Pediatric Trials: The Impact of U.S. Legislative and Regulatory Efforts


Applied Clinical Trials

Applied Clinical TrialsApplied Clinical Trials-01-01-2005

The Pediatric Rule made everyone begin to assess, think, and plan for pediatric needs.

It is not intuitive that scientists, clinicians, and parents would allow the most complex, constantly evolving human beings—the pediatric population—to be treated with unstudied medicines and therapies, while demanding a high level of evidence for therapies for the adult population. Unfortunately, this happened during the recent decades of rapid scientific and therapeutic discoveries. Why would it be acceptable that a population that is growing, developing, and inherently highly variable would not be studied while the more stable, not growing, and less variable adult population would be? No one would argue that the 500- to 1000-gram infant is the same metabolically, physiologically or behaviorally as a preschooler or adolescent, much less a 70-kg adult. And yet we have prescribed, dosed and treated the pediatric population without pediatric studies of a drug's absorption, distribution, metabolism, elimination, or dosing, or without clinical trials to determine pharmacokinetics, pharmacodynamics, safety, and efficacy of the prescribed therapy.

Pediatric Trials: The Impact of U.S. Legislative and Regulatory Efforts

In 1963, Dr. Harry Shirkey coined the phrase "therapeutic orphans" to denote the evolving situation with therapies used in the pediatric population.1 In 1977, the American Academy of Pediatrics called for adequate and well-controlled trials of the same quality and standards applied to therapies marketed for use in adults.2 In 1979, the Food and Drug Administration added a "pediatric" subsection to its label to permit more pediatric-specific information to be in the label.3 Despite the public call for more and better information on the therapies being used in children, we entered the 1980s with the majority of therapies being used in children having not been studied in that population.4 The era of development of therapies for HIV infections forced all concerned to recognize the serious consequences of such a failure. The first therapy approved for treatment of HIV (AZT-Zidovudine) was not available for children for many years after it had been studied and approved in adults. If a therapy is not being developed for the pediatric population, then there are no clinical trials in that population and limited access to a potentially new, life-saving therapy. Adults with HIV fought hard to have access to new therapies through such mechanisms as large, open treatment, investigational new drug (IND) programs and accelerated approval of new therapies for HIV. Therefore, new therapies were available not only through the usual approved and marketed drug process, but also available through the large expanded access programs and clinical trials programs for HIV therapies. This effort only highlighted both the lack of approved therapies and lack of access to clinical trials for new and promising therapies for the growing pediatric HIV population.

The crises of having children die because of lack of access or approved therapies propelled both NIH and FDA to develop approaches which would facilitate the development of pediatric trials of therapies for HIV. This approach would also illuminate the need for determination of new pediatric endpoints as well as pediatric trial design approaches. Pediatric trials became an important component of the drug development program for didanosine (ddi-Videx) and many subsequent therapies for HIV.

In an effort to recognize that some data generated from adult trials could be used to avoid exposing children unnecessarily to duplicative information gathering, the FDA proposed a process called "extrapolation" in the early 1990s. Extrapolation was appropriate if the "course of the disease and the effects of the drug are sufficiently similar in adults and may conclude that pediatric effectiveness can be extrapolated from adequate and well controlled studies in adults, usually supplemented with other information obtained in pediatric patients..." This mechanism was officially adopted by FDA in 1994.5 Though extrapolation is an important scientific and regulatory approach, it is not appropriate for many diseases or conditions.

In 1997, the FDA proposed, and in 1998 finalized, what was called the "Pediatric Rule."6 This regulation required all sponsors to develop studies for the pediatric population if they were to submit an application when there would be, or already was, substantial use of the product in the pediatric population or if the development of the product would result in a "meaningful therapeutic benefit" for pediatric patients. The limitations of this regulation were that it functionally applied only to applications submitted or to be submitted to the agency and to the adult indication under development. It was, however, very important in making everyone (sponsors, FDA, and researchers) begin to assess, think, and plan for pediatric needs early on in the drug development process. The Pediatric Rule did not go into effect until April of 1999, and FDA could not require studies to be submitted until December 2000, 20 months after the effective date. By October 2002, subsequent to a Court ruling, FDA was enjoined from enforcing the Pediatric Rule. The Pediatric Rule was effectively in force for less than two years before being enjoined. In December 2003, the Pediatric Research Equity Act (PREA) was enacted. This Act put into legislation most components of the Pediatric Rule and made the Act apply to all applications submitted since April 1999.7

There was an important pediatric legislative initiative involving incentives to develop appropriate use information for drugs being used in the pediatric population at the same time as the activities surrounding FDA's Pediatric Rule efforts. Encompassed in the 1997 Food and Drug Administration Modernization Act was Section 111,8 an important step that provided an incentive for manufacturers to study products for which there would be a health benefit in the pediatric population to have studies conducted. This legislation enacted a voluntary process where FDA would define the products which needed pediatric studies, outline the necessary studies, and issue sponsors a Written Request (WR). The WR would contain the critical components (e.g., types of trials, number of patients) required to be performed if the sponsor were to be granted pediatric exclusivity. If the sponsor submitted studies which "fairly responded" to the WR, as determined by FDA's Pediatric Exclusivity Board, the sponsor received six additional months of marketing exclusivity. This process has been the "engine" that has moved pediatric drug development and, coupled with the Pediatric Rule and legislation, has been a highly effective pediatric drug development program. By September 2004, FDA had identified 294 products needing pediatric information, had defined the studies needed for these products, and had issued the WR. By this same date, studies have been submitted on 110 products and new labels with new pediatric information have been completed for 79 of these products.

By the time of FDA's 2001 Report to Congress on the effectiveness and gaps in this incentive program, it was clear that the exclusivity incentive legislation was working for certain products.9 The gaps identified by the FDA were partially addressed by the Best Pharmaceuticals for Children Act of 2002.10 This Act, among other things, renewed the exclusivity incentives, created an off-patent process involving government contracts for pediatric studies, and mandated public disclosure of trial results from trials conducted under this authority.

Efforts to define the impact of the Pediatric Rule have produced evidence that pediatric drug development was occurring as part of processes established by the rule, and had contributed to almost as many pediatric applications to the agency as the exclusivity provision. Because we cannot ascribe the reasons why a sponsor conducts pediatric studies, it is more difficult to directly link the effect of the Pediatric Rule. If the studies for a product were not in response to an FDA-issued Written Request, it was assumed the studies were not conducted because of Exclusivity. Confounding this issue is the agency's approach to its use of the carrot and stick (exclusivity and the Pediatric Rule). If a product was subject to the Pediatric Rule (embodied now in The Pediatric Research Equity Act [PREA]),7 the agency would also assess the appropriateness of applying its options to utilizing exclusivity pathways. If the product had patents or marketing exclusivity and studies were needed, both processes of the Pediatric Rule and Pediatric Exclusivity, where appropriate, would be employed. In other words, the studies asked for in the WR would parallel those requested under PREA. In some instances, the WR would be broader as there may exist a number of indications applicable to the pediatric population in addition to the adult indication for which an application was submitted.

What was learned

The impact of these regulatory and legislative activities can be seen in many areas beyond the resultant production of new labeling information. In addition to ethical issues that arose early in the course of implementation of pediatric trials, two issues which became immediately apparent were the lack of scientific information needed to permit development of appropriate trials and the emergence of deficits in pediatric trial infrastructure and trained personnel. Subsequent to conduct and review of many of these studies, the results submitted revealed that we knew even less than we had previously thought.


Studies defined a new dosing regimen, new safety issues, or a lack of efficacy for 1/4 to 1/3 of the products studied. Some labels would have two or three types of changes incorporated (e.g., dosing and safety information; see Table 1).

Table 1. Exclusivity: Summary of important findings from 79 labels

Of particular importance was the ability to define products where efficacy could not be demonstrated. In one clinical trial involving solid tumors, the trial was halted because of a high rate of disease progression and early deaths. This information was included in the label to better inform the practitioner concerning the results of this study (see Table 2).

Table 2. Not sufficient evidence of effectiveness: N = 9

Effects on growth were seen in studies involving antidepressants, treatments for Hepatitis C, inhaled steroids (dose dependent effect) and attention deficit/hyperactivity disorder. Topicals containing betamethasone and mometasone demonstrated adrenal-axis suppression in the populations studied. A high percentage (28% to 75%) of children in all age ranges demonstrated hypothalamic-pituitary-adrenal (HPA) axis suppression with topical application to even a limited body surface area. Topical calcineurin inhibitors [e.g., Elidel (pinecrolimus)] studied in patients two years and older were associated with an increased incidence of pyrexia, respiratory illness, and diarrhea. Bone demineralization was described in patients after a single course of therapy with Accutane, and other therapies were associated with newly described aggressive behavior or suicidal ideation. Table 3 provides examples of new adverse events that were defined during the conduct of pediatric studies.

Table 3. New Adverse Events examples

In general, the following has been learned: pharmacokinetics are more variable than expected; pediatric specific adverse effects will be defined only if adequately studied in well-controlled trials; and therapies that work in adults may not be effective in the pediatric population. From the trials that have been conducted, we are learning that we need better endpoints and assessment tools and sometimes different trial designs to answer questions that have arisen from the conduct of these trials. The trials conducted to assess the safety and efficacy of anti-depressants in the pediatric population are examples of many of these lessons.

The lessons learned from the implementation of our legislative and regulatory mandates have also been numerous. Important observations relate to timing of the incentive, disclosure of negative findings, postapproval monitoring for safety signals and dissemination of new labeling information. Making a decision on the application's responsiveness to the terms of a Written Request, as far as determining their compliance with conducting the number and types of trials requested, can be made in the three months legislatively required. What does happen, however, is that findings of poor trial implementation, issues of improper enrollment, or conduct of the study and other variances from good clinical practices or commonly accepted scientific principles may not be discovered until well into the review. This information would, therefore, not be available at the time of the exclusivity determination. Lack of adherence to good scientific principles is considered a reason to deny exclusivity.

Disclosure of information from pediatric trials that were not approved has become an increasingly debated topic. For certain products which will less frequently have completed pediatric Phase III trials, such as some oncologic therapeutics, it has been common to put negative information in the label. Outcomes defined in Phase II trials are important information for the physician considering use of these unapproved pediatric therapies in patients who are often considering their last chance at a new therapy. In small pediatric populations, such as those with McCune-Albright, effectiveness on short-term endpoints and one-year safety are the best data that could be gathered. This information was placed in the label despite the nonavailability of long-term data.

An important reality that regulators have to grapple with is the fact that multiple pediatric trials will not be performed. Once a sponsor has conducted the pediatric trials that respond either to the FDA's Written Request or pediatric requirement, it is not likely additional trials will occur. This is unlike adult drug development where sponsors, in an effort to expand their market population and to answer required postmarketing approval requirements, will conduct additional trials. Because the pediatric market is often insignificant, additional pediatric trials are unlikely. In this milieu, negative trials become increasingly important as they may comprise a significant proportion of the total knowledge base about the performance of a therapeutic in the pediatric population. This limitation is accentuated in the context of increasing use of medications in the pediatric population.12

Ethical aspects

Because of the smaller numbers, when compared to adults, of children who have a condition or disease, it is common for pediatric efficacy and safety trials to be not only multicenter but international studies. The globalization of pharmaceutical drug development has been apparent for a number of years and has increased the need for harmonisation of certain aspects of the regulatory approaches. In 1990, experts from industry and regulators from the United States, Europe, and Japan established the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use. The primary objective of ICH is to avoid unnecessary duplication.

Early in the implementation processes involving pediatric trials, it was apparent that clearly defined goals for the ethical conduct of pediatric trials throughout the world needed to be articulated. In 2000, the International Conference on Harmonisation issued a guidance (E-11) on clinical investigation of medicinal products in the pediatric population. This document provides an overview of general principles which should be applied for the conduct of pediatric trials.13 In addition, FDA has had three public advisory meetings to discuss ethical issues surrounding the conduct of pediatric studies. These topics included a discussion of the need for direct benefit (subject vs. patient), placebo controlled trials in pediatric studies and approaches to the conduct of trials in a special needs pediatric population. The consensus statements from these meetings are available in FDA's Web site at:

In April 2001, FDA published in the Federal Register14 its final interim rule indicating it had adopted Subpart D (additional protections for children) of the Common Rule. Now Subpart D of the Common Rule is applicable to federally regulated products in addition to federally funded studies.

Presently data from studies involving over 40,000 children have been submitted to FDA in response to FDA's issued Written Requests. The enormity and complexity of the new pediatric drug development program is obvious. It places an enormous responsibility on all the parties and countries involved to ensure trials enrolling children are designed, implemented, conducted, and completed with rigor in monitoring and adherence to both good scientific and ethical principles.


1. H. Shirkey, "Therapeutic Orphans,"


, 72, 119-120 (1968).

2. American Academy of Pediatrics, Committee on Drugs. Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations. Pediatrics, 60, 91-101 (1977).

3. Labeling and Prescription Drug Advertising: Content and Format for Labeling for Human Prescription Drugs. 44 Federal Register 37434 (1979).

4. J.T. Wilson, Update on the Therapeutic Orphan, Pediatrics, 104, supp: 598-590 (1999).

5. Specific Requirements on Content and Format of Labeling for Human Prescription Drugs: Revision of "Pediatric Use" Subsection in Labeling. 59 Federal Register 64240 (1994).

6. Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biologic Products in Pediatric Patients. 63 Federal Register 66631 (1998).

7. Pediatric Research Equity Act of 2003. Public L. No. 108-155, Dec. 2003.

8. U.S. Food and Drug Administration Modernization Act of 1997. Public L. 105-115, 105th Cong. (Nov 21, 1997).

9. U.S. Food and Drug Administration. Pediatric Exclusivity Provision: Status Report to Congress. January 2001. Department of Health and Human Services.

10. Best Pharmaceuticals for Children Act, Public L. No. 107-109, Jan. 2002.

11. R. Roberts, W. Rodriguez, D. Murphy, "Pediatric Labeling: Improving the Safety and Efficacy of Pediatric Therapeutics," JAMA, 290, 1-7 (2003).

12. R. Steinbrook, "Testing Medications in Children," NEJM, 347, 1462-1469 (2002).

13. International Conference on Harmonisation: Guidance (E11) on Clinical Investigation of Medicinal Products in the Pediatric Population, 65 Federal Register 78493 (2000).

14. Additional Safeguards for Children in Clinical Investigations of FDA Regulated Products, 66 Federal Register 20589 (2001).

Dianne Murphy, MD, is Director, Office of Pediatric Therapeutics, U.S. Food and Drug Administration, 5600 Fishers Lane,Room 4B-44, Rockville, MD 20857, (301) 827-9218, fax (301) 827-1017.

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