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Clinical trials: what are they and how do they relate to research in autism? (EP On Autism).


Information about "new" treatments for children with autism are brought to the attention of parents through a number of channels such as the news media, word of mouth through other parents, advocacy groups and professional web sites. The amount of information available can be daunting. How are parents to evaluate whether treatments they hear about are appropriate to try for their children?

It is easy to understand that many parents will try an unproven treatment out of desperation based on the small possibility that it will help. But that possible benefit needs to be weighed against the short- and long-term safety of the unproven therapy, as well as cost in terms of a family's time and financial resources. Autism and related conditions include a number of different signs and symptoms, and what is most problematic may differ from one child to the next; it is unlikely that one treatment will be effective for all. Many treatments, such as those related to immunotherapy, eradication of yeast infections, homeopathic herbal treatments, "alternative" medicines, etc., have been proposed, yet none has been studied with the scientific rigor that is necessary to safeguard children or to be certain of real benefit.


It is expected that novel therapies for the treatment of children with autism will be developed at an increasing rate over the next decade. Before a new treatment can be recommended for use in patients, however, it must be shown to be both safe and effective. It is important for parents to understand how new treatments are tested for safety and effectiveness. Scientifically designed clinical trials are the most important--and accepted--means of determining whether a new treatment is safe, whether it works, for what symptoms and in which children.

A clinical trial is a research study designed to answer specific questions about the safety and effectiveness of new therapies as well as to study new ways of using known treatments. Clinical trials are designed to: compare one treatment to another; compare different doses or methods of administering a treatment; or compare a new treatment to no treatment or to customary standards of care. Clinical trials may be used to study drugs as well as behavioral interventions.

Phases of Clinical Trials

Clinical trials are conducted in phases. Each phase is designed to answer different types of questions. In phase I trials, researchers test a new drug or treatment in a small group of individuals, usually healthy volunteers, who do not have the disorder that might be affected by the drug or treatment. The purpose of this phase is to evaluate the drug or treatment's safety, determine a safe dosage range and identify common side effects. In Phase II trials, the study drug or treatment is given to a larger group of people who may have the targeted disorder to see if the drug or treatment has the potential for favorably affecting a specific disorder or condition. Phase II trials also can help in further evaluating the safety and best dose. In phase I and phase II trials, only very common side effects can be identified because the number of subjects is small. In Phase III trials, the study drug or treatment is given to larger groups of affected people to determine its efficacy, identify side effects and collect information that will allow the drug or treatment to be used safely. In some trials, the effects of the drug or treatment are compared to commonly used treatments. Phase IV trials, which are post-marketing studies conducted after the new drug or treatment has been approved for use in patients, provide additional information on the risks, benefits and optimal use of the treatment.


A protocol is a study plan carefully designed to safeguard the participants in the study as well as to answer specific research questions. The study protocol describes: who may participate in the trial; the schedule of tests, visits, procedures, medications and dosages; what outcomes will be measured and how and when they will be assessed; and the length of follow-up. While in a clinical trial, participants following a protocol are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of treatment.

Controls and Randomization

An important design feature of most phase III--and some phase II--clinical trials is the inclusion of a control population. In a scientific experiment, a control is a standard, or comparison, by which experimental observations can be measured. In clinical trials, one group of patients receives the experimental treatment while the control group is given either a standard treatment or an inactive treatment, which looks and tastes like the active one. All other study procedures are identical for the treatment and control groups. Without the control group, it would be impossible to be sure whether any apparent improvement (or side effect) is due to the experimental treatment. For example, if a child's behavior seemed to improve while being treated with a new drug, the apparent benefit might be due to effective treatment, but it could also just be a result of the extra attention received as a participant in a study. Also, without a control group, any side effects--such as nausea or headache--will be attributed to the new treatment, when some of them would probably occur even in the absence of treatment. Thus, a control group permits the identification of benefits and risks over and above those that may occur routinely.

Randomization is the usual method of determining which patients will receive the experimental treatment and which ones will be in the control group. Random treatment assignment is a statistical method that assigns the tested treatment or placebo/ standard treatment purely by chance. The main purpose of a random treatment assignment is to come up with comparison groups that are very similar to each other in all characteristics except the treatment that is being evaluated. Randomization also helps to avoid "biasing" or affecting the study's outcome, which could happen if the study investigator, the parent or the patient were to decide on the treatment to be given.

What is a placebo?

In clinical trials, experimental treatments are often compared with placebo to assess both effectiveness and side effects when there is no standard accepted therapy for the condition. In a drug study, a placebo is an inactive pill, liquid or powder that should be identical in shape and taste to the study drug but has no treatment value. In studies of behavioral or other types of treatments, a "placebo intervention" is usually difficult to design, but approximations can be made. Placebos are not usually used when there is a standard medication or treatment approach, in which case the control group would receive a non-experimental treatment. A placebo is different from "no treatment." In a well-designed clinical trial, patients receiving placebo often exhibit some apparent benefit--the "placebo effect." Documentation of the placebo effect is often an important goal of the research.

What does it mean to do a "blinded" or "masked" study?

Blinding (also often called "masking") is a procedure that is designed to prevent the participants or investigators from knowing the patients' treatment assignment. In a single-blinded study, either the investigator or the participant is unaware of which participants receive the experimental treatment and which ones receive the control treatment. In a double-blinded study, neither the participating individuals nor the investigators know to which group the participants are assigned. Blinding is commonly used when there is a concern that the patients' or investigators' knowledge of which treatment is being received might affect their response to the treatment or evaluation of treatment effects. For example, if the investigator believes that a new treatment should result in improved behavior, he or she might tend to score patients receiving the new treatment differently from those in the control group. When the investigator and patient are blinded with respect to treatment, the actual treatment assignment information is maintained by a central individual who is not involved with patient care, and is always available when necessary in the event of serious side effects or other safety concerns.

What are baseline measurements?

At the beginning of a study, baseline measurements are gathered. Baseline measurements are information that describe characteristics of the study subjects that may have some importance in interpreting the results. Baseline measurements serve as a reference point by which the safety and efficacy of a treatment can be determined. For example, if a study is evaluating a new medication for a child with autism and is using different types of standardized behavioral or other rating scales to monitor the effects, then the child is evaluated using these rating scales before treatment is started and at various time points during and after the study. Baseline values are also used to evaluate safety; for example, blood tests may be done in order to monitor if there are any changes after taking medication.

What happens during a clinical trial?

Some trials are done in one institution (single center), whereas large clinical trials are done at multiple institutions (multicenter) in which the investigators all agree to use the same protocol and procedures.

After enrollment, the protocol for the study is followed. Potential participants are identified, the study is described in detail, families have the opportunity to ask questions and, if they agree to participate, an informed consent form is signed. Children over the age of seven years who are able to understand what they are being asked to do sign a separate assent form.

Once the family (and child) have consented to participate, the investigators will begin study evaluations. For example, in a study that examines whether a particular drug may be beneficial for children with autism, standardized rating scores would be given over a period of time to get baseline measurements. Children would then be randomly assigned to receive the experimental drug or a control treatment (placebo or standard drug therapy) and, in a double-blind study, neither the patient (and/or their family) nor the investigator would know which children are being treated with active medication. All patients would then be evaluated at predetermined time points and the rating scales repeated until the study is completed. At that point the data from the treatment and control groups would be analyzed to see if the treatment was beneficial and safe.

How is patient safety protected in a clinical trial?

All clinical trials have procedures in place to protect patient safety. Clinical trials are conducted after review and approval by an Institutional Review Board (IRB). The IRB members are independent of the researchers doing the study; they review the protocol and determine whether adequate protections are in place to ensure the safety of patients. The investigators must report regularly to the their IRB about the study's progress, and must report any serious adverse events that occur. In addition, a data and safety monitoring committee is appointed to monitor most phase Ill trials and some phase II trials to safeguard the well-being of study subjects and ensure the scientific integrity of the research. The members of the data and safety monitoring committee are from outside the institution in which the study is being conducted. If the committee identifies any serious safety or ethical concerns, the study protocol may be modified or the study could be stopped.

An example of a medication treatment trial:

A trial on the effect of a medication, risperidone, recently published in the New England Journal of Medicine, can be used as an example of a well-designed treatment trial. * This trial targeted symptoms of severe tantrums, aggression or self-injurious behavior in 101 children with autism between ages five and 17 years. To be eligible for the study, the diagnosis of autism was confirmed by standard evaluations and children with the targeted symptoms were invited to participate. Written informed consent was obtained from parents or guardians. To exclude children whose symptoms might improve in response to just coming to the clinic, the behaviors had to be present at the first or baseline examination, as well as at visits one week and two weeks later. This trial was conducted at multiple sites and children received the study drug, risperidone, or a placebo that looked and tasted exactly like the study drug. Whether a child was given placebo or risperidone was determined by chance on a random basis. Neither parents nor investigators knew which treatment the child was taking (double-blinded).

Both parents and a clinician evaluated the child's response to medication. Each child was seen weekly for eight weeks. Examinations, laboratory tests and electrocardiographic studies were done periodically to monitor for side effects, and parents answered extensive questionnaires with regard to possible health and behavioral effects. The study revealed some mild side effects that resolved within a few weeks, and concluded that the treatment was well-tolerated and effective for the short-term treatment of tantrums, aggression and self-injurious behavior in children with autism.

An example of a non-medication treatment trial:

Clinical trials are also done to test the safety and effectiveness of devices and behavioral interventions. "Grandin's Hug Machine" is an example of a very different kind of therapy tested in a clinical trial. This therapy for autism involves a device that allows self-administration of lateral body pressure. The clinical trial, which was reported in the American Journal of Occupational Therapy, investigated the effects of this therapy on arousal and anxiety reduction in people with autism. * The design involved random assignment to an experimental group, which received the deep pressure, or a "placebo" group, which was placed in the machine but did not receive the deep pressure. All participants were administered two sessions per week for six weeks, and outcome was measured by a parent rating scale and by a skin response test that examined physiologic arousal. Parents were "blinded," that is, they did not know which treatment their children received. There were no adverse reactions and there appeared to be some evidence of benefit. However, the number of patients included (five in the deep pressure group and seven in the placebo group) was too small to determine whether the treatment was useful. Nevertheless, the study brought into focus important questions for further study in a larger sample about: whether children with high anxiety could benefit most from this treatment; whether use of this treatment, during self-determined times, would be more useful than scheduled sessions; and how the children perceived the experience.

What next?

Parents should be able to critically review evidence about effectiveness and safety before embarking on any new course of treatment. There are many resources now available to help guide parents. Many of the national autism societies have useful information and suggestions on their web sites.

Clinical trials provide the best information about the risks and benefits of new treatments. While clinical trial results obviously apply to the children enrolled in the study, well-designed studies yield results that can also be generalized to children similar to those who participated in the study. The more similar a child is to children in the study, the more reliably the information can be used.

Advances in therapeutic management of a wide spectrum of diseases increasingly depend on completion of well-designed trials to establish the benefits, risks and best way to administer new therapies as well as those therapies in current use that have never been adequately tested. The participation in clinical trials of children with autism is increasingly important, both for the potential benefit of the children who directly participate as well as for the possible benefits that may be offered to a broad range of affected children.

* For a list of references and resources to this article please e-mail requests to:

Dr. Stephen Ashwal is Professor of Child Neurology at Loma Linda University School of Medicine and currently serves as President of the Child Neurology Society.

Dr. Deborah Hirtz is a Child Neurologist and a program director for clinical trials at the National Institute of Neurological Disorders and Stroke, National Institutes of Health. She is a member of the NIH Autism Coordinating Committee and works with the NIH-funded autism research networks.
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Author:Hirtz, Deborah; Ashwal, Stephen
Publication:The Exceptional Parent
Geographic Code:1USA
Date:May 1, 2003
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