Открытые вопросы клинических исследований с участием детей в качестве субъектов исследования: обзор литературы

В данной обзорной статье приведены сведения о дефиците клинически доказанных данных по применению препаратов в педиатрической практике. Проанализированы вопросы, почему дети широко получают терапию препаратами, которые предназначены для применения у взрослых пациентов, без предварительной качественной оценки их безопасности и эффективности в ходе соответствующих клинических исследований (КИ) с участием детей. Авторами рассмотрены вопросы проведения КИ с участием детей в качестве субъектов исследований — этические, регуляторные и психологические аспекты этой сложной задачи. По каждому из перечисленных пунктов приведены решения, которые, по мнению авторов проанализированных материалов и авторов данной статьи, могут помочь решить эти трудности и обойти неправильную оценку и интерпретацию исходных данных родителями детей и их усыновителями (законными представителями). Отдельно рассмотрены вопросы по настороженности со стороны врачей и приведены информация и выдержки из нормативно-правовых актов, а также сведения из публикаций для повышения осведомленности и в поддержку врачам-исследователям. Текущий литературный обзор проведен с целью решения проблемы недостатка информации по безопасности и эффективности препаратов, используемых в педиатрической практике. Раскрытие предмета обсуждения проведения КИ с участием детей в конечном счете поможет повысить качество оказываемой помощи детям в будущем и использовать у пациентов детского возраста возможности новейших технологий, применяемых в популяциях пациентов других возрастных групп.

1. Joseph PD, Craig JC, Caldwell PH. Clinical trials in children. Br J Clin Pharmacol. 2015;79(3):357–369. doi: https://doi.org/10.1111/bcp.12305

2. Pharmacokinetics and Pharmacodynamics in Children versus Adults. In: Rational Therapeutics for Infants and Children: Workshop Summary. Institute of Medicine (US) Roundtable on Research and Development of Drugs, Biologics, and Medical Devices; Yaffe S, ed. Washington (DC): National Academies Press (US); 2000. Available online: https://www.ncbi.nlm.nih.gov/books/NBK225507. Accessed on November 25, 2021.

3. van den Anker J, Reed MD, Allegaert K, Kearns GL. Developmental Changes in Pharmacokinetics and Pharmacodynamics. J Clin Pharmacol. 2018;58(Suppl 10):S10–S25. doi: https://doi.org/10.1002/jcph.1284

4. Germovsek E, Barker CIS, Sharland M, et al. Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance. Clin Pharmacokinet. 2019;58(1):39–52. doi: https://doi.org/10.1007/s40262-018-0659-0

5. Schrier L, Hadjipanayis A, Stiris T, et al. Off-label use of medicines in neonates, infants, children, and adolescents: a joint policy statement by the European Academy of Paediatrics and the European society for Developmental Perinatal and Pediatric Pharmacology. Eur J Pediatr. 2020;179(5):839–847. doi: https://doi.org/10.1007/s00431-019-03556-9

6. Nir-Neuman H, Abu-Kishk I, Toledano M, et al. Unlicensed and Off-Label Medication Use in Pediatric and Neonatal Intensive Care Units: No Change Over a Decade. Adv Ther. 2018;35(7):1122–1132. doi: https://doi.org/10.1007/s12325-018-0732-y

7. Ballentine C. Sulfanilamide Disaster. FDA Consumer magazine. June 1981. Available online: https://www.fda.gov/files/about%20fda/published/The-Sulfanilamide-Disaster.pdf. Accessed on November 25, 2021.

8. Curran WJ. The thalidomide tragedy in Germany: the end of a historic medicolegal trial. N Engl J Med. 1971;284(9):481–482. doi: https://doi.org/10.1056/NEJM197103042840906

9. Ackerman TF. The ethics of drug research in children. Paediatr Drugs. 2001;3(1):29–41. doi: https://doi.org/10.2165/00128072-200103010-00003

10. Institute of Medicines of the National Academies: Committee on Clinical Research Involving Children. The Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press; 2004.

11. Burns LE, Hodgman JE, Cass AB. Fatal Circulatory Collapse in Premature Infants Receiving Chloramphenicol. N Engl J Med. 1959;261:1318–1321. doi: https://doi.org/10.1056/NEJM195912242612604

12. Vanchieri C, Butler AS, Knutsen A. Addressing the Barriers to Pediatric Drug Development: Workshop Summary. Washington, DC: The National Academies Press; 2008.

13. Shirkey HC. Therapeutic orphans — everybody’s business. Ann Pharmacother. 2006;40(6):1174. doi: https://doi.org/10.1345/aph.140023

14. Shirkey HC. Therapeutic orphans 1970. J Infect Dis. 1970; 121(3):348–350. doi: https://doi.org/10.1093/infdis/121.3.348

15. Burckart GJ, Kim C. The Revolution in Pediatric Drug Development and Drug Use: Therapeutic Orphans No More. J Pediatr Pharmacol Ther. 2020;25(7):565–573. doi: https://doi.org/10.5863/1551-6776-25.7.565

16. Christensen ML, Helms RA, Chesney RW. Is pediatric labeling really necessary? Pediatrics. 1999;104(Suppl 3):593–597.

17. European Medicinec Agency. Human regulatory. Paediatric Regulation. Available online: https://www.ema.europa.eu/en/human-regulatory/overview/paediatric-medicines/paediatricregulation. Accessed on November 25, 2021.

18. Regulation (EC) No. 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No. 1768/92, Directive No. 2001/20/EC, Directive No. 2001/83/EC and Regulation (EC) No. 726/2004. Available online: https://wipolex.wipo.int/ru/legislation/details/5940. Accessed on November 25, 2021.

19. Bren L. The Road to the Biotech Revolution — Highlights of 100 Years of Biologics Regulation. FDA Consumer magazine. Centennial Edition (Jan.-Feb. 2006). Available online: https://www.fda.gov/files/about%20fda/published/The-Road-to-the-Biotech-Revolution-Highlights-of-100-Years-of-Biologics-Regulation.pdf. Accessed on December 12, 2021.

20. Завидова С.С., Намазова-Баранова Л.С., Тополянская С.В. Клинические исследования лекарственных препаратов в педиатрии: проблемы и достижения // Педиатрическая фармакология. — 2010. — Т. 7. — № 1. — С. 6–14.

21. Peltzman S. An Evaluation of Consumer Protection Legislation: The 1962 Drug Amendments. The Journal of Political Economy. 1973;81(5):1051. doi: https://doi.org/10.1086/260107

22. Code of Federal Regulation: A point in time eCFR system. Available online: https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-A/part-46?toc=1. Accessed on December 12, 2021.

23. Labson MS. Pediatric Priorities: Legislative and Regulatory Initiatives to Expand Research on the Use of Medicines in Pediatric Patients. J Health Care Law Policy. 2002;6(1):34–72.

24. Frakking NJ, van der Lee JH, Klassen TP, Offringa M. Survey of current guidance for child health clinical trials. The StaR Child Health Project: Standards for Research with Children. Available online: https://www.who.int/childmedicines/publications/GUIDANCECHILDHEALTH.pdf?ua=1. Accessed on December 12, 2021.

25. Food and Drug Regulations, CRC c 870, C.08.004.1(4).

26. Watts G. WHO launches campaign to make drugs safer for children. BMJ. 2007;335(7632):1227. doi: https://doi.org/10.1136/bmj.39423.581042.DB

27. Department of Health and Human Services Food and Drug Administration. Best Pharmaceuticals for Children Act and Pediatric Research Equity Act. July 2016 Status Report to Congress. Available online: https://www.fda.gov/media/99184/download. Assessed on December 20, 2021.

28. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. J Am Geriatr Soc. 2019;67(4):674–694. doi: https://doi.org/10.1111/jgs.15767

29. Meyers RS, Thackray J, Matson KL, et al. Key Potentially Inappropriate Drugs in Pediatrics: The KIDs List. J Pediatr Pharmacol Ther. 2020;25(3):175–191. doi: https://doi.org/10.5863/1551-6776-25.3.175

30. Butler E, Ludwig K, Pacenta HL, et al. Recent progress in the treatment of cancer in children. CA Cancer J Clin. 2021;71(4):315–332. doi: https://doi.org/10.3322/caac.21665

31. Ivanovska V, Rademaker CM, van Dijk L, et al. Pediatric drug formulations: a review of challenges and progress. Pediatrics. 2014; 134(2):361–372. doi: https://doi.org/10.1542/peds.2013-3225.

32. AMA. Pediatric Decision Making. Available online: https://www.ama-assn.org/delivering-care/ethics/pediatric-decision-making. Assessed on December 14, 2021.

33. Neyro V, Elie V, Thiele N, Jacqz-Aigrain E. Clinical trials in neonates: How to optimise informed consent and decision making? A European Delphi survey of parent representatives and clinicians. PLoS ONE. 2018;13(6):e0198097. doi: https://doi.org/10.1371/journal.pone.0198097

34. Pace RA, Ciruzzi S, Ferreres AR. The Pediatric Patient as a Self-Individual and Decision-Maker. In: Surgical Ethics. Ferreres A, ed. Cham: Springer; 2019. pp. 231–238. doi: https://doi.org/10.1007/978-3-030-05964-4_21

35. Ethical considerations for clinical trials on medicinal products conducted with minors Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use Revision 1 18 September 2017. Available online: https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-10/2017_09_18_ethical_consid_ct_with_minors.pdf. Accessed on December 13, 2021.

36. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Available online: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02014R0536-20140527&from=EN. Accessed on December 12, 2021.

37. Незнанов Н.Г., Никитин Е.Н., Мирошенков П.В. Биомедицинские исследования в педиатрии // Качественная клиническая практика. — 2002. —№ 2. — С. 40–48.

38. Семейный кодекс РФ (СК РФ) от 29 декабря 1995 г. № 223-ФЗ. [Family Code of the Russian Federation dated December 29, 1995 N 223-FZ. (In Russ).]

39. Тополянская С.В. Этические аспекты проведения клинических исследований у детей // Педиатрическая фармакология. — 2010. — № 3. — С. 6–11.

40. Gu S, Wang F, Patel Nitesh P, et al. A Model for Basic Emotions Using Observations of Behavior in Drosophila. Fron Psychol. 2019;10:781. doi: https://doi.org/10.3389/fpsyg.2019.00781

41. Izard CE. The Psychology of Emotions, Springer Science & Business Media. Springer US; 1991. 452 p.

42. Shilling V, Young B. How do parents experience being asked to enter a child in a randomised controlled trial? BMC Med Ethics. 2009;10:1. doi: https://doi.org/10.1186/1472-6939-10-1

43. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191–2194. doi: https://doi.org/10.1001/jama.2013.281053

44. ГОСТ Р 52379-2005 «Национальный стандарт Российской Федерации Надлежащая клиническая практика. Good Clinical Practice (GCP)». Дата введения 01.04.2006. Доступно по: https://docs.cntd.ru/document/1200041147. Ссылка активна на 25.11.2021.

45. Woolfall K, Shilling V, Hickey H, et al, Parents’ agendas in paediatric clinical trial recruitment are different from researchers’ and often remain unvoiced: a qualitative study. PLoS One. 2013;8(7):e67352. doi: https://doi.org/10.1371/journal.pone.0067352

46. European Union. Ethical considerations for clinical trials on medicinal products conducted with the pediatric population. Eur J Health Law. 2008l;15(2):223–250. doi: https://doi.org/10.1163/157180908x333228

47. de Wildt SN, Ito S, Koren G. Challenges for drug studies in children: CYP3A phenotyping as example. Drug Discov Today. 2009;14(1–2):6–15. doi: https://doi.org/10.1016/j.drudis.2008.07.007

48. Shakhnovich V, Hornik CP, Kearns GL, et al. How to Conduct Clinical Trials in Children: A Tutorial. Clin Transl Sci. 2019;12(3):218–230. doi: https://doi.org/10.1111/cts.12615

49. Turner MA. Clinical trials of medicines in neonates: the influence of ethical and practical issues on design and conduct. Br J Clin Pharmacol. 2015;79(3):370–378. doi: https://doi.org/10.1111/bcp.12467

50. General Clinical Pharmacology Considerations for Neonatal Studies 2 for Drugs and Biological Products Guidance for Industry, draft version. Available online: https://www.fda.gov/media/129532/download. Assessed on December 14, 2021.

51. Greenberg RG, Corneli A, Bradley J, et al. Perceived barriers to pediatrician and family practitioner participation in pediatric clinical trials: Findings from the Clinical Trials Transformation Initiative. Contemp Clin Trials Commun. 2017;9:7–12. doi: https://doi.org/10.1016/j.conctc.2017.11.006

52. PPA. The mission of the Pediatric Pharmacy Association. Available online: https://www.ppag.org/?pg=Mission. Accessed on November 25, 2021.

53. Stultz JS, Knoderer CA, Manasco KB, et al. Identification of Factors Associated With the Desire to Participate in a Pediatric Pharmacy Practice-Based Research Network. J Pediatr Pharmacol Ther. 2018;23(6):479–485. doi: https://doi.org/10.5863/1551-6776-23.6.479

54. Pica N, Bourgeois F. Discontinuation and nonpublication of randomized clinical trials conducted in children. Pediatrics. 2016;138(3):e20160223. doi: https://doi.org/10.1542/peds.2016-0223

55. Glasser SP, Howard G. Clinical trial design issues: at least 10 things you should look for in clinical trials. J Clin Pharmacol. 2006;46(10):1106– 1115. doi: https://doi.org/10.1177/0091270006290336