How Transparent are Regulatory Agencies with regard to Review Timelines? Disclaimer

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1 How Transparent are Regulatory Agencies with regard to Review Timelines? A Global Review Rosanna Melchior Sr Manager, Reg.Intelligence THOMSON REUTERS, France Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. ( DIA ) DIA), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, Drug Information Association Inc., DIA and DIA logo are registered trademarks. All other trademarks are the property of their respective owners. 2 1

2 Agenda Tranparency: legislated timelines (timeframes to be met) vs performance reports (timeframes actually met) Bench mark agencies (EMA, FDA, HC, PMDA, TGA and Medsafe) Other Agencies in Latin America Middle East Africa Ai Asia Focus on NCE standard applications 3 Preliminary Considerations Agency s performance targets vs legislated review/procedural timelines p Days, Calendar Days, Working Days (CD, WD) Review times may include applicants time to respond Review timelines vs time to obtain a marketing authorization/approval 2

3 EU/EMA: centralised procedure D -10 Submission Day 0 Start of procedure D 210 Adoption of CHMP Opinion D 277 Adoption of EC Decision Validation Scientific evaluation (Co)-Rapporteurs AR, Comments from CHMP Members, List of Questions, Clock Stop (day 180) Answer to Questions Transmission of opinion (15) Draft EC opinion (15) Standing Committee (22) Adoption of EC opinion (15) Compulsory for medicinal products derived from biotechnology, advanced therapy medicinal products, new active substances for certain therapeutic areas and for orphan medicinal products. Applications are submitted directly to the European Medicines Agency. At the conclusion of the scientific evaluation the CHMP opinion is transmitted to the European Commission to be transformed into a single Community marketing authorisation applying throughout the European Union. 5 EMA transparency initiative The submission deadlines and full procedural timetables are published on EMA website The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones The submission/start/chmp dates are generally fixed, other dates may be subject to adjustments until the CHMP Scientific committee proceeds to their adoption for every individual application. At the start of a procedure, the adopted final timetable will be formally notified in writing to applicants. According to EMA Annual report 2009, 99 % of applications have been reviewed within 210 days 6 3

4 EU MSs: national procedures Validation phase ranges between 10 and 60 days (AT, ES, SW vs IRL, SLO) National Authority Review Times: 210 days (Ireland 150, Slovakia 180). In practice it exceeds legislated timelines for some countries (the longest being Spain, Norway, Turkey) 7 USA According to FDA s Guidance for Review Staff and Industry : Good Review Management Principles and Practices, FDA staff should establish and observe internal review timelines to help ensure efficiency and consistency in the review process. Timelines are established by the Prescription Drug User Fee Program (PDUFA). PDUFA IV goals, as reauthorized by FDAAA of 2007, are to review and act within 10 months of receipt on 90% of standard BLAs and NDAs filed during fiscal years 2007 to 2012 and within 6 months for priority applications. 4

5 Performances for FY 2009 and 2010 FY 2009 Submissions FY 2010 Submissions 9 CANADA There are no legal time limits for review of submissions in Canada. The Guidance for the Management of Drug Submissions (MDSG) outlines the way in which the Therapeutic Products Directorate (TPD) and Biologics and Genetic Therapies Directorate (BGTD) manage information and material submitted by sponsors in accordance with the Food and Drugs Act and Regulations. Time frames referred to in the guidance are the current Health Canada Target Performance Standards TARGET = 90% of the submissions in a category to be processed TARGET = 90% of the submissions in a category to be processed within the time shown. 5

6 Drug Submission Performance Reports TPD Jan-Mar 2010 Quarterly Drug Submission Performance Report BGTD, Jan-Mar 2010 Quarterly Drug Submission Performance Report 6

7 JAPAN Following open criticism, open transparency Targeted review time in FY 2009 to 2013 policy from MHLW/PMDA with regard to the review system for drugs and devices was adopted*: Standard Drug review In 2004, the Pharmaceuticals and Medical Devices Agency (PMDA) was founded Substantial increase in the number of its 12 staff including reviewers 10 the process from clinical trial 8 consultations until reviews conducted by 6 the same team with the same staff 4 members 2 Reinforcement of personnel in key 0 FY 2009 (*) FY 2010 FY 2011 FY 2012 FY 2013 therapeutic areas Reinforcement and improvement in the transparency of the progress management of reviews Standard Drug review * PMDA annual report from website JAPAN: Standard Products In FY 2009, the median total review time for standard products was shortened to 19.2 months, compared with 22.0 months in FY The median regulatory review time was shortened by 0.8 months compared with that in FY 2008, and the median applicant s time was also shortened by 0.7 months. The number of approved applications was markedly increased from the previous fiscal year. In practice: Time needed for approval is about months in total 7

8 AUSTRALIA The Therapeutic Goods Administration (TGA) is undergoing changes to the way that the submission and evaluation of prescription medicines are made. Transitional arrangements are expected to last until end of 2011 The streamlined submission i process consists of 8 phases with 8 milestones, allowing effective planning and tracking by the TGA and sponsors. Depending on the type of submission different phases will be required which will affect the overall length of time to complete the regulatory process. While the legislated TGA commitment of 40 WD between receipt of a submission and notification of acceptance/rejection will initially remain, this process will be replaced by a period of 15 CD. The legislated TGA commitment of 255 WD * between acceptance for evaluation through to decision on the application will also remain for the time being but will not be used for planning or for target times. (* 255 WD = 357 CD = 12 months) 15 The streamlined submission process is designed to take no more than 300 CD (10 months), including the time for sponsor activities. TGA Transparency initiative Category 1 applications Standard route of application ( WD) Category 2 applications Products that have been approved for marketing in at least two acceptable countries (UK, Canada, Sweden, USA, Netherlands), and for which 2 independent evaluation reports are provided ( WD) Category 3 applications involving changes to the quality data of medicines already included on the ARTG (45 WD) 16 8

9 NEW ZEALAND Medsafe has made changes to new medicine application processing times and the evaluation process. The following process applies since August 2006: The initial evaluation should be completed with 200 CD, or less. Where a Request for Further Information (RFI) resulting from an initial evaluation is made, the applicant has a maximum of 200 CD to provide a complete response to this letter. The applicant s RFI response will be evaluated within 120 CD or less, following receipt by Medsafe. If an additional RFI letter is required the applicant has a maximum of 120 CD to provide a complete response to this second letter. The applicant s second RFI response will be evaluated within 120 CD, during which time Medsafe will make a decision to accept, or decline the new medicine application. 17 NEW ZEALAND:Processing Times Processing times (in calendar days): Times taken to complete the processes concerned for the majority (80%) of applications and notifications during the 12- month period July 1999 to June These times are given to provide applicants with a general guide to the times that Medsafe s processing of the different types of applications and notifications can be expected to take. 18 9

10 OVERVIEW Clock stop (7 + 3) Includes sponsor s time Includes sponsor s time Months COLOMBIA According to Decree No. 677/95 the estimated review times are: 210 WD for a new product (Includes pharmacological and pharmaceutical evaluation) 30 WD for a medicinal product included within the pharmacological regulations (Only pharmaceutical evaluation) Sponsor has 60 days to address request for additional information. Time for obtain a marketing authorization is then extended to include WD for legal checking / administrative i ti purposes. PERU Products classification defines the requirements for regulatory procedures and review timelines : Category 1 products: 60 CD (Products whose API or associations are in the National List of Essential Drugs ) Category 2 products: CD (Products whose API or associations are not in the National List of Essential Drugs but are registered in countries with a high health vigilance system.) Category 3 Products:12 months (Products whose API are not classified in Cat. 1 and 2) LATIN AMERICA BRAZIL Although Law determines that the registration approval should be granted within a period of 90 CD days from the date of filing, the actual time for a New Product Registration approval is rarely shorter than 12 months. The type of product defines the format and contents of the Product Registration Dossier, PRD and as a consequence the timetable for the Approval Procedure ARGENTINA Review timelines are established by Disposition 5755/96 ( WD). Although mandatory, due to the notorious gap between workload and resources currently existing at ANMAT, these deadlines are usually never met and the whole process may take up to 12 months and even longer. CHILE Review timelines are identified by Decree 1876/95 (Art. 47): the Public Health Institute has 90 WD to approve or reject a MAA. Time for review can be extended of 30 additional days if the application includes a new API. April 2011: Argentina's has developed a new strategy to generate timely national and international information about the products and processes within its remit. The so called ANMAT Observatory is expected to strengthen the regulator's decision making process as it will co-ordinate for the first time such information and activities

11 MIDDLE EAST AFRICA Expected Review Time for MAA Standard Review ISRAEL 360 Medicinal Products are evaluated and registered within 360 days, except for: - Generics which have been approved by the FDA/EMA (70 days). - Additional dosages of registered products (180 days). There are some contradictions in Guideline s timetables and it is advisable to clarify the situation ti with the particular clerk dealing with the specific problem. EGYPT SAUDI ARABIA 255 WD (357 CD) WD Drug Registration process depends on the status of the product (Brand or generic; imported, locally or Toll manufactured). Generally, MA procedure takes around months as an average. It includes: Pre-inquiry Notification (15), Pricing file Submission (60), Scientific Committee Review (60), Registration file Submission (15), Stability file Submission (60), NODCAR file Submission (45 ). Target performance timeline from the date of acceptance to SFDA decision is of 290 days (10 days validation days assessments "pricing +testing + dossier review" + 35 days licensing). Applicant has 30 days to answer to inquiries raised during evaluation. UAE 365 There is no official text dealing with registration timelines. The registration procedure in the UAE is a long process lasting usually 6 to 12 months. It can be shortened to 3 to 6 months for New innovative drug, New therapeutic class, Products manufactured by GCC countries or having GCC certification. SOUTH AFRICA Registration timelines are sub-optimal. Delays are however not only caused by the MRA/MCC. Some of the dossiers or clinical trial applications are substandard. The MCC has committed to improve the evaluation time of applications and the Minister of Health appointed a task team to address the current back log at the MCC. A newly proposed process (adapted from Australian and Singapore models) ) aims to conduct a full review in 210 WD (+ 60 for regulatory decision making). In practice, lengthy process up to 40 months 11

12 THAILAND The timeframe for new drug registration is approximately 210 WD + 70 if submitted to subcommittee. The estimated actual time spent for registration is ranging from months depending on the quality of the information and the completeness of the documents. ASEAN COUNTRIES * VIETNAM Within 6 months from the date of receiving the full legitimate dossier, the Ministry of Health shall issue registration number for the drugs registered for the first time MALAYSIA 12 months for hard copy submissions, 6 months for online submissions. Average length for entire process is 6 to 12 months. (not officially stated) SINGAPORE INDONESIA * Excluding: PHILIPPINES Myanmar, Cambodia, Laos, Brunei Darussalam Have adopted a registration system that relies on product assessment and approval of other competent Drug regulatory Agencies 23 INDONESIA SINGAPORE PHILIPPINES 3 distinct review processes and timelines INDONESIA SINGAPORE PHILIPPINES Path III 300 working days Full dossier 270 working days working days Products that have not been approved by any competent regulatory agency Path II 150 days Products that have been already approved by one of the competent regulatory agencies with whom Indonesia has signed the mutual recognition agreement and other agreements Products that have not been approved by any drug regulatory agency at the time of submission Abridged dossier 180 (NDA) or 240 days (GDA) Products that have been evaluated and approved by at least one drug regulatory agency Products that have not been approved by any agency working days Products that have already received approval from other agencies with whom the Philippines signed a MRA Path I 100 days Verification dossier 60 (NDA) or to 210 working days. For generic products/copy drugs (essential drug for Government program) that do not required nonclinical and clinical data to establish safety and efficacy days (GDA) Products that have been evaluated and approved by HAS s reference drug regulatory agencies, which include EMA (for CP), US FDA, Health Canada, TGA, and UK MHRA (for MRP/DCP) For generics products/copy products/similar products which do not require clinical and non-clinical data 24 12

13 ASIAN COUNTRIES Expected RA Review Time for MAA Standard Review CHINA WD Legislated MAA review timelines are of 250 days, however time for obtaining a decision from the authority varies from product to product. The total time to approve a drug is estimated to range between 26 to 40 months. Recently y( (March 2011), the Guideline on Principles and Procedures for Drug Scientific Review introduced the principles of openness and transparency to be applied to pharmaceutical product review (Art. XLV). The information on review procedures (status reports on products reviews, the targeted review time) will be made public on government website. HONG KONG WD The Pharmaceutical Service has a performance pledge to approve applications for registration of pharmaceutical products within 5 months (Agency website).the whole process is 6 months (including the evaluation and decision delivery) INDIA 270 CD India's new draft guidance on test licence applications aims to shorten review times. The Indian Central Drugs Standard Control Organization has issued revised draft guidance explaining the content and format of applications that companies need to submit for obtaining a licence to import drugs for examination, analysis and testing purposes. The aim is to establish harmonised submission procedures, res which in turn would shorten the application processing time and facilitate uniform decisions by examiners/reviewers. SOUTH KOREA 203 CD 203 days as per regulation (60 days for S/E review, 120 for CMC). TAIWAN CD According to the current practice, market authorization is granted within 90 to 270 days. In Nov 2010 and in order to shorten the evaluation timeline, the Dept. of Health (DOH) has decided that a Letter of Approval will be issued as soon as the application has satisfactorily passed the review process without waiting for the results of the package insert review. 25 WHAT MAKES AGENCIES REVIEW TIMELINES SO DIFFERENT? Agency s maturity and experience Reliance upon assessment conducted by bench mark agencies (FDA, EMA, etc) for several agencies (TGA, Asean, etc) Distinct evaluation processes (CTA + CMC + samples + pricing in parallel or sequential ) Type of product type of dossier type of review N of submissions (crf. Agency s performance targets) For each Agency/Country the granularity of information varies 13

14 Conclusion How Transparent are Regulatory Agencies with regard to Review Timelines? 27 Conclusion Information on legislated review timelines is available for most of the Agencies considered Explicit information for some countries, customers practicebased for others Information on review performances is available for few countries Agencies willing to increase transparency and improve review procedures and shorten delays (PMDA, TGA, SFDA China, CDSCO India, ANMAT Argentina, South Africa) How much do legislated/target and experienced/actual review times concorde? 28 14

15 References Argentina: Disposition 5755/96 (Marketing Authorization Application Procedure for New Medicinal Products, 03-Feb-1997, as amended, 29-Nov-2000); ANMAT Disposition 907/2011, Boletín Oficial de la República Argentina, No , 15 February 2011 Australia: Guideline: Transitional Prescription Medicine Streamlined Submission Process (Applicable to pre-submission planning forms received by the TGA from 1 March 2011 and submissions lodged under the streamlined submission process and received by the TGA from 1 March 2011), Jan-2011; (Therapeutic Goods Regulations 1990, Consolidated d Version as of 29-Oct-2010) 2010) Canada: Guidance for Industry: Management of Drug Submissions, 16-Mar-2011; Agency s performance reviews info available through quarterly/annual submission performance reports, HC Website China: Guideline: Principles and Procedures for Drug Scientific Review, 23-Mar-2011, SFDA Order No. 28: Regulations on Drug Registration Administration, Revision, 10-Jul-2007 Colombia: Decree 677: Regulates the Process of Registration, the Granting of Licences, Quality Control and Sanitary Surveillance of Medicinal Products, Cosmetics, Herbal Medicinal Products, Personal Hygiene Products and Other Products for Domestic Use, 26- Apr-1995 Israel: Title Guideline 72: Medicinal Products Approval Schedule, 30-Jul-2007 Mexico: Regulation of Health Sector Products, 03-Feb-1998 (Drug Law) New Zealand: Guideline: New Zealand Regulatory Guidelines for Medicines, Volume 1, Part F: Medsafe s evaluation procedures, edition 6.13, Mar-2011 Peru: Law 29316: Amends, Adds and Regulates Provisions to Implement the United States-Peru Trade Promotion Agreement, 13-Jan Saudi Arabia: Guideline: Regulatory Framework for Drugs Approvals, Version 4, Jun-2009 South Africa: Report Of The Ministerial Task Team On The Restructuring Of The Medicines Regulatory Affairs and Medicines Control Council and Recommendations For The New Regulatory Authority For Health Products Of South Africa, 25-Feb-2008 Singapore: Guidance on Medicinal Product Registration in Singapore, Revised version, Apr-2011 USA: FDA s Guidance for Review Staff and Industry: Good Review Management Principles and Practices; The Food and Drug Administration Amendments Act of 2007 (FDAAA) 29 THANK YOU rosanna.melchior@thomsonreuters.com 30 15