Pediatric Medication Studies: A New Challenge for Institutional Review Boards, Ethics Committees

With modern science and technology developing during the 20th century, experimental research in humans gained weight worldwide. For a while after World War II, it was believed that atrocities committed during the war could only be carried out by cruel and insane researchers in unjust regimes.

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However, the uncovering of numerous questionable studies performed by American academic researchers,¹ such as the Tuskegee Study conducted from 1932-1972 by the US Public Health Service,^2,3 caused a shift in public opinion that eventually led to the National Research Act of 1974⁴ and the Belmont Report in 1978—which outlined the primary ethical principles in research with human subjects^5,6—and finally to the establishment of US institutional review boards (IRBs).⁷ US IRBs, which are regulated by the Office for Human Research Protection, approve research projects, can demand their modification, or can reject them.

In 1964, the World Medical Association (WMA), representing physicians worldwide,^8,9 adopted the Declaration of Helsinki (DoH) in an effort to come to terms with the research atrocities and wrongdoings committed during World War II.^10,11 Although addressing theoretically just medical doctors, the DoH is today widely regarded as a cornerstone document on human research ethics.

Since 1964 it has been revised and updated several times. Although the DoH was from the very beginning international, the Belmont Report was US national, created in 1978 by a US commission. It formulated the 3 key principles of respect for persons, beneficence, and justice.

Although the DoH and the Belmont Report are 2 separate documents and address different audiences, they both outline the basic priniciples that should be followed when research in humans is performed, including that participation in research must be voluntary, that the research must make medical sense, helps advance health care, and more. Outside the United States, the equivalent to IRBs are ethics committees (ECs). IRBs and ECs should ensure that medical experimentation and human subject research is carried out in an ethical manner.¹²

Several cruel Nazi experiments were performed on minors, most notably the Mengele experiments performed on twins.^13,14 With the growing importance of experimental treatments in modern medicine, especially in cancer, a growing general willingness developed that accepted experimental treatments also in minors.

The concept of children as "therapeutic orphans" then caused the allegation of a general lack of pediatric drug studies.¹⁵ It was supported by the American Academy of Pediatrics, the newly emerged discipline of developmental pharmacology, and the FDA, resulting in the first US pediatric law in 1997 demanding separate proof of efficacy and safety (E&S) for drugs in minors.^16-18

But this justification for pediatric studies is on shaky ground.It pretends that the 17th/18th birthday is also a physiological age limit before which everything is different in young humans and that, therefore, the E&S of drugs must be shown again in minors, as if they were a different species.

Although preterm babies are quite different from adults, children mature with each year. With puberty, the child's body grows up, even if the mind lags behind. In addition, the onset and end of puberty has shifted progressively toward an earlier age over the past 100 years.

Children cannot on their own consent to clinical studies. Depending on their age, they are asked to assent as soon as they are mature enough, usually from 7 years on. Legally, the caregivers—mostly the parents—must consent.

Interestingly, the DoH does not mention children at all. It discusses only research subjects deemed incapable of giving informed consent and demands that the physician seeks the consent of the legally authorised representative.¹⁰ Clinical research in children is discussed in the Belmont Report under the principle of beneficence, assuming that the respective study directly or indirectly contributes to better child health care.⁵

Although IRBs and ECs have seen it as their main task in the past few decades to protect children from questionable studies, they are faced with a new task with "pediatric drug development." This is the distinction between pediatric drug studies that are scientifically solid and those thatare required by the regulatory authorities in a dogmatic approach, justified by the “therapeutic orphans” concept.

Such studies are scientifically and medically pointless in adolescents, exaggerated in studies that demand e.g. separate proof of E&S of antibiotics or biologics in school age children, and often even harm young patients when comparing new treatments to outdated therapies.^16-18

Pediatric drug trials are conducted worldwide. Those required by the FDA also in the European Union (EU), and those required by the European Medicines Agency (EMA), also in the United States. Wherever such studies make no medical sense or are even harmful, IRBs and ECs face a new challenge.

Such studies are formally covered by the demands of a regulatory authority, but are nevertheless medically and scientifically questionable or even harmful. Neither the DoH nor the Belmont Report accept regulatory demands for separate proof of E&S as acceptable justifications for clinical research in humans.

In history, we often see the pendulum swinging back and forth. Although for awhile, the main belief was that minors had to be protected from clinical research. With the introduction of the first US pediatric legislation in 1997, every pediatric clinical study was regarded as beneficial, at least if it was demanded by the FDA. The EU pediatric regulation, in place since 2007, has expanded the demands for separate clinical studies in minors.^19-21

It is now time for the pendulum to swing back toward a balanced judgment on clinical trials in minors, even when they are required by the FDA or the EMA. It is time for IRBs and ECs to heighten their scrutiny on studies in minors, whether those studies make medical and scientific sense, whether they are demanded by a regulatory authority for regulatory purposes only, or if they can potentially harm young patients.

Several examples of harmful studies have already been published. One study claimed that nasopharyngeal carcinoma was a pediatric disease and performed on this basis a large international “pediatric” study comparing chemotherapy alone with chemotherapy plus an additional treatment.²²

The reason for the drug company to sponsor this study was to get a 6-month US patent extension. The reason for the involved researchers was career advancement: funds for the study, networking, and publication in a renowned international medical journal. But nasopharyngeal carcinoma is not a pediatric disease. It occurs in minors, such as the flu occurs in minors as well.^16-18

The EMA demanded 2 studies in adolescents with malignant melanoma with just 1 drug, while medically, combination treatment had become the standard-of-care in the meantime. Both studies recruited a number of patients but then had to be terminated.²³

An EMA-demanded placebo-controlled study in young mothers with perinatal depression should prove that the drug in question also works before the 18th birthday.^16-18 Such studies represent a new challenge for IRBs and ECs. They are formally covered by the current regulatory and legal framework but are nevertheless scientifically and medically pointless, and often even have the potential to harm.²⁴

Furthermore, these studies are supported and promoted by a section of mainstream science researchers, particularly those who have made their life's work measuring drug concentrations in the blood and serum of minors. This discipline of developmental pharmacology was instrumental—along with the American Academy of Pediatrics and the FDA—in lobbying for the first US pediatric legislation. Its representatives continue to justify these approaches.^25-27

There are now a number of areas within pediatrics in which relevant academic researchers are openly opposed to separate pediatric studies in people under 18 years of age, particularly in epilepsy and rheumatic diseases, which can also affect young people.^16-18 But there is still strong academic support for “pediatric drug development,” also called "Better Medicines for Children" by the EU.²⁸

IRBs and ECs are faced with the challenging task of using the key requirements of the DoH and the Belmont Report when reviewing submitted studies. They may conclude that the respective study in question is unethical, even if it was based on a demand from the FDA or the EMA.

This is a very controversial issue. Hopefully, more IRBs and ECs will take up this task in the near future and also communicate the results of their experiences.

About the Authors

Earl B Ettienne, BScPharm, MBA, LPD,Assistant Dean of Graduate Programs and Industrial Partnerships, Howard University, College of Pharmacy, Washington, DC; and Klaus Rose, MD, MS, klausrose Consulting, Riehen (BS), Switzerland.

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