Science & Research

October 19, 2009 AAP Generics Presentation Accessible Text Version

Slide 1
American Academy of
Pediatrics Meeting: Section on
Clinical Pharmacology and
Therapeutics Program
Dr. Dianne Murphy
Director, Office of Pediatric Therapeutics, Office of the Commissioner, FDA
October 19, 2009

Slide 2

  • Background on Pediatric Drug Studies.
  • You cannot copy what is not there.
  • How does the generic process differ?
  • Why do I need to know about this?

Slide 3
What I Might Learn

  • Why you need to know about pediatric product development
  • How to obtain the latest information on pediatric therapeutics
  • What to look for on a generic label
  • How a generic drug might differ from the originator drug and how it will be the same

Slide 4

  • Products should be safely manufactured
  • Products should tell you what is in them
  • Products should not harm you
  • Products should do what they say they will do
  • Products to be used in children should be studied in children. (Not Bioequivalence)

Slide 5
FDA and Pediatric Health

  • Crises which involved children, resulted in laws benefitting adults
  • Information on use of therapeutics in children remained inadequate
  • Finally, in the late part of the 20st century, laws were passed to specifically address drug use in children

Slide 6
History of USA Pediatric Regulations/Legislation

  • FDAMA Pediatric Exclusivity (incentive for sponsor) 1997
  • Pediatric Rule Regulation (requirement) 1998
    (enjoined 2002 by court-FDA not have authority)
  • January 2002: FDAMA Exclusivity Sunsets
  • January 2002: (BPCA)
    • Best Pharmaceuticals for Children Act (incentive)
  • December 2003: (PREA)
    • Pediatric Research Equity Act (requirement)
  • October 2007: Sunset for BPCA & PREA
  • September 2007: Food & Drug Administration Amendments Act ( FDAAA) –now includes Devices

Slide 7
How a Drug Product might be studied in the pediatric population

  • Incentive Program (BPCA= Exclusivity, On-patent)
    • Written Request Process (if sponsor accepts)
    • Declined WR’s can be sent to NIH
  • Requirement Program (PREA-adult indication)
  • “Off-patent”or generic process(List and contracting process coordinated by NICHD)
  • Orphans Program
  • None of the above: usually for product to treat pediatric disease or condition.

Slide 8
What This Means for You

  • There is now legislation in Europe which is similar to the US legislation. This legislation means there are going to continue to be more pediatric therapeutic trials
  • There are going to be more labels with NEW PEDIATRIC INFORMATION
  • NICHD is focusing on Translational research and has funding for this type of research, including generic products
  • There is now legislation to encourage development of pediatric devices, including $2 million in FDA funding

Slide 9
Pediatric Legislative Accomplishments:

June 1998-September 2009

  • FDA Requests for studies: N= 372
  • Products with new labeling N= 355
  • Breakout of Labeling changes for 355
    • Expanded age:n= 258
    • Safety and efficacy not established: n= 57
    • New/enhanced safety information: n= 64
    • Specific dosing change/adjustment: n= 31
    • Pediatric formulation: n= 23
    • PK differences (pediatrics vs. adults): n= 7

Slide 10
US:10 years: Where are we?

  • Approximately 50% of products used in the pediatric population have had SOME subset of the pediatric population studied for some indication. (early data)
    • Over 335 products now have some pediatric information in the label
    • Specific Dosing Change/adjustment –31
    • S&E Not Established in Pediatrics –57
    • New or Enhanced Safety Information –64
  • Development for 57 of 335 product failed to demonstrate efficacy-usually no further development for individual product to determine why or answer evolved questions. Dose finding needs to establish the dose for the trial.
  • Neonates remain mostly unstudied
  • Ethical issues (examples): healthy children participation in trials, pre-clinical data relevance when no adult model, scientific rigor of trials.
  • Size of trials for safety assessments remain small and post marketing passive reporting remains an issue.
  • Device Product development is where we were in 1990’s

Slide 11
Areas of Ongoing Need for Research

  • Neonates
  • Devices
  • Endpoints
  • Apparent increase in pediatric for CNS adverse events for all types of products
  • Basic physiology of responses that may be causing us to not asses the correct endpoint

Slide 12
Recent data indicate that more children in the United States are taking prescription medications and that the annual percentage increase in spending on drugs is greater for children than for adults.

  • NEJM 347(18):2002; 1462-70.

Slide 13
NO Labeling for Pediatrics = NO generics

  • You cannot copy something that does not have an original
  • If the innovator product (reference labeled drug) did not have a pediatric indication the generic will NOT have any information for pediatrics
  • Therefore, the major problem still exists of getting products studied in children
  • There is a program at NIH for getting off-patent products, or products industry has declined to study after a Written Request from FDA, studied but we are still waiting for our first pediatric label from that program
  • Thus, we really need to get the products studied while they have patent or exclusivity rights

Slide 14
Assuming we have a pediatric indication in the innovator product

  • The generic product will have the same indication and information on pediatrics
  • A generic product may not be developed for all the dosing forms that the originator developed.
  • The generic product may have different excipients
  • The generic product may not taste the same if there are different excipients

Slide 15
The Big Difference

The approved reference drug is already known to be safe and effective. The generic is the same drug in a similar formulation. Safety and effectiveness do not need to be demonstrated again. The focus is on showing bioequivalence and pharmaceutical equivalence.

Slide 16
Brand Name Drug NDARequirements

  1. Chemistry
  2. Manufacturing
  3. Controls
  4. Labeling
  5. Testing
  6. Animal Studies
  7. Clinical Studies
  8. Bioavailability

Generic Drug ANDA Requirements

  1. Chemistry
  2. Manufacturing
  3. Controls
  4. Labeling
  5. Testing
  6. Bioequivalence

NDA vs. ANDA Review Process

Slide 17
Flowchart showing the various steps of the generic drug review process.

Slide 18
Manufacturing Compliance Programs

  • Purpose -To assure quality of marketed drug products
  • Mechanisms - Product Testing
    • Surveillance
    • Manufacturing/Testing Site Inspections (EERs)
    • Assess firm’s compliance with good manufacturing/laboratory processes

Slide 19
Chemistry Review

  • Components and Composition
  • Manufacturing and Controls
  • Batch Formulation and Records
  • Description of Facilities
  • Specifications and Tests
  • Packaging
  • Stability

Slide 20
Labeling Review

  • “Same” as brand name labeling
  • May delete portions of labeling protected by patents or exclusivity
  • May differ in excipients, PK data and How Supplied

Slide 21
Definition of Bioequivalence (BE).

The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug actions when administered at the same molar dose under similar conditions in an appropriately designed study. (from 21 CFR 20.1)

Slide 22
Approaches to Determining Bioequivalence

(21 CFR 320.24). In vivo measurement in biologic fluid. In vivo pharmacodynamic comparison. In vivo limited clinical comparison. In vitro comparison. Any other approach deemed appropriate by FDA.

Slide 23
Methods to Establish BE. In vivo measurements of active moiety or moieties in biological fluid. Rate is measured by Cmax. Cmax is the maximum observed concentration. Cmax tends to have higher variability. Measurements should be based on adequate sampling time-points.

Slide 24
Methods to Establish BE. In vivo measurements of active moiety or moieties in biological fluid. Extent of Absorptions measured by the Area Under Curve (AUC). AUCt is a measure of the total exposure of drug to the body from time zero to the last sampling time t, where t is the last time point with measurable concentration for individual formulation. AUC 0-inf is a theoretical measure of the total exposure of drug to the body of time zero to time infinity (AUC 0-inf).

Slide 25
Therapeutic Equivalence

Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions

Slide 26
Purpose of BE Review

  • Therapeutic equivalence (TE)
  • Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring
  • The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner

Slide 27
Regulatory Requirements


  • Adequate and well- controlled studies to demonstrate safety and efficacy
  • Studies usually done under IND


  • Same active drug substance in same amount as approved reference product
  • Acceptable inactive ingredients
  • Bioequivalent to RLD
  • Same label as RLD
  • No pre-review of data

Slide 28
Inactive Ingredients

  • If not the same as the RLD, need information to ensure that it will not change the safety and/or efficacy of the product
  • Usually acceptable if it has previously been used in another drug product for the same route of administration and in the same or higher daily amount

Slide 29
Generic Considerations

  • It is not fair to deny approval of a generic drug because the RLD has marginal safety or efficacy.
  • We cannot hold a generic to a higher standard than the RLD.
  • Safety and effectiveness have already been shown for the RLD. The generic has to meet bioequivalence criteria.

Slides 30
So Where are we now?

Slide 31
Clinical Assessment

  • If your patient is not seeming to have the same response to a generic therapy, what should you consider?
    • 1st: Did the patient get what you ordered
    • 2nd: Has anything else changed: other meds, new care giver, new diet ?
    • 3rd: Are other tests appropriate?
    • 4th: Is switching back helpful?

Slide 32
Main OGD website homepage (

Slide 33
Portion of OGD website with instructions to contact us (

Slide 34
Immediate OGD office contact info (

Slide 35
Recognition: Whose slides I have lifted and minds I have picked

  • Dr. Dena Hixon
  • Robert West, M.S., R.Ph
  • Timothy Ames, R.Ph, M.P.H.
  • Dr. Gary Buehler
  • All of the above individuals are in the Office of Generic Drugs within the Center for Drugs at FDA.

Slide 36
FDA website homepage (

Slide 37
Pediatrics Science & Research section on FDA's web site (

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