1、2018/10/10,1,Bridging Studies - A Genomic Approach,By Jen-pei Liu, Ph.D., Professor 劉仁沛教授 Division of Biometry, Department of Agronomy National Taiwan University Division of Biostatistics and Bioinformatics , National Health Research Institutes,atThe 34 Training Course on Clinical Trials Foundation
2、of Medical Professionals Alliance in Taiwan October 14, 2005,The views expressed in this paper are professional opinions of the presenter and may not necessarily represent the position of the National Taiwan University and National Health Research Institutes, Taiwan.,2018/10/10,2,Acknowledgements an
3、d Thanks, Herng-Der Chen, MD, PhD, Center for Drug Evaluation Mey Wang, PhD, Center for Drug Evaluation Chin-Fu Hsiao, PhD, National Health Research Institutes,2018/10/10,3,Outline,I. Statistical Interpretation of ICH E5 II. Implementation of Bridging Studies III. Examples of Bridging Studies IV. Cu
4、rrent Statistical Approaches V. A Statistical Genomic Approach VI. Summary,2018/10/10,4,Statistical Interpretation of ICH E5,ICH E5 ICH Harmonised Tripartite Guideline (Feb. 5, 1998)Ethnic Factors in the Acceptability of Foreign Clinical Data A US FDA Guidance (Federal Register, June 10, 1998),2018/
5、10/10,5,Statistical Interpretation of ICH E5,ICH E5 Ethnic Factors in the Acceptability of Foreign Clinical DataThe purpose of this guidance is to facilitate the registration of medicines among ICH regions by recommending a framework for evaluating the impact of ethnic factors upon a medicines effec
6、t, i.e., its efficacy and safety at a particular dosage and dose regimen.,2018/10/10,6,Statistical Interpretation of ICH E5,Objectives of ICH E5 (Section 1.1) To describe the characteristics of foreign clinical data that will facilitate their extrapolation to different population and support their a
7、cceptance as a basis for registration of a medicine in a new region. To describe regulatory strategies that minimize duplication of clinical data and facilitate acceptance of foreign clinical data in the new region. To describe the use of bridging study, when necessary, to allow extrapolation of for
8、eign clinical data to a new region. To describe development strategies capable of characterizing ethnic factor influences on safety, efficacy and dose region,2018/10/10,7,Statistical Interpretation of ICH E5,ICH E5 Ethnic Factors in the Acceptability of Foreign Data BRIDGING DATA PACKAGE (Section 3.
9、2)A bridging data package consists of1) selected information from the Complete Data Clinical Package that is relevant to the population of the new region, including pharmacokinetic data, and any preliminary pharmacodynamic and dose-response data,and2) if needed, a bridging study to extrapolate the f
10、oreign efficacy and/or safety data to the new region.,2018/10/10,8,Statistical Interpretation of ICH E5,Complete Clinical Data Package (CCDP)A clinical data package intended for registration containing clinical data that fulfills regulatory requirements of the new region and pharmacokinetic data rel
11、evant to the population in the new region,2018/10/10,9,Statistical Interpretation of ICH E5,Bridging StudyA bridging study is defined as a study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extr
12、apolation of the foreign clinical data to the population in the new region,2018/10/10,10,Extrapolation and Similarity,ICH E5 Ethnic Factors in the Acceptability of Foreign DataIf the bridging study shows that dose response, safety and efficacy in the new region are similar, then the study is readily
13、 interpreted as capable of “bridging“ the foreign dataIf a bridging study, properly executed, indicates that a different dose in the new region results in a safety and efficacy profile that is not substantially different from that derived in the original region, it will often be possible to extrapol
14、ate the foreign data to the new region, with appropriate dose adjustment, if this can be adequately justified (e.g., by pharmacokinetic and/or pharmacodynamic data).,2018/10/10,11,Ethnic Factors,Intrinsic Ethnic Factors are more genetic and physiologic in nature e.g., genetic polymorphism, age, gend
15、er, height, weight, lean body mass, body composition, and disease conditions, etc. Extrinsic Ethnic Factors are more social and cultural in nature e.g., environment, culture, medical practice, health insurance, practices in clinical trials or conduct,2018/10/10,12,An approved report of a local clini
16、cal trial study is required for the new drug application in TaiwanJuly 7. 1993: Double 7 AnnouncementDisadvantages: A minimal sample size of 40 as required could be difficult to provide conclusive and substantial evidence ofefficacy and safetyThe study design of the local trial usually only repeated
17、 a study that has been done in the foreign countries but in a smaller sample size;The study has not been designed based on the medical situation in Taiwan,Taiwans Strategy to Implement Bridging Study,2018/10/10,13,Taiwans Strategy to Implement Bridging Study,Smoothly convert compulsory Local Clinica
18、l Trials (LCT) to meaningful bridging studies Gradually, stepwise announce waived local clinical trials Create an environment: (1) meet international regulations, ICH (2) require optimized dosage forTaiwanese patients Communicate with local and international pharmaceutical industry Announce new regu
19、lations according to the international norm and the consensus from communications Create an international platform “APEC Taipei” Implement Double Twelve Announcement Bridging Study,2018/10/10,14,Stepwise Implementation,Two years after the 1998 announcement, switch from LCT to bridging study Many com
20、munications and negotiations with local and international pharmaceutical industry Dec. 12, 2000: (Double Twelve Announcement) public announcement of the bridging study regulations 1998: Five announcements of LCT wavier A two-year transition period: both LCT and bridging studies concurrently acceptab
21、le from 2000 2002 Many international conferences held in Taipei and other Asian countries, regarding BS, through the APEC platform Consult with CDE to complete the practical issues related to implementation of BS Jan. 1, 2004: Bridging evaluation,2018/10/10,15,Products Requiring No Verification of E
22、thnic Insensitivity,Drugs for treatment of AIDS Drugs for organ transplantation Topical agents Nutrition supplements Cathartics prior to surgery Radio-labelled diagnostic pharmaceuticals The drug is the only choice of treatment for a given severe disease Drugs for life-threatening disease have demon
23、strated a breakthrough efficacy Lacking adequate trial subjects for any drug used for rare disease,2018/10/10,16,Products Requiring Verification of Ethnic Insensitivity,Anticancer drugs Drugs with breakthrough efficacy Drugs of single use Drugs with different salt of the same composition and the sam
24、e administered route have been approved internal Drugs for chronic psychological or immunological diseases and conducting clinical trails internal difficultly Each compounds of new combination drug have been proved internal, and the efficacy is the same as the single compound Drugs with the mechanis
25、m, administered route, efficacy and adverse effect, similar to the approved drugs New combination composed of single compound of approved combination or compounds of approved combination has the same efficacy as approved combination,2018/10/10,17,Bridging Data Package Summary for the Consideration o
26、f Bridging Study,Accept submission Checking List,Technical Review (Designate reviewer),Review meeting,Sponsor meeting,Supplement,Clinical Review Committee,Review report and Recommendation: 1. No Bridging study required 2. Bridging study is required Type of Bridging study,Result of Evaluation: 1. No
27、Bridging study required 2. Bridging study is required Type of Bridging study,Notification,Sponsor,BoPA,CDE,CDE acceptance,verification,Expert Consultants (Statistical, Clinical, Pharmacokinetics reviewers),Schedule Sponsor meeting,Evaluation Process,2018/10/10,18,2018/10/10,19,2018/10/10,20,Examples
28、,Example I Drug A is a fixed combination of two anti-platelet agents with indication for secondary prevention of thromboembolic stroke After the standard process of BSE, we decided to request a bridging study due to an ethnic difference in medical practice (much lower dose for one of the components
29、in Taiwan) and higher headache-associated dropout rate in previous Philippine study,2018/10/10,21,Examples,Case I Fixed combination 200mg dipyridamole/25mg aspirin 1bid for prevention of recurrent stroke Headache drop out rate: Phillipino Caucasian Local Bridging Study Result : first 4 weeksReduced
30、Dose 2wk Full DosePlacebo Full Dose 2wk 4wk Headache 8.7% 6.7% 16.3%Risk Management: Change labelings instruction for use,2018/10/10,22,Examples,Case II Drug B is a new potent lipid-lowering agent The PK study in Japanese shows that Cmax of Japanese is 1.92.5 times of that for Caucasian while AUC is
31、 22.5 times of that for Caucasian Although the mean interracial difference is not substantial, Taiwan approved the drug with reduced maximal dosage due to the dose-dependent, drug-related rare SAE of rhabdomyolysis,2018/10/10,23,Examples,Case II The decision was further echoed by US FDA After review
32、ing the results of a Phase IV PK study in Asian-Americans, FDA urged the physicians to reduce the starting dose and prescribe high dose with caution for Asians in Labeling in March, 2005,2018/10/10,24,Current Statistical Approaches,“Similarity”Positive Rx effect Equivalence Non-inferiority,2018/10/1
33、0,25,Extrapolation and SimilarityPositive treatment effect (better than control)The efficacy or safety of the test drug is better than control in the new regionHo: NT - NC 0 vs. Ha: NT - NC 0,Current Statistical Approaches,2018/10/10,26,Current Statistical Approaches Positive Rx Effect,0,2018/10/10,
34、27,Current Statistical Approaches,Similarity (No substantial difference) Two-sided equivalence The relative efficacy or safety (test - control) of the new region is within some clinically acceptance limit of that of the original regionLet = (NT - NC) - (OT - OC)Ho: - or vs. Ha: - where is some clini
35、cally acceptable limit (equivalence limit).,2018/10/10,28,Current Statistical Approaches Equivalence,0,2018/10/10,29,Current Statistical Approaches,Similarity (No substantial difference) One-sided non-inferiorityThe relative efficacy or safety (test - control) of the new region is not inferior to th
36、e original region by some clinically acceptance limit.Ho: - vs. Ha: -.,2018/10/10,30,Current Statistical Approaches Non-inferiority,0,2018/10/10,31,Current Statistical Approaches,Between-study Analysis: Equivalence or non-inferiorityHierarchical Model (Liu, Hsueh, and Chen 2002, Biometrical J.)Step
37、1: From the complete clinical data package, under the hierarchical model, use the clinical data from the original region to obtain the estimate of relative efficacy and its estimated standard error. Step 2: From the data of the bridging study, obtain the estimate of relative efficacy and its estimat
38、ed standard error in the new region. Step 3: Based on the estimated relative efficacy and its standard error from both the new and original regions and equivalence limit , perform the usual two one-sided tests procedure or one-sided non-inferiority test procedure (or confidence interval).,2018/10/10
39、,32,Empirical Bayesian ApproachBridging studies Small sample size Need to borrow “strength” from CCDP of original region. Information on dose response, efficacy and safety of theoriginal region can and should be incorporated in a statistically sound manner to evaluate bridging evidence by the bridgi
40、ng studies in the new region. Positive treatment effect: (Liu, Hsiao, and Hsueh, 2002, JBS) Noninferiority approach: (Liu, Hsueh, and Hsiao 2004, JBS),Current Statistical Approaches,2018/10/10,33,Between-study Analysis: Bayesian Approach (Liu, Hsiao, and Hsueh, 2002) Use the estimate of treatment ef
41、fect from theoriginal region formulated as a normal prior Compute the posterior treatment effect with the data from the new regionCompute the posterior probability of similarity, Psp as theposterior probability of a positive treatment effect Conclude the results of the foreign region can be extrapol
42、atedto the new region if Psp is sufficiently large. Sample size might be determined based on thedifference between the posterior and prior treatmenteffect,Current Statistical Approaches,2018/10/10,34,Current Statistical Approaches,For a positive treatment effect The model (Liu, Hsiao, and Hsueh, 200
43、2)Yi = P(1-Xi) + Nzi + O(1-Zi)Xi + i, I N(0, 2), whereP: control effect N: treatment effect of the new region O: treatment effect of the original region X = 1(0) treatment (control) group Z = 1(0) new (original region),2018/10/10,35,Current Statistical Approaches,For a positive treatment effect Empi
44、rical Bayesian Approach (Liu, Hsiao, and Hsueh, 2002) Given P, N, the estimates of P, N, say p and aN follows abivariate normal distribution with mean vector (P, N) and thediagonal covariance matrix diag(VP, VN). In addition, the prior distribution of (P, N, O) follows a trivariate normal distributi
45、on with mean vector (p, N, O) anddiagonal covariance matrix diag(2p, 2N, 2O). Conclude a positive treatment effect if posterior probability of similarity P(N - P 0data and prior) 1 - , for some 0.5. (Simon, 1999),2018/10/10,36,Current Statistical Approaches,For a positive treatment effect Empirical
46、Bayesian Approach (Liu, Hsiao, Hsueh, 2002) Under assumption that N = O, for P(N - P 0data and prior) 1 - , the following equation must be satisfied(O - p)/2O+2p = -1(1-q),where -1(1-q) represents the evidence for positive treatment effect in the original region.,2018/10/10,37,Current Statistical Ap
47、proaches,Results from Original Region Change from baseline in sitting DBP at week 12 Region Statistics Test Placebo I n 138 132Mean -18 -3SD 11 12 II n 185 179Mean -17 -2SD 10 11 III n 141 143Mean -15 -5SD 13 14,2018/10/10,38,Current Statistical Approaches,Results from New Region:Change from baselin
48、e in Sitting DBP at week 12 Region Statistics Test Placebo New n 64 65Mean -4.5 -3.8SD 11 11Posterior probability of similarity: Psp 1,2018/10/10,39,Current Statistical Approaches,Original region: Efficacy of the test drug is superior to the placebo.New Region: Reduction of sitting BP of the test dr
49、ug is same as that of the placebo.Conclusion: The results of the original region can be extrapolated to the new region despite of inconsistent results between original and new regions. Evaluation of bridging studies is overwhelmingly by the results of original region due to imbalance of information provided by the two regions. .,
