impact on a trial design and labeling

Transcription

1 Genotyping-impact impact on a trial design and labeling Yoshiaki Uyama,, Ph.D. Office of New Drug III (PMDA)

2 Benefit of Pharmacogenomics Improving benefit/risk ratio More safe, more effective Adjusting Dose Can determine the best dose Increasing successful rate of clinical trials Focusing on data in responder More drug, more appropriately What should be thought on pharmacogenomic approach

3 How to use Pharmacogenomics on Drug development

4 EGFR Mutation & IRESSA (Gefitinib( Gefitinib) ) Therapy Response Rate in Phase II trial 27.5 % in Japanese, 10.4 % in Caucasian Paez JG et al., Science, 304: 1497, ) Race Japanese Caucasian 26 % (15/58) 2 % (1/61) 2) Response Responder Non-responder 100 % (5/5) 0 % (0/4) L858R 1 in-frame deletion 4 ( ) 753)

5 Screening for EGFR mutations may be useful to discriminate responder / non-responder to Gefitinib. regulatory submission The results are suggestive but not confirmative. Small sample size & Retrospective approach What is relationships of the EGFR mutation to safety of Gefitinib? Can decrease adverse event (ILD etc.)? Is this screening test applicable and reliable in practical medicine?

6 The results in example are Suggestive and Useful for establishing hypothesis Not confirmative data Data from Retrospective approaches are less useful for drug review More study would be necessary for regulatory decision

7 Designs of clinical study using Phramcogenomics

8 Retrospective Design Randomized, Double Blind, Placebo-control control Trial Placebo Drug A entry Treatment period Genetic analysis (+) (-) (+) (-) sampling Patient numbers in a arm maybe unbalanced? Sampling maybe limited in some patients? Results are not confirmative? Confirmative trial would be necessary

9 Prospective Design 1 Randomized, Double Blind, Placebo-control control Trial Genetic analysis (+) randomised Placebo Drug A Treatment period sampling (-) No entry Enrichment approach Increase analytical power of trial Results are confirmative But, data in gene(-) ) patients can not be obtained May lose a chance of treatment for (-)( ) patients

10 Point to consider for applying enrichment Broader patients can be a target for drug administration in practical medicine Regular Clinical Trial Gene Positive (+) Gene Negative (-)( PG What is happen for (-)( ) patients Does drug have really no benefit? Can be excluded from the indication? How can we evaluate benefit/risk without data? Enriched Clinical Trial (-): No data Appropriateness of exclusion of gene(-) ) patients should be carefully examined

11 Prospective Design 2 Randomized, Double Blind, Placebo-control control Trial Genetic analysis (+) (-) randomised Placebo Drug A Placebo Drug A Treatment period sampling

12 Results are confirmative Benefit/Risk for gene(-) ) patients can be evaluated Enough numbers of gene (-)( ) patients should be included Enrichment effect is still present Analyze data in gene(+) patients This types of data would be useful for regulatory decision

13 Real target in practical medicine General target in clinical trial Out of Indication Limited target Target Patient small Enrichment effect large Too much enrichment may limit target patients/indication Enriched population may not represent a real population in a practical medicine Enriched approach may increase off label use How much enrichment effect is useful and reasonable?

14 Pharmacogenomics would be beneficial in clinical trial for regulatory submission, if Genetic assay is reliable/validated Results are prospectively confirmed Benefit/Risk can be evaluated even in gene (-)( ) patients Enrichment effect is reasonable and acceptable etc.

15 Impact of PG data in the label

16 Indication & Usage: HERCEPTIN (trastuzumab( trastuzumab) The treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein Insurance coverage for HER2 DNA tests Test Test device is also approved

17 OMEPRAL (Omeprazole( Omeprazole) Metabolized by CYP2C19 & CYP3A4 PM for CYP2C19 is % in Mongolian including Japanese, % in Caucasian AUC is times higher in PM than that in EM (based on t 1/2 value)

18 Strattera (Atomoxetine) Approved by FDA in July 2003 for AD-HD <attentiondeficit/hyperactive disorder> Recommend Dose (up tp 70kg b.w.): Initial 0.5 mg/kg/day and then increase to 1.2 mg/kg/day Metabolism primarily cleared by CYP2D6 EM PM AUC(.hr/.hr/mL) CL (L/hr/kg)(

19 Adverse Event Differences on adverse event rates were observed between EM and PM EM PM decreased appetite 16 % 23 % insomnia 7 % 13 % depression 2 % 6 % sedation 2 % 4 % tremor 1 % 4 % What was FDA s decision on the label

20 Label for Atomoxetine Many section include Information/data about CYP2D6 EM/PM Laboratory Tests Routine laboratory tests are not required No official test is approved Dosing adjustment For use with a strong CYP2D6 inhibitor (paroxetine, fluoxetine, quinidine) Initial: 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and initial dose is well tolerated.

21 PG information has already included in the label (prescribing information) useful as one of information May be no impact for regular use For use the information appropriately in practical medicine, test method should be available at the time of drug approval

22 Establishment of guidance for appropriate Pharmacogenomic approach in Clinical Trial & Review in Japan

23 June 8, 2004 Official announcement was made for inviting the comments Submission of Information to Regulatory Authorities for Preparation of Guideline for the Use of Pharmacogenomics in Clinical Studies (draft) July 9, 2004 Comments invitation was closed

24 Contents in the draft Recommend to submit information (List) about Pharmacogenomic Study (conducting, planning, or conducted in the past) Informations include a target disease, a target gene, sample size, purpose of a study. More detail information maybe requested to a sponsor Re-evaluation evaluation period (Exclusive period) after approval maybe extended, if pharmacogenomic data are conclusive for approval

25 Submitted Comments (1) Time frame to develop the guideline Submission is Voluntary or Mandatory? Directions of future guideline for PG clinical trial, based on the submitted information? How to provide old genomic data which informed consent may not cover submission of genomic data to MHLW Is there any incentive for off-patent drugs? Possibility applying orphan status Provide another incentive such as priority review, higher price etc.

26 Submitted Comments (2) How MHLW &PMDA review submitted data? How to review diagnosis devices (genetic tests) simultaneously with drug review? Harmonization of approaches among Japan, USA and EU How to protect proprietary information after submission How feed-back of analyzed data will be made What date is time-limit for submission

27 Future Harmonization of regulatory approach Discussion at ICH etc. Public acceptance & Transparency More frequent discussions among interested parties (patient, academia, sponsor, regulatory) PMDA will contribute issues on Pharmacogenomic drug development

28 (Established on April 1 st, 2004 PMDEC OPSR JAAME (PMDA)

29 IND review NDA review PMDA GCP compliance PMS monitoring

30 Information PMDA HOMEPAGE PMDA DRUG Information