임상시험이란? - kaim.or.kr

1 ? Young Suk Park, Medical Center Speed : , , Quality : With ICH-GCP guidelineSpeed part IRB Speed : .. / ..Speed : (%) 83 80 75 75 72 Speed : (%) 25 24 15 Speed : BarriersPATIENT RELATED Doctor never discussed or offered Unaware of trials as option Concerns about insurance coverage Fear of receiving placeboPHYSICIAN 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 , . (Protocol) (SOP) (GCP).

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

3 Unable to confirm eligibility Enrollment of ineligible patientsMajor 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 treatmentMajor 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 followedMajor 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 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)

4 Recurrent under- or over-reporting of AE/SAEM ajor Deficiencies/Deviation General Data Quality Recurrent missing documentation , charts Protocol-specified laboratory tests not documented Protocol-specified diagnostic studies not documented Frequent data inaccuracies Errors in submitted data Delinquent data submission 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 Speed & Quality Monitoring / ? ? Clinical Research Coordinator Clinical Research Nurse, CRN , , , Sponsor PICRCC linical Research CoordinatorCRC , , , , CRC , , ?

5 Hypothesis Know what has been done before Systematic review or meta-analysis Trials & literatures search Safe dose, evidence of activity ? Comparative trial, sufficiently strong ? ? 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) ? 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 indicationHas a safe dose or schedule been established in clinical use ?NoYesPhase I study may be neededIs there evidence of activity at this dose or schedule?NoNot yet investigatedYesAbandon or review potentialto enhance activity?

6 Phase II trial may be neededHas the treatment been used in a comparative trial? NoYesIs there sufficient evidence ofpotential improvement over standard tojustify a randomized trial? Has the trial(s) answered the questions of interest reliably?NoYesNoYesRandomized phase III trialmay be neededCould a systematic review meta-analysis answer the question?NoYesTrial may not be required Efficacy Randomized Controlled Investigators Trial subjects with eligibility Case Report Form Statistical power based on hypothesis Small N GCP required Mandatory Final Report Efficacy Randomized Controlled Investigators Trial subjects with eligibility Case Report Form Statistical power based on hypothesis Small N GCP required Mandatory Final Report 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 Effectiveness Observational Real World Investigators=Participating Physicians Subject = patient in practice Data Collection Form Hypothesis generating (flexible)

7 Large N GCP limited but, directed Opportunistic Ongoing CommunicationClinical TrialClinical TrialClinical TrialObservational StudyObservational StudyObservational StudyTypes of Clinical Studies PubMed Search : QOL / Cancer0500100015002000 Years1991-2004 : 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 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 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 ?

8 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 data0510152025 ImprovedSameWorseNumber of patientsLife quality(patient)Physicalcondition(patien t) Overallcondition(physician) Is it a randomized trial?YesQOL may not be relevant as interpretation of results may be difficult. Non-randomized trials can be used as aquestion the trial aiming for cure?Is the likely to be an importantdifference in QOL?Include an assessment of QOLQOL may not be relevant as patientsmay be willing to accept a lower QOLif there is a chance of small QOL differences detectedmay not affect the interpretationof the ? Differences : Medicines, Medical devices, Surgery CharacteristicsMedicinesMedicaldevicesSu rgicaloperationsPatientprotectionUsually SometimesRarelySource ofinnovation &developmentCorporationCorporationIndivi dual orgroup of professionalsCost ofdevelopmentVery highModerateLowDouble-blindmethodsYesSel domAlmost neverPlacebo ?

9 Trials with Surgical Procedures1. Evaluation of medicines used during surgical procedures ( , neuromuscular blocking agents)2. Evaluation of disease treated either by surgery or medicines( , angina, peptic ulcers)3. Evaluation of a disease( , cancer) treated either by surgery or nonmedical modalities( , radiation, hyperthermia)4. Comparison of surgical procedures ( , new versus old method, modified versus original method)Trials with Surgical Procedures5. 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( , stereotaxic device, prosthetic heart valves), either used or implanted during surgical procedures8. Evaluation of surgical materials ( , adhesives, suture materials, pins, staples) used during surgery / Comparison of procedures new method vs.

10 Old method modified method vs. original method Methods : Lumpectomy, TEM, laparoscopic surgery, VATS, EMR Modality : Neoadjuvant study, Adjuvant studyConsiderations in Surgical Trials1. Preoperative period Premedication : doses, time of administration Preparation : bowel prep, patient s diet, exercise2. During surgery Anesthetic(s), neuromuscular blocking agent Specific instrumentation and equipment3. Postoperative period Postoperative care and monitoring Outpatient or inpatient careConsiderations in Surgical Trials Training and technique of personnel Surgeons and the rest of the surgical team( , 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 surgeonParameters 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 Parameters with Surgery After Surgery Morbidity and/or mortality rates Improvements of endpoints : Clinical , recurrence, survival Cosmetic Performance Length of hospital stay Total Cost QOL Independent Review.