Effective Communication for GRM - Practices in PMDA- November 15, 2016 Eriko Yamazaki Office of New Drug I Pharmaceuticals and Medical Devices Agency (PMDA), Japan 1
Disclaimer The views expressed in this presentation are those of the presenter and do not necessarily reflected the official views of the PMDA. 2
Outline • Introduction • Communication between applicant and regulatory agency • Pre-submission • Post-submission • Post-approval • Q&A/Discussion 3
Concept of Good Registration Management (GRM) Good Registration Management Good Review Good Submission Practice Practice (GRevP) (GSubP) Review Applicants Applicants Authorities Synergic effects by parallel promotion of GRevP and GSubP 4
GRevP and GSubP: Table of Contents GRevP: GSubP Guideline Guidelines for national and for Applicants regional regulatory authorities 1. Introduction 1. Introduction 2. Principles of good 2. Glossary submission 3. Principles of a good 3. Management of review submission 4. Managing the review 4. Communications 5. Communications 5. Competency and 6. Review personnel training 7. Conducting the review 6. Glossary Bibliography 7. Reference 5.1 Intra-agency 5.2 Interagency APEC-LSIF-RHSC endorsed 5.3 With applicants 4.1 With review authorities GSubP Guideline in April 2016 5.4 With external experts 4.2 Within applicant’s organization 5.5 With the public
Communication in GRevP Regulatory agency academia Regulatory agency Health Care Professional s Collaboration Transparency Reviewer s Efficient development Patients and Efficient review Family Additional Product A Product B perspective External Experts
Communication between regulator and applicants Non- J-NDA Phase 1 Phase 2 Phase 3 clinical prep Review PMS and PhV Review time is limited… Good submission is needed for regulatory authority to shorten NDA review time No additional study and massive analysis Less inquiry/response and additional analysis To accomplish good submission and shorten review time… 7
Communication between regulator and applicants Non- J-NDA Phase 1 Phase 2 Phase 3 clinical prep ★ ★ ★ ★ Scientific Advices during development phase Review Review PMS and PhV Review time is limited… Good submission is needed for regulatory authority to shorten NDA review time No additional study and massive analysis Less inquiry/response and additional analysis To accomplish good submission and shorten review time, communication between applicants and regulatory authority is needed from development stage 8
Communication between regulator and applicants Prompt reply to the queries applicant ・・・ s Good PMS Review Review and PhV communications Shorten review time ・・・ Regulator s Managing the review process To accomplish effective registration, good communication between the regulators and applicants is needed after submission 9
Number of approvals and review periods in Japan New Drugs Months # of approvals 19.2 20 140 120 14.7 15 （ 12 12 ） 100 11.3 11.9 11.3 11.9 11.5 80 10.3 ～ FY2013: 9.2 10 50th percentile 8.8 8.7 60 7.2 FY2014 ～ : 6.5 6.1 60th percentile 40 （ 9 ） 5 20 107 112 130 134 138 117 116 0 0 FY2009 FY2010 FY2011 FY2012 FY2013 FY2014 FY2015 Number of approved applicants Priority Review Products 10 Standard Review Products
Principle of new drug evaluation in Japan • New drug evaluation processes based on the Pharmaceutical and Medical Device Act should be undertaken by confirming that the new drug applied for does not fall under the “conditions for refusal of approval” defined in the Act. 11
Condition for refusal of approval • The applicant does not have the marketing business license (for the category of the product applied). • The manufacturing sites are not licensed or accredited for manufacturing of pharmaceutical products (for the category of the product applied). (According to Pharmaceutical and Medical Device Act Article 14 Paragraph 2) 12
Condition for refusal of approval • Manufacturing site of the drug applied does not comply with the standard for manufacturing control and quality control defined in Ministerial Ordinances. (According to Pharmaceutical and Medical Device Act Article 14 Paragraph 2) 13
Condition for refusal of approval • When the drug applied for approval falls under the followings, as a result of review of its quality, efficacy and safety: – The indication of the drug applied has not been demonstrated. – The drug applied is found to have harmful effect that outweighs its intended effect, thus considered not of value as a drug. – The drug applied corresponds to a case specified in a Ministerial Ordinance as inappropriate, other than the above. (According to Pharmaceutical and Medical Device Act Article 14 Paragraph 2) 14
Benefit/risk balance • Approvals are not granted when – The indication of the drug applied has not been demonstrated. (lack of efficacy) – The drug applied is found to have harmful effect that outweighs its intended effect, thus considered not of value as a drug (too much risk) The approval does not mean the drug has no risk . 15
Roles of PMDA and MHLW MHLW PMDA • Approval • Scientific review • Enforcement of • Discussion with the administrative applicant and measures external experts • Management of the • Inspection Committees 16
ICH Guidelines Category Topic Quality Q1:Stability, Q2:Analytical Procedures, Q3: Impurities, Q4: Pharmacopoeial Texts, Q6:Specifications, Q8-Q11: QbD, etc. Safety S1: Carcinogenicity, S2; Genotoxicity, S3: Toxicokinetics, S4: Chronic Toxicity, S5: Toxicity to Reproduction, etc. Efficacy E1: Clinical Safety for Drugs used in Long-term Treatment, E2: Pharmacovigilance, E3: Clinical Study Reports, E4: Dose Response Studies, E5: Ethnic Factors, E9: Statistics Principles etc. Multidisciplinary M1: MedDRA, M3: Nonclinical Safety Studies for Conduct of Clinical Studies, M4: CTD, M7: Genotoxic Impurities, M8: eCTD, etc. 17
Good Review Practice Points to Be Considered by the Review Staff Involved in the Evaluation Process of New Drug (FINAL)* Japanese: http://www.pmda.go.jp/files/000164631.pdf English: https://www.pmda.go.jp/files/000153830.pdf 18
Objective and Scope The objective of this document is to promote an understanding among the review staff involved in the evaluation of new drugs, of the basic principles and major points that need to be considered in being involved in the drug evaluation process at PMDA. Scope • This document summarizes basic points to be considered during the actual evaluation process after submitting new drug application. • This document mainly describes points related to clinical studies, because it has been major issues of discussion for approval in the past. 19
Review Points 1. Has the reliability of the conducted studies and submitted documents been ensured? 2. Is the efficacy in the study population considered to be more effective than placebo according to the results of properly designed clinical studies? 3. Do the obtained results have clinical significance? 4. Are there any unacceptable risks as compared to the benefits? 5. Can the drug be supplied continuously with stable efficacy and safety from a quality assurance standpoint? 20
Check Sheet in Good Review Practice Check sheet is based on the accumulating review information/experience of various disease area (cross-sectional discussion) 21
Scientific Consultations & Drug Development Stage Non-Clinical Clinical Review Post-Market Phase I IND NDA Phase II Phase III Phase IV Pre P-II Pre P-I End of P-II Pre NDA Pre-post End of Re- marketing evaluation <Clinical trial consultations> period Pharmaceutical Affairs Prior-Assessment Consultation on R&D strategy Consultation Modified from Figure by Ichimaru K et al, Clin Pharmacol Therapeut , 88: 454-457, 2010 22
Consultation Category So many categories to support a drug development - a sponsor can consult basically on ANYTHING, ANYTIME! NOTE: The list shown here is only on drugs. Another list available for medical devices 23
PMDA consultation process (example) 2 mo. in advance of the request Aug 1 Sponsor Submit Request for Consultation month, on the 1 st working day Approx 1 week from request Date arranged Aug 8 submission Sept 9 Sponsor submit consultation questions and materials Monday -5 wks Pre-Inquiry - 4 weeks Oct Pre- FAX Response PMDA Inquiries Submit -2 weeks Oct 11 PMDA’s Opinion -1 week Oct 17 Sponsor’s response to PMDA’s opinion View Oct 24 0 day PMDA consultation Draft minutes Minutes finalized Within By Dec 7 30 working days 24
Pre-meeting • Seek advise on the following Consultation items (questions) Background information to be included What kind of data should be presented • Evaluation of data will not be done until the consultation meeting • No charge, no minutes, applied at any timing 25
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