4 January 2023

FDA Posts Draft Guidance on Pediatric Clinical Trials

In September 2022, the FDA issued draft guidance intended to provide additional protections of children in clinical trials. The draft guidance is intended to assist industry, sponsors and institutional review boards (IRBs) when considering the enrollment of children in clinical investigations of drugs, biological products and medical devices.

“Children need access to safe and effective medical products and health care professionals need data to make evidence-based decisions when treating children. However, children are a vulnerable population who can’t provide consent for themselves and are afforded additional safeguards when participating in a clinical investigation,” said Dionna Green, M.D., director of the FDA’s Office of Pediatric Therapeutics. “The best way to provide children with safe and effective treatment options is by including them in clinical research and providing these additional safeguards to protect them during clinical trials.”

As we wrote in November 2021, many drugs prescribed to children have not been thoroughly tested in children through adequate, well-controlled, and validated clinical trials. Ethical principles to safeguard  children involved in research are already included in 21 CFR part 50, subpart D, which parallels the Department of Health and Human Services regulations found in 45 CFR part 46, subpart D.

The draft guidance outlines and explains fundamental concepts for the ethical framework that IRBs, sponsors, and industry should consider when reviewing or conducting clinical trials involving children, including:

  • Scientific necessity of conducting a clinical investigation in children
  • Risk categories for interventions or procedures that do not offer a prospect of direct benefit to the child
  • How to evaluate whether an intervention or procedure offers a prospect of direct benefit to the child
  • Assessment of risk for interventions or procedures with a prospect of direct benefit
  • Component analysis of the risks of interventions or procedures
  • Potential for review, under 21 CFR 50.54 , when the research  is not otherwise approvable by an IRB
  • Parental or guardian permission and child assent

Scientific Necessity

IRBs should consider the scientific necessity of including children in a clinical trial. Their participation should be necessary to answer an important scientific or public health question directly relevant to children. For example, if the research involves a condition affecting both adults and children, and studies have been done in adults but data specific to children is still needed.

The IRB should carefully evaluate the research protocol to ensure its design includes the selection of appropriate control groups and study endpoints relevant in the pediatric population.

In writing the protocol for pediatric clinical trials, investigators can use multiple sources of information to inform the design the investigation. Information from nonclinical studies, bench testing or modeling and simulation (especially in the case of devices), and literature are useful resources on which to base the potential risks and benefits of initiating the investigation in children.

The equitable selection of subjects must also be evaluated when determining scientific necessity keeping in mind the unique challenges related to research involving children.

Risk Categories

Any intervention or procedure, including the administration of an investigational drug or use of an investigational medical device, undertaken as part of a clinical investigation in children may be associated with risk. Clinical investigations involving children should be designed to maximize the amount of  information gained and minimize the number of subjects involved.

The guidance offers contexts for identifying age-specific ‘minimal risk’ and ‘minor increase over minimal risk.’ IRBs need to consider the duration of exposure to the risk, the characteristics of the risk, and the reversibility of the harm. These considerations apply to the intervention being investigated as well as any procedures that are part of the protocol, such as blood draws, x-rays, etc.  Whenever possible procedures already being performed as part of clinical care should be used for the research.

Direct Benefit

Prospect of direct benefit refers to the potential benefit to the individual child from exposure to the research intervention or procedure in the clinical trial. It does not apply to the potential benefit from ancillary procedures that are part of the protocol, such as physical exams that are conducted as part of the trial.

Evidence to determine prospect of direct benefit can be drawn from several sources, including:

  • Evidence of clinical benefit for adults with conditions that exist in both children and adults
  • Animal or relevant device modeling or simulation data, particularly in cases of conditions that occur exclusively in children
  • Demonstration of a drug’s favorable effect on a biomarker or surrogate endpoint linked to the causal pathway, in cases when a pediatric condition has a phenotype that extends into adulthood

Balancing risk with prospect of direct benefit

21 CFR 50.52(a) requires that the IRBs find that the risk is justified by the anticipated benefit to subjects. Assessment of the risk is predicated on adequate safety data. IRBs should evaluate all available safety data, in children and adults, to conduct the risk analysis.

Factors to consider when designing a clinical investigation and assessing the potential risks to children involved in the study include the:

  • Age and degree of physiological maturity of the child;
  • Nature and natural history of the clinical condition to be treated;
  • Current severity of the condition to be treated in the child;
  • Presence of other complicating clinical conditions;
  • Safety and effectiveness of the drug or device that may have been demonstrated in older subjects, or that is expected based on other clinical or nonclinical investigations; and
  • Likely duration of drug or device use and its impact on the growth and development of the child, including behavioral and psychosocial effects.

Analyzing the components of the protocol

Analysis of the research protocol includes not only evaluating the risk-benefit of the intervention under investigation, but also the procedures that may be part of the trial. Different components of a trial may or may not offer prospect of direct benefit.

Different arms of a study, for example the placebo-controlled arm has no prospect of direct benefit for the child, but children enrolled in the arm receiving the investigational agent there is prospect of direct benefit.  For children in the placebo arm of a study, IRBs should consider the following in assessing risk:

  • Routes of administration (oral, infusion, etc.) — for example, if an intravenous catheter will be placed solely to administer placebo and is not needed for clinical management or is not needed for routine clinical care, the risk of the insertion and management of the catheter should be considered as part of the risk assessment.
  • Frequency or duration of the administration of the placebo — a single injection may be considered minimal risk, but multiple and repeated injections may be considered a minor increase over minimal risk.
  • Risk of withholding known effective therapies — If withholding or withdrawing a known effective therapy may result in significant harm to the child, the risk may exceed the minor increase over minimal risk threshold, and the use of a placebo may not be justified

If an intervention or a procedure in a pediatric protocol exceeds a minor increase over minimal risk and does not offer prospect of direct benefit, the protocol is not approvable by an IRB under 271 21 CFR 50.51, 50.52, or 50.53. However, the FDA offers guidance for exceptions to this rule.

Informed Consent

Children cannot provide informed consent and rely on their parent or guardian to give permission. Children, as well as their parents or guardians, should have the opportunity ask questions and researchers are obliged to provide information as the study progresses or the situation requires.

While children cannot provide informed consent, they should when appropriate provide assent. This means that children that are capable of providing assent, generally those over seven years of age, should provide positive agreement to participate in the research. IRBs should require provisions for obtaining assent. In some cases, this may not be possible, depending on the maturity, cognitive capacity, or developmental stage of the child. In those cases in which it is not possible to obtain assent, the IRB may waive the requirement when specific criteria are met in accordance with 21 CFR 50.55(d).

Clinical investigations in children are essential for obtaining data on the safety and effectiveness of drugs, biological products, and medical devices in children. They are also important to protect children from the risks associated with exposure to medical products that may be unsafe or ineffective. However, children are a vulnerable population that require additional safeguards and ethical considerations.

The draft guidance can be downloaded here from the FDA website: https://www.fda.gov/media/161740/download. The deadline for comments is December 27, 2022.