SAFETY EFFORTS IN PEDIATRICDRUG DEVELOPMENT -- SAFETY EFFORTS IN PEDIATRIC DRUG DEVELOPMENT -- CHAPTER SOURCES -- CONTENTS -- PREFACE -- FDA'S AUTHORITY TO ENSURE THAT DRUGSPRESCRIBED TO CHILDREN ARESAFE AND EFFECTIVE -- SUMMARY -- INTRODUCTION -- NEED FOR PEDIATRIC LABELING -- MANUFACTURERS HAVE BEEN RELUCTANTTO TEST DRUGS IN CHILDREN -- THE CURRENT LAWS EVOLVED FROM EARLIER ATTEMPTS -- 1979: Rule on Drug Labeling -- 1994: Revised Rule -- Food and Drug Administration Modernization Act of 1997 -- 1997: The Pediatric Rule -- BPCA 2002 AND PREA 2003: LAWS TO ENCOURAGEPEDIATRIC DRUG RESEARCH -- The Best Pharmaceuticals for Children Act of 2002 -- Pediatric Exclusivity -- FDA-NIH Collaboration -- Off-patent products -- Sponsor-declined studies -- Other Provisions -- Pediatric Research Equity Act of 2003 -- New Applications. -- Products on the Market -- Other Provisions -- Comparison of BPCA and PREA -- PEDIATRIC PROVISIONS IN FDAAA 2007 -- Best Pharmaceuticals for Children Act of 2007 -- Pediatric Exclusivity -- Internal Review Committee -- Study Requirements -- Reporting, Labeling, and Timing -- Adverse Event Reports -- Required Public Notice -- Dispute Resolution -- FDA-NIH Collaboration -- Off-Patent Products -- Sponsor-Declined Studies -- Other Provisions -- Pediatric Research Equity Act of 2007 -- New Applications -- Products on the Market -- Other Provisions -- BPCA AND PREA IMPACT ON PEDIATRIC DRUG RESEARCH -- Best Pharmaceuticals for Children Act -- On-Patent Drugs -- NIH Route for Off-Patent Drugs and On-Patent Drugs for WhichManufacturersDeclined FDA's Requests for Study -- GAO Study -- Pediatric Research Equity Act -- FDA Activities -- RECURRING ISSUES FOR CONGRESS -- Exclusivity -- Cost -- Labeling -- Enforcement -- Sunset -- Concluding Comments -- AUTHOR CONTACT INFORMATION -- End Notes.

GUIDANCE FOR INDUSTRY1 NONCLINICALSAFETY EVALUATION OF PEDIATRIC DRUGPRODUCTS -- I. INTRODUCTION -- II. BACKGROUND -- III. GENERAL CONSIDERATIONS REGARDING THE NEED FORSTUDIES IN JUVENILE ANIMALS -- A. Differences in Drug Safety Profiles between Mature andImmature Systems -- B. The Utility of Studies in Juvenile Animals -- IV. GENERAL CONSIDERATIONS FOR EVALUATION OFPHARMACEUTICALS IN JUVENILE ANIMALS -- A. Scope of Nonclinical Safety Evaluation -- B. Timing of Juvenile Animal Studies in Relation to ClinicalTesting -- 1. Long-Term Exposure in Pediatric Subjects -- 2. Short-Term Exposure in Pediatric Subjects -- 3. Insufficient Clinical Data to Support Initiation of Pediatric Studies -- C. Issues to Consider Regarding Juvenile Animal Studies -- 1. Developmental Stage of Intended Population -- 2. Evaluating Data to Determine When Juvenile Animal Studies Should BeUsed -- 3. Considering Developmental Windows When Determining Duration ofClinical Use -- 4. Timing of Exposure -- 5. Selection of Study Models -- V. GENERAL CONSIDERATIONS IN DESIGNING TOXICITYSTUDIES IN JUVENILE ANIMALS -- A. Types of Studies -- B. Animals -- 1. Species -- 2. Age -- 3. Sex and Sample Size -- C. Exposure -- 1. Route of Administration and Dosage Formulation -- 2. Frequency and Duration of Exposure -- 3. Dose Selection -- D. Toxicological Endpoints and Timing of Monitoring -- VI. GENERAL CONSIDERATIONS FOR APPLICATION OFJUVENILE ANIMAL DATA IN RISK MANAGEMENT -- A. Use in Clinical Trials -- B. Use in Product Approval -- VII. HUMAN-TO-ANIMAL COMPARISONS OFDEVELOPMENTAL PERIODS -- REFERENCES -- End Notes -- PEDIATRIC DRUG RESEARCH: STUDIESCONDUCTED UNDER BESTPHARMACEUTICALSFOR CHILDREN ACT -- WHY GAO DID THIS STUDY -- WHAT GAO FOUND -- ABBREVIATIONS -- RESULTS IN BRIEF -- BACKGROUND -- BPCA Process -- BPCA Provisions for Pediatric Drug Studies Declined by DrugSponsors.

Making Labeling Changes under BPCA for On-Patent Drugs -- DRUG SPONSORS AGREED TO STUDY THE MAJORITY OF ONPATENTDRUGS WITH WRITTEN REQUESTS UNDER BPCA,BUT NO STUDIES WERE CONDUCTED WHEN DRUGSPONSORSDECLINED THE WRITTEN REQUESTS -- Drug Sponsors Agreed to Conduct Pediatric Drug Studies for MostOn-Patent Drugs with Written Requests Issued under BPCA -- FNIH Had Not Funded the Study of Any On-Patent Drugs inChildren -- MOST DRUGS GRANTED PEDIATRIC EXCLUSIVITY UNDERBPCA HAD LABELING CHANGES, BUT THE PROCESS FORMAKING CHANGES WAS SOMETIMES LENGTHY -- Most Drugs Granted Pediatric Exclusivity Had Labeling Changes -- Labeling Changes for Drugs Studied under BPCA Had ImportantImplications for Pediatric Use -- The Process for Reviewing Study Results and Approving LabelingChanges Was Sometimes Lengthy, Particularly When FDARequired Additional Information from Drug Sponsors -- DRUGS STUDIED UNDER BPCA ADDRESS A WIDE RANGE OFDISEASES, INCLUDING SOME THAT ARE COMMON, SERIOUS,OR LIFE THREATENING TO CHILDREN -- AGENCY COMMENTS AND OUR EVALUATION -- APPENDIX I: SCOPE AND METHODOLOGY -- APPENDIX II: FDA AND NIH EFFORTS TO ENCOURAGE THESTUDY OF DRUGS IN NEONATES SINCE PASSAGE OF BPCA -- NIH Workshops -- NIH Initiatives -- Pediatric Drug Studies Requiring the Study of Neonates -- APPENDIX III: NIH EFFORTS TO SUPPORTPEDIATRIC DRUG STUDIES -- NIH Funding -- Pediatric Pharmacology Research Units -- Meetings and Forums -- APPENDIX IV: STUDIES OF OFF-PATENT DRUGS UNDERBPCA -- Written Requests for Studies of Off-Patent Drugs under BPCA -- Funding for Studies of Off-Patent Drugs under BPCA -- APPENDIX V: STATUS OF PEDIATRIC DRUG STUDIESREQUESTED BY FDA -- Written Requests Issued under BPCA Compared to FDAMA -- Reasons for Decline in Written Requests Issued and Acceptedunder BPCA Compared to FDAMA -- APPENDIX VI: COMPLEXITY OF COMPLETEDPEDIATRIC DRUG STUDIES.

APPENDIX VII: STRENGTHS OF AND SUGGESTEDCHANGES FOR BPCA -- Strengths of BPCA Identified by FDA and NIH Officials -- Suggestions for Changes to BPCA -- APPENDIX VIII: COMMENTS FROM THE DEPARTMENTOF HEALTH AND HUMAN SERVICES -- APPENDIX VIII. (CONTINUED) -- APPENDIX VIII. (CONTINUED) -- APPENDIX IX: GAO CONTACT AND STAFFACKNOWLEDGMENTS -- GAO Contact -- Acknowledgments -- GAO's Mission -- Obtaining Copies of GAO Reports and Testimony -- Order by Mail or Phone -- TO REPORT FRAUD, WASTE, AND ABUSE IN FEDERALPROGRAMS -- CONGRESSIONAL RELATIONS -- PUBLIC AFFAIRS -- End Notes -- PEDIATRIC DRUG RESEARCH: THE STUDYAND LABELING OF DRUGS FOR PEDIATRICUSE UNDER THE BEST PHARMACEUTICALSFOR CHILDREN ACT -- WHY GAO DID THIS STUDY -- WHAT GAO FOUND -- BACKGROUND -- BPCA Process -- BPCA Provisions for Pediatric Drug Studies Declined by DrugSponsors -- Making Labeling Changes under BPCA for On-Patent Drugs -- DRUG SPONSORS AGREED TO STUDY THE MAJORITY OF ONPATENTDRUGS WITH WRITTEN REQUESTS UNDER BPCA,BUT NO STUDIES WERE CONDUCTED WHEN DRUGSPONSORS DECLINED THE WRITTEN REQUESTS -- FEW OFF-PATENT DRUGS HAVE BEEN STUDIED UNDERBPCA -- MOST DRUGS GRANTED PEDIATRIC EXCLUSIVITY UNDERBPCA HAD LABELING CHANGES, BUT THE PROCESS FORMAKING CHANGES WAS SOMETIMES LENGTHY -- GAO's Mission -- Obtaining Copies of GAO Reports and Testimony -- Order by Mail or Phone -- TO REPORT FRAUD, WASTE, AND ABUSE IN FEDERALPROGRAMS -- CONGRESSIONAL RELATIONS -- PUBLIC AFFAIRS -- End Notes -- INDEX.