[Federal Register Volume 71, Number 79 (Tuesday, April 25, 2006)]
[Notices]
[Pages 23931-23936]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-6122]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


List of Drugs for Which Pediatric Studies Are Needed

ACTION: Notice.

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SUMMARY: The National Institutes of Health (NIH) is providing notice of 
the

[[Page 23932]]

``List of Drugs for Which Pediatric Studies Are Needed.'' The NIH 
developed the list in consultation with the Food and Drug 
Administration (FDA) and pediatric experts, as mandated by the Best 
Pharmaceuticals for Children Act. This list prioritizes certain drugs 
most in need of study for use by children to ensure their safety and 
efficacy. The NIH will update the list at least annually until the Act 
expires on October 1, 2007.

DATES: The list is effective upon publication.

FOR FURTHER INFORMATION CONTACT: Dr. Perdita Taylor-Zapata, National 
Institute of Child Health and Human Development (NICHD), 6100 Executive 
Boulevard, Suite 4A-01, Bethesda, MD 20892-7510, e-mail 
[email protected] or [email protected], telephone 
301-496-9584 (not a toll-free number).

SUPPLEMENTARY INFORMATION: The NIH is providing notice of the ``List of 
Drugs for Which Pediatric Studies Are Needed,'' as authorized under 
Section 3, Pub. L. 107-109 (42 U.S.C. 409I). On January 4, 2002, 
President Bush signed into law the Best Pharmaceuticals for Children 
Act (BPCA). The BPCA mandates that not later than one year after the 
date of enactment, the NIH in consultation with the FDA and experts in 
pediatric research shall develop, prioritize, and publish an annual 
list of certain approved drugs for which pediatric studies are needed. 
For inclusion on the list, an approved drug must meet the following 
criteria: (1) There is an approved application under section 505(j) of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)); (2) there 
is a submitted application that could be approved under the criteria of 
section 505(j) of the Federal Food, Drug, and Cosmetic Act; (3) there 
is no patent protection or market exclusivity protection under the 
Federal Food, Drug, and Cosmetic Act; or (4) there is a referral for 
inclusion on the list under section 505A(d)(4)(c); and additional 
studies are needed to assess the safety and effectiveness of the use of 
the drug in the pediatric population. The BPCA further stipulates that 
in developing and prioritizing the list, the NIH shall consider, for 
each drug on the list: (1) The availability of information concerning 
the safe and effective use of the drug in the pediatric population; (2) 
whether additional information is needed; (3) whether new pediatric 
studies concerning the drug may produce health benefits in the 
pediatric population; and (4) whether reformulation of the drug is 
necessary. For this year, we are providing an update on all of the 
drugs listed since the enactment of BPCA and a brief status report on 
each of the drugs (see Table 1).

                                     Table 1.--Current Status of Drugs That Have Been Listed by NIH (NICHD) for BPCA
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                  Written request/   Clinical trial     Current status and/or  clinical
             Drug                   Indication      Listing     Patent status           RFP           primary site               trial design
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acyclovir*....................  Herpetic                2005  On-patent........  FDA..............  N/A.............  Recommended for systematic review
                                 infections.                                                                           for potential re-labeling based
                                                                                                                       on published literature.
Ampicillin....................  Infection........       2004  Off-patent.......  NICHD............  N/A.............  Awaiting systematic literature
                                                                                                                       review for the development of
                                                                                                                       RFP.
Ampicillin/sulbactam..........  Infection........       2003  Off-patent.......  FDA..............  N/A.............  Inactive. Being reconsidered due
                                                                                                                       to feasibility issues.
Azithromycin (IV).............  Prevention of           2003  Off-patent.......  NICHD............  N/A.............  PK, safety, efficacy, tolerability
                                 bronchopulmonary                                                                      studies proposed. Currently
                                 dysplasia (BPD)                                                                       reviewing scientific issues.
                                 in neonates
                                 colonized with
                                 Ureaplasma
                                 urealyticum.
Azithromycin (PO).............  Prevention              2003  Off-patent.......  NICHD............  N/A.............  Inactive for this indication.
                                 treatment of                                                                          Initial Studies proposed
                                 Chlamydia                                                                             difficult to conduct due to
                                 conjunctivitis                                                                        feasibility issues. RFP released
                                 and pneumonia.                                                                        but no responses received.
                                                                                                                       Indication being reconsidered.
Baclofen*.....................  Oral treatment of       2003  On-patent........  FNIH, NICHD......  Negotiations      Plan is for Pharmacokinetics,
                                 spasticity from                                                     ongoing.          safety and efficacy studies. FNIH
                                 cerebral palsy.                                                                       considering funding.
Bumetanide....................  Diuresis.........       2003  Off-patent.......  FDA..............  N/A.............  Has been recommended for
                                                                                                                       consultation with scientific
                                                                                                                       community concerning diagnosis
                                                                                                                       and treatment of pediatric
                                                                                                                       hypertension, and the role of
                                                                                                                       diuretics in treatment.
Bupropion*....................  Treatment of            2004  On-patent........  FNIH, NICHD......  N/A.............  Recommended for systematic review
                                 Depression.                                                                           and consultation with scientific
                                                                                                                       community. Written Request
                                                                                                                       referred to FNIH.
Bupropion*....................  Treatment for           2004  On-patent........  FNIH, NICHD......  N/A.............  Written Request referred to FNIH.
                                 smoking
                                 cessation.

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Clonidine.....................  Autism...........       2005  Off-patent.......  FDA..............  N/A.............  Data gathering in process.
                                                                                                                       Indication being reconsidered due
                                                                                                                       to feasibility issues.
Clonidine.....................  Attention deficit       2005  Off-patent.......  FDA..............  N/A.............  Recommended for systematic review
                                 disorder.                                                                             and consultation with scientific
                                                                                                                       community. Reconsidered for
                                                                                                                       listing for 2006 under condition-
                                                                                                                       based approach.
Cyclosporine..................  Cardiac                 2005  Off-patent.......  FDA..............  N/A.............  Recommended for systematic review
                                 transplant                                                                            and consultation with scientific
                                 rejection.                                                                            community to discuss feasibility
                                                                                                                       and study design in cardiac
                                                                                                                       transplant patients.
Dactinomycin..................  Cancer...........       2004  Off-patent.......  NICHD............  NICHD             Clinical studies being conducted
                                                                                                     Partnership       by Children's Oncology Group in
                                                                                                     with NCI/         conjunction with NCI to better
                                                                                                     Children's        define safety, efficacy, PK.
                                                                                                     Oncology Group.
Daunomycin....................  Cancer...........       2006  Off-patent.......  FDA..............  N/A.............  WR in process.
Dexrazoxane*..................  Prophylaxis from        2005  On-patent........  FNIH, NICHD......  N/A.............  WR referred to FNIH.
                                 cardiotoxicity
                                 of doxorubicin.
Diazoxide.....................  Hypoglycemia.....       2003  Off-patent.......  FDA..............  N/A.............  Inactive. Being considered for
                                                                                                                       labeling based on literature
                                                                                                                       review.
Dobutamine....................  Hypotension, low        2003  Off-patent.......  FDA..............  N/A.............  Inactive due to issues with
                                 cardiac output                                                                        feasibility and clinical trial
                                 in neonates.                                                                          design.
Dopamine......................  Hypotension, low        2003  Off-patent.......  FDA..............  N/A.............  Inactive due to issues with
                                 cardiac output                                                                        feasibility and clinical trial
                                 in neonates.                                                                          design.
Eletriptan*...................  Migraine                2005  On-patent........  FNIH, NICHD......  N/A.............  WR referred to FNIH.
                                 headaches in
                                 adolescents.
Ethambutol....................  Tuberculosis.....       2005  Off-patent.......  FDA..............  N/A.............  Data gathering in process.
Flecainide....................  Ventricular             2005  Off-patent.......  FDA..............  N/A.............  Recommended for systematic review
                                 arrhythmia.                                                                           and consultation with scientific
                                                                                                                       community to determine
                                                                                                                       feasibility and study design.
Furosemide....................  Diuresis.........       2003  Off-patent.......  FDA..............  N/A.............  Recommend consultation with
                                                                                                                       scientific community concerning
                                                                                                                       diagnosis and treatment of
                                                                                                                       pediatric hypertension, and the
                                                                                                                       role of diuretics in treatment.
Griseofulvin..................  Tinea capitis....       2005  Off-patent.......  NICHD............  N/A.............  Development of RFP in progress.
Heparin.......................  Anticoagulation..       2003  Off-patent.......  FDA..............  ................  Already labeled for patients >= 1
                                                                                                                       kg.
Hydrochlorothiazide...........  Hypertension.....       2005  Off-patent.......  FDA..............  N/A.............  Recommend consultation with
                                                                                                                       scientific community concerning
                                                                                                                       diagnosis and treatment of
                                                                                                                       pediatric hypertension, and the
                                                                                                                       role of diuretics in treatment.
Hydrocortisone valerate         Dermatitis.......       2005  On-patent........  FDA..............  N/A.............  Inactive.
 ointment and cream*.
Hydroxychloroquine............  Connective tissue       2005  Off-patent.......  FDA..............  N/A.............  WR in process.
                                 disorders.
Hydroxyurea*..................  Sickle Cell             2006  On-patent........  FNIH, NICHD......  NICHD             PK, efficacy and safety studies
                                 Disease.                                                            Partnership       under way. FNIH considering
                                                                                                     with NHLBI.       funding.

[[Page 23934]]

 
Isofluorane...................  Maintenance of          2003  Off-patent.......  FDA..............  N/A.............  Awaiting results of Ketamine
                                 general                                                                               preclinical study and results to
                                 anesthesia.                                                                           be extrapolated.
Ivermectin....................  Scabies..........       2005  Off-patent.......  FDA..............  N/A.............  Formulation issues may preclude
                                                                                                                       study.
Ketamine......................  Sedation.........       2004  Off-patent.......  FDA..............  NICHD             Preclinical toxicology studies
                                                                                                     Partnership       under way. Clinical studies will
                                                                                                     with NCTR, FDA.   not be designed until the
                                                                                                                       preclinical studies are
                                                                                                                       completed.
Lindane.......................  Second line             2003  Off-patent.......  FDA..............  N/A.............  WR accepted by NDA holder.
                                 treatment of
                                 scabies.
Lithium.......................  Treatment of            2003  Off-patent.......  NICHD............  Case Western      PK, safety, efficacy, and
                                 mania in bipolar                                                    Reserve           tolerability studies to be
                                 disorder.                                                           University.       performed.
Lorazepam.....................  Treatment of            2003  Off-patent.......  NICHD............  Children's        PK, efficacy, and safety.
                                 Status                                                              National          Participants are currently being
                                 Epilepticus.                                                        Medical Center.   enrolled in PK study. Feasibility
                                                                                                                       issues with efficacy trial.
Lorazepam.....................  Sedation in the         2003  Off-patent.......  NICHD............  Case Western      Pharmacokinetics, safety, efficacy
                                 intensive care                                                      Reserve           by randomized double-blind active
                                 unit for                                                            University.       comparator study. Participants
                                 children on                                                                           are currently being enrolled.
                                 respirators.
Meropenem.....................  Infection........       2003  Off-patent.......  NICHD............  N/A.............  Currently in negotiations.
Methadone.....................  Neonates with           2005  Off-patent.......  FDA..............  N/A.............  Data gathering in process.
                                 opioid
                                 withdrawal.
Methotrexate..................  Cancer...........       2006  Off-patent.......  FDA..............  N/A.............  WR in process.
Metoclopramide*...............  Gastro-esophageal       2003  On-patent........  NICHD............  N/A.............  Inactive due to change in patent
                                 reflux.                                                                               status after listing.
Metolazone....................  Diuresis.........       2004  Off-patent.......  FDA..............  N/A.............  Recommend consultation with
                                                                                                                       scientific community concerning
                                                                                                                       diagnosis and treatment of
                                                                                                                       pediatric hypertension and the
                                                                                                                       role of diuretics in treatment.
Morphine*.....................  Analgesia........       2004  On-patent........  FNIH, NICHD......  Children's        Basic science studies are needed
                                                                                                     National          to determine the developmental
                                                                                                     Medical Center.   expression and function of opioid
                                                                                                                       receptors. FNIH considering
                                                                                                                       funding. Grant awarded by NICHD
                                                                                                                       in 2005 for study in neonates.
Piperacillin/tazobactam.......  Infection........       2003  Off-patent.......  FDA..............  N/A.............  Inactive. Being reconsidered due
                                                                                                                       to feasibility issues.
Pralidoxime...................  Organophosphate         2006  Off-patent.......  Pending..........  N/A.............  Recommended for systemic
                                 Poisoning.                                                                            literature review.
Promethazine..................  Nausea and              2003  Off-patent.......  FDA..............  N/A.............  Inactive. Under consideration for
                                 vomiting.                                                                             removal from list due to current
                                                                                                                       black boxed warning.
Rifampin......................  Methicillin-            2003  Off-patent.......  NICHD............  N/A.............  Inactive. Frequency of condition
                                 resistant                                                                             being reviewed.
                                 Staphylococcus
                                 aureus
                                 endocarditis.
Rifampin......................  Central nervous         2003  Off-patent.......  NICHD............  N/A.............  Inactive. Frequency of condition
                                 system shunt                                                                          being reviewed.
                                 infection.
Sevelamer*....................  Hyperphosphatemia       2005  On-patent........  FNIH, NICHD......  N/A.............  Written Request referred to FNIH.
                                 in chronic renal
                                 failure.

[[Page 23935]]

 
Sodium nitroprusside..........  Control of blood        2003  Off-patent.......  NICHD............  Duke and          Pharmacokinetics, safety, efficacy
                                 pressure.                                                           Stanford          by randomized double-blind
                                                                                                     Universities.     parallel group study design.
                                                                                                                       Participants are currently being
                                                                                                                       enrolled.
Spironolactone................  Diuresis.........       2003  Off-patent.......  FDA..............  N/A.............  Recommend consultation with
                                                                                                                       scientific community concerning
                                                                                                                       diagnosis and treatment of
                                                                                                                       pediatric hypertension and the
                                                                                                                       role of diuretics in treatment.
Vincristine...................  Cancer...........       2004  Off-patent.......  NICHD............  NICHD             Clinical studies being conducted
                                                                                                     Partnership       by Children's Oncology Group with
                                                                                                     with NCI/         National Cancer Institute to
                                                                                                     Children's        better define safety, efficacy,
                                                                                                     Oncology Group.   and PK.
Zonisamide*...................  Partial Seizures.       2005  On-patent........  FNIH, NICHD......  N/A.............  Written Request referred to FNIH.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Key: Drug is the generic name. Indication summarizes the indication or condition for which the drug is to be tested. Listing notes the year in which the
  drug was added to the list for testing. Patent Status is the on- or off-patent status of the drug. WR indicates a Written Request has been issued by
  the FDA and denotes where the request for and the processing of information currently resides (FDA, Foundation for NIH (FNIH) or NIH). Request for
  Proposals (RFP) indicates the RFP was published by NICHD and its current status. Clinical Trial Primary Site identifies the institution that has
  received the contract and has designed and implemented the preclinical or clinical protocol. Clinical Trial Design indicates in general terms the
  format of the proposed or actual preclinical or clinical trials and the phases of drug development being conducted. N/A refers to a process that is
  not applicable to a particular drug at this time. NHLBI is the National Heart, Lung, and Blood Institute; NCI is the National Cancer Institute; NIEHS
  is the National Institute of Environmental Health Sciences; NIMH is the National Institute of Mental Health; and NCTR is the National Center for
  Toxicological Research, part of the FDA.
* Indicates that a drug is currently on-patent and will be studied under a different funding mechanism than the off-patent process as described in the
  BPCA Legislation of 2002. For an on-patent drug, if the manufacturer has denied or failed to respond to the WR issued by the FDA in 120 days, the FDA
  refers the drug to the FNIH and requests that it be considered for FNIH support of pediatric studies. These drugs are also discussed at the annual
  scientific listing meetings.

    As previously stated, NICHD and the FDA have reviewed the progress 
of the drugs currently listed under BPCA in addition to a review of the 
entire listing process since its inception. There are drugs listed that 
are currently considered inactive or are being reconsidered due to 
multiple factors. Many of the factors for reconsideration are based on 
feasibility issues related to clinical trial design and the overall 
conduct of a study with that particular drug and/or indication--such as 
frequency of condition, statistical power, and safety. A drug may also 
be considered inactive if there has been a change in patent status 
since its original listing. These drugs will continue to be reevaluated 
throughout the year and an update will be provided no later than 
January 2007.
    Upon review of the BPCA listing process and based on our goal of 
improving pediatric therapeutics, NIH and FDA have decided to change 
our listing system to a therapeutic class-based approach. We believe 
that this approach will allow us to compare drugs within a therapeutic 
class (on- and off-patent) and give a broader description for the 
availability and use of these drugs in children. This will also allow 
us to obtain focused expertise in therapeutic areas that will 
subsequently give us more insight into feasibility and study designs. 
We drafted and categorized a preliminary list of drugs for the 2006 
Priority List based on the newly developed condition-based approach in 
an effort to identify areas in pediatrics that may contain gaps in 
knowledge in the area of therapeutic options. In developing this list, 
the NIH consulted with the FDA and experts in pediatric research and 
practice. The following are the conditions and the drugs discussed in 
our November 8-9, 2005, scientific meeting with experts in pediatric 
research and determined to need more scientific evidence before studies 
can be conducted in children: Attention Deficit and Hyperactivity 
Disorder (ADHD), Hypertension, Parasitic Diseases, Influenza, Cancer, 
Poisonings, and Sickle Cell Anemia. The drugs thought to be effective 
for treatment in each of these conditions were then prioritized based 
on the potential for providing a health benefit in the general 
pediatric population.
    ADHD was identified as a therapeutic area of interest because of 
its tremendous impact on the use of psychotropic medications in 
children--remaining the most commonly diagnosed behavioral disorder of 
childhood. Clonidine and Guanfacine were discussed as off-patent drugs 
that require further information in children. We determined that we 
need further discussion with the primary care and mental health 
communities to determine if studies of these agents are warranted for 
the treatment of ADHD or if the primary use of these agents is as 
adjunctive agents because of their sedative properties. In 2005, NICHD 
learned of a published report in Cancer Letters discussing possible 
cytogenetic effects in children treated with Methylphenidate 
(Cytogenetic effects in children treated with methylphenidate, El-Zein, 
R. et al., Cancer Letters xx (2005), 1-8.). NICHD developed a 
partnership with the National Institute of Environmental Health 
Sciences, the National Institute of Mental Health, the National Center 
for Toxicology Research, and the FDA to further evaluate this finding.
    Hypertension was identified as a therapeutic area of interest due 
to the recent ``Fourth Report on the Diagnosis, Evaluation, and 
Treatment of High Blood Pressure in Children and Adolescents,'' 
published in Pediatrics in 2004, which identified a need to determine a 
treatment strategy for high blood pressure in children, especially

[[Page 23936]]

with the increasing epidemic of obesity and obesity-related diseases in 
this country. The therapeutic drugs class of Diuretics (Bumetanide, 
Furosemide, Hydrochlorothiazide, Spironolactone) were discussed as off-
patent drugs that require further information in children. It was 
determined that we need further discussion with the pediatric experts 
involved in the development of the ``Fourth Report'' to determine if, 
and how, this particular class of drugs is used in primary pediatric 
hypertension and how a clinical study might be structured to address 
the complex issues that have recently arisen, such as obesity-related 
hypertension, in the diagnosis and treatment of this disease.
    Parasitic Diseases was identified as a therapeutic area of interest 
due to the tremendous impact on morbidity and mortality that these 
diseases have in children worldwide. Albendazole and Mebendazole were 
discussed as off-patent drugs that require further information in 
children. It was determined that we need to consult with domestic 
(Centers for Disease Control and Prevention) and foreign sources (World 
Health Organization) and other areas where these agents are 
predominantly monitored and used to obtain safety information. It was 
also determined that a liquid formulation of Albendazole would be 
advantageous for children of developing countries, in whom these 
diseases occur more often.
    Influenza was identified as a therapeutic area of interest because 
of the emerging threat of pandemic flu and the lack of dosing and 
efficacy data in our most vulnerable pediatric population--children 
less than 1 year of age. Amantidine and Rimantidine were discussed as 
off-patent drugs that require further information in children. It was 
determined that we need more information on the effectiveness of these 
drugs to provide additional insight into the use of these agents in the 
population of children less than 1 year of age.
    Cancer has been identified as an ongoing therapeutic area of 
interest because of the extensive morbidity and mortality that this 
disease continues to exhibit in pediatric patients of all ages.
    Poisoning was identified as a therapeutic area of interest due to 
the fact that injuries and poisonings remain as one of the top 5 
conditions that lead to the highest morbidity and mortality in young 
children and adolescents.
    Sickle Cell Anemia was identified as a therapeutic area of interest 
because of the extensive morbidity caused by, and paucity of treatment 
options for, this disease.
    The following are the conditions and drugs discussed in our 
November 8-9, 2005, scientific meeting with experts in pediatric 
research. We will add these conditions and drugs to the 2006 priority 
list for which pediatric studies are most urgently needed, along with 
their indications for use:

Treatment of Pediatric Cancers: Methotrexate and Daunomycin

    There is an urgent need for information regarding the 
pharmacokinetics and toxicity of daunomycin in obese children. There is 
an urgent need to evaluate the neurotoxicity and long-term cognitive 
outcomes of children receiving methotrexate.

Treatment of Sickle Cell Anemia: Hydroxyurea

    There is an urgent need for further pharmacokinetic and long-term 
safety data in the use of this drug in children with sickle cell 
anemia.

Treatment of Organophosphate Poisoning: Pralidoxime

    There is an urgent need for further dosing information of the use 
of this drug in children.
    For the coming year, NICHD is planning a series of discussions with 
experts in the field of pediatric cancers (NCI/COG), pediatric 
infectious diseases, emergency care in pediatrics (PECARN), pediatric-
based research networks (PBRN), pediatric hypertension, and pediatric 
psychiatry, in addition to our ongoing discussions with the other NIH 
Institutes and Centers. The goal of these discussions will be to 
specifically identify current gaps in scientific knowledge regarding 
research and treatment of these various pediatric conditions, with the 
ultimate goal of determining future approved drugs for which pediatric 
studies are needed. NICHD will continue scientific discussions and 
planning throughout 2006 and will provide an update in January 2007.

    Dated: April 11, 2006.
Elias A. Zerhouni,
Director, National Institutes of Health.
[FR Doc. E6-6122 Filed 4-24-06; 8:45 am]
BILLING CODE 4140-01-P