The following is an excerpt from the second edition of this book:

The two decades since the foregoing material was written has witnessed remarkable progress in drug studies in infants and children. The introductions to the first three editions of this book detailed the historical perspectives related to pediatric pharmacology and lamented the lack of studies in infants and children, which led to inadequate labeling of drugs for use in this special, vulnerable population. As a consequence, infants and children were considered therapeutic orphans. The situation changed dramatically around the time of the publication of the second edition in 1992. The following paragraphs describe the changes that have occurred, the rationale for the changes, and a glimpse into the future as well as a description of the regulatory environment in the United States and Europe.

During the last several decades, many individuals and organizations within the pediatric community, including academia and the American Academy of Pediatrics (AAP), working with the National Institutes of Health (NIH), the Food and Drug Administration (FDA), and the pharmaceutical industry, have sought to find ways to increase pediatric drug research and, consequently, labeling for children. These efforts culminated in a 1990 workshop titled Drug Development and Pediatric Populations, which was jointly sponsored by the Institute of Medicine of the National Academy of Sciences, the National Institute of Child Health and Human Development (NICHD), the FDA, the pharmaceutical industry, and the AAP. The workshop made recommendations regarding impediments to drug development for the pediatric population and their solutions. In retrospect, this was a watershed meeting. Recommendations from the workshop included (a) that the FDA explore ways to facilitate the approval of drugs for children and inclusion of pediatric information in drug labeling, (b) that economic incentives to drug development for children be addressed by granting extended patent exclusivity to sponsors for drugs that are studied in children and for which data are submitted to the FDA in support of pediatric labeling, (c) that the pharmaceutical industry take a more proactive stance with respect to drug development for children, and (d) that the National Institutes of Health establish a network of pediatric centers to facilitate the conduct of pediatric clinical studies. During the last decade, each of these recommendations has been implemented. In 1997, the FDA Modernization Act (FDAMA) was passed by Congress, giving extended patent exclusivity to companies for performing pediatric studies; in 1994 and 1998, the FDA implemented new regulations to facilitate and require pediatric studies of drugs; and in 1994, NICHD funded the first group of pediatric centers to inaugurate the Pediatric Pharmacology Research Unit (PPRU) network.

The FDA’s regulatory position was first articulated in 1970, when the agency stated that “drugs used for children must be tested in children”; the Committee on Drugs (COD) of the American Academy of Pediatrics supported this view in a position paper that appeared in the journal Pediatrics in 1995. The COD pointed out that every time a physician prescribes an unlabeled drug for a child, he or she is performing an uncontrolled experiment with an enrollment of one with no protocol or outside overview. The COD further stated that it is unethical not to study drugs in children.

One of the Institute of Medicine’s recommendations asked the FDA to take a more positive role in solving the problem of the therapeutic orphan. Several recent actions by the FDA in this regard are cited in what follows.

The FDA has taken a more proactive role in recent years in ensuring that inclusion of pediatric use information in drug labels, derived from information from clinical studies, is standard. The pediatric regulatory initiatives issued in recent years have provided an economic incentive for pharmaceutical manufacturers to conduct studies in children and have set standards and requirements for pediatric studies that the industry must meet.

A description of the regulations and law provide an understanding of the incentive for manufacturers to conduct pediatric studies as well as the current requirements for pediatric studies that the pharmaceutical industry must meet. A brief history of the regulatory efforts made to address the lack of information for children in prescription drug labeling will allow the reader to realize what a sea change has taken place both at the FDA, the academic community, and the European Medication Evaluation Agency over the last 15 years. The process by which new drugs are developed and approved for marketing in the United States and in Europe is not well understood by most observers, and the process by which drugs are developed for use in children is probably even less clear.

In the United States, the FDA is responsible for assuring that new drugs and biologics are safe and effective for their proposed uses before they are approved for marketing. The FDA’s role as a regulatory agency is not to develop therapeutic agents or to conduct clinical trials to determine the safety and efficacy of the product. New drug development is the responsibility of pharmaceutical manufacturers and government or private research institutions. The FDA’s responsibility is to ensure that the rights and safety of human subjects are protected during the clinical testing of investigational drugs, to review and evaluate the safety and efficacy of proposed new therapeutics on the basis of data submitted by the sponsor, and to determine whether the balance between the benefits and the risks associated with a new drug is sufficiently favorable to justify approval for marketing.

After preclinical testing of a potential new drug is completed and before clinical trials in humans can begin, the sponsor of the new drug must file an Investigational New Drug (IND) application with the FDA. Requirements for this submission are outlined in the regulations and include the results of the preclinical testing describing the pharmacologic and toxicity profile of the drug and the chemistry; the manufacturing controls; and the purity, potency, and stability of the agent. In addition, a proposed protocol for the initial phase 1 and phase 2 clinical trial in humans is included. This initial protocol may not be initiated until the FDA notifies the sponsor that based on a complete evaluation by a multidisciplinary review team the study is safe to proceed. The FDA has 30 days to complete this review and notify the sponsor of its decision.

Following this, studies to define a safe and tolerable dose and to determine the activity of the agent are undertaken in phase 1 and phase 2 studies. The sponsor may initiate these studies as soon as the protocols are approved. However, any study deemed to represent an undue risk to participants may be put on hold for safety concerns at any time information sufficient to make this assessment is obtained.

When there are data adequate to support the continuation of the new drug development process, the sponsors meet with the FDA to review the data obtained from the phase 1 and phase 2 studies and to plan for the phase 3 studies. The phase 2 and phase 3 studies should be designed with the intent to demonstrate substantial evidence of efficacy and safety. Studies likely to provide such data are described in the Code of Federal Regulations as adequate and well controlled. As such, these studies should include clear objective criteria for assessing positive and negative effects, an appropriate control group to allow valid comparison with the group receiving the investigational drug, a well-defined patient population that is randomized to assure comparability among the treatment groups, and measures to eliminate bias, such as blinding or randomization.

The completed and analyzed results of the clinical trials are submitted along with proposed labeling and technical information as a New Drug Application (NDA) by the applicant for FDA review. The FDA must determine whether the data submitted satisfy the statutory requirements for safety and effectiveness, that is, “adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed,” and “substantial evidence [of efficacy] consisting of adequate and well controlled investigations.” The standard time to review and take an action (i.e., approval or nonapproval) on an application is approximately 10 months. Priority applications are reviewed and have an action taken in 6 months.

Once an NDA is approved, new information about the drug’s safety profile is monitored by periodic safety updates submitted by the applicant as well as reports received from the MedWatch program. MedWatch is a reporting system designed to detect rare and serious adverse events after approval of a therapeutic agent. Premarketing clinical trials do not reflect the actual use of the drug after approval. In clinical trials, the populations studied are likely to be narrow, only patients with those indications for which efficacy is being studied are included in the trials, the drug is frequently used for shorter time periods than may be the case in actual use, and most NDAs usually include between 3,000 and 4,000 patients, so that rare adverse events would be very difficult to detect.

In addition, at the time of approval, the applicant may agree to conduct further clinical trials during phase 4 (which is the time after approval), to provide additional important information regarding appropriate use of the drug. These studies are usually intended to answer questions raised during the review of the clinical data that are not substantial enough to delay approval, but are sufficiently important to warrant a request for further investigation.

Prior to 1979, it was considered unethical to enroll children in “experiments,” that is, clinical trials. They were considered to be “protected.” In 1977, the American Academy of Pediatrics, reacting to the paucity of information for children in drug labels, asserted that it was unethical to adhere to a system that forced physicians to use drugs in what was basically an uncontrolled experiment whenever they wrote prescriptions for children. The Academy stated that it was imperative that new drugs that were to be used in children should be studied in children under controlled circumstances so that the benefits of therapeutic advances would become available to all who would need them. This was a powerful, yet simple statement: Children deserve the same standard as adults. If adequate and well-controlled studies were required to determine the efficacy of the products used in adults, then the same should be true for products used to treat children. It was now considered unethical not to study children. Following this unprecedented statement, in 1979, the FDA confirmed the need to have information on how best to use a product in the pediatric population. Thereafter, a number of milestones in Pediatric Drug Development in the United States and in Europe occurred (see Table 1.1) The FDA issued a regulation in 1994 that required that statements on pediatric use of a drug for an indication approved for adults must be based on substantial evidence derived from adequate and well-controlled studies conducted in children, unless the requirement was waived.

The intent of the initial regulation (1994 rule) was to encourage manufacturers to conduct the necessary trials so that adequate prescribing information would be available to physicians. Unfortunately, it did not generate the response intended. Few clinical trials were initiated in the pediatric population. Manufacturers cited financial, medicolegal, and methodological disincentives, especially for products already approved for adults. These products were available to physicians for prescription use outside of labeled indications through the practice of medicine. The FDA could encourage but not require that a sponsor conduct the appropriate trials to support pediatric labeling.