Enrichment Strategies in Pediatric Drug Development: An Analysis of Trials Submitted to the US Food and Drug Administration

Green, Dionna J.; Liu, Xiaomei I.; Hua, Tianyi; Burnham, Janelle M.; Schuck, Robert N.; Pacanowski, Michael; Yao, Lynne; McCune, Susan K.; Burckart, Gilbert J.; Zineh, Issam

doi:10.1002/cpt.971

Cited by 11 publications

(11 citation statements)

References 6 publications

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Section: Discussionmentioning

confidence: 99%

“…Patient selection criteria and enrichment of the pediatric study population are additional considerations for trial success, and a recent review of pediatric enrichment has been published. 26 Although our cohort contained more than 200 trials, this should be considered an exploratory analysis because of the relatively small numbers of trials in some therapeutic areas. It can also be difficult to determine any one isolated reason why a trial may have failed, and there are often multiple factors contributing to trial outcome.…”

Section: Discussionmentioning

confidence: 99%

“…This approach also helps to address the problem of having a small sample size in pediatric trials, which is a common problem. Patient selection criteria and enrichment of the pediatric study population are additional considerations for trial success, and a recent review of pediatric enrichment has been published …”

Section: Discussionmentioning

confidence: 99%

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Primary Endpoints in Pediatric Efficacy Trials Submitted to the US FDA

Green

Burnham

Schuette

et al. 2018

The Journal of Clinical Pharma

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The selection of appropriate endpoints in pediatric drug development trials is a critical aspect of trial design. Given the high pediatric trial failure rate, selecting optimal trial design elements, such as the primary efficacy endpoint, is essential to ensuring increased potential for trial success. The objectives of this study were to identify the primary efficacy endpoints measured in pediatric drug development trials submitted to the US Food and Drug Administration and to relate endpoint attributes to trial and label outcome. The analysis included pediatric pivotal efficacy studies submitted from September 2007 to July 2016 for which there was a corresponding adult trial for the same indication.Two hundred and thirty-four efficacy trials on 138 unique products studied in pediatric patients were assessed. The adult and pediatric endpoints were the same in 141 of the 234 trials (60.3%), and these trials succeeded in meeting their primary endpoint more often (122 of 141 [86.5%]) than when the adult and pediatric endpoints differed (57 of 93 [61.3%]; odds ratio, 4.03; 95%CI, 2.10–7.80). Trials that included both pediatric and adult patients succeeded more frequently than those trials that did not combine pediatric and adult patients (85 of 95 versus 94 of 139, respectively; odds ratio, 4.05; 95%CI, 1.94–9.31). No differences were observed in pediatric trial success between those using subjective and objective endpoints. Using the same endpoint in the pediatric trial as was measured in the corresponding adult trial and enrolling pediatric and adult patients in the same trial were attributes associated with trial success.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Primary Endpoints in Pediatric Efficacy Trials Submitted to the US FDA

Green

Burnham

Schuette

et al. 2018

The Journal of Clinical Pharma

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“…In the case of pediatric product development trials of triptans for treatment of migraines, a systematic review by Sun et al 1 suggested that utilizing enrichment strategies is a way to overcome the challenge of a true high placebo response rate in pediatric patients. 18 The report found that applying the nonrandomization of patients with an early placebo response have produced successful reductions in the high placebo response rate in the pediatric population and led to product (rizatriptan) approval by the FDA for a pediatric migraine indication. Other reasonable approaches are (1) combined trials 19 with a separate subgroup analysis and (2) a composite endpoint that includes both subjective and objective components.…”

Section: Discussionmentioning

confidence: 99%

Pediatric and Adult Placebo Response Rates in Placebo‐Controlled Clinical Trials Submitted to the US Food and Drug Administration 2012–2020

Park

Tran

Momper

et al. 2022

The Journal of Clinical Pharma

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The use of placebo concurrent control (placebo‐controlled) is the most rigorous method of evaluating the safety and efficacy of investigational treatments. However, the use of a placebo group in pediatric product development can be challenging due to ethical considerations and potential differences in placebo response rates between adults and children. This study reports the US Food and Drug Administration's experience with placebo response rates in the pediatric population. Products studied under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act between 2012 and 2020 were screened. Study characteristics including study type, primary efficacy endpoint(s), placebo response rates for the primary efficacy endpoint(s) and studied age range were collected. A total of 71 drug products used a placebo‐controlled trial. Of these, thirteen products had an identical study design and trial characteristics including the primary efficacy endpoints between pediatric and adult studies. Fifteen products were studied in trials with identical study design but only different primary efficacy endpoints in pediatric and adult populations. Ten products had combined adolescent and adult trials with separate pediatric trials in younger age groups. In each of these cases, the pediatric placebo response was greater, for some trials, and less, for other trials, than the adult placebo response. The pediatric placebo response can vary within an age group for a drug product. Future studies should examine the factors leading to a similarity or dissimilarity in placebo response between pediatric patients and adults.

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“…Including biomarkers in development plans has been associated with greater success rates across therapeutic areas [15, 21, 87]. The use of several types of biomarkers (predictive, prognostic) in development programs is associated with higher success rates in trials compared to trials with no or few biomarkers [88]. The “right” biomarker varies by the type of information needed to inform a development program and the specific phase of drug development.…”

Section: The Right Biomarkermentioning

confidence: 99%

The “rights” of precision drug development for Alzheimer’s disease

2019

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There is a high rate of failure in Alzheimer’s disease (AD) drug development with 99% of trials showing no drug-placebo difference. This low rate of success delays new treatments for patients and discourages investment in AD drug development. Studies across drug development programs in multiple disorders have identified important strategies for decreasing the risk and increasing the likelihood of success in drug development programs. These experiences provide guidance for the optimization of AD drug development. The “rights” of AD drug development include the right target, right drug, right biomarker, right participant, and right trial. The right target identifies the appropriate biologic process for an AD therapeutic intervention. The right drug must have well-understood pharmacokinetic and pharmacodynamic features, ability to penetrate the blood-brain barrier, efficacy demonstrated in animals, maximum tolerated dose established in phase I, and acceptable toxicity. The right biomarkers include participant selection biomarkers, target engagement biomarkers, biomarkers supportive of disease modification, and biomarkers for side effect monitoring. The right participant hinges on the identification of the phase of AD (preclinical, prodromal, dementia). Severity of disease and drug mechanism both have a role in defining the right participant. The right trial is a well-conducted trial with appropriate clinical and biomarker outcomes collected over an appropriate period of time, powered to detect a clinically meaningful drug-placebo difference, and anticipating variability introduced by globalization. We lack understanding of some critical aspects of disease biology and drug action that may affect the success of development programs even when the “rights” are adhered to. Attention to disciplined drug development will increase the likelihood of success, decrease the risks associated with AD drug development, enhance the ability to attract investment, and make it more likely that new therapies will become available to those with or vulnerable to the emergence of AD.

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Enrichment Strategies in Pediatric Drug Development: An Analysis of Trials Submitted to the US Food and Drug Administration

Cited by 11 publications

References 6 publications

Primary Endpoints in Pediatric Efficacy Trials Submitted to the US FDA

Primary Endpoints in Pediatric Efficacy Trials Submitted to the US FDA

Pediatric and Adult Placebo Response Rates in Placebo‐Controlled Clinical Trials Submitted to the US Food and Drug Administration 2012–2020

The “rights” of precision drug development for Alzheimer’s disease

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