In January 2025, the Food and Drug Administration (FDA) and The Office for Human Research Protections (OHRP) issued a draft guidance on recommendations to industry, investigators, institutions, and Institutional Review Boards (IRBs) when tissue biopsies are included in clinical trials to evaluate investigational medical products. The draft guidance defines a biopsy as a procedure that involves the collection of tissue from a study participant as part of a clinical trial protocol. The draft guidance reflects a potential change in approach on how the assessment of risk and benefit for a child might be evaluated in a trial that includes a research biopsy.

Biopsies for Research Purposes

Biopsies are often needed to ensure that a participant has a particular condition or biomarker that is targeted by the drug or biologic product before enrollment in a trial, to obtain other data related to eligibility, or to evaluate a primary or secondary endpoint. Of note, any time a biopsy is considered for inclusion in a clinical trial, the risks of obtaining the biopsy must be weighed against the anticipated benefits and the importance of any knowledge gained from collection of the biopsy. When a biopsy is included in a clinical trial, the rationale and scientific justification should be clearly outlined in the protocol. If a biopsy for a particular participant includes an unacceptable level of risk, that participant should not be included in the trial. If biopsies are included in protocols as non-key secondary or exploratory endpoints, are not needed for determining eligibility, or are solely collected for future use, the FDA and OHRP state that these biopsies should be optional (protocol specified but not necessary to participate) since these biopsies may unnecessarily increase risks and burdens to participants and may discourage participation in the trial. 

Informed consent should be obtained before any research related biopsies are collected. It should outline if the biopsy is required or optional, describe the risks and benefits associated with the collection of the biopsy, and be conducted in an environment where there is no possibility of coercion or undue influence. Participants should have the right to withdraw their consent to provide a biopsy at any point during the trial, noting that if a biopsy is required, not collecting the biopsy may impact the participant’s ability to continue in the trial. Withdrawal of consent for optional biopsies would not have an impact on continued trial enrollment.

Certain types of biopsies may involve more risk. For example, a brain biopsy involves significantly more risk than a skin biopsy. In situations where the biopsy involves considerable risk, a strong scientific rationale for the biopsy should be provided and alternative approaches, such as collecting information from existing pathology, rather than obtaining a new biopsy, should be considered whenever possible.

A biopsy could be required in adults in the following situations:

• To identify participants with a particular finding that may make them more likely to respond to a particular treatment, like human epidermal growth factor 2 (HER2) positive disease for HER2-targeted therapies.
• To identify participants who may be more likely to have side effects or toxicities from use of the investigational treatment, (e.g., increased toxicities for patients with Kirsten rat sarcoma viral oncogene homolog [KRAS] and/or neuroblastoma Ras viral oncogene homolog [NRAS] mutated colon cancer treated with certain epidermal growth factor receptor antagonists).
• To identify participants who would not be likely to benefit from the treatment (e.g., a patient with significant renal scar tissue may have no signs of inflammation and therefore may not respond to immunosuppression).
• To evaluate primary and key secondary trial endpoints.
• To evaluate treatment response.
• Obtain tissue to produce a gold standard (truth standard) by a known high-validity diagnostic method to test an investigational diagnostic product. For example, to verify that an imaging agent is effective in recognizing a tumor compared to histology.^1,2

Biopsies for Pediatric Participants

A biopsy done in children as part of a clinical trial must comply with special considerations under 21 CFR 50, subpart D and 45 CFR 46, subpart D.³ A biopsy (and any biopsy associated procedures, such as procedural sedation) that is performed solely for research purposes and not needed for clinical management or routine clinical care should be evaluated to determine whether it offers prospect of direct benefit to the enrolled child.

One nuance outlined in this draft guidance is that if a biopsy is performed to establish whether a child is likely to benefit from treatment with the investigational agent, performing the biopsy as part of the clinical trial could also be considered a benefit. For example, if a drug or biologic targets a particular biomarker or condition, the biopsy may be needed to establish whether the child has the biomarker or condition and is more likely to respond to the therapy and thus benefit from the treatment. Otherwise, in situations where there is no benefit and a biopsy is performed for research purposes, such as to evaluate a primary or key secondary endpoint, the risk must be limited to “minimal risk” or a “minor increase over minimal risk.” Biopsies that exceed minimal risk but are considered to meet criteria as a minor increase over minimal risk must also contribute to generalizable knowledge about the child’s disorder or condition. Large organ biopsies are generally considered to exceed the minor increase over minimal risk threshold and should not be done in a clinical trial unless needed for clinical purposes or offer a prospect of direct benefit as described above.

In pediatric trials, particularly those in oncology where treatments may be focused on a specific molecular marker,⁴ establishing whether the child is likely to benefit from the treatment is important. Unnecessarily exposing a child to a treatment without establishing a tumor type or tumor biomarker targeted by the investigational agent would expose the child to unnecessary risk without any anticipated benefit. In the past, these biopsies may have been considered by IRBs to not offer a benefit, thus limiting enrollment to children who either had previously had a biopsy done for clinical purposes or who had stored tissue for analysis. This approach may have inadvertently excluded children who would have benefited if the biopsy could have been done as part of the trial.

Conclusion

The draft guidance provided by the FDA and OHRP underscores the critical considerations necessary when including tissue biopsies in clinical trials. It highlights the importance of weighing the risks and benefits, obtaining informed consent, and ensuring that the scientific rationale is robust and justified. Biopsies should be optional if not essential for determining eligibility or other primary trial endpoints. For children, a biopsy and any biopsy associated procedures performed solely for research purposes and not needed for clinical management or routine clinical care should be evaluated to determine whether performing the biopsy offers a prospect of direct benefit to the enrolled child. A biopsy performed as part of a research study could be considered to offer a benefit to the child if the biopsy is performed to establish whether a child is likely to benefit from treatment with the investigational agent, such as to identify a specific molecular target or condition.

If you have additional questions regarding biopsies in adult or pediatric studies or other IRB-related inquiries, please don’t hesitate to contact us by completing the form below. WCG’s IRB experts are here to assist you with any ethical or regulatory questions. Reach out today.

References:

1. Guidance for Industry Developing Medical Imaging Drug and Biological Products Part 2: Clinical Indications, accessed January 7, 2025, https://www.fda.gov/media/71226/download.
2. Guidance for Industry Developing Medical Imaging Drug and Biological Products, Part 3: Design, Analysis, and Interpretation of Clinical Studies, accessed January 7, 2025, https://www.fda.gov/media/71237/download.
3. Ethical Considerations for Clinical Investigations of Medical Products Involving Children Guidance for Industry, Sponsors, and IRBs, accessed January 7, 2025, https://www.fda.gov/media/161740/download.
4. How to Navigate Researching Targeted Therapies in Pediatric Oncology Clinical Trials, Fierce Biotech, accessed January 7, 2025, How to Navigate Researching Targeted Therapies in Pediatric Oncology Clinical Trials | Fierce Biotech.

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Defining AI and Its Role in Drug Development

AI is defined in the guidance as “a machine-based system that can, for a given set of human-defined objectives, make predictions, recommendations, or decisions influencing real or virtual environments.” It also notes that “AI systems (1) use machine- and human-based inputs to perceive real and virtual environments, (2) abstract such perceptions into models through analysis in an automated manner, and (3) use model inference to formulate options for information or action.” The guidance states that machine learning (ML), one of the subsets of AI, is most used in drug development, but that the guidance is not intended to be limited to those techniques.

AI may contribute to information to support the safety, efficacy or quality of drugs by (1) decreasing the number of nonclinical pharmacokinetic (PK), pharmacodynamic (PD), and toxicologic studies, (2) utilizing predictive modeling for clinical PK and/or exposure-response analyses, (3) combining various databases (natural history, genetic, registries, social media, clinical trials, etc.,) to help better understand disease presentations, disease progression, disease differences, and predictors of progression, (4) utilizing existing real-world data or data from digital health technologies to develop clinical trial endpoints or assessments of outcomes, (5) handling reports on post marketing adverse drug experience information, and (6) helping select appropriate drug manufacturing conditions.

Challenges and Concerns with AI Implementation

There are challenges to using AI in drug development. Because of the variability of datasets used to train AI models, there is concern about the reliability of the results and biases that might be generated depending on the data source. Emphasis is placed on the data being “fit for use” or relevant and reliable. Additionally, the guidance notes that methodological transparency in the development of AI models may be necessary, specifically outlining in the regulatory submission how a particular AI model was developed. The potential for an AI model’s performance to change over time (i.e., data drift) is highlighted and requires life cycle maintenance of AI models.

Steps for Establishing a Credibility Assessment Framework

The risk-based credibility assessment framework is outlined in the guidance and is a stepwise approach which includes defining the question of interest, defining the COU for the AI model, assessing the AI model risk, developing a plan to establish the credibility of the AI model as it pertains to the COU, executing the plan, documenting the results of the credibility assessment plan and any deviations, and determining the adequacy of the AI model for the COU. The guidance includes two examples to illustrate the implementation of the first three steps of the framework, one in clinical development and one in manufacturing, noting the remaining steps are intended to provide a general list of activities to be considered when establishing an AI model’s credibility and cannot be easily applied to the examples.

What is clear from the examples, is that having a “human in the loop” is important to reduce risk. When assessing risk, there are two main components. The first is the AI model’s influence to answer the question of interest, or what is the contribution of the model relative to other evidence . The second is the decision consequence, or what is the significance of any adverse outcome if use of the model results in an incorrect decision. In the clinical development example, the AI model is the sole determinant of whether a participant undergoes more rigorous monitoring, making it possible that if the model is wrong, that some participants will not be adequately monitored and may have a significant adverse outcome. The model influence is high, and this model is considered high risk. But in the case of the manufacturing example used in the draft guidance, where AI is used to direct vial fill volume, the vial fill point is batch checked by a human, mitigating the risk of the vials being filled incorrectly and contributing to dosing errors. The risk of using the AI model in this example is considered medium since although the consequences of a dosing error could be high, the model’s influence is low.

The next steps involve establishing a credibility assessment plan which is contingent on the model risk and the COU. The guidance urges sponsors and developers to engage early with the FDA to discuss credibility assessment activities. High-risk AI models will necessitate that more detailed information be submitted. The FDA will require that the model and model development process be described, including model inputs and outputs, model architecture (what type of model, e.g., neural network), model features and model parameters. The data used to train and tune the model in the development phase, prior to testing the model,  should also be described. Sponsors should include information on whether the data is fit for the COU, how the data is relevant and reliable, and whether federated learning is utilized.

The submission should also describe how the model was trained, the learning methodology used to develop the model, performance metrics used to evaluate the model, whether a pre-trained or multiple pre-trained models were used, and what calibration and quality control procedures are in place. The limitations of the modeling approach, including any potential biases,  should be described. After the credibility assessment plan is established, the plan should be executed, and a report should be generated to establish the credibility of the AI model for the COU. If there are deviations encountered with execution of the plan, these should be described. Depending on what is pre-agreed upon with the FDA, the report may be submitted to the agency or held and made available to the FDA on request.

If after executing the plan the model credibility is not adequate to support the model risk, then there are several actions that the sponsor may take: 1) Additional evidence can be incorporated to answer the question of interest in addition to the evidence generated from the AI model. This will decrease the model’s influence and lower the risk. 2) The sponsor can add additional development data or increase the rigor of the credibility assessment. 3) The sponsor can add additional controls to mitigate risk. 4) The modeling approach can be changed. 5) The sponsor may determine that the AI model’s output is inadequate for the COU and the model’s COU could be revised or refined.

Plans for life cycle maintenance of the AI model should be in place to monitor and ensure the suitability of the model’s performance over time within the COU. Although at the point of regulatory decision making the data used to inform the model is likely locked, there are models that will continue to be utilized during the drug development life cycle. Some models are self-evolving and can adapt and change without human interaction. It is important that these models be evaluated from time to time to ensure that they are “fit for use” for the COU and that risk is assessed. If necessary, changes may need to be made in the model or with the use of the model to mitigate risk and the credibility assessment plan may need to be re-applied and modified. Plans for life cycle maintenance should be included in submissions to the FDA, as appropriate.

Importance of Early Engagement with the FDA

As noted earlier, the FDA stresses the importance of early engagement with the agency when a drug development plan includes utilizing an AI model. This is important to “(1) set expectations regarding the appropriate credibility assessment activities for the proposed model based on model risk and COU and (2) help identify potential challenges and how such challenges may be addressed.” In addition to formal meetings with the agency, the guidance includes a list of other options to engage with the FDA. The path chosen will likely depend on the AI model and the COU.

In the Federal Register Notice for the guidance the FDA notes that the risk-based credibility assessment framework is informed by: “(1) over 800 comments received on the 2023 discussion papers published by CDER [Center for Drug Evaluation and Research] entitled “Using Artificial Intelligence & Machine Learning in the Development of Drug & Biological Products” and “Artificial Intelligence in Drug Manufacturing”; (2) [the] FDA’s experience with reviewing over 300 submissions with AI and machine learning components across all phases of the drug development process; and (3) current regulatory science research.” Noting that this is a rapidly evolving field, the FDA asks for specific feedback on how well the risk-based credibility assessment framework aligns with the experience of the industry and if the options for engagement with the FDA on AI are adequate.

Conclusion

The FDA’s draft guidance detailing considerations for using AI to support regulatory decision-making for drugs and biological products adopts a risk-based credibility assessment framework and focuses on AI applications for ensuring drug safety, effectiveness, and quality. It outlines definitions, potential benefits, challenges, and the necessity of methodological transparency and life cycle maintenance of AI models. The guidance emphasizes early engagement with the FDA, describing a stepwise approach to establishing AI model credibility for specific contexts of use and highlighting the importance of human oversight. The document also seeks public comment on its alignment with industry experience and sufficiency of engagement options with the FDA.

For ethical review and regulatory inquiries, contact WCG’s IRB experts by completing the form below. Our team, comprising of nearly 200 board members, is prepared to provide guidance. Complete the form today for a free consultation.

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On August 21, 2024, the International Council for Harmonization of Technical Requirements for Pharmaceutical Use for Human Use (ICH) finalized Guideline E11A on Pediatric Extrapolation. The purpose of the guideline is to provide recommendations and facilitate global harmonization for the use of pediatric extrapolation to support the development and approval of pediatric medicines. The Food and Drug Administration (FDA) adopted this guideline as FDA guidance in December 2024. The guidance contains additional information specific to pediatric extrapolation and builds on information in the ICH E11 (R1) guideline “Clinical Investigation of Medical Products in the Pediatric Population: Guideline and Addendum,” which was also adopted by the FDA as guidance. By exploring the ICH E11A guideline, this piece defines pediatric extrapolation and the regulatory expectations, describes ethical considerations, and shares study design adaptations for pediatric extrapolation.

Background for Pediatric Extrapolation

Pediatric extrapolation is a concept used in drug development to apply the efficacy and safety data obtained from adult clinical trials to pediatric populations. This approach assumes that the course of the disease and the response to the investigational drug are sufficiently similar in both adults and children. It also assumes that children will benefit from exposure to the investigational drug so that studies in children will offer sufficient prospect of direct benefit to justify the risk. By using pediatric extrapolation, researchers can reduce the need for extensive clinical trials in children, thereby accelerating the availability of safe and effective drugs for pediatric use.

In the past, specific categories, full, partial, and no extrapolation, were used to describe the level of extrapolation allowed for an indication or condition. E11A states that extrapolation occurs on a continuum. The degree upon which similarity is determined is accomplished by a multidisciplinary review of the strength of the evidence, the confidence in the data available, and any remaining knowledge gaps. The amount of information needed will vary based on the condition and how it manifests in adults compared to children. See Figure 1 below from the FDA guidance.

The guidance also includes a framework for using extrapolation within a pediatric drug development plan that builds on figure 1. As new clinical and scientific data is collected for a condition or disease, the extrapolation plan can evolve over time. As gaps in knowledge are addressed, less data may be required when executing the pediatric extrapolation plan. This allows the framework to be modified as new information is collected. See figure 2 from the guidance below for a description of the framework.

Inclusion of Pediatric Participants in Adult Clinical Trials

If researchers are confident that pediatric extrapolation can be applied to the development of a drug, it may be possible to include children in the adult drug development program before the drug is approved for adult use. Adolescent participants are often considered first because additional information to support dosing may not be necessary. In most cases, the pharmacokinetics (PK) in adults and adolescents are similar. Often, the barriers to enrollment of adolescents in adult trials can be as much operational as scientific and ethical.

Scientific considerations include aligning the primary endpoint to allow pooled analysis of data and using similar safety assessments to allow safety comparisons. Ethical considerations include whether a placebo control is appropriate for pediatric participants. Operational issues include the added complexities of parental permission and adolescent assent, and whether sites that enroll adults have access or the capability to enroll =adolescent participants. Younger children may be included in adult studies, but often because of differences in dosing and varying safety concerns, it may be more expeditious to conduct a separate pediatric study, unless the overall study population is so small (e.g., rare disease clinical trials) that separate adult and pediatric studies may be difficult to conduct.

The Roles of Modeling and Simulation

Modeling and simulation play a significant role in supporting a pediatric extrapolation plan and in pediatric drug development in general. Modeling and simulation may be used, for example, to evaluate similarity of disease and response to therapy, inform study design, develop dosing recommendations, and anticipate the effects of the drug in the relevant population. It can also be used to confirm the underlying extrapolation concept when the pediatric study is completed.

Appropriate dose selection is important in pediatric studies, but separate PK/pharmacodynamic (PD) studies may not be necessary. Often PK data can be collected within the pediatric efficacy study or as a lead in to a pediatric study to fine tune the dose, or modeling and simulation can be used to predict a dose if the effect of the disease on the PK is known. For example, in cases where the drug has already been studied in a pediatric population for another indication and the exposure is known or when there is exposure data in adults for the indication and matching exposure data for another indication in a pediatric population. Occasionally dose ranging data may be required as part of an extrapolation plan, such as in cases where there is uncertainty about disease similarity and/or response to treatment, if there are potential age-related differences in target expression, or for locally acting drugs where there is no correlation between therapeutic response and systemic drug exposures.

When designing the adult drug development program, it is important for sponsors to consider the pediatric program when it comes to what biomarkers and endpoints are included in adult studies. For example, if an endpoint or biomarker may be relevant to the pediatric program, it could be included in the adult study and then utilized in the pediatric program to support efficacy. If there are differences in endpoints, then an evaluation of relationships of the endpoint in the adult population compared to the pediatric population should be conducted to support the pediatric program. For example, a six-minute walk test may not be appropriate for pre-ambulatory pediatric participants, so other measures should be explored that may be used in the pediatric study. If the endpoint in the pediatric study differs from that in adult studies, then the acceptability of the use of the endpoint in the extrapolation plan should be discussed with regulatory authorities while studies are in the planning stages.

If safety will be extrapolated, it is critical to provide strong justification as to why the safety data from the reference population (usually adults) is applicable to the pediatric population. Safety data collection should address the scientific questions to be answered, identify any knowledge gaps, and address any uncertainties that exist. Selected safety issues might need to be evaluated in a pediatric study that are not addressed with the existing safety database to support the safety of the drug in the pediatric population under study. There also may be cases where the existing safety data is sufficient to support the use of the drug in the pediatric population and no further safety data will need to be collected.

Study Design & Extrapolation Plan

The type of studies required when pediatric extrapolation is utilized can vary depending on the drug development program. As noted in figure 1, there is a continuum when extrapolation is considered based on the confidence in the similarity of disease and response to treatment. Studies may range from matching effective and safe exposures in the adult population to the pediatric population, to PK/PD studies when exposure matching alone is not sufficient to establish a dose, to studies evaluating efficacy. Embedded exposure matching or PK/PD components may be included in efficacy studies as noted above. Whatever study design is chosen, the extrapolation plan should be discussed with regulatory authorities and based on the extrapolation concept.

When required, efficacy studies within an extrapolation plan may vary. Often, additional efficacy information is needed to support use of the drug in the pediatric population since the effect of treatment on outcome in the pediatric population could be different than that in adults. However, it may be possible to utilize Bayesian techniques in the pediatric population to reduce the number of pediatric participants needed to address the scientific question. Single arm studies may be appropriate when considered sufficient to establish efficacy or when a suitable control arm does not exist. When a single arm study is thought to be sufficient, prespecified criteria should be established that define how the primary efficacy objective will be evaluated.

Studies that utilize external control, such as relevant existing control arms from other studies or real-world data (RWD), can also be considered under an extrapolation plan. In the case where an external control is used, statistical methods should consider the potential for bias and confounding when comparing data.

Finally, controlled studies may be needed in some situations to establish efficacy, but because some degree of extrapolation is utilized, the study design may be different from adult studies. It may be difficult to conduct placebo studies in the pediatric population if there is some expectation based on extrapolation that the drug will be effective in children. Additionally, when non-inferiority study designs are used, the study may be powered to meet a relaxed success criterion—or the non-inferiority margin widened compared to the adult program—since the adult data may be relied upon to some extent based on the extrapolation concept. It is essential to affirm that the point estimate of the treatment effect in the pediatric study does not result in questions regarding inferiority.

Conclusion

In summary, the FDA’s acceptance of the ICH E11A Pediatric Extrapolation Guideline marks a significant advancement in the harmonization of pediatric drug development. The guidance describes how pediatric extrapolation can be utilized when designing studies for pediatric drug development programs. This should expedite the availability of safe and effective medications for children while minimizing the need for extensive clinical trials. This collaborative effort underscores the importance of innovative approaches in addressing the unique challenges of pediatric medicine and ensuring that children receive timely access to essential therapies.

Do you have additional questions about pediatric participants in your clinical study or other ethical review questions? WCG’s Institutional Review Board (IRB) experts are here to support you in navigating all the complexities of trial development and reviews, including pediatric extrapolation and more. Please complete our form below to get in touch today.

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The following Insight is a featured article from WCG’s 2025 Trends & Insights Report. If you would like to read more insights from this report, please click here.

The Office of Management and Budget has noted in its Unified Agenda that the single IRB final rule is expected to be issued in May 2025, but this date is not guaranteed and is subject to change. Although sponsors, investigators, and institutions may have already implemented changes in processes and standard operating procedures (SOPs) in advance of the rule’s finalization, some may wonder why the rulemaking process takes so long and why the timing of implementation is so unpredictable.   

Rulemaking is a complex process outlined under the Administrative Procedures Act (5 USC §553 (1946)). The Act requires that a Notice of Proposed Rulemaking (NPRM) be published in the Federal Register to allow for public comments unless the agency issuing the rule finds the notice and public comments to be impracticable, unnecessary, or not in the public’s interest.  

Public comments generally close 60 days after publication of the Federal Register notice. FDA staff then review the comments and decide if points raised in the comments require modification of the proposed rule. Any revisions require consensus among the stakeholders involved in the rule writing. In addition to this, many internal agency and interagency steps occur from the time rule making is initiated until a final rule is published, further lengthening the timeline.  

At the FDA, many offices can be involved in the process of rulemaking or in modifying a draft rule. Changes made by one office may require re-review by another office, depending on the significance of the change, to ensure agreement. Once the language is agreed upon, a formal clearance process takes place that may include additional offices. Agency priorities may slow the process. The immediate public health issues resulting from the COVID-19 pandemic are one example of a situation that directed agency resources away from more routine processes and may have delayed the work on the proposed rule.   

Interagency review occurs after the FDA finishes its review. Although the additional agencies may not be disclosed, for the single IRB rule, review by the Department of Health and Human Services (HHS), as well as the Office of Human Research Protections (OHRP), will certainly need to take place given the impact on the existing regulations on cooperative research under the Common Rule.  

Once the rule is finalized, the FDA will likely allow a grace period for implementation, but whether a grace period is allowed and/or the length of any grace period is not stipulated in the NPRM.  

Consequences of Not Being Prepared 

Once the rule is finalized, the FDA is likely to allow a grace period for implementation, although the specifics are not guaranteed in the NPRM. Below are the possible consequences for sponsors, institutions, and investigators who are not ready when the final rule goes into effect: 

Operational Disruptions: Institutions that have not yet adopted changes in SOPs and processes may face significant operational disruptions. The need for rapid implementation of new procedures could overwhelm administrative and operational capacities, leading to delays in research activities and potentially impacting ongoing studies. 

Regulatory Non-compliance: Failure to comply with the new single IRB mandate could result in regulatory non-compliance. This could lead to warnings, fines, or other penalties from regulatory bodies. Non-compliance might also jeopardize funding and sponsorships as adherence to regulatory guidelines is often a pre-requisite for financial support. 

Loss of Credibility and Trust: Non-compliance with the single IRB rule can damage an institution’s or investigator’s credibility. It may lead to a loss of trust among stakeholders, including funding bodies, collaborators, and study participants. Maintaining compliance with regulatory requirements is essential for preserving the integrity and reputation of research entities. 

Legal Implications: Institutions and sponsors that fail to comply may face legal consequences. Non-compliance can lead to lawsuits or legal actions, particularly if the failure to implement changes results in harm or risk to study participants. Legal battles can be costly and time-consuming, further straining resources and tarnishing reputations. 

Sponsors, institutions, and investigators that have yet to implement changes in processes to conform with the single IRB mandate should consider making those changes now in order to be ready when the final rule goes into effect.  

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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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The single IRB mandate will require that many institutions that do not wish or lack the capacity to act as single IRBs rely on other central IRBs. Although the goal of the single IRB mandate is to decrease administrative burdens at the institutional and investigator level, the transition will result in changes in institutional policies and structures. Sponsors will be required to use a single IRB. Institutions or investigators will need to use the single IRB chosen by the sponsor or choose not to participate in the research. Many institutions are putting processes in place now, with anticipation that the final rule will be issued soon. The FDA has noted in its Unified Agenda that the final rule is expected to be issued in January 2026, but this date is not guaranteed and is subject to change. 

Why Does It Take so Long for Regulations to be Issued by the FDA and Other Federal Agencies?

Rulemaking is a complex process that is outlined under the Administrative Procedures Act (5 USC §553 (1946)). The Act requires that an NPRM be published in the federal register to allow for public comments unless the agency issuing the rule finds the notice and public comments to be impracticable, unnecessary, or not in the public interest. Public comments generally close after 60 days of publication of the federal register notice. In cases where it is determined that an NPRM is not needed, an interim or final rule may be issued, depending on the specific situation. Once the comment period has closed, FDA staff must then go through the process of reviewing those comments and deciding if points raised in the comments require modification of the proposed rule. Any revisions will require consensus among the stakeholders involved in writing the rule. In addition to this, there are many internal agency and interagency steps that occur from the time rule making is initiated until a final rule is published, further lengthening the timeline. 

For FDA review, many offices can be involved in the process of rulemaking. Relevant offices such as the Office of Clinical Policy, Office of Medical Policy, Office of the Chief Counsel, and the Office of the Commissioner might be involved in developing the rule. Other offices, depending on the topic of the rule may also be engaged. For example, for topics related to human subject protection, the Office of Clinical Policy is generally included in the discussions, or if the topic is pediatric, the Office of Pediatric Therapeutics may be engaged. Often working groups are created that include the appropriate office and subject matter experts and these groups meet regularly. However, in some cases competing priorities may disrupt the meeting schedule and some time may lapse between meetings. 

Once a draft rule is created by a working group, the proposed rule circulates through various levels of review at the FDA. If significant changes are made as part of the review process by one office, re-review may be necessary to ensure agreement. This is the most time-consuming part, because some offices may need to re-review several times if certain aspects of their input are revised by other groups. Each office needs sufficient time to review, which may take several weeks within each office. Once draft language is agreed upon, a formal clearance process takes place. This may include additional offices and stakeholders that may not have been involved initially. Again, adequate time for review is needed by each office and stakeholder. At the FDA, certain agency priorities may slow the process. For example, the COVID-19 pandemic directed agency resources to develop guidance for COVID-19-related issues and away from ongoing routine processes. If legislation is enacted that requires guidance to be written within specific timelines, the attention from the work on rulemaking may be redirected to handle these time-sensitive projects. 

Once FDA clearance is complete, interagency review occurs. The more complex or impactful the rule, the more likely that several agencies will need to review it. Although those agencies may not be disclosed, for the single IRB rule, review by the Department of Health and Human Services (HHS), as well as the Office of Human Research Protections (OHRP) would certainly need to take place given the impact on the existing regulations on cooperative research under the Common Rule. 

When a final rule is issued, the FDA is likely to allow a grace period for implementation. However, whether a grace period is allowed and/or the length of any grace period is not stipulated in the NPRM. Regarding the single IRB mandate, some may have processes in place for single IRB review for NIH-supported research. If not, it would be prudent for sponsors and institutions to consider any changes in processes that might need to be made now, so that they are ready when the rule goes into effect. 

Consult the Experts to Prepare for the Single IRB

WCG has unmatched expertise in supporting all stakeholders in clinical research with navigating changes so your organization remains compliant and efficient. Leverage the industry-leading IRB review vendor by completing the form below.

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Join our Chief Data & Analytics Officer Silvio Galea, along with Dr. Donna Snyder & Dr. Barbara Bierer to discuss opportunities on the ethical and regulatory challenges regarding artificial intelligence in clinical trials. The discussion is focused through the lens of the IRB review, and how a multi-stakeholder task force led by the Multi-Regional Clinical Trials (MRCT) Center of Brigham and Women’s Hospital and WCG will address the growing need for guidance in this rapidly evolving area of research.

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About the Webinar

This webinar is aimed at all stakeholders in clinical research, including sponsors, CROs, institutions, and sites. Our experts dive into the intricacies of the Food and Drug Administration’s (FDA) proposed single Institutional Review Board (sIRB) mandate, providing crucial insights and updates to ensure your organization remains compliant and efficient in multi-site clinical trials.

Topics covered include:

• Recap of the 2023 NPRMs: We start by revisiting the key points of the 2023 Notices of Proposed Rulemaking (NPRM), highlighting the proposed changes and their potential impact on clinical research stakeholders.
• Update on Changes: Get up-to-date with the latest developments surrounding the FDA’s proposed single IRB mandate. We explore what has changed since the NPRM and discuss how these changes may affect your organization’s operations and procedures.
• Demystifying the FDA: Ever wonder why FDA mandates seem to take forever to become final rules? We demystify this process, providing clarity on the intricacies and timelines involved in regulatory decision-making at the FDA.

Plus, our experts discuss why aligning to the sIRB mandate sooner rather than later is advantageous to accelerating your research. Don’t miss this opportunity to gain valuable insights and strategies for navigating the FDA’s proposed single IRB mandate. Watch the recording now to stay ahead in the ever-evolving landscape of clinical research compliance.

The post Revisiting the FDA’s Proposed Single IRB Mandate: Navigating Changes and Aligning for Success appeared first on WCG.

However, The Secretary’s Advisory Committee on Human Research Protections (SACHRP) recently opined on this issue and noted that the “AI/ML [machine learning] and BD [big data] research expose the limits of the traditional concept of identifiability that serves as the basis for privacy protections under the Common Rule.” As technology advances, what was considered private in the past may no longer be, so IRBs may need to evaluate the data sources used in research more closely and consider whether adequate protections are in place before establishing that a protocol is exempt from IRB review.   

Once a protocol is determined to require IRB review, there are a variety of areas where AI might be incorporated into the research. For example, AI may be incorporated into software as part of a medical device. It may be used as part of drug and biologics development. It could be used to help select what participants might be enrolled in a clinical trial, or it may be integrated into digital technologies as a study outcome measure.  

The IRB is tasked with evaluating how AI will impact the IRB’s analysis of benefit and risk, particularly harm related to the validity and bias of models used to train AI, as well as how the privacy of the individual will be protected in the research. The IRB is also tasked with ensuring that the informed consent form and process includes information on the use of AI as part of the research if AI is being used to make treatment decisions during the study and is clear on any secondary use of data after the study is complete. IRBs may consider having an individual with expertise in AI/ML available for consultation for complex protocols utilizing AI to ensure that participants are adequately protected.  

The post The Impact of Artificial Intelligence (AI) on Ethical Review by IRBs  appeared first on WCG.

The final guidance references where the differences exist between FDA regulations and the 2018 Common Rule, where there are plans to update the regulations and how IRBs, investigators and sponsors might navigate the differences between the two processes in the meantime (see guidance entitled Impact of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical Investigations for more on this topic). In particular, FDA has not yet harmonized on the waiver or alteration of informed consent requirements for minimal risk research to align with requirements under 45 CFR 46.116(f)(3); however, does note that FDA will not object to the IRB approving a consent procedure that does not include, or that alters, some or all of the elements of informed consent, as long as the specified additional requirements are satisfied. Further information on this process can be found in the guidance entitled, IRB Waiver or Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human Subjects

Most IRBs are familiar with the content of the 2014 draft guidance, “Informed Consent Information Sheet.” The final Informed Consent guidance duplicates the categories in the 2014 draft guidance with the exception that “Additional Considerations” have been rearranged under a section entitled “Frequently Asked Questions.” The summary here focuses on the changes or additions included in the final guidance when compared to the 2014 draft guidance.

Summary of the Consent Process

The final guidance emphasizes that the informed consent process, which involves not only signing the consent form, but also providing subjects with adequate information to make an informed decision about study participation, starts with the recruitment of subjects and continues throughout the study. The information included in recruitment material should be limited to the minimal information needed for a prospective subject to determine interest and eligibility. Recruitment materials should be consistent with the informed consent document. Additionally, the final guidance notes that providing new information to subjects as it emerges is an important aspect of the informed consent process. Augmented information on processes for informing subjects of new information during study participation is included in the final guidance.

General Requirements for Informed Consent

The final guidance includes a statement that FDA does not consider reimbursement for reasonable travel expenses and associated costs to raise issues of coercion and undue influence. Reimbursement for other expenses is considered an acceptable practice and may be considered by IRBs on a case-by-case basis; payment for participation should be just and fair. However, any payments should not be considered a benefit to justify the risks of the research when IRBs evaluate whether the risk to patients is justified in relation to the anticipated benefit as per 21 CFR 56.111(a)(2).²

Basic Elements of Informed Consent

Regarding the basic element of consent requiring a description of risks and discomforts, the final guidance has been updated to include a statement that “where relevant, participants should also be made aware of the possibility of unintended disclosures of private information and be provided with an explanation of measures to protect a subject’s privacy and data and limitations to those measures.” This further emphasizes the requirement under 21 CFR 56.111(a)(7) that IRBs are required to determine, where appropriate, that there are adequate provisions to protect the privacy of subjects and to maintain confidentiality of data.

Regarding the description of benefits, the final guidance restates that information about the investigational agent and control should include relevant information about the potential benefits of each. The final guidance adds, for studies involving a comparison of an investigational agent to standard of care, it may be acceptable to generally describe the benefits of the standard of care in the informed consent form and provide more detailed information on the benefits of the standard of care during the consent discussion. This point follows a general trend in the final guidance to find ways to streamline the consent form and process. Although not directly addressed in the guidance, this approach should also apply to the description of potential risks as well as the potential benefits for the investigational agent, control, and standard of care based on what information is known at the time consent is obtained.

The language on what is required to be described in the consent form regarding alternatives has been softened. The 2014 draft guidance stated that a description of the risks and benefits for appropriate alternative procedures or courses on treatments were required to be disclosed. The final guidance no longer requires this, but instead recommends that these alternatives be disclosed as part of the consent discussion but not necessarily included in the informed consent document. This change will allow IRBs to make qualitative decisions on what is necessary to include in this section to adequately inform participants without an undue burden on the information required to be included in the consent form.

Although not directly discussed in the body of the final guidance, changes to the application of Certificates of Confidentiality (CoC) are pertinent as they relate to participant confidentiality. The 21st Century Cures Act amended the statutes relating to the issuance of CoCs. The statute broadened the protections for research participants by specifically prohibiting holders of CoCs from disclosing identifiable, private information unless specific exemptions apply. The Cures Act also required that CoCs be issued for any federally funded research that collects or uses identifiable, sensitive information. Sponsors and sponsor investigators should be aware that they may request a discretionary CoC for FDA regulated research from the FDA. FDA will review the request and determine if the CoC will be granted for the research.³ Sponsors and sponsor investigators may want to consider a CoC for research that may collect particularly sensitive information.

Additional Elements of Consent

If a statement on unforeseeable risks to subjects (or to the embryo or fetus) is considered appropriate for the informed consent document, the final guidance recommends that “sponsors may want to consider whether appropriate birth control measures and notifying the investigator of pregnancy should be included in the protocol and addressed in the informed consent document.”

Under additional costs to subjects, the final guidance emphasizes that the informed consent document should include sufficient information on the protocol requirements and time commitment so that the participant can appreciate how much time may be needed away from work, childcare, or elder care and how much of the cost will be borne by the sponsor or paid by the subject.

Under consequences of the subject’s decision to withdraw from the study, the final guidance discusses that subjects may need to be counseled that they should not participate in the trial if they do not foresee staying in the study. Subjects should also be made aware of the number of visits and time required to ensure they are committed to completing the research. Encouraging potential study participants to consider the commitment and costs associated with the research in advance of study participation might help with study retention once participants are enrolled in the trial.

The section on significant new findings to subjects has been expanded to include additional situations that may impact a subject’s willingness to continue in the study. These may include the results from interim analyses, information on alternative procedures or treatments that come available during the trial, efficacy results from other trials using the investigational product or information on the effectiveness of a comparator. If the information is significant, the IRB should consider whether patients in the trial should be contacted to determine whether the new information might impact their desire to stay in the trial. The final guidance further expounds on this topic under “Frequently Asked Questions.”

Documentation of Informed Consent

The final guidance provides an alternate way of providing a signed consent form, for example if a participant is in strict isolation for a highly transmissible infectious disease and electronic consent is not available. A photographic image of the signed consent form can be retained in the records. The person entering the photograph into the medical record needs to state how the photograph was obtained and that it is a photograph of the informed consent signed by the subject.

A discussion on the use of short forms notes that because a witness is needed when a short form is used, and a written summary of the verbally supplied informed consent discussion must be supplied, which is generally the English version of the long form, that using a short form may not ease or expedite the informed consent process compared to the use of a long form.

IRB Responsibilities

Additional language has been added to state that the IRB should inquire who will conduct the consent discussion and what procedures will be followed. If other than a face-to-face discussion is proposed, such as by telephone, the IRB should consider whether the procedures will impact effective communication. Alternative methods for obtaining informed consent might be of concern if the clinical trial includes complex procedures or risks that might be difficult to comprehend.

Updates to consent forms for typographical or spelling errors and changes to telephone numbers do not need formal IRB review, but the updated documents need to be sent to the IRB, so the IRB has current copies of the documents.

The final guidance notes that other visual aids, in addition to pictures and diagrams, may be used to improve understanding of the research during the consent process.

Clinical Investigator Responsibilities

The final guidance states that although the clinical investigator should consider whether financial relationships and interests may impact the informed consent process, the IRB has the final responsibility in determining whether subjects should be provided with information regarding the source of funding, funding arrangement or financial interests of parties involved in the clinical investigation as part of the informed consent process.

Sponsor Responsibilities

For multicenter clinical investigations, the final guidance expands on the concept that if local review of a consent form results in significant changes, that those changes should be shared with all the investigators or IRBs and if a central IRB is involved local changes should be shared with the central IRB. Not noted in the previous draft guidance but required by regulation (21 CFR 812.35(a)) is that these changes must be shared with the FDA for medical devices that require an IDE (Investigational Device Exemption).

The final guidance notes that for some medical device studies a sponsor representative or field engineer may be present during the procedure and/or follow-up visits. If this occurs, or sponsor activities directly affect the subject, these activities should be described in the consent form.

Frequently Asked Questions

Much of what is in this section was found in the “Additional Considerations” section of the 2014 draft “Informed Consent Information Sheet.” Clarifications and additions are discussed below.

For “What are some considerations for enrolling a child in a clinical investigation?” a section on mature minors and emancipated minors is described. In these situations, depending on the laws of the local jurisdiction where the study is being conducted, a minor may no longer meet the definition of a child⁴ and may be able to consent for themselves without parental or guardian permission.

Under “Are there any additional protections required when enrolling children who are wards of the state?” the enrollment of children in clinical investigations who are wards of the state, as described under 21 CFR 50.56, is clarified in the final guidance. An advocate is required for clinical investigations conducted under 21 CFR 50.53 and 50.54, where other conditions are met, but is not required for clinical investigations under 21 CFR 50.51 and 50.52. However, FDA recommends an advocate be appointed for all research conducted with wards of the state. The advocate should not be associated with the clinical investigation, investigator, or guardian organization except in their role as an advocate.

Under “What process should be followed when the enrollment of subjects who do not understand English is not expected?” the process for use of a translated short form and English long form clarifies that the witness does not need to be fluent in the language but must have sufficient proficiency to attest that the information was presented orally to the potential participant and also notes that the witness, if possible, should not be related to the subject. Further emphasis is added that whenever subjects who do not understand English are enrolled in a study that appropriate interpreter services should be available to the subject throughout the research.

For “What should be considered when enrolling subjects with physical or sensory disabilities?” it is noted that unless required by state or local law that a LAR (legally authorized representative) is not required to be involved in the informed consent process or to sign the consent form. The participant can signal consent as is consistent with applicable law.

A section has been added on who can serve as a LAR and what their role is in a section entitled ‘Who can serve as a legally authorized representative (LAR) and what is their role?” This section discusses that the legal authority as to who can serve as a LAR is established by State and local law. IRBs, investigators and/or sponsors may need to consult with legal counsel or their institution to determine who may serve as a LAR. A LAR may be included as part of the consent process, but individuals with impaired consent capacity should be included in the consent process to the extent that they are capable of participating. An individual capable of consent at the beginning of a study but expected to experience cognitive decline over time may elect to designate someone who can serve as LAR once they can no longer consent for themselves.

A section, “How can informed consent be obtained through electronic methods?” has been added to note that FDA supports the use of informed consent through electronic methods, noting that the consent process may employ interactive methods that may facilitate comprehension, “may promote timely entry of any electronic informed consent into a study database and facilitate collection of informed consent from remote locations.” The final guidance refers the reader to the specific FDA guidance entitled, “Use of Electronic Informed Consent – Questions and Answers.”

The question “Can a subject participate in more than one clinical investigation simultaneously?” includes a new consideration that, in some cases, it may be appropriate for a subject to enroll in more than one trial. A few examples are given, such as rare disease studies that are evaluating different aspects of the disease and participating in one study does not impact the other study or for appropriately designed studies where a companion device needed for the safe and effective use of the drug may be tested alongside the clinical investigation of a novel drug. The section also adds that the risks of participating in more than one clinical trial should be discussed during the consent process, but these risks do not necessarily need to be included in the consent form.

The final guidance adds that the FDA supports supplying subjects with aggregate study results (“Should subjects be informed of aggregate study results at the completion of a trial?)” As previously noted in the 2014 draft guidance, for clinical trials that are required to register in www.ClinicalTrials.gov, aggregate summary results will be posted, however sponsors and investigators can voluntarily register trials and submit summary results for trials even if they are not required to register the trial. What has been added to the final guidance is an explanation that the regulations do not address IRB review of aggregate results. The final guidance recommends that when there is a plan to return aggregate results at the initiation of the trial or if a decision is made to share results after initial approval but while the study is still open with the IRB, the IRB should review the plan on how results will be shared. If the plan to share aggregate results is made after the study is closed with the IRB, the IRB does not need to review the sponsor’s plan to share the results with the subject.

The final guidance includes an expanded section on informing subjects of new information that may impact their willingness to continue to participate in the research under a question entitled “How should subjects be informed of new information that may affect their willingness to continue participation in the research?” The IRB has significant flexibility in determining the procedures that the IRB believes are appropriate to affirm the subject’s willingness to continue in the research. If the consent form is revised, the IRB may determine that currently enrolled subjects should also be informed and if a revised informed consent or an addendum are appropriate. In situations where a revised informed consent is used to provide new information to subjects and document willingness to continue in the trial, the FDA recommends that the investigator prepare a summary of the changes to the informed consent document to reduce any confusion about any of the changes and aid in presenting the new information. FDA notes that subjects currently participating in the trial do not need to be informed if the new information is unlikely to affect their decision to continue to participate and subjects who have completed a trial do not need to be informed of new information unless the new information relates to a risk that may still be of concern after study participation. However, the IRB has the option to recommend that the investigator provide the summary prepared for the reconsent discussion to all subjects currently and previously enrolled, for their awareness.    

Conclusion

The final FDA guidance, “Informed Consent, Guidance for IRBs, Clinical Investigators, and Sponsors,” does not include any significant new concepts but does expound on some old ones to address contemporary issues, such as the utility of electronic informed consent, subject payment, protecting confidentiality and details on how to address new findings in research. It is a substantial document that will serve as a valuable resource for IRBs, investigators and sponsors when considering the informed consent process and developing and reviewing the informed consent document.

[1] On September 28, 2022, FDA issued proposed rules to harmonize certain provisions of 21 CFR parts 50 and 56 with the 2018 Common Rule with some exceptions to maintain consistency with other FDA statutory provisions.

[2] FDA Information Sheet, Payment and Reimbursement to Research Subjects Guidance for Institutional Review Boards and Clinical Investigators, January 2018

[3] Certificates of Confidentiality, Guidance for Sponsors, Sponsor-Investigators, Researchers, Industry, and Food and Drug Administration Staff

[4] 21 CFR 50.3(o) defines children as “persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations, under the applicable law of the jurisdiction in which the clinical investigation will be conducted.”

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