1999
- Pediatric Exclusivity
- Pediatric Rule
- Interactions
- Pediatric Studies
- November 15 - 16, 1999, Holiday Inn Silver Spring
- Ethics Issues
- Disease Course Issues

## Ultimate Goal

- Changes in the labeling to provide useful information on
- appropriate dose,
- use and
- safety
-    in the pediatric population.
- If pediatric studies do not result in a labeling change, why not?

## To Find out More

- Internet:
- www.fda.gov/cder/pediatric
- PEDS Line:
- 301-594-PEDS (7337)
- EMail
- pdit@cder.fda.gov