The IATT Optimal Paediatric ARV Formulary: Global
Perspective and Country Implementation
Summary
Introduction
WHO Paediatric ART recommendations
Rationale for Paediatric ARV Formulary Optimization
Revised Optimal and Limited-use Paediatric ARV formularies
Country level implementation
Q&A
Developed
IATT Overview Established in 1998 and included 5 UN agencies working in HIV and health
(WHO, UNICEF, UNFPA, UNAIDS, World Bank) 2003: membership expanded to include global partners in PMTCT and HIV care
and treatment in children (23 agencies currently involved) Provides a forum for:
Information sharing
Consensus building
What is the IATT? Intra-agency Task Team on Prevention of HIV Infection in Pregnant Women, Mothers and their Children
Paediatric Working Group
Child Survival Working Group
Infant feeding Working Group
Paediatric Working Group► Sub-committee of the main IATT
► Focused on issues related to paediatric care and treatment issues
► 2011 restructuring of IATT: consolidation of 2 working groups
+
IATT Subcommittees
Optimal Paediatric Formulary List
Agenda and Speakers► Introductions IATT Secretariat
► WHO Paediatric ART guidelines Martina Penazzato, IATT Secretariat, WHO
► Rationale for optimization UNICEF, Atieno Ojoo, IATT PSM WG, UNICEF
► Revised Optimal and Limited use list David Jamieson, IATT PSM WG, PFSCMS
► Implementation at country level Nandita Sugandhi, IATT CSWG, CHAI
► Q&A Session Marianne Guval, IATT CSWG, CHAI & Jessica Rodrigues, IATT Secretariat
Choosing a Preferred Paediatric Regimen: Many Options Possible
Children < 3 years
Children 3 years to < 10 years
Adolescents > 10 years
Preferred ABC + 3TC + LPV/r
orAZT + 3TC + LPV/r
ABC + 3TC + EFV
TDF + 3TC + EFV
Alternative
ABC + 3TC + NVPAZT + 3TC + NVP
ABC + 3TC + NVPAZT + 3TC + EFVAZT + 3TC + NVPTDF + 3TC (or FTC) + EFVTDF + 3TC (or FTC) + NVP
AZT + 3TC + EFVAZT + 3TC + NVPTDF + 3TC (or FTC) + NVP
But at the national program level fewer choices may be easier to implement:
• Simplifies guidance for HCW• Streamlines procurement and supply chain
WHO Recommendations on ARV Formulations
The principles that were followed in developing the WHO simplified tables include:
It is preferable to use an age-appropriate FDC for any regimen if available
Oral liquid or syrup formulations should be avoided especially if volumes are large
Dispersible tablets (or tablets for oral solution) are the preferred solid oral dosage forms
Young children should be switched to available solid oral dosage forms as soon as possible
Where adult formulations have to be used by children, care must be taken to avoid underdosing. Adult tablets that are scored are more easily split. For those tablets that are not easily split, WHO recommends that this be done in the dispensing pharmacy using appropriate tablet cutters.
Some tablets such as LPV/r heat stable tablets are made in a special embedded matrix formulation and should not be cut, split or crushed as they lose bioavailability.
Different dosing between morning and evening doses should be avoided.
Children have to be weighed at each clinic visit, and dose changes are required as children grow and/or gain weight.
Availability of Drug Formulations Impacts Implementation of Regimen Recommendations ► Two formulations of LPV/r are available: LPV/r
100 mg/25 mg heat-stable tablet for children >10 kg and LPV/r oral liquid 80/20 mg per 1 ml for use among infants.
► TDF is currently available in 3 different formulations for use across weight bands but a TDF-containing FDC is yet to be developed
Paediatric ARV Market is Small (but complex)
93 adult patients
All ages & weight bands
One pill, once-a-day
7 paediatric patients
Multiple ages and weight bands
Multiple formulations
There are Over 61 Different Paediatric ARVs on the Market
NRTI’s
ABCTablet (disp,scored) as sulfate 60 mg
ABC Tablet (scored) as sulfate 60 mgABC Oral liquid as sulfate 100 mg/5ml
AZT Tablet (disp, scored) 60 mgAZT Oral liquid 50 mg/5mlAZT Tablet (scored) 60 mgAZT Capsule 100 mgAZT Tablet 100 mg3TC Oral liquid 50 mg/5ml3TC Tablet (disp) 30 mg3TC Tablet 30 mgD4T Capsule 15 mgD4T Capsule 20 mgD4T Powder for oral solution 5 mg/5ml
DDICapsule (unbuffered, enteric coated) 125 mg
DDICapsule (unbuffered, enteric coated) 200 mg
DDITablet (buffered, chewable, disp) 25mg
DDITablet (buffered, chewable, disp) 50 mg
DDITablet (buffered, chewable, disp) 100 mg
DDI Powder for oral liquid (Buffered) 2g, 4g bottle
FTC Oral liquid 10 mg/ml
TDF Oral powder 40mg/scoopTDF Tablet (unscored) 150 mgTDF Tablet (unscored) 200mg
NNRTI’sEFV Tablet (scored) 200 mgEFV Tablet 50 mg EFV Tablet (unscored) 200 mgEFV Tablet (disp, scored) 100 mgEFV Tablet 100 mgEFV Capsule 50 mgEFV Capsule 100 mgEFV Capsule 200 mgEFV Oral liquid 150 mg/5ml
NVP Tablet (disp, scored) 50 mg
NVP Oral liquid 50 mg/5ml
NVP Tablet (disp) 100 mgETV Tablet 25 mg
ETV Tablet 100 mg
FDC’s
AZT/3TCTablet (disp, scored) 60/30 mg
AZT/3TC Tablet (scored) 60/30 mg
AZT/3TC/NVPTablet (disp, scored)
60/30/50 mg
D4T/3TC/NVPTablet (disp, scored) 6/30/50 mg
D4T/3TC/NVPTablet (disp, scored)
12/60/100 mg
D4T/3TC Tablet (disp, scored) 6/30 mg
D4T/3TCTablet (disp, scored) 12/30 mg
ABC/3TCTablet (disp, scored) 60/30 mg
ABC/3TC Tablet (scored) 60/30 mg
ABC/3TC/AZTTablet (non disp, scored)
60/30/60 mgPI’s
LPV/r Tablet (HS) 100 mg/25mgLPV/r Oral liquid 80/20 mg/ml
RTV Oral liquid 400 mg/5ml
DRV Tablet 75 mgDRV Tablet 150 mg
DRV Oral liquid 500 mg/5ml
ATV Solid oral dosage form 100 mg
ATV Solid oral dosage form 150 mg
ATV Solid oral dosage form 200 mg
TPV Oral liquid 500 mg/5mL
FPV Oral liquid 250 mg/5mL
Integrase Inhibitors
RALChewable tablet (scored) 100 mg
RAL Chewable tablet 25 mg
Low Volumes and Fragmentation are Problematic
Suppliers are limited by minimum batch requirements
► Manufacturers produce a minimum of generally several thousand packs of a particular product, called the “minimum batch requirement”
► A product will not be produced until orders are meet the minimum batch requirement; otherwise, supplier risks incurring losses from carrying stocks which fall below country shelf-life requirements
► Supply timelines can become highly unstable without ordering coordination
0
5,000
10,000
15,000
20,000
25,000
# Pa
cks
Illustrative example of orders needed by country to fill a minimum batch
Minimum batch size
Inability to procure low volume formulations• Highly fragmented low volume
products may not be supplied (e.g. non-essential IATT list)
Limited registration coverage• Suppliers have lower
incentives to register products in low volume markets
Limited new product options• Creates further challenges to
suppliers realizing a return on investment for new products
Market risks include…
• Low or medium volume country
• Procuring a large number of formulations including multiple/redundant formulations for the same patient population
• Procuring formulations or drugs considered clinically inferior that most countries have transitioned away from (e.g. liquid formulations, ddI etc..)
Who is at greatest risk…
The Market Risks
2007 2008 2009 2010 2011 2012
0,2M 0,28M 0,35M 0,46M 0,56M 0,65M
2,8M
3,8M
4,9M
6,2M
7,4M
9,1M
Adults receiv-ing ART
Children receiving ART Paediatric AZT Formulations
1. AZT 50 mg/5 ml2. AZT 60 mg,100 mg3. AZT/3TC 60/30 mg4. AZT/3TC 60/30 mg dispersible5. AZT/3TC/NVP 60/30/50 mg6. AZT 300 mg7. AZT/3TC 300/150 mg8. AZT/3TC/NVP 300/150/200 mg et plus
Low Volumes of Multiple Redundant Formulations Make the Paediatric ARV Marketplace Unstable
Adult AZT Formulations1. AZT 300 mg2. AZT/3TC 300/150 mg3. AZT/3TC/NVP 300/150/200 mg
Patients on ART (in millions)
EXAMPLE: AZT+3TC+NVP regimen for 3 - 24.9 kg weight band
AZT syrupAZT syrup
3TC syrup3TC syrup
NVP syrupNVP syrup
AZT singleAZT single
3TC single3TC single
NVP singleNVP single
AZT/3TC dual FDC (non-
dispersible)
AZT/3TC dual FDC (non-
dispersible)
AZT/3TC/NVP triple FDC
AZT/3TC/NVP triple FDC
Product Consolidation(to improved formulations)
• Multiple formulations procured for one regimen
• Improve patient outcomes• Limit supply risks • Decrease costs
Product Fragmentation
AZT syrup
3TC syrup
NVP syrup
AZT single
3TC single
AZT/3TC/NVP triple FDC
AZT/3TC/NVP triple FDC
Meets minimum batch size requireme
nt
AZT/3TC dual FDC (dispersible)
AZT/3TC dual FDC (dispersible)
AZT/3TC dual FDC (non-
dispersible)
AZT/3TC dual FDC (non-
dispersible)
AZT/3TC dual FDC (dispersible)
AZT/3TC dual FDC (dispersible)
Consolidation of Demand Around a Subset of Optimal Paediatric ARV Formulations is Essential To Ensure a Sustainable Supply
NVP singleNVP single
2013 WHO Treatment Guidelines The 2013 WHO treatment guidelines provide specific guidance on
preferred and alternative first- and second-line regimens
However, guidance on specific formulation selection is not included
WHO Model Essential Medicines List (EML) Identifies medicines that satisfy the needs of the majority of the
population, to be available at all times, affordable, and in appropriate dosage forms
Broad: organized into 29 therapeutic classes (e.g., antibiotics, anti-malarials…)
Next update: begins July 2014 and will be completed by Q2 2015
Until Recently, Guidance on Formulation Selection For Paediatric ART Has Been Limited…
• First adult EML list published
• ARV’s added to EML• Evidence based process for selection and revision adopted
• Adult 17th & Paediatric 3rd Ed. released
1977 1978 1979 1980- - -
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
• First model list for children developed
In mid-2011, the IATT began a selection process for optimal paediatric formulations given the following:
Proliferation of product choices and market fragmentation leading to instability in the paediatric marketplace
Normative guidance was needed on the best options to deliver all required 1st and 2nd line regimens for paediatric HIV patients
An optimal formulary can serve as guidance for national programs, procurement agencies, manufacturers
2011: First IATT Optimal Paediatric ARV Formulary Created by IATT Optimal Paediatric Formulary List
To be updated and revised when the WHO updates regimen
guidance– or –
when new products and formulations become available in
low-income settings
IATT ART Formulary
• Minimum number of ARV formulations needed to provide all currently recommended preferred and alternative 1st and 2nd line WHO recommended regimens for all paediatric weight bands
Optimal
• Formulations that may be needed during transition and /or for special circumstances
Limited-use
• Everything else (not needed)Non-essential
IATT Paediatric ART Formulary: 2013 Revision
There are Over 61 Different Paediatric ARVs on the Market - Far Too Many To Serve This Patient Population or Commercially Viable For The Manufactures
NRTI’s
ABCTablet (disp,scored) as sulfate 60 mg
ABC Tablet (scored) as sulfate 60 mgABC Oral liquid as sulfate 100 mg/5ml
AZT Tablet (disp, scored) 60 mgAZT Oral liquid 50 mg/5mlAZT Tablet (scored) 60 mgAZT Capsule 100 mgAZT Tablet 100 mg3TC Oral liquid 50 mg/5ml3TC Tablet (disp) 30 mg3TC Tablet 30 mgD4T Capsule 15 mgD4T Capsule 20 mgD4T Powder for oral solution 5 mg/5ml
DDICapsule (unbuffered, enteric coated) 125 mg
DDICapsule (unbuffered, enteric coated) 200 mg
DDITablet (buffered, chewable, disp) 25mg
DDITablet (buffered, chewable, disp) 50 mg
DDITablet (buffered, chewable, disp) 100 mg
DDI Powder for oral liquid (Buffered) 2g, 4g bottle
FTC Oral liquid 10 mg/ml
TDF Oral powder 40mg/scoopTDF Tablet (unscored) 150 mgTDF Tablet (unscored) 200mg
NNRTI’sEFV Tablet (scored) 200 mgEFV Tablet 50 mg EFV Tablet (unscored) 200 mgEFV Tablet (disp, scored) 100 mgEFV Tablet 100 mgEFV Capsule 50 mgEFV Capsule 100 mgEFV Capsule 200 mgEFV Oral liquid 150 mg/5ml
NVP Tablet (disp, scored) 50 mg
NVP Oral liquid 50 mg/5ml
NVP Tablet (disp) 100 mgETV Tablet 25 mg
ETV Tablet 100 mg
FDC’s
AZT/3TCTablet (disp, scored) 60/30 mg
AZT/3TC Tablet (scored) 60/30 mg
AZT/3TC/NVPTablet (disp, scored)
60/30/50 mg
D4T/3TC/NVPTablet (disp, scored) 6/30/50 mg
D4T/3TC/NVPTablet (disp, scored)
12/60/100 mg
D4T/3TC Tablet (disp, scored) 6/30 mg
D4T/3TCTablet (disp, scored) 12/30 mg
ABC/3TCTablet (disp, scored) 60/30 mg
ABC/3TC Tablet (scored) 60/30 mg
ABC/3TC/AZTTablet (non disp, scored)
60/30/60 mgPI’s
LPV/r Tablet (HS) 100 mg/25mgLPV/r Oral liquid 80/20 mg/ml
RTV Oral liquid 400 mg/5ml
DRV Tablet 75 mgDRV Tablet 150 mg
DRV Oral liquid 500 mg/5ml
ATV Solid oral dosage form 100 mg
ATV Solid oral dosage form 150 mg
ATV Solid oral dosage form 200 mg
TPV Oral liquid 500 mg/5mL
FPV Oral liquid 250 mg/5mL
Integrase Inhibitors
RALChewable tablet (scored) 100 mg
RAL Chewable tablet 25 mg
Evaluation CriteriaCriteria Description
Meets WHO requirements Includes in the latest WHO guidelines for paediatric treatment
Dosing flexibility Allows for the widest range of dosing options
Approved by SRA/WHO PQ ≥ 1 quality assured product available
User friendly Easy for HCWs to prescribeEasy for caregivers to administerSupports adherence in children
Optimizes supply chain Easy to transportEasy to storeEasy to distribute
Available in resource limited settings
In country registrationReliable supply
Comparative cost Cost should NOT be the deciding factor in selection of a drug but comparative cost of similar drugs/drug formulations should be considered
Aim of the List: Address Both Adherence and Market Challenges For Paediatric HIV Treatment
Decreases pill burden and eases administration for caregiver and patient
Promotes adherence with simplified regimens, fewer bottles, fewer liquids, more temperature tolerance
Decreases costs over time Improves availability by reducing
complications in procurement, storage and distribution
Simplifies and clarifies the market for suppliers
2013 IATT Optimal Paediatric ARV FormularyDrug Class Drug Formulation Dose
NRTI AZT Oral liquid* 50 mg/5mL
NNRTI EFV Tablet (scored) 200 mg
NNRTI NVP Tablet (disp, scored) 50 mg
NNRTI NVP Oral liquid* 50 mg/5mL
PI LPV/r Tablet (heat stable) 100 mg/25mg
PI LPV/r Oral liquid 80 mg/20 mg/mL
FDC AZT/3TC Tablet (disp, scored) 60 mg/30 mg
FDC AZT/3TC/NVP
Tablet (disp, scored) 60 mg/30 mg/50 mg
FDC ABC/3TC Tablet (disp, scored) 60 mg/30 mg
FDC ABC/AZT/3TC
Tablet (non disp, scored)
60 mg/60 mg/30 mg
* Oral liquid to be used to provide infant prophylaxis for PMTCT
Drug Class
Drug Formulation Dose Rationale
NRTI 3TC Tablet (disp) 30 mg For use with TDF single
NRTI TDF Oral powder 40 mg/scoop
Until FDC available
NRTI TDF Tablet (unscored) 150 mg Until FDC available
NRTI TDF Tablet (unscored) 200 mg Until FDC available
NNRTI ETV Tablet 25 mg Special circumstances
NNRTI ETV Tablet 100 mg Special circumstances
PI DRV Tablet 75 mg Special circumstances
PI RTV Oral liquid 400 mg/5mL
For boosting non-co-formulated PI’s
PI ATV Solid oral dosage form
100 mg Alternative 2nd line
PI ATV Solid oral dosage form
150 mg Alternative 2nd line
Int Inh RAL Chew tab (scored) 100 mg Special circumstances
FDC d4T/3TC/NVP
Tablet (disp, scored)
6 mg/30 mg/ 50 mg
To be phased out
FDC d4T/3TC Tablet (disp, scored)
6 mg/30 mg
To be phased out Special circumstances
2013 IATT Limited-Use Paediatric list
The IATT List is a Living Document That Will Be Reviewed on a Regular BasisRevision triggers: Major Review every 2 years when WHO issues
new recommendations for paediatric ART Minor Review every 6 months to evaluate if:
► New and better paediatric ARV products available
► New paediatric drug/formulation SRA or WHO pre-qual approvals
► Actual or anticipated supplier side changes
► Significant shifts in HIV paediatric treatment practices
► Use of list (e.g., d4T-based formulations; ABC/AZT/3TC; AZT syrup; DRV)
The List is Now Used by Multiple Stakeholders
Paediatric ARV Procurement Working Group (PAPWG) which now coordinates across:
Major agencies funding paediatric ARVs Major buyers of paediatric ARVs Ministries of Health, national drug regulatory
agencies, national HIV/AIDS programmes and procurement offices
Civil society stakeholders in paediatric HIV Community organization of people living with
HIV Manufacturers of paediatric ARVs
National Level Adoption
The IATT formulary is meant as a model list
However since paediatric volumes are small overall- global and regional trends are critical to understand
Country programs should consider options and select the formulations most relevant to their needs
Why should countries rationalize their paediatric formularies
When should countries rationalize their formularies
Who are the stakeholders involved How should the formulary be rationalized What should be done after rationalization
Steps To Consider For Country Adaptation of the IATT Formulary
Why: Country Advantages To Optimization of Paediatric ARV Formulary
Ensure quality of care (right doses and right drugs)
Ease administration to support adherence
Simplify prescribing practices
Streamline supply chain management
Potential for cost savings
Ensure demand so manufacturers continue to make paediatric formulations
Incentivize manufacturers to invest in R&D for new drugs
Consolidate regimens used
► Ensure National paediatric ART recommendations are up to date
► Optimization of regimens also essential to simplify treatment
► Identify regimens and products that can be phased out of formulary (eg. d4T, ddI)
When: After Treatment Guidelines Have Been Updated
2013 WHO Recommended Paediatric ART Regimens
Who: Country Stakeholders
► National HIV/AIDS Program- to lead the process
► National Essential Medicines Committee
► Paediatric Technical Working Group
► Procurement and Supply Chain (Logisitics)
► Central Medical Store
► National Drug Authority
► Finance
► HCW (Prescribers)
► Pharmacists (Dispensers)
► Others
Product/Supplier Selection
Forecasting
Procurement
Distribution
Use
Inventory Management
Supply Chain Cycle
How: Country Optimization Bring together stakeholders Explain rationale for formulary
optimization Review prescribing and dispensing
practices Develop criteria for evaluation based on
country resources, needs, preferences Anticipate changes/transitions Review current procurement list
Identify suboptimal drugs/products Identify duplications Identify optimal new products to be
added to procurement
1
3
4
6
5
2
Before Optimization
3TC (150mg) ABC (20mg/ml) 3TC (150mg) + AZT
(300mg) ABC (300mg) 3TC (30mg) + ABC
(60mg) 3TC (30mg) +
AZT (60mg)
AZT (100mg)
3TC (30mg) + AZT (60mg) + NVP (50mg)
3TC (30mg) + d4T (6mg) 3TC (50mg/5ml)
3TC (30mg) + d4T (6mg) + NVP (50mg)
3TC (60mg) + d4T (12mg)
DDI (125mg) 3TC (60mg) + d4T (12mg) +
NVP (100mg) DDI (25mg)
DDI (200mg) EC LPV/r
(100/25mg)
LPV/r (200/50mg) LPV/r (80 + 20
mg/ml)
NVP (200mg) NVP (50mg/5ml)
EFV (200mg) EFV (50mg)
After Optimization
3TC (30mg) + ABC (60mg)
3TC (30mg) + AZT (60mg)
3TC (30mg) + AZT (60mg) + NVP (50mg)
3TC (30mg) + d4T (6mg)
3TC (30mg) + d4T (6mg) + NVP (50mg)
EFV (200mg)
LPV/r (100/25mg)
LPV/r (80 + 20 mg/ml)
824
Country Example: Malawi
Optimization Opportunities► Consolidate around optimal FDC formulations: e.g.
d4T/3TC/NVP 6mg/30mg/50mg triple FDC► Remove outdated drugs: e.g. ddI► Identify duplicative formulations: e.g. AZT 100mg
capsule► Limit use of liquid formulations : e.g. 3TC
50mg/5ml liquid► Distinguish between optimal and non-essential
formulations: e.g. EFV 200mg scored tablet
Optimization is Not Enough So What Next? Consensus
Dissemination and communication
Advance planning
Low volume products
Lead times
Drug/product transitions
Registration
Intellectual property considerations
Coordinated procurement (PAPWG)
Product/Supplier Selection
Forecasting
Procurement
Distribution
Use
Inventory Management
Steps For Country Programs:► Select the most optimal paediatric ARV
products prior to procurement
► Forecast & quantify paediatric ARVs
► Generate supply plans (annually at a minimum)
► Use the coordinated/pooled procurement mechanism or follow the quarterly order cycle timeline
Key Points The IATT Optimal Formulary is designed to guide
selection and procurement of paediatric ARV’s around a subset of optimal products
Consolidation of demand stabilizes supplies of paediatric ARVS
Success will require global consensus, regional collaboration and country implementation to ensure paediatric ARV’s will continue to be available to children in need
Country process for optimization should include:
Regimen selection
Product selection
Coordinated procurement
PAPWG is the global body created to support and coordinate procurement of paediatric ARV’s
Feedback and Questions Further resources
2013 Optimal Formulary Meeting report: http://www.emtct-iatt.org/wp-content/uploads/2014/04/IATT-Sept-2013-Updated-Paediatric-ART-Formulary-Report1.pdf
Chapter 10, WHO March 2014 supplement: http://www.who.int/hiv/pub/guidelines/arv2013/arvs2013upplement_march2014/en/
For additional information or technical assistance please contact:
► Atieno Ojoo ([email protected])
► David Jamieson ([email protected])
► Nandita Sugandhi ([email protected])
► Marianne Gauval ([email protected])
► Gitanjali Sakhuja ([email protected])
Thank you!
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