1. Product Development Partnerships March 11, 2010 MIT HST590: Global Health for Biomedical Researchers William Wells Director, Market Access, TB Alliance

2. Today’s session  How the TB Alliance and PDPs work  Reality check: why products need to be simple  How PDP’s define “access”

3. How can US Americans* contribute?  The vast, vast majority of services in health, education, etc in low income settings are, and always will be, provided by national staff  That leaves several types of activities for internationals:  Provide centralized, predictable, broad-based funding  Provide a technical buffer between that funding and the national programs  Provide guidance by generating evidence, global consensus and technical norms (WHO and others)  Provide technical assistance with true transfer of knowledge (not easy!)  Provide new technologies suited to low income settings *With apologies to Miss South Carolina

4. How the TB Alliance and PDPs work

5. Founding of PDPs  Charismatic leader (iOWH)  Charismatic NGO (DNDi)  Charismatic donor (TB Alliance)  Requires substantial core rather than project funding  Now receiving ~US$600m / year in funding

6. Who are the PDPs?

7. Why are PDPs needed?

8.  There is a “market failure” for diseases found solely or predominantly in low income countries  Academic researchers:  Publicly funded  Have the interest in pursuing neglected diseases  But do not have the means to do so (large chemical libraries, screening facilities, networks of trials sites and the staff to fund them)  Private sector:  Cannot justify such large expenditure when the returns are so low (e.g., global market for first-line TB drugs ~US$315m/year, and even that is split between 4 drugs and multiple local markets)  Prior to the PDPs, most products that were useful only in low income countries were discovered by “accident” (e.g., veterinary product) or for military or tourists  Good cause ≠ easy. Neglected disease = neglected research infrastructure.

9. How PDPs Work Courtesy International Partnerships for Microbicides

10. What does a PDP look like?  Distribute funding, or active project management, with coordination of multiple partners.  Can take on ‘public good’ projects that no pharma would touch (trial site database; combination regimens; regulatory improvements).  A functional PDP requires:  Discovery team (chemists and biologists)  Pre-clinical team (animal studies)  Clinical team (oversee trial design, patient enrollment, drug supplies, patient monitoring, coordination between multiple sites in multiple countries)  Access team (how will products get from Phase III to the field)  Policy, communications and fundraising team (funding / maintaining the political visibility of the disease and need for new tools)  Business management (IP, deals with partners)  Accountants, lawyers, HR

11. Partners and Collaborators Beijing TB and Thoracic Tumor Research Institute (China) British Medical Research Council (UK) Centers for Disease Control and Prevention (USA) Infectious Disease Research Institute (USA) Institute of Materia Medica (China) Korea Research Institute of Chemical Technology (South Korea) Medical Research Council (South Africa) Research Triangle Institute (USA) Research and Government Institutes Academia Colorado State University (USA) Johns Hopkins University (USA) Rutgers University (USA) Texas Agricultural & Mechanical University (USA) University of Auckland (New Zealand) University College London (UK) University of Illinois at Chicago (USA) University of Munich (Germany) University of Pennsylvania (USA) Yonsei University (Korea) Bayer HealthCare AG (Germany) GlaxoSmithKline (UK/Spain) Novartis (Switzerland/Singapore) sanofi-aventis (France) Industry

12. Commitments Donate moxifloxacin for each clinical trial site Cover costs of regulatory filings Provide moxifloxacin at an affordable price for patients with TB in the developing world Coordinate and help cover the costs of the clinical trials Ensure coordination of information and results towards the goal of registration Leverage substantial support from CDC, FDA, EDCTP, JHU Bayer:TB Alliance: Bayer/TB Alliance Partnership

13. Why would industry get involved with a PDP?

14.  Public relations benefit  Fund multi-use programs (e.g., anti-bacterial)  High volume / low margin business model  Entrée to emerging markets (BRICs)  PDP can:  Provide expertise in an unfamiliar disease and unknown market  Interface with the public health world (WHO, NGOs)  Strike deals that combine expertise from disparate sources  Take over or share burden when the real money demands hit (i.e., Phase II and III trials)

15. The first rule of Access: Keep a firm grip on in-country realities

16. Conditions in Kibera  This is a typical landscape within walking distance of one of our trial sites in Kibera (Nairobi).  ~800,000 people live in Kibera; average population density is ~1 person/37 sq ft. The throughways are narrow paths; there are no “streets” or transport.  In this shot: 2 toilets (right and left) empty into the drain next to a makeshift primary school.

17. Patient packs require significant space in small TB clinics, but they simplify drug management

18. Drug management in a vertical program  Drug management is left to nurses with no training in commodities (picture on left).  According to the nurse in this picture: “"It's a big assignment: you are a drug manager; you are a doctor; you are a counselor; you are a nurse."  In most district hospitals, the general pharmacy does not want to handle the TB drugs, as they are bulky, and the pharmacists perceive the TB program as a separate entity.  Therefore the staff must find storage space in TB clinics (picture on right).

19. Patient packs do have their drawbacks  …and/or a box of loose blisters of continuation phase drugs (left).  Both photos are from a private mission clinic. Many patients come here for privacy (to avoid stigma) but are eventually convinced to transfer back to a public treatment site closer to home.  When patients transfer (from diagnostic to treatment sites, and/or to a site closer to home), they leave behind half-used patient packs.  The result is an excess of continuation phase boxes (right)…

20. Getting the products to the people: How PDPs define “access”

21. How PDPs define Access  First: Survey end users, and make sure trials are testing products that are needed and wanted.  Second: Build the case for WHO recommendation and country adoption (model impact, cost effectiveness, etc).  Third: Solve the practical, logistical problems that arise after a positive clinical trial result (global regulatory strategy, manufacturing, country-based financing).  Fourth: Support demonstration projects, product launch, and Phase IV activities.

22. TB Alliance Market Access  Focused on the AAA strategy:  Available (supply chain, forecasting, registration, distribution strategy);  Affordable (pricing strategy, donor policies);  Adopted (issues and evidence for key decision makers).  Formulate strategy, but work through partners and existing structures.  Need to understand the process so we can facilitate coordination.  WHO recommendation is essential.  Existing Ministry of Health and NGO programs will deliver the drugs.

23. Demand Forecast (Moxi Demand Forecast) Demand Forecast (Moxi Demand Forecast) Define issues for users (Value Proposition Study) Define issues for users (Value Proposition Study) Understand the regimen change process (Country Introduction Study) Understand the regimen change process (Country Introduction Study) Support local decision-making (cost-benefit) Support local decision-making (cost-benefit) Devise local launch strategy Stakeholder and partner mapping and engagement Document resources for operational research, financing, TA, retraining Devise local launch strategy Stakeholder and partner mapping and engagement Document resources for operational research, financing, TA, retraining Engage funding and procurement agencies Engage funding and procurement agencies Market Access Strategy Market Access Strategy Regulatory Strategy Manufacturing Strategy Manufacturing Strategy Understand Existing Market (Market Study) Understand Existing Market (Market Study) IP agreements Engage guideline- setting agencies (WHO and others) Engage guideline- setting agencies (WHO and others) Pricing Strategy Consumer marketing

24. Market Study Conducted with IMS Health Published May 2007  Map TB drug market in 6 key high burden & 4 high income countries  Understand flow of drugs to prepare for launch  Fragmented, local markets  Size the existing global TB drug market  Estimate to inform TB Alliance deals and strategy  Global market of ~US$315m including all four first-line drugs

25. What Countries Want Value Proposition Study Published August 2009 Most stakeholders would welcome treatment shortening as the primary goal. Unacceptable trade-offs in all countries: Decreased efficacy Additional safety concerns or side effects requiring monitoring or expensive adjuvant therapies Significant drug interactions with other commonly- used drugs (including ARVs) Unacceptable trade-offs in some countries: Treatment frequency significantly different from current TB program (e.g., India) Unavailability in fixed-dose combination (FDC)

26. The Country Introduction Study Lessons from past regimen changes  Timelines of public sector regimen change are acceptable, but delays can occur.  Decision-making is a balance of cost, risk and benefit.  Stakeholders are conservative because there are so few options.  Their concerns are often program-based (e.g., logistics, cost) rather than patient-focused (e.g., side effects).  Decision-making procedures are variable. Many require local evidence.  Funding solutions need to be in place for new regimens.  The private or non-NTP sector can lead regimen change.  Current treatment regimens are converging to a single standard. This makes comparisons to new regimens easier.  FDC usage is widespread – new regimens must take this into account.

27. Simplicity of Product Patient kits Blister packs with FDCs Blister packs with multiple drugs Single drugs in bottles or blister packs Ease of use Ease of Production

28. Who will adopt, and why? “Crab may taste delicious, but we don’t want to be the first person to eat crab.” - TB program decision-maker at Centers for Disease Control and Prevention, Tianjin, China