Journal of Genetic Medicine

Korean Society of Medical Genetics and Genomics (대한의학유전학회)
권호 표지
DOI QR코드

DOI QR Code

Clinical Trials and Accuracy of Diagnostic Tests

진단법의 임상시험연구와 진단정확도

  • Lee, You-Kyoung (Department of Laboratory Medicine and Genetics, Soonchunhyang University College of Medicine) ;
  • Lee, Sang-Moo (National Evidence-based Healthcare Collaborating Agency)
  • 이유경 (순천향대학교 의과대학 진단검사의학교실) ;
  • 이상무 (한국보건의료연구원)
  • Received : 2011.06.03
  • Accepted : 2011.06.17
  • Published : 2011.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Most clinicians understand clinical trials as the evaluation process for new medicine before their use. However, clinical trials can also be applied to laboratory diagnostic tests (LDTs) to verify diagnostic accuracy and efficacy before their clinical laboratory implementation for patients. The clinical trial of LDT has two distinctive characteristics that are different from the case of pharmaceuticals and thus worth special consideration. One of them is the level of evidence. The well-designed randomized controlled trials (RCTs) are known to provide the best evidence to prove the clinical efficacy of any pharmaceutical products. However, RCTs lose practicality when applied to LDTs due to various issues including ethical complications. For this reason, comparative study format is considered more feasible approach for LDTs. In addition pharmaceuticals and LDTs are different in that the user's intervention is not required for the former but critical to the latter. Moreover, in the case of pharmaceuticals, end-products are produced by manufacturers before being used by clinicians. However, in LDTs, once reagents and instruments are provided by manufacturers, they are first utilized by clinical laboratories to produce test results in order for clinicians to use them later. In other words, when it comes to LDTs, clinical laboratories play the role of manufacturers, providing reliable test results with improved quality assurance. Considering the distinctive characteristics of LDTs, we would like to offer detailed suggestions to successfully perform clinical trials in LDTs, which include analytical performance measures, clinical test performance measures, diagnostic test accuracy measures, clinical effectiveness measures, and post-implementation surveillance.

대부분의 의사들은 임상시험을 치료약제개발 후 의료현장에서 사용하기 위해 진행되는 과정으로 생각할 것이다. 실험실에서 개발된 기술이 진단검사로써 도입되기 위해서는 치료약제의 경우와 유사한 임상시험 과정을 거쳐 그 안정성과 유효성에 대한 검증을 필요로 한다. 치료약제의 효과검증에서 가장 우수한 근거를 얻을 수 있는 연구방법은 무작위대조연구 방법이지만, 이를 검체진단검사에 그대로 적용하기는 어렵다. 검체진단검사의 경우 비교연구가 진단정확도의 검증을 위해 현실적으로 사용할 수 있는 연구방법이지만 대상군의 모집 방법과 구분 방법, 질환대상자의 질환 심각도, 참고표준의 선택과 적용, 눈가림 여부 등 여러 요인들이 진단정확도 지표에 직접적인 영향을 주기 때문에, 좋은 근거수준의 연구결과를 얻기 위해서는 이러한 요소들을 고려한 잘 고안된 연구디자인이 중요하다. 또한 검체진단검사는 치료약제의 경우와 달리 결과를 얻기 위한 검사과정이 사용자인 일선 검사실에 의해 계속 생산되어야 하고, 검사의 개발과 발전의 속도가 빠르며, 일선검사실이 최종사용자이자 개발자인 경우가 흔하다는 특성이 있다. 저자들은 이러한 검사의 특성을 고려하여 검사법 자체의 수행능력에 대한 검증으로부터 검사법 성능평가를 위한 질환확진군과 정상군에 대한 비교연구, 일련의 질환의심자 대상의 진단정확도 평가와 임상 효과성 평가, 도입 후 일상감시로 이어지는 임상시험의 진행단계를 제안하고자 한다.

Keywords

References

  1. Deeks J. Assessing outcomes following tests. In evidence based laboratory medicine. In Price CP, Christenson RH, eds., Washington DC, AACC Press, 2007.
  2. FDA. Guidance for Industry and FDA Staff: In Vitro Diagnostic 2009 H1N1 Tests for Use in the 2009 H1N1 Emergency. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM188679.pdf. Accessed Jun 3, 2011
  3. Lijmer JG, Mol BW, Heisterkamp S, Bonsel GJ, Prins MH, van der Meulen JH, et al. Empirical evidence of design-related bias in studies of diagnostic tests. JAMA 1999;282:1061-6. https://doi.org/10.1001/jama.282.11.1061
  4. Philbrick JT, Horwitz RI, Feinstein AR, Langou RA, Chandler JP. The limited spectrum of patients studied in exercise test research. Analyzing the tip of the iceberg. JAMA 1982;248:2467-70. https://doi.org/10.1001/jama.1982.03330190031026
  5. Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med 1978;299:926-30. https://doi.org/10.1056/NEJM197810262991705
  6. Whiting P, Rutjes AW, Reitsma JB, Glas AS, Bossuyt PM, Kleijnen J. Sources of variation and bias in studies of diagnostic accuracy: a systematic review. Ann Intern Med 2004;140:189-202. https://doi.org/10.7326/0003-4819-140-3-200402030-00010
  7. Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ 2001;323:334-6.
  8. Meads CA, Davenport CF. Quality assessment of diagnostic before-after studies: development of methodology in the context of a systematic review. BMC Med Res Methodol 2009;9:3. https://doi.org/10.1186/1471-2288-9-3
  9. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Standards for Reporting of Diagnostic Accuracy. Clin Chem 2003;49:1-6. https://doi.org/10.1373/49.1.1
  10. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Ann Intern Med 2003;138:W1-12. https://doi.org/10.7326/0003-4819-138-1-200301070-00012-w1
  11. McQueen M. Evidence-based laboratory medicine: addressing bias, generalisability and applicability in studies on diagnostic accuracy: the STARD initiative. Clin Biochem 2003;36:1-2. https://doi.org/10.1016/S0009-9120(02)00443-5
  12. Bossuyt PM. The quality of reporting in diagnostic test research: getting better, still not optimal. Clin Chem 2004;50:465-6. https://doi.org/10.1373/clinchem.2003.029736
  13. Fischer JE, Bachmann LM, Jaeschke R. A readers' guide to the interpretation of diagnostic test properties: clinical example of sepsis. Intensive Care Med 2003;29:1043-51. https://doi.org/10.1007/s00134-003-1761-8
  14. Leeflang MM, Bossuyt PM, Irwig L. Diagnostic test accuracy may vary with prevalence: implications for evidence-based diagnosis. J Clin Epidemiol 2009;62:5-12. https://doi.org/10.1016/j.jclinepi.2008.04.007
  15. Rutjes AW, Reitsma JB, Vandenbroucke JP, Glas AS, Bossuyt PM. Case-control and two-gate designs in diagnostic accuracy studies. Clin Chem 2005;51:1335-41. https://doi.org/10.1373/clinchem.2005.048595
  16. Pai M, Flores LL, Pai N, Hubbard A, Riley LW, Colford JM, Jr. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2003;3:633-43. https://doi.org/10.1016/S1473-3099(03)00772-2
  17. Reitsma JB, Rutjes AW, Khan KS, Coomarasamy A, Bossuyt PM. A review of solutions for diagnostic accuracy studies with an imperfect or missing reference standard. J Clin Epidemiol 2009;62:797-806. https://doi.org/10.1016/j.jclinepi.2009.02.005
  18. Bandolier Extra. Evidence and Diagnostics. http://www.medicine.ox.ac.uk/bandolier/booth/diagnos/Diagessy.html. Accessed Jun 3, 2011.
  19. Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653. Accessed Jun 3, 2011.
  20. Lee YK. Consideration of ELSI for Genetic Testing. Kor J Int Med 2010;79:S106-8.
  21. Sackett D, Haynes R. The architecture of diagnostic research. In: Knottnerus J, ed. The evidence base of clinical diagnosis, London, BMJ, 2002
  22. Gluud C, Gluud LL. Evidence based diagnostics. BMJ 2005;330:724-6. https://doi.org/10.1136/bmj.330.7493.724
  23. Guyatt G, Rennie D. Users' guide to the medical literature: a manual for evidence-based clinical practice. Chicago: AMA Press, 2002.