From Medscape Medical News

Court Overturns FDA Pediatric Rule: An Expert Interview With Philip Walson, MD

Laurie Barclay, MD

Authors and Disclosures

Nov. 6, 2002 — Editor's Note: On Oct. 17, the U.S. District Court for the District of Columbia held that the Food and Drug Administration (FDA) lacked the statutory authority to require drug companies to study drugs in children, and the court overturned the FDA's Pediatric Rule. As of January 2002, the Best Pharmaceuticals for Children Act (BPCA) has offered financial incentives to pharmaceutical companies that voluntarily study their drugs in children. The Pediatric Rule went one step further, imposing requirements on companies not doing pediatric testing of drugs approved for adult indications when the drug was highly likely to be used for comparable pediatric indications. Citing metabolic and pharmacokinetic differences between adults and children, many medical experts underscore the need for pediatric drug testing and formulations appropriate for children in all drugs likely to be prescribed to children.

To learn more about the rationale behind new legislation proposed by Sen. Hillary Clinton (D-NY), Sen. Edward Kennedy(D-MA), and others, which is designed to replace the Pediatric Rule and mandate drug testing in children, Medscape's Laurie Barclay interviewed Philip Walson, MD, director of Cincinnati Children's Hospital Medical Center and a professor of pediatrics at the University of Cincinnati. Dr. Walson has two decades of experience in clinical trials; he is a member of the American Academy of Pediatrics (AAP) Committee on Drugs and the USP Nomenclature Committee; and he was cofounder, medical director, and chief scientific officer of Pediatric Clinical Trials International, a subsidiary of Children's Hospital in Columbus, which is dedicated to development of pediatric therapeutics. He is editor of Current Therapeutics , past editor of Current Therapeutic Research , and past president of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

Medscape: What was the rationale behind the Pediatric Rule being overthrown?

Dr. Walson: The Judge [Henry H. Kennedy, Jr] felt that the FDA lacked the authority to mandate drug testing in children, because the BPCA offered financial incentives for pediatric drug testing rather than requiring it. If the drafters of the BPCA had wanted the FDA to enforce mandatory drug testing, they should have included that provision in the original legislation. When we helped draft the Pediatric Rule, we thought it would meet with less resistance if we left it as a rule rather than making it legislation. The judge basically agreed in principle with the Pediatric Rule and called it "wonderful legislation," but said, in effect, that it was only a rule, not a law.

Medscape: What new legislation would the AAP and other professional societies like to see in place of the Pediatric Rule?

Dr. Walson: The American Academy of Pharmaceutical Physicians, a group which, interestingly, is mostly composed of drug industry physicians, recommended on Oct. 26 that Congress authorize the FDA to require testing of safety and efficacy of appropriate new and marketed drugs in children. Essentially, they want the new authorization to contain all enforcement provisions of the Pediatric Rule. The AAP agrees, because we feel that it's unethical not to test drugs in children. The only professional group that I know of who is opposed to this proposed legislation is the Association of American Physicians and Surgeons. Frankly, I don't know who these people are, but I seriously doubt that there are very many physicians or surgeons among them.

Medscape: What is the medical basis for recommending drug testing in children as well as in adults?

Dr. Walson: Everything is different in kids — tolerability, kidney function, metabolism. Creatinine clearance is normally 100 mg/mL in adults and twice that — 200 mg/mL — in children. What makes pharmacology even more challenging in children is that they change so rapidly with development. A preterm infant hospitalized for complications might quadruple his weight during a single hospitalization.

The FDA Modernization Act (FDAMA) of 1997 authorized about 200 studies of drugs in children, with unexpected and unpredictable results. We learned that you can't guess about the best dose in a child or extrapolate from adult data; you have to test each drug. For example, the proper Neurontin dose for seizures in kids is 30% more per unit of body weight than in adults. For phenytoin, a four-year-old child may require more than 300 mg/day, not only more than adults require per unit of body weight, but a larger total dose even though the child is so much smaller.

If the tables were turned and we told adults that we'd have to guess what dose to give them based on results of pediatric testing, or that they'd have to swallow a few gallons of the formulation used in children because there is no pill form, they wouldn't stand for it for a minute. But adults vote, and kids don't, so kids don't really have a voice when it comes to drug testing.

Medscape: What are the current legal limits of the FDA's statutory authority to enforce the proposed legislation?

Dr. Walson: The FDA is now authorized to regulate drugs only in that population to whom the industry wants to sell. Judge Kennedy in effect said that the FDA has no authority to mandate testing in a population not specifically targeted by the drug label. If the industry doesn't label a drug as being indicated in children, and if they don't advertise pediatric uses, they don't have to test the drug in children even though they end up selling it for use in kids. The drug industry is trying to skirt federal authority. If they're not purposefully selling to children or targeting advertising to them, they're off the hook, even if we all know the drug is used in kids. If we want to protect our children and the public health, we need to give the FDA the authority to mandate testing in kids. There are some changes going on in the FDA — those people who have been working on drug testing in children need support and will get it.

Medscape: Would all drugs have to be tested in children, or only those with specific pediatric indications?

Dr. Walson: There needs to be a rationale for testing drugs in kids. New drugs should be appropriately evaluated in children when there is no other life-saving therapy or when we can anticipate a meaningful therapeutic benefit, and when a substantial number of pediatric patients are likely to use the drug. Already-marketed drugs should be tested when absence of adequate labeling could put children at risk, and when the drug is already used in many pediatric patients for the labeled indications, or when we have reason to believe that the drug could provide a significant advance over existing treatments for pediatric patients for at least one of the claimed indications. Basically, we should test drugs used widely in pediatric patients, or likely to be used in children, whether for approved or unapproved adult indications.

Medscape: Would all drugs have to be issued in pediatric formulations, or only those with clear applicability to diseases affecting children?

Dr. Walson: We shouldn't think of pediatric formulations per se, but rather of formulations for people who can't swallow well, including the elderly, the disabled, and those with gastrointestinal problems. But sometimes we do need specific formulations, especially for newborns, for inhalers, and for safe dilutions of oral or injectable solutions.

Medscape: Could the proposed legislation have unintended negative effects, such as delaying availability or increasing costs of new drugs?

Dr. Walson: The Government Accounting Office did a study showing that testing increases drug costsby only one-half of 1%. I know very few parents who wouldn't pay half a penny more on the dollar to have the drugs their children need tested first. Neither the drug industry nor the group objecting to the proposed legislation has presented any evidence that testing would significantly increase costs. Additional testing needed to determine safety in children is often not all that burdensome. In some cases, only pharmacokinetic studies or small dosing studies in children are needed to get a pediatric indication on the label. Nevertheless, it's possible that the proposed legislation could delay drug availability. There needs to be an appeals process. You need to have checks and balances for any legislation.

Medscape: What is the advantage of legislation mandating drug testing in children over financial incentives for testing drugs in children?

Dr. Walson: Because we learn more about drugs all the time, we need both. I don't like either the government or the drug industry determining whether drugs should be tested in kids, but if I had to make a choice, I'd go with the government. No matter how smart the pharmacologists are, there are always surprises. Thalidomide was developed as a sedative, but it turns out to be a great drug for leprosy. Legislation based on the Pediatric Rule would ensure that drugs are tested initially, but if new indications are discovered and the drug is already patented, financial incentives would encourage drug companies to test the new indications in children. We need legislation that enables evaluation of drugs in small populations, like the Orphan Drug Act, although the effect of that law is limited. We don't want to destroy the pharmaceutical industry — we have the best in the world. We want to work with them.

Medscape: What are the ethical issues concerning drug testing and informed consent in minors?

Dr. Walson: Of course there are ethical issues concerning informed consent in children, but many of these relate to the ethical and practical difficulties in getting informed consent from anyone. How do we get truly informed consent from the elderly, the mentally handicapped, or prison volunteers? If an adult is dying of cancer and agrees to participate in a clinical trial of a potentially life-saving drug, is that truly informed consent? Of course there are ethical issues, but everything is relative. Is it ethical to continue using these drugs in children without testing? It's an uncontrolled experiment every time we give a drug to kids which hasn't been tested in their age group.

In children, we need to differentiate between consent, assent, and active dissent. If a child agrees to have his blood drawn and sits still for it, that's consent. If he says no and makes a fuss, but allows the blood drawing anyway, that's assent. If he tries to run away, that's active dissent. Sometimes, like if he has leukemia, we're justified in holding him down. The benefits to the child clearly make a difference.

Difficulties inherent in testing and in getting informed consent haven't stopped the drug industry from testing in populations they target. It's more difficult in kids, but it's not an absolute barrier. FDAMA proves that it can be done. Over the past 30 years that I've been involved in this type of research, we've developed ways to do studies well in adults. In children, we're about 25 years behind, but now we're catching up. We have new techniques, like transcutaneous drug monitoring so that we don't have to draw blood, and specially trained physicians, nurses, and other professionals who now know how to do studies well in children. Society is learning how to deal with ethical issues like consent. The next frontier is in obstetrics: we don't yet have the techniques we need to test drugs as safely as possible in pregnant women.

Reviewed by Gary D. Vogin, MD

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