# Presentation: 388847

## FDA Perspective on FDAMA:Successes, Failures; Future Directions

**Rosemary Roberts, MD**
**Deputy Director**
**Office of Counterterrorism and Pediatric Drug Development**
**Center for Drug Evaluation and Research**
- May 3, 2004

## 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**

## Historical Perspective

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

## BENCHMARKSPediatric Drug Development 

**1977 – AAP statement concerning the need to conduct ****	****	****trials in children**
**1979 – FDA requires trials in children parallel to adult ****	****	****process**
**1994 – FDA requires sponsors to update label; ****	****	****	****introduces “extrapolation concept” **
**1997 – Congress passes FDAMA/Exclusivity Provision ****	****	****“Incentives” (voluntary)**
**1998 – FDA publishes Pediatric Rule (mandatory)**

## BENCHMARKSPediatric Drug Development (cont.)

**2002 –**** ****Congress passes Best Pharmaceuticals for Children Act (BPCA)**** **
**   ****renewed Exclusivity**
**   ****provides process for “off-patent” drug development **
**   ****public posting of results **
**   ****reporting of all AE’s for 1 year after Exclusivity granted**
**2003 – Congress passes Pediatric Research Equity Act (PREA)**
**Requires the study of drugs and biologics for pediatric population except in defined situations**
**Creates Pediatric Advisory Committee**

## Goal

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

**Goal**

## Process for the Study of On-Patent Drugs

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

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

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

**Referral to Foundation**
** ****for NIH**

**Industry has 180 days to respond**

**Industry submits**
**a Proposed Pediatric Study Request**

**FDA determines**
**public health benefit **
**to support pediatric studies**

** ****yes**

** ****yes**

** ****no**

**Process for the Study of ****On-Patent Drugs**

## Impact of Legislation(as of March 31, 2004)

**Proposals from Industry****	****	****346**
**FDA-issued Written Requests****	****284 ****	**
**Exclusivity Determinations****	****	****107****	**** **
**Exclusivity Granted****	****	****	****97**
**New Labels****	****	****	****	****	****70**

## Examples of Antihypertensive Drugs Granted Pediatric Exclusivity

**Beta-Blockers**
**Bisoprolol (Zebeta) β1  **
**Esmolol (Brevibloc) β1**
**ACE Inhibitors**
**Benazepril (Lotensin) **
**Enalapril (Vasotec) ****	****	****	**
**Fosinopril (Monopril) ****	****	**
**Lisinopril (Prinivil, Zestril)****	**
**Quinapril (Accupril)**

## Examples of Antihypertensive Drugs Granted Pediatric Exclusivity (cont.)

**Angiotensin II antagonists **
**Losartan (Cozaar)**
**Calcium channel blockers**
**Amlodipine (Norvasc) ****	****	**
**Felodipine (Plendil)****	**

## The True Scoop!

## Examples of Labeling Changes of Antihypertensive Drugs in Response to a Written Request 

## Fenoldopam (Corlopam)

**Intravenous dopamine D1 receptor agonist labeled in pediatric patients from 1 month to 12 years due to studies submitted in response to a WR**
**Pharmacokinetic (PK) parameters including weight-adjusted volume of distribution similar to adults**
**Efficacy:  0.2 mcg/kg/min was the  lowest dose at which decrease in mean arterial pressure (MAP) was observed.  Maximum effect was observed at 0.8 mcg/kg/min and higher doses generally produced no decrease in blood pressure**
**The most common adverse events reported in the short term (30 minutes) administration were hypotension and tachycardia.  These adverse events were also seen in adults**

## Enalapril (Vasotec) 

**PK, efficacy and safety information in patients 1 month to 16 yrs**
**PK parameters are consistent across the age groups and consistent with historic healthy adult data**
**The dose dependent  efficacy was consistent across all age groups.  The lowest doses studied 0.625 mg and 1.25mg (.02mg/kg QD) were not efficacious**
**Adverse event profile similar to adults**

## Benazepril (Lotensin)

**Information on dose, PK in pediatric patients 6-16 years of age. **
**The clearance rate was substantially higher in hypertensive children and adolescents than that of healthy adults**
**The terminal half-life (t****1/2****) in pediatric patients was one-third of that observed in adults**
**Information on preparation of a suspension**

## Losartan (Cozaar)

**Antihypertensive effects established in hypertensive patients 6-16 years of age**
**Not recommended for pediatric patients less than 6 years or with glomerular filtration rate <30mL/min due to no data**
**Information on PK and dose in pediatric patients 6-16 years of age**
**No relevant differences between the AE profile for pediatric patients compared to reported AEs for adults**
**Information on preparation of a suspension**

## Drug Research and Children

## Need for Age-Appropriate Formulations

**Many adult dosage forms such as tablets and capsules are inappropriate for infants and preschool children **
**As part of their studies for exclusivity, some sponsors develop an extemporaneous formulation**
**FDA hopes to include information on the preparation of the extemporaneous formulation in the product label in the absence of a suitable commercial age-appropriate formulation**

## Enalapril (Vasotec)

**Preparation of a 1mg/ml suspension instructions **** ****in label:**
**Add 50 mls of Bicitra****®**** ****to a plastic bottle containing ten 20mg tablets of Vasotec and shake for at least 2 minutes**
**Let concentrate stand for 60 minutes. Shake the concentrate for an additional minute**
**Add 150ml of Ora-Sweet SF ****TM  ****and shake the bottle to disperse the ingredients**
**Stable for 30 days when refrigerated**

## Amlodopine (Norvasc)

**PK, efficacy and safety information in patients 6 - 16 years**
**PK parameters including weight-adjusted clearance and volume of distribution are similar to adults**
**The magnitude of treatment effect is difficult to interpret - a blood pressure reduction of less than 5mm Hg systolic occurs with 5mg dose**
**Adverse event profile similar to adults**
** ****No suitable age-appropriate formulations for pediatric patients**

## Fosinopril (Monopril)

**Labeled for use in  pediatric patients > 50kg**
**PK parameters, efficacy and safety information for pediatric patients 6 – 16 years**
**PK parameters similar to adults**
**No dose response seen**
**Adverse event profile similar to adults**
**The formulations designed & used for pediatric studies are not available to the pediatric population.  No suitable formulations available for children less than 50kg; hence, the labeled use > 50 kg**

## 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**

**Process for the Study of ****Off-Patent Drugs**

## Examples of Off-Patent Antihypertensive Drugs Appearing on the Pediatric Priority List

**Thiazide Diuretics**
**Metolazone (Zaroxolyn) **
**Loop Diuretics**
**Bumetanide (Bumex)****	****	**
**Furosemide (Lasix) **
**Aldosterone receptor blockers **
**Spironolactone (Aldactone) **
**Direct Vasodilator**
**Sodium Nitroprusside:**
**    ****RFP from NICHD for post-operative hypertension**

## Ongoing Lessons Learned with Antihypertensive Drugs

**1-****	****Antihypertensive pharmacokinetics generally similar in adult and pediatric patients**
**2- Magnitude of effect appears smaller in pediatric patients than adults**
**3-In the absence of a suitable age-appropriate commercial formulation, the presence of extemporaneous formulation information in the product label is needed to allow for appropriate use in pediatric patients who cannot swallow tablets or capsules**

## 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 Bullets

**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.**

## Consensus Bullets (cont.)

**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.**

## Trial Designs

**A- Placebo controlled dose ranging study**
**B- Dose Ranging Study w/o placebo arm**
**C- Dose ranging study  (trial B) for at least 2 ****	****weeks then rerandomized withdrawal to ****	****placebo or prior dose**
**D- Forced titration to maximum tolerated ****	****dose with withdrawal to lower doses ****	****(including placebo)**

## Trial Designs (cont.)

**Of the 4 outlined trial designs, sponsors have conducted pediatric studies in patients hypertension using designs A,  C and D**

## “Further Improvement. . .”

**“****Further improvement in the treatment of hypertension in children will depend on such ongoing collaboration of pediatric  investigators with industry and government, all working to ensure that children with hypertension and other significant health conditions receive drugs that are safe, effective, and appropriate to their unique needs.”**
**Flynn JT,  AHC 2003; 16:889-891**

## FDA Web Page

- www.fda.gov

**FDA Web Page**

## Contact Information

_**Peds Line:**_
**(301) 594-7337**
_**Office Line:**_
**(301) 827-7777**
_**Internet:**_
**http://www.fda.gov/cder/pediatric**

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