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    By Passing drug test.

    Pediatric R.Ph.s buoyed by new proposals for drug testing

    Medications are administered to sick children in the United States every day. Yet many of these products have not been proven safe and effective for pediatric use. One would think any move toward that assurance would meet with wholehearted support. However, when President Clinton proposed last August that pharmaceutical companies be required to determine the safety and proper dosage of all drugs in children prior to Food & Drug Administration approval, questions were raised about whether all drugs need such testing--and, if not all drugs, which ones. Some manufacturers say testing on children might be unethical, would be expensive, and could delay getting drugs to market.

    The proposed change is in addition to the FDA Modernization & Accountability Act of 1997, passed in early November, which provides incentives for research into children's drugs. Because the President announced proposed mandatory pediatric testing during negotiations before the act's passage, the portion of the act pertaining to pediatric drugs was amended to give manufacturers the benefit of six months of market exclusivity for their products if they conduct mandatory tests.

    Widespread off-label use

    The problem of untested pediatric drugs is a major one. According to Dave Grinder, M.S., R.Ph., director of pharmacy at All Children's Hospital, St. Petersburg, Fla., 60% of all drugs have no indication for use in children under age 12. Grinder is president of the Pediatric Pharmacy Advocacy Group. Hank Wedemeyer, M.S., R.Ph., of Paramount Data, L.L.C., Littleton, Colo., and president-elect of PPAG, believes the percentage may be over 70%.

    Robert M. Ward, M.D., chair of the American Academy of Pediatrics Committee on Drugs, told the FDA that 95% of drugs used in neonatology are used off label. And "100% of kids receive a drug each year," he said. These include vaccinations, antibiotics, pain relievers, and antipyretics.

    Although some protease inhibitors for treating AIDS have been approved for use in children, none has been approved for children under age two, said John Rodman, Pharm.D., vice chairman of pharmacy service at St. Jude Children's Research Hospital, Memphis. When diseases occur in children for which there is not an approved drug, adult drugs are used, with their dosages adjusted to fit a child. Although most such drugs are used safely, drug metabolism is different in children under age two; some drugs need different pediatric dosages based on weight, and some may not work at all, he said. "Children have been called 'therapeutic orphans.' "

    "The main reason [for this] is the huge expense of testing for pharmaceutical companies and the limited return from pediatric drugs," Wedemeyer said. Two areas of special need are AIDS and cardiac problems in children.

    Using a drug off label on a child means pharmacists and physicians have to calculate the proper dosage based on the weight and age. In addition, premature infants may react to a medication differently from a full-term infant or an older baby. An R.Ph. may need to compound an oral dose or prepare an intravenous solution based on medical and pharmacy experience.

    Grinder cited intravenous azithromycin (Zithromax, Pfizer), used to treat otitis media. "We use tons of this. Although there is an IV dose available, there is no pediatric dosage." His hospital pharmacy has to compound pediatric doses. Captopril, another example, is highly effective for neonates, but the smallest dose--a tablet suitable for adults--is far too large for a baby. R.Ph.s must compound the tablet into a suitably sized dose, and this compounding can vary from pharmacy to pharmacy, even for widely used drugs.

    Retail pharmacists may make errors in compounding by putting a drug into an oral solution with the wrong pH, and the compounded formulation may lack stability or cause the drug to break down rapidly, Wedemeyer said. A child given a month's supply of an antihypertensive in a syrup that is useless after a few days may end up back in the hospital with uncontrolled hypertension. Worse, he said, the problem may be chalked up to too low a dose of the drug, so a new Rx is written, filled the same way, and the problem starts again.

    "Even when there are published formulas with known stability, pharmacists may not be aware of the literature," he said. "A bad formulation means the medicine does not work." And published studies may be no help when drug manufacturers try to use the information to get pediatric approvals. Merck tried to use published independent studies to gain pediatric approval for one of its drugs and was rebuffed by the FDA because the studies used different formulations, he said.

    Adverse reactions due to wrong drug dosages land children in the hospital on a weekly or daily basis, Grinder said. "I know that because we see them." In the first 10 months of 1997, out of 712 adverse drug reactions reported to the Pediatric Adverse Drug Reaction reporting program, 24 were dose related; of these, only four involved drugs with an approved pediatric indication, he said.

    What is proposed

    President Clinton's proposal applies to new drugs coming onto the market. As for drugs already on the market, the proposed regulation would require pediatric studies only when the lack of pediatric labeling could pose significant health risks to pediatric patients or when additional information is needed to use the product safely and effectively in children.

    Pharmaceutical Research & Manufacturers of America, a pharmaceutical industry lobbying association, has stated that the FDA may have no legal authority for this requirement, since a manufacturer that does not intend its product to be used in children cannot be required to conduct such tests. Alan F. Holmer, PhRMA president, has also stated that such a requirement might delay approval of drugs needed for adults.

    No one has a problem with waiving the proposed changes for drugs with no known pediatric use, said Grinder. A drug needed to fight breast cancer or Alzheimer's disease would be easy to decide on, but a policy must be put in place for other drugs, he said. One proposal--that drugs expected to be used on children fewer than 100,000 times a year be waived--is being discussed.

    There are fewer than 30,000 children in the United States with cystic fibrosis, about 22,000 hemophiliac children, and only 24,000 infants treated for respiratory distress syndrome, Grinder pointed out. A cutoff of 100,000 Rxs would be too high, he noted. He suggested a cutoff of 10,000 pediatric Rxs per year as more appropriate. Another proposal is to have no cut-off but instead set up a committee to evaluate each drug on a case-by-case basis.

    As to the ethics of testing drugs in children, since such use requires the informed consent of the parent but not the child, "it is exceptionally difficult to put an individual at risk at a time when the benefit-to-risk ratio of a drug is unknown," said St. Jude's Rodman. But testing is still a necessity, he said.

    "The issue of informed consent is a smokescreen," said Grinder. Manufacturers say it is unethical to test drugs on children, he noted. "I would suggest it is more unethical to use in children drugs that have never been tested."

    A question of formulation

    PhRMA also raised the point that creating formulations of drugs specifically for children is an expensive and lengthy process. Holmer noted that one firm has tested more than 1,000 formulations for a pediatric version of one antibiotic without success.

    Grinder agreed that creating a pediatric formulation is difficult. However, it may not be necessary unless the company chooses to market a pediatric version of its drug. Some drugs will never have a large enough pediatric market to justify the effort. As long as pediatric dosing has been established, all that a pharmacist needs is a standardized recipe for compounding an adult dose into a dose suitable for children, he said. "The FDA could simply publish these formulas in the Orange Book."

    The timing of pediatric testing within the approval process also needs to be hashed out, he said. Most people agree that phase I is too early for a drug to be tested on children. The number of children that would need to be enrolled in such tests would depend on the indication for the drug, he added. One with a marginal benefit, such as the third or fourth entry in a class of antibiotics, would need a larger test population than a drug that is the first of its kind and potentially lifesaving. Whether a drug that is beneficial to adults should be delayed while pediatric testing is completed is an ethical question, Grinder said. There is a possibility that pediatric testing could be performed after a drug has been marketed for some drugs.

    The bottom line

    The matter of pediatric testing for drugs is one that calls for compromise, said Wedemeyer. The new regulation will be passed in some form, but it is in the best interests of all concerned that the regulation be of service to everyone, he said. And the major pharmaceutical manufacturers will do a good job of testing, because they do not want to compromise their reputations.

    Rodman agreed. "The drug industry recognizes the need, but their decisions may be driven by cost," he said.

    The American Academy of Pharmaceutical Scientists in cooperation with the FDA will hold a symposium on the subject of pediatric testing of drugs May 11 through 13 in Washington, D.C.