In: Drug

15 Jun 2010

After several years of clinical studies, important label changes have had an impact on the use of these drugs in children (Table 1).

2002 and 2003

In January 2003, the Secretary of DHHS revealed that 12 commonly prescribed drugs would now require clinical testing for use in children. The governmental agencies (DHHS and FDA) have planned to support the testing of the drugs starting this year. Pediatric drug testing is required, according to the BPCA, as signed into law in 2002. The law provides for DHHS agencies or pharmaceutical companies to sponsor pediatric tests of certain drugs that have already been approved for marketing but have never been tested specifically for their effects in children. These drugs are the dozen highest-priority agents needing pediatric review. DHHS contends that now is the time to understand fully the effects of these medications in children (younger than 21 years of age). Table 1 Label Changes Affecting Drug Use in Children

Drug Trade Name Reason for Label Change
Midazolam Versed® (Roche) Higher risk of serious life-threatening situations in children with congenital heart disease and pulmonary hypertension who need lower doses than predicted to prevent respiratory compromise
Etodolac Lodine® (Wyeth-Ayerst) Recognition of a need for a dose two to three times (in mg/kg) the dose used in adults for effective treatment of childhood arthritis
maleate (Solvay) Inadequate dosing of adolescents leading to ineffective therapy or no effect for obsessive-compulsive disorder while some girls, aged 8 to 11 years, were receiving potential over­doses with levels up to two times higher than expected
  (Pfizer) A need to use higher doses in children younger than five years of age in order to control seizures and new adverse events, such as hostility and aggression, identified in children younger than 12 years of age
Propofol Diprivan® (AstraZeneca) Increased mortality when used for pediatric sedation in intensive-care units; potential of concomitant administration with fentanyl to result in serious slowing of heart rate
Sevoflurane Ultane® (Abbott) New precaution about potential of product to cause seizures in children without a previous history of them

The list of drugs to be studied was developed by the NICHHD, part of the NIH, in consultation with the FDA and experts in pediatric research. The list is to be updated each year. After a drug has been approved for a particular use, physicians may prescribe it for other uses as deemed necessary. The 12 drugs on the list are currently prescribed for children, but their safety and effectiveness have been established only in adults. The drugs and their indications are summarized in Table 2. Each drug is expected to undergo approximately two years of testing, followed by an evaluation of test results by the FDA. The NICHHD will oversee the testing process and will consult closely with other NIH branches and the FDA. These drugs are no longer under patent and therefore are not the property of any single drug firm. For this reason, the BPCA provided for government sponsorship of these pediatric drug trials. At the same time, DHHS is taking separate action to test new drugs in children. The agency will seek new legislation from Congress to clearly establish the FDA’s authority to require pharmaceutical manufacturers to conduct appropriate pediatric clinical trials on new drugs and biologicals. Pursuing the legislative authority would be quicker and more decisive than legal appeals. On October 17, 2002, a federal court struck down the FDA’s effort to require drug manufacturers to conduct tests in children to determine whether new drugs would be safe and effective for pediatric use. In a challenge to the Pediatric Rule by the Association of American Physicians and Surgeons, Inc., the U.S. District Court for the District of Columbia said that Congress did not authorize the FDA to set a pediatric requirement when it passed the Food, Drug, and Cosmetic Act years ago. The court pointed out that many drugs are tested for safety and effectiveness in adults only, because of the difficulty in finding substantial pediatric populations to undergo tests, along with the ethical complications associated with testing new drugs on children.

Table 2 Drugs Requested by the U.S. DHHS for Clinical Evaluation in Pediatric Patients

Drug Indication
(Pfizer) Antibiotic; treats many types of bacterial infections
(Watson) Muscle relaxant; relieves spasms, cramping, and tightness of muscles caused by medical problems (e.g., multiple sclerosis, spinal injuries)
Bumetanide (Baxter Anesthesia) Diuretic; reduces swelling and fluid retention caused by various medical problems (e.g., heart or liver disease); antihypertensive agent; aids kidneys in eliminating unneeded water and salt from the body
Dobutamine (e.g., Dobutrex®, Eli Lilly) Heart stimulant
Dopamine Parkinson’s disease, schizophrenia
(Aventis) Diuretic; reduces swelling and water retention
Heparin Antithrombotic agent; decreases clotting ability of blood; helps prevent harmful clots from forming in blood vessels
Lithium (e.g.,  GlaxoSmithKline; Lithobid®,Solvay) Bipolar disorder (extreme mood changes from depression or anger to elation)
Rifampin (Rifadin®, Rifamate®, Rifater®, Aventis) Tuberculosis; also treats carriers of meningitis-causing bacteria (in combination with other medications)
Sodium nitroprusside (Baxter Anesthesia) Hypertension
(Geneva, Mylan) Hypertension
Lorazepam (Ativan®,Wyeth-Ayerst) Anxiety

Although the court ruling presented a problem for the FDA, the agency still actively encouraged manufacturers to conduct pediatric testing of new drug entities. Meanwhile, the FDA could take its case to appeals courts and possibly even to the Supreme Court, or Congress could amend the Food, Drug, and Cosmetic Act to give the FDA specific authority to require pediatric testing. Currently, the incentive for voluntary pediatric testing by drug companies in return for market protection remains in place under the BPCA, Public Law (P.L.) 107-109, passed by Congress in 2002. DHHS will seek new legislation from Congress to clearly establish the FDA’s authority to require pharmaceutical manufacturers to conduct appropriate pediatric clinical trials on new drugs and biologicals. In 2003, the Secretary of DHHS said that legislative authority would be pursued because it was quicker and more decisive than legal appeals. He did not want to go back to the U.S. District Court for the District of Columbia for an appeal of its negative decision of the Pediatric Rule.

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