# Presentation: 335947

## Impact of Pediatric Initiatives

**Dianne Murphy, MD**
**Director**
**Office of Pediatric Therapeutics, OC &**
**OCTAP, CDER, FDA**

## Overview

- Pediatric Initiatives: Timeline & Summary
- BPCA:  “On-patent” vs “Off-Patent” and the 	List
- PREA Review
- Update on US Results
- Important Label Changes
- Lessons Learned

## Acronyms

**FDAMA** – Food and Drug Administration 					Modernization Act
**BPCA** 	– Best Pharmaceuticals for 						Children Act
**PREA** 	– Pediatric Research Equity Act
**WR ****	**– Written Request
**PPSR ** 	– Proposed Pediatric Study 						Request
**ICH**	– International Conference in Harmonization

## Pediatric Benchmarks

- 1977 AAP, Committee on Drugs
- 1979 Pediatric Sub-Section
- 1992 Proposed: Pediatric Labeling and 		    	  Extrapolation
- 1994 Final: Pediatric Labeling and Extrapolation
- 1997 Proposed Rule: Pediatric Studies Required
- 1997 FDAMA Exclusivity
- 1998 Final Rule: Pediatric Studies Required

## History of Pediatric Regulations/Legislation

**January 2002**
**FDAMA Exclusivity sunsets**
**January 2002 **
**Best Pharmaceuticals for Children Act (BPCA)**
**October 2002 **
**Pediatric Rule enjoined**
**December 2003**
**Pediatric Research Equity Act (PREA)**

## 2002 Best Pharmaceuticals for Children Act (BPCA)

- Became law January 4, 2002
- Re-authorizes exclusivity incentive program under FDAMA
- Establishes an additional mechanism for obtaining information in the pediatric populations for off-patent drugs

## Best Pharmaceuticals for Children Act (cont.)

- Mandates that FDA and NIH collaborate in the study of “off-patent” and “on-patent” drugs that industry does not want to study
- Public dissemination of studies conducted as result of Exclusivity
- Mandated public review of safety reporting on products granted Exclusivity

## Goal

**On-Patent Exclusivity Process**
** ****and**
**Off-Patent Process**
**New Pediatric Information in Label**

## BPCA- Provisions

**      ****“****On-Patent”**
**FDA issues Written Request to holders of approved application *****protected by patent or market exclusivity***

## Written Request (WR)

** ****A legal document written and sent by  the FDA to sponsors requesting studies in the pediatric population**
** ****Specifies: **
**-****	****indication****	****	****	**
**-****	****population**
**-****	****type of studies****	****	**
**-****	****safety parameters**
**-****	****longer term follow-up****	**
**-****	****timeframe for response**

**Notes:**
A Written Request is a legal document that requests pediatric information for a product. Compliance with a Written Request is voluntary. The FDA has issued guidance documents on the format and content of Pediatric Written Requests in general and has specific templates for Written Requests for some therapeutic areas including oncology. These are posted on the Internet on the FDA Center for Drug Evaluation and Research Pediatric Page.

The components of a Written Request typically include the intended pediatric indication- meaning the disease or condition to be studied, the population, the types and numbers of studies, any general safety parameters and any drug product specific safety parameters that should be monitored, plans for long term follow up and a time frame within which the studies should be completed and the results submitted to the FDA. The specific components of a Written Request may vary according to the indication, population, and product.

## FDA On-Patent Drug Exclusivity Process

**Background Research/Extensive Literature Review **
**          ****Sponsor**
**Proposed Pediatric****	****Development of Written Request by **
**Study Request (PPSR) ****	****Reviewing Division**
**	****	****Reviewed by PdIT         ****	****     **
**	****      ****FDA            ****	****WR Issued**
**            ****	****        ****	****	**
**	****    ****	****Sponsor Completes Studies****	****	**
**	****or FDA****	****Exclusivity Determined by**
**	****	****Exclusivity Board (60-90 days)**
- 		**Action on Application (6-10 months)**

## BPCAOff-Patent Drugs

## BPCA

**“****Off-Patent”**
**	****- ****FDA issues Written             Request to holders of approved application *****for drugs that have NO patent or market exclusivity protection***

## FDA/NIH Partnership

** ****Develop “List of Drugs for Which Pediatric    Studies are Needed”****                      **
** ****Long, involved iterative process lead by Bill     ****	****      ****	****Rodriguez/George Giacoia**
** ****Input obtained from Advisory Committee, FDA ****	****Divisions, NIH Divisions, AAP, USP, and ****	****Experts**
** ****List of 12 drugs published in Federal Register 1/21/03 and 8 drugs (8/13/03) -- will be updated annually**

## Development of the List

**FDA legal/policy decision -- off-patent drugs will only be studied:**
**in a particular age group in which they are not already labeled**
**if already labeled for Pediatrics drugs will be studied only if:**
**significant new safety information**
**significant new scientific information**

## 2003 List of Drugs for Which Pediatric Studies Are Needed

_**Drug**_**	****	****	**_**Indications for pediatric use**_
**Lorazepam** 	Sedation in the ICU; Treatment 					of status epilepticus
**Nitroprusside****	**Reduction of blood pressure** ****	**
**Baclofen****	****	**Oral treatment of spasticity of 					cerebral palsy
**Azithromycin**	Prevention of broncho-pulmonary					dysplasia in neonates; treatment of     				Clamydia pneumonia, prevention of 					Chlamydia conjunctivities and pneumonia
**Lithium****	**	Treatment of mania in bipolar disorder

## 2003 List of Drugs for Which Pediatric Studies Are Needed

_**Drug**_**	****	****	****	**_**Indications for pediatric use**_
**Diazoxide** 			Hypoglycemia
**Isoflurane****	****	****	**Maintenance of general anesthesia
**Meropenem****	****	**Pediatric infections
**Metoclopramide**		Gastroesophageal reflux
**Piperacillin/tazobactam    **Pediatric infections
**Promethazine****	****	**Nausea/vomiting
**Rifampin**			Staphylococcus endocarditis**	**

## 2003 List of Drugs for Which Pediatric Studies Are Needed

_**Drug**_**	****	****	****	**_**Indications for pediatric use**_
**Lindane****	** 		2nd line treatment of scabies
**Heparin****	****	****	**Anticoagulant** ****	**
**Bumetanide****	****	**Diuresis
**Furosemide****	**	Diuresis
**Dobutamine****	****	**Increase cardiac output
**Dopamine****	****	****	**Increase cardiac output
**Spironolactone**		Diuresis
**Ampicillin/sulbactam****	**Pediatric infections**	**

## Update of the List

**NIH “owns” this process**
**FDA will have major input**
**Will include publication in the FR to solicit input from the public**

## Process for the Study of Off-Patent Drugs

**Priority List of**
**Off-Patent Drugs**

**FDA issues **
**Written Request**

**Industry agrees **
**to conduct studies**

**Industry declines**
**to conduct studies**

**Referral to NIH/RFC**

**Industry has 30 days to respond**

**yes**

**no**

## Where are we in the process?

** ****WR completed and RFCs being issued by NIH           **
**Lorazepam - long-term, continuous sedation in ICU  **
**Lorazepam - treatment of status epilepticus **
**Nitroprusside - to reduce blood pressure in pediatric patients**
** ****Five more Off-patent WR sent to NICHD after 30-day response**
**Four On-patent Written Request turned down by industry referred to Foundation of NIH**

## 2003 Pediatric Research Equity Act (PREA)

- Became law December 3, 2003
- Legislation mimics Pediatric Rule
- Retroactive for all applications back to April 1, 1999

## Pediatric Research Equity Act (cont.) 

- Requires pediatric studies of certain drugs & biological products
- New indication
- New dosage form
- New route
- New dosing regimen
- New active ingredient
- FDA Guidance under development
- Establishes Pediatric Advisory Committee

## PREA : Meaningful Therapeutic Benefit

- (1) Represents a significant improvement in the treatment, diagnosis, or prevention of a disease compared with existing adequately labeled therapies used in the pediatric population
- (2) There is a need for additional options

## PREA: Deferrals

- 	Permits the submission of pediatric assessments to be deferred until a _**SPECIFIED DATE**_ after approval _***if***__:_
- adult approval is ready
- pediatric studies should be delayed until additional safety or effectiveness data are collected
_**OR**_

## PREA: Deferrals (cont.)

- there is another appropriate reason
_**AND**_
- 	the applicant submits certification of grounds for deferring
_**AND**_
- 	a description of planned studies
_**AND**_
- 	evidence of due diligence

##     PREA: Waiver

- Necessary studies are impossible or highly impracticable
- There is evidence strongly suggesting therapy would be ineffective or unsafe in pediatric age groups
_**OR**_

##     PREA: Waiver (cont.)

**The therapy: **
**Does not represent a meaningful therapeutic benefit over existing therapies**
_**AND**_
**It is not likely to be used in a substantial number of pediatric patients**

## Results

## RESULTSMay 4, 2004

_**Exclusivity Initiative**_
**New labels: ****	****	****	****	****	****73**
**Products with completed studies: ****	****107****	**
**Products Issued a WR: ****	****	****	****284**
_**Off-patent Drugs**_
**WRs issued by FDA: ****	****	****	****7**
**RFPs published by NIH:****	****	****	****3**

## Exclusivity:  On-Patent  Summary of Important Findings

**Dosing Changes/Recommendations****	**** ****	****N=13**
**New/Enhanced Safety Information****	****	****N=14**
**New Pediatric Formulation****	****	****	****N=6**
**New Lower Age Limit****	****	****	****	****N=31**
**NMEs/New Products****	****	****	****	****N=10**
**(June 2003)**

## Growth and Development

**Gabapentin – Neurontin (Seizures)**
**oral clearance normalized per body weight increased in children < 5 years**
**higher doses of gabapentin required in children < 5 years**

## Growth and Development

**Fluoxetine - Prozac**
**effectiveness established in Major Depressive Disorder 8-17 yrs. & Obsessive Compulsive Disorder 7-17 yrs.**
**In 19 week clinical trial pediatric patients treated with fluoxetine gained an average of 1.1cm less in height (p=0.04) than those treated with placebo**
**height and weight should be monitored periodically in pediatric patients treated with fluoxetine**

## Growth and Development

**Atomoxetine (Strattera)**
**18 mo treatment**
**gained average 6.5 kg while mean weight percentile decreased slightly from 68-60**
**Among pts treated at least 6 months**
**mean weight gain was lower for poor metabolizer (PM) patients as compared with extensive metabolizer (EM) patients**
**+ 0.7 kg for PM vs + 3.0 kg for EM**
**no difference in height PM vs EM**

## Cognition and Behavior

**Gabapentin – Neurontin**
**Warnings**
**Neuropsychiatric Adverse Events - pediatric**
**patients 3-12 years of age****	**
**emotional lability 6% vs 1.3%**
**hostility 5.2% vs 1.3%**
**thought disorder 1.7% vs 0%**

##   Progress: Product Labeling with Significant Changes for Dosing or Risk

_**Betamethasone**_** (Diprolene AF): Corticosteroid responsive dermatoses; NOT RECOMMENDED in pediatric patients <12 years of age; HPA axis suppression; local adverse reactions, including signs of skin atrophy in 10% of patients 3 mo-12 years of age**
_**Betamethasone**_** (Diprosone Cream, Ointment, Lotion):**
**    ****NOT RECOMMENDED in patients <12 years of age; HPA axis suppression; local adverse reactions included signs of skin atrophy (telangectasia, bruising, shininess) in cream and ointment but not lotion**
_**Betamethasone**_** (Lotrisone): NOT RECOMMENDED in patients <17 years of age; HPA axis suppression**

## Progress: Product Labeling with Significant Changes for Dosing or Risk

_**Gabapentin**_** ****(Neurontin):**** - adjunctive Rx in partial seizures - higher doses required in children less than 5 years of age in order to control seizures; new adverse events (e.g. hostility and aggression) identified in children less than 12 years**
_**Propofol**_** ****(Diprivan):**** -induction and/or maintenance of anesthesia - increased mortality when used for pediatric ICU sedation over standard sedative agents (9% vs. 4%); causality not determined;  serious bradycardia when propofol is concomitantly administered with fentanyl **
_**Sevoflurane**_** ****(Ultane):**** induction and maintenance of general anesthesia - rare cases of seizures reported in children without a previous seizure history **

## Progress: Product Labeling with Significant Changes for Dosing or Risk

_**Midazolam**_** ****(Versed):**** Sedation/anxiolysis/amnesia- higher risk of serious life-threatening situations in children with congenital heart disease and pulmonary hypertension and identified need to begin therapy at lower end of dosing range in this subpopulation to prevent respiratory compromise**
_**Etodolac**_** ****(Lodine):**** JRA sign/symptom relief (6yr-16yr)**
**  ****-higher dose (per kg basis) needed in younger children approximately 2 times the lower dose recommended in adults for effective treatment **
_**Fluvoxamine**_** ****(Luvox):**** Rx of OCD - higher doses in adolescents than previously recommended; girls ages 8-11 years may require lower doses.**

##  Progress: Product Labeling with Significant Changes for Dosing or Risk

_**Ribavirin/Intron A**_** – Rebetron**
**	****increased incidence of suicidal ideation or attempts among pediatric patients as compared with adults (2.4% vs. 1%); decreased rate of linear growth and weight gain during therapy, with general reversal in the post treatment period**
_**Pimecrolimus**_** – Elidel**
**	**** ****indicated for short-term and intermittent long-term therapy in mild-moderate atopic dermatitis in non-immunocompromised patients >2years of age; (NOT RECOMMENDED in patients <2 years of age for safety concerns including infections, pyrexia, and diarrhea) **

##   Progress: Identification of a Safety and Effectiveness Issue

_**Buspirone**_** – Buspar**** **
**Safety and effectiveness were NOT established in patients 6-17 years of age for treatment of General Anxiety  Disorder at doses recommended for adults;**
** ****AUC and Cmax of buspirone and active metabolite were  equal to or higher in children and adolescents as compared with adult PK parameters**

##  Progress: Product Labeling with Significant Changes for Dosing or Risk 

_**Famotidine**_** ****(Pepcid):**** gastroesophageal reflux**
**  ****Lower dose recommended in patients <3 months of age;**
**  ****Pediatric patients 0-3 months of age had clearance values 2 to 4-fold less than those in older patients and adults;**
**  ****In a clinical study of 35 pediatric patients <1 year of age, agitation was observed in 5 patients on Famotidine and resolved upon discontinuation of the drug.  **

## Progress: Product Labeling with Significant Changes for Dosing or Risk

_**Isotretinoin**_** ****(Accutane):****  severe recalcitrant ****	****	****nodular acne **
**	****Identified an increased incidence of back pain, ****	****arthralgia and myalgia in pediatric patients;**
**	****New general precautions subsection regarding ****	****pediatric patients with disorders of bone ****	****metabolism;**
**	****Adolescents who participate in sports with a ****	****repetitive impact may be at increased risk for ****	****bone related injuries;**
**	****Decreases in lumbar spine bone mineral density ****	****(BMD) and decreases in total hip BMD seen in ****	****open-label study**

## Lessons   Learned

## What Have We Learned

**Children are even more dynamic and variable than anticipated**
**Drug development historically has NOT required the same level of evidence for pediatrics as it has for adults**
**New legislation is having a profound impact on development of therapies for children**
**These pediatric initiatives have identified some gaps and how much we don’t know **

## ONGOING LESSONS LEARNED

- 1-	Pharmacokinetics are more variable than
- 	anticipated
- 2-Adverse reactions that are pediatric specific are being defined
- 3-Trial designs are being modified as we learn from submitted studies
- 4-Ethical issues have to be reassessed from the pediatric perspective

## Ethical Issues

- Pediatric Advisory Subcommittee Meetings have addressed:
- Patients vs. subjects in pediatric trials (11/15/99)
- Placebo controlled trials (9/11/00)
- Vulnerable pediatric populations (4/24/01)

## General Principles ICH  E-11

- Pediatric patients should be given medicines that have been properly evaluated for their use in the intended population
- Product development programs should include pediatric studies when pediatric use is anticipated
- Pediatric development should not delay adult studies nor adult availability
- Shared responsibility among companies, regulatory authorities, health professionals, and society as a whole**                                                 **

## FDA Web Page

- www.fda.gov

## Summaries of Pediatric Reviews on the Web

**Alendronate - Fosamax**
**Atovaquone and Proguanil- Malarone **
**Benazepril – Lotensin**
**Budesonide - Pulmicort**
**Ciprofloxacin - Ciloxan**
**Esmolol – Brevibloc**
**Fentanyl – Duragesic**
**Fexofenadine – Allegra**
**Fludarabine – Fludara**
**Fluticasone – Flonase**

**Fluticasone – Flovent**
**Fosinopril – Monopril**
**Glyburide and Metformin - Glucovance**
**Ofloxacin – Ocuflox**
**Orlistat - Xenical**
**Oxybutynin – Ditropan**
**Temozolomide - Temodar**
**Topotecan - Hycamtin**
**Venlafaxine - Effexor**
**(N=19)**

## Examples of Important Findings from Summaries Available on FDA Pediatrics Web (N=19)

_**Budesonide**_**: dose-dependent effect on growth velocity**
_**Fentanyl**_**: New warning – should be administered only in opioid tolerant pts 2 yrs and older**
_**Topotecan**_**: Safety & Efficacy not demonstrated in Pediatric Cancer population**
_**Fludarabine**_**: Data insufficient to establish efficacy in any childhood malignancy (N=62)**
_**Effexor**_**: Safety & Efficacy not established**