30 November 2021

Clinical Trials in Children

Pediatric clinical trials for the COVID-19 vaccine have started in the United States for children as young as six months. The COVID-19 vaccine made by Pfizer-BioNTech is already authorized for emergency use in anyone 12 and older in the U.S., Canada, and the European Union. The company is seeking FDA approval for use of the vaccine for children over five years old.

Many drugs prescribed to children have not been thoroughly tested in children through adequate, well-controlled, and validated clinical trials. Before the FDA initiated a pediatric program, only about 20 percent of drugs approved by the FDA were labeled for pediatric use.

The historical lack of pediatric clinical trials stems from a variety of reasons.

Running a clinical trial in children has special considerations, particularly since children have specific needs. Among those needs are the logistics of carrying out the studies. You need child-friendly environments, from age-appropriate equipment and medical techniques to pediatric specialists who are sensitive to a child’s fear, according to an article on the FDA website. Some procedures that may be easier for adults can pose challenges for children, such as on-demand urine samples or blood draws.

There are also clinical concerns, such as appropriate dosing and children’s biology, metabolism, and development. Children may metabolize active ingredients differently. Simply reducing a dose is often not sufficient to determine efficacy and safety of a drug in children. Studies must use appropriate formulations for each age group.

Increasing Pediatric Trials

The Pediatric Research Equity Act (PREA) gave the FDA the authority to require pediatric studies in certain drugs and biological products. A sponsor who will be submitting an application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial Pediatric Study Plan (PSP) within 60 calendar days after the date of the end-of-Phase 2 meeting with FDA (unless FDA and Sponsor agree to another time). Sponsors who do not meet this requirement risk receiving a Non-Compliance Letter under 505B(d)(1) of the Federal Food, Drug, and Cosmetic Act.

Aside from the rebuke of a non-compliance letter, the Act also incentivizes sponsors and investigators to include pediatric arms in their clinical trials. Sponsors receive certain protections, such as marketing exclusivity, if they include studies in children in their drug development.

For antibiotics and drugs that are already on the market, the FDA offers mechanisms through the National Institutes of Health (NIH) to fund pediatric studies. The NIH, in consultation with the FDA and other pediatric experts, publishes an annual Best Pharmaceutical for Children Act (BPCA) Priority List of Needs in Pediatric Therapeutics.  This list must include drugs for which pediatric clinical trials are needed but funds are not available to support such trials.

Since the passage of PREA, there has been a dramatic increase in research that has resulted in drug labeling additions for over 80 drugs. As a result, physicians have more accurate drug dosing parameters.

IRB Review of Pediatric Trials

The federal regulations related to FDA-regulated products (21 CFR 50.50 to 50.56) outline requirements that institutional review boards (IRB) must follow to ensure additional safeguards are in place for children who will be involved in research.

In assessing the risks and potential benefits, an IRB should consider the circumstances of the children to be enrolled in the study. For example, an IRB should consider the  health status, age, and ability to understand what is involved in the research. The IRB should also review the degree of risk and potential benefits to the individual child, other children with the same disease or condition, and society as a whole.

For any protocol involving children, the IRB must determine which of the following three categories of research apply to that study, if any. The IRB must also determine whether one or two parent signatures are required, although typically two parent signatures are only required for the third category.

Research not involving greater than minimal risk to the children.

To approve this category of research, the IRB must make the following determinations:

  • the research presents no greater than minimal risk to the children; and
  • adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in HHS regulations at 45 CFR 46.408.

Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual child subjects involved in the research.

To approve research in this category, the IRB must make the following determinations:

  • the risk is justified by the anticipated benefits to the subjects;
  • the relation of the anticipated benefit to the risk presented by the study is at least as favorable to the subjects as that provided by available alternative approaches; and
  • adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in HHS regulations at 45 CFR 46.408.

Research involving greater than minimal risk and no prospect of direct benefit to the individual child subjects involved in the research, but likely to yield generalizable knowledge about the subject’s disorder or condition.

In order to approve research in this category, the IRB must make the following determinations:

  • the risk of the research represents a minor increase over minimal risk;
  • the intervention or procedure presents experiences to the child subjects that are reasonably commensurate with those inherent in their actual, or expected medical, dental, psychological, social, or educational situations;
  • the intervention or procedure is likely to yield generalizable knowledge about the subject’s disorder or condition which is of vital importance for the understanding or amelioration of the disorder or condition; and
  • adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in HHS regulations at 45 CFR 46.408.

If the IRB believes that the research does not meet the requirements for any of the above categories, but finds that it presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, it may refer the protocol to the Commissioner of FDA for review.

Children who are part of clinical research deserve additional protections. Several U.S. regulatory agencies have developed mechanisms and guidance both to encourage additional research and to protect the children in that research. IRBs that may be reviewing protocols that include pediatric patients should be up to date with any requirements or additional guidelines.