# Presentation: 275483

## The Federal Government:  Recent Changes at FDA and the Implications for Pediatric Clinical Trials

- Rosemary Roberts, M.D.
- Deputy Director
- Office of Counter-Terrorism and Pediatric Drug Development
- Center for Drug Evaluation and Research

## Why the increased concern about children in research?

## Children in Research

- 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)

## Overview

- Historical Perspective
- Benchmarks
- Results of Legislation
- Health Impact
- Ethical Issues

## Historical Perspective

**Historical Perspective**

-  Tragedies in children lead to regulations
-  1902 - Biologics Control Act
- -diphtheria antitoxin contaminated with live tetanus bacilli
- 1938 - Food, Drug, and Cosmetic Act
- -sulfanilamide
- 1962 - Amendments
- -thalidomide

## “OFF-LABEL” USE

- Gilman, Gal: Clinical Pharmacokinetics, 1992

***“******OFF-LABEL” USE***

## Is “Off-label” use bad?

- Pediatric patient in “experiment” with every use
- not accruing data to learn how to administer the drug in a safe and efficacious manner

## “There is a moral imperative to formally study drugs in children so that they can enjoy equal access to existing as well as new therapeutic agents”PEDIATRICS Vol. 95 No. 2 February 1995

## BenchmarksPediatric Drug Development

- 1979 - Labeling Requirement
- 1994 - Final:  Pediatric labeling-extrapolation of efficacy
- 1997 - FDAMA/Exclusivity Provision
- 1998 - Final Rule:  Pediatric Studies Required
- 2001-  Subpart D- Final Rule: Additional Safeguards for Children in Clinical Investigations of FDA-regulated products
- 2002 - Best Pharmaceuticals for Children Act  (BPCA)

## New LegislationBPCA

- Best Pharmaceuticals for Children Act (BPCA) was signed into law  January 4, 2002
- As originally authorized in the 1997 FDAMA and re-authorized in BPCA, pediatric exclusivity applies to drugs* approved under Section 505 of the Federal Food, Drug and Cosmetic Act
-   ( *most biologic pharmaceuticals are approved under the Public Health Service  (PHS) Act and therefore do not qualify for pediatric exclusivity)

## BPCA

- On-Patent Drugs:
- Renews exclusivity incentives for conducting pediatric studies on drugs with existing exclusivity and patent protection
- Specifies a process of referral to the Foundation for the NIH

## BPCA

- Off-Patent Drugs: have no exclusivity or patent protection
- Requires development of a priority list of off-patent  therapies
- Establishes a procedure to study off-patent drugs in collaboration with NICHD

## BPCA

- Other Provisions
- Requires that written protocols take into account adequate representation of racial and ethnic minorities
- Specifies that a review of federal regulations be performed that considers how informed consent and assent are obtained and defined, how minimal risk is defined, and considers payment, compliance and role of IRBs in research involving children.

## BPCA

- Mandates an Office of Pediatric Therapeutics
- 2 special areas designated by BPCA (OPT)
- 	(A) Ethical issues regarding pediatric testing and  use of FDA-regulated products
- 	(B) post-marketing safety issues regarding use of FDA-regulated products in the pediatric population

## What has happened as a result of the legislation?

## Progress: Industry Response as of September 2002

- Proposals from sponsor  	             317
- FDA issued Written Requests         256
- Products with studies submitted       71
- Exclusivity Determined		   71
- Exclusivity Granted		   63
- New Labels			               40

## Progress: Studies Requested as of September 2002 

**    **Efficacy/Safety: 	210  (35%)
- PK/Safety: 		181  (30%)
- PK/PD: 		  	  56  (9%)
- Safety:			  98  (16%)
- Other: 		  	  56   (9%)
- TOTAL STUDIES REQUESTED:  601
-    WRITTEN REQUESTS ISSUED:   256

##   Progress: Pediatric Rule UpdateApril 1999 - March 2002

**•  **NDA and Supplement actions               404
- Waivers (complete or partial)        195
- Complete Waivers		           130
- Deferrals                                         172
- Completed Studies:		             94
**  **

## How have these studies impacted children?

## Progress: Health Impact of1997 FDAMA 

- Important information has resulted from the first 40 moieties for which we have labeling
- 33% (12/40) of recently labeled products had significant changes for dosing or risk
- 70% (28/40) of recently labeled products extended age and safety profile

## 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%);  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

- 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

## “There is a moral imperative to formally study drugs in children so that they can enjoy equal access to existing as well as new therapeutic agents”PEDIATRICS Vol. 95 No. 2 February 1995

## What have we learned?

- Children of various age groups may metabolize drugs at different rates compared to adults. Hence, the potential for under dosing or over dosing when extrapolating from adult doses
- Adverse events in children may not be predicted from the adult experience
- In the conduct of studies, constant attention to ethical issues must continue to be implemented.

## Ethical Issues

**•  **Children must not become a commodity
-  •  As of September 1, 2002, over 35,000 children could   potentially be enrolled in studies requested by the FDA.

## Ethical Issues

- FDA is not an IRB and the companies are not required to submit informed consent unless we ask for it
- Assent or informed consent is not always included in the review.
- Reviewers of pediatric studies are encouraged to request & review the informed consent if there are specific areas the agency has identified as important in ensuring the safe conduct of a study.

## 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)

## FDA Ethics Working Group Consensus Statement on the   Pediatric Advisory Subcommittee’s November 15, 1999 Meeting  (Patients vs. subjects in pediatric trials)

- 1) In general, pediatric studies should be conducted in subjects who may benefit from participation in the trial. Usually this implies the subject has or is susceptible to the disease under study. The Advisory Subcommittee utilized a broad definition of potential benefit. For example, any child has the potential to benefit from a treatment for otitis media.
- 2) In general, children who can give assent should be enrolled in a study in preference to, or prior to, children who cannot give assent. Careful consideration must be given to the importance of the potential benefit of the study. In certain circumstances, the potential benefit that may be derived from studying children who cannot give assent may override the preference for first enrolling assenting children.

## Pediatric Advisory Subcommittee’s November 15, 1999 FDA Ethics Working Group Consensus Statement on the Meeting (Patients vs. subjects in pediatric trials continued)

- 3) FDA should adopt the principles described in Subpart D-Additional Protections for Children Involved as Subjects in Research (_[45 CFR Subtitle A: 46.401-46.409](http://www.access.gpo.gov/nara/cfr/waisidx_99/45cfr46_99.html)_). This recommendation has been endorsed by the American Academy of Pediatrics and PhRMA.
- UPDATE
- Children’s Health Act of 2000 mandated that all regulated research be in compliance with Subpart D of part 46 of  Title 45 CFR  (IRB requirements addressing risk, assent of child, and permission of parent). FDA published an interim rule on April 24, 2001, effective April 29, 2001.

## General Principles*

- 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  *from ICH  E-11
- *E11 Clinical Investigation of Medicinal Products in the Pediatric Population
- December 2000  *** ***http://www.fda.gov/cder/pediatric

## To Find out More

**    **_***Internet***_***:***
***    ******http://www.fda.gov/cder/pediatric***
***    ***_***Peds Line***_***:***_***                                       ***_
***    ******(301) 594-7337                                         ***
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_***Subpart D: ***_***www.fda.gov/OHRMS/DOCKETS/98fr/cd0030.pdf***

## Slide 32

## Background Slides

## 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: 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

##   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: Products with Labeling Changes as of September 2002

**Lovastatin**
**Ibuprofen - Motrin**
**Ibuprofen - Advil**
**Midazolam***
**Abacavir**
**Ranitidine**
**Insulin glargine**
**Pemirolast**
**Azelastine **
**Oxaprozin**

**Isotretinoin***
**Lamivudine-HBV**
**Pimecrolimus***
**Brimonidine**
**Buspirone***
**Ibuprofen/ pseudoephedrine (Motrin)**
**Sotalol**
**Didanosine**
**Famotidine***

## Progress: Products with Labeling Changes as of September 2002 (continued)

**Ibuprofen/pseudophedrine**
**	****(Advil)**
**Ammonium lactate**
**Etodolac***
**Fluvoxamine***
**Sevoflurane***
**Atovaquone/proguanil**
**Betamethasone***
**Ribavirin/Intron A***
**Omeprazole**
**Mometasone**
**N=40**

**Stavudine**
**Gabapentin***
**Loratadine**
**Metformin**
**Enalapril**
**Propofol***
**Cromolyn**
**Calcitriol**
**Ketorolac**
**Montelukast**
**Tamoxifen**
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## FDA Ethics Working Group Consensus Statement on the Pediatric Advisory Subcommittee’s September 11, 2000 Meeting - (Placebo controlled trials)

- 1.    Placebo controlled trials may be acceptable if there are no approved or adequately studied therapies for children with the condition under study.  For serious or life threatening conditions, a Data Monitoring Committee (DMC) should be used with planned interim monitoring and stopping rules to permit early termination of a study that has shown clear evidence of effectiveness or unacceptable risks prior to completion of planned studies.  In studies of symptomatic therapy for less serious conditions, it may be helpful to build in individual patient discontinuation criteria, (early escape) so that exposure to ineffective treatment is limited.

## FDA Ethics Working Group Consensus Statement on the Pediatric Advisory Subcommittee’s September 11, 2000 Meeting (Placebo controlled trials cont’d.)

**2.  **Add on placebo controlled trials that do not deny any element(s) of the standard of care (SOC) are generally acceptable if individual patient study discontinuation criteria are defined.  These studies would require a DMC under the same circumstances as would any other trial.
- 3.  In placebo controlled studies of minor illnesses and symptomatic conditions, exposure to placebo and patient discomfort can often be minimized by use of a randomized withdrawal design, usually with defined individual patient discontinuation criteria (escape rules) so that the time of exposure to ineffective treatment is minimized.  These studies can be used to demonstrate long term effectiveness when a long-term placebo controlled trial would be unacceptable.  DMC’s generally are not needed for studies of symptomatic conditions but would be desirable if there were important safety concerns.

## DRAFT: Pediatric Advisory SubcommitteeMeeting April 24, 2001

- Proposed Consensus Areas
- 1.  Formulations appropriate for pediatric use should be developed to ensure safety and consistency in administration.  These formulations should be palatable and permit easy dose titration.  In some cases it would be desirable to have more than one formulation available (e.g., suspensions, chewable tablets, sustained release, transdermal).

## DRAFT Proposed Consensus Areas (cont’d.)

- 2.  In most cases, the child will be unable to identify expected and unexpected adverse events associated with antimuscarinics.  Caregivers will need to take responsibility for this and these assessments should be done in conjunction with regular evaluation by medical professionals.
- 3.  A major component of clinical trials should involve caregiver training for assessment of adverse events.  Tools for the assessment of safety and efficacy that will permit the development of an optimal dosing strategy should be developed in clinical trials.  If these tools are successful, then they should become part of the instructions for use (i.e., direct patient instructions, parent package information, "Dosage and Administration" section of labeling).

## DRAFT Proposed Consensus Areas (cont’d.)

- 3. The trial should reflect the clinical care setting, which is usually a team based, multidisciplinary approach (e.g., subspecialties such as Physical Medicine and Rehabilitation, Otolaryngology and Gastroenterology; Dentistry; and Nursing).