Thank you for joining us for another episode of the Guidance Recap Podcast. My name is Kylie Haskins, and I am today’s host. In this episode, I am excited to be talking with Donna Snyder, Senior Pediatric Ethicist and Team Leader in the Office of Pediatric Therapeutics. She will be sharing some thoughts with us on the newly published draft guidance titled, “Ethical Considerations for Clinical Investigations of Medical Products Involving Children.” Welcome, Dr. Snyder! Thank you for speaking with us today.

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For listeners less familiar with this topic, can you provide a brief background about the ethical considerations for pediatric clinical trials?

Sure, historically, children weren’t included in clinical trials because they’re a vulnerable population that can’t provide informed consent for themselves. For the purposes of the regulations we will be discussing today, the term “children” refers to any individual who hasn’t reached the legal age of majority, which in most states is 18 years. For many years, it was believed that not including children in clinical trials protected them. However, children, just like adults, are susceptible to illness and disease and may need medicine. Because in the past many medicines weren’t tested for children, doctors routinely gave drugs approved for adults to children, with the dosing often adjusted to account for children’s smaller weight without really knowing if the dose was correct or if the medicine would work the same way in children as it did in adults. Over time it became clear that children aren't small adults and using drugs off-label in pediatric patients by adjusting the dosage for weight may not provide the most effective dose and may lead to unanticipated side effects.

We know that for drugs and biologics, children can have unique absorption, distribution, metabolism, and excretion characteristics that differ from adults, and, for medical devices, we know that the performance characteristics of a device in children may differ when compared to adults. Because of these differences, it is important to study medical products directly in children. Today, we recognize that we can better protect children by including them in clinical research.

In the 1970s there was a major turning point for including children in clinical research with the creation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. This Commission identified the basic ethical principles that underlie the conduct of research with human subjects that we still follow today, such as respect for persons, beneficence, and justice. The National Commission helped to define an ethical path by which children could participate in clinical research when the information obtained in the research is necessary to improve the health and welfare of children. Their recommendations provided a foundation for the development of FDA’s human subject protection regulations, including the recommendations for children.

The pediatric human subject protection regulations were promulgated by the Department of Health and Human Services in 1983 and adopted by FDA in 2001 as an interim rule; the rule was finalized in 2013. Around the same time, Congress also passed laws to foster drug development for the pediatric population: the Best Pharmaceuticals for Children Act or BPCA in 2002 and Pediatric Research and Equity Act, or PREA in 2003. BPCA and PREA have resulted in an increase of pediatric studies. It is important that investigators, pharmaceutical industry sponsors, and institutional review boards or IRBs understand how to implement the human subject protection regulations in the context of a pediatric study.

So, the major goal of this guidance is to provide FDA’s perspective on the ethical considerations for including children in clinical trials and specifically to help investigators, sponsors, and IRBs understand and interpret the regulations that apply to children as human subjects within the context of a pediatric clinical investigation.

This guidance describes FDA’s current thinking on ethical considerations for including children in clinical investigations. Can you provide an overview of the additional safeguards for children enrolled in clinical studies that are included in FDA’s regulations, often referred to as subpart D, and explain how they inform the regulatory review process?

Of course. The Additional Safeguards for Children in Clinical Investigations are found in Title 21 of the Code of Federal Regulations under Part 50, subpart D and, as you mentioned, we often simply refer to them as subpart D. These regulations establish requirements for parent or guardian permission and child assent to participate in a study. The regulations also outline a limit on the risk to which children can be exposed based on whether they have the prospect of directly benefiting from the research or not.

If there are no data to support that the children enrolled in a clinical trial have a prospect of direct clinical benefit from the intervention or procedure included in the study, then the risks to which children are exposed must be low. Low risk can fall into one of the following two categories: minimal risk or minor increase over minimal risk. Minimal risk is considered a level of risk that is not greater than what would normally be encountered in the everyday life of a healthy child or in routine physical or psychological exams or tests. An example of a procedure that might be considered minimal risk would a be single blood draw. Minor increase over minimal risk, meanwhile, signifies a slight increase over minimal risk that poses no significant threat to a child’s overall health or well-being. Any potential harm should be expected to be transient and reversible, and the probability for severe pain, discomfort, or harm should be extremely small or nonexistent. An example of a procedure that might be considered minor increase over minimal risk would be a lumbar puncture with topical pain relief. If a child will be exposed to an intervention or procedure in a study that does not offer a prospect of direct benefit, and is more than minimal risk, then the findings resulting from that study should be likely to contribute to important knowledge that is vital for understanding or ameliorating the child’s disorder or condition.

However, most clinical trials involving investigational medical products present higher risks. Under subpart D, those risks must be balanced by the prospect of direct benefit and the balance of potential benefits and risks must be at least as favorable as any available accepted alternative treatments. So, it’s really a benefit/risk assessment to determine whether it’s appropriate for children to enroll in a clinical trial. The level of evidence to support prospect of direct benefit may vary based on the situation. For rare diseases that are exclusively or primarily seen in children, or are more severe in children, nonclinical data alone might support prospect of direct benefit, but for conditions that exist in adults and children, we may want some adult data before initiating pediatric studies.

One example where nonclinical data supported initial studies in children were the clinical studies conducted for the approval of nusinersen for the treatment of spinal muscular atrophy (or SMA).  Although SMA exists in adults and children, the most severe form of the disease exists in children. Children were considered to be the most likely to benefit from study of this product, so studies were initiated in children without first collecting adult data. Although approval was ultimately extended to adults with less severe forms of the disease, waiting for studies in adults before allowing studies in children would have delayed the availability of this product for the children who needed it the most.

For products that are being developed in adults and children and for which we have existing therapies for children, we generally want some adult data to support prospect of direct benefit to initiate studies in children. For cases where we can extrapolate effectiveness from adults to children, if we have adult data, studies in children can be streamlined, potentially limiting pediatric studies to those needed to evaluate safety and dosing.  

Can you describe a few key considerations for assessing risk in pediatric clinical study protocols that sponsors and IRBs should follow?

Yes, of course. When considering the risks of a study, sponsors and IRBs should conduct an analysis of the risks associated with the pediatric clinical investigation, evaluating the various procedures or interventions in the trial to establish first if they offer a prospect of benefit, and if not, then whether these interventions or procedures meet the criteria of minimal risk or no more than a minor increase over minimal risk. This is known as a component analysis of risk.

When discussing component analysis, one topic that comes up frequently is the use of placebos in a pediatric clinical trial. In the guidance, we note that for children enrolled in the active arm of a placebo-controlled study, there is prospect of direct benefit that is offered by the investigational medical product to justify a higher risk; but for children in the placebo arm, there is no prospect of direct benefit from the placebo, and, therefore, the risks should be low, meaning the risk shouldn’t exceed minimal risk or minor increase over minimal risk. We evaluate each arm as a different component of the trial.

There are a number of issues to consider when assessing risk with the use of a placebo. First there is the placebo itself and how it is given. A placebo pill given orally over a period of a few weeks has a very different risk profile than an IV saline infusion given weekly over several months. The first situation might be considered to be minimal risk, the second would likely be evaluated in terms of whether it meets criteria as a minor increase over minimal risk.

Other factors to consider are the risk of withholding known effective therapy for the children that are getting placebo. If there are no other treatments available for the condition the evaluation may be easy, but the evaluation might be more difficult if there are treatments available. Some ways to address this are to maintain standard of care therapies in the placebo arm, with the placebo used as add on. If there are scientific reasons for needing to withhold known effective therapy, the time that the treatment is withheld should be limited to the shortest time needed to evaluate the effect and it should be established that withholding the therapy won’t exceed the minor increase over minimal risk threshold or result in any irreversible harm to the children in the study.

Can you explain to the audience why these additional safeguards are important and provide some of the reasons that FDA issued this document?

We know children are a vulnerable population and they can't provide consent to be included in clinical studies. However, we need pediatric studies to provide safe and effective products for children and allow health care providers to make evidence-based decisions regarding the use of medical products in children. Additional safeguards are important to ensure pediatric studies are scientifically and ethically sound and to encourage including children in clinical research. To that end, in this guidance, we have taken the information from our regulations and tried to condense it in a way that we hope IRBs, sponsors, and investigators can interpret and use to inform the design and conduct of pediatric studies to further support the availability of medical products for children.

How do you anticipate this guidance will affect external and internal stakeholders?

The guidance will help streamline pediatric medical product development by guiding sponsors when they’re preparing and designing pediatric study protocols for submission to FDA and the IRB. We also believe the guidance will help IRBs interpret these regulations when they’re evaluating pediatric clinical study protocols.

We want to stress that there isn’t a one size fits all approach for conducting pediatric clinical trials, but there is a methodical, step-by-step process by which investigators, sponsors, and IRBs can evaluate the potential benefits and risks in a pediatric protocol to ensure we’re doing what’s right for children enrolled in clinical investigations. The belief that it’s unethical to initiate pediatric studies in children without adult data is not correct. It is sometimes not only appropriate but necessary to initiate studies in children, but the appropriateness is very specific to the clinical situation.

Can you provide a couple of key items that you especially want listeners to remember?

Yes. Therapies designed specifically for children need to be developed. All pediatric clinical studies must meet certain ethical standards because children are a vulnerable population who can’t consent for themselves and need additional safeguards when participating in a clinical investigation.

The guidance outlines the limit on the allowed risk for children enrolled in clinical studies based on the direct benefit to the child enrolled in the clinical trial.  For interventions that exceed the minimal risk threshold, if there is no direct clinical benefit to the child by participating in the study, the risk to the child must be low, or no more than a minor increase over minimal risk, and the knowledge gained should be important for understanding or ameliorating the child’s disorder or condition.

In general, the assessment of benefit must be made in relation to the risk to the individual child who's enrolled in a study. Because of this, it’s critical that medical product developers use a dose or treatment level expected to be effective for the child in the study and plan the study to be long enough to have some positive impact on that child's life.

Lastly, if the IRB determines that a study cannot be approved based on these requirements but believes the study can be ethically conducted, the IRB may refer the study to the FDA for review by a federal panel. After soliciting public comment, and after FDA review, if the FDA Commissioner agrees that the study is ethical and evaluates a serious problem affecting the health or welfare of children, the study may be allowed to proceed.

What if an IRB or sponsor needs help interpreting regulations for pediatric clinical investigations?

FDA’s Office of Pediatric Therapeutics is available to help both groups! A sponsor can reach out to the product review division, which can consult with us if there is a question about a particular investigational medical product application. We are also available to answer general questions about study design or interpretation of the regulations. Email us at OPTPediatricEthics@fda.hhs.gov. We are happy to help.

Dr. Snyder, thank you for speaking with us today about the draft guidance on ethical considerations for pediatric clinical trials. We have learned so much from your informative discussion on the document. We would also like to thank the guidance working group for writing and publishing this draft guidance.

To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the guidance.


Speaker Biography

Donna L Snyder, MD, MBE

Donna L Snyder, MD, MBE, is team leader for the Ethics and International Team and Senior Pediatric Ethicist in the Office of Pediatric Therapeutics (OPT) in the Office of the Clinical Policy and Programs (OCPP) at the U.S. Food and Drug Administration (FDA). Dr. Snyder is a board-certified pediatrician with training in bioethics.  Prior to joining FDA in 2012, her wide-ranging experience included general pediatric practice, work in research ethics, for both an independent Institutional Review Board (IRB) and the NICHD IRB, clinical research, and consulting for the pharmaceutical industry.