Workshop K Parallel review experience of vacine by two authorities (Thailand & India): benefits for providers/recipients & lessons learned

Presented by : Prapassorn.T, FDA*, ThailandSurinder Singh, CDSCO, DCG(I), India

International Conference of Drug Regulatory Authorities (ICDRA)

Singapore, 29 Nov.3 Dec.2010

•Thailand Food Drug Administration•** Drug Controller of India•*** Central Drug S

BackgroundBackground• WHO has developed a programme to strengthen

National Regulatory Authorities (NRAs)for Vaccines and Biologicals since 1996 following a five steps capacity building programme: benchmarking, assessment, developing plan, providing technical support, implementation of plan, and monitoring and evaluation.

• WHO conducted NRA assessments in 101 countries between 1997 and 2010.

• In Aug 2007 and Oct 2008 respectively both NRAs (India and Thailand) where re-assessed to allow vaccine prequalification.

• Findings recommended to strengthen vaccine evaluation process and skills & to identify functional NRAs to assist in a capacity building programme.

Parallel Review as defined by WHO Parallel Review as defined by WHO

“Parallel review implies the coordinationbetween two NRA one name the Leading NRAand the second named the Recipient NRA,leading NRA will have the duty to providescientific opinion about the submission madeto the recipients NRA, WHO will act as afacilitator and not participant in the scientificreview process. The framework is coordinatedby WHO.”

1. Work under the WHO framework and sign confidentialityagreement.

2. CTD must be used and implemented in both NRAs3. WHO will act as a facilitator and not participle in the

scientific review process.4. It implies the coordination between two NRA One name

"the leading NRA" and the second name "The RecipientNRA".

5. Leading NRA will provide scientific opinion re submissionmade to the recipients NRA

6. Both NRA are bound to participate Application & Scientificreview managed electronically through WHO web site(SharePoint) only.

7. Comply with the proposed time lines and consistent withconcerned NRA regulations.

Terms of References of the Parallel ReviewTerms of References of the Parallel Review

Recipient NRA Leading NRA Vaccine reviewed Manufacturer(applicants)

Thailand Food Drug Administration (TFDA)

Therapeutic Goods Administration (TGA), Australia

Japanese Encephalitis vaccine

GPO-MBP Sanofi Pasteur, Thailand.

India: Central Drug Control Organization (CDSCO)

Biologicals and Genetics Therapies Directorate (BGTD), Health Canada

Meningococcal A Conjugate Vaccine

Serum Institute of India (SII), Pune, India.

Facilitator & Coordinator of the framework and process: World Health Organisation (WHO), Geneva, Department of Immunization, Vaccines & Biologicals (IVB), Quality Safety & Standards (QSS)

Participants: Recipients NRA, Leading NRAs, Facilitator

Participants: Recipients NRA, Leading NRAs, Facilitator

Parallel Review:Thailand experience & lessons learned

Thailand, TFDA – Recipient NRA• Mr.U.Vinit, Director Drug Control Div , Project Superviser • Mrs.L.Tasanee and Mr.P. Morakot, TFDA, Product Team Leader on Quality• Mr.A.Pramote and Mr. L. Kritsada, TFDA, Product Team Leader on Non

clinical• Mrs.T. Prapassorn and Ms.T. Jaruwan, TFDA, Product Team Leader on

Clinical• Dr. L. Yupin, Leader on SPC and product labelingAustralia, TGA: Leading NRA • Dr Mohammed Alali: Quality expert.• Dr Philip Harrison: Non clinical expert.• Dr Graham Dickson: Clinical expert.

World Health Organisation (WHO): facilitator & coordination of the process

• Dr Manfred Hasse, former PEI expert, short term consultant; Germany

• Dr Marion Gruber: Non clinical expert. US, FDA/CBER, temporary adviser

• Dr Jeff Roberts, Clinical expert, US, FDA/CBER, temporary adviser• Mr.Lahouari Belgharbi, project manager of the parallel review process• Mr. Stephane Guichard, WHO/SEARO, Bangkok, regional facilitator.• Dr.Anil Chawla, WHO/SEARO, Delhi, India, Regional facilitator• Dr.David Wood, Coordinator QSS.

Parallel review of Japanese encephalitisvaccine

Coordination &Financial

support

Thailand: Focal Persons in Parallel Review Process

Thailand: Focal Persons in Parallel Review Process

OSSC Receiving center Centralized registrationCheck & distribute the file to the Drug Control Division: 26 Jun 09

Drug Control Division – HQ - Nonthaburi

CTD

Vaccine Licensing Process : Thailand

MA Dossier (CTD)

Processing + Screening + Validating: 30 Oct 09

preliminary & in-depth assessment of Quality, Non-Clinical & Clinical aspects by TFDA PTL and appropriate external experts according to Guidelines: 30 Nov 09

Non Clinical & Clinical Quality

1.Evaluate non clinical data: 12 Apr/ 21 Jun 102.Evaluate pivotal clinical studies (phase I, II & III): 7 Apr/ 6 Oct10

3.For imported product: Evaluate CTs for Thai population 4.Verify product monograph, SPC, PL & labelling information supported by clinical data: 18 Jun/ 6 Oct 10

5.Evaluate Pharmacovigilance plan: 10 Jun/ 6 Oct 10

Evaluate Chemical/Pharmaceutical/Biological data + Manufacturing: 7 May/8 Oct 10

Consistency testingBy NCL:5 Apr 10 Inspection

By GMP Inspectors:27 Aug 10

Vaccine Licensing Process: Thailand

Product team leaders(internal assessors)+ external experts-Start reviewing process: 30 Nov 09-Adopt List of Q sent to applicant:24 Feb10-Reply from applicant: 26 Feb 10-Send to external experts: 31 Mar 10

Meeting

Questionsto applicants:

10 Jun 10

Quality: 7 May 10

Non-clinical: 12 Apr 10

Clinical: 7 Apr 10

Pharmaco-Vigilance (SMP): 10 Jun 10

SPC& Product labelling:18 Jun 10

Preliminaryassessment

Reply fromApplicant:17 Jun

10

Quality: 8 Oct 10

Non-clinical: 21 Jun 10

Clinical:6 Oct 10

Pharmaco-Vigilance (SMP): 6 Oct 10

SPC& Product labelling: 6 Oct 10

In depthassessmentI II

Final Assessment report: 21 Oct 10

Vaccine Licensing Process: Thailand• Guidelines: two national guidelines +

International guidelines (WHO, EMA, USFDA)

• Full submission: Final screening & validating : 30 Oct 2009

• Start reviewing process: 30 Nov 2009• Legal timeline:

-Fast track review: 280 working days-Standard review: 480 working days

• Expected due date for MA: 2 Mar 2011• Assessment completed by: Oct 2010 • Decision to license : 29 Oct 2010= 228 WD

with Post approval commitment

Product specifications• JE Vaccine : live attenuated recombinant SA14-14-2 strain of JE

virus propagated on vero cell• Trade name: IMOJEV• Dosage form: Freeze dried vaccine to be diluted in diluent (0.4% NaCl

soln). -Colorless to amber suspension after reconstitution. -Each dose (0.5 ml) contains:Live, attenuated, recombinant Japanese encephalitis virus: 4.0 -5.8 log PFU

• Shelf life: 3 years when stored in refrigerator at 2-8o C• Indication: For prophylaxis of JE caused by JE virus in subjects from

12 months of age and over• Dosage & administration: 1 single dose (0.5 ml) via SC• Contraindication: Pregnancy & lactation, immune deficiency subjects,

persons with symptomatic and asymptomatic HIV infection.• Applicant (Manufacturer & MAH): GPO-MBP, Thailand• Product Owner: Sanofi pasteur, France

National expertiseSupervisor : U.Vinit, Director Drug Control Div.

• Quality aspect: *TFDA PTL:Tasanee L & Morakot P.*External experts:-Group of Experts from NCL, DMSc-2 Experts from Academic Institutions 1.Assoc Prof Dr Wilai N. from Faculty of Sciences, Mahidol U. 2.Adjunct Prof Dr Maneewan S. from Faculty of Pharmaceutical Sciences, Chulalongkorn U.

• Non clinical aspect: *TFDA PTL: Pramote A.& Kritsada L.*External experts: -Assoc Prof Dr Nongluck S., Faculty of Pharmaceutical Science, Mahidol U.-Assoc Prof Sopit T., Faculty of Medicine, Chulalongkorn U.

• Clinical aspect: *TFDA PTL: Prapassorn T. & Jaruwan T.*Externa l experts:-Assoc Prof Dr Chantapong W., Department of Virology, Faculty of Medicine, Siriraj Hos, Mahidol U.-Dr Piyanit T., EPI Program Manager, DDC, MOPH

• SPC & product labeling: Dr Yupin L.

Lessons learned (I) 1. Became more knowledgeable in scientific background

on all aspects (Q, S & E) related to JE vaccine .2. Became more confident and able to select appropriate

international guidelines i.e WHO. TGA, EMA & CBER/USFDA as source references in reviewing JEV.

3. Able to implement and review full CTD.4. Increased credibility and confident in making

scientific justification.5. Increase good networking and information exchange

system among Australia, USA and Thailand.6. Need minimum funding to support activities (100%

supported by WHO), possibilities of fees to be included in the application submission as WHO do not want to be funded to avoid potential conflict of interest.

Lessons learned (II) 7. Became more knowledgeable in writing full

assessment report at international standard8. Able to put in place of practical knowledge

through good net working with international experts from TGA and CBER/USFDA

9. Able to sustain good cooperation and technical consultation with immediate response from international experts

10. NRA assessment and institutional Development Plan are key for initiating such activity and address technical gaps

Recommendations (I)

1. Would strongly recommend and request WHO for continued support in providing parallel review for other new vaccines in the future (Dengue, HIV, Malarial Vaccines)

2. Would encourage other NRAs to seek support from WHO for parallel review as evidently proved by following reasons:

2.1 Parallel review is a trustworthy pathway introduced by WHO, with design to protect and safeguard confidential nature of documents.

Recommendations (II)

2.2 Parallel review is very useful regulatory pathway to strengthen DCVR in reviewing vaccines for MA

2.3 Parallel review is very unique IT system with introduction of reliable sharepoint to allow uploading of documents and facilitating communication among stakeholders

2.4 Parallel review provides good opportunity for DCVR to become familiarize with licensing system of developed countries like Australia and US

2.5 Parallel review provides mutual understanding among NRAs by having WHO as coordinator and facilitator

Parallel Review:Indian experience & lessons learned

•Mumbai

New Delhi

Chennai

CDSCO North Zone (Ghaziabad)

Kolkata.

CDSCO West Zone (Mumbai)

CDSCO South Zone (Chennai)

CDSCO East Zone (Kolkata)

CDSCO, HQCDSCO, HQCDSCO – Geographical Location Zonal /Sub ZonalOffices(9)

•Hyderabad

Ahmadabad

Port Offices/Airports : 11Laboratories : 8Port Offices/Airports : 11Laboratories : 8

29 States

6 Union Territories

29 States

6 Union Territories

CDSCO Zone (Ahmadabad)

CDSCO Zone (Hyderabad)

•Proposed Zonal/Sub Zonal Offices (3) :•Guwahati, Indore, Goa

CDSCO Sub Zone (Bangaluru)

Bangaluru

Ghaziabad

CDSCO Sub Zone (Chandigarh)

Chandigarh

Jammu

CDSCO Sub Zone (Jammu)

India, 2010

Vaccines from India are

exported to more than 151 countries

Indian National Regulatory Authority (Status from 2007 to 2009)

WHO H.Q. conducted NRA assessment in India : 2001, 2004,2007 & 2009.

In year 2007- WHO observed that the Indian NRA was non-compliant tonumber of critical and non-critical indicators of assessment tools.

In January 2008 – WHO put Embargo on pre qualification of any newerapplications from India due to disqualification of NRA.

March 2008- WHO facilitated establishment of collaborative workingrelationship between Indian NRA and Health Canada to strengthen itsregulatory capacity .

13th April to 17th April, 2009- WHO NRA assessment of Indian NRA .

On 9TH July 2009- WHO re-qualified the Indian NRA and declared IndianNRA again functional against the WHO NRA published indicators.

CAPACITY BUILDING OF NRA

Parallel review : training

NRA assessment

New building

Electronic management &Improved facilities

Establishment of the Biological DivisionStrengthening of Biological Staff

Jan.2008

March2008

July2008

Sept.2008

Dec.2008

Before : No CTD for registration

2 Officers (TO/DI)1 TDA, 1 DEO

Biological division is being constantly strengthened

Training AbroadCanada

In country training

March2009

July2009

Training abroadWHO Geneva &

Canada

NRA functionalNRA functionalNRA assessed as not functional against WHO NRA indicatorsNRA assessed as not functional against WHO NRA indicators

Present status: 30 staff,2 Deputy Drug Controllers, 4 Ast.Drugs Controllers, 7 officers (TO/DI),

12 TDAs & 5DEOs

In country training

Establishment of the Biological DivisionStrengthening of Biological Staff

Dec.2007

March2008

July2008

Sept.2008

Dec.2008

Before : NO CTD forregistration

Development of documentation & quality management system

Guidance for Industry published4th Dec, 2008

March2009

July2009

NRA functionalNRA functionalNRA assessed as not functional against WHO NRA indicatorsNRA assessed as not functional against WHO NRA indicators

After: CTD implemented for all Biologicals

Module I: Administration/Legal Information

Module II: Overall Summaries of Module III, IV & V

Module III: Quality Information (Chemical, Pharmaceutical and Biological)

Module IV: Non-Clinical InformationModule V: Clinical Information

Preparation of the Quality Information for Drug Submission for New Drug

Preparation of the Quality Information for Drug

Submission for New Drug Approval:

Biotechnological/Biological Products

SOPS for evaluation for marketing authorisation & clinical trials

Development/Update of Institutional Development Plan

Recipient NRA Leading NRA Vaccine reviewed Manufacturer(applicants)

Thailand Food Drug Administration (TFDA)

Therapeutic Goods Administration (TGA), Australia

Japanese Encephalitis vaccine

GPO-MBP Sanofi Pasteur, Thailand.

India: Central Drug Control Organization (CDSCO)

Biologicals and Genetics Therapies Directorate (BGTD), Health Canada

Meningococcal A Conjugate Vaccine

Serum Institute of India (SII), Pune, India.

Facilitator & Coordinator of the framework and process: World Health Organisation (WHO), Geneva, Department of Immunization, Vaccines & Biologicals (IVB), Quality Safety & Standards (QSS)

Participants: Recipients NRA, Leading NRAs, Facilitator

Participants: Recipients NRA, Leading NRAs, Facilitator

Parallel Review Process: PRODUCT Vaccine- Meningococcal A Conjugate Vaccine Lyophilized (MenAfrivac)manufactured by Serum Institute of India, Pune.

Quantitative composition:-Each dose of 0.5 mL contains:

Composition QuantityMeningococcal A polysaccharide 10 mcgTT (carrier protein) 10-33 mcgManitol 2.85mgSucrose 0.72mgTris (hydroxymethyl) aminomethane 0.05mgWFI q.sDiluentAl3+++ as AlPO4 (Adjuvant) 0.6mg Al+3

Thiomersal (Preservative) 0.01%Sodium Chloride 0.09%WFI q.s.

Dose and Administration:- Single dose of 0.5mL for Intramuscular useIndication:- For active immunization against invasive meningococcal disease caused by meningococcal group A only for the age group of 1 to 29 years of age.

India, Canada & WHO:Focal Persons in Parallel Review Process

India, Canada & WHO:Focal Persons in Parallel Review Process

CDSCO IndiaManagers/Supervisors

• Dr. Surinder Singh, DCG(I)• Mr. S.P. Shani, ADC(I)• Ms. Swati Srivastava, DI• Dr. I.S.Hura,TO

Review Team Headed by DCG(I)• Mr. S.P. Shani, ADC(I)• Ms. Swati Srivastava, DI• Dr. I.S.Hura,TO• Mr. Sandeep Kumar, TDA• Mr. Arun Mishra, TDA• Ms. Garima Singh, TDA

Review Team at NCL (CDL Kasauli)

• Dr. Arun Bhardwaj• Ms Kiran Pandey • Mr. Sunil Goel

BGTD Health Canada (as on the share point)

1. Dr. Dean Smith 2. Dr. Tong Wu3. Dr. Joanne Xiong 4. Dr. Ghosh Basanti 5. Dr. Sherri Boucher 6. Dr. Miga Chultem 7. Dr. Gina Coleman 8. Dr. Elwyn Griffiths 9. Dr. Farid Hindieh 10. Dr. Agnes Klein 11. Dr. Huw Lloyd 12. Dr. Meera Makim 13. Dr. Cathy Parker 14. Dr. Abdou Rahman

World Health Organisation 1. Mr. Lahouari Belgharbi, WHO/HQ, project manager2. Dr. Anil Chawla, WHO SEARO, TIP3. Dr.Nora Dellepiane, WHO HQ, team leader VQR4. Dr. David Wood, WHO HQ, Coordinator QSS

Sharing information through NRA WHO Share Point:Sharing information through NRA WHO Share Point:

Activity Time Frame decided Responsibility Activity done

Permission to Export the indigenously developed Vaccine to African Countries

After submission of complete report of Phase II/III study (India) of vaccine developed from Importedpolysaccharide and safety data of Phase II clinical Trial in infants (Africa) with indigenously developed vaccine

Serum Institute of India Ltd. & CDSCO

Permission to Export the indigenously developed vaccine to African Countries granted on 23rd Dec, 2009

The Meningococcal A conjugate vaccine (MenAfriVac, produced by theSerum Institute of India Ltd.) was prequalified by WHO on 23 June2010. This is the first meningococcal A conjugate vaccine to beprequalified by WHO.

Time Frames Followed in consultation with WHO & Health CanadaMain outcome: Vaccine Prequalified started in Dec.2009 based on parallel review outcome, then prequalification

completed in June 2010

Main outcome: Vaccine Prequalified started in Dec.2009 based on parallel review outcome, then prequalification

completed in June 2010

Benefits of Parallel review Benefits of Parallel review

1. Exchange of Scientific Knowledge about the review process.

2. Identifying the gaps in review process

3. Learning of product and process review during the on-site evaluation

4. Interaction and Dialogue through Teleconferences to gain level of

confidence.

5. Exchange of Scientific Knowledge about the review process.

6. Identifying the gaps in review process

7. Learning of product and process review during the on-site evaluation

8. Interaction and Dialogue through Teleconferences to gain level of

confidence.

Thank you for your attention