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Up until the last decade, children were rarely included in studies of medical treatments. As a result, much is still unknown about how children respond to drugs, some biologics (such as gene therapy), and medical devices.
"We had the peculiar situation of demanding a very high level of proof before a product was marketed for adults, but then having it used 'off-label' in children," says Dianne Murphy, M.D., Director of the Office of Pediatric Therapeutics at the Food and Drug Administration. This means that FDA did not have studies on how the product did or did not work in children, what different kinds of reactions children might have, or what the proper dose would be over the wide range of children's ages, weights, and developmental stages, Murphy says.
But FDA's pediatric program, backed by federal laws, has helped propel more clinical trials to be conducted in children. And more parents may be considering whether to enroll a child in a clinical trial.
By taking part in a trial, your child may be offered a new treatment that may or may not be better than those that already exist. Your child can also help the medical community understand how the treatment works and how it should be used in children. "Some studies have shown that children, especially with chronic diseases, have a strong altruistic tendency and may want to contribute to knowledge of their own disease," Murphy says.
Clinical trials yield important information on a medical product's safety, dosing, and effectiveness, which is the basis for FDA approval and product labeling. Health care providers use labeling information to prescribe the right product for their patients and to monitor them for potential side effects. This includes prescribing the right drug at the right dose.
Historically, only 20–30% of drugs approved by FDA have been labeled for use in children. So, by necessity, doctors routinely give drugs to children off label." We need to do clinical trials in children so that a child will not be an experiment of one every time a doctor prescribes a drug," says Murphy.
Children's responses to drugs can't always be predicted from data collected in adult studies, says FDA's Pediatric Bioethicist Robert Nelson, M.D., M.Div., Ph.D. A child grows and the metabolism changes as he or she gets older, he says. "These changes mean the child has a different susceptibility to side effects over time. We may think we can predict some of these differences, but we really can't without studying them."
Clinical trials in children, by law, must provide the potential for at least a minimal benefit, and the child must have the disease or condition being studied or be at risk for it. For example, many children have had otitis media (middle ear infections), says William Rodriguez, M.D., FDA's Science Director for Pediatrics, and they have the potential to benefit from studies of a treatment for otitis media. But a child could not be in a study to test a diabetes drug or a glucose monitor unless the child has diabetes or is at risk for it.
Depending on the type of trial and the product being tested, a child may get an experimental drug, a standard treatment, or an inactive pill (placebo).
If a placebo is used in a trial, it is because either the period of time the child is on the placebo is short and doesn't pose risks (for example, a couple of weeks without a therapy for a mild condition of high blood pressure) or because the therapy being tested is being used to treat discomfort or symptoms of a disease but not the underlying disease (for example, a runny nose).
A child should not be deprived of a treatment in a clinical trial that is necessary for the child's health. For example, if the child has seizures, an experimental drug may be added on to a medication the child is already taking to help control seizures, or added onto another treatment that is known to work.
People often think that a clinical trial that tests an experimental drug is riskier than being treated in your doctor's office with an already approved drug, says Nelson. "Some research is riskier, but some is safer than being prescribed a drug in an off-label environment where you don't know the implications. Monitoring for adverse events would be much more intensive in a research study than in an off-label practice."
FDA works to protect people in clinical trials and to ensure that they have reliable information as they decide whether to join a study. "A fundamental concept of research is that it cannot take place without informed consent," says Murphy. "Otherwise, it would be experimenting on people without their permission." Adult participants must sign an informed consent document before joining a clinical trial.
Children, however, cannot give informed consent because consent implies a full understanding of the potential risks and other considerations of a clinical trial. "Parents, as the child's advocates, must decide if they wish to give permission in place of informed consent," says Murphy. Then, depending on the child's age, maturity, psychological state, and other considerations, the child may be asked to "assent" or "dissent." This means the child can agree or disagree to participate in a study, which can be indicated simply by a nod of the head or a signature.
Depending on the child's health and the potential benefit of an experimental treatment, parents can override a child's dissent. For example, if the child has a life-threatening illness for which there is no effective approved treatment, the child's opinion is secondary to the parents' opinion, says Rodriguez . But if the child has a mild condition, such as otitis media, parents should not force the child to enroll in a clinical trial.
The basic parts of an informed consent document include:
Nelson urges parents to use the child's pediatrician as an advisor before enrolling in, and during, a clinical trial. "A pediatrician can help a parent evaluate the risks and potential benefits, assess the qualifications of the research team, clarify a child's understanding of the research, and support the parent and child throughout the research study."
Parents should also ask if their child's doctor is participating in the trial, adds Murphy, and, if so, what role the doctor has and if he or she is being reimbursed for participating.
Parents who are considering enrolling a child will be invited to the research site to talk with the study investigator or other scientist or health care professional on the research team. FDA experts offer some suggestions for this discussion:
Parents can take their child out of a clinical trial at any time, and may want to if the treatment is not working for their child or if the side effects are intolerable. Before withdrawing a child from a trial, you should:
After withdrawing a child from a trial, parents should report to any new doctors who see the child, even years later, that the child was in a clinical trial and may have received a certain treatment.
FDA has taken a carrot-and-stick approach to encourage studies in children, says Rodriguez. The "carrot" is the Pediatric Exclusivity Provision of the FDA Modernization Act, passed initially in 1997 and becoming law under the Best Pharmaceuticals for Children Act (BPCA) in 2002. BPCA gives drug manufacturers a voluntary incentive of an additional six months of marketing exclusivity—the ability to sell their drug without competition from generic drugs—if they conduct pediatric studies of drugs that FDA determines may be useful to children.
The "stick" has been the Pediatric Rule, finalized in 1998 and basically passed as the Pediatric Research Equity Act (PREA) in 2003. PREA authorizes FDA to require manufacturers of new drug and biologics products to conduct pediatric studies in certain circumstances.
Together these two acts have encouraged the development of important new information for drugs used in children.
As of August 31, 2007, labeling changes have been made to nearly 200 drugs that were studied in children under BPCA or PREA. Of the more than 150 drugs studied just under the exclusivity incentive program within the BPCA, 133 have new pediatric labeling information including:
"This means that before these drugs were studied in children, we were giving children the wrong dose for at least some part of the pediatric populations for one-fifth of these drugs," says Murphy. "In addition, we found that one-fifth of them didn't work in children and one-third of them raised a new pediatric safety issue."
One of the safety issues that arose during the studies was concerns with suicidal thinking for antidepressants called selective serotonin reuptake inhibitors (SSRIs). These antidepressants now carry a black box warning—FDA's strongest warning—on their labeling about increased risk of suicidal thinking and behavior in children, adolescents, and young adults. The warning does not mean that the product shouldn't be used if a depressed child needs treatment, but it gives parents, caretakers, and physicians signs to monitor when beginning or changing the treatment.
FDA's Office of Pediatric Therapeutics
http://www.fda.gov/oc/opt
For safety issues found when products were studied in children
http://www.fda.gov/oc/opt/pediatricsafety.html
For brief summaries of trials that have been conducted in children
http://www.fda.gov/cder/pediatric/Summaryreview.htm
Basic questions and answers about clinical trials
http://www.fda.gov/oashi/clinicaltrials/clintrialdoc.html
To search for clinical trials now being conducted
clinicaltrials.gov
Date Posted: October 15, 2007
