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 (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!