Why FDA Is Encouraging Drug Testing in Children
By Paula Botstein, M.D.
Paula Botstein, M.D., is deputy director of the FDA's Office of Drug Evaluation I. As a
pediatrician, she takes more than a casual interest in the development and testing of
drugs for children. She was interviewed on this subject by Lawrence Bachorik of the FDA's
Office of Public Affairs. An edited text of that interview follows.
Q. Dr. Botstein, the FDA has been focusing more attention recently on drugs for
children. Why is that?
A. There's a simple answer to your question: Pediatricians are infiltrating the
FDA.
Q. (Laughing) Perhaps. But what's the real reason?
A. It's that children need medicines. Some drugs have already been well studied
and approved for use in adults. To use one of these drugs for the same disease in
children, it's important to figure out what doses work best in kids and what kinds of
adverse reactions are likely to occur.
Other drugs are for diseases specific to children, and these need adequate and
well-controlled studies of their effectiveness and safety.
Q. Can you tell me about the current situation? Are there lots of drugs approved
for adults that are perhaps not well understood or well labeled for use in children?
A. The majority of drugs have been studied in adults and labeled for use in
adults. Their physician labeling includes a disclaimer that says safety and effectiveness
have not been established for use in children. That's the usual and common situation.
Q. So it's much more often the case that drugs have not been studied in
children?
A. That's right. Even a drug like morphine, which is a standard, necessary pain
medicine, has not had explicit labeling for use in children.
Q. Why haven't these drugs been studied in children?
A. In 1963, Dr. Harry Shirkey coined the phrase "therapeutic orphans"
to describe children. Shirkey was alluding to the plight of children for whom many drugs
have not been studied. The reasons for this are complicated. Pharmaceutical firms have had
little incentive to study drugs for use in children because the population--and therefore
the financial return--is likely to be small. Moreover, testing drugs in children is more
complicated than in adults. Pediatric drug trials are often done in children's hospitals
and may be more involved because people take pains to make sure that parents and children
understand what's going on. Children are less likely than adults to be used as
"normal" volunteers in clinical trials; most children in trials have the disease
in question.
People are more reluctant to use a drug in children if there is no potential benefit to
the specific child.
Q. But is this really a problem? Why can't physicians simply give a child less
of a particular drug than would be given an adult?
A. It's not that simple. Young children may metabolize or absorb drugs at a
different rate from adults, and therefore a suitable dose is difficult to estimate from
the size of the children. The same is true for older adults, compared to younger adults.
In recent years, the FDA has paid more attention to establishing specific dosages for
elderly patients, and we are now doing the same for children.
Q. So how do pediatricians know the proper dose of a drug if it is not
specifically labeled for use in children?
A. That question goes to the heart of why the FDA is encouraging clinical trials
in children.
The answer is that there is no standard source of information. Pediatrics textbooks
usually give drug dosages, but the source and reliability of the information are seldom
specified. Mostly, pediatric doses of drugs that have not been formally studied in
children are simply established by experience. Some drugs are used all the time in
children. Anesthesia drugs would be a good example. They may not be labeled or approved
specifically for children, but children routinely need major surgery. So physicians build
up the experience in using the drugs. It's not the ideal way.
Q. You've established that many drugs currently approved for use in adults are
not specifically labeled for use in children. But you mentioned a second category of
drugs--new drugs specifically for childhood diseases.
A. Children have various types of diseases, the most common kind being acute
infectious diseases--for which they need antibiotics, anti-fungal agents, and anti-viral
agents. Some antibiotics are in fact studied and labeled for use in children--for
meningitis or otitis media [middle ear infection], for example--while they are being
studied for adults. But other major antibiotics, such as piperacillin or metronidazole,
have no labeling for use in children.
Q. What are some other types of pediatric diseases for which adequate testing of
drugs in children might be an issue?
A. In addition to the acute diseases, there are the chronic diseases of
childhood, such as seizure disorders. Children also can have congenital diseases, such as
cystic fibrosis and enzyme deficiencies.
Q. Are the drugs on the market without labeling for pediatric indications being
used illegally?
A. No, doctors may legally use approved drugs for whatever uses they think
appropriate, according to their medical judgment.
Q. As a pediatrician, you must be concerned. What sort of things is the FDA
doing to make more drugs available for children?
A. We're doing a number of things to be active in this area and are about to
launch a plan for more. As we meet with drug companies to discuss the drugs they are
studying, we are encouraging them to test those drugs in children when appropriate. We are
finding that companies are often responsive to the need.
We are changing our internal procedures to foster the availability of new drugs for
youngsters. We routinely ask our the the FDA drug review divisions to sift through their
INDs [the formal requests to test a new drug] to identify drugs that might show particular
promise in children. It is these drugs with potential pediatric uses that we encourage
drug companies to develop for children, either before or after approval for use in adults.
We have created what we call a "pediatric page" as part of our review of new
drug applications. This is a summary of what is known about the drug from the perspective
of pediatrics: whether it has been tested in children, what uses are promising, and the
like. It's basically a management tool, so that FDA's own people will think more in terms
of drugs for children--and to explore this potential with the drug sponsors.
We are going to ask sponsors to tell us early in a drug's development about expected
use in children and plans for studying the drug in children. We are also going to focus on
actual use in children after marketing.
Q. Those steps might help with drugs now under development and testing. What
about drugs already on the market?
A. We have a way of dealing with that, too. Currently, according to the
regulations, no drug may be labeled for use in children unless it has been subjected to
"adequate and well-controlled studies" in children. But the regulations also
give the FDA the authority to waive that requirement, if there have been adequate and
well-controlled studies in adults.
Q. Under what circumstances will the FDA consider granting this waiver?
A. We have specific criteria. First, the disease has to be the same in adults.
Then, the drug must have been well studied in adults. To use the drug appropriately in
children, you need to have information on dosing and on adverse reactions, which may be
different in children.
Q. Can you explain the new regulation about the "pediatric use"
section in drug labeling for physicians?
A. We published a final regulation Dec. 13, 1994, revising the present pediatric
use section in physician labeling for all marketed drugs for diseases for which the safety
and effectiveness trials in adults are relevant for children. The change will allow use of
information from other sources, such as blood level data or adverse event data--if we
think it appropriate.
Q. Have the FDA's increased efforts begun to pay off?
A. We are encouraged. In the past few years, we have seen a definite increase in
the number of new drugs approved specifically for children. The FDA has approved major new
drugs for pediatric diseases. Exosurf and Survanta are pulmonary surfactants for
respiratory distress syndrome in newborn babies. Adagen is an enzyme, ADA, to replace an
enzyme missing in children with a severe immunodeficiency. Chemet is an oral drug for
treatment of lead poisoning in children. The FDA has classified these drugs as important
new therapies.
We are seeing a burst of pediatric studies; other drugs for pediatric diseases are
being studied or are close to approval.
Q. Do you see any areas where there is a particular need?
A. One in particular stands out: drugs for newborns. With the advent of neonatal
intensive-care units and increased survival of tiny babies, we are seeing the need for new
drugs to treat these small creatures. One success involves the pulmonary surfactants,
drugs that help the survival of premature infants whose lungs have not yet fully
developed. Pharmaceutical manufacturers have been vigorous in developing surfactants. We
at the FDA have considered it important to make these life-saving therapies available as
rapidly as possible. We approved two treatment INDs for therapy before approval, and the
first surfactant was approved for marketing in a near-record five months after an
application was submitted.
Q. Dr. Botstein, what should parents do if they have any questions about drugs
their children are taking?
A. If parents have any questions about drugs, such as the proper dosage or
possible side effects, they should always check with their physician or pharmacist.
Q. Can parents do anything to help make more drugs available for children?
A. Perhaps the most important thing they can do is to consider allowing their
own child or children to participate in clinical drug testing if the opportunity is
available. People often think of the practical difficulties--such as the need to draw
blood samples--of studying drugs in the young. But we have found that parents are often
eager to have their children participate, especially if they feel they can help family
members or other children.
New Rules for Children's Medicines
New measures to provide health-care professionals with the information necessary to more
safely prescribe medicine for children were announced by the FDA in December 1994.
Previously, most prescription drugs were tested primarily in adults and the labeling
lacked information about appropriate use in children.
A 1979 regulation had required full clinical trials in the pediatric population as the
basis for labeling for children. A new rule, published in the Dec. 13, 1994, Federal
Register, revised the "Pediatric Use" section to allow companies in some
situations to base pediatric labeling on data extrapolated from adequate and
well-controlled adult studies together with other information on treating children.
However, the rule makes it clear that such pediatric use statements can be made only if
the course of the disease and the drug's effects are sufficiently similar in children and
adults.
Also, under the new rule, manufacturers must reexamine existing information to see if
pediatric labeling of already marketed products can be modified on the basis of adult
studies and other available data. If so, the manufacturers must take the necessary steps
to modify existing labeling.
In addition, the new regulation clarifies the agency's authority to request specific
pediatric use information. For example, the FDA might request pediatric use data for a
drug that is widely used, represents a safety hazard, or is therapeutically important in
children. The rule, however, does not limit the manner in which a practitioner may
prescribe an approved drug.
A special pediatric subcommittee will track implementation of the new regulations and
take steps to ensure that the various possibilities of pediatric testing and use are
explored. The FDA's Center for Drug Evaluation and Research has taken steps to increase
the number of pediatric studies included in submissions for new prescription medicines.
The agency also will work closely with the National Institute of Child Health and Human
Development to conduct pediatric studies and will work with sponsors of new products to
ensure that necessary pediatric data are included.
Source: Food and Drug Administration (FDA)
"Why FDA Is Encouraging Drug Testing in Children" originally
appeared in the July-August 1991 FDA Consumer and was substantially revised for the FDA
Consumer Special Report on New Drug Development in the United States (January 1995).
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