1. WHO Prequalification of Diagnostic and Laboratory Technologies Business Plan September 26, 2005

2. Outline Context Methodology Findings Path Forward

3. Need for diagnostic prequalification project is urgent Testing needed for diagnosis, clinical staging & monitoring –Large volume of testing is required to meet treatment targets –Capacity has to cater for a wide distribution of patients and clinical sites To meet testing demand new technology is needed that is cost effective and appropriate for resource poor settings –Testing now more expensive than drug pricing in some regions of the world –To fully expand program technology needs to be simple, cost-effective robust and provide reliable, accurate results Promising, low-cost technology beginning to be developed but needs independent validation –Could allow price reductions of up to 70% in low volume labs –Potentially more appropriate for rural settings (small, robust, allows for % read) –Not yet validated by independent group and anecdotal reports of quality problems Large scale procurement planned over the next two years and purchasers left with few good options

4. Substantially expanded testing capacity is required in order to meet treatment targets 100,000 ARV treatment target # people HIV+ not eligible for treatment 300,000 # HIV diagnostic tests required 2,400,000 Illustrative 400,000 # HIV+ people # HIV- people tested 2,000,000 Number of HIV Diagnostic Tests Needed in Country with Treatment Target of 100,000

5. Courtesy of Dr. Trevor Peter 300 5,600 CD4 testing volumes per month expand rapidly as scale-up progresses

6. Courtesy of Dr. Trevor Peter 2,800 300 VL testing volumes per month expand rapidly as scale-up progresses

7. Cost effective technologies are required to ensure sustainability of programs 44.4% 23.3% 10.2% 6.3% 3.6% 3.5% 2.5% 100% Treatment Budget – Country X ILLUSTRATIVE In Country X, lab costs constitute 23.3% of total treatment budget

8. South Africa Figures presume scale-up of 53,000 people on ARVs by end 2005 and ~800,000 people on ARVs by end 2010 in South Africa The cost implications for high volume countries are dramatic

9. Appropriate technology is beginning to be developed but needs independent evaluation New technology that is cost-effective and appropriate for resource poor settings is beginning to be developed –Point of Care technology for CD4 & VL –Platforms that allow for multiplexed assays –Combination rapid tests (e.g. HIV/Hep B, HIV/Hep C) –Test kits with longer shelf life and lower refrigeration requirements Proliferation of small manufactures including a number of manufacturers in poorly regulated markets Few National Regulatory Authorities (NRA’s) that can adequately monitor market –NRAs is resource poor settings lack capacity –Stringent regulatory authorities limited in scope  Non-representative samples  Technology not validated in appropriate settings  Lack of interest in products aimed at resource poor settings (e.g. infant diagnostics)

10. Seventeen years of experience managing evaluation program for test kits Existing relationships with WHO collaborating centers around the world Network of regulators and other experts Relationship with National Laboratories in resource poor settings The WHO’s EHT team is uniquely positioned to take on this responsibility

11. Outline Context Methodology Findings Path Forward

12. WHO/CHAI team conducted an assessment to determine resource req. for expanded program Consulted leading experts to determine process improvements required Interviewed industry leaders and implementing partners to develop demand projections Reviewed WHO supplier database to collect historical data on success rates through various stages of the program, average time to approval and average annual demand Reviewed contracts with collaborating centers and vendor invoices to collect cost information Mapped current evaluation process Developed demand and resource model Developed business plan including work plan and milestones Overview of process

13. 200620072008 CD4535 VL Technologies533 HIV Rapid & Elisa23*22 Hep B & Hep C017 Demand was estimated based on interviews with industry and implementing partners Demand Estimates for 2006 & 2007 * Note: The EHT team will put its evaluation process for rapid tests on hold until mid-2006 while it is implementing certain process changes. At that time it will resume dossier review. It will begin conducting GMP inspections in approx. ten of the companies (most currently on the bulk procurement list) Assumptions CD4 VL HIV Diagnostics 2006: Products currently available on market 2007: Point of care technology in pipe-line 2008: Platforms that allow for multiplex assays, dipstick technology 2006: DBS protocol with market leaders & infant diagnosis 2007: New technology in pipeline 2008: New technology in pipeline Combination rapid tests (e.g. HIV/ Hep B) Tests with improved performance Major manufacturing changes Antigen/ antibody tests New companies

14. Ind. Report Lab Eval. The team has developed a business plan to ensure that it can meet projected demand Activity Time Required # Days Required Direct Cost Initial contact w/ company Background research conducted Process explained LOA Dossier Review Formal Request Initial Contact Evaluation Process Plan to add GMP Inspections 1 -3 months (dossiers never close) 1-3 days/ suppliers Materials reviewed by technical officer Missing materials gathered 1 -7 months 0.5 -7 days/ suppliers Short-list of suppliers reviewed by full team Prioritization for lab eval. developed 3-5 months 0.5-1 days/ suppliers Letter of Agreement sent to companies Companies pay fee 0.5-1 month 0.5-1 days/ suppliers Tests evaluated by WHO Collaborating Center (performance & ease of use) 1-2 month 1-3 days/ suppliers 2-3 month Data collected Company sent draft report Report published

15. Outline Context Methodology Findings Path Forward

16. EHT needs to enhance its evaluation protocols and formalize its review process A.Enhance current evaluation protocols and formalize review process B.Implement procedural changes to reduce cost of process and improve time to approval C.Improve communication to internal and external stakeholders

17. EHT needs to enhance its evaluation protocols and formalize its review process 1.Increase stringency of dossier requirements to bring in-line with Global Harmonization Task Force 2.Implement GMP inspections of manufacturing sites 3.Implement feasibility studies at clinical sites, where appropriate 4.Seek oversight from WHO Expert committee

18. Source: Rapid HIV Tests: Guidelines for Use in HIV Counseling and Testing Services in Resource-Constrained Settings, WHO 2004 There are inefficiencies built into the current evaluation process that have added cost.. Cost/ Evaluation (USD Thousands) HighLowAvg. Avg. (inc. failures) Avg. w/o failures Quality of Dossier Quality of Product Quality of Dossier Only 10% of dossiers submitted include all of the documentation required The EHT team spends up to $30k/company helping them organize their dossier submissions Quality of Product For every product approved nearly $20k is spent evaluating sub-standard products

19. Ind. Report Lab Eval. LOA Dossier Review Formal Request Initial Contact Evaluation Process Plan to add GMP Inspections Initial Contact Formal Request Dossier Review LOALab Eval.Ind. Report Total WHO10.61.50.5 Supplier1.31.50.5 0.751 Collab. Center 1.511 Toltal2.32.13.511.752.513.18 … and caused delays in the review process Avg. Time Through Process It currently can take between 8 and 24 from the time a supplier submits a request to the time that they are fully evaluated

20. Outline Context Methodology Findings Path Forward

21. Procedural changes can be made that will help speed review process and save money Adjust WHO HR Policy Clarify Guidelines Strengthen Contracts Recommended Change 1.Publish document that clarifies evaluation requirements 2.Hold annual meetings with industry to review process 1.Include requirements for 2 week turn around time with WHO collaborating centers 1.Create fixed term positions within team to ensure consistency 2.Add capacity to team Problem First few steps of process are time consuming and costly Close dossier after period of time (3 months) Up to a two month lag time between dossier approval and lab evaluation b/c of scheduling problems at Laboratory Suppliers left in queue for up to one year b/c of inadequate staffing Program coordinator spends time getting new staff up learning curve Recommended Procedural Improvements

22. Procedural changes can be made that will help speed review process and save money Strengthen Coordination b/w WHO teams Close Dossiers Improve Communications Recommended Change 1.Once guidelines are clear can close dossiers after period of time (3 months) 1.Create formal prequalification list 2.Conduct regular survey of stakeholders to ensure communications reaching users 1.Revive diagnostics working group Problem Team spends substantial amount of time following up with companies that never make it through the process Evaluation reports published two times/year which can lead to a delay in time to market Not all Member States aware of Bulk Procurement Scheme Validation of diagnostic products for HIV, TB, Malaria and STIs all managed in different WHO groups Recommended Procedural Improvements

23. Baseline20062007 Total Cost (USD MM)$1.2$2.3$2.1 Staffing (# FTEs)2.566 Project will need additional resources to add new products and to enhance review process Summary of Resources Required Staffing Plan 1 Coordinating Technical Officer – oversee process 1 Non-technical Officer (budgeting & planning, contract negotiation, external and internal communications) 3 Technical Officers - manage product evaluation, review dossiers; write evaluation reports, write guidelines 1 Administrative Assistant 2 External Consultants to support CD4 evaluation process & 2 consultants to support VL process- Train field sites, assist in protocol development GMP Inspectors -6 in 2006,

24. A number of challenges that will need to be managed to ensure success of program Key Challenges Plan Inspector/ Consultant availability Coordination between groups at WHO Sustainability Management Support Utilize network to develop a pool of inspectors & develop inspection schedule Develop back-up plan including use of private consultants Revive diagnostic working group & include group in protocol development and ongoing planning Build capacity at regional and national level Ensure annual prioritization of products in pipeline Include focus on fundraising in TOR for non-technical officer Ensure management support so that decisions are made quickly & appropriate resources made available

25. Secure approval to hire technical officer to manage CD4 process Draft new evaluation protocols Recruit assessors & consultants Recruit 2 additional technical officers and 1 non-technical officer Next Steps Immediate Next Steps