General Considerations

Treatment for both pediatric UC and CD should focus on resolution and reduction of signs and symptoms of active disease to provide relief to the patient and to reduce the underlying inflammation, thereby reducing the recurrence of symptoms. Given the similarity in disease characteristics between adult and pediatric patients with these conditions, the FDA notes that extrapolation of demonstrated efficacy from well-controlled clinical trials in adults for the same indication is permissible.

Generally, the pediatric study design should be aligned with the adult Phase III program’s design, study population, endpoints, and timing of assessments. The same criteria can be used for both participant populations to define disease activity and endpoints. The FDA recommends the use of modified Mayo Score (mMS) for Ulcerative Colitis and the Pediatric Crohn’s Disease Activity Index (PCDAI) for Crohn’s Disease. The FDA notes that the PCDAI does have some limitations associated with evaluating intestinal inflammation and recommends assessing inflammation with ileocolonoscopy as an additional assessment.

Study Population

The FDA considers pediatric participants for IBD to extend from two to 17 years of age. For potential participants less than six years of age, the screening process should include an evaluation to exclude monogenic IBD and inherited conditions that present similarly to IBD to exclude these participants prior to enrollment. The IBD diagnosis should be based on documented findings on endoscopy and histopathology. Diagnostic scores from the mMS and PCDAI can be used to evaluate inclusion for UC and CD, respectively.

If the drug is being developed to treat moderate to severe pediatric UC or CD, then the enrollment should encompass participants across the range of severity categories. The protocol should aim to enroll a balanced representation of treatment-naïve participants and participants who have received one or more prior treatments that were inadequate. The FDA also recommends enrolling a participant population that reflects the characteristics of the clinically relevant populations, including race and ethnicity. Sponsors should consider clinical sites with a higher proportion of minorities to ensure recruitment of a diverse population.

When there is preliminary safety and efficacy data for adult participants, the FDA encourages sponsors to consider adding adolescent cohorts (12-17 years old) to ongoing Phase III adult trials. If there are questions about sample size, the sponsor can contact the Division of Gastroenterology (the Division) to discuss this further.

Study Design

The preferred design is a randomized, double-blind study of at least two doses for each age and/or weight-based cohort. This recommendation comes with an important caveat: When the study drug is already approved for use in an adult population, the risks of randomizing pediatric participants with active disease to placebo may outweigh the potential benefits of study enrollment. A placebo arm in such a study would not be appropriate under the subpart D regulations.^[iii],[iv] Therefore, sponsors interested in pursuing an active comparator study should discuss the design with the appropriate review division.

The FDA recommends a minimum 52-week blinded treatment period for drugs that are administered chronically. This is needed to assess early efficacy and durability of response over time, and to ensure adequate data concerning safety of longer-term exposure.

The dose selection should be guided by the dose/exposure-response relationship previously seen in adults for the same indication, including data about pharmacokinetics (PK) and pharmacodynamics (PD). A range of doses should be examined to identify an optimal pediatric dose. The guidance notes that a PK lead-in period can be used to confirm predicted exposures for the dose levels. If a lead-in period is used, the protocol should include a planned interim analysis to adjust the dose, if needed. All selected doses should be expected to provide some therapeutic benefit.

The sample size for any study should be large enough to ensure collection of adequate data through week 52 to inform efficacy and safety findings for chronic use in pediatric participants. This should be at least 50-60 participants per treatment arm to ensure enough participants complete the study to provide the data. There should be protocol-defined enrollment targets for each age cohort thereby ensuring adequate data across a range of ages and body weights.

Efficacy Considerations

For both UC and CD studies, the same primary and secondary endpoints used in the adult studies should be followed. The protocol should follow the same timing of scheduled assessments as adult studies to ensure analogously timed results for later comparison.

Considerations for Pediatric Ulcerative Colitis

The primary endpoint should be achieving clinical remission. The FDA recommends centralized reading of endoscopies for evaluating endpoints. Both the endoscopist and central reader should be blinded to treatment assignment when documenting their findings. If there are discrepancies between the endoscopist and the central reader, the protocol should advise how to handle this when conducting the efficacy analysis. The FDA suggests adjudication by a third reader. The FDA also recommends implementing standardized training across sites to minimize bias and standardize readings across sites.

The secondary endpoints should include clinical response, corticosteroid-free remission, endoscopic improvement, endoscopic remission, and maintenance of remission. The maintenance of remission can be evaluated by implementing a re-randomization in the research’s maintenance phase. This will help determine if the therapy can maintain a durable state of remission.

Considerations for Pediatric Crohn’s Disease

The FDA notes that co-primary endpoints may be used for this condition, namely: clinical remission (defined by a PCDAI score of 10 or less) and endoscopic remission. The FDA notes that for some drugs, it may not be possible to achieve complete remission by the end of the study. In these cases, it may be permissible to use endoscopic response as a primary endpoint and endoscopic remission as a secondary endpoint.

As for secondary endpoints, the FDA recommends evaluating clinical response, endoscopic response, corticosteroid-free remission, and maintenance of remission. Like the UC recommendation noted above, the FDA notes that re-randomization during the maintenance phase may be an effective way to demonstrate the therapy can maintain a durable state of remission.

The FDA noted the importance of including analysis of a composite endpoint, namely determining how many participants attain both clinical and endoscopic remission by the end of 52 weeks.

Statistical Considerations for UC and CD Studies

Given the possibility of a study conducted without a placebo control arm, the FDA offers the following suggested comparisons for analysis:

• Comparison of the remission rate in pediatrics on treatment to the remission rate in adults on both active treatment and placebo.
• Comparison of the clinical remission rate in pediatric participants to adult participants on placebo.
• Comparison of the remission rates between dose levels for primary and secondary endpoints.
• Comparison of exposure-response for efficacy between pediatric and adult participants.

Bayesian methods utilizing adult data to support the analysis of the pediatric study should be considered. The FDA notes that comparison to external control arms is permissible. To reduce bias, the analyses should be adjusted to account for participant characteristics at baseline, (e.g., disease severity, concurrent use of corticosteroids, prior biological product use).

The FDA welcomes sponsors to consider developing a new Clinical Outcome Assessment (COA) measure for pediatric participants. If they have a proposed COA, they can contact the Division for review.

Safety Considerations

Research studies should collect adequate data to characterize safety in pediatric participants for the benefit-risk assessment. The safety information obtained from adult studies may assist in this process, but primary safety data from pediatric participants is needed. The FDA may permit the use of real-world data but requests sponsors to contact the Division to discuss this early in the development process. They prefer randomized/blinded data to inform the risk assessment.

Safety analyses should be planned to compare treatment groups with respect to risk. The weaning of corticosteroids should be permitted and standardized in the protocol, ideally at the earliest feasible point following randomization.

The FDA has previously recommended washout periods for prior therapies to be a minimum of five half-lives or undetectable serum level (when available). To promote timely enrollment of pediatric participants and to reduce possible need for corticosteroid bridging therapy, the FDA welcomes sponsors to propose shorter washout periods with supporting rationale to justify it. If there is a shorter washout period, the protocol and consent form should acknowledge the potential increased risk of adverse events (serious infections) and include close monitoring/risk mitigation plans in the scheduled assessments.

If a drug is intended for long-term treatment, there should be data from enough pediatric participants on the to-be-marketed dosing regimen for at least 52 weeks to characterize the safety profile of the drug.

The FDA notes that there may be additional considerations for therapeutic protein products like monoclonal antibodies. They have another guidance covering this topic.^[v] In these circumstances, it may be advisable to contact the Division for further discussion.

Discussion of Pediatric Extrapolation and Use of Placebo

This guidance makes recommendations on study design and conduct based on the concept of pediatric extrapolation. In August 2024, the International Council for Harmonization (ICH), working in collaboration with the FDA, issued final guidelines discussing this concept.^[vi] Pediatric extrapolation assumes that the course of the disease and the expected response to the investigational product should be sufficiently similar in adult and pediatric participants such that efficacy established in adults can be extrapolated to the pediatric population. Additionally, if efficacy is established in one pediatric population (e.g., adolescents), efficacy may be extrapolated to younger children. Although this concept generally applies to efficacy, some extrapolation of safety may be reasonable, depending on what safety data has previously been collected. The level of data needed to use an extrapolation approach depends on the level of certainty on similarity and whether any knowledge gaps exist. The amount of data needed will vary based on the condition and how it manifests in adults compared to children. See figure below from the ICH guidance.^[vi]

For pediatric clinical trials for UC and CD, collection of some efficacy data is recommended, but the comparator is generally an active treatment rather than placebo. However, a smaller sample size is acceptable when adult data can be applied. Aligning the adult and pediatric endpoints is essential to allow efficacy comparisons between the adult and pediatric study results. Usually, PK and PD data are needed in the pediatric study to compare exposure/response (E/R) in children to that in adults and to establish pediatric dosing. Differences in E/R can also be used to determine efficacy; if one dose level performs better than another, that information can support an efficacy claim.   

Pediatric extrapolation is reinforced by the concept of Scientific Necessity outlined in the guidance, “Ethical Considerations for Clinical Investigations of Medical Products Involving Children.”^[iv] “Children should not be enrolled into a clinical investigation unless their participation is necessary to answer an important scientific and/or public health question directly relevant to the health and welfare of children.” Clinical investigations in children evaluating efficacy may not be necessary when pediatric extrapolation applies, or studies may be streamlined to reduce the burden on children when enrolled in clinical trials depending on the level of data needed to identify any uncertainties when applying pediatric extrapolation.

Of note, this guidance does not recommend a placebo-controlled trial in pediatric patients. Even when pediatric extrapolation is not applicable, it may be inappropriate to conduct a trial in children using a placebo. If placing the child on placebo places the child at a significant risk of disease progression during a clinical trial, especially when there are alternative treatments available, it may not be ethical to use a placebo. ^{[iv] [vii]}  

Conclusion

The FDA has issued a comprehensive draft guidance to assist investigators and sponsors in developing pediatric studies for IBD, specifically UC and CD. The guidance outlines the requirements for clinical trials and addresses: 1) Study Population, 2) Study Design, 3) Efficacy Considerations, and 4) Safety Considerations. Given the similarity in disease characteristics between adult and pediatric participants with UC and CD, the FDA notes that pediatric extrapolation of demonstrated efficacy from well-controlled clinical trials in adults for the same indication is permissible. However, some collection of data on efficacy in pediatric studies is recommended. Alignment of scheduled assessments and study endpoints from adult studies is important to allow comparison between pediatric and adult study results and apply pediatric extrapolation. Given the duration of the pediatric studies (52 weeks) and the availability of alternative treatments, using a placebo in pediatric studies for IBD is not considered ethical since withholding therapy would expose children to unnecessary risks without any clinical benefit.

References:

[i] Pediatric Inflammatory Bowel Disease: Developing Drugs for Treatment (July 2024), available https://www.fda.gov/media/180126/download.

[ii] The FDA noted that sponsors seeking to develop drugs for pediatric subjects only should contact the Division of Gastroenterology (the Division) to discuss their plans.

[iii] Subpart D risk categories, 21 CFR 50.52, et. seq.  https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50&showFR=1&subpartNode=21:1.0.1.1.20.4

[iv] Ethical Considerations for Clinical Investigations of Medical Products Involving Children (September 2022), available https://www.fda.gov/media/161740/download.

[v] Immunogenicity Assessment for Therapeutic Protein Products (August 2014), available https://www.fda.gov/media/85017/download.

[vi] E11A Pediatric Extrapolation (August, 2024), available https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-e11a-pediatric-extrapolation-step-5_en.pdf.

[vii] ICH Harmonised Tripartite Guideline Choice of Control Group and Related Issues in Clinical Trials E10 (July 2000), available https://database.ich.org/sites/default/files/E10_Guideline.pdf.

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To draw the distinction, in this paper, the term ‘simple consent form’ is used to denote a word-processed, text-only, standard format informed consent document.

Detailing Study Procedures and Activities in a Table Versus in Paragraphs or Lists

It is fairly common for sites and sponsors to list all of the study procedures and activities in a table, either in the body of the consent form or as an appendix.

Strengths

A table of study procedures

• puts all of the study procedures together and often makes it easier to see what will happen and when. 
• makes consent forms shorter as information does not need to be repeated for each study visit
• can provide the information in an efficient way.
• breaks up the consent form and creates white space which can increase readability and understandability of the consent form as a whole.
• makes it easy to update an entire table, by copy and pasting the table(s) from the protocol.
• helps to reduce copy-paste errors and inconsistent or contrary information between the study visits.
• makes it easier to update the information as it is in one spot on the table as opposed to updating the information for each study visit where the change may occur. 

Challenges

When using a table of study procedures

• some participants may have trouble reading and understanding tables and may not grasp which procedures will be done and when. 
• there may be space limitations for the columns and there may not be sufficient explanations of what the procedures entail, or explanations require complicated footnotes.
• editing or modifying parts of tables can be challenging, particularly when new procedures or study visits are being added.  This will often change how the table appears and may require the table to be reformatted. 
• it is often challenging to format the text in a way that can be easily readable to the participants within the space limitations.

One possible approach would be to describe the research procedures in the consent form and then also include a table as a consent form addendum or additional participant information that can be used as a quick reference.

Using Separate Consent Forms for Different Participant Populations or Cohorts

Sometimes a research study will recruit from multiple different participant populations (e.g., minors consented via parental permission and adults who consent for themselves) or will involve multiple cohorts (e.g., a study comparing different treatment regimens with their own respective risks and procedures) and there could be a different consent form for each group.  

Strengths

The benefits of using multiple separate consent forms include that

• the language in the body of the consent form can be tailored to each participant population. If the procedures, dosages, or compensation offered varies between groups, the consent language can be made specific to that individual participant without including information that does not apply to them.
• the document will require fewer signature lines. If decision-making adult participants have their own consent form, then the document will not also require signature lines for documenting parental permission for the adolescent participants or documenting the signature of a legally authorized representative if the participant is lacking capacity. This approach will help prevent errors that may occur when a participant or study team member signs the wrong section of the consent form.
• if a participant population or cohort completes the research, or if a part of the study completes (e.g, optional first-dose intensive PK sampling, after everyone has completed the first dose) then that consent document will no longer need to be maintained going forward.

Challenges

Some of the challenges of having multiple separate consent forms are that

• having multiple consent forms for different groups means having multiple documents to maintain and revise as the research changes with protocol revisions and amendments. Keeping track of these documents and ensuring they are consistent can be burdensome over time. If the differences between the consent forms for each group are minimal, it might be preferable to use one document and add language that clarifies whether certain sections to apply to a participant.
• using multiple consent forms for the same research study can also introduce the possibility of documentation errors if the study team member obtaining consent uses the wrong consent form. For example: if a participant gives consent for Cohort A, but  later  the research staff inadvertently uses the consent form for Cohort B, to re consent the participant, there is a possibility the participant did not receive the new information that is most pertinent to their participation.

Reconsenting Active Participants Using and Addendum Instead of a Revised Consent Form

The question of whether an active participant should be “reconsented” arises whenever there is a protocol revision, new or updated study risk, or an update to the consent form language. As noted in this WCG White paper, Providing Research Participants with New Information: Is “Re-Consent” Always Necessary?, reconsenting participants should be performed whenever significant new findings may affect a participant’s decision to continue in the research. Reconsenting is most often done in one of two ways: 1) having the participant review the revised consent form in its entirety and consent again, or 2) having the participant review a consent form addendum that outlines the key changes in the research, or that changes that apply to their stage in the study.

Strengths

When using a consent addendum

• it is easier for the participant to understand the key changes without having to re-review information that has not changed since they initially joined the research.
• the consent form addendum will be much shorter than a revised consent form, and the reconsenting process will be take less time for study team members to administer. 

Challenges

When using a consent addendum

• this approach introduces another document that will need to be revised and maintained over the course of a study. If the research is still enrolling, the existing consent form will also need to be updated to incorporate the revised information for new participants. The addendum approach to reconsenting is best suited for situations where enrollment is permanently closed, but there is new information that needs to be communicated to active participants.

Including Optional Components in the Main Consent Form

Sometimes research will involve sub-studies or optional procedures that require separate consent. This information can either be appended to the main consent form or conveyed in a separate consent form addendum.

Strengths

When keeping sub-study information in the main consent form

• there will be fewer documents to maintain and update over the life of the research. This will be easier for study teams, CROs, and IRBs to manage.
• if all decisions related to participation are in one document, it will be easier for the person obtaining consent to ensure all relevant consent has been obtained. There will be fewer consent documentation errors that occur when a study team fails to document one or more of the participant’s choices.

Challenges

• Including optional components in the main consent form can introduce the possibility of other errors. For example, this approach can lead to situations where a study team member fails to obtain a signature or participant decision on one of the optional sections.
• It can also lead to situations during reconsenting where a participant makes a different choice than they originally did. If this discrepancy is not noticed or resolved, it can make it difficult to determine whether the participant meant to change their prior consent or simply forgot the choice they made earlier. If a single consent form for all procedures, both required and optional, is used, it is a good practice for the study team member to have the participant’s prior choices available to reference during the reconsenting process.

Electronic Consent (eConsent)

The term electronic consent (often abbreviated as “eConsent”) can mean multiple things, including uploading an approved consent document onto a platform that can be viewed on a tablet , phone, or computerror the use of electronic platforms that incorporate the consent form with dictionaries, storyboards, animation, videos, graphics, and/or images.  Since these involve two different processes, we will discuss the strengths and challenges of them separately.

Uploaded Consent Document

Strengths

When uploading a simple consent document to be used electronically

• once the IRB has approved the simple consent form it is generally very easy to upload into an electronic document. If there are no changes to the consent form, uploading it does not require any additional review by the IRB.
• the research site will not need to have printed versions of the consent form available for each participant; rather the site would be using the same file on the tablet each time and saving it as a separate file once the participant has signed the form.
• the site may not need to keep paper copies of the signed consent form which could help in decreasing the space needed to store study records, as well as reducing the risk that the consent forms get lost, or inadvertently destroyed, particularly if the data system is backed up.
• if the data system is searchable, then it could also be quicker and easier to determine if a particular participant has signed the consent form(s), and when.

Challenges

When uploading a simple consent document to be used electronically

• the system used to obtain consent and store the electronic consent forms must be compliant with 21 CFR Part 11 for any clinical trials regulated by the FDA¹. Note that if participants are physically signing the consent form using a stylus or their finger, rather than typing a “signature”, this is considered to be a “wet signature” and the system does not need to be compliant with 21 CFR Part 11.
• the site will likely still need to print off the signed consent form to provide the signed version to the participants (per ICH GCP )², but this would be the case even if the site was using paper based consent forms.
• if the electronic form gets corrupted or inadvertently deleted, the site may not have a usable consent form

The site should maintain at least one current copy of the simple consent form to serve as a back-up in case there are technical issues or the electronic version can’t be used.

Electronic platforms incorporating dictionaries, animation, storyboards, and/or videos

Increasingly sites and sponsors are using consent processes that are incorporated into an electronic platform and will include embedded dictionaries, animation, videos, storyboards, and other visual information to help explain the study.  The text of the consent form is also generally incorporated as part of the electronic platform and the participants may digitally or physically sign the consent form as part of the electronic platform.

Strengths

When using multi-format electronic platforms for the informed consent process

• this format may improve participant satisfaction with the consent process, and help increases the participants’ comprehension of the study and the associated procedures, risks, benefits, and alternatives by providing an interactive learning approach.³
• electronic platforms make it easy for the participants to go back to specific sections to re-review information if they have questions.
• the multi-modality platforms help people with different learning styles, such as auditory and visual learners understand the consent form as opposed to simply relying on reading the consent form.
• When consent information needs to be updated during a study, once changes have been approved by the central IRB, they could be pushed out to all of the sites simultaneously. This helps to make sure all of the sites are always using the most current version of the consent form.
• the integration of videos, images and other tools may make it easier to visualize complex ideas or procedures

Challenges

When using multi-format electronic platforms for the informed consent process

• they are expensive, compared to paper-based forms or simple electronic forms
• they can be time-consuming to develop initially and to change when needed
• consent incorporating tools such as voice-overs, videos, or animations will generally require a second IRB review (following initial review of the simple consent document) as the content is different than what is included in the simple consent document.
• if using both a simple consent document and the multi-modality electronic format, the site and sponsor may need to update multiple documents when there are changes, including the simple consent document and the consent form provided as part of the electronic platform.
• this electronic platform will need to comply with 21 CFR Part 11 and the site will still need to provide a printed copy of the consent form to the participants.

Concluding Thoughts

There are many formatting options to consider when drafting an informed consent form, each with their own advantages and disadvantages. The format of the ideal consent form may vary by situation and study. When drafting an informed consent form, the sponsor and study team should evaluate their needs and constraints to design an informed consent form that will be easy to understand for potential participants and efficient to implement for study teams. The IRB can be a resource for discussing options and implications on the review and implementation process.

References

1. 21 CFR § 11.1
2. See Integrated Addendum To ICH E6(R1):Guideline For Good Clinical Practice Section 4.8.11, https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf
3. See for example Abudjarad, et al, Comparing a Multimedia Digital Informed Consent Tool With Traditional Paper-Based Methods: Randomized Controlled Trial, JMIR Form Res. 2021 Oct 19;5(10):e20458. doi: 10.2196/20458. PMID: 34665142; PMCID: PMC8564662. (https://pubmed.ncbi.nlm.nih.gov/34665142/ Accessed 02-16-2023) and Gesualdo F, et al. Digital tools in the informed consent process: a systematic review. BMC Med Ethics. 2021 Feb 27;22(1):18. doi: 10.1186/s12910-021-00585-8. PMID: 33639926; PMCID: PMC7913441. (https://pubmed.ncbi.nlm.nih.gov/33639926/ Accessed 02-16-2023)

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May a subject with worsening cognitive decline continue participation in a clinical trial when study drug administration is complete but follow up visits are ongoing?

– Principal Investigator, Research Institute

Response:

If a participant is no longer able to provide legally effective consent for themselves, the principal investigator needs to notify the IRB and the sponsor to determine if the subject may remain in the study. 

If the IRB determines that ongoing participation is permissible, the IRB will require consent by a LAR and may require assent by the participant (when feasible) to continue enrollment in the study.  The IRB will also determine how assent will be documented.

Brief Question:

Why does WCG IRB require assent from adults who lack decisional capacity when consent was already provided by a legally authorized representative (LAR)?

– Contract Regulatory Document Reviewer for a Pharmaceutical Company

Response:

Although the FDA regulations do not explicitly mandate the IRB to consider requiring assent from adults who lack the capacity to provide legally effective consent, there is support for this requirement in multiple regulatory frameworks. These frameworks include the guiding principles of the Belmont Report and FDA guidance on informed consent.

The Belmont Report states three basic ethical principles to guide IRB review of human subjects research. These principles are Respect for Persons, Beneficence, and Justice. The first principle of Respect for Persons advocates for two ethical convictions, “first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection.” The second conviction is addressed by requiring consent be obtained from a legally authorized representative whenever an adult subject lacks capacity to consent. The IRB acknowledges that decisional capacity is not a binary attribute. Subjects may fall along a spectrum of capacity and awareness. In order to ensure a subject’s autonomy is respected, the IRB requires investigators to obtain assent whenever a subject is capable of being reasonably consulted. 

The FDA states the following in a guidance document on informed consent:

IRBs and investigators should carefully consider whether the inclusion in research of individuals who lack consent capacity is ethically appropriate and scientifically necessary. Whenever individuals with impaired consent capacity (partial, fluctuating, or complete) are or may be enrolled in clinical studies, ethical and procedural challenges arise. Considerations that may help address these challenges, and provide additional safeguards, include:

Assessing whether individuals who cannot provide legally effective consent on their own behalf may nonetheless be able to provide some form of oral agreement (e.g., assent) at the outset of the study and, as appropriate, throughout the course of the research (e.g., for subjects with progressive disorders), and how such oral agreement would be documented. In such a circumstance, a legally authorized representative would need to provide documented written consent.

In conclusion, although the requirement for obtaining assent from adult subjects who lack the capacity to provide legally effective consent is not formally established in the federal regulations, WCG IRB has determined that this process is necessary to ensure respect for their autonomy.

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