การวิจัยในคน : ข้อกฎหมายและจริยธรรม นายแพทย์ เกรียง อัศวรุ่งนิรันดร์

1. การวิจัยในคน:ข้อกฎหมายและจริยธรรมการวิจัยในคน:ข้อกฎหมายและจริยธรรม นายแพทย์ เกรียง อัศวรุ่งนิรันดร์ อนุมัติบัตรประสาทวิทยา อนุมัติบัตรเวชศาสตร์ครอบครัว นิติศาสตร์บัณฑิต เนติบัณฑิตไทย ประกาศนียบัตรทนายความ

2. คดีจริยธรรมการวิจัยในคน

3. คดีจริยธรรมฯ คดีที่ 1 - Ellen Roche, a 24-year-old technician in the Johns Hopkins Asthma and Allergy Center, - was recruited as a normal volunteer in an NIH-funded study of asthma directed by Dr. AlkisTogias

4. The purpose of the study was to understand how 1. bronchodilationis maintained in normal people by deep inspirations in the face of a bronchoconstrictive stimulus, 2. bronchial wall nerves and nitric oxide release play important roles in this process.

5. - Ms. Roche consented to participate in the study on 4/16/01 and underwent a series of methacholine challenges over a period of 2 weeks, in accord with the IRB-approved protocol.

6. - 5/4/01 she received approximately 1 gm of hexamethonium by inhalation, given to produce ganglionic neural blockade. - 5/5/01 she developed a dry cough and dyspnea on exertion (reported 5/7/01).

7. - 5/7/01, she had flu-like symptoms and her FEV1 was reduced. - 5/9/01, she was febrile, a chest X-ray revealed streaky densities in the right perihilar region, and her arterial oxygen saturation fell to 84% after walking a short distance.

8. - She was admitted to The Johns Hopkins BayviewMedical Center (JHBMC) for observation, and developed progressive dyspnea - and was transferred to the ICU on 5/12/01.

9. - she developed pulmonary infiltrates and worsening hypoxia, was intubated and ventilated, - suffered bilateral pneumothorax, and presented a clinical picture of adult respiratory distress syndrome (ARDS).

10. - 6/2/01 She died with progressive hypotension and multiorganfailure.

11. - Of the 9 subjects who signed the consent form and began the study, - only 3 reached the point in the protocol calling for hexamethonium inhalation.

12. - The following outlines what transpired in each of these 3 subjects

13. SUBJECT #1 April 9,2001: Consent form signed April 9,2001:Methacholine-Bronchodilation

14. April 25,2001:Clinical Follow-up - Subject reported mild shortness of breath and a non-productive cough associated with deep inspiration. - No other symptoms such as sputum production, fever, or chest pain were reported, no abnormal physical findings

15. May 3,2001:Clinical Follow-up - The volunteer reported complete resolution of symptoms

16. SUBJECT#2 April 10,2001:Consent form signed April 10,2001:Methacholine-Bronchodilation

17. May 1,2001:Methacholine Hexamethanium- Bronchoprotection - the investigators reported that there was ptosis and that the patient appeared tired

18. SUBJECT#3 April 16,2001:Consent form signed April 16,2001:Methacholine-Bronchodilation

19. May 4,2001:Methacholine-Hexamethonium- Bronchodilation - Hexamethoniumwas administered through completion of the anticipated dose (1 gram). - 5/5/01 The subject experienced cough with inspiration.

20. - May 7, 2001 she reported rhinorrhea and feeling hot - May 8th she was not feeling well and was going to see her primary care provider (which she did and received a prescription for an anti-tussivemedication)

21. - May 9th, the symptoms had not resolved and the subject was asked by the investigator to return to the laboratory for further evaluation.

22. - A chest radiograph showed abnormalities consistent with pneumonitis, - her temperature was 101 F and her oxyhemoglobin saturation decreased from 92% to 84% after walking a short distance.

23. - She was admitted to the hospital on May 9th. - 5/12/2001, a chest CT scan demonstrated a ground glass appearance of the lungs, worse at the lung bases. - Participation in the research study and exposure to hexamethonium were known and considered as a cause of her illness. Steroid therapy was initiated.

24. - 5/14/2001, Ms. Roche was intubated and mechanically ventilated due to progressive respiratory failure. - A pneumothorax developed, was treated with a tube thoracostomy. - Her family elected to withdraw support and Ms. Roche died on 6/2/2001.

25. 1. Was the study designed to address an important scientific question? - The research study addressed an important scientific question about the role of bronchial nerves in human asthma. - The study had solid scientific rationale and was well designed to answer the questions posed.

26. - The study required human subjects and could not have been adequately done in experimental animals. - The research was of particular importance given the increasingly high prevalence of asthma

27. 2. Was the review of the study protocol by the JHBMC IRB appropriate? - The majority of the committee concluded that an adequate evidence base did not exist for the IRB to be confident that - inhaled hexamethonium was safe for use in research subjects.

28. - The four published papers provided to the IRB did not mention any pulmonary toxicity; but even in the absence of pulmonary adverse events in the 20 subjects, - there was uncertainty regarding the true risk of inhaled hexamethonium.

29. The pulmonary toxicity associated with oral, intramuscular, and/or subcutaneous hexamethonium administration for hypertension was first reported in 1953

30. . The National Academy of Sciences assisted the FDA in this review by setting up review panels. The panels believed hexamethonium was ineffective in the treatment of hypertension. FDA removed the product from the market on 8/5/72.

31. - The committee believes that the IRB should have required more safety evidence for a non-FDA approved drug no longer in clinical use, - and administered by a non-standard route.

32. - A way to obtain evidence of safety would have been to have - Dr. Togias submit an IND application to the FDA for review.

33. 3. Was the consent form appropriate? - it was inadequate in the description of the research risks, and should have indicated that (a) hexamethonium was not FDA approved and was no longer used clinically, (b) hexamethonium as an inhalant was used only experimentally, never clinically,

34. (c) the safety of inhaled hexamethonium was not known with certainty since it was based on published reports involving a total of only 20 people, and (d) there was a possibility of serious adverse event or death related to study participation.

35. 4. Was any coercion involved in the recruitment of the research subject? - The committee believes that Ms. Roche was not coerced to join Dr. Togias’ study. Although Ms. Roche worked in the Asthma and Allergy Center, - she did not work in the laboratory of the investigators who conducted this research.

36. 5. Was the study carried out appropriately? (a) Who performed the study? - The study was carried out by a postdoctoral Research Fellow, Dr. George Pyrgos, under Dr. Togias’ direct supervision.

37. (b) Was the experiment conducted in accordance with the approved protocol? - A description of the proposed preparation of the hexamethonium was approved by the IRB, - but the actual preparation used for Ms. Roche was modified without IRB approval.

38. - However, it is likely that the IRB would have approved the changes in protocol, - since the modifications were made to improve subject comfort and make the control solution more comparable to the hexamethonium solution in terms of osmolarity.

39. (c) What were the results in the three research subjects? - Dr. Togiasdid not inform the IRB that Subject #1 developed a cough and exertionaldyspnea lasting 1 week following exposure to hexamethonium

40. - until after Ms. Roche developed a significant adverse pulmonary complication and was admitted to the hospital.

41. - He explained that the adverse event in Subject #1 was not an "unexpected and serious adverse event," - because it was self-limited and required no treatment and therefore did not require immediate reporting to the IRB.

42. He further explained that - he thought the symptoms were related to a URI which was prevalent in the A&AC or - possibly to the low pH of the hexamethonium solution

43. Dr. Togias also said that - he did not seriously consider the possibility of hexamethoniumtoxicity. - Subject #2 was exposed to hexamethonium while Subject #1 still had pulmonary symptoms. - Subject #2 did not report any symptoms.

44. - Subject #3 (Ms. Roche) was exposed 1 day after the symptoms disappeared in Subject #1. - The committee believes that Dr. Togiasshould have considered the possibility of hexamethonium- induced pulmonary toxicity in Subject #1.

45. - Most members believe that he should have reported the event promptly to the IRB, - delayed the exposure of the next subject to hexamethoniumuntil the symptoms resolved in subject #1,

46. - and searched more comprehensively for previous reports of hexamethonium- induced pulmonary toxicity.

47. 6. Was medical care provided promptly and appropriately? - The committee believes that medical care was delivered promptly and appropriately at the JHBMC, independent of the research team.

48. 7. What was the cause of the serious adverse event? - The autopsy on Ms. Roche demonstrated diffuse alveolar damage but provided no specific etiologic diagnosis.

49. The committee also believes that - the death was most likely the result of participation in the hexamethonium phase of the experiment.

50. This belief is based on the following considerations: (a) the timing between hexamethonium inhalation and the development of pulmonary symptoms, (b) the lack of any identifiable cause, including negative cultures and serological tests for a wide variety of infectious agents,