Pediatric Drug Development


Applied Clinical Trials

Applied Clinical TrialsApplied Clinical Trials-01-01-2005

Pharmaceutical companies need to integrate pediatric assessments into the standard drug development process and build up pediatric competence.

Although children enjoy the best health care in history in developed countries, they are still not benefiting sufficiently from modern advances in pharmaceutical treatment. In some parts of the world, measures to address this situation are underway. Pediatric legislation is being addressed in the United States, and the issue is discussed within the European Union and in Japan. In fact, pediatric assessment of new drugs at an early development stage is now mandatory in the United States. This will result in the commitment of pharmaceutical companies to perform pediatric research once safety and efficacy data are available in adults. If the disease doesn't exist in children, then this requirement will be waived. In exceptional cases, where a new drug offers hope in a lethal or severe disease, an accelerated clinical development will be considered.

Pediatric drug development is evolving into an area of shared responsibility of health authorities, clinicians, and pharmaceutical industry and parentpatient advocacy groups. Implementation will require ethical, therapeutic, and resource considerations. In addition, a fair compensation must be considered for those companies that are making additional investments in this area.

Child health care and progress of modern pharmaceutical treatment

Pharmaceutical treatment of children has undergone fundamental changes over the last hundred years. Changes in this framework were provoked by catastrophes that mobilized enough public concern to address this issue.


One such catastrophe occurred in the early 20th century. A number of children in the United States died of contaminated diphtheria vaccine. This led to the U.S. Biologics Control Act in 1902.


In 1937, 105 patients, including 34 children, died after drinking an antibiotic preparation named Elixir Sulfanilamide. No one had performed human safety testing prior to prescribing of the drug. This tragedy led to the passing of the Federal Food, Drug and Cosmetic Act in 1938,


and required pharmaceutical companies to submit a new drug application report to the FDA showing drug safety before the interstate shipping of any new pharmaceutical agent. The Act also banned dangerous drugs as well as false and misleading labeling.

In the 1960s, the use of thalidomide in pregnant women led to thousands of children born with phocomelia, a shortening or complete absence of one or several limbs.4 Legislation was introduced in the United States that required companies to prove both safety and efficacy of new drugs only after this catastrophe.

Drug discovery and clinical drug development

Drug discovery and clinical drug development were processes hardly separated from each other a century ago. Chemists who synthesized new substances often tested the agents on themselves or members of their family. The Declaration of Helsinki


was established by the World Medical Association following unacceptable trials by medical doctors in various countries. The evaluation of a new drug or treatment scheme is a fairly new concept, and is legitimate as systematically conducting experiments in patients. It took decades to establish the standard that patients should be fully informed when they participate in such an experiment. The framework that resulted, Good Clinical Practice (GCP), was first developed in the United States. It has expanded over the last decades and gained worldwide recognition.


Although many have found it to be bureaucratic, GCP adherence ensures standardization and acceptability by most health authorities. The European Union's Clinical Trial Directive


has been greatly influenced by this framework.

In 1963, Harry Shirkey described how the legislative changes introduced in response to drug toxicity in children proved advantageous to adults. However, this led to fewer drugs being recommended for use in children due to the insufficient clinical evidence of safety and efficacy. Shirkey used the term "therapeutic orphan" to describe this situation.8 This transfers the responsibility and the liability of treating a child to the treating physician/pediatrician and leaves the pediatrician with the alternative to not prescribe the drug as well as withhold potent medicine—or to prescribe the drug off-label.

Pediatricians and physicians have learned to improvise their treatment. In most countries dosing regimens were developed for children—but with different frameworks. Most countries have one or several dosing schemes published by different institutions.9,10 Experiences with children's treatment have been published, and over time the pediatric community gained aconsiderable body of experience. Still, the pediatric/medical community remains several years to decades behind. As a result, children are disproportionally treated with older, less modern drugs.

Globalization of modern drug development

A century ago, drug discovery was done by a multitude of national companies. Until a few decades ago, national states were eager to protect their own market and industry. Clinical trials performed abroad were often not accepted and had to be repeated in the respective country or region where registration was requested. Today, large international companies plan the drug development on a worldwide basis; it is not relevant where the clinical trial is performed. What


important is that the data can be compared from the different countries where patients have been recruited. In Europe, some people believe that increased requirements for pediatric data will lead to more research conducted there. This will not happen automatically: European pediatric research institutions and networks are presently competing with investigation sites elsewhere. Some countries, such as Germany, are establishing national pediatric clinical research networks. At present, the research networks are not European-wide. In some disease-specific areas, e.g., oncology or pneumology, international cooperation has advanced further.

Several key factors have facilitated this internationalization. Most important are the two processes known as GCP and the International Council on Harmonisation, ICH. GCP applies to clinical trials6 while ICH sets the framework for the entire drug development and registration process. This must also be agreed upon by the health authorities and pharmaceutical industry of the United States, Europe, and Japan regions.7

Integration of pediatric assessments into the general drug development process

In the United States, there have been several attempts to inspire the pharmaceutical industry to generate more data in children. The first successful attempt was the creation of the voluntary Pediatric Exclusivity (PE) within the FDA Modernization Act (FDAMA) 1997, re-authorized as BPCA (Best Pharmaceuticals for Children Act) in 2002.


In 1997, PE was accompanied by the Pediatric Rule, which gave the FDA authority to mandate pediatric clinical development in drugs where the authority saw a high clinical need. When the Pediatric Rule was struck down by a U.S. federal court in 2002, both houses of the government rapidly agreed with the new legislation: the Pediatric Research Equity Act (PREA).


The rule re-established the FDA's authority to mandate pediatric drug development. PREA makes a pediatric assessment mandatory at the pre-IND meeting with the FDA. PREA and BPCA are linked by a common sunset of 30 September 2007, and it will be a political decision of both the U.S. Senate and Congress if this legislation will be continued. Through the link between PREA and BPCA, pharmaceutical companies and FDA are encouraged to negotiate a pediatric development plan that will at the end of the patent life result in a six-month prolonged exclusivity that protects drugs from generic erosion.

Following the U.S. example, a draft pediatric regulation was published by the EU Commission on 29 September 200413 and will be debated in the EU parliament and by the EU Health Council in the coming months and years. A final EU legislation can be expected no earlier than 2006. The draft EU regulation provides mandatory pediatric drug development combined with a reward of six months patent exclusivity, but focuses more on mandatory requirements. A Pediatric Committee will supervise inclusion of a Pediatric Investigation Plan into all drug development plans.

Due to the evolving framework in the U.S., the EU, and in Japan,14 pharmaceutical companies need to integrate pediatric assessments into the standard drug development process and to build up pediatric competence. ICH E 1115 describes three major scenarios of drug development in children:

1). severe or life-threatening diseases in children only, and no sufficient therapeutic alternatives are available

2). severe or life-threatening diseases in children and adults and no sufficient therapeutic alternatives are available

3). all other conditions and diseases.

Only in scenario 1) or 2) is an early development of a new drug in children ethically justified, taking into consideration the risk of exposure to a new substance.

The discussions of the evolving pediatric legislative framework in the United States and Europe have helped to highlight the place of pediatric issues in drug development. Safety and efficacy data in adults will have to be generated before clinical trials in children are initiated where acceptable therapeutic alternatives are on the market and a "deferral" is issued for pediatric development. If the health authority confirms that the disease does not exist in children, no pediatric development will be required ("waiver"). Scenario 1) and 2), i.e., early pediatric development of a drug targeting a life threatening or serious disease for which no acceptable therapeutic alternatives exist, will therefore remain an exception. The major diseases of this type of scenario could be cancer or genetic diseases that cause early death in children.

If a company decides to accelerate clinical drug development in children, test batteries in preclinical safety & toxicology and the development of pediatric formulations will have to be shifted into earlier development stages. Pediatric formulations can take up to two years for development. The decision to accelerate pediatric drug development requires a careful balance of therapeutic, financial, and logistic risks and benefits. No company has unlimited resources, and resources that are invested into failed projects will be missed in other projects with a high therapeutic potential.

New partners

The 20th century witnessed significant changes in child health care. The general increase in the level of education, and the availability of information combined with technological advances, allows parents to communicate among each other and become partners in the complex process of child health care. Parents' knowledge of their children are now increasingly recognized by the medical community. Parents and advocacy groups should be treated as partners in child health care. This can be demanding, but the potential benefit of using the knowledge of parents and the influence of advocacy groups in campaigning for children's health issues far outweighs the challenges.


Pharmaceutical companies and health authorities are developing a shared responsibility in assuring that children benefit as early as possible from innovative therapies and new drugs. To achieve this goal, both sides need to strive towards a high level of trust between each other. For pharmaceutical companies this will mean keeping commitments made to health authorities and complying with the social responsibility of the respective company. For health authorities this will mean not to overload pharmaceutical companies with research requests that might result in unacceptable bureaucratic burden. It is further hoped that the health authorities of Japan, the United States, and EU, as well as other regions, harmonize their requests to pharmaceutical companies.

The more we push forward the boundaries of scientific knowledge, the more we see how children could benefit further. It would be desirable if the 21st century was described in the future as the time when children fully benefited from pharmaceutical progress.16


1. P.J. Hilts,

Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation

(New York: 2003).

2. I. Choonara et al., "Paediatric Medicines: Global Development and Clinical Investigations," Scrip Report (PJB Publications Ltd, 2000).

3. P. Wax, "Elixirs, Diluents, and the Passage of the 1938 Federal Food, drug and Cosmetic Act," Ann Intern Med (122) 456-461 (1995).

4. H.B. Taussig, "A Study of the German Outbreak of Phocomelia," JAMA 1962 (180) 1106-1114 (1962).

5. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects.

6. ICH E 6 Guideline for Good Clinical Practice


8. American Academy of Pediatrics, Committee on Drugs, "Unapproved Uses of Approved Drugs: the Physician, the Package Insert, and the Food and Drug Administration: Subject Review," Pediatrics, 98, 143-145 (1996).

9. UK pediatric formulatry Medicines for Children,

10. G.A. Von Harnack, Pädiatrische Dosistabellen, Wissenschaftliche Verlagsgesellschaft, Germany, June 2003.



13. Proposal for a regulation on medicinal products for paediatric use and amending Council Regulation (EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC) No 726/2004 (presented by the Commission), http://

14. A. Uchiyama, "Pediatric Clinical Studies in Japan: Regulations and Current Status," Applied Clinical Trials, 11 (7) 57-59 (2002).

15. ICH E 11: Clinical Investigation of Medicinal Products in the Pediatric Population.

16. P.H.Y. Caldwell et al., "Clinical Trials in Children," Lancet (2004).

Klaus Rose, MD, is head of pediatrics, Novartis Pharma AG, Clinical Development and Medical Affairs, and chairman of the Novartis Pediatric Advisory Group (PAG), 4002 Basel, Switzerland, +41 61 324 2707, fax +41 61 24 2813, email: He is also chairmanof the Medicines for Children Working Party, EFGCP.

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