Accelerating Innovation and Access to Medicines for Tuberculosis through Open Collaboration

Standard Template for a Candidate Demonstration Project Note: the questions with asterisk should be filled.

1.*

Title of the project: Accelerating Innovation and Access to Medicines for Tuberculosis through Open Collaboration: A Push, Pull, Pool Approach (“the 3P Project”)

2.*

Submitted by: Médecins Sans Frontières/ Doctors without Borders (MSF) Contact information: Dr Manica Balasegaram, Executive Director, Médecins Sans Frontières- Access Campaign, Rue de Lausanne 78, 1211 Geneva, Switzerland.

Email: Access@msf.org Phone: + 41(0) 22 849 8902

3.*

Target disease or health condition: (Focus on type II and III diseases and special R&D needs of developing countries in type I diseases where there is an identified health technology gap.)

Tuberculosis (TB): both drug-sensitive (DS-TB) and drug-resistant (DR-TB)

4.*

The suggested health technology that project seeks to develop: (e.g. medicine; diagnostic test; medical device; vaccine etc.)

TB medicines: single drugs, regimens, fixed-dose combinations, and pediatric formulations

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5.*

Project summary:

In 2011, there were 12 million people who needed TB treatment worldwide; 95% of whom live in low- and middle-income countries (L&MICs). Because the TB mycobacterium mutates quickly and requires prolonged therapy under the best of circumstances, it needs to be treated using drugs in combination. Multiple Drug Resistant TB (MDR-TB) infected over 310,000 people in 2011, and there are reports of Extensively Drug Resistant TB (XDRTB) and even Totally Drug Resistant TB (TDR-TB).

However, current TB medicines are over 50 years old. The first new TB medicine in 50 years was recently approved by the United States Food and Drug Administration (bedaquiline); however, it has mainly been tested with older medicines, and as yet no novel ‘pan-TB’ regimens (effective against drug-sensitive and drug-resistant TB) have been fully developed. In essence, while TB treatment and TB drug research and development has recently taken positive steps forward, the current R&D system has failed to deliver the giant leap forward that is needed – that is, a more effective, shorter and safe combination of multiple new TB drugs, active against both drug sensitive and drug resistant TB. Furthermore, a healthy pipeline is needed due to the expected emergence of drug resistance. However, there are not enough candidate drugs in the pipeline, and many of those that exist are stalled or moving forward too slowly. TB is not a high priority in commercial drug development, as it predominately affects patients in L&MICs and often vulnerable populations, such as the homeless, prisoners, migrants and those co-infected with HIV. The ultimate goal in TB treatment is a combination of medicines that effectively, safely and quickly treats all forms of TB in as few pills as possible(i.e., a fixed-dose combination).

There is an urgent need to improve MDR-TB treatment especially: the current treatment for DS-TB takes 6 months and MDR-TB treatment takes 2 years, including daily injections for at least 8 months. MDR-TB treatment is particularly difficult, because many medicines are toxic with side effects, such as deafness, psychosis and severe nausea. Thus, MDR-TB patients have difficulty in completing their treatment, making them less likely to be cured of TB, exacerbating their drug resistance and left with very limited future treatment options.

Today, existing incentives drive commercial drug developers to develop individual compounds in isolation. However, what is required is the simultaneous development of multiple compounds tested in combination with each other.

We propose to transform R&D for new TB treatments through the “3P Project” – incorporating novel approaches to financing R&D (Push, Pull) and managing intellectual property (Pool) in order to accelerate innovation and achieve more equitable access to 2

better medicines. In this open, collaborative framework, researchers and clinicians will be incentivized to share scientific data and clinical trial results, and to conduct medically appropriate research on multiple compounds. A Technical/Scientific Advisory Committee, which could be hosted by organizations such as the WHO or the Critical Path to TB Drug Regimens (CPTR), will set technical priorities and define Target Regimen Profiles for TB treatment, including an improved treatment for MDR-TB. This system offers four benefits over the current system: 1) reducing the duplication of research efforts thereby saving time and money, 2) “de-risking� potential combinations as early and as affordably as possible, 3) accelerating drug combination development, and 4) reducing the risk of resistance to new compounds.

In addition, the project will have key milestone prizes for combination regimens of TB medicines that progress through major hurdles in the R&D process; these could include entry into clinical development (Phase I), proof of concept that a novel compound has TB activity in humans, and commitment to start Phase III, alongside a prize for entering the open collaborative framework. Discretionary grant funding would also be a major component of the initiative as the present availability of grant funding (the Push component) is woefully insufficient to support even the present activities in new TB drug R&D. Where such Pull and Push incentives are not sufficient, royalty-bearing licenses could be negotiated between the patent pool and the IP holder(s).

The project would seek to leverage as much as possible the existing capacity and expertise in TB in novel ways to foster greater collaboration. Through this open collaborative approach to R&D, it is expected that new combinations of TB medicines to be delivered faster and made more accessible to millions of people in need.

The 3P Project responds to WHA Resolution 66.22 and the recommendations of the CEWG. It applies four CEWG-recommended mechanisms (prizes, grants, open-sharing of knowledge and patent pooling) to address a high-burden disease that disproportionately affects developing countries, where there are clear failures of the existing R&D system. It would ensure that innovators are fairly rewarded. And it would de-link the financing of R&D from medicines prices in an area where existing market incentives have proven to be inadequate, and thereby take a major step forward for affordability and access.

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6.*

Public health need that the proposed project aims to address: (Explain the public health need in terms of burden of disease; prevalence; incidence; fatality rate; geographical spread; current interventions and their limitations; and what proposed new technology would change in terms of disease prevention, control, diagnosis, treatment etc. If detailed information is not possible at present then please provide some basic level information)

TB is a major global health threat with 12 million cases worldwide (prevalence), of which 8.7 million were new infections (incidence) in 2011. TB disproportionately affects L&MICs, home to 95% of TB cases. The four medicines used in combination to treat DS-TB were developed over 50 years ago.

MDR-TB is an increasing worldwide threat with an estimated 310,000 cases in 2011. MDRTB is defined as TB resistant to at least rifampicin and isoniazid. Approximately 4% of new TB cases and 20% of retreated cases are multidrug resistant, with some countries reporting substantially higher figures [i].

Detection and treatment of MDR-TB remains a huge challenge. The WHO reports that the number of MDR-TB cases notified in 2011 represented only 19% of the estimated 310 000 cases of MDR-TB among reported TB patients with pulmonary TB, and less than 10% in the two countries with the largest number of cases, China and India[ii]. Further, the WHO reports that levels of MDR-TB are worryingly high in some parts of the world, notably countries in Eastern Europe and Central Asia. In several of these countries, 9–32% of new cases are MDR-TB and for previously treated cases, this figure rises to over 50%.

Currently, fewer than 20% of MDR-TB patients are on treatment, and there is an urgent need to scale up treatment [i]. One of the biggest barriers to scaling up MDR-TB treatment is the lengthy, complex, ineffective, poorly tolerated and expensive treatment regimen. The current WHO-recommended MDR-TB treatment regimen [iii] requires daily injections for a minimum of 8 months and has a total duration of at least 20 months. The drugs are less efficacious than those used to treat DS-TB and have more adverse side effects. Outcomes are poor, with only a 54% success rate, and default, death and failure rates of 23%, 15% and 8%, respectively[iv]. Each course costs around $4000 per patient, which is likely to be unaffordable or unsustainable for many L&MICs [v].

To effectively scale up treatment and stop the further spread of MDR-TB, a new treatment regimen is needed consisting of a combination of multiple new TB medicines that is shorter, less toxic, all oral, suitable for patients co-infected with HIV, and affordable[vi].

For the first time in over 50 years, new drugs are being developed to treat TB with a specific emphasis by some sponsors on MDR-TB. One new compound, bedaquiline, 4

received FDA accelerated approval in December 2012 and a second, delamanid, is in Phase III awaiting approval from a stringent regulatory authority (SRA). A third compound PA824, will potentially enter Phase III development for TB in 2014, predominantly for DS-TB, but with the potential to treat some forms of MDR-TB. While the development of new drugs is good news, the current R&D process has incentivized the development of these new drugs in isolation from each other, leaving unanswered the key questions, “will these drugs work together to treat TB, is it safe to use them together, and if so, how?”. While organizations and collaborations, such as the Global Alliance for TB Drug Development (TB Alliance), Critical Path to TB Drug Regimens (CPTR) and RESIST-TB are working on developing new TB regimens, some of which would target both DS and MDR-TB, all these organizations have encountered various challenges, which could be, in part, addressed by this proposal.

This proposal seeks to answer the types of questions outlined above about how different potential TB medicines could work together in specific combinations earlier in the R&D process through an open collaborative framework. The project will also address “sticking points” in TB R&D through a mix of pull (prize) and push (grant) funding. This will “delink” the investment in TB R&D from the final price of the TB combination regimen, enabling greater access to affordable, safe, effective and convenient medicines where the vast majority of TB patients are, in L&MICs.

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7.*

Explain which new and innovative approaches and mechanisms to supporting financing and coordination of R&D this project would demonstrate?

(This is a very important part to be filled. The idea of these demonstrations projects is “to address identified gaps that disproportionately affect developing countries, particularly the poor, and for which immediate action can be taken” (WHA66.22).

66th WHA considered these demonstration projects as part of the efforts to “take forward action in relation to monitoring, coordination and financing for health research and development”. The assembly decided to identify such projects that: “(a) address identified research and development gaps related to discovery, development and/or delivery, including promising product pipelines, for diseases that disproportionally affect developing countries, particularly the poor, and for which immediate action can be taken; (b) utilize collaborative approaches, including openknowledge approaches, for research and development coordination; (c) promote the de-linkage of the cost of research and development from product price; and (d) propose and foster financing mechanisms including innovative, sustainable and pooled funding; (2) The demonstration projects should provide evidence for long-term sustainable solutions.”)

For the first time in decades, there is progress in developing new TB medicines. However, many challenges remain. Principally, the current R&D framework within the commercial sectors and specifically within the pharmaceutical industry incentivizes the development of new potential TB medicines in isolation (e.g., in combination with older TB drugs, rather than with other new compounds to create superior regimens), while the actual medical need is for combinations of novel TB medicines. Moreover, a general lack of market incentives for TB drug development leads to multiple, if not continuous “sticking points” in the TB R&D pipeline, including organizations entering the area of TB drug R&D, the Preclinical to Clinical transition point, and commitment to the most expensive phases of drug development (Phase IIb and Phase III) (Diagram 1). Eventually, multiple gaps in the pipeline develop, as demonstrated by the lack of potential medicines in early clinical development (Phase I) and the dearth of late stage clinical projects testing novel regimens.

We propose to address these challenges in the TB R&D pipeline through the creation of a new open collaborative framework for regimen development based on the sharing of data, the pooling of IP and the creation of incentives for multiple actors to enter the R&D process in order to accelerate development timelines. The open collaborative framework for the development of compounds is the central element of the proposal. Pooling of relevant intellectual property will be part of participating in the open collaborative framework.

Incentives, such as prizes and grant funding for R&D studies, are included to encourage participation in the open collaborative framework and to intervene at multiple strategic stages of the R&D process in order to accelerate development (see also Diagram 1 for examples of two potential areas of prize intervention).Ultimately, participants would be able to access a range of TB compounds to conduct R&D that is in line with the Target Regimen Profiles set by the Technical/Scientific Advisory Committee. Without the 6

impediment of restrictive patents especially in the high TB burden countries, multiple players, including producers, could work in the field and manufacturers could obtain sublicenses to manufacture and sell new TB regimens once they are approved. Thus, this project would de-link the cost of R&D from the price of the final product and also overcome the impediment of patents blocking organizations from developing novel regimens.

Diagram 1a. An example of a schematic for proposed mechanism including proposed prizes, grants and patent pooling.

Step 1: Increase drug discovery activity through smaller, early-stage milestone prizes: Creativity and novel approaches are especially important in the earliest phases of drug discovery, when potential drug candidates are identified. Milestone prizes are particularly well-suited for spurring innovative effort from a large, diverse pool of Research Organizations (ROs) who could be working anywhere worldwide with a wide range of scientific approaches.vii (Note that ROs could include academic, public, non-profit, or private labs, from small to large-scale).

During the Discovery phase (Hit-to-Lead and Lead Optimization), lead compounds are licensed to a patent pool, which is a central component of the open collaborative framework. In exchange for a relatively small (Size 1) milestone prize, which would be a mix of financial and recognition prizes depending upon the technology, ROs would agree to 7

openly share all of the scientific data via publication or other platform and to allow others also to carry out research on the compound (e.g. in combinations) by licensing relevant intellectual property rights (IPR) to the patent pool. In general, the project would seek to license in compounds as early as possible to enable early open-knowledge sharing and avoid costly duplication of research efforts. In order to ensure only promising compounds enter the pool, a Technical/Scientific Advisory Committee would be used to assess whether or not to include the compound into the open collaborative framework, using the Target Product Profile as a basis for the evaluation.

Step 2: Attract in and accelerate progress of compounds stalled in preclinical development through milestone prizes and grants: Compounds that have progressed through the stages of Lead Optimization, Preclinical, and GLP toxicity studies where there is a very high attrition rate of compounds and are ready to enter clinical development (Phase I) would be candidates for medium (Size 2) milestone prizes. Such prizes would be used to spur the development of compounds already in the open collaborative framework and to attract in new compounds from outside. The milestone prizes would be awarded on the condition that all relevant IPR is licensed to the patent pool (if not already) and all research findings openly published. For compounds licensed in earlier in the R&D process, the mechanism would also make available, on a discretionary basis, grants to fund further Preclinical research, such as GLP toxicity studies for promising compounds (as assessed by a Technical/Scientific Advisory Committee). The size of a milestone prize available to a RO that has received grant funding from ‘the 3P Project’ would be adjusted accordingly to avoid over payment. Both are offered on the understanding that different ROs may need different incentives depending on their access to alternative sources of funding.

Step 3: Accelerate progress of regimens through Phase I and II trials through milestone prizes and grants: As with Step 2, moving compounds and regimens through Phase I and II trials in Step 3 could be financed through two routes: one, the project will offer a large (Size 3) milestone prize ex post for a regimen that meets the TPP and successfully completes Phase IIb studies. Alternately, ROs could apply for grant funding ex ante to carry out Phase I and II trials on promising regimens (as assessed by the Technical/Scientific Advisory Committee). Neither milestone prizes nor grants would be available for single drugs, but rather, would be restricted to drug regimens, unless these were specific agreed upon studies that are required to demonstrate clear activity or benefit of the single test drug. If the relevant IP for research and production had not yet been licensed to the patent pool, ROs would need to grant such licenses and publish or otherwise share data in order to receive any milestone prizes or grants. At this stage, the size of a milestone prize available to a RO that has received grant funding from ‘the 3P Project’ would be adjusted accordingly to avoid over payment.

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Step 4: Publicly-financed Phase III trials: By the time compounds have completed Phase II trials, risk and uncertainty are considerably lowered, but costs are relatively high. At this point, public funds would be needed to pay for Phase III clinical trials and submission to an SRA and to high burden countries regulatory agencies. This would be allocated through grants. Synergies with existing sources of public funding for clinical trials would be sought in order to maximize value for money.

Step 5: Production: Once a regimen receives regulatory approval, it could be manufactured by multiple competing producers taking licenses from the patent pool (see further details in Question 12 below).

8.*

Evidence of market failure/research landscape: (Explain why there has been no investment in this technology or why investment has not resulted in access to the health care product.)

As a disease of poverty mainly affecting L&MICs, TB has suffered from chronic under investment and a lack of commercial interest. Although financing for TB R&D has increased in recent years, only about 30% of the projected needed funding is currently being invested,viiiwith an estimated gap of $1.4 billion per year.ix While thanks to the efforts of the present funders of TB drug R&D, the pipeline is in much better condition than it was a decade ago (see Diagram 2), the current R&D funding as well as the system in which it operates continues to be deficient. For example, many of the compounds currently in Phase II and Phase III are older “repurposed’ compounds that have already been used for MDRTB. One of the compounds is no longer approved for use in high-income markets due to safety concerns. This means that although the late stage pipeline is improved over 5 to 10 years ago, upon close examination, only three new classes of compounds (diarlyquinolines, nitroimidazoles and oxazolidinones) have been introduced into clinical development, and even then, the commercial sponsors have largely opted to develop these compounds individually, thus missing the overall goal of the development of a TB combination regimen with multiple new TB drugs.

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Diagram 2. Global TB Drug Pipeline June 2013.

x

The weaknesses in the TB R&D pipeline have multiple causes, including: Inadequate incentive for research organizations to enter the field of TB drug discovery.

Inadequate incentives for open-knowledge innovation: In all phases of R&D, from Discovery to product development, there are insufficient incentives for researchers to share information openly and collaborate, resulting in much work, especially by the pharmaceutical industry, being carried out in isolation.

Incentives poorly aligned for combination therapy: TB needs to be treated using a combination of drugs as the bacterium easily develops resistance to single compounds.

However, the current drug development framework is failing to deliver optimized combination regimens. Due to weak incentives for information sharing and collaborative development, competition among drug developers and limited access to IP of others, some of the potential new drugs are being developed in isolation and would then be released onto the market with little knowledge of how to effectively combine them with existing and new drugs. This presents dangers to patients, as the drugs will likely be combined in

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clinical practice without the necessary supporting evidence. Introducing new drugs in untested and inadequate regimens also puts the efficacy of the drugs at risk as it has the potential to encourage resistance to develop. As an illustration, some of the most promising drugs in late-stage MDR-TB development (including delamanid and the first new drug to have received regulatory approval in decades - bedaquiline) have not been sufficiently tested with the others as part of new MDR-regimens.

Intellectual property needs to be managed to promote sharing and licensing: At each stage, from discovery to market, lack of access to the requisite IPR inhibits collaborative research, follow-on innovation, the testing of combinations and affordability of the end product.

Inadequate incentives for private sector financing: In all phases of R&D, but especially in the clinical development phase, funding is needed to carry out the work, but the incentive for industry to do so is inadequate, since the market is far less lucrative than for competing diseases. Less than 30% of total TB R&D spending in 2011 came from the private sector, and only about $220 million was invested in drug R&D. While there are several compounds in the pre-clinical stage, there are no candidate compounds in Phase 1 trials. Lack of financing means slow or stalled scientific progress, as the work in TB drug discovery is woefully inadequate and promising compounds languish at the pre-clinical stage.

An example of the challenges outlined in this proposal is demonstrated by the slow progress of the compound sutezolid. Sutezolid has moved very slowly through the early Phase I and IIa trials. The results of these trials have not yet been published, and collaboration with other ROs has been very limited. Sutezolid has since been exclusively licensed to another pharmaceutical company, but a pathway for inclusion of sutezolid in novel regimen development still is not defined and time has been lost. Similarly, delamanid, a compound in Phase III, has not yet been combined with other new drugs in trials. Thus, without effective incentives, some of the private sector based ROs have either not combined and/or not developed potentially useful compounds further.

Further detail on these weaknesses is provided in the response to Question 9 below.

9.

The scientific and technical feasibility: (Describe the scientific and technical basis for the proposed technology in terms of the state of the art e.g. candidate molecules; biomarkers; pipeline; previous efforts, if any, to develop same or similar technology etc. Include some risk analysis)

The need for new TB drug combinations is not a new problem in public health. The scientific techniques for TB research, such as mycobacterial culture, are well established,

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enabling researchers to focus most of their efforts on drug development. In Discovery and Preclinical, the majority of compounds are being developed by public research institutions, small pharmaceutical companies or product development partnerships (PDPs)xi, but it is unclear if many of these entities have the necessary capital and resources to bring sufficient numbers of these products forward to Phase I trials. However, a mix of scientific coordination, open access to information and funding options (i.e., milestone prizes or grants), as outlined in this proposal, can provide the necessary incentives and coordination to stimulate more organizations to enter this field and then to move promising TB compounds and combinations from Preclinical to Clinical.

The drug pipeline for TB currently has no drugs in Phase I and ten drugs in clinical Phase II and III testing (4 repurposed, 6 new drugs [not all of which promise major therapeutic advance, as explained above] and 3 new classes of drugs; see Diagram 2). The new drugs, with the exception of PA-824 and bedaquiline for drug sensitive TB (both of which are being developed by the TB Alliance), are being developed as single products and are not involved in combination trials or new regimen trials. The gap in the TB pipeline at Phase I is particularly worrisome, as a robust pipeline with a constant flow of new or improved compounds is especially important for TB, as the mycobacterium has repeatedly shown that it can develop resistance to compounds. Stimulating new players to enter the field, opening up the pipeline to promote collaboration for drug combinations and regimen development, and offering incentives to facilitate progression, will help ensure a more robust pipeline that will progress in both a timely and efficient manner. Drug-drug interaction and potential beneficial drug combinations can be discovered early if products are tested together at an early stage, thereby speeding up the development of new regimens.

With regards to new MDR-TB regimen development, there are at least five main entities working in this area: TB Alliance, the UK’s Medical Research Council (MRC), Critical Path to TB Drug Regimens (CPTR), the Open Source Drug Discovery (OSDD) and RESIST TB. • TB Alliance is developing PA-824 (a nitromidoxazole) and bedaquiline for drug sensitive TB with the intention of using these drugs as components of novel regimens. This work has, however, been hindered by the lack of other sponsors to commit their compounds to novel regimen development.

• The MRC is conducting a trial for a new shorter regimen for MDR-TB, the STREAM trial. This would reduce duration of treatment to 9 months, but unfortunately still contains an injectable agent and does not contain any new drugs.

• The CPTR initiative has provided a venue for all interested in regimen development to work together to advance the field, but there are no required provisions in areas such as patent licensing and the initiative does not provide any funding or prizes for actual R&D activities.

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•

OSDD and RESIST TB have new regimen trials in late stages of planning. These trials are hoping to combine more than one new drug.

These organizations have been unable to access some of the new compounds for testing combination regimens. This has constrained the development of these much-needed regimens. Nevertheless, this activity highlights that new regimen trials can be designed and commenced if the framework and incentives to conduct the R&D is strengthened.

Risks associated with this proposal include the standard R&D risks. However, for antibiotics, such as anti-TB drugs, the risks can be minimized by testing novel TB compounds in combination earlier in R&D rather than later during proof of concept (Phase II) clinical trials.

Specific risks associated with this proposal will be further delineated as the proposal continues to develop, but a selection include: recruiting participants to share their data and in-license their IP into the open collaborative framework, sourcing adequate funding for the milestone prizes and push funding, especially for late stage clinical trials, competing incentive frameworks that may discourage ROs from licensing their IP, finding producers to manufacture and sell an approved TB combination developed through this mechanism, and ensuring open and transparent governance.

10.

Reasons for proposing: (Provide details if any priority setting and/or selection criteria that has underpinned the consideration to take up this area of technology for development.)

Fundamentally, this proposal is put forth in light of insufficient funding and resources, inadequate incentives, along with a lack of coordination in developing a TB combination regimen composed of novel medicines, the time delays in moving even an individual novel TB medicine through R&D, and the lack of knowledge in how to best use and the lack of accessibility to the first new TB drug developed in over half a century by the vast majority of TB patients in need of the medicine, due to the fact that the drug was not developed by the sponsor in a manner to optimize its utility and to address affordability issues.

From a public health and medical perspective, three factors make this project a high priority: the heavy existing burden of disease, the risks posed by ongoing spread of MDRand XDR-TB, and the severe shortcomings of existing technologies (all described earlier in this proposal).

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From an innovation policy perspective, two factors make this a high priority: there is a well-identified shortfall in R&D investment, and there is adequate scientific understanding of the disease to make drug development a promising endeavor such that intervening in the system now is likely to yield fruitful results. As a result, TB drug development is an area amenable to testing out new models for push- and pull-financing, IP management and coordination that could yield broader lessons for new approaches to R&D.

11.

Who could potentially develop the technology/carry out the research?

(Provide known details: individual researcher? Group of researchers/Research/coordination organization including PDPs/Group of research organizations working together? Combination of these; What would be the process of selection of developers?)

The project would be open to all entities with relevant compounds to license in, and to all ROs interested in conducting research to advance the development of new drugs and regimens. As noted above, ROs could include universities, public research institutions, small/medium and large private firms, contract research organizations, and product development partnerships. In earlier stages when pull-incentives are being offered, the objective would be to attract and incentivize new and existing ROs, rather than to select just a few. At later stages, selection of promising compounds and projects would be done by a Technical/Scientific Advisory Committee.

For the five ROs currently working on new regimen development (listed in Question 9 above), the project would help these groups accelerate their regimen development trials and make available additional compounds for potential inclusion in their research by facilitating access to IP and offering competitive grant funding, as needed.

12.

Who could potentially manufacture the final product?

Multinational company? Local production? Joint venture? How the decision will be made about the producer?

Given the high numbers of patients, the volumes of drugs required for DS-TB would potentially be large; therefore, production would benefit from economies of scale. Multiple manufacturers with proven capacity to produce quality-assured drugs (stringent regulatory authority (SRA)/WHO Pre-Qualification) and deliver them in a timely manner (whether originator companies, generic companies, local producers, or other) would be eligible for licenses to manufacture. For DR-TB, if volumes are small, production could be carried out by just one or two of the handful of existing DR-TB drug manufacturers that

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have received SRA/WHO Pre-Qualification. If DR-TB drug volumes increase with improved access to diagnostics, as is hoped, and if a pan TB regimen is eventually developed, production could eventually transition to a larger number of competing producers. (An updated list of pre-qualified manufacturers is available at http://apps.who.int/prequal/)

13.

What could be the role of WHO, if any, in this demonstration project to bring this venture to fruition?

WHO would have a central role to play in several aspects of this project: • Normative/standard-setting: First, WHO might be well placed to participate in gathering the world’s best TB drug development experts into a Technical/Scientific Advisory Committee that would first develop a Target Regimen Profile for new TB regimens, including those for MDR-TB. This could be done in conjunction with other organizations and initiatives such as CPTR. The developed profiles would be used to guide decisions on awarding prize funds. The Technical/Scientific Advisory Committee could also select early-stage promising “hit to lead” efforts for recognition, and at later-stages, assess which projects would be most promising to receive grant funding, or to be awarded prize funds. (Such committee could be convened jointly with, or build upon, existing technical advisory committees already working on TB.) • Advice to countries: WHO could also offer guidance to country regulators on requirements for clinical trials for new TB regimens and recommendations and guidance on the use of new regimens as they progress through clinical trials. Finally, once useful regimens are developed, WHO could rapidly incorporate them into international guidelines (e.g. treatment guidelines, Model List of Essential Medicines), and facilitate registration and uptake at national level and ensure that the WHO PQ department facilitates process for QA of new drugs and combinations (if FDC products are developed).

• Leadership: WHO could add its political weight to efforts to convince ROs to participate in the initiative.

• Information and Evidence: WHO could act as a repository of data on adverse effects to facilitate international post-marketing surveillance.

• Convening for monitoring: WHO could periodically convene a wide range of stakeholders to monitor progress and ensure accountability. This could also be done jointly with others, such as the International Union Against Tuberculosis and Lung Disease and CPTR.

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The proposal would seek to leverage the existing expertise and capacity within the WHO TB Department, the Stop TB Partnership, the Global Drug Facility and the Special Programme for Research and Training in Tropical Diseases in these efforts.

14.

Please outline a timeframe and projected milestones for the project covering the first 5 years. This should also highlight the immediate actions that need to be taken?

It is estimated that it will take a 12-18 months to set up the mechanism proposed above. A high-level work plan is outlined in Diagram 3.

Diagram 3. Draft Work Plan

Proposed Milestones: Milestones will be developed on an annual basis and will measure progress against the overall five-year goal of recruiting participants to share their scientific and clinical data, license their intellectual property and to advance combination drug regimens through the R&D pipeline. Actual milestones will depend upon the stage of compounds put in the mechanism. Milestones should focus on getting more compounds into phase I and advancing combination drug regimens through the R&D process while measuring 16

progress, such as recruiting participants to the mechanism. Year 1 milestones will also include the tasks of setting up the appropriate organizational, governance, stakeholder management, analytical (e.g., compound prioritization) and financial systems to manage the mechanism.

Immediate actions are outlined at a high-level in Diagram 3 before “Project Approval.�

Specific activities include: 1. Assess stakeholder interest and gain buy-in, as necessary. Stakeholders include: intergovernmental organizations, such as WHO, Stop TB Partnership; nongovernmental organizations, such as TB Alliance; small and large originator and generic pharmaceutical companies; potential entities that could host the patent pool; universities; public research institutions; governments; among others; 2. Develop the cost calculation for the prizes and grant (push) funding; 3. Define the organizational and governance structure for the mechanism; 4. Develop a cost calculation for the operation of the mechanism, depending upon the organizational structure; 5. Establish draft Target Regimen Profiles; 6. Develop a draft evaluation framework for assessing potential recruits to the mechanism to ensure that all recruits meet a minimum threshold (TBD).

15.

What is the intellectual property (IP) landscape relative to this project? Is there any IP, e.g. patents that need to be licensed in to be able to develop and market the product in developing countries? How would IP and related intellectual assets, including knowhow, proposed to be managed in this project?

Almost all new TB drugs are under patent protection and multiple patents have been granted or are under consideration, especially in countries with a high disease burden. The patent barriers for new TB drugs are considerable, and represent a dramatic departure from the current situation, where nearly all existing drugs are off patent. The existing IP landscape on promising TB candidates presents potential obstacles to the development of regimens that may be patented by several different entities, and fails to guarantee the affordable access of the final product once developed. Thus, a central feature of this proposal is to incentivize the pooling of the relevant IP at the earliest stages to ensure that open, collaborative approaches to R&D are facilitated, and to ensure that the IP for the final product(s) is made widely available to ensure equitable access. In the process, the project will confer two significant additional benefits: (1) become a repository of information relating to the IP status of TB drug candidates throughout the developing world; and (2) promote greater transparency into the licensing process.

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At each stage where grant or prize funding is made available, a condition of receiving funding will be to license any existing IP on a target compound into the patent pool. Thus, the size of the grant or prize funding will have to be carefully calibrated to ensure that it serves as a real incentive for IP holders to participate in the patent pool. Where such incentives are not sufficient, royalty-bearing licenses could be negotiated between the patent pool and the IP holder(s). These licenses will enable any interested RO to engage in a wide area of research, including the ability to investigate the compound in combination with other compounds. In turn, as a condition for taking a license, the RO will be contractually obliged to publish the results of its research (see Diagram 4). Moreover, the licenses in the patent pool will stipulate that any further IP (including know-how) that is generated as a result of an RO's participation in the patent pool will be licensed back into the patent pool on similar terms and conditions. Thus, once a regimen is successfully developed and approved, all of the necessary IP will already have been licensed in the patent pool. This IP would then be made available for out-licensing to interested and qualified licensees that can manufacture affordable, quality-assured products. All of the licenses in the patent pool would be made publicly available.

Diagram 4. Open Collaborative Framework

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16.*

What would be the strategy to ensure access to the product once it is developed?

(Access is an important dimension of these demonstration projects, it is important for the projects to begin with the end in mind, explain how this project would deliver the technologies to the needy patients i.e. price and affordability; modes of supply; storage; prescription; dispensing; and compliance; WHO will develop guiding principles for ensuring access to any products coming out of the demonstration projects)

A new TB combination regimen developed through this open collaborative framework would contribute to improving patient access in multiple ways. First, a simplified regimen would facilitate scale-up of MDR-TB treatment in national TB programs (NTPs). TB care is generally provided free of charge by NTPs, though in some countries there are private providers who may charge patients for care and medication. With the current treatment for MDR-TB being so programmatically burdensome and expensive there is a limit on what a NTP can provide, meaning patients often die waiting for treatment. By simplifying and shortening the current MDR-TB regimen it will become less expensive and more accessible than the current regimen. This will create the potential for NTPs to implement widespread scale up to adequately meet needs, decreasing the potential exploitation of vulnerable groups by private providers, and unnecessary deaths.

Once an all-oral regimen is developed it will be possible to further simplify treatment from the current standard of care in MDR-TB, which includes eight months of daily injections.

This would allow for the development of fixed-dose combinations (FDCs), predefined prescription pads and patient packs that allow easier prescribing and dispensing.

Removing the medications with the worst side effects from the current MDR-TB treatment regimen and reducing the length of treatment will also facilitate patient adherence to treatment, thereby contributing to improved outcomes and ultimately reducing the burden of MDR-TB. The ultimate goal would be to devise totally novel TB drug regimens which are equally effective against all forms of TB, whether resistant or not to any of the presently available compounds.

Finally, the project would contribute to affordable, sustainable prices for novel TB regimens by building access provisions in from the earliest stages of drug development.

Because the costs for R&D will be paid for by public funds, manufacturers would no longer need to recoup its R&D costs through the price of the final product. Accordingly, a central condition of receiving prize money and/or grant funding is licensing the relevant IP to enable competitive production of the novel TB regimen upon regulatory approval. Since the demonstration project focuses on product development, rather than national level issues, it is assumed that existing institutions (e.g. WHO, Stop TB’s Global Drug Facility, Global Fund) would continue offering support to national TB programs.

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17.

How could the project be financed paying particular attention to the need to demonstrate new and innovative forms of financing? Also provide an estimated cost of the project.

The project could be financed by a consortium of governments and other research funders.

However, given the current shortfall in TB R&D funding, it is critical that such funding be in addition to and leverage existing funds, where available, rather than simply divert existing funding to this mechanism. One “value-add” of this mechanism would be to coordinate disparate, but relevant sources of funding and to connect the funding to the obligation to share scientific and clinical data and IPR, ultimately leading to the de-linkage of R&D costs from the final price of the new TB combination regimen. The group of government donors should include TB endemic countries at all levels of development.

Prizes are defined below. Developing cost estimates is an immediate action as outlined in Question #14 (bullet #2).

1. Size 1 Prize: small prizes for licensing IP and sharing research data in the hit-to-lead phase.

2. Size 2 Prize: This prize should be larger than the costs to do lead optimization, preclinical and GLP toxicology studies, perhaps by an order of 2-3x.

3. Size 3 Prize: Two main factors would shape the amount offered for the prize: 1) The net private cost of R&D (Total R&D cost minus public/philanthropic contributions) through Phase I and II,) and 2) Total public health value of the product (calculated using pharmacoeconomic methods). Total prize should exceed cost of R&D but be less than the ‘public health value’ of the technology.

Cost estimates for the amount of grant funding required for each phase of R&D also need to be developed.

A high-level estimate of the total cost of the project ranges from $83 M - $250 M. The low estimate is the estimated costs for R&D for a regimen composed of four novel drugs from the beginning (Discovery) through proof of concept (Phase IIb completion), or how much it costs to push fund the entire process. Another way to consider the low estimate is that the prizes are only to recoup a reasonable investment made in R&D; however, the attractiveness of a prize that only reimburses costs is debatable. The high estimate is approximately three times the estimated R&D costs as an example of a perhaps compelling set of prizes; however, the high estimate needs to be validated through a pharmacoeconomic analysis of the public health value of the regimen, as noted in point 3 above. It is worth noting that by pooling the IP significant cost savings will be possible once 20

the regimens reach the market. Whereas the traditional IP incentive model allows developers to recoup their R&D costs through the sale of newly developed products under monopoly conditions for a term of 20 years, the pooling of IP and immediate facilitation of competition amongst multiple suppliers will drive the cost of the regimen down and save significant outlays in the short, medium and long term.

All estimates do not include the cost of Phase III regimen trials. As the Phase III trials are substantially “de-risked” in this case, Phase III should be grant funded, likely through existing sources, such as EDCTP.

18.

How could the project be governed and coordinated paying particular attention to the need to demonstrate better way of coordination?

We propose that the governance structure and coordination be defined by Member States of the WHO that opt to form part of a steering committee working to set up the project.

There are several governance options which will depend in part on decisions taken by this committee as to where to host the various aspects of the proposal, such as the patent pooling mechanism and the handling of grants and prizes. However, there are a set of principles that should guide the establishment of the governance structure which include, ensuring those contributing financially and technically to the success of the project are including in the project’s governance structure alongside countries with a high burden of TB and civil society representatives from affected communities such as patient groups and health care workers.

In order to ensure north/south and south/south collaboration, funding for the project should potentially be available from all WHO Member States, with increased leadership from emerging economies. Voluntary funds could be largely pooled in one hosting mechanism with a decision-making committee that manages the funds’ disbursements and awards associated with the overall project.

The set up and governance of the project should also avoid unnecessary new (and potentially costly and time-consuming) administrative set ups by making use of existing mechanisms. In this respect the steering committee should seek to ensure the project complements existing initiatives in the area of TB drug R&D.

19.

Have any donor agencies/governments already indicated interest in supporting the project?

On October 23rd 2013, representatives of health authorities from 19 countries in the Americas selected, by consensus, four demonstration projects to represent the region before the Committee of World Experts that meets in December in the World Health

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Organization (WHO). Three other projects were selected as alternatives. This proposal was one of the three alternatives.

The Governments of France and Spain support the proposal. France will co-submit the proposal to the WHO EURO regional consultation on demonstration projects.

Discussions are currently on going with the potential partners mentioned in the proposal and other actors.

iWHO

Global Tuberculosis report 2012. Geneva. Available: http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf ii P.41, WHO Global Tuberculosis report 2012. Geneva. Available: http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf WHO. Guidelines for the programmatic management of drug-resistant tuberculosis 2011 update.

WHO/HTM/TB/2011.6 Available: http://apps.who.int/iris/bitstream/10665/44597/1/9789241501583_eng.pdf. iii

ivAhuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, et al. (2012)Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients.PLoS Med 9:e1001300.doi:10.1371/journal.pmed.1001300

DR-TB Drugs Under the Microscope: Sources and Prices for Drug Resistant TB medications. Médecins Sans Frontières / International Union Against Tuberculosis and Lung Disease 2nd Edition November 2012. viPrinciples in designing a new DRTB regimen.G. Brigden, BT Nyang’wa, P Du Cros et al. Accepted for publication WHO Bulletin. viiWilson P, Palriwala A. 2011.Prizes for global health technologies. Washington D.C.: Results for Development Institute. Available: http://r4d.org/sites/resultsfordevelopment.org/files/R4D-PrizesReport.pdf viiiIbid, Jiménez-Levi E. 2012 ixJiménez-Levi E. 2012 Report on tuberculosis research funding trends, 2005–2011. New York: Treatment Action Group and Stop TB Partnership; 2012. Available from: http://www.treatmentactiongroup. org/tbrd2012. x http://www.newtbdrugs.org/pipeline.php xi Working group on new TB drugs. http://www.newtbdrugs.org/pipeline.php v

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