Skip to main content

Advertisement

SpringerLink
Log in

Sequential analysis in neonatal research—systematic review

  • Original Article
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

As more new drugs are discovered, traditional designs come at their limits. Ten years after the adoption of the European Paediatric Regulation, we performed a systematic review on the US National Library of Medicine and Excerpta Medica database of sequential trials involving newborns. Out of 326 identified scientific reports, 21 trials were included. They enrolled 2832 patients, of whom 2099 were analyzed: the median number of neonates included per trial was 48 (IQR 22–87), median gestational age was 28.7 (IQR 27.9–30.9) weeks. Eighteen trials used sequential techniques to determine sample size, while 3 used continual reassessment methods for dose-finding. In 16 studies reporting sufficient data, the sequential design allowed to non-significantly reduce the number of enrolled neonates by a median of 24 (31%) patients (IQR − 4.75 to 136.5, p = 0.0674) with respect to a traditional trial. When the number of neonates finally included in the analysis was considered, the difference became significant: 35 (57%) patients (IQR 10 to 136.5, p = 0.0033).

Conclusion: Sequential trial designs have not been frequently used in Neonatology. They might potentially be able to reduce the number of patients in drug trials, although this is not always the case.

What is known:

• In evaluating rare diseases in fragile populations, traditional designs come at their limits. About 20% of pediatric trials are discontinued, mainly because of recruitment problems.

What is new:

• Sequential trials involving newborns were infrequently used and only a few (n = 21) are available for analysis.

• The sequential design allowed to non-significantly reduce the number of enrolled neonates by a median of 24 (31%) patients (IQR − 4.75 to 136.5, p = 0.0674).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

CONSORT:

Consolidated Standards of Reporting Trials

IQR:

Interquartile range

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

SAGL:

Sebastiano A.G. Lava

VE:

Valéry Elie

References

  1. Algra SO, Jansen NJG, van der Tweel I, Schouten AN, Groenendaal F, Toet M, van Oeveren W, van Haastert IC, Schoof PH, de Vries LS, Haas F (2014) Neurological injury after neonatal cardiac surgery: a randomized, controlled trial of 2 perfusion techniques. Circulation 129:224–233

    Article  PubMed  Google Scholar 

  2. Allegaert K, Sherwin C (2016) Neonates and medicines: a roadmap to further improve neonatal pharmaceutical care. Eur J Pediatr 175(6):743–746

    Article  PubMed  Google Scholar 

  3. Avery GB, Fletcher AB, Kaplan M, Brudno DS (1985) Controlled trial of dexamethasone in respirator-dependent infants with bronchopulmonary dysplasia. Pediatrics 75:106–111

    CAS  PubMed  Google Scholar 

  4. Baiardi P, Giaquinto C, Girotto S, Manfredi C, Ceci A, TEDDY Network of Excellence (2011) Innovative study design for paediatric clinical trials. Eur J Clin Pharmacol 67:109–115

    Article  PubMed  Google Scholar 

  5. Barrington KJ, Denson-Lino J, Bloch R, Finer NN (2001) Sequential analysis for quality control in the neonatal intensive care unit. J Pediatr 139:778–784

    Article  CAS  PubMed  Google Scholar 

  6. Bell EF, Warburton D, Stonestreet BS, Oh W (1980) Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. N Engl J Med 302:598–604

    Article  CAS  PubMed  Google Scholar 

  7. Bhatt DL, Mehta C (2016) Adaptive designs for clinical trials. N Engl J Med 375:65–74

    Article  PubMed  Google Scholar 

  8. Brok J, Thorlund K, Gluud C, Wetterslev J (2008) Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol 61:763–769

    Article  PubMed  Google Scholar 

  9. Carlo WA, Siner B, Chatburn RL, Robertson S, Martin RJ (1990) Early randomized intervention with high-frequency jet ventilation in respiratory distress syndrome. J Pediatr 117:765–770

    Article  CAS  PubMed  Google Scholar 

  10. Carswell F, Kerr MM, Dunsmore IR (1972) Sequential trial of effect of phenobarbitone on serum bilirubin of preterm infants. Arch Dis Child 47:621–625

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Cebulla M, Stürzebecher E (2015) Automated auditory response detection: further improvement of the statistical test strategy by using progressive test steps of iteration. Int J Audiol 54:568–572

    Article  PubMed  Google Scholar 

  12. Chin WW, Joos A (2016) Moving toward a paradigm shift in the regulatory requirements for pediatric medicines. Eur J Pediatr 175:1881–1891

    Article  PubMed  Google Scholar 

  13. de Leval MR, François K, Bull C, Brawn W, Spiegelhalter D (1994) Analysis of a cluster of surgical failures. Application to a series of neonatal arterial switch operations. J Thorac Cardiovasc Surg 107:914–923 discussion 923-4

    PubMed  Google Scholar 

  14. Desfrere L, Zohar S, Morville P, Brunhes A, Chevret S, Pons G, Moriette G, Rey E, Treluyer JM (2005) Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. J Clin Pharm Ther 30:121–132

    Article  CAS  PubMed  Google Scholar 

  15. Gortner L, Bartmann P, Pohlandt F, Bernsau U, Porz F, Hellwege HH, Seitz RC, Hieronimi G, Bremer C, Jorch G, Hentschel R, Reiter HL, Wolf H, Ball F (1992) Early treatment of respiratory distress syndrome with bovine surfactant in very preterm infants: a multicenter controlled clinical trial. Pediatr Pulmonol 14:4–9

    Article  CAS  PubMed  Google Scholar 

  16. Gortner L, Pohlandt F, Bartmann P, Bernsau U, Porz F, Hellwege HH, Seitz RC, Hieronimi G, Kuhls E, Jorch G, Hentschel R, Reiter HL, Bauer J, Versmold H, Meiler B (1994) High-dose versus low-dose bovine surfactant treatment in very premature infants. Acta Paediatr 83:135–141

    Article  CAS  PubMed  Google Scholar 

  17. Harrington D, Parmigiani G (2016) I-SPY 2- a glimpse of the future of phase 2 drug development? N Engl J Med 375:7–9

    Article  PubMed  Google Scholar 

  18. Huusom LD, Secher NJ, Pryds O, Whitfield K, Gluud C, Brok J (2011) Antenatal magnesium sulphate may prevent cerebral palsy in preterm infants—but are we convinced? Evaluation of an apparently conclusive meta-analysis with trial sequential analysis. BJOG 118:1–5

    Article  CAS  PubMed  Google Scholar 

  19. Kaguelidou F, Alberti C, Biran V, Bourdon O, Farnoux C, Zohar S, Jacqz-Aigrain E (2016) Dose-finding study of omeprazole on gastric pH in neonates with gastro-esophageal acid reflux using a Bayesian sequential approach. PLoS One 11:e0166207

    Article  PubMed Central  PubMed  Google Scholar 

  20. Kao LC, Warburton D, Cheng MH, Cedeño C, Platzker AC, Keens TG (1984) Effect of oral diuretics on pulmonary mechanics in infants with chronic bronchopulmonary dysplasia: results of a double-blind crossover sequential trial. Pediatrics 74:37–44

    CAS  PubMed  Google Scholar 

  21. Lin YJ, Yeh TF, Hsieh WS, Chi YC, Lin HC, Lin CH (1999) Prevention of chronic lung disease in preterm infants by early postnatal dexamethasone therapy. Pediatr Pulmonol 27:21–26

    Article  CAS  PubMed  Google Scholar 

  22. Mammel MC, Green TP, Johnson DE, Thompson TR (1983) Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia. Lancet 1:1356–1358

    Article  CAS  PubMed  Google Scholar 

  23. Mencher GT, McCulloch B, Derbyshire AJ, Dethlefs R (1977) Observer bias as a factor in neonatal hearing screening. J Speech Hear Res 20:27–34

    Article  CAS  PubMed  Google Scholar 

  24. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(264–9):W64

    Google Scholar 

  25. No authors listed (1992) Early or selective surfactant (colfosceril palmitate, Exosurf) for intubated babies at 26 to 29 weeks gestation. A European double-blind trial with sequential analysis. European Exosurf Study Group. Online J Curr Clin Trials Doc No 28: [3886 words; 47 paragraphs]

  26. No authors listed (2000) Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics 105:295–310

  27. Pica N, Bourgeois F (2016) Discontinuation and nonpublication of randomized clinical trials conducted in children. Pediatrics 138(3)

    Article  PubMed Central  PubMed  Google Scholar 

  28. Pohlandt F, Saule H, Schröder H, Leonhardt A, Hörnchen H, Wolff C, Bernsau U, Oppermann HC, Obladen M, Feilen KD (1992) Decreased incidence of extra-alveolar air leakage or death prior to air leakage in high versus low rate positive pressure ventilation: results of a randomised seven-centre trial in preterm infants. Eur J Pediatr 151:904–909

    Article  CAS  PubMed  Google Scholar 

  29. Rougé C, Piloquet H, Butel M-J, Berger B, Rochat F, Ferraris L, Des Robert C, Legrand A, de la Cochetière MF, N'Guyen JM, Vodovar M, Voyer M, Darmaun D, Rozé JC (2009) Oral supplementation with probiotics in very-low-birth-weight preterm infants: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 89:1828–1835

    Article  PubMed  Google Scholar 

  30. Samuels MP, Raine J, Wright T, Alexander JA, Lockyer K, Spencer SA, Brookfield DS, Modi N, Harvey D, Bose C, Southall DP (1996) Continuous negative extrathoracic pressure in neonatal respiratory failure. Pediatrics 98:1154–1160

    CAS  PubMed  Google Scholar 

  31. Sibanda N, Lewsey JD, van der Meulen JH, Stringer MD (2007) Continuous monitoring tools for pediatric surgical outcomes: an example using biliary atresia. J Pediatr Surg 42:1919–1925

    Article  PubMed  Google Scholar 

  32. Silverman WA, Agate FJ, Fertig JW (1963) A sequential trial of the nonthermal effect of atmospheric humidity on survival of newborn infants of low birth weight. Pediatrics 31:719–724

    CAS  PubMed  Google Scholar 

  33. Stürzebecher E, Cebulla M (2013) Automated auditory response detection: improvement of the statistical test strategy. Int J Audiol 52:861–864

    Article  PubMed  Google Scholar 

  34. Treluyer J-M, Zohar S, Rey E, Hubert P, Iserin F, Jugie M, Lenclen R, Chevret S, Pons G (2005) Minimum effective dose of midazolam for sedation of mechanically ventilated neonates. J Clin Pharm Ther 30:479–485

    Article  CAS  PubMed  Google Scholar 

  35. Valaes T, Drummond GS, Kappas A (1998) Control of hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient newborns using an inhibitor of bilirubin production, Sn-mesoporphyrin. Pediatrics 101:E1

    Article  CAS  PubMed  Google Scholar 

  36. van der Lee JH, Wesseling J, Tanck MW, Offringa M (2010) Sequential design with boundaries approach in pediatric intervention research reduces sample size. J Clin Epidemiol 63:19–27

    Article  PubMed  Google Scholar 

  37. Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14:135

    Article  PubMed Central  PubMed  Google Scholar 

  38. Wetterslev J, Thorlund K, Brok J, Gluud C (2008) Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol 61:64–75

    Article  PubMed  Google Scholar 

  39. Yasuda N (1984) A surveillance system for metabolic disorders in Japan. Hum Hered 34:321–327

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Authors would like to thank Dr. Alec Villa for his assistance in linguistic revision.

Funding

Dr. Lava is the current recipient of research grants from the Fondazione Ettore e Valeria Rossi, the Batzebär foundation and the Swiss National Science Foundation.

Author information

Authors and Affiliations

  1. Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France

    Sebastiano A. G. Lava, Valéry Elie, Phuong Thi Viet Ha & Evelyne Jacqz-Aigrain

  2. University Children’s Hospital, Inselspital, University of Bern, Bern, Switzerland

    Sebastiano A. G. Lava

  3. Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland

    Sebastiano A. G. Lava

  4. University Paris Diderot, Sorbonne Paris-Cité, Paris, France

    Evelyne Jacqz-Aigrain

Authors
  1. Sebastiano A. G. Lava
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valéry Elie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Phuong Thi Viet Ha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Evelyne Jacqz-Aigrain
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study idea, study design: Dr. Lava, Prof. Jacqz-Aigrain

Article screening, article selection, data extraction: Dr. Lava, Dr. Elie

Statistical analysis: Dr. Lava, Ms. Ha

First draft of the manuscript: Dr. Lava

Figures: Dr. Lava

Critical revision of the manuscript: Prof. Jacqz-Aigrain, Dr. Lava

Approval of the final manuscript: Dr. Lava, Dr. Elie, Dr. Ha, Prof. Jacqz-Aigrain

Corresponding author

Correspondence to Sebastiano A. G. Lava.

Ethics declarations

Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical approval

This study is a systematic review of the literature. Therefore, it involves neither direct patient contact nor animal exposure. This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Communicated by Mario Bianchetti

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lava, S.A.G., Elie, V., Ha, P.T.V. et al. Sequential analysis in neonatal research—systematic review. Eur J Pediatr 177, 733–740 (2018). https://doi.org/10.1007/s00431-018-3110-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-018-3110-5

Keywords

Search

Navigation