1. A Demand Forecasting Tool for Pediatric Antiretroviral Medications November 3, 2004

2. Acknowledgements This talk was developed by: Alex Hurd Lynn Margherio Kate Condliffe Stephen Nicholas Special thanks to: Mark Klein, Elaine Abrams, Consuelo Beck-Sague

3. 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 treatment 4)Strategic partnerships with other international HIV/AIDS organizations Access to high quality, low-cost ARVs and diagnostic testing Aim: 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

4. 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 Africa90% of cases in Caribbean Africa Caribbean Asia/Pacific LesothoBahamas China MozambiqueDominican Republic India RwandaHaiti South AfricaJamaica TanzaniaOrganization of Eastern Caribbean States 85% of cases in Asia

5. Cost of Antiretroviral drugs

6. 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

7. 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

8. * 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 AdultPediatric # of generic suppliers w/WHO approval for at least 1 product 51* Lowest available WHO pre-qualified price (d4T+3TC+NVP) $132-140$1,000-1,150 Price reduction since October 2000** 93%62%

9. ARV procurement for children living with HIV/AIDS

10. 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

11. 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 remain  Forecasting will be more exact once agreement on universal guide is reached

12. National planning activities National operational plan for treatment, including: Pediatric ARV treatment protocols (1 st and 2 nd 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

13. 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

14. A Demand Forecasting Tool for Pediatric Antiretroviral Medications

15. 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

16. 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)

17. Demand Forecast: Dosage & Formulation (cont.) Weight Abacavir (Ziagen ® ) Stavudine (Zerit ®, d4T) Lamivudine (Epivir ®, 3TC) Zidovudine (Retrovir ®, ZDV, AZT) Didanosine (Videx ®, DDI) 8 mg/KG twice daily 1 mg/KG twice daily 4 mg/KG twice daily 240 mg/m 2 twice daily 120 mg/m 2 twice daily KGLiquid 20 mg/ml Tablet 300 mg Capsules 15, 20, 30 mg Liquid 10 mg/ml Tablet 150 mg Liquid 10 mg/ ml Capsule 100 mg Chewable tablets 25, 50, 100 mg 5 – 6. 92 ml 7 ml 7 – 9. 93 ml15 mg3 ml9 ml1 cap25mg + 25mg 10 – 11. 94 ml15 mg or (20 mg 1 ) 4 ml12 ml1 cap25mg + 25mg 12 – 14. 95 ml15 mg or (20 mg 1 ) 5 ml14 ml1 cap50mg + 25mg 15 - 16. 96 ml15 mg or (20 mg 1 ) 6 ml½ tab15 ml2 caps50mg + 25mg 17 – 19.97 ml½ tab20 mg7 ml½ tab17 ml2 caps50mg + 50mg From: Pediatric Antiretroviral and Cotrimoxazole Dosing guide, CDC, Baylor, Columbia; March 2004

18. Demand Forecast: Dosage & Formulation (cont.)  Liquid formulation vs. caps/tabs assumptions :

19. Clinical Assumptions RegimenRegimen Sequencing Initial regimen used for treatment naïve patientsAZT + 3TC + NVP100% At end of year 1, Clinical assumptions project following regimen sequencing First Line Initial RegimenAZT + 3TC + NVP80% Toxicity to NVPAZT + 3TC + EFV10% Toxicity to AZTd4T +3TC + NVP4% Toxicity to AZT & NVPd4T + 3TC + EFV4% Second Line After treatment failureABC + ddI + Lop/rit2% Protocols and regimen sequencing assumptions may need to be adjusted overtime Demand Forecast: National Protocol ILLUSTRATION

20. 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

21. Weight Distribution Assumptions Demand Forecast: Weight Distribution Weight % of patients 3-5 kg6% 5-10 kg8% 10-15 kg17% 15 - 20 kg25% 20 - 25 kg23% 25 - 30 kg12% 30 - 40 kg9% 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%).

22. 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.

23. 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

24. Sample page

25. Sample page (cont.)

26. 3 month security stock per quarter = 25% additional stock Prices and box sizes must be verified with suppliers before placing order Total Cost for 1 year (4 quarterly orders): $US 2,058,715

27. Summary

28. 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

29. 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