who prequalification of medicines programme
TRANSCRIPT
WHO Prequalification of WHO Prequalification of Medicines ProgrammeMedicines Programme
General overview and update
Milan Smid, M.D., Ph.D.Slides benefiting from presentations of WHO PQP colleagues and BioBridge Strategies
WHO PQP tutorial, 27th September, 2012, Mumbai
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PQP updateMumbai, 27 Sept, 2012
UN Prequalification Programmefor Priority Essential Medicines
Action plan of UN from 2001 for expanding access to selected priority medicines
Objective: • To ensure quality, efficacy and safety of medicines
procured using international funds (e.g. GFTAM, UNITAID) to serve patients in developing countries
Components:• Evaluation of Quality, Safety and Efficacy of prioritised Essential
medicines (FPPs and APIs), inspections of manufacturers and monitoring of the products after their prequalification.
• Prequalification of quality control laboratories. • Building capacity of regulators, manufacturers and quality control
laboratories.
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Categories of medicines invited• Primary categories of medicines:
– HIV/AIDS– Malaria– Tuberculosis
• Later added:– Reproductive health– Influenza– Acute diarrhoea– Neglected tropical diseases
• Potentially other categories of products, if there is the need
• Prequalification also applicable for APIs!
• Published in invitations for Expression of Interest (EOI) on Prequalification website
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5th Invitation for EOI, May 2010Reproductive health medicines (1)
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3rd Invitation for EOIActive Pharmaceutical Ingredients
Invited Active Pharmaceutical IngredientsTherapeutic area
Abacavir, Atazanavir, Darunavir, Didanosine, Efavirenz, Emtricitabine, Etravirine, Lamivudine, Lopinavir, Nelfinavir, Nevirapine, Raltegravir, Ritonavir, Stavudine, Tenofovir, Zidovudine
HIV/AIDS
Amodiaquine, Artemether, Artesunate, Dihydroartemisinin, Lumefantrine, Mefloquine, Piperaquine, Pyrimethamine, Pyronaridine, Sulfadoxine
Malaria
Amikacin, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Kanamycin, Levofloxacin, Moxifloxacin, Ofloxacin, Para-Aminosalicylic Acid (PAS), Prothionamide, Pyrazinamide, Rifampicin, Streptomycin, Terizidone
Tuberculosis
Desogestrel, Estradiol, Ethinylestradiol, Etonogestrel, Levonorgestrel, Medroxyprogesterone, Mifepristone, Misoprostol, Norethisterone, Norgestrel, Oxytocin
Reproductive health
Diethylcarbamazine, MebendazoleNeglected tropical diseases
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Expression of Interest
Dossier and SMF submitted for assessment
Two prequalification routes
Medicine assessedby SRA
Medicine notassessed by SRA
WHO assessmentand inspections
organized
Compliance Prequalification Acceptance
Simplified review
Valid for innovators and generics
SRA registration (assessment and
compliance check)
Invitation for expression of Interest
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Essential steps of PQ evaluation procedure
• Need is specified and agreed by WHO treatment programmes• Invitation for Expression of Interest (EOI) is published • Interested parties submit dossiers – 'Expression of interest'• Dossiers receive initial screening• Full dossiers are assessed• Inspections are conducted at manufacturing sites and at CROs• Samples are tested, if needed• If outcome is positive, pharmaceutical product is listed on the
website, including product information (SPC, PIL), assessment report (WHOPAR) and inspection report (WHOPIR)
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Expressionof Interest
Compliance
Additional informationand data
Correctiveactions
Compliance
Assessment Inspections
Steps in WHO prequalification
Prequalification
Maintenance and monitoring
Product dossierSMF
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PQP updateMumbai, 27 Sept, 2012
Essential steps of monitoring of PQ product
• Variations to the dossier of prequalified product
• Sampling and Testing
• Re-inspections
• Requalification
• Management of complaints
• De-listing or suspension (if and when appropriate)
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Principles
• Same principles apply as for national regulatory approvals by stringent authorities
– Data on quality (FPP, API)
– Data on efficacy and safety or interchangeability
– Compliance with GMP (FPP, API), GCP/GLP (bioequivalence studies)
– Benefits prevail risks
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PQP updateMumbai, 27 Sept, 2012
Assessment of product dossiers
• One week meeting at least every 2 months, team of professionals from NMRAs– Botswana, Canada, China, Congo, Ethiopia, France, Georgia, Germany,
Ghana, Israel, Italy, Kenya, Malaysia, Netherlands, New Zealand, Portugal, Singapore, Spain, South Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zambia, Zimbabwe ...
• Combined with capacity building• Quality assurance of outcomes
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PQP updateMumbai, 27 Sept, 2012
Inspections• Team of inspectors for each inspection
• WHO PQ inspector plus PIC/S member country plus local country inspector (observer)
• Some cases – capacity building (recipient country)
• Preparation includes SMF, product information, inspection reports, complaints etc
• Inspections are product oriented and include data verification
• APIs and Bioequivalence studies inspected based on risk assessment
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Standards• WHO standards as defined in WHO guidelines are applied in
prequalification process
• If these not exist, ICH guidelines are applied
• In case of need, guidelines of stringent regulatory authorities involved in ICH process
• Pharmacopoeias (Ph.Int., USP, BP, Ph.Eur., JP) as minimum standard – Depending on product, assessors may ask for additional tests or
tightening limits
• WHO GMP guidelines (compatible with PIC/S; references to pharmacopoeias, e.g. harmonized monographs)
• WHO GCP guidelines + Additional guidance for organizations performing in vivo bioequivalence studies (compatible with ICH)
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Adapting the CTD-NDS (new drug) to CTD-ANDS (generic)
RegionalAdmin
InformationModule 1
NonclinicalOverview
NonclinicalSummary
ClinicalOverview
ClinicalSummary
QualityOverall
Summary
Quality NonclinicalStudy Reports
ClinicalStudy Reports
Module 3 Module 4 Module 5
Module 2
Not Part ofthe CTD
The CTD
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Demonstration of bioequivalence
PD studies Clinicalstudies
In vitromethods
Bioequivalence study
ONLY EXCEPTIONAL!
or
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WHO BCS-based biowaiver
Active substances selected for biowaivingby WHO
HIV/AIDS:• Lamivudine (BCS 3)• Stavudine (BCS 1)• Zidovudine (BCS 1)• Abacavir sulphate
(BCS 3)• Emtricitabine (BCS 1)
TB:• Levofloxacin (BCS 1)• Ofloxacin (BCS 1)• Ethambutol ((BCS 3)• Isoniazid (BCS 3)• Pyrazinamide (BCS 3)
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PQP updateMumbai, 27 Sept, 2012
Time to PQP Approval• The time to PQP approval can vary significantly but is influenced
principally by the quality of the application and company response time
• The mean time to approval in 2011 was 24 months– 8.4 months PQP processing time (35%)– 15.6 months manufacturer response time (65%)
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PQP updateMumbai, 27 Sept, 2012
Outcomes of PQ procedureInformation in public domain:
http://www.who.int/prequal/• List of PQ medicinal products• WHOPAR (SPC, PIL, labelling)• WHOPIR (both FPP and API)• Notices of Concern and Suspensions• Information on progress of assessment procedure and
inspections • Supportive documents: WHO guidelines, description of
PQ procedure, training materials
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Prequalified medicines1 June 2012
+ 93 listed based on the– approval by US FDA = 16 (HIV only)– tentative approval by US FDA = 73 (HIV only)– approval within Canada's Access to Medicines Regime = 1 (HIV)– approval by EMA according to Article 58 = 3 (2 HIV + 1 Malaria)
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Prequalified medicines according to countries of manufacture (1 June 2012)
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Capacity building - objectives• Good quality submissions for PQ supported by
compliance with "good practices"– platform for improvement of drug development, manufacturing,
documentation and quality control• Fast regulatory approvals of PQ medicines in recipient
countries– technical education of regulators as a platform for strengthening
expertise, regulatory efficiency and networking• Reliable quality monitoring
– technical education of staff of QCLs to strengthen expertise, effectiveness of quality monitoring and networking
PQP standards and PQP example support strengthening of regulatory systems and capacity of manufacturers in general
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PQP updateMumbai, 27 Sept, 2012TBS
, Nov
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Technical Assistance• Provision of expert consultants to
– Manufacturers – Quality control laboratories– Regulators
• Assistance focuses on – GMP, GCP or GLP compliance– Dossier development
• Assistance is separated from the assessment / inspections and may be followed by specific trainings
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Conditions for provision of technical assistance
Manufacturers:• Participation in the prequalification programme,• Found to be capable and willing to improve• Location in a developing country
Products:• Inclusion in the list of expression of interest• High value for Public Health purpose • Poor representation on the Prequalification list.
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Technical assistances in countries
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Frequent misunderstandings• Manufacturers/manufacturing sites are
prequalified• PQP issues WHO GMP certificates• PQP provides direct financial support• Prequalification gives right to succeed in tenders• PQ substitutes national authorization
(registration) in recipient countries• All medicines used in treatment of HIV/AIDS and
tropical diseases are invited for PQ• Prequalified medicines may bear WHO logo
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Principles of proposed processPrinciples of proposed process• Availability of PQP assessment, inspection outcomes and
advice to facilitate national regulatory decisions making (registrations, variations, withdrawals)
• No interference with national legislation, decision making process and regulatory fees
• Co-operation among product manufacturer (PQP holder), NMRA in interested country and PQP to overcome confidentiality issues and assure information flow
• Procedure applicable for individual products
• Procedure voluntary for manufacturers and NMRAs
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Steps of the procedure: agreement Steps of the procedure: agreement
Interested NMRAs agree to participate in the procedure
PQP lists committed NMRAson its website
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Manufacturer informs PQP about national submission and
gives consent with information sharing
Participating NMRA confirms its interest to participate in procedure for specific product
PQP shares with participating NMRA outcomes of assessment and inspections
Participating NMRA reviews WHO PQP outcomes, decides within 90 days decides upon the national registration and informs PQP about its decision
Steps of the procedure: registrationSteps of the procedure: registrationPQ product is submitted for national registration
to NMRA participating in the procedureNMRA is informed about the interest to follow PQP
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PQP updateMumbai, 27 Sept, 2012
WinWin--win outcomes for all stakeholderswin outcomes for all stakeholders• NMRAs
– Availability of WHO assessment and inspection outcomes to support national decisions
– Opportunity for learning from experienced assessors– Saving internal capacities– Demonstrating NMRA efficiency
• WHO– Prequalified medicines are faster available to patients
• Procurers– Faster start of procurement
• Manufacturers– Harmonized data for PQ and national registration– Facilitated interaction with NMRAs in assessment and
inspections– Accelerated registration
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• A panel of experts hosted by WHO since 2009• Assesses the potential risks/benefits associated with the
use of FPPs that are not yet WHO-prequalified or SRA-authorized
• Eligibility criteria for dossier submission: product manufactured in GMP compliant site and dossier submitted to and accepted for review by WHO PQP or a SRA
• Assesses abbreviated product dossiers submitted by manufacturers (questionnaire + annexes)
• Makes time limited recommendations: validity maximum 12 months-contracts can be signed any time up to one year
Expert Review Panel (ERP)Expert Review Panel (ERP)
ERP status does not replace WHO PQ/SRA approval ERP status does not replace WHO PQ/SRA approval but should be seen as a step towards WHO PQ/SRA approvalbut should be seen as a step towards WHO PQ/SRA approval
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PQP updateMumbai, 27 Sept, 2012
Products reviewed by the ERP since 2009Data from Dec 2011
• 5 rounds completed
• 348 product dossiers were submitted and reviewed by ERP;
• 69 products were permitted for use for a one year period;
• during the ERP period validity:– 30 products have been WHO prequalified– 7 products have been authorized by an SRA
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PQP updateMumbai, 27 Sept, 2012
Reported Procurement information http://www.theglobalfund.org/en/procurement/pqr/
• Products/Manufacturers distribution
ARV Anti-malarial
anti-TB
Branded: 34%
Branded: 70%
Branded: 22%
Generic: 66%
Generic: 30%
Generic:78%
Over 1, 400 million* US$ of transactions reported in the PQR system
Sophie Logez, GFATM, March 2011
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PQP updateMumbai, 27 Sept, 2012
HIV / AIDS51 recipient countries
Malaria29 recipient countries
Tuberculosis76 recipient countries
> US$600 mil > US$300 mil- Cross cutting programs: US$109 m for PQ of drugs & diagnostics and transversal programs
> US$200 mil
COUNTRIES RECEIVING COMMODITIESUS$1.1Billion UNITAID funds
Lorenzo Witherspoon, UNITAID, March 2011
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PQP updateMumbai, 27 Sept, 2012
What kind of investments does a company haveto make to in seeking prequalification of a product?
Bioequivalence
Formulation development
Stability studies
Dossier preparation
Capital
Clinical and analytical studies to validate the equivalence to the established comparator
If a company does not have a product on the market, it has to develop the formulation as specified by the EOI.
Stability studies have to be carried out on multiple batches of material for climatic zone IV
PQP requires CTD format of dossier and few additional specific documents and has well-defined requirements. The preparation and support require investment of personnel.
Money may be needed for investment in both R&D and manufacturing equipment as well as quality control systems. Capital is also needed for facilities upgrades and construction of new facilities.
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Investments varies depending on the experience of a company
Global companyBioequivalence Low
Dossier Preparation Low
Capital $ 0
InexperiencedBioequivalence High
Dossier Preparation High
Capital High
Local manufacturerBioequivalence Medium - High
Dossier Preparation Medium
Capital Low - Medium
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PQP updateMumbai, 27 Sept, 2012
Potential benefits for manufacturers• Participation in tender procedures organized by national and
international procurers and financial profit• Recognition as being WHO listed company• Demonstration of social responsibility • Facilitated registration in some recipient countries• Reduction of inspections from recipient countries• Possibility to be assisted by expert consultants (GMP, dossier,
BE)• Learning process improving company's chance to succeed
with submissions to SRAs• Identified sources of quality assured APIs• Potential additional incentives (pro-export and pricing policies)
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Who should you contact at the WHO Prequalification of Medicines Programme• General enquiries: Jacqueline Sawyer, Liaison Officer,
[email protected]• Dossier submission and assessment: Dr Matthias Stahl, Head
of Assessments, [email protected]• Prequalification of APIs: Dr Antony Fake, [email protected]• Inspections: Ian Thrussell, Head of Inspections,
[email protected]• Training and technical assistance: Dr Milan Smid,
[email protected]• Prequalification of medicines quality control laboratories: Dr
Jitka Sabartova, [email protected]