WHO Prequalification of Medicines Programme - Indian ...

WHO Prequalification of
Medicines 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, 27 th September, 2012, Mumbai

UN Prequalification Programme
for 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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5 th Invitation for EOI, May 2010
Reproductive health medicines (1)
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3 rd Invitation for EOI
Active Pharmaceutical Ingredients
Therapeutic area
HIV/AIDS
Malaria
Tuberculosis
Invited Active Pharmaceutical Ingredients
Abacavir, Atazanavir, Darunavir, Didanosine, Efavirenz, Emtricitabine,
Etravirine, Lamivudine, Lopinavir, Nelfinavir, Nevirapine, Raltegravir,
Ritonavir, Stavudine, Tenofovir, Zidovudine
Amodiaquine, Artemether, Artesunate, Dihydroartemisinin,
Lumefantrine, Mefloquine, Piperaquine, Pyrimethamine, Pyronaridine,
Sulfadoxine
Amikacin, Capreomycin, Cycloserine, Ethambutol, Ethionamide,
Isoniazid, Kanamycin, Levofloxacin, Moxifloxacin, Ofloxacin, Para-
Aminosalicylic Acid (PAS), Prothionamide, Pyrazinamide, Rifampicin,
Streptomycin, Terizidone
Reproductive
health
Neglected tropical
diseases
Desogestrel, Estradiol, Ethinylestradiol, Etonogestrel, Levonorgestrel,
Medroxyprogesterone, Mifepristone, Misoprostol, Norethisterone,
Norgestrel, Oxytocin
Diethylcarbamazine, Mebendazole
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Two prequalification routes
Invitation for
expression of Interest
Expression of Interest
Medicine not
assessed by SRA
Medicine assessed
by SRA
Dossier and SMF
submitted for assessment
WHO assessment
and inspections
organized
Valid for innovators and generics
SRA registration
(assessment and
compliance check)
Simplified review
Compliance Prequalification Acceptance
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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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Steps in WHO prequalification
I
Expression
of Interest
Assessment
Additional information
and data
Compliance
Product dossier
SMF
Prequalification
Inspections
Corrective
actions
Compliance
Maintenance and monitoring
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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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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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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)
Regional
Admin
Information
Module 1
Not Part of
the CTD
Module 2
Quality
Overall
Summary
Nonclinical
Overview
Nonclinical
Summary
Clinical
Overview
Clinical
Summary
The CTD
Quality
Nonclinical
Study Reports
Clinical
Study Reports
Module 3 Module 4 Module 5
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Demonstration of bioequivalence
Bioequivalence study
or
PD studies
Clinical
studies
ONLY EXCEPTIONAL!
In vitro
methods
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WHO BCS-based biowaiver
Active substances selected for biowaiving
by 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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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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Outcomes of PQ procedure
Information 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 medicines
1 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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TBS
2,
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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
Manufacturers:
assistance
• 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 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
Interested NMRAs agree
to participate in the procedure
PQP lists committed NMRAs
on its website
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Steps of the procedure: registration
PQ product is submitted for national registration
to NMRA participating in the procedure
NMRA is informed about the interest to follow PQP
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
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Win-win 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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Expert Review Panel (ERP)
• 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 SRAauthorized
• 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
ERP status does not replace WHO PQ/SRA approval
but should be seen as a step towards WHO PQ/SRA approval
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Products reviewed by the ERP since 2009
Data 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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Reported Procurement information
http://www.theglobalfund.org/en/procurement/pqr/
Over 1, 400 million* US$ of transactions reported in the PQR system
• Products/Manufacturers distribution
ARV
Branded:
34%
Antimalarial
Branded:
70%
anti-TB
Branded:
22%
Generic:
66%
Generic:
30%
Generic:7
8%
Sophie Logez, GFATM, March 2011
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COUNTRIES RECEIVING COMMODITIES
US$1.1Billion UNITAID funds
HIV / AIDS
51 recipient
countries
Malaria
29 recipient
countries
> US$600 mil > US$300 mil
Tuberculosis
76 recipient
countries
> US$200 mil
- Cross cutting programs: US$109 m for PQ of drugs &
diagnostics and transversal programs
Lorenzo Witherspoon, UNITAID, March 2011
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What kind of investments does a company have
to 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
Inexperienced
Bioequivalence
Dossier Preparation
Capital
High
High
High
Local manufacturer
Bioequivalence
Dossier Preparation
Capital
Medium - High
Medium
Low - Medium
Global company
Bioequivalence
Dossier Preparation
Low
Low
Capital $ 0
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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,
sawyerj@who.int
• Dossier submission and assessment: Dr Matthias Stahl, Head
of Assessments, stahlm@who.int
• Prequalification of APIs: Dr Antony Fake, fakea@who.int
• Inspections: Ian Thrussell, Head of Inspections,
thrusselli@who.int
• Training and technical assistance: Dr Milan Smid,
smidm@who.int
• Prequalification of medicines quality control laboratories: Dr
Jitka Sabartova, sabartovaj@who.int
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Thank you for the attention
smidm@who.int
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