# Presentation: 381125

## Impact of Pediatric Legislative Initiatives:USA

**Dianne Murphy, MD, FAAP**
**Director**
**Office of Pediatric Therapeutics **
**OC/ FDA**

## 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 on Harmonization

## 2002: Best Pharmaceuticals for Children Act (BPCA)

- Became law January 4, 2002
- Re-authorizes exclusivity incentive program under FDAMA for products with remaining patents or exclusivity marketing rights. ( “on-patent”)
- FDA determines needed studies and Issues Written Request for “on patent” products
- Major force resulting in new studies, new prescribing information and new labeling for pediatrics

## 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
- Establishes an additional mechanism for obtaining information in the pediatric populations for “off-patent” drugs
- Mandates Public dissemination of studies conducted as result of Exclusivity
- Mandates public review of safety reporting on products granted Exclusivity

## Goal

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

## FDA/NIH Partnership

**“****Off-Patent” products**

** ****Develop “List of Drugs for Which Pediatric  Studies ****	****	****	****are Needed”****                    **
**       ****-Long, iterative process**
** ****Input obtained from Advisory Committee, FDA ****	****Divisions, NIH Divisions, AAP, USP, and ****	****Experts**
** ****List of 12 drugs published in Federal Register 1/21/03, 8 ****	****drugs (8/13/03) and status of 20 drugs was updated 2/04.**
**NIH contracts are developed from this list. FDA issues Written Request to innovator &, if rejected, is sent to NIH**

## Update of the List

**NIH “owns” this process**
**FDA has major input**
**Includes publication in the Federal Register. Solicits public input.**

## 2003: Pediatric Research Equity Act (PREA)

- Became law December 3, 2003
- Legislation mimics Pediatric Rule of 1998
- Requires pediatric studies for certain applications
- Retroactive for all applications back to April 1, 1999
- Established Pediatric Advisory Committee

## Results

## Exclusivity Results:December 2004

- Products issued Written Requests:	298
- 		Number of studies requested:	 691
- Products with submitted studies:		116
- New Labels with Pediatric Information:  87
- Number of Children Involved:		43,461 (Not including 40,000 in Ibuprofen study)

## EXCLUSIVITY OUTCOMES:DECEMBER 2004

- PRODUCTS WITH NEW LABELS:  87
- NEW DOSING RECOMMENDATIONS:  17
- NEW SAFETY INFORMATION:  21
- Effectiveness NOT ESTABLISHED:  11

## Pediatric Rule: 1999- 2002

- The Pediatric Rule was enjoined in October 2002=FDA ceased enforcing
- Congress reinstated most elements of the Pediatric Rule in December 2003
- RESULTS: As of 2002
- 46 products had new labels
-   that were not related to Exclusivity

## What Pediatric Trials Have Taught(what we were doing before we knew better)

- Unnecessary Exposure to Ineffective Drugs
- Ineffective Dosing of an Effective Drug
- Overdosing of an Effective Drug
- Undefined Unique Pediatric AE’s
- Effects on Growth and Behavior

## Unnecessary Exposure to Ineffective Therapies

- Many therapies for treatment of depression
- Navelbine (Vinorelbine) for recurrent, solid, malignant tumors
- Detrol LA (Tolterodine) in pediatric patients 5-10 years of age
- Buspar (Buspirone) for general anxiety disorder
- Camptosar (Irinotecan) in previously untreated rhabomyosarcoma

## Inability to demonstrate 	Effectiveness : N=11      12/04	

- Temozolomide: Recurrent brain stem glioma, astrocytoma & other tumor
- Vinorelbine: No meaningful clinical activity in 46 patients with recurrent solid tumors
- Buspirone: GAD in 6-17 year olds types
- Fludarabine: Data insufficient to establish efficacy in any childhood malignancy
- Tolterodine LA: 2 randomized trials involving 710 children 5-10 years old

## Inability to demonstrate effectiveness (cont”d)

- Glyburide/Metformin: Combination not superior to either component
- Leflunomide: 68% of Arava vs 89% of comparator demonstrated improvement in polyarticular JRA
- Venlafaxine: for both MDD and GAD
- Irinotecan: Trial halted in untreated rhabdomyosarcoma because of high rate of progressive disease
- Sumatriptan: 5 trials in 12-17 year olds when compared to placebo
- Zolmitriptan: 12-17 year olds in placebo controlled trial

## Ineffective Dosing of an Effective Therapy

- Higher dosing required for adolescents taking Luvox (Fluvoxamine) and children <5 years taking Neurontin (Gabapentin)
- Higher clearance of Lotensin (Benazepril) in hypertensive children
- Double the clearance rate of Ultiva (Remifentanil) in neonates

## Overdosing of an Effective Therapy

- Dosing of Luvox (Fluvoxamine) in girls 8-11 years of age
- Reduced clearance of Arava (Leflunomide) in pediatric patients <40 kg
- Decreased clearance of  Pepcid (Famotidine) in infants 0-3 months of age and of Epivir (Lamivudine) for HIV in 1 week old neonates

## Undefined Unique Pediatric Adverse Effects

- Occurrence of rare seizures in patients without a prior history of seizures when exposed to Ultane (Sevoflurane)
- Hypopituitary Adrenal axis suppression with Diprolene (Betamethasone)
- Increase of suicidal ideation with Rebetron (Ribavirin/Intron A)

## New Adverse EventsExamples

- Accutane – bone demineralization
- Rebetron – increase in suicidal ideation & attempts
- Elidel – increase in infections, fever & diarrhea
- Ultane – rare cases of seizures without previous history
- Gabapentin – emotional lability, hostility and thought disorder
- Propofol – increased mortality in Peds ICU & serious bradycardia when used with Fentanyl
- Betamethasone – adrenal-axis suppression
- Antidepressants - suicidality signal

## Effects on Growth and Developmental Behavior

- Detrol LA (Tolterodine); Hyperactive behavior and attention disorder occurred 3 times as frequently in treated vs. placebo population
- Neurontin (Gabapentin); Neuropsychiatric AE’s identified in 3-12 year olds, including aggressive behavior and school problems

## Growth and Development

- Prozac (Fluoxetine): 19-week trial, effects on ht & wt were statistically significant
- Effexor XR (Venlafaxine): 18% vs 3.6% in placebo had wt loss; height increase 0.3 vs 1cm in placebo.

## Growth and Development

- Strattera (Atomoxetine): weight percentile decreased over 18 months of treatment and appeared to be correlated with poor metabolizers
- Ribavirin/Intron (Rebetron): Hepatitis C trial; decrease in rate of linear growth during 48 weeks of treatment. Reversal in 24 wks post-treatment

## What Have We Learned?

- Historically drugs been used in children WITHOUT the same level of evidence as has been obtained for adults and this data confirm such a approach is not good public policy
- Children are even more dynamic and variable than anticipated
- New legislation is having a positive impact on development of therapies for children
- These pediatric initiatives have identified some gaps and how much we don’t know

## ONGOING LESSONS LEARNED

- PK is more variable, even within the pediatric population, than anticipated
- Adverse reactions that are pediatric specific will not be defined without pediatric studies
- Trial designs are being modified as we learn from submitted studies
- Ethical issues have to be reassessed from the pediatric perspective
- Safety studies, of sufficient duration and longer term follow-up studies, remain problematic

## 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)
- Consensus statements: _[http://www.fda.gov/cder/pediatric/index.htm#advisory](http://www.fda.gov/cder/pediatric/index.htm#advisory)_
- 1st Subpart D Referral from IRB: Sept. 2004

## 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

**Link to Peds page**