recognized that such work should be broadly based, and this study was the first phase of a larger research plan. Consistent with this plan, the investigators subsequently submitted to the IRB a proposal to conduct similar research in a larger and more geographically and ethnically diverse sample. This proposal was also approved by the IRB, and was submitted to and reviewed by NIH, but not funded, with no criticism whatsoever of the human subjects

safeguards.

Benefits to Participants

It was hoped that this study would result in new knowledge about identifying youngsters at highest risk for developing antisocial behavior and about ways to prevent the development of this behavior. Although the study was not primarily designed to provide direct benefit to the participants, it was anticipated that each child would receive a number of indirect benefits, including comprehensive medical and neuropsychological evaluations designed to detect learning, emotional or medical problems. When problems were detected, families were assisted in obtaining appropriate services. For example, a serious heart problem was discovered in one child, and the family of another sought help from the research staff for a child who was dealing with his father's suicide.

The Consent Process

Recruitment into the larger study was initiated by a letter mailed by the investigators to the families. If the parents and child were interested, the study was explained in detail and consent was obtained. Only families who had participated in the larger study were considered for the fenfluramine study, on which we are focusing today. Families were told that a related study was underway, and asked if they might be interested. If they were, they were referred to the lead investigator who explained the study in detail. The consent process occurred over several visits,

and children participated only if both parents and children fully agreed to the procedure at all times. If a parent expressed interest but a child did not, the child did not undergo the procedure. For example, those children who objected to having their blood drawn did not participate. As is customary in research studies of this type, participants were compensated for their time (6 to 8 hours, including transportation) and effort; parents were given $100, and children were given a $25 gift certificate.

The Use of Fenfluramine

A large body of scientific evidence suggests that the brain chemical serotonin plays an important role in the regulation of violent behavior, both outwardly directed, such as aggression, and inwardly directed, such as suicide. The investigators were interested in obtaining a measure of brain serotonin function in these youngsters, and, since brain serotonin cannot be measured directly, proposed to give subjects a single oral dose of the medication fenfluramine. By measuring changes in the level of hormones in the blood after fenfluramine, the investigators could obtain an indirect measure of brain serotonin function. An analogy might be the glucose tolerance test: a dose of glucose is given to individuals at risk for diabetes, and blood sugar levels are measured as an indication of the body's release of insulin.

At the time this study was proposed, fenfluramine had been marketed as Pondimin for over twenty years for the treatment of obesity. The NYPI IRB, which included a pediatric neurologist, carefully reviewed the potential risks of fenfluramine known at that time, and obtained information from other investigators who were familiar with its use in children. After a thorough and lengthy review, the IRB concluded that the use of fenfluramine in this study entailed "no more than a minor increase over minimal risk" and therefore could be conducted under the applicable federal regulations governing research with children. Fenfluramine studies

were carried out in 36 youngsters, and, to the best of our knowledge, none experienced

significant problems.

Concern about the use of fenfluramine has subsequently developed because of the association between the use of fenfluramine, marketed as Redux, and the development of heart valve abnormalities. It may therefore be useful to review some additional information about fenfluramine. First, concerns about valvular damage emerged in 1997, well after the IRB's review and the conclusion of the NYPI study in 1995. Second, the data which have emerged suggest that valve damage occurs in a fraction of obese individuals who took fenfluramine for months, often in combination with another medication, phentermine. There are no data of which we are aware suggesting that a single, low dose of fenfluramine alone, as used in this study, is associated with any risk of cardiac damage. In fact, even after fenfluramine was withdrawn from the market for the treatment of obesity, the FDA has continued to permit the use of a single dose of fenfluramine in research studies. Finally, researchers outside of NYPI have described experience with more than 1,000 research subjects, including over 200 children and adolescents, who have participated in fenfluramine studies. All of these studies were presumably approved by the relevant IRB's, and many or most were conducted with support from NIH, which carries out a separate ethics review. The widespread use of fenfluramine in these research studies supports the view, taken by the NYPI IRB, that this procedure was of low risk.

The Research Findings

This study provided important information for developing prevention and treatment strategies for children with anti-social behavior. First, it demonstrated that the relationship between behavior and brain chemistry may change during development. While nerve cells

which use serotonin appear to be underactive in certain adult psychiatric illnesses, the opposite (overactivity) may occur in certain child psychiatric disorders. Second, the researchers found that this difference may relate to the rearing environment. Children who were reared in nurturing environments generally had serotonin levels associated with lower levels of aggressive behavior.

These findings emphasize the potential importance of early interventions to prevent the development of problems in young people. For example, the results of the study suggest that some forms of treatment might not only help behavioral problems, but also prevent changes in the chemistry of the brain which may make later treatment more difficult. Moreover, by describing the link between nurturing behavior and serotonin, the study may ultimately allow us to understand those aspects of the parent-child relationship that are most protective against the development of antisocial behavior.

The importance of the published results of this fenfluramine research was recognized in an editorial in a leading medical journal and by the American Academy of Child and Adolescent Psychiatry.

In closing, we would emphasize our belief that research on the development and prevention of violent behavior among young people is critical for our country. Studies on this sensitive topic must be carried out with the strictest attention to safeguards for the research participants. In the study under consideration today, the NYPI IRB carefully applied the federal regulations governing research and the ethical principles on which they are based.

Mr. SNOWBARGER. Thank you. Next, Dr. Bert Spilker from Scientific and Regulatory Affairs, Pharmaceutical Research and Manufacturers. Dr. Spilker.

Dr. SPILKER. Mr. Chairman and members of the subcommittee, I am Bert Spilker, senior vice president of Scientific and Regulatory Affairs of the Pharmaceutical Research and Manufacturers of America. PhRMA represents the Nation's leading research-based pharmaceutical and biotechnology companies.

I am pleased to be here today to present PhRMA's views on the way in which IRBs are exercising their oversight of pharmaceutical company-sponsored clinical trials.

PhRMA believes that the IRB system is sound and is working well for pharmaceutical company-sponsored clinical trials. Patients are being informed of their rights in accordance with the basic elements required in the informed consent document that they must read and sign. Their safety is being fully considered and drugs are being appropriately researched.

Modest reforms can be made without new legislative authority to improve the efficiency of the IRB process, and reduce duplication of efforts, allow IRBS to spend more time on ethical and safety considerations, and make new cures and treatments available sooner to patients.

IRBs are a critical safeguard to ensure that the rights and safety of patients, who enter clinical trials, are fully considered. This is absolutely essential and this is occurring in clinical trials sponsored by pharmaceutical companies. With any clinical trial, as with any drug, there are always risks. The potential risks to patients of any trial must be balanced against the potential benefits to be gained from the development and approval of the drug being tested. It is the job of IRBS to determine that the potential benefits to patients exceed the potential risks before they allow a clinical trial to proceed.

PhRMA agrees with the March 1998 draft report of the Inspector General on IRBs that changes are needed to streamline the IRB process. Improvements, such as the four I will mention, can be made by FDA and the OPRR on their own without new legislative authority.

First, a procedure should be established for regional and/or national IRBS to function more broadly and to meet more frequently than local IRBs do now. This would help facilitate the initiation of multi-centered clinical research and also reduce the growing workload of local IRBS. Duplication of effort would be reduced, local IRBS would be able to spend more time on ethical and safety considerations relating to their own single-site trials and new medicines would be made available sooner to patients.

Two, IRBS should be encouraged to hold regional and/or national meetings where they would discuss best practices and help each other improve their efficiency.

Three, IRBS should be urged to provide all patients with a copy of their informed consent form.

Four, FDA and OPRR should increase the flexibility of IRBS in whatever ways they deem appropriate. For example, they could encourage IRB chairs to appoint one or two members who would have