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채아 영
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1 임상시험이란? 분과전문의로서의역할 Young Suk Park, M.D. Samsung Medical Center

2 임상시험에서고려할사항 Speed : 빠른심사, 계약, 피험자등록 Quality : 믿을수있는자료 With ICH-GCP guideline

3 Speed 행정 병원행정 part 의지원 IRB 의체계적인운영 병원집행부의의지 연구자 환자

4 Speed : 연구자 환자와상담할시간이없다. 상담과권유에익숙치않다. 새로운임상시험이면본인도잘모른다. 상담기술을배운다. 임상시험의이익에대해확인 / 확신한다. 도와줄인력을확보한다.

5 Speed : 환자 암환자가임상시험참여를결정하는요인 선호하는요인 점수 (%) 치료에대한기대 83 의료진의관심 80 의학발전에대한참여 75 병에대한많은정보 75 새로운치료를받음 72

6 Speed : 환자 암환자가임상시험참여를결정하는요인 거부하는요인점수 (%) 환자스스로치료를결정치못함 25 의료진이아닌시험자체에서치료의결정 24 시험적치료를받을가능성 15

7 Speed : Barriers PATIENT RELATED Doctor never discussed or offered Unaware of trials as option Concerns about insurance coverage Fear of receiving placebo PHYSICIAN RELATED Burdensome regulatory requirements - Institutional Review Board - Informed consent - Conflict of interest Lack of time Inadequate funding for personnel Inadequate reimbursement Resistance by third-party payers

8 Quality 임상시험은다음에따라실시, 기록되어야한다. 시험계획서 (Protocol) 표준작업지침서 (SOP) 임상시험관리기준 (GCP) 및관련규정 임상시험과관련된모든자료는정확, 완전, 검증가능해야한다. 그결과로자료는신뢰를받는다.

9 Major Deficiencies/Deviation A variance from protocol-specified procedures that makes the resulting data questionable Evidence of significant deviation from protocol treatment, data alteration, data falsification, or non-reporting of data that effects protocol eligibility, treatment or disease status

10 Major Deficiencies/Deviation Informed Consent Eligibility Treatment Disease Outcome/Response Toxicity General Data Quality

11 Major Deficiencies/Deviation Informed Consent Form missing not signed and dated by the patient signed after patient started on treatment does not contain all required signatures used was not current IRB-approved version at the time of patient registration not protocol specific does not include updates or information required by IRB.

12 Major Deficiencies/Deviation Eligibility Review of documentation available at the time of the audit confirms patient did not meet all eligibility criteria as specified by the protocol Documentation missing. Unable to confirm eligibility Enrollment of ineligible patients

13 Major Deficiencies/Deviation Treatment Incorrect agent/treatment used Additional agent/treatment used which is not permitted by protocol Dose deviations incorrect (error greater than +/- 10%) Dose modifications not per protocol Treatment doses incorrectly administered, calculated or documented Unjustified delays in treatment

14 Major Deficiencies/Deviation Disease Outcome/Response Failure to evaluate response according to the protocol, for example; Inaccurate documentation of initial sites of involvement Tumor measurements/evaluation of status or disease not performed according to protocol Protocol-directed response criteria not being followed

15 Major Deficiencies/Deviation Disease Outcome/Response Failure to evaluate response according to the protocol, for example; Claimed response (PR, CR, etc) cannot be verified Failure to detect cancer (as in a prevention study) or failure to identify cancer progression

16 Major Deficiencies/Deviation AE/SAE Failure to assess and report AE and SAE according to the protocol Grades, types, or dates/duration of SAE inaccurately recorded Follow-up studies necessary to assess AE/SAE not performed Failure to report a toxicity that would require filing an Adverse Event Report (AER) Recurrent under- or over-reporting of AE/SAE

17 Major Deficiencies/Deviation General Data Quality Recurrent missing documentation e.g., charts Protocol-specified laboratory tests not documented Protocol-specified diagnostic studies not documented Frequent data inaccuracies Errors in submitted data Delinquent data submission

18 Lesser Deficiency/Minor Deviation Deficiency that is judged to not have a significant impact on the outcome or interpretation of the study and is not described above as a major deficiency. Transcriptional errors An unacceptable frequency of lesser deficiencies(exceed 5%) should be treated as a major deficiency in determining the final assessment of a component.

19 For Speed & Quality Monitoring 인력 전임의 / 전공의? 일반간호사? 임상시험관련전문인력

20 Clinical Research Coordinator Clinical Research Nurse, CRN 의뢰자와시험자사이에서조정자 시험책임자의감독하에 임상시험관련규정의원칙에따라 전문적인지식과기술 환자의존엄성과피험자의권리를보호 신뢰성있는자료를수집, 기록, 보관 윤리적이고과학적인임상시험을추구 실질적인조정과수행에책임, 건강전문가

21 Clinical Research Coordinator 환자 CRC Sponsor PI

22 CRC 의자격요건 지식 의약학관련분야전공 임상약리학, 면역학, 생화학등의지식 임상시험수행훈련 임상시험관련각종규정, 지침서및임상시험계획서 기술 임상간호술및임상경험 의사소통및상담기술 기록, 컴퓨터및어학능력 태도 임상시험질향상에공헌하려는마음가짐과태도

23 임상시험에서 CRC 의위치 교육자 피험자의대변자 직접간호제공자 임상시험진행자 의견의충돌 의사결정, 책임한도의갈등 환자를위한윤리적, 도덕적문제 피험자보호

24 어떠한임상시험을할수있을까? Hypothesis Know what has been done before Systematic review or meta-analysis Trials & literatures search Safe dose, evidence of activity? Comparative trial, sufficiently strong?

25 어떠한임상시험을할수있을까? If the difference between treatments in a clinical trial is declared not statistically significant, this does not mean that there are no clinically important differences between the two treatments. Not enough evidence to draw any conclusions Might be due to too low power(too small sample size)

26 어떠한임상시험을할수있을까? Modified study and new evidence? Not truly randomized study Changed gold standard Statistically underpowered study Lacking important outcome measure Highly selected population New combination and/or new indication

27 Has a safe dose or schedule been established in clinical use? No Phase I study may be needed Yes Is there evidence of activity at this dose or schedule? No Not yet investigated Yes Abandon or review potential to enhance activity? Phase Ⅱ trial may be needed Has the treatment been used in a comparative trial? * No Is there sufficient evidence of potential improvement over standard to justify a randomized trial? Yes Has the trial(s) answered the questions of interest reliably? No Yes Randomized phase Ⅲ trial may be needed No Could a systematic review ± meta-analysis answer the question? Yes No Yes Trial may not be required

28 Types of Clinical Studies Efficacy Randomized Controlled Investigators Clinical Trial Trial subjects with eligibility Case Report Form Statistical power based on hypothesis Small N GCP required Mandatory Final Report Observational Study Effectiveness Observational Real World Investigators =Participating Physicians Subject = patient in practice Data Collection Form Hypothesis generating (flexible) Large N GCP limited but, directed Opportunistic Ongoing Communication

29 삶의질관련 임상시험

30 PubMed Search : QOL / Cancer Years

31 삶의질 : Quality of Life Assessment of QOL into every new trial Decision not to include QOL in a trial We don t care about patients QOL Results of many trials with QOL Largely irrelevant data Use of considerable resources Overburdening of patients

32 암치료와삶의질 Chance of cure toxicity & QOL : reasonable No chance of cure Giving treatment with longer survival but poorer QOL Reducing or stopping treatment with shorter survival but better QOL Treatment can be recommended in metastatic cancer even without an improvement of survival, if it improves quality of life ASCO guidelines 1995

33 QOL in Clinical Trials Determine your QOL objective Choose an instrument Select a design (time schedule) linked to your objective Develop an analysis plan To go or not to go?

34 삶의질임상시험에서고려할사항 Who should assess QOL? Response shift Timepoints Compliance questionnaire, item, patients, center How many patients are required? Choosing the questionnaire QOL coordinator Information sheets Quality and analysis of data

35 삶의질에대한평가자의차이 Life quality (patient) Number of patients Physical condition(patient) Overall condition(physician) 5 0 Improved Same Worse

36 삶의질관련설문지의번역

37 삶의질임상시험의결정 Is it a randomized trial? Yes No Is the trial aiming for cure? QOL may not be relevant as interpretation of results may be difficult. Non-randomized trials can be used as a question test-bed. No Yes Is the likely to be an important difference in QOL? QOL may not be relevant as patients may be willing to accept a lower QOL if there is a chance of cure. Yes No The small QOL differences detected may not affect the interpretation of the results. Include an assessment of QOL

38 임상시험에서 내가할수있는 일은?

39 Differences : Medicines, Medical devices, Surgery Characteristics Medicines Medical devices Surgical operations Patient protection Usually Sometimes Rarely Source of innovation & development Corporation Corporation Individual or group of professionals Cost of development Very high Moderate Low Double-blind methods Yes Seldom Almost never Placebo?

40 Trials with Surgical Procedures 1. Evaluation of medicines used during surgical procedures (e.g., neuromuscular blocking agents) 2. Evaluation of disease treated either by surgery or medicines(e.g., angina, peptic ulcers) 3. Evaluation of a disease(e.g., cancer) treated either by surgery or nonmedical modalities(e.g., radiation, hyperthermia) 4. Comparison of surgical procedures (e.g., new versus old method, modified versus original method)

41 Trials with Surgical Procedures 5. Evaluation of one surgical procedure (usually a novel technique) compared with historical controls 6. Comparison of a surgical procedure performed with and without medical adjunct therapy(neoadjuvant or adjuvant treatment) 7. Evaluation of equipment used in surgery(e.g., stereotaxic device, prosthetic heart valves), either used or implanted during surgical procedures 8. Evaluation of surgical materials (e.g., adhesives, suture materials, pins, staples) used during surgery

42 외과 / 타과와의임상시험 Comparison of procedures new method vs. old method modified method vs. original method Methods : Lumpectomy, TEM, laparoscopic surgery, VATS, EMR Modality : Neoadjuvant study, Adjuvant study

43 Considerations in Surgical Trials 1. Preoperative period Premedication : doses, time of administration Preparation : bowel prep, patient s diet, exercise 2. During surgery Anesthetic(s), neuromuscular blocking agent Specific instrumentation and equipment 3. Postoperative period Postoperative care and monitoring Outpatient or inpatient care

44 Considerations in Surgical Trials Training and technique of personnel Surgeons and the rest of the surgical team(e.g., fellows, residents, PA, anesthesiologists, pathologists, scrub team) Training of the techniques Single surgeon or a group of surgeons Single or group of anesthesiologists Replacing surgeon with another surgeon

45 Parameters with Surgery During Surgery Technical ease or difficulty of procedure Amount of practice to perfect technique Duration of surgery Rate and nature of severe complications Number and expertise of staff required

46 Parameters with Surgery After Surgery Morbidity and/or mortality rates Improvements of endpoints : Clinical e.g., recurrence, survival Cosmetic Performance Length of hospital stay Total Cost QOL Independent Review

47 임상시험에서내과와외과의차이 내과계 치료를위하여여러번치료 진단, 치료법은같다. 같은약을투여한다. 내과적인 care 에서의차이가있다 부작용에대한 supportive care 병발하는질환에대한지식과대처 계속치료할것이냐말것이냐의결정

48 임상시험에서내과와외과의차이 외과계 한번의수술로이루어지며비가역적이다. 새로운수술법을기존의 data 와비교한다 (historical control). Randomized study? Surgeon Thinks Shame vs. Fame

49 우리의전략 참여할기회가있으면참여한다. 본인이 idea 를제시한다. 다른과를참여시킨다. 다른과의임상시험을도와준다. CRC 를확보한다. IRB 에참여한다.

50 Thanks!

기관고유연구사업결과보고

기관고유연구사업결과보고 작성요령 2001 ~ 2004 2005 ~ 2007 2008 ~ 2010 2001 ~ 2004 2005 ~ 2007 2008 ~ 2010 1 2/3 2 1 0 2 3 52 0 31 83 12 6 3 21 593 404 304 1,301 4 3 1 8 159 191 116 466 6 11 (`1: (1: 16 33 44 106