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"This text contains Dr. Henney's prepared remarks. It should be used with the understanding that some of the material may have been added or deleted during actual deliver."

Remarks by

Jane E. Henney, M.D.

Commissioner of Food and Drugs








MAY 24, 1999

Good morning. It is a pleasure to be here. You are discussing an issue important to all of us. The development of a strategy for rational therapeutics for infants and children has received a great deal of attention during recent years from the Administration including our efforts at the Food and Drug Administration, from Congress, and from the regulated industry. We are gaining momentum, but there is still much to be done for the quality of the medical care received by our children is at stake.

The history of our mutual efforts provides both perspective and some interesting lessons. While some people believe that the FDA is the Federal Drug Administration, the Agency has had only limited authority with respect to drugs until the 1930’s. At this time, the Agency was first charged with overseeing the evaluation of the safety of drugs. It was not until the 1960’s that FDA had the regulatory authority to require companies to provide evidence through the use of clinical trials that a product was effective prior to marketing. For the next three decades, this demonstration of safety and particularly effectiveness was largely confined to adults. Children were not usually entered in clinical studies, with the exception of the development of vaccines. There was a real hesitation, and very genuine concerns, regarding studying therapies in the pediatric population on the part of many. The dogma of the day was simple it was considered unethical to enroll children in experiments. They were simply "protected." Physicians and parents wanted to have adequate use information for the products given to children, but parents feared having their children be the ones who are tested. Of course, the dynamic was and remains different for the parents of a child affected by a serious or life-threatening disease or illness--such as the studies of drugs and drug combinations for the treatment of children with leukemia--but no parent ever wants to make an affirmative decision to allow testing that could ultimately harm his or her child.

The industry was also reluctant to study children. Liability and high investments for a potentially small market kept most from participating. Likewise, the agency did exceedingly little to encourage medical product testing in children. In sum, there was very little advocacy from any quarter for far too long on the part of children.

It was not until 1977, when the American Academy of Pediatrics made a first move in an attempt to change the status quo. The Academy asserted that it was unethical to adhere to a system which forces physicians to use therapeutic agents in an uncontrolled experimental situation nearly every time that they write a prescription for a child. Further, the Academy stated that it was imperative that new drugs that were to be used in children be studied in them under controlled circumstances so that the benefits of therapeutic advances would become available to all who need them.

The Academy made a powerful, yet simple statement children deserve and should have the same standard as adults. If adequate and well-controlled trials are needed to determine the efficacy of the products used in adults, then the same should be true for products used in children. This statement began a shift in the profession’s, the policy makers’ and the public’s thinking about clinical testing of medical products in the pediatric population. No longer were the experts focused on the dogma of how unethical it was to study in children it was unethical not to study in children.

Following this remarkable event, in 1979, FDA confirmed the need to have information on how best to use a product in the pediatric population. And the regulatory Agency did what a regulatory Agency does best--regulations were issued. It was the Agency’s position that if statements were made regarding pediatric use of a drug for an indication approved for adults, such statements were required to be based on substantial evidence derived from adequate and well-controlled studies, unless the requirement is waived. Unfortunately, this regulation did not generate the response intended. Few clinical trials were initiated in the pediatric population. The regulation did not provide incentives for companies to do so, nor were there repercussions for not initiating the studies. Thus, two thirds to three quarters of all drugs used in the pediatric population did not have directions for use in that population based on clinical trials.

Over a decade passed before the Agency took a more assertive stance. In 1994, FDA issued a final rule requiring drug manufacturers to survey existing data and determine whether those data were sufficient to support additional pediatric use information in the drug's labeling. The rule explicitly recognized that controlled clinical studies to support pediatric use need not have been carried out in pediatric patients, but the course of the disease and the effects of the drug needed to be sufficiently similar in children and adults in these cases. Extrapolation from the adult effectiveness data to pediatric patients was permitted. In these cases, controlled clinical studies in adults, together with other information, such as pharmacokinetic and adverse reaction data in pediatric patients, could be found to be sufficient to establish pediatric safety and effectiveness. Under the 1994 rule, if a manufacturer determined that existing data permitted modification of the label's pediatric use information, the manufacturer had to submit a supplemental new drug application to FDA seeking approval of the labeling change.

It is important to recognize that the 1994 rule did not impose a general requirement that manufacturers carry out studies if existing information was not sufficient to support pediatric use information. Instead, where there was insufficient information to support a pediatric indication or pediatric use statement, the 1994 rule allowed the manufacturer instead to include in the drug's labeling the statement: "Safety and effectiveness in pediatric patients have not been established." Unfortunately, over half of the responses to the rule used this approach. Approximately 75% of the applications submitted did not significantly improve pediatric use information.

The actions taken by FDA produced some gains in pediatric labeling, but had not substantially increased the number of drugs and biological products for which there is adequate pediatric use information. Indeed, when FDA compared the number of new molecular entities approved in 1991 and 1996 with potential usefulness in pediatric patients, using a specific process to assess the adequacy of pediatric labeling for those drugs. Fifty-six percent of the products approved in 1991 had some pediatric labeling at the time of approval. Yet, in 1996, this number had fallen to only 37 percent. Of the seven new molecular entities approved in 1991 for which postapproval pediatric studies were promised, only one had pediatric labeling by 1997.

Clearly, if the goal of ensuring the safety and effectiveness of drug and biological products for pediatric patients was to be met, additional steps needed to be taken. Accordingly, in August 1997, the Agency proposed a rule with provisions that required the manufacturers of certain new and marketed drugs and biological products to evaluate the safety and effectiveness of their products in pediatric patients. This included new drug or biological products which would provide a meaningful therapeutic benefit to pediatric patients over existing treatments or were likely to be used in a substantial number of pediatric patients. The proposed regulation also included certain marketed drugs or biological products such as those indicated for a very significant or life threatening illness.

At the time that the Agency issued the proposed rule, FDA also initiated other actions to encourage the development of adequate pediatric use information. These actions included: publication of guidance on clinical trial designs for assessing pediatric pharmacokinetic studies for drug and biological products; development of an additional guidance document on pediatric clinical trials; and discussions with the pharmaceutical industry on a policy exempting user fees for pediatric supplements. In the preamble to the proposed rule, the agency had noted that "financial and other incentives to manufacturers, although largely beyond FDA's current authority, could further increase the number of drugs and biologics with adequate pediatric labeling.

The incentive approach was provided by Congress in the Food and Drug Administration Modernization Act, enacted in November 1997. This legislation included section 111 the "pediatric exclusivity provision." This provision created a financial incentive--an additional six months of market exclusivity to industry for conducting pediatric studies on new drugs, as well as drugs that are already on the market.

In late 1998, FDA finalized its previously proposed regulations regarding pediatric studies. While no products found safe and effective in adults are to be delayed or denied approval due to lack of trials in the pediatric population, there would now be a requirement for a manufacturer to do trials in children expeditiously.

Later in this session, Dr. Murphy will provide much greater detail about the Agency’s final rule, the pediatric exclusivity provision, and how they interact. However, I want to make just a few comments about these two regulatory tools. The final rule and the pediatric exclusivity provision are critical in ensuring needed and timely pediatric drug development. In the past 18 months--November 1997 to May 1999, we have seen more interest and activity in this field than in the past several decades. Between June of 1998 and May of 1999, we have received over 115 proposals from sponsors for various studies they are requesting to perform in the pediatric population as compared with 70 Phase IV commitments made from 1991 to 1997. We are finally gaining ground on this important issue.

We also have seen a needed shift in attitude toward clinical testing in the pediatric population on the part of all involved the Agency, industry, researchers, and parents. However laudable the progress, challenges still exist.

What are the barriers? First, the term "pediatric population" is not really one homogeneous group of patients, but is really a collection of highly variable subgroups. From neonates to infants to teenagers they are all lumped in under this heading, and yet they all provide their unique issues. Neonates are often seen as one of the most difficult age groups to test in because of the potential differences in how their bodies will metabolize a given drug. However, that age group usually has the advantage of being highly monitored by a variety of almost "Star Trek" quality devices and highly skilled hospital staff. Infants, on the other hand, often don’t have the 24 hour monitoring that neonates get, or if they do, it is by their parents--not always the most unbiased observers.

On the other end of the spectrum, adolescent patients, while being quite able to communicate with providers and parents unlike neonates or infants, may not always do so. Teenagers throughout the ages have never been the most compliant. The differences I’ve notes are not a comprehensive list, only a few of the most obvious, to underscore that each age group that falls under the heading of "pediatrics" has its own unique considerations that must be taken into account.

Recruitment of subjects for trials is also a challenge. It requires individuals who can understand parental concerns and communicate that understanding. Often a number of family members need to be involved in this decision making activity, and the investigator’s ability to explain things a number of times to both parents, the grandparents and other significant family members becomes critical to success. Defining what benefit a child may derive from the additional discomforts of blood drawing, frequent hospital or clinic visits, or other discomforts the child may experience is an important aspect of assuring the ethical implementation of a trial.

Trial design issues such as the requirement for hospitalization, duration of the study, number and timing during the day versus evenings or weekends--of evaluation visits, the need to decrease or stop current therapy to initiate study therapy are all challenges that make study recruitment difficult. The parent, caretaker--or older child--must weigh the benefit of the study to the patient--or themselves--versus the loss of work or school, and disruption to the family and daily living that may result from participation in a study.

Another critical variable in children that must be considered involves growth and maturation. These are the "expected" changes throughout infancy, childhood and adolescence. It becomes more difficult to define the effects of some chronic therapies in children and to differentiate their positive effects or possible negative impact on these dynamic processes of childhood. Long-term follow-up, often several years, of therapeutic interventions may be needed to assess neurodevelopment, behavior, bone and joint growth.

Another challenge regarding where the simple in an adult study becomes complex in pediatric population is exemplified in determining appropriate endpoints. Fundamental measurements, such as vital signs, height, and weight taken for granted in adults, are very labor and time intensive in pediatrics. Weight is also an example of the "same" measurement as obtained for adults, only in children it is a dynamic growth curve against which weight must be assessed. The important outcome measure is the maintenance of the rate of weight gain, not simply weight maintenance or weight gain.

In order to determine appropriate endpoints, we must look beyond our traditional tools such as spirometry and utilize other tools such as observation scales for respiratory distress. Another example is pain scales. The pain scales used in adult studies are a bar with numerical options extending from one extreme to the other. This concept is often not transferable as ordinal numbers to children. A pain scale utilizing sad and happy faces is sometimes used in an attempt to capture the same endpoint measurement.

And, of course, there is the cost of completing these trials. There is no argument that having children participate in clinical trials often requiring long-term follow-up requires more expertise, technology and personnel time, which is expensive.

However, even as we acknowledge the many challenges presented by testing in children, allowing doctors to prescribe without adequate pediatric use information is simply unacceptable. Incorrect dosing not only decreases the likelihood of benefit, but also increases the potential for adverse events

Research is providing those who conduct clinical trials with technologies and methods that allow studies to be conducted where it was not possible before. Blood sampling, blood diagnostics; methodologies such as population PK and PK/PD studies; and improved diagnostic equipment are tools and methods that will help us to reach our goal of better labeling information for pediatric medicine. The days of rejection and reluctance of clinical testing for drugs for pediatrics are over we now all have our unique roles to play to see that this testing is well done.

For FDA’s part, we will have the very important task of defining what pediatric studies are needed and requesting or requiring sponsors to perform these studies. It is our commitment to work with the scientific, professional and consumer communities, to see that we do the best for the health and well-being of our children. They deserve no less than the best science and the deepest compassion that we can provide to meet their needs.