A Demand Forecasting Tool for Pediatric

Antiretroviral Medications

November 3, 2004

Acknowledgements

This talk was developed by:

Alex Hurd

Lynn Margherio

Kate Condliffe

Stephen Nicholas

Special thanks to:

Mark Klein, Elaine Abrams, Consuelo Beck-Sague

Clinton HIV/AIDS Initiative Overview

To be effective, programs must:•combine prevention, care, and treatment•be integrated into public health infrastructure•have strong in-country political and policy support•be viewed as an emergency, not as business as usual

1) Mobilize political will (donor and host governments)2) Combine business and clinical expertise in operational planning and

ongoing implementation support 3) Change economics of care and treatment4) Strategic partnerships with other international HIV/AIDS organizations

Access to high quality, low-cost ARVs and diagnostic testingAim: 2 million people on ARVs by the end of 2008 in partner countries

Philosophy

Value-Add

Goals

To bring high-quality medical care and treatment to people living with HIV/AIDS, and to improve healthcare systems in resource-poor countries

Mission

Clinton HIV/AIDS Initiative Overview (cont.)

At the invitation of government leaders, the Clinton HIV/AIDS Initiative is currently working in the following countries:

33% of cases in Africa 90% of cases in Caribbean

Africa Caribbean Asia/Pacific

Lesotho Bahamas China

Mozambique Dominican Republic India

Rwanda Haiti

South Africa Jamaica

Tanzania Organization of Eastern Caribbean States

85% of cases in Asia

Cost of Antiretroviral drugs

Characteristics of early ARV market

• ARV market was fragmented and characterized by small orders, resulting in sub-optimal production

• Lack of harmonization of treatment guidelines

• Lack of dependable demand forecasts

• Weak supply management systems

•Price reductions were achieved through generic competition, fixed-dose drug production, and better organization of market, driving predictable and sustainable cost reductions

•The effect of increased volume of production has also begun to lower the cost of ARVs

Source: Médecins Sans Frontières, Untangling the Web of Price Reductions, April 2004 Note: Benchmark pricing is lowest global price; prices outside of selected African countries are substantially higher

ARV Price History - WHO recommended first line drug regimens

The introduction of generic competition into the ARV market resulted in a substantial reduction in the price of adult formulations

History of Antiretroviral Pricing

* Cipla is currently the only generic supplier with pediatric formulations approved by the WHO**Source for price comparison: “Selected drugs used in the care of people living with HIV,” MSF, October 2000

High Cost of Pediatric Formulations

Adult Pediatric

# of generic suppliers w/WHO approval for at least 1 product 5 1*

Lowest available WHO pre-qualified price (d4T+3TC+NVP) $132-140 $1,000-1,150

Price reduction since October 2000** 93% 62%

ARV procurement for children living with HIV/AIDS

Challenges to Procurement of Pediatric ARVs

• High cost of pediatric formulations of ARVs

• Pediatric AIDS low priority for pharmaceutical companies, governments

• Lack of universal international treatment guidelines for children living with HIV/AIDS

• Complicated dosing scheme based on weight or surface area and age

• Issues of palatability, storage, adherence, et al.

Challenges to HIV/AIDS procurement for

pediatrics

Effective procurement for pediatric ARVs is based on the following principles:

• Standardization of international treatment guidelines for pediatric patients living with HIV/AIDS, with simplification where possible

• Advocacy for the inclusion of pediatric HIV care and ARV treatment in every national operational and procurement plan

• Training and monitoring to ensure clinician awareness and compliance with national guidelines

• Development of global demand forecasts based on agreed guidelines and proper dosing to spur production of high quality-low cost generic pediatric ARVs

International Treatment Guidelines

The following guidelines for treatment of children living with HIV/AIDS have been developed:

• Scaling Up ARV Therapy in Resource-Limited Settings, WHO 3 by 5 Initiative; (2003)

• HIV Drug Dose Ranges, Harvard AIDS Institute, MSF, ACHAP; (May 2003)

• Pediatric ARV & Cotrimoxazole Dosing, CDC, Baylor, Columbia; (March 2004)

Slight variations between guidelines remainForecasting will be more exact once agreement on universal guide is reached

National planning activities

• National operational plan for treatment, including:• Pediatric ARV treatment protocols (1st and 2nd line)• Regimen change assumptions due to toxicity & treatment failure• Projection of pediatric patients on treatment (“patient targets”)

• National drug ordering, storage, distribution and tracking system operational

• Forecasting tool completion and drug ordering: • Dosage, formulations

• Weight distribution

• Security stock

Implementation activities

• Clinician training:• International pediatric HIV treatment guidelines• National protocol with standardization, simplification

• Monitoring:• Efficiency of national drug distribution system• Physician prescribing practices• Patient adherence• Drug consumption data• National viral resistance monitoring

• Ongoing projection updates, revision of toxicity, treatment failure assumptions if necessary

• Regular ordering to improve supply management and reduce risk of stock-outs and drug wastage through expiration

A Demand Forecasting Tool for Pediatric

Antiretroviral Medications

Demand Forecast Model: Steps

• Identify appropriate dosage and formulation for each weight class

• Include following assumptions from National Plan:

• First and second line regimens

• Regimen sequencing

• Single drug toxicity

• Treatment failure rate

• Patient targets per month

• Weight distribution of patients coming onto treatment

• Security stock

Demand Forecast Model: Dosage & Formulation

• Dosage assumptions for the ARV forecasting model are based on the following sources :

HIV Drug Dose Ranges, Harvard AIDS Institute, MSF, ACHAP; (May 2003)

Pediatric ARV & Cotrimoxazole Dosing, CDC, Baylor, Columbia; (March 2004)

Demand Forecast: Dosage & Formulation (cont.)

WeightAbacavir(Ziagen®)

Stavudine(Zerit®, d4T)

Lamivudine(Epivir®, 3TC)

Zidovudine(Retrovir®, ZDV,

AZT)

Didanosine(Videx®, DDI)

8 mg/KGtwice daily

1 mg/KGtwice daily

4 mg/KGtwice daily

240 mg/m2

twice daily120 mg/m2

twice daily

KG Liquid20 mg/ml

Tablet300 mg

Capsules15, 20, 30 mg

Liquid10 mg/ml

Tablet150 mg

Liquid10 mg/

ml

Capsule100 mg

Chewable tablets25, 50, 100 mg

5 – 6. 9 2 ml 2 ml 7 ml

7 – 9. 9 3 ml 15 mg 3 ml 9 ml 1 cap 25mg + 25mg

10 – 11. 9 4 ml 15 mgor

(20 mg1)

4 ml 12 ml 1 cap 25mg + 25mg

12 – 14. 9 5 ml 15 mgor

(20 mg1)

5 ml 14 ml 1 cap 50mg + 25mg

15 - 16. 9 6 ml 15 mgor

(20 mg1)

6 ml ½ tab 15 ml 2 caps 50mg + 25mg

17 – 19 .9 7 ml ½ tab 20 mg 7 ml ½ tab 17 ml 2 caps 50mg + 50mg

From: Pediatric Antiretroviral and Cotrimoxazole Dosing guide, CDC, Baylor, Columbia; March 2004

Demand Forecast: Dosage & Formulation (cont.)

Liquid formulation vs. caps/tabs assumptions:

Weight Liquid Tabs/Caps

3-5 kg 100% 0%

5-10 kg 100% 0%

10-15 kg 100% 0%

15 - 20 kg 100% 0%

20 - 25 kg 50% 50%

25 - 30 kg 50% 50%

30 - 40 kg 50% 50%

Clinical Assumptions

Regimen Regimen Sequencing

Initial regimen used for treatment naïve patients AZT + 3TC + NVP 100%

At end of year 1, Clinical assumptions project following regimen sequencing

First Line

Initial Regimen AZT + 3TC + NVP 80%

Toxicity to NVP AZT + 3TC + EFV 10%

Toxicity to AZT d4T +3TC + NVP 4%

Toxicity to AZT & NVP d4T + 3TC + EFV 4%

Second Line

After treatment failure ABC + ddI + Lop/rit 2%

Protocols and regimen sequencing assumptions may need to be

adjusted overtime

Demand Forecast: National Protocol

ILLUSTRATION

Patient Target Assumptions

Demand Forecast: Patient Targets

ILLUSTRATION

Project accrual of patients receiving treatment per month

  Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

# of pediatric patients 275 550 825

1,100

1,375

1,650 1,925

2,200

2,475

2,750

3,025

3,300

Assumptions:3300 pediatric patients are projected to be on treatment by the end of year 1

Weight Distribution Assumptions

Demand Forecast: Weight Distribution

Weight

% of patients

3-5 kg 6%

5-10 kg 8%

10-15 kg 17%

15 - 20 kg 25%

20 - 25 kg 23%

25 - 30 kg 12%

30 - 40 kg 9%

Project the amount of patients per weight class and calculation of weight distribution percentages

ILLUSTRATION

Assumptions:Weight distribution provided by country in this example. When weight distribution is unknown, each weight class receives an even weight distribution (14.3%).

Security stock Assumptions

Demand Forecast: Security Stock

Establish security stock as additional number of months of treatment.

ILLUSTRATION

Assumptions:Example: Country orders once per quarter. 3 month additional security stock added to each quarterly order.

Security Stock/Buffer (Number of months): 3

Outputs of model:

• # of patients/month/ weight class/formulation

• # of units (ml, caps, tabs) per month

• # of units/quarter (with security stock)

• # of boxes/quarter (with security stock)

• Cost per quarter

Demand Forecast: Calculations

Sample page

Drug

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Suspension

D4T 15 30 45 59 74 89 104 119 134 149 163 178

3-5 kg 1 3 4 5 7 8 9 11 12 13 15 16

5-10 kg 2 4 5 7 9 11 12 14 16 18 19 21

10-15 kg 4 7 11 15 19 22 26 30 34 37 41 45

15 - 20 kg 6 11 17 22 28 33 39 44 50 55 61 66

20 - 25 kg 3 5 8 10 13 15 18 20 23 25 28 30

25 - 30 kg - - - - - - - - - - - -

30 - 40 kg - - - - - - - - - - - -

3TC 210 420 631 841 1,051 1,261 1,471 1,682 1,892 2,102 2,312 2,523

NVP 180 360 541 721 901 1,081 1,261 1,441 1,622 1,802 1,982 2,162

AZT 193 386 579 772 965 1,158 1,351 1,544 1,737 1,931 2,124 2,317

DDI 4 8 12 16 20 24 28 32 36 40 44 49

Lop/Rit 4 9 13 17 21 26 30 34 39 43 47 51

ABC 4 9 13 17 21 26 30 34 39 43 47 51

NFV - - - - - - - - - - - -

Capsules

D4T (15mg) - - - - - - - - - - - -

D4T (20mg) 3 5 8 10 13 15 18 20 23 25 28 30

D4T (30mg) 7 14 21 29 36 43 50 57 64 72 79 86

Patients Per Month Taking Drug

Sample page (cont.)

Drug Formulation

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov DecSuspension

D4T ml 13,286 26,573 39,859 53,145 66,432 79,718 93,004 106,290 119,577 132,863 146,149 159,436

3-5 kg 8 321 642 964 1,285 1,606 1,927 2,248 2,570 2,891 3,212 3,533 3,854

5-10 kg 15 803 1,606 2,409 3,212 4,015 4,818 5,621 6,424 7,227 8,030 8,833 9,636

10-15 kg 25 2,844 5,688 8,532 11,376 14,220 17,064 19,908 22,752 25,596 28,440 31,284 34,128

15 - 20 kg 35 5,855 11,710 17,566 23,421 29,276 35,131 40,986 46,842 52,697 58,552 64,407 70,263

20 - 25 kg 45 3,463 6,926 10,389 13,852 17,315 20,778 24,241 27,704 31,166 34,629 38,092 41,555

25 - 30 kg - - - - - - - - - - - -

30 - 40 kg - - - - - - - - - - - -

3TC ml 85,883 171,766 257,649 343,532 429,415 515,298 601,181 687,064 772,947 858,830 944,713 1,030,596

NVP ml 122,316 244,633 366,949 489,266 611,582 733,899 856,215 978,532 1,100,848 1,223,165 1,345,481 1,467,798

AZT ml 181,082 362,163 543,245 724,326 905,408 1,086,489 1,267,571 1,448,652 1,629,734 1,810,815 1,991,897 2,172,978

DDI ml 1,849 3,699 5,548 7,397 9,247 11,096 12,945 14,795 16,644 18,493 20,343 22,192

Lop/Rit ml 570 1,140 1,710 2,281 2,851 3,421 3,991 4,561 5,131 5,701 6,271 6,842

ABC ml 1,753 3,505 5,258 7,011 8,764 10,516 12,269 14,022 15,774 17,527 19,280 21,033

NFV mg - - - - - - - - - - - -

Capsules

D4T (15mg) Caps - - - - - - - - - -

D4T (20mg) Caps 154 308 462 616 770 923 1,077 1,231 1,385 1,539 1,693 1,847

D4T (30mg) Caps 281 562 843 1,124 1,405 1,686 1,967 2,248 2,529 2,811 3,092 3,373

Units Needed Per Month

Sample page (cont.)

Security Stock/Buffer (Number of months) 3

3 month security stock per quarter = 25% additional

stock Prices and box sizes must be verified with suppliers before placing order

DrugUnits per

Bottle/Box

Cost Per Box/Bottle

(MSF)

Import Duties and Freight

Costs

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

(US$) (US$)

Suspension

D4T 200 9.500 10.93 99,647 249,118 398,589 548,060 498 1,246 1,993 2,740 5,443 13,608 21,773 29,938

3TC 240 6.73 8.75 644,123 1,610,307 2,576,491 3,542,675 2,684 6,710 10,735 14,761 23,481 58,702 93,924 129,145

NVP 240 17.50 20.13 917,374 2,293,434 3,669,494 5,045,555 3,822 9,556 15,290 21,023 76,926 192,314 307,702 423,091

AZT 100 1.53 1.99 1,358,111 3,395,278 5,432,446 7,469,613 13,581 33,953 54,324 74,696 27,013 67,532 108,051 148,571

DDI 200 14.74 16.95 13,870 34,675 55,480 76,285 69 173 277 381 1,176 2,939 4,702 6,466

Lop/Rit 200 14.74 16.95 4,276 10,690 17,104 23,518 21 53 86 118 362 906 1,450 1,993

ABC 240 34.80 40.02 13,145 32,863 52,581 72,299 55 137 219 301 2,192 5,480 8,768 12,056

NFV 7,200 35.37 40.68 - - - - - - - - - - - -

Capsules

D4T (15mg) 56 5.25 6.04 - - - - - - - - - - - -

D4T (20mg) 56 5.25 6.04 1,154 2,886 4,617 6,349 21 52 82 113 124 311 498 684

D4T (30mg) 60 3.7 4.81 2,108 5,270 8,432 11,593 35 88 141 193 169 422 676 929

Total Boxes/Bottles per Quarter (includes Security Stock)

Total units per quarter (includes Security Stock) Total Cost Per Quarter (includes Security Stock)

(US $)

Total Cost for 1 year (4 quarterly orders): $US 2,058,715

Summary

• National drug distribution system inefficiencies may render this model less effective

• Physician practices may not be consistent with national plans, thereby rendering model less effective

• Regular communication between program management and implementing physicians is crucial

• Strength of model depends on validity of data – regular reporting of updates allows for more accurate projections

Challenges

• The development and use of demand forecasting tools will spur production of lower cost – high quality ARV pediatric formulations

• Ordering guided by model output will make stock-outs and drug wastage less likely by making national drug distribution programs operate more smoothly

• Physician prescribing practices, regimen sequencing, and treatment costs can be tracked

• Model becomes more accurate over time with introduction of updated information and will provide important national program overview data

Benefits Forecasting Tools