Microsoft PowerPoint - Early Phase Clinical Trial.pptx

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1 Early Phase Clinical Trial : Phase I and II 김정렬삼성서울병원임상약리학과

2 Contents Introduction First-in-Human Study (Phase Ia) Other Phase I Studies (Phase Ic) Phase II Study Proof-of-Concept (PoC) Study Adaptive Design Summary

3 용어정의 임상시험 (clinical study) 임상시험용의약품의안전성과유효성을증명할목적으로사람을대상으로실시하는시험또는연구 비임상시험 (nonclinical study) 사람을대상으로하지않는생의학적연구 전임상시험 (preclinical study): 과거용어 총리령. 의약품등의안전에관한규칙 ( 별표 4)

4 용어정의 시험자 (investigator) 시험책임자, 시험담당자, 임상시험조정자 시험담당자 : 시험책임자의위임및감독하에임상시험과관련된업무를담당하거나필요한사항을결정하는사람 의뢰자 (sponsor) 임상시험의계획 관리 재정등에관련된책임을갖고있는개인, 회사, 실시기관, 단체등 식약처고시. 의약품임상시험기본문서관리에관한규정

5 용어정의 의뢰자임상시험 Sponsor-initiated trial, SIT 연구자임상시험 Sponsor-investigator trial (ICH-GCP) Investigator-initiated trial, IIT 시험자가외부의의뢰없이안전성 유효성이검증되지않은의약품또는허가 ( 신고 ) 되지아니한새로운효능 효과, 새로운용법 용량에대해독자적으로수행하는임상시험 식약처고시. 의약품임상시험계획승인에관한규정

6 용어정의 MTD (maximum tolerated dose) The highest dose of a drug or treatment that does not cause unacceptable side effects (ex. DLT < 33% or 25%) DLT (dose-limiting toxicity) Side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment US National Cancer Institute

7 Clinical Trial A prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about interventions (drugs, treatments, devices, or new way of using known drugs, Tx, or devices) cf. case-control study cf. animal / in-vitro study cf. prospective cohort study US National Institutes of Health

8 Safety vs. Efficacy Safety Efficacy

9 Safety? Efficacy? Early phase clinical trial Safety >> Efficacy Late phase clinical trial Safety << Efficacy Long-term safety evaluation (PMS) Rofecoxib (Vioxx ), tegaserod (Zelnorm ), sibutramine (Reductil )

10 Safety? Efficacy? TGN1412 tragedy, 2006 First-in-human trial of immunomodulatory drug Cytokine release syndrome All six healthy volunteers transferred to the ICU within 16 hours and suffered from multiple organ dysfunction

11 Type of Study By stage Phase I ~ IV Traditional classification By objective Human pharmacology Therapeutic exploratory Therapeutic confirmatory Therapeutic use

12 Type of Study ICH Harmonised Tripartite Guideline E

13 임상시험목적에따른분류 식약처. 임상시험정보

14 We Want to Know in Early Stage Is the drug safe in human? What is the maximum tolerated dose? What dose the body do to the drug? What dose the drug do to the body? Might the drug work in patients? What is the shape of the dose/concentration-response curve? Chien JY. AAPS J. 2005

15 Human Pharmacology Assess tolerance, maximum tolerated dose (MTD) Describe pharmacokinetics (PK) and pharmacodynamics (PD) Explore drug metabolism and drug interaction Estimate preliminary activity

16 Human Pharmacology Phase Ia study First-in-human/man (FIH/FIM) study Healthy volunteers or patients Dose-escalation design Phase Ib study MTD for target population Step 1 in combined phase study (Ib/II)

17 Human Pharmacology Phase Ic study Comparative PK/PD study Drug interaction study Subpopulation study

18 First-in-Human Study New chemical/biological entity Single ascending dose (SAD) design Multiple ascending dose (MAD) design Investigate safety and tolerability Define MTD Evaluate PK and PD Explore possible biomarkers

19 First-in-Human Study An initial dose for human Based on the highest safe dose Based on the lowest effective dose Dose needs to be low enough to avoid toxicity at initial dose Dose needs to be high enough to allow reasonably rapid attainment of phase I trial objectives

20 First-in-Human Study Selection of a safe starting dose Based on toxicology and pharmacology data of in vivo and in vitro studies Calculation from NOAEL and MABEL Maximum Recommended Starting Dose

21 First-in-Human Study Muller PY. Curr Opin Biotechnol. 2009

22 First-in-Human Study Muller PY. Curr Opin Biotechnol. 2009

23 First-in-Human Study Starting dose in TGN1412 case 0.1 mg/kg 90% receptor occupancy was estimated A dose of 3 ug/kg was required to obtain minimum effective concentration for in vitro stimulation of human T cells 10% receptor occupancy may be acceptable 1~5 ug/kg (20~100 fold less than the dose)

24 First-in-Human Study Conducted in healthy volunteers Mostly non-cytotoxic agents Same dose level in each cohort O Farrell AM. Clin Ther. 2007

25 First-in-Human Study SAD study 6~12 subjects per dose cohort 3~5 dose cohorts Placebo group in each dose cohort Dose escalation scheme Simply doubling from starting dose Modified Fibonacci method

26 First-in-Human Study MAD study Less dose cohorts and not less subjects per dose cohort than SAD Dosing to reach steady state Evaluate Safety profile in accumulation Linear or non-linear PK/PD Preliminary validity of biomarker

27 First-in-Human Study Dose escalation scheme Fibonacci sequence: 0, 1, 1, 2, 3, 5, 8 Modified Fibonacci: initial values other than 0 and 1 (5 mg, 10, 15, 25, 40 ) Predefined dose levels: 100%, 67%, 50%, 40%, 33%...

28 First-in-Human Study Cytotoxic agents for oncology MTD (maximum tolerated dose) Toxicity-guided escalation Cytostatic/targeted agents for oncology OBD (optimal biologically effective dose) Biomarker-guided escalation

29 First-in-Human Study Traditional 3+3 design

30 First-in-Human Study Dose escalation in cytotoxic agents Empirical Traditional 3+3 Accelerated titration Pharmacologically guided Model-based Le Tourneau C. J Natl Cancer Inst. 2009

31 First-in-Human Study

32 First-in-Human Study

33 First-in-Human Study

34 First-in-Human Study

35 Comparative PK/PD Study Compare with reference PK (Bioavailability, AUC, Cmax) PD (serum glucose, blood pressure, QTc) Crossover (parallel) design Formulation study Dosing regimen study Thorough QT study

36 Comparative PK/PD Study

37 Drug Interaction Study 시판허가전후제품설명서업데이트 Crossover design Drug-drug interaction Drug-food interaction Drug-alcohol interaction Drug-herbal medicine interaction

38 Drug Interaction Study

39 Subpopulation Study 시판허가전후제품설명서업데이트 Parallel-group design Geriatric Pediatric Pregnant/breast-feeding women Patients with hepatic/renal impairment Patients with specific ethnicity/genotype

40 Subpopulation Study

41 New Drug Development Phase I Phase II Phase III Safety MTD PK/PD How much? How often? Value/Risk Effectiveness Compared with a standard Tx 41

42 Phase II Study Therapeutic exploratory study Explore use for the targeted indication Estimate dosage for subsequent studies Provide basis for confirmatory study design, endpoints, methodologies Earliest trials of relatively short duration in well-defined narrow patient populations, using surrogate or pharmacological endpoints or clinical measures Dose-response exploration studies ICH. E8 Guideline

43 Dose-Response Relationship Challenges in obtaining dose-response relationships Characterization of exposure or dose Assessment of response Selection of dose-response model to fit the observed data 43

44 Dose-Response Curve Maximal effect Slop (steepness) Threshold Potency Image from 44

45 Dose-Response Curve Image from 45

46 Dose-Response Study Designs Parallel-group Crossover Forced titration Optional titration ICH. E4 Guideline

47 Parallel-group Design Siproudhis L. Colorectal Dis

48 Crossover Design Mainardi F. J Pain

49 Forced Titration Design Tack CJ. J Diabetes Sci Technol

50 Optional Titration Design Newcorn JH. J Child Adolesc Psychopharmacol

51 Combination Therapy 동일한적응증에대해서로다른작용기전의 Drug A 와 Drug B Drug A 의효과를증가시키거나부작용을줄여주는 Drug B 51

52 Combination Therapy Abrams P. Eur Urol

53 Combination Therapy Belani CP. BMC Cancer

54 Combination Therapy LoRusso PM. Clin Cancer Res

55 Titration Designs Careful analysis needed A tendency to spontaneous improvement over time that is not easily distinguishable from an increased response to higher doses or cumulative drug exposure Increased undesirable effects 55

56 Dose-Response Relationship Goldstein S. Thromb Haemost

57 Dose-Response Relationship Singh D. Int J Gen Med

58 Types of Phase II Study Seymour L. Clin Cancer Res

59 Flow for Phase II Study Design Seymour L. Clin Cancer Res

60 Phase II Study with Biomarker Randomized Phase II biomarker trial Possible recommendations for future Phase III trial design Biomarker-enrichment Biomarker-stratified Drop biomarker (standard Phase III) No further testing of new therapy Freidlin B. J Clin Oncol

61 Phase II Study with Biomarker Freidlin B. J Clin Oncol

62 Phase II Study with Biomarker Freidlin B. J Clin Oncol

63 Phase II Study with Biomarker Buch MH. Nat Rev Rheumatol

64 Phase II Study with Biomarker Barker AD. Clin Pharmacol Ther

65 Phase II Study with Biomarker Kim ES. Cancer Discov

66 Trends in Clinical Trials Paul SM. Nat Rev Drug Discov

67 Proof-of-Concept Study Chien JY. AAPS J

68 Proof-of-Concept Study Phase IIa, Phase I/II Determine if there is early evidence of clinical efficacy using a small, targeted number of subjects Help to decide further development (Go vs. No-Go) 68

69 Adaptive Study Design 69

70 Adaptive Study Design Allow the modification of one or more specified aspects of the study design and hypotheses based on analysis of data from subjects in the study Prospectively planned FDA. Guidance for Industry

71 Adaptive Study Design Adaptive randomization Group sequential Sample size re-estimation Drop-the-loser Adaptive dose finding Biomarker-adaptive Adaptive treatment-switching Adaptive seamless phase II/III trial 71

72 Summary 1 상임상시험의가장중요한목적은신약 / 신의료기기안전성확인이다. 건강한자원자또는치료대안이없는말기환자를대상으로하는 1 상임상시험은근본적으로윤리적문제가수반된다. 목적에따라다양한디자인의 1 상임상시험이가능하다.

73 Summary 2 상임상시험의가장중요한목적은신약 / 신의료기기유효성확인이다. (PoC study) 표적치료제인경우, dose-response design 보다 biomarker 를활용한 randomized design 이선호되고있다. 3 상임상시험실패를줄이기위해다양한 2 상임상시험디자인이시도되고있다. 73

74 Thank You for Your Attention

878 Yu Kim, Dongjae Kim 지막 용량수준까지도 멈춤 규칙이 만족되지 않아 시행이 종료되지 않는 경우에는 MTD의 추정이 불가 능하다는 단점이 있다. 최근 이 SM방법의 단점을 보완하기 위해 O Quigley 등 (1990)이 제안한 CRM(Continu

878 Yu Kim, Dongjae Kim 지막 용량수준까지도 멈춤 규칙이 만족되지 않아 시행이 종료되지 않는 경우에는 MTD의 추정이 불가 능하다는 단점이 있다. 최근 이 SM방법의 단점을 보완하기 위해 O Quigley 등 (1990)이 제안한 CRM(Continu 한 국 통 계 학 회 논 문 집 2012, 19권, 6호, 877 884 DOI: http://dx.doi.org/10.5351/ckss.2012.19.6.877 Maximum Tolerated Dose Estimation Applied Biased Coin Design in a Phase Ⅰ Clinical Trial Yu Kim a, Dongjae Kim