Properly-designed and conducted open label extension studies can provide rigorous information on the long-term safety and tolerability of a new unapproved drug or off-label indication of an approved drug. This information can strengthen the licensing application for a given drug by providing longer-term data that would not otherwise be available prior to its approval. Furthermore, open label extension studies provide an opportunity for subjects who participate in a prior double-blind placebo trial, to appreciate the potential benefit of the drug, as some may have received placebo only.
However, open label extension studies among children with behavioral disorders seem especially prone to a number of ethical and scientific concerns that every IRB would need to consider. We revisit some of these issues and suggest a path forward in the review of such studies.
Open Label Extension Studies in Pediatric Populations with Behavioral Conditions
Use of open label studies after Phase II and Phase III trials is relatively common. They typically follow a double-blind randomized placebo-controlled trial of a new drug, a new indication for an existing drug, or in the case of children with behavioral disorders, a drug approved for adults and currently used off-label for children. At the end of the double-blind phase, participants and their guardians are invited to enroll in an extension study. The study is typically longer than the randomized trial and may continue until the drug is approved for use in the pediatric population or until such time as the manufacturer has enough data to submit for regulatory evaluation. All participants in the extension study are given the study drug, irrespective of whether or not they were included in the active arm or the placebo arm of the prior study. These studies in children with behavioral conditions highlight a number of issues related to informed consent, selection bias, and placebo effect.
In randomized, placebo-controlled trials that included children, response rates in the placebo arm were reported to be higher in children when compared with adolescents and adults (for example, for attention deficit hyperactivity disorder and for depression). It is widely accepted that expectations and experiences of others (parents, siblings, relatives, and friends) rather than one’s own expectations generate the placebo response (placebo by proxy).
In 2009, Bridge et al. reported on a meta-analysis of 12 trials using second generation anti-depressant drugs, involving a total of 2,862 children and adolescents with major depression. They concluded that lower baseline illness severity and younger age were associated with higher placebo response. The strongest predictor of the placebo response (but not the response to active medication) was the number of study sites.
Minor participants, their guardians and the study team are not privy to the child’s allocation in the randomized controlled Phase III study, even after it is complete, as the Sponsor will keep the blind and perform an unbiased analysis of the data. This despite the fact that placebo effect may have taken place, and the child’s condition improved after having been in the placebo arm of the study.
Minors and their guardians will base their decision to enroll in the open label extension without the evidence that the study drug is any better than the standard treatment (which may include pharmacological and or non-pharmaceutical modalities) or that it may potentially be worse. In the absence of a clear child best interests review by the study investigator, the decision to enroll could result in participants taking a drug that was not clinically justified (perhaps for a long time).
Prior to enrollment in open label extension studies, a proportion of the participants in the study, will have already taken the study drug. Two groups may be excluded from the extension study—those unable to tolerate the drug in the double blind study and those whose response did not meet the expectations of their parents, and show further symptomatology. The absence of these groups in the open label extension period will introduce bias and increase the apparent tolerability of the new drug.
Implications for Ethics Review of Open Label Extension Studies in Pediatric Populations
Often little justification can be found to treat children in an open label study given that some respond to the placebo effect in the double-blind study. The extent and duration of the placebo effect is frequently unknown. A delay of the extension or opening of the blind by the sponsor (not to participants and investigator, nor to those that assess the effectiveness of the drug) would prevent enrollment of responders to placebo.
All too frequently, consent forms contain information on a study’s design but not on the placebo. Parents often have difficulty in understanding the research protocol or underestimate the possible risks, and can be influenced by researcher requests. Open label extension studies involving children with behavioral conditions that have consent forms containing accessible language which explains “placebo,” “placebo effect,” and “placebo risk” would serve to mitigate any therapeutic misconception among parents.
In the view of the authors there are a number of factors for the IRB to consider in the review of pediatric behavioral open label extension studies. Studies such as these may be ethically acceptable when:
- The informed consent process makes clear there that because neither the sponsor nor the study doctor knows which children received the study drug, evidence is not available to suggest that continuation in the study is any better than standard treatment or no treatment at all.
- The informed consent process specifies that continuation in the extension may increase risk by continued exposure to the study drug for which there is no there is no clinical justification.
- The risk posed by participation in the open label extension remains proportionate to any benefit, direct or indirect.
- The data strategy will provide unbiased estimates of safety and tolerability.
- No other feasible trial design exists.
The key ethical dilemma in open label extension studies lies in avoiding exposing children to unnecessary risk versus meeting the need for adequate information to guide clinical care. The IRB faces a manifestation of this same dilemma in each review that it undertakes. As such the IRB is to be guided by the regulations to ensure the proposed activity is primarily research. If so, the federal regulations for the protection of human subjects require that risks be balanced by benefits (45 CFR part 46). Indeed, in research involving children the IRB is to be guided by the specific understanding of “risk” as defined in the Sub part D determination.
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Taylor, G.J Wainright P. p.573
Taylor, G.J Wainright P. p. 572.
Ibid. p. 573.
Crites, J.S. When Should Open Label Extension Studies Be Stopped? The American Journal of Bioethics. 2014. 14(4): p.60.
Di Pietro, M. Cutrera, R. Teleman, A.A. Barbaccia Placebo Controlled trials in pediatrics and the child’s best interest Italian Journal of Pediatrics, 2015 41:11 p.5.
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