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How Transparent are Regulatory Agencies with regard to Review Timelines? A Global ReviewA Global Review

Rosanna MelchiorSr Manager, Reg.IntelligenceTHOMSON 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”) itsattributed to Drug Information Association, Inc. ( 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 ypermission. 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.

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Agenda

• Tranparency: legislated timelines (timeframes to be met) vsperformance reports (timeframes actually met)

• Bench mark agencies (EMA, FDA, HC, PMDA, TGA and Medsafe)

• Other Agencies in – Latin America– Middle East Africa

A i– Asia• Focus on NCE standard applications

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Preliminary Considerations

• Agency’s performance targets vs legislated review/procedural timelinesp

• 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

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EU/EMA: centralised procedure

• ValidationD -10

Submission

• Compulsory for medicinal products derived from biotechnology, advanced therapy medicinal products new activeSubmission

• Scientific evaluation•(Co)-Rapporteurs AR, •Comments from CHMP Members, •List of Questions, •Clock Stop (day 180)•Answer to Questions

Day 0 Start of

procedure

D 210 Adoption of

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 CHMP Opinion

• Transmission of opinion (15) • Draft EC opinion (15)• Standing Committee (22)• Adoption of EC opinion (15)D 277

Adoption of EC Decision

evaluation the CHMP opinion is transmitted to the European Commission to be transformed into a single Community marketing authorisation applying throughout the European Union.

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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

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EU MSs: national procedures

• Validation phase ranges between 10 and 60 daysbetween 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)

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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.

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Performances for FY 2009 and 2010

FY 2009 Submissions FY 2010 Submissions

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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.

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Drug Submission Performance Reports

TPD Jan-Mar 2010 Quarterly Drug Submission Performance Report

BGTD, Jan-Mar 2010 Quarterly Drug Submission Performance Report

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JAPAN

Following open criticism, open transparency policy from MHLW/PMDA with regard to the review system for drugs and devices was

Targeted review time in FY 2009 to 2013

adopted*:– In 2004, the Pharmaceuticals and

Medical Devices Agency (PMDA) was founded

– Substantial increase in the number of its staff including reviewers

– the process from clinical trial consultations until reviews conducted by the same team with the same staff members 2

468101214161820

Standard Drug review

Standard Drug review

– Reinforcement of personnel in key therapeutic areas

– Reinforcement and improvement in the transparency of the progress management of reviews

0FY 2009 (*) FY 2010  FY 2011  FY 2012  FY 2013 

* 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 0months, compared with 22.0 months in FY 2008.

• 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 markedlyapplications was markedly increased from the previous fiscal year.

• In practice: Time needed for approval is about 19 - 21 months in total

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AUSTRALIAThe 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

Th t li d b i i i t f• The streamlined submission 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

The streamlined submission process is designed to take no more than 300 CD (10 months), including the time for sponsor activities.

p j y ,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

TGA Transparency initiative

Category 1 applications– Standard route of application (40 + 255 WD)

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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 (20 + 175 WD)

Category 3 applications – involving changes to the quality data of medicines already included on the ARTG (45 WD)

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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 lettercomplete 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.

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NEW ZEALAND:Processing Times

Processing times (in calendar days):• Times taken to complete the

processes concerned for theprocesses concerned for the majority (80%) of applications and notifications during the 12-month period July 1999 to June 2000.

• 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 canapplications and notifications can be expected to take.

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OVERVIEWClock stop (7 + 3)

Includes sponsor’s time

Includes sponsor’s time

Months

LATIN AMERICABRAZILAlthough Law 6.360 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

COLOMBIAAccording 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 20 + 10 WD for legal checking /

d i i t ti

ARGENTINAReview timelines are established by Disposition 5755/96 (8 + 69 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.

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

administrative purposes.

PERUProducts 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: 45-90 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)

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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.

CHILEReview 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.

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MIDDLE EAST AFRICAExpected 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 it ti ith th ti l l k d li ith th ifi blsituation with the particular clerk dealing with the specific problem.

EGYPT 255 WD (357 CD)

Drug Registration process depends on the status of the product (Brand or generic; imported, locally or Toll manufactured). Generally, MA procedure takes around 12-18 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 ).

SAUDI ARABIA

10 + 245 WD

Target performance timeline from the date of acceptance to SFDA decision is of 290 days (10 days validation + 245 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 clinicalMRA/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 A t li d Si d l ) iAustralian 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

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ASEAN COUNTRIES *THAILANDThe timeframe for new drug registration is approximately 210 WD + 70 if submitted to

VIETNAMWithin 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

MALAYSIA12 months for hard copy submissions, 6 months for online submissions.Average length for entire process

subcommittee. The estimated actual time spent for registration is ranging from 10-24 months depending on the quality of the information and the completeness of the documents.

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for entire process is 6 to 12 months.(not officially stated)

* Excluding: Myanmar, Cambodia, Laos, Brunei DarussalamSINGAPORE – INDONESIA – PHILIPPINESHave adopted a registration system that relies on product assessment and approval of other competent Drug regulatory Agencies

INDONESIA – SINGAPORE – PHILIPPINES 3 distinct review processes and timelines

INDONESIA SINGAPORE PHILIPPINES

Path III – 300 working days Full dossier – 270 working days 220-600 working daysPath III 300 working days Products that have not been approved by any competent regulatory agency

Full dossier 270 working daysProducts that have not been approved by any drug regulatory agency at the time of submission

220 600 working daysProducts that have not been approved by any 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

Abridged dossier – 180 (NDA) or 240 days (GDA)Products that have been evaluated and approved by at least one drug regulatory agency

•150-180 working daysProducts that have already received approval from other agencies with whom the Philippines signed a MRA

Path I – 100 days Verification dossier – 60 (NDA) or 120 130 to 210 working days. For generic products/copy drugs (essential drug for Government program) that do not required non-clinical 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

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ASIAN COUNTRIESExpected RA Review Time for MAA Standard Review

CHINA 30 + 250 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 (March 2011), the g g y ( ),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 1 + 180 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 p rposes The aim is to establish harmonised s bmission proced res hichtesting purposes. The aim is to establish harmonised submission procedures, 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 10 + 360 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.

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WHAT MAKES AGENCIES’ REVIEW TIMELINES SO DIFFERENT ?

• Agency’s maturity and experience– Reliance upon assessment conducted by bench mark p y

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)• N of submissions (crf. Agency s performance targets)• For each Agency/Country the granularity of information

varies

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Conclusion

How Transparent are Regulatory Agencies with regard to Review Timelines?

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Conclusion

• Information on legislated review timelines is available for most of the Agencies considered

• Explicit information for some countries, customers’ practice-based 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, SFDAreview 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?

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ReferencesArgentina: 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 32.092, 15 February 2011Australia: 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 f 1 M h 2011) J 2011 (Th ti G d R l ti 1990 C lid t d V i f 29 O t 2010)TGA from 1 March 2011), Jan-2011; (Therapeutic Goods Regulations 1990, Consolidated Version as of 29-Oct-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-2011Peru: Law 29316: Amends Adds and Regulates Provisions to Implement the United States-Peru Trade Promotion Agreement 13-Jan-Peru: Law 29316: Amends, Adds and Regulates Provisions to Implement the United States-Peru Trade Promotion Agreement, 13-Jan-

2009 Saudi Arabia: Guideline: Regulatory Framework for Drugs Approvals, Version 4, Jun-2009South 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-2011USA: FDA’s Guidance for Review Staff and Industry: Good Review Management Principles and Practices; The Food and Drug

Administration Amendments Act of 2007 (FDAAA)

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OTHANK YOU

rosanna.melchior@thomsonreuters.com

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