# Presentation: 450297

## Pediatric Issues in Clinical Trials

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

**August 26, 2004**

## OVERVIEW

- History: lack of pediatric trials
- Initiatives which changed process
- Scientific Issues:
- Extrapolation
- Bridging studies
- Safety studies
- Endpoint & Validation issues

## OVERVIEW (cont.)

- Ethical Issues:
- Lack of direct benefit
- Placebo-controlled trials
- Vulnerable pediatric populations
- Current Status

## The Knowledge Gap in Pediatric Therapeutics

- How did we get to this state of ignorance?
- Why was it acceptable that a population that is growing, developing and inherently highly variable would not be studied while the more stable, not growing and less variable adult population was?

## The Knowledge Gap: Possible Reasons

- Ethical concerns
- Limited populations for certain diseases
- Difficulties in conducting trials in pediatrics:  logistical to technical reasons
- Belief dosing could be determined by weight based calculations (“little adults”)
- Lack of accepted endpoints and validated pediatric assessment tools
- Limited marketing potential compared to adults

## Pediatric Benchmarks

- 1977 AAP, Committee on Drugs
- 1979 Pediatric Use 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 Pediatric Exclusivity
- Mandated public review of safety reporting on products granted Pediatric  Exclusivity

## 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 of administration
- 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

## Extrapolation of Efficacy(from adults or older pediatric population)

- If the course of the disease and the effects of the drug are sufficiently similar in adults and pediatrics, . . . may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults, usually supplemented with other information obtained in pediatric patients. . .

## Examples of Extrapolation

- Antiretrovirals for HIV
- 	despite differences in acquisition, manifestation and laboratory criteria of disease stage, the etiologic agent, mechanism, viral load and immune suppression are considered sufficiently similar
- Antihistamines
- 	Pathophysiology and manifestations sufficiently similar to require only pharmacokinetic and safety trials

## Example 1: Pediatrics Bridging

- Anti-arrhythmic with class II (beta-blocker) and class III properties
- Approved indication in adults:  Life threatening ventricular arrhythmias
- Sponsor sought same indication in pediatrics
- Biomarker for Efficacy:  QTc change

## Studies in Pediatrics with SVT/VT

- Multi-center
- 70 mg/m2 single-dose
- Only PK
- 10 plasma samples

- Multi-center
- Escalating doses
- 10, 30, 70 mg/m2 q8h
- PK / QTc, RR
- 4 plasma samples

**PK Study****	****	****	****PK/PD Study**

- Age groups: neonates, infants, pre-school, school-age

## PK in Pediatrics

***Per BSA dosing for peds with BSA>0.33 m******2****** offers comparable ***
***exposure as in adults***

- 0.33 m2

## Safety Studies

- Ibuprofen
- Ages 2 to 6 months; over 40,000 children evaluated
- Cromolyn-Nasalcrom
- In addition to dose finding studies, assessment of safety and compliance data gathered for 2 to 6 year olds
- Betamethasone – various types of _topicals_
- Open label studies consistently demonstrated HPA Axis suppression; the younger the age group, the greater the proportion of patients suppressed

## End Point & Validation Issues

- Endpoints for children may be different
- Example: young children not being able to perform pulmonary function tests so other endpoints must be utilized
- Assessment scales need validation as to predictability of endpoint
- Example: pain scale use in neonatal population

## 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

## Consensus Statement-1999

**FINAL**
- On November 15, 1999, the Pediatric Advisory Subcommittee met and was supplemented by a number of ethicists. The committee was charged with providing guidance on the ethical consideration for the conduct of pediatric clinical trials, namely the role of pediatric volunteers who do not have the disease under study.
- The FDA Pediatric Ethics Working Group has summarized the discussion of the Pediatric Advisory Subcommittee meeting on ethical issues relating to trials involving "normal volunteers." The consensus areas of the discussion are as follows:
- 	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.

## Consensus Statement-1999 (cont.)

**	**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.
- 	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. Note: The Pediatric Ethics Working Group agreed that it is appropriate for FDA to consider adoption of a similar statement. A committee has been established to address this issue.

## Consensus Statement-2000

**FINAL**
- On September 11, 2000, the Pediatric Advisory Subcommittee met and was supplemented by a group of ethicists and international experts. The subcommittee was charged with providing guidance on the ethical considerations of placebo-controlled trials in the pediatric population.
- The FDA Pediatric Ethics Working Group has summarized the discussion of this subcommittee meeting. The consensus areas of discussion are as follows:

## Consensus Statement-2000 (cont.)

**FINAL**
- 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.

## Consensus Statement-2000 (cont.)

**FINAL**
- 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.
- 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.

## Consensus Statement-2001

- FDA Pediatric Ethics Working Group Consensus Statement on the Pediatric Advisory Subcommittee’s April 24, 2001 Meeting
- On April 24, 2001, the Pediatric Advisory Subcommittee met and was supplemented by a number of ethicists, clinicians who care for patients with special needs, and representatives from the cerebral palsy (CP) advocacy community. The subcommittee was charged with providing guidance on the development of antimuscarinic products to control drooling in children with neurologic impairment, especially the development of an optimal dosing strategy that balances benefit and risk.
- The FDA Pediatric Ethics Working Group has summarized the discussion of the Pediatric Advisory Subcommittee meeting on development of these products. The consensus areas of discussion were as follows:

## Consensus Statement-2001 (cont.)

- With regard to study design and implementation:
- 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).
- 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.
- 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).

## Consensus Statement-2001 (cont.)

- 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).
- Comments regarding the ethical conduct of clinical trials in vulnerable populations:
- Children with disabilities in the care of their parents or legal guardians and who are incapable of effective communication, should not be excluded from clinical trials based solely on their disability.
- As described in 45 CFR 46.406, patients from vulnerable populations with the condition of interest should have access to clinical trials directed at their disease or condition.

## Results

## RESULTSJune, 2004

_**Exclusivity Initiative**_
**New labels: ****	****	****	****	****	****76**
**Products: studies submitted:****	**** ****	****108****	**
**Products Issued a WR: ****	****	****	****291**
_**Off-patent Drugs**_
**WRs issued by FDA: ****	****	****	****7**
**RFPs published by NIH:****	****	****	****3**
_**# of Pediatric Patients**_**	****	****	****	****42,249**

## 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Examples

- Prozac (Fluoxetine): in a 19-week trial effects on ht & wt were statistically significant and new directions for monitoring placed in label
- Strattera (Atomoxetine): weight percentile decreased over 18 months of treatment and appeared to be correlated with poor metabolizers

## 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

## New Dosing RecommendationsExamples

- Neurontin (Gabapentin): higher doses in children < 5 years
- Lodine (Etodolac): higher than expected doses required in younger children (2x the lower dose in adults
- Luvox (Fluvoxamine): adolescents need higher doses than previously recommended and girls 8-11 may have been overdosed

## Lessons   Learned

## What Have We Learned

- Drugs have historically been used in children WITH OUT the same level of evidence as has been obtained for adults and this 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

- 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

## 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**

## To Contact Us:

_**OPT Line:**_
**	****	****301-827-1996**
**	****	****301-827-1017 (fax)**
_**OCTAP Line:**_
**	****	****301-827-7777**
_**Peds Line:**_**	**
**	****	****301-594-PEDS**
_**Internet:**_**	**
**	****	****www.fda.gov/cder/pediatrics**
_**Email:**_**	**
**	****	****opt@fda.gov**
**	****	****pdit@cder.fda.gov**

**BACK-UP**

## 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

## Informed Consent: Basic Elements

- Study involves research
- Purpose
- Expected duration
- Description of procedures/experimental components
- Reasonably foreseen risks or discomforts
- Reasonably foreseen benefits to the subject or to others
- Appropriate alternatives

- Confidentiality
- Compensation in general and for research-related injury
- Point of contact
- Participation is voluntary

## Informed Consent: Additional Elements

- The particular procedure may involve risk to the subject (embryo or fetus)
- Circumstances of termination
- Costs to the subject

- Consequences of withdrawal
- Significant new findings may be communicated
- Approximate number of subjects

## Assent

- Respect for persons
- Provides information
- Offers shared decision-making
- Honors dissent
- Allows independent decision-making as appropriate

## Loratadine (Claritin)

- From a well-established therapeutic class,
- Antihistamines
-  class previously approved in pediatrics (as low as 18 months OTC)
- Original agreement with the sponsor was for clinical studies in 188 patients, ages 6 – 12 years, at adult dose based on PK
- Studies examined traditional endpoints – patient-rated nasal and non-nasal symptom scores

## Loratadine (Claritin)

- While the data from the clinical studies showed comparable safety experience to adults, the efficacy data were negative
- Division considered in light of pediatric paradigm, other information
- Disease is substantially the same
- Mechanism of action/expected response is substantially the same
- Could study have failed due to subjective endpoints and reporting???
- Antihistamine trials frequently fail in adults
- Drug had good safety record and peds data showed no unexpected new issues
- Antihistamines broadly used and even approved for pediatrics

## Application of Extrapolation

- Product labeling of imitinab mesylate (Gleevec) for pediatric chronic myelocytic leukemia
- Basis was adult efficacy data with pediatric dosing data and proof of concept
- Principle- combination of genetics, immunophenotyping, morphology, and clinical history