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Zeno Swijtink
11-23-2007, 09:45 AM
Most prescription drugs for children still are not tested on them
Rob Stein, Washington Post
Friday, November 23, 2007

A decade after the government began trying to ensure that prescription drugs used to treat children are effective and safe, doctors still have scant information to guide them when they administer many medications to kids.

Although federal regulators have enticed or forced pharmaceutical companies to conduct hundreds of studies that have produced vital results about more than 200 drugs, perhaps two-thirds of the thousands of medications given to children remain untested on them.

"Are there children dying because of this? I don't know. Are there children being less effectively treated because of this? Probably yes. But I can't tell you because I don't know," said Richard Gorman of the American Academy of Pediatrics. "That's the problem: We don't know what we don't know."

What researchers have discovered has been disturbing: A highly effective adult migraine drug turned out to be worthless in children, sometimes causing serious side effects, including strokes; an asthma inhaler could inhibit growth; doctors were giving far too little of a medicine used to prevent seizures.

The alarming gap in medical knowledge is the legacy of many factors. The testing of drugs in children was shunned for decades as unnecessary and unethical; Congress and the pharmaceutical industry failed to provide adequate funding; and conducting medical experiments on children is difficult.

The quandary stems from the same dynamics that left over-the-counter pediatric cold remedies on drug store shelves despite little evidence they helped and mounting evidence that they could be dangerous. Drug companies, regulators and researchers long thought doctors could safely extrapolate the results of studies in adults and simply scale down the doses.

"Up to the late 1990s, children were mostly left out of new drug development," said Ralph Kauffman, an emeritus professor of pediatrics at the University of Missouri School of Medicine. "It just wasn't thought necessary."

And pharmaceutical developers had little incentive to focus on children.

"Pediatric patients were always the orphans. People didn't pay enough attention to them. They're just not a big enough market share," said Lisa Mathis, associate director for the pediatric and maternal health staff at the FDA's office of new drugs.

But researchers started to realize that children react to many drugs in surprising ways.

"Children are different - they are not just small adults," said Gregory Kearns, a professor of pharmacology and pediatrics at the University of Missouri in Kansas City. "They are not just fractions of adults."

In 1997, Congress began to address the problem. The FDA Modernization Act gave the agency a crucial tool - it could offer companies six precious extra months to sell a drug without competition if they studied it in children.

Congress renewed FDA's authority in 2002 with the Best Pharmaceuticals for Children Act, which also established mechanisms for the FDA to work with the National Institutes of Health to start scrutinizing some drugs companies ignored or had no incentive to study because they had already had generic competitors.

The legislation called for Congress to appropriate $200 million for the NIH to study the highest-priority medications. And in response to criticism that the pharmaceutical industry was getting a windfall from profitable patent extensions, the legislation established a fund to help finance studies companies would not at the Foundation for the National Institutes of Health, a private nonprofit entity.

Advocates pushed for a written commitment from the industry to provide $6 million a year, said Elaine Zining, who was the American Academy of Pediatrics' chief lobbyist. Then-Rep. Billy Tauzin, R-La., chaired the House committee that negotiated the legislation.

"Unfortunately for children, that money never materialized," said Zining. Tauzin subsequently took over as the head of the Pharmaceutical Research and Manufacturers of America (PhARMA).

The foundation has raised just $4.2 million - barely enough to pay half of one study of one drug.

Industry representatives said there was never a formal obligation to contribute to the fund. Noting companies were spending tens of millions of dollars sponsoring studies of patented drugs, they blamed the shortfall primarily on the failure of Congress to appropriate the promised money.

In the absence of the congressional funding, the NIH has spent just $25 million a year for each of the last three years to study a handful of the drugs identified as the biggest concerns.

Of about 50 drugs that have been deemed high priority, the NIH has managed to start studies of 14 , including Ritalin, lithium and morphine. But only preliminary steps have been completed.



This article appeared on page A - 6 of the San Francisco Chronicle

Braggi
11-23-2007, 09:41 PM
Think about it: would you offer up your child as a test animal for a drug company? Didn't think so. I'd also be reluctant unless it was some possible miracle drug for some hideous condition where any risk was worth it.

This is a big problem. If they prescribe and distribute the drugs, "big pharma" is faulted as a bad guy whether they are "safe and effective" or not because the drugs haven't been tested on kids. If they do tests, assuming they could find a willing audience, and some kids are harmed, think of the lawsuits. If you were the drug companies' insurance agent, would you encourage them to get into testing on kids?

So they do adult tests and try to extrapolate dosage for kids. This leaves the doctor for risk for malpractice suits. If the doctor doesn't prescribe, and a kid dies, and then the parent finds out the doctor could have prescribed drugs for the condition that any other doctor would have prescribed in a "reasonable and customary fashion," the doctor gets sued. Damned if he do, damned if he don't.

There is no way I would become a pediatrician. It's amazing any doctors do. Fewer and fewer are.

-Jeff

PS. It's weird they're testing opiates on kids since that's one of the few drugs with 5,000 years of recorded medicinal use (some would argue 20,000 years) that have proven opiates "safe and effective." I think ritalin is basically poison. Perhaps it helps a few kids, but not nearly so many as are on it. Lithium? Wouldn't feed that to a kid. Neither would most docs.

Zeno Swijtink
11-23-2007, 10:50 PM
There is no way I would become a pediatrician. It's amazing any doctors do. Fewer and fewer are.


Thanks, Jeff. As always a measured and knowledgeable response.

This article from Pediatrics gives some further background:


Title:
Editorial Comment: Therapeutic Orphans. By: Shirkey, Harry, Pediatrics, 00314005, Sep99 Part 2 of 3, Vol. 104, Issue 3
Database:
Academic Search Premier
EDITORIAL COMMENT: THERAPEUTIC ORPHANS
Contents
REFERENCES
By an odd and unfortunate twist of fate, infants and children are becoming "therapeutic or pharmaceutical orphans."( n1) Since 1962 they have been denied the use of many new drugs. The Drug Laws of 1962 had their inception following a pediatric tragedy--the thalidomide catastrophe. The laws of 1938 followed another which resulted from the use of a pediatric dosage form, "elixir" of sulfanilamide. By "legal" definition, drugs introduced since 1962 must be safe and efficacious, but only a small number of these have been studied in the pediatric age group. Certainly, there are some drugs which have an anticipated use only in adults; it would be unreasonable to ask for certification of these for use in infants and children. There are a small number of new drugs, released since 1962, which had an anticipated use for infants and children as well as for adults, and their applications for approval have been passed after the required studies in pediatric and adult patients. However, many of the drugs released since 1962 carry an "orphaning" clause, eg, "Not to be used in children . . . is not recommended for use in infants and young children since few studies have been conducted in this age group . . . clinical studies have been insufficient to establish any recommendations for use in infants and children . . . should not be given to children."( n2, n3)

Despite such clear cautions, many physicians have ignored the warnings and have prescribed the restricted drugs. It requires little imagination to wonder what a jury of laymen would decide after a defending physician admitted in court to the use of a drug despite such a clear warning.

Although the laws were designed to ensure the efficacy and safety of drugs, the age group responsible for their passage is now often deprived of the use of the medications. Testing of these drugs can not always be in controlled situations but is sometimes in the situation of use--by ordeal and often against advice. Inevitably this "unlawful" procedure will be associated with some adverse reactions, including toxic reactions, side effects, and idiosyncrasy. These reactions are common to all drugs. History has also taught that drugs previously considered harmless may be associated with temporary and permanent reactions unique to the newly born infant; even oxygen falls into this category.

It seems unfair that the use of some drugs will be denied based on relatively infrequent use and small sales potential. For example, should a child with peptic ulcer be denied the advantages of a drug which is proved to be of value to adults because that drug has not been tested in the pediatric age group? Other examples could be mentioned relative to diseases of greater frequency, but in which the needs for drugs fall below the anticipated sales volume required to warrant study in children. After cursory consideration, one might place the blame for this growing problem on the drug industry alone. However, many groups are responsible, including the government (especially the Food and Drug Administration), academic pediatric centers, and practicing physicians.

The pharmaceutical industry in the past has supplied many "service items" and will continue to supply these at a financial loss, although it would prefer to supply drugs for a large and profitable market. However, pharmaceutical firms have difficulty finding a sufficient number of clinical investigators with interest, experience, and patients for the study of new drugs. These difficulties are inversely proportional to the frequency of the disease and to the age and size of the patient. Yet it is quite clear that those who desire better drugs must inevitably include clinical investigation of drugs among their responsibilities. The Food and Drug Administration has statutory responsibility for ensuring that drugs are safe and effective. It cannot have different criteria for depth of study of drugs intended for adults as compared with those for infants and children. It recognizes, as does industry, an increasing reluctance on the part of pediatricians and others treating children to investigate the effect of drugs in the pediatric age group. At the same time, the Food and Drug Administration discouraged such studies by their interpretation of the law into guidelines which clearly indicated that written consent of patients (or their representatives) had to be given "except in unusual circumstances." The guidelines lacked clearly defined limitations, or provisions specifically outlining requirements for studies in infants and children. This interpretation has been changed, easing the difficulty somewhat and demonstrating that reasonable cooperation can be effected. However, the climate created by present regulation of human experimentation makes drug testing difficult, and especially so unless a warm and close relationship exists between the doctor who gains the permission and the parent or guardian who grants it. The continuing close patient-parent-doctor relationship existing in the private practice of medicine may permit a greater ease of meeting these legal requirements.

The Food and Drug Administration recognizes the responsibility of industry to provide adequate directions and accurate dosage for use of drugs in children; likewise, it recognizes the difficulties encountered in gaining this information. It also recognizes a pressing public issue developing in the face of the above difficulties. It is trying to face the problem and to develop positive attitudes; for instance, it has recently sponsored a Conference on Pediatric Pharmacology.

Every practicing physician, especially pediatricians and pediatric surgeons, departments of pediatrics, and departments of pharmacology should closely examine their own capacities and performance in this area of greatly needed activity. If we are to have drugs of better efficacy and safety for children, those responsible for child care will have to assume this responsibility for developing active programs of clinical pharmacology and drug testing in infants and children. The alternative is to accept the status of "Therapeutic Orphans" for their patients.

REFERENCES
(n1.) Shirkey HC. Conference of Professional and Scientific Societies, Chicago. Commission on Drug Safety (sponsor); Chicago, IL; June 27-28, 1963

(n2.) New Drugs, 1967. Chicago, IL: The American Medical Association; 1967

(n3.) Physicians' Desk Reference to Pharmaceutical Specialties and Biologicals. 21st ed. Oradell, NJ: Medical Economics, Inc; 1967

From the Department of Pediatrics, Children's Hospital, Birmingham, Alabama.

Reprinted with the permission of The Journal of Pediatrics, 1968;72( 1):119-120.

Received for publication Mar 30, 1999; accepted Mar 31, 1999.

Address correspondence to Harry Shirkey, MD, Department of Pediatrics, Children's Hospital, Birmingham, AL.

Braggi
11-24-2007, 12:36 PM
Thanks, Jeff. As always a measured and knowledgeable response.



You're welcome [taking a little bow].

This is a very tough problem. There are current articles in the news (see Google news) on kids as second class health care citizens. Lack of drug testing is one of the problems, as well as a lack of qualified pediatricians.

There are no easy answers. The politicians talk about "tort reform" but they're really just trying to protect their big campaign donors: the drug companies and insurance companies. It's not about protecting doctors and individuals from frivolous lawsuits and junk science in the courtrooms.

Oh well. This is another reason for health care consumers to learn what they can about prevention (including vaccinating), home treatment and the uselessness of wasting money on "supplements." Most especially if you have kids in the family.

-Jeff

PS. Zeno, you must be a voracious reader.