Considerations for selecting control groups in pediatric clinical trials

Feature ArticlesFeature Articles | 28 March 2022 | Citation

ICH E10 provides specific guidance on the choice of control groups for clinical trials, but there are additional considerations for choosing a control group for a pediatric trial. In this article, the author looks at different types of control groups and the specific challenges that present when considering the design for a pediatric trial, such as the medical condition being treated, the potential patient population, suitability of comparators, and availability of real-world data (RWD).
There are numerous items a sponsor needs to consider when designing a clinical trial. First, the purpose of the trial needs to be established and the chances of success of the trial purpose must be considered. The study purpose may be to look at the safety of the investigational medicinal product (IMP) or to determine the efficacy of the IMP for the treatment or prevention of a disease, or both. Alternatively, the trial may be investigating the relative safety and/or efficacy of the IMP compared with another treatment option, or in combination with another treatment. It is neither ethical nor responsible to conduct a trial whose design does not have a credible chance of producing scientifically robust and reliable results. Using a control within the clinical trial allows investigators to demonstrate what would have happened had the patients had not received the IMP or had received another treatment known to be effective. It is important that the sample populations in each group are similar so that the differences between the control and treatment groups can be determined.
The World Medical Association (WMA) Declaration of Helsinki states: “The benefits, risks, burdens, and effectiveness of a new intervention must be tested against those of the best proven intervention(s).”1 The International Council for Harmonisation’s ICH E102 guideline provides specific guidance on the choice of control groups for clinical trials, but there are often more points to consider when choosing a control group for a pediatric trial. These additional considerations include the size of the potential patient population, as well as statistical considerations, availability of suitable comparators for patient population, availability of RWD or registry information for the patient population, and the marketing status of the same IMP for adults. The acceptability of the clinical trial to regulators, parents, and patients must also be considered.
The choice of a suitable control group is a key element to the success of a clinical trial and overall clinical development program. There are a number of points to consider when determining which type of control group to use. ICH E102 lists six different types of controls:
  • Placebo concurrent control,
  • No-treatment concurrent control,
  • Dose-response concurrent control,
  • Active (positive) concurrent control,
  • External control (including historical control),and
  • Multiple control groups.
The option for shared control arms in complex clinical trial designs allows different IMPs to be tested using one control arm, which can help in those pediatric studies in which the number of potential participants is low and control group selection is a challenge. The use of shared control arms is also beneficial to participants because it reduces their chances of receiving placebo if it is a shared placebo control group.
Placebo control groups
In a placebo-controlled trial, a group of participants would receive a placebo, which is an inactive substance that looks like the drug or treatment being tested. Randomized, placebo-controlled trials are still seen as the gold standard in trial design because they are considered to best minimize bias since they are typically double blinded. Use of a placebo arm can mean a smaller sample size is required for the trial, as opposed to other control group types. It is necessary to ensure that the amount of risk to which pediatric patients are exposed without benefit is limited.3 When there is an effective treatment, the condition itself must be considered as well as the impact of nontreatment on patient well-being and disease progression. Having a placebo control group does not necessarily mean this group is untreated because the IMP or placebo can be added to standard-of-care therapy.
Use of a placebo control group raises questions about ethics. Use of a placebo control is widely seen as ethically acceptable for a condition with no effective treatment, or for which the current treatment has severe toxic effects. Alternatively, the ethics of the use of the placebo control arm is questioned and is closely scrutinized in pediatric clinical trials because of the greater vulnerability of the pediatric participants.
Three key points should be considered in planning pediatric studies and placebo control groups:
  • First, is an effective treatment available and if there is, is it also available for the pediatric population? It may be that the current effective treatment has been approved for use in adults, with possible off-label use for pediatrics. However, it may be that the current effective treatment has not been tested in the pediatric population and a suitable dose or suitable formulation may not be available for the full age spectrum of the pediatric population. If the effective alternative is only marketed for the adult population, then consideration needs to be given to the age limit for the trial because, when the child reaches the age of 18 years, the marketed alternative treatment could be prescribed and use of the placebo may not be ethical.
  • Second, the medical condition being treated must be considered from the pediatric perspective. What is the impact of nontreatment of the condition in children? The answer to this question may well be different than the situation in adults with the same medical condition, for whom progression may be slower, the condition may be less severe, or it may not have a significant impact due to developmental differences between adults and children.
  • Third, the mode of administration must be considered. If the IMP is administered by injection, then any matched placebo would also be required to be administered by injection. Giving pediatric participants sham injections adds to the ethical consideration, especially in considerations related to the need to minimize risk, discomfort, and distress, all of which are applicable when including sham injections for a placebo arm.
The COVID-19 pandemic has also highlighted the challenges of using a placebo arm in a rapidly evolving development environment. As vaccines have been developed and approved, the acceptability of using a placebo control arm has shifted. This is particularly the case for pediatric COVID-19 vaccine trials, where placebo-controlled vaccine trials have been ongoing in 2021. Approved vaccines are now available for children down to the age of 5 years, meaning that a study design with a placebo arm is now more challenging to justify but a suitable control is still required. In addition, the availability of vaccines for use as controls in clinical trials is also limited due to the ongoing demand for vaccine supplies globally.
No-treatment control groups
A no-treatment control trial involves one group of participants receiving no treatment. The investigator and the participant are both aware of the treatment or nontreatment being received. The use of this type of control group is usually acceptable only when it is not possible to double blind the trial and when there is reasonable confidence that the study endpoints are objective. This may be particularly relevant for pediatric trials in which the IMP administration is invasive, such as by injection, and administering placebo by injection would generally not be acceptable in a pediatric trial. Again, the medical condition being treated must be considered and the impact of nontreatment on disease severity, progression, or development for the child, particularly if a standard-of-care treatment option is available and the impact of the disease progression is irreversible. The trial may also involve standard-of-care background treatment, which all participants are receiving, or the no-treatment arm may receive a delayed treatment to allow for a period of observation during which no treatment is administered, followed by a period of treatment.
Dose response concurrent control
A dose response concurrent control is when each group in the trial receives a different dose or dose regimen. This design can allow for any relationship between the dose and the safety and efficacy to be investigated. Of note, the differences in safety and efficacy may be very small, making interpretation of the study results more difficult. For pediatric trials, there are some additional considerations for this type of control compared to adult trials. The dose range may not yet have been established or may be established at one age range but not at lower age ranges. The fact that children are at different stages of development throughout their childhood must be considered because it can affect the safety and efficacy of the dose, meaning the suitable dose or dose range would vary at each age range. This variability can make a dose response control more challenging because it would have to be done at each relevant age range, increasing the overall number of trial participants required.
Active (positive) control group
Although trial designs with active control groups usually require a larger sample size, these studies can be more appealing to patients and investigators than placebo-controlled trials. Participants are allocated to receive either the IMP or an active control treatment. Where possible, these trial designs would be double blinded, though that may not always be possible, particularly if the IMP and the active comparator have different dosing forms or dosing regimens. It is necessary for any comparison of treatments to be fair, especially in ensuring that the dose and dosing regimen of the active comparator are appropriate. The selection and timing of endpoints is also important to ensure one treatment group is not favored. Ethically, active control groups are seen has being less of an issue than placebo control groups because all participants are receiving an active treatment that has shown efficacy for the medical condition. However, it must be remembered that those on the IMP may be receiving a treatment that is ineffective or has serious side effects.
The operational consideration for an active control is whether the proposed active control drug is efficacious at the dose planned and approved for the same indication and in the region(s) where the trial will be conducted. This is particularly relevant for pediatric clinical trials. If the active control drug is not approved in the pediatric population, then the sponsor would have to treat the active control as an IMP in the trial. Alternatively, the control may be approved only for certain age ranges in the pediatric population, such as over 12 years old, meaning that the same control may not be able to be used for all age ranges. The active control may also not be available or have been tested in formulations suitable for all pediatric age ranges. For example, if the control is available only in a tablet formulation but the trial is designed to include very young children, then this control may not be suitable for the youngest participants, potentially excluding them from the trial and requiring a separate trial with a different design to capture the necessary information for this age group.
External control
A trial with an external control group compares the group of participants in the trial receiving the IMP with a group of patients not involved in the trial. The external control group may be a historical control group, where patients have previously received treatment or a group of patients being treated with a different treatment at the same time as the trial but outside of the trial.
There are concerns over the use of external control groups, especially around whether such a control group can be compared with a test group and minimize bias. For pediatric trials, particularly for rare diseases, in which the patient population is very small and use of an internal control arm is not ethical or feasible, external control groups may be the only option available to sponsors. For example, an external control arm using retrospective natural history data was successfully used to support the FDA4 and European Medicines Agency (EMA)5 approvals of Zolgensma for spinal muscular atrophy.
The use of RWD sources, such as medical records, claims data, and registry data, and of real-world evidence (RWE) can be an option for supporting marketing applications. There seems to be some acceptance of the need to use RWD. For example, regulatory agencies, such as the EMA6 and the Japanese Pharmaceuticals and Medical Device Agency,7,8 have issued guidelines, providing the basic principles for using registries, and the FDA has set up the RWE program9 and issued draft guidance10,11 on the use of RWD to support regulatory decisions. Discussions with the relevant regulatory agency are recommended to ensure the proposed study design and selected control group will meet the requirements of the regulator.
It is important to consider whether the identified data source is relevant and appropriate for addressing the question being asked in the clinical trial and to understand the possible limitations. Use of disease registry information can be used to develop external controls for studies where other types of control arm are not an option. The use of such RWD does require the quality and reliability of the collected data to be considered to ensure it is appropriate. The registry used should be representative of the target patient population of the proposed trial and should include information comparable with that being collected in the treatment group. This involves extracting the patient population from the registry data based on the inclusion and exclusion criteria of the trial and matching patient characteristics for those patients participating in the study with those in the registry to develop an external control group. Any differences should be carefully considered to determine the impact the differences may have and whether use of the registry RWD is still appropriate as an external control group. A patient may also act as their own control, comparing their disease status before treatment in the clinical trial.
Multiple control groups
The choice of control group does not always have to be limited to one; the trial design may involve more than one control group. For example, a trial may be designed with patients receiving no treatment or a placebo during the first phase of the study, known as the run-in phase, with the patients then moving on to receive the IMP for the next phase of the trial, the open label phase. Another example would be a crossover design where patients swap from the IMP arm to a placebo arm or active control arm part way through the study, either at a set time point or when the patient presents side effects or disease worsening. Alternatively, a study may have a placebo arm, active control arm and IMP arm, utilizing additional control groups to limit the number of patients receiving placebo. Selection of relevant multiple control groups requires the same considerations for pediatrics as outlined above; however, it can also provide solutions to some of the hurdles encountered when using certain control groups in pediatric trials.
Selection of the most suitable control arm can be key to ensuring a successful trial because it can affect participant enrollment and retention, which are often important given the frequently limited pediatric population and the need for statistically significant data. There are numerous factors that are applicable to a many types of control groups specific to the pediatric population. These include:
  • The number of suitable participants,
  • The medical condition, its severity and progression rate,
  • The ethical use of a placebo, whether due to the impact on the participant of not receiving treatment or the difficulty of producing a suitable placebo,
  • The current standard of care, whether this is through off-label use or through use of a product marketed for the relevant age ranges,
  • The availability of suitable active controls, again considering whether these are marketed and available in the proposed countries for the trial for all relevant age ranges or whether these are still experimental in pediatrics, and
  • The availability of suitable RWD that is representative of the pediatric population being studied in the trial.
The pediatric trial design must factor in these considerations when selecting a control group to help ensure that the trial design is suitable and feasible to make sure it can meet its objectives.
EMA, European Medicines Agency; FDA, [US] Food and Drug Administration; ICH, International Council for Harmonisation; IMP, investigational medicinal product; RWD, real-world data; RWE, real-world evidence.
About the author
Josephine Dewhurst, BSc, LLB Dip, is a director of ICON’s Centre for Pediatric Clinical Development. She has almost 20 years of global regulatory affairs experience across a range of therapeutic areas, with a focus on pediatric clinical development. Dewhurst has a bachelor of science degree from the University of Glasgow and a law degree from the University of Strathclyde. She can be contacted at
Citation Dewhurst J. Considerations for selecting control groups in pediatric clinical trials. Regulatory Focus. Published online 28 March 2022. 
All references accessed 21 February 2022.
  1. World Medical Association (WMA) Declaration of Helsinki. Dated 09 July 2018
  2. International Council for Harmonization. ICH harmonised tripartite guideline: Choice of control group and related issues in clinical trials E10 [current step 4 version]. Dated 20 July 2000.
  3. Food and Drug Administration. 21 CFR 50, subpart D, Additional Safeguards for Children in Clinical Investigations. Last amended 17 February 2022
  4. Food and Drug Administration. Summary basis for regulatory action [for Zolgensma]. Dated 24 May 2018.
  5. European Medicines Agency. Assessment report [for Zolgensma]. Dated 26 March 2020.
  6. European Medicines Agency. Guideline on registry-based studies [EMA/426390/2021]. Last updated 22 October 2021.
  7. [Japanese] Pharmaceuticals and Medical Device Agency. Basic principles on utilization of registry for applications. Dated 23 March 2021.
  8. [Japanese] Pharmaceuticals and Medical Device Agency. Points to consider for ensuring the reliability in utilization of registry data for applications. Dated 23 March 2021.
  9. Food and Drug Administration. Framework for FDA’s real-world evidence program Dated December 2018.
  10. Food and Drug Administration. Real-world data: Assessing electronic health records and medical claims data to support regulatory decision-making for drug and biological products [draft guidance for industry]. Dated September 2021.
  11. Food and Drug Administration. Data standards for drug and biological product submissions containing real-world data [draft guidance for industry]. Dated October 2021.


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