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
What is the IATT? Intra-agency Task Team on Prevention of HIV
Infection in Pregnant Women, Mothers and their Children
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
Paediatric Working Group
IATT Subcommittees
Paediatric
Infant feeding
+
Working Group
Working Group
► Sub-committee of the main IATT
► Focused on issues related to paediatric care and
treatment issues
Child Survival Working Group
► 2011 restructuring of IATT: consolidation of 2
working groups
Developed
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
Preferred
Children < 3 years
Children 3 years to <
10 years
Adolescents > 10
years
ABC + 3TC +
LPV/r
or
AZT + 3TC +
LPV/r
ABC + 3TC + EFV
TDF + 3TC + EFV
ABC + 3TC + NVP
AZT + 3TC + EFV
AZT + 3TC + NVP
TDF + 3TC (or FTC) +
EFV
TDF + 3TC (or FTC) +
NVP
AZT + 3TC + EFV
AZT + 3TC + NVP
TDF + 3TC (or FTC) +
NVP
Alternative ABC + 3TC + NVP
AZT + 3TC + 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
7 paediatric
patients
All ages & weight
bands
Multiple ages and
weight bands
One pill, once-aday
Multiple
formulations
There are Over 61 Different Paediatric ARVs on
the Market
NRTI’s
DDI
FTC
Tablet (disp,scored) as
sulfate
Tablet (scored) as sulfate
Oral liquid as sulfate
Tablet (disp, scored)
Oral liquid
Tablet (scored)
Capsule
Tablet
Oral liquid
Tablet (disp)
Tablet
Capsule
Capsule
Powder for oral solution
Capsule (unbuffered, enteric
coated)
Capsule (unbuffered, enteric
coated)
Tablet (buffered, chewable,
disp)
Tablet (buffered, chewable,
disp)
Tablet (buffered, chewable,
disp)
Powder for oral liquid
(Buffered)
Oral liquid
TDF
TDF
TDF
Oral powder
Tablet (unscored)
Tablet (unscored)
ABC
ABC
ABC
AZT
AZT
AZT
AZT
AZT
3TC
3TC
3TC
D4T
D4T
D4T
DDI
DDI
DDI
DDI
DDI
FDC’s
NNRTI’s
60 mg
60 mg
100 mg/5ml
60 mg
50 mg/5ml
60 mg
100 mg
100 mg
50 mg/5ml
30 mg
30 mg
15 mg
20 mg
5 mg/5ml
EFV
EFV
EFV
EFV
EFV
EFV
EFV
EFV
EFV
Tablet (scored)
Tablet
Tablet (unscored)
Tablet (disp, scored)
Tablet
Capsule
Capsule
Capsule
Oral liquid
NVP Tablet (disp, scored)
50 mg
NVP Oral liquid
50 mg/5ml
NVP Tablet (disp)
ETV Tablet
100 mg
25 mg
ETV Tablet
100 mg
PI’s
125 mg
200 mg
25mg
50 mg
100 mg
200 mg
50 mg
200 mg
100 mg
100 mg
50 mg
100 mg
200 mg
150 mg/5ml
LPV/r
LPV/r
Tablet (HS)
Oral liquid
100 mg/25mg
80/20 mg/ml
RTV
Oral liquid
400 mg/5ml
DRV
DRV
Tablet
Tablet
75 mg
150 mg
DRV
Oral liquid
500 mg/5ml
Solid oral dosage form
Solid oral dosage form
Solid oral dosage form
Oral liquid
Oral liquid
100 mg
150 mg
200 mg
500 mg/5mL
250 mg/5mL
2g, 4g bottle ATV
10 mg/ml
ATV
40mg/scoop ATV
TPV
150 mg
200mg
FPV
Tablet (disp,
scored)
Tablet (scored)
Tablet (disp,
AZT/3TC/NVP scored)
Tablet (disp,
D4T/3TC/NVP scored)
Tablet (disp,
D4T/3TC/NVP scored)
AZT/3TC
AZT/3TC
Tablet (disp,
scored)
Tablet (disp,
D4T/3TC
scored)
Tablet (disp,
ABC/3TC
scored)
ABC/3TC
Tablet (scored)
Tablet (non
ABC/3TC/AZT disp, scored)
D4T/3TC
60/30 mg
60/30 mg
60/30/50
mg
6/30/50 mg
12/60/100
mg
6/30 mg
12/30 mg
60/30 mg
60/30 mg
60/30/60
mg
Integrase Inhibitors
RAL
Chewable 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
Illustrative example of orders needed by country to fill a minimum
batch
25,000
# Packs
20,000
15,000
10,000
5,000
0
Minimum batch size
The Market Risks
Market risks include…
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
Who is at greatest risk…
• 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..)
Low Volumes of Multiple Redundant Formulations
Make the Paediatric ARV Marketplace Unstable
Patients on ART (in millions)
Adults
receiving ART
9,1M
Children
receiving ART
7,4M
6,2M
4,9M
3,8M
2,8M
0,2M
0,28M
0,35M
0,46M
0,56M
0,65M
2007 2008 2009 2010 2011 2012
Adult AZT Formulations
1. AZT 300 mg
2. AZT/3TC 300/150 mg
3. AZT/3TC/NVP 300/150/200 mg
Paediatric AZT Formulations
1. AZT 50 mg/5 ml
2. AZT 60 mg,100 mg
3. AZT/3TC 60/30 mg
4. AZT/3TC 60/30 mg dispersible
5. AZT/3TC/NVP 60/30/50 mg
6. AZT 300 mg
7. AZT/3TC 300/150 mg
8. AZT/3TC/NVP 300/150/200 mg et plus
Consolidation of Demand Around a Subset of Optimal Paediatric ARV
Formulations is Essential To Ensure a Sustainable Supply
EXAMPLE: AZT+3TC+NVP regimen for 3 - 24.9 kg weight band
Product Fragmentation
• Multiple formulations
procured for one regimen
Product Consolidation
(to improved formulations)
• Improve patient outcomes
• Limit supply risks
• Decrease costs
AZT syrup
AZT single
AZT syrup
AZT single
3TC syrup
3TC single
3TC syrup
3TC single
NVP syrup
NVP single
NVP syrup
NVP single
AZT/3TC dual FDC
(non-dispersible)
AZT/3TC dual FDC
(non-dispersible)
AZT/3TC dual FDC
(dispersible)
AZT/3TC dual FDC
(dispersible)
AZT/3TC/NVP
triple FDC
AZT/3TC/NVP
triple FDC
Meets
minimum
batch size
requirement
Until Recently, Guidance on Formulation Selection
For Paediatric ART Has Been Limited…
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
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
- - -
2000
1980
1979
1978
1977
• First adult EML list published
• Evidence based process for selection and revision adopted
• ARV’s added to EML
• First model list for children developed
• Adult 17th &
Paediatric 3rd Ed.
released
2011: First IATT Optimal Paediatric ARV Formulary
Created by IATT Optimal Paediatric Formulary List
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
To be updated and revised when the WHO
updates regimen guidance
– or –
when new products and formulations
become available in low-income settings
IATT Paediatric ART Formulary: 2013 Revision
Optimal
• 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
• Formulations that may be needed during transition
Limited-use IATT
andART
/or for
special circumstances
Formulary
Nonessential
• Everything else (not needed)
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
DDI
FTC
Tablet (disp,scored) as
sulfate
Tablet (scored) as sulfate
Oral liquid as sulfate
Tablet (disp, scored)
Oral liquid
Tablet (scored)
Capsule
Tablet
Oral liquid
Tablet (disp)
Tablet
Capsule
Capsule
Powder for oral solution
Capsule (unbuffered, enteric
coated)
Capsule (unbuffered, enteric
coated)
Tablet (buffered, chewable,
disp)
Tablet (buffered, chewable,
disp)
Tablet (buffered, chewable,
disp)
Powder for oral liquid
(Buffered)
Oral liquid
TDF
TDF
TDF
Oral powder
Tablet (unscored)
Tablet (unscored)
ABC
ABC
ABC
AZT
AZT
AZT
AZT
AZT
3TC
3TC
3TC
D4T
D4T
D4T
DDI
DDI
DDI
DDI
DDI
FDC’s
NNRTI’s
60 mg
60 mg
100 mg/5ml
60 mg
50 mg/5ml
60 mg
100 mg
100 mg
50 mg/5ml
30 mg
30 mg
15 mg
20 mg
5 mg/5ml
EFV
EFV
EFV
EFV
EFV
EFV
EFV
EFV
EFV
Tablet (scored)
Tablet
Tablet (unscored)
Tablet (disp, scored)
Tablet
Capsule
Capsule
Capsule
Oral liquid
NVP Tablet (disp, scored)
50 mg
NVP Oral liquid
50 mg/5ml
NVP Tablet (disp)
ETV Tablet
100 mg
25 mg
ETV Tablet
100 mg
PI’s
125 mg
200 mg
25mg
50 mg
100 mg
200 mg
50 mg
200 mg
100 mg
100 mg
50 mg
100 mg
200 mg
150 mg/5ml
LPV/r
LPV/r
Tablet (HS)
Oral liquid
100 mg/25mg
80/20 mg/ml
RTV
Oral liquid
400 mg/5ml
DRV
DRV
Tablet
Tablet
75 mg
150 mg
DRV
Oral liquid
500 mg/5ml
Solid oral dosage form
Solid oral dosage form
Solid oral dosage form
Oral liquid
Oral liquid
100 mg
150 mg
200 mg
500 mg/5mL
250 mg/5mL
2g, 4g bottle ATV
10 mg/ml
ATV
40mg/scoop ATV
TPV
150 mg
200mg
FPV
Tablet (disp,
scored)
Tablet (scored)
Tablet (disp,
AZT/3TC/NVP scored)
Tablet (disp,
D4T/3TC/NVP scored)
Tablet (disp,
D4T/3TC/NVP scored)
AZT/3TC
AZT/3TC
Tablet (disp,
scored)
Tablet (disp,
D4T/3TC
scored)
Tablet (disp,
ABC/3TC
scored)
ABC/3TC
Tablet (scored)
Tablet (non
ABC/3TC/AZT disp, scored)
D4T/3TC
60/30 mg
60/30 mg
60/30/50
mg
6/30/50 mg
12/60/100
mg
6/30 mg
12/30 mg
60/30 mg
60/30 mg
60/30/60
mg
Integrase Inhibitors
RAL
Chewable tablet
(scored)
100 mg
RAL
Chewable tablet
25 mg
Evaluation Criteria
Criteria
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 prescribe
Easy for caregivers to administer
Supports adherence in children
Optimizes supply chain
Easy to transport
Easy to store
Easy to distribute
Available in resource limited
settings
In country registration
Reliable 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 Formulary
Drug 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/N
VP
Tablet (disp, scored)
60 mg/30 mg/50 mg
FDC
ABC/3TC
Tablet (disp, scored)
60 mg/30 mg
FDC
ABC/AZT/3
TC
Tablet (non disp, scored)
60 mg/60 mg/30 mg
* Oral liquid to be used to provide infant prophylaxis for PMTCT
2013 IATT Limited-Use Paediatric list
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 nonco-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
The IATT List is a Living Document
That Will Be Reviewed on a Regular Basis
Revision 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 prequal 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
Steps To Consider For Country Adaptation of the
IATT Formulary

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
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
When: After Treatment Guidelines
Have Been Updated
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)
2013 WHO Recommended Paediatric ART Regimens
Who: Country Stakeholders
► National HIV/AIDS Program- to lead the process
► National Essential Medicines Committee
Supply Chain
Cycle
► Paediatric Technical Working Group
► Procurement and Supply Chain (Logisitics)
Product/Supplier
Selection
► Central Medical Store
► National Drug Authority
Inventory
Management
Forecasting
► Finance
► HCW (Prescribers)
► Pharmacists (Dispensers)
► Others
Use
Procurement
Distribution
How: Country Optimization
1
2
3
4
5
6
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

Country Example: Malawi
Before Optimization
8
24
After Optimization
3TC (150mg)
3TC (150mg) + AZT
(300mg)
3TC (30mg) + ABC
(60mg)
ABC (300mg)
3TC (30mg) + AZT
(60mg)
3TC (30mg) + ABC (60mg)
AZT (100mg)
3TC (30mg) + AZT
(60mg) + NVP (50mg)
3TC (30mg) + AZT (60mg) + NVP
(50mg)
3TC (30mg) + d4T (6mg)
3TC (30mg) + d4T (6mg)
+ NVP (50mg)
DDI (125mg)
DDI (25mg)
DDI (200mg) EC
ABC (20mg/ml)
3TC (50mg/5ml)
3TC (60mg) + d4T
(12mg)
3TC (60mg) + d4T
(12mg) +
NVP (100mg)
LPV/r (200/50mg)
LPV/r (100/25mg)
LPV/r (80 + 20
mg/ml)
NVP (200mg)
NVP (50mg/5ml)
EFV (200mg)
EFV (50mg)
3TC (30mg) + AZT (60mg)
3TC (30mg) + d4T (6mg)
3TC (30mg) + d4T (6mg) + NVP
(50mg)
EFV (200mg)
LPV/r (100/25mg)
LPV/r (80 + 20 mg/ml)
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
Inventory
Management
Forecasting
Use
Procurement
Distribution
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.emtctiatt.org/wp-content/uploads/2014/04/IATT-Sept-2013-UpdatedPaediatric-ART-Formulary-Report1.pdf

Chapter 10, WHO March 2014 supplement:
http://www.who.int/hiv/pub/guidelines/arv2013/arvs2013upplemen
t_march2014/en/
For additional information or technical assistance please contact:
►
Atieno Ojoo (aojoo@unicef.org)
►
David Jamieson (djamieson@pfscm.org)
►
Nandita Sugandhi (nsugandhi@clintonhealthaccess.org)
►
Marianne Gauval (mgauval@clintonhealthaccess.org)
►
Gitanjali Sakhuja (gsakhuja@unicef.org)
Thank you!