- Access to diagnostics at lower prices: Xpert MTB/RIF, GenoType MTBDRplus
- Responsible marketing of diagnostics: QuantiFERON-TB Gold, Immucheck TB Platinum, Determine TB Lipoarabinomannan
- Drug-drug interactions
- Compassionate use – bedaquiline
- Compassionate use – delamanid
- Compassionate use – pretomanid
- Access to linezolid
- Rifapentine U.S. pricing
- Bedaquiline pricing
- Intellectual property
- World Health Organization Model List of Essential Medicines
- Accelerating access to TB drugs
- Regulatory guidance
- Regulatory approvals
- Drug stock-outs
- Community engagement
- Kochon Prize
- Zeroes Campaign
Access to diagnostics at lower prices: Xpert MTB/RIF, GenoType MTBDRplus
GeneXpert (Xpert MTB/RIF) by Cepheid is a new TB diagnostic system that incorporates a nucleic acid amplification technology for rapid detection of TB and of rifampicin resistance. Treatment Action Group (TAG) and the Global TB Community Advisory Board (TB CAB) sent an open letter to Cepheid in 2012 calling on them to reduce the price of the GeneXpert machines and the Xpert MTB/RIF cartridges. In early July 2012, an agreement to reduce the price of Xpert MTB/RIF cartridges was made between the manufacturer and UNITAID, the President’s Emergency Plan for AIDS Relief (PEPFAR), the United States Agency for International Development (USAID), and the Bill & Melinda Gates Foundation. However, the 40 percent reduction in cartridge prices to US$10 applies only to a set number of preapproved public-sector purchasers in resource-poor countries with high burdens of multidrug-resistant TB (MDR-TB) and TB/HIV coinfection. In addition, the price of the GeneXpert machine itself is still unacceptably high at US$17,000 per device for the public sector in eligible countries.
After a World Health Organization (WHO) policy update in 2013 recommended Xpert MTB/RIF as the initial TB test in adults with presumed TB, large volumes of GeneXpert systems and Xpert MTB/RIF cartridges were purchased or projected for 2014. As such, in January 2014, TAG and the TB CAB sent a second open letter to Cepheid requesting they: further reduce the price of Xpert MTB/RIF cartridges and decrease the price of GeneXpert machines; provide extended machine warranties free of charge; and address barriers to public sector procurement of cartridges and machines at the negotiated concessional prices in Russia and China.
GenoType MTBDRplus by HainLifescience is another molecular diagnostic test that can detect resistance to both rifampicin and isoniazid. In 2013, Hain Lifescience doubled the price per test for the second version of GenoType MTBDRplus, placing undue burden on cash-strapped TB program budgets and jeopardizing fragile progress made in implementing improved diagnostic tools that increase access to life-saving treatment. The price increase is said to include training and technical support services. For countries with high TB burdens like South Africa, the inclusion of training and technical support services costs in every test means governments over-pay for country training needs, limiting their ability to scale up availability of GenoType MTBDRplus.
In August 2013, Médecins Sans Frontières (MSF), the TB CAB, and 50 other organizations sent a letter to HainLifescience urging it to make the pricing of Genotype MTBDRplus more transparent, separate the costs for service from the cost of the reagents, and lower the price for Genotype MTBDRplus to a level that ensures access to the technology in poor countries. The letter resulted in a meeting between HainLifescience, MSF Access Campaign, the WHO, Global Drug Facility (GDF), and Foundation for Innovative New Diagnostics (FIND), and TAG where HainLifescience agreed to: improve transparency of the pricing structure for Genotype MTBDRplus and publish a breakdown of the bundled pricing; clarify items included in the service and support fee (i.e. installation, training, after sales service, support, instrument maintenance and upgrades); and allow an independent third party contracted by UNITAID to conduct a cost assessment of Genotype MTBDRplus.
Responsible marketing of diagnostics: QuantiFERON-TB Gold, Immucheck TB Platinum, Determine TB Lipoarabinomannan
Inappropriate and off-label use of certain TB diagnostics is a great concern in many countries, as diagnostics are poorly regulated. In particular, interferon gamma release assays (IGRAs), which cannot differentiate between active TB disease and latent TB infection, are marketed inappropriately for detection of active disease. Treatment Action Group (TAG) and the Global TB Community Advisory Board (TB CAB) sent letters to Qiagen, the manufacturer of QuantiFERON-TB Gold, and Immunoshop, which makes Immucheck TB Platinum, expressing concerns about their aggressive marketing polices and off-label use of these tests in India and other high-burden countries.
Immunoshop has been responsive to these concerns. It revised its website and product insert in 2014, and sent materials raising these issues to its laboratory networks. Qiagen has been less than cooperative, showing little effort to address its misleading marketing techniques in India, where its tests have nearly no utility, as latent TB is not routinely treated in India.
In anticipation of potential misuse of Alere’s novel Determine TB Lipoarabinomannan antigen test (TB LAM)– sensitive in HIV co-infected patients with CD4 counts less than 100 cells/mm3– in August 2013, the TB CAB and other civil society and community groups in India and Eastern Europe issued an open letter to Alere. The letter urged Alere to register, affordably price, and responsibly market its TB LAM assay in areas of Eastern Europe and Central Asia where there are high rates of TB and HIV co-infection; and ensure that the test is not used inappropriately in India and elsewhere. Following receipt of the letter, Alere held a teleconference to further discuss the issues raised by TAG and the TB CAB.
Drug-drug interactions - bedaquiline and delamanid
TB treatment regimens containing multiple new drugs could potentially improve care, especially for people whose TB is resistant to several drugs. But bedaquiline and delamanid, two new drugs to treat drug-resistant TB, have not yet been studied together. Both drugs have a side effect that affects the heart (called QT prolongation), and it is unclear if they are safe to use together. In May 2012, the Global TB Community Advisory Board (TB CAB) advocated for Janssen and Otsuka to work with a third party, such as the U.S. National Institutes of Health’s (NIH) AIDS Clinical Trials Group (ACTG) or the TB Alliance, to ensure that sufficient data are available to inform guidance for appropriate use of delamanid and bedaquiline in combination. The TB CAB also advocated for both drug developers to accelerate the process of planning and initiating studies in children and encouraged Janssen and Otsuka to participate in discussions with the TB Alliance about a potential study for people with XDR-TB.
Treatment Action Group (TAG) and the TB CAB followed up with letters to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on concerns about the lack of drug-drug interaction data for novel TB drugs delamanid and bedaquiline, particularly given their potential safety issues and inevitable co-administration in the field.
The ACTG is planning a study (A5343) to evaluate whether bedaquiline and delamanid are safe to use together.
Compassionate use – bedaquiline in South Africa
The Global TB Community Advisory Board (TB CAB) and Treatment Action Group (TAG) supported South African advocates, doctors, and organizations in their call for early access to novel TB drug bedaquiline by sending an open letter to the South African Medicines Control Council (MCC). The TB CAB had heard from Janssen that the MCC’s August 2011 decision to provide Médecins Sans Frontières (MSF) with authorization to administer the compassionate use of bedaquiline had been verbally retracted, and as a result Janssen would stop distributing the drug until they received clarification from the MCC.
The MCC registrar of medicines responded to the TB CAB, stating that the available data were limited and premature, and that the MCC believed providing patients with access to bedaquiline would be better achieved through an open-label clinical trial design.
Though the MCC’s initial response indicated a lack of cooperation, in December 2012, after much advocacy to allow for preapproval access to bedaquiline, the MCC authorized a clinical access program. Patients infected by resistant strains of TB with no other effective treatment options were then able to receive the drug at approved sites in South Africa and were closely monitored to collect more safety data on bedaquiline. Following bedaquiline’s approval by the MCC in late 2014, this clinical access program was expanded to reach 3,000 South African patients with MDR-TB in 2015.
In September 2015, following approval of bedaquiline in 40 countries, including Russia, South Africa, India, South Korea, Peru, and the Philippines, and the drug’s availability through the Global Drug Facility (GDF), Janssen announced the closure of it’s compassionate use program. Between the program’s start in December 2011 and its end in September 2015, Janssen provided 700 courses of bedaquiline to patients in 45 countries.
Compassionate use – delamanid
The European Medicines Agency (EMA) approved novel TB drug delamanid for drug-resistant TB (DR-TB) in April 2014. However, pre-approval access to delamanid was non-existent for patients outside of clinical trials. Before EMA approval, delamanid’s sponsor, Otsuka was slow to make delamanid available under a compassionate use or early access program. As early as May 2012, Treatment Action Group (TAG) and the Global TB Community Advisory Board (TB CAB) requested that Otsuka expedite plans to develop a pre-approval access program for patients in urgent need, determine if delamanid is safe to use with bedaquiline, and develop the drug for pediatric use as rapidly and safely as possible.
By December 2013, Otsuka’s phase III trial completed enrollment, its pediatric studies were well under way, and the drug was poised for EMA approval —and yet, not a single patient had accessed delamanid outside of a clinical trial. This prompted the TB CAB to send a urgent appeal for Otsuka to initiate its long overdue compassionate use program. Following receipt of the TB CAB’s second letter, Otsuka confirmed plans to launch a compassionate use program in the first quarter of 2014, piloting the program first with Médecins Sans Frontières (MSF). However, many access issues remain, as detailed in another letter sent March 2014.
As of April 2014, Otsuka is assessing individual compassionate use requests on a case-by-case basis and say they have granted access to “over a hundred” patients outside of a clinical trial. Requests from clinicians to access the drug on an individual patient basis can be sent to email@example.com. Compassionate use programs are imperative for patients with pre-extensively and extensively drug-resistant TB (XDR-TB), and for patients who cannot tolerate existing second-line drugs for multidrug-resistant TB (MDR-TB), especially in the many countries where Otsuka has yet to register delamanid (including places where the drug was studied: Moldova, the Philippines, Peru, and South Africa).
In response to Otsuka’s continued lack of progress expanding access to delamanid, activists attending the 45th Union World Conference on Lung Health in Barcelona, interrupted an Otsuka-sponsored symposium to amplify their call for widespread registration of and immediate broad compassionate use access to delamanid.
Compassionate use – pretomanid
Despite initiating a phase III trial in early 2015 to evaluate the treatment shortening potential of novel drug pretomanid (PA-824), the TB Alliance remains without a mechanism to provide pre-approval access to pretomanid for patients with few treatment options or issues tolerating existing drugs. The Community Research Advisors Group (CRAG) and Global TB Community Advisory Board (TB CAB) each met with the TB Alliance separately in October 2014 to stress the importance of compassionate use.
While the TB Alliance has expressed desire to establish a compassionate use program, funding and human resources remain significant barriers to implementation. In parallel with efforts to estimate potential resource needs and identify funds, the TB Alliance should initiate work to seek funding and develop a mechanism and eligibility criteria for the program.
Ideally, pre-approval access mechanisms should be a considered a critical component of any development program and whether public or private, institutions should plan to facilitate compassionate use access following indications of safety and efficacy in a phase IIb study.
Access to linezolid
Access to repurposed drugs– originally developed for other diseases and now being used to treat some forms of drug-resistant TB (DR-TB)– is important for constructing an effective background regimen required to accompany the use of new drugs. However, high costs and lack of indication for TB limit their availability and can sometimes force patients to buy in the private sector at exorbitant prices.
In South Africa, patients who access care outside of Médecins Sans Frontières’ (MSF) Khayelitsha program are unable to access linezolid in either the public or private sector, due to the high cost of the brand name product– the only linezolid approved at that time by the Medicines Control Council (MCC). In October 2014, a letter sent to the MCC, signed by over 100 clinicians, organizations, and patients with DR-TB, demanded immediate registration of a generic version of linezolid– the dossier for which was under “fast-track” review since May 2013– that costs 88% less than Pfizer’s product. Another letter was sent to various medical schemes urging them to commit to covering linezolid at the full dose and length prescribed for the treatment of DR-TB. While the MCC has since approved generic linezolid, the drug is still not available in South Africa at the low price it is globally.
Rifapentine U.S. pricing
Rifapentine — currently approved to treat drug-sensitive TB (DS-TB) and latent TB infection (LTBI)—shows great promise for shortening treatment for active disease. However, Sanofi, rifapentine’s sponsor, needs to continue investing in the drug’s development, and ensure broader access through registration, especially in countries where it conducted trials to support the drug’s registration.
In the United States, in July 2013, Treatment Action Group (TAG) and other leading advocacy groups, TB clinicians, controllers, researchers, and medical organizations issued an open letter to Sanofi to request that the 340B Public Health Service Act price be lowered from $51 per box to $35 per box, and that Sanofi commit to further funding to complement the tremendous public resources that have been invested in rifapentine’s development. The 340B Drug Pricing Program requires manufacturers to provide drugs at significantly reduced prices for eligible health care organizations and entities, a complete list of which can be found here.
After four months of silence from Sanofi, the Community Research Advisors Group (CRAG) issued a second open letter demanding that Sanofi provide an official and favorable response in writing within seven days. The request for a lower price was supported by a recent survey of domestic TB controllers, in which price was the most frequently cited barrier to using the drug (complete survey findings presented by Andrea Deluca in February 2014 at the 18th Conference of the Union North America Region in Boston, MA) and a recent cost-effectiveness study comparing nine months of isoniazid and three months of weekly rifapentine plus isoniazid for the treatment of latent TB infection. Following increased pressure with media coverage and a #shameSanofi twitter countdown, Sanofi committed to lowering the price of rifapentine in December 2013 to $32 per box under 340B Public Health Service Act pricing.
By listening to communities and pricing the drug more affordably, Sanofi has set an important precedent that other pharmaceutical companies should follow. We have not seen a price reduction of this magnitude in TB or even HIV since 1989, when Burroughs Wellcome Company reduced the price of the HIV drug azidothymidine (AZT) by 20 percent. The reduced price of rifapentine will make TB treatment more cost-effective for U.S. programs and simplify treatment for patients (see updated cost-effectiveness study).
In December 2013, following the announcement of a price reduction, TAG and other leading advocacy groups, TB clinicians, controllers, researchers, and medical organizations sent a letter to commend Sanofi U.S. for its commitment to reduce the price of rifapentine and to encourage continued support of rifapentine’s development and TB research.
In effort to measure the impact of the 2013 price reduction, TAG, the CRAG, and the National TB Controllers Association (NTCA) conducted a follow up survey to determine changes in U.S. TB Program use of rifapentine and to identify continued barriers. Survey results have been shared with members of the NTCA and will be presented at the 46th Union World Conference on Lung Health in December 2015.
In 2015, Sanofi shared its plans to prioritize registration in the 33 countries identified in the World Health Organization’s (WHO) TB Elimination Framework for Low-Incidence Countries as well as other countries that have expressed interest in using rifapentine. This approach however, leaves out several countries where the drug has been studied, including Botswana, Zambia, and Uganda. Sanofi has also announced a global price ceiling of 50 Euro per treatment course. Much work remains to be done to expand access to rifapentine outside of the U.S. by encouraging Sanofi to make the drug available via the Global Drug Facility (GDF), and register it for approval in other countries, particularly those where the drug has been studied but is not yet available to patients (including Kenya, South Africa, Zimbabwe, Zambia, Uganda, Brazil, Hong Kong, Botswana, Viet Nam, Spain, and Peru).
Following the December 2012 U.S. Food and Drug Administration (FDA)-approval of bedaquiline, Treatment Action Group (TAG) and the Global TB Community Advisory Board (TB CAB) sent an open letter to Janssen encouraging the company to set concessional, fair, and affordable pricing essential for timely approval and appropriate domestic and global access for people with drug-resistant tuberculosis (DR-TB).
In late April 2014, Johnson & Johnson and the Stichting International Dispensary Association (IDA), a procurement agent of the Stop TB Partnership’s Global Drug Facility (GDF) announced their partnership to facilitate the distribution of bedaquiline to some low- and middle-income countries. However, bedaquiline will be sold under Janssen’s existing tiered pricing structure for the drug, which fixes the price of a 6-month course of bedaquiline at three levels: $30,000 for high-income countries, $3,000 for middle-income countries, and $900 for low-income countries. The low- and middle-income country prices are still unaffordable for many country programs, especially as bedaquiline is just one drug in a multi-drug regimen for a disease that requires 18–24 months of treatment. In an open letter sent to Janssen in September 2014, TB-community and civil society groups documented the shortcomings of tiered pricing as an access strategy and called on Janssen to reduce bedaquiline’s price for all non-high-income countries.
Following a meeting with the TB community and civil society organizations and two months of internal dialogue, in December 2014, Janssen announced an agreement with the U.S. Agency for International Development (USAID) to donate 30,000 treatment courses of bedaquiline to eligible country programs. However, the announcement came without further information as to the planned procurement mechanism or details for eligibility or how to access the donation. By the end of 2014, 600 patients had received bedaquiline through expanded access programs. In January 2015, the TB community responded to Janssen’s announcement and reiterated its request for a sustainable access strategy that lowers the price for low- and middle-income countries and eliminates existing tiered pricing.
In April 2015, USAID launched the bedaquiline donation program for patients with DR-TB in more than 100 countries and with the Stop TB Partnership, issued a step-by-step guide for accessing the donated drugs. While the donation program will facilitate access to bedaquiline for some, Janssen has not taken additional steps necessary to expand access to bedaquiline more broadly and sustainably through an acceptable long-term pricing strategy. Furthermore, while a donation is a temporary salve, it does not contribute to country ownership of drug forecasting and procurement.
Compulsory licensing – when a government allows the production of a patented product without consent of the patent owner – a flexibility built into the World Trade Organizations agreement on intellectual property, the Trade-Related Aspects of Intellectual Property Rights (TRIPS), is one route governments can take to promote access to patented products for which availability is limited. Countries are free to determine the grounds for granting compulsory licenses, which might include lack of registration or in some cases, exorbitant price. In recent years, developing countries have faced pressure when negotiating Free-Trade Agreements (FTA) to implement more restrictive patent laws under TRIPS-Plus, including provisions that limit the use of compulsory licenses and restrict generic competition. In April 2013, the Global TB Community Advisory Board (TB CAB) sent open letters to India’s Prime Minister and Minister of Health supporting India’s refusal of TRIPS-Plus provisions in their FTA negotiations with the European Union, as these provisions could have devastating global effects on access to medicines, especially given India’s role supplying affordable medicines throughout the developing world.
In May 2015, civil society sent a letter to the World Trade Organization demanding that it grant least-developed countries (LDCs) an extension of the transition period with respect to pharmaceutical products and for waivers from their obligations under the TRIPS agreement. This decision would combat the health challenges that LDCs face by improving access to medicines for as long as said countries remain LDCs. The TB CAB endorsed this letter.
In May 2015, the TB CAB and Treatment Action Group (TAG) sent an open letter to Johns Hopkins University regarding its discussions with Sequella to transfer its intellectual property rights to sutezolid. The letter requested that Johns Hopkins encourage rapid development of sutezolid through the creation of deadlines for Sequella, ensure specific and strong access provisions for collaborative research, and allow TB-affected communities to comment on the draft agreement with Sequella. Given the few candidates in the TB pipeline, this letter calls for both timely development and clinical trials and widespread and responsible post-trial access to the drug. In September 2015, with support from TAG and the TB CAB, Universities Allied for Essential Medicines (UAEM) led a global coalition to continue to push for transparency and a non-exclusive license.
World Health Organization Model List of Essential Medicines
In January 2015, the Global TB Community Advisory Board (TB CAB) along with Treatment Action Group (TAG), the Community Research Advisors Group (CRAG), and TB Proof wrote open letters to the World Health Organization’s (WHO) Expert Committee on the Selection and Use of Essential Medicines supporting the addition of bedaquiline, linezolid, rifapentine, and delamanid to the WHO Model Essential Medicines List (EML). The letters focused on trial data, WHO recommendations supporting the use of the drugs, and the dire need for a wider range of tools to fight drug-resistant TB. In April 2015, the WHO updated its EML to include these four drugs.
Accelerating access to TB drugs
In March 2015, the Global TB Community Advisory Board (TB CAB) and 84 other organizations including, Médecins Sans Frontières (MSF), ACTION Global Health Advocacy Partnership, SWIFT Response Project, Treatment Action Campaign (TAC), and Treatment Action Group (TAG), called on global health actors to take steps to ensure access to new and repurposed TB drugs. The letter called on global funders, procurement agencies, and organizations to work with governments and in-country partners to accelerate access to DR-TB drugs in 52 countries by 2019; and sponsors of TB drugs to rapidly and widely register their products and to create transparent and fair pricing and licensing policies for low- and middle-income countries.
In May 2012, the Global TB Community Advisory Board (TB CAB) advocated for stringent regulatory authorities to ensure that their microbiological endpoint requirements for clinical trials were harmonized and for the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to require TB drug developers to ensure the safety of their drugs used in combination with other drugs in late-stage development as a requirement for approval.
In June 2012, the FDA responded that requiring drug-drug interaction (DDI) studies as a precondition to approval is extreme and done only in rare cases; a labeling requirement and commitment to phase IV postmarketing surveillance is more likely if there are concerns about co-administration with other drug entities. The FDA confirmed that early culture conversion is being accepted as a clinical endpoint for accelerated approval and discussed the potential of looking at symptomatic endpoints, which could be used to expedite approval.
In July 2012, the EMA responded that they would transmit the TB CAB suggestions to the EMA main Scientific Committee, the CHMP, for consideration.
In February 2014, the TB CAB submitted a public comment on FDA docket No FDA-2013-D-1319-0001, “Guidance for Industry on Pulmonary Tuberculosis: Developing Drugs for Treatment” where in addition to line edits, the TB CAB recommended that the FDA develop future guidance to inform drug development for latent TB infection and extra-pulmonary TB and that they more explicitly encourage industry to engage with TB-affected communities and other important stakeholders, per the Good Participatory Practice Guidelines for Tuberculosis Drug Trials (GPP-TB).
Recognizing the immediate need for more efficacious, safe and tolerable drugs to treat multi- and extensively drug-resistant tuberculosis (M/XDR-TB), advocates supported approvals of new drugs for TB. Treatment Action Group (TAG) urged the U.S. Food and Drug Administration (FDA) to grant accelerated approval of bedaquiline in 2012, but to be stringent in requiring that post-marketing commitments be met. In 2013 the Global TB Community Advisory Board (TB CAB) sent a letter to the European Medicines Agency (EMA) calling for the approval of both bedaquiline and delamanid for drug-resistant TB (DR-TB). The EMA quickly responded to the TB CAB and a year later approved both novel drugs for MDR-TB.
A confirmatory phase III trial is a condition of bedaquiline’s accelerated approval by the FDA. Bedaquiline’s phase III trial will be the second stage of the STREAM trial. The first stage of the STREAM trial aims to test whether the so-called modified Bangladesh regimen (a nine-month, multidrug regimen) is non-inferior to the current World Health Organization (WHO) 18-24 month standard of care for the treatment of MDR-TB. The original study design for STREAM’s stage II planned to compare the bedaquiline-containing study arms (one a 6-month regimen, and the other a nine-month, all-oral regimen) against the modified Bangladesh regimen rather than the WHO standard of care for MDR-TB. This was unacceptable as the modified Bangladesh regimen is still experimental and un-validated (this and other issues with the original design of STREAM stage II are detailed further in the Spring 2014 edition of Tagline). TAG and the TB CAB provided feedback on the design of STREAM stage II to the study coordinator and co-sponsors including the International Union Against Tuberculosis and Lung Disease, Janssen, and the U.S. Agency for International Development (USAID). TAG and the TB CAB specifically asked that the study continue enrollment of the WHO control arm from stage I throughout stage II. After initial resistance to this feedback, the TB CAB, Community Research Advisors Group (CRAG), AIDS Treatment Activists Coalition (ATAC), and European AIDS Treatment Group (EATG) sent an open letter to the FDA and EMA stressing concern over the regulators’ purported support for the use of an experimental regimen as the control arm in the confirmatory safety and efficacy study of bedaquiline. Following these advocacy efforts and additional multi-stakeholder conversations, the design of STREAM stage II was revised to continue enrollment of the WHO control arm throughout stage II of the trial.
In 2013, Indian advocates identified a critical problem of shortages of TB medicines. In June 2013, members of the Global TB Community Advisory Board (TB CAB) supported a letter urging the Prime Minister of India to immediately address TB drug stock-outs in the Revised National Tuberculosis Control Program (RNTCP). Following inaction by the Indian government and denial of the issue by the RNTCP, the TB CAB led a protest at the 44th Union World Conference on Lung Health, taking over the stage and microphone during a plenary presentation being delivered by Chandra Kishore Mishra, an additional secretary in India’s Ministry of Health and Family Welfare, and demanding that Indian officials stop denying the issue and address the underlying causes of stock-outs in their country.
A majority of U.S. TB programs have had difficulty getting drugs to treat TB and drug-resistant TB, either because of nationwide shortages or stock-outs, or because the drugs were too expensive to purchase. Since 2005, there have been shortages of the following TB medications: isoniazid, rifampin, cycloserine, ethionamide, rifabutin, amikacin, capreomycin, kanamycin, streptomycin, and aminoglycosides. Shortages of the TB diagnostic product Tubersol have also been widely reported. The reasons for the drug shortages are numerous, but programs frequently cite manufacturing difficulties and delays; shipping delays; shortages of active pharmaceutical ingredients; and manufacturing decisions based on perceived low demand. Inadequate or interrupted treatment for TB drugs can have grave consequences, including increased drug resistance, disease spread, and deaths. Further, the challenges posed by drug shortages and stock-outs are causing already-underfunded TB programs are spending inordinate amounts of time and resources dealing with.
In January 2013, in Washington, D.C., Treatment Action Group (TAG) convened a consultation to address domestic TB drug shortages, and is taking concrete steps with the U.S. Food and Drug Administration (FDA), U.S. Centers for Disease Control and Prevention (CDC), and the Global Drug Facility (GDF) to remedy the problem.
Members of the TB CAB weighed in on a public comment submitted by TAG regarding FDA docket No. FDA-2011-N-0898, “Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biologic Products” advocating for the FDA rule under the FDA Safety and Innovation Act (FDASIA) to be revised to better empower the FDA to address domestic TB drug and biologics shortages and stock-outs.
Treatment Action Group’s (TAG) annual Report on Tuberculosis Research Funding Trends, which measures investments in TB research and development against the Stop TB Partnership’s 2011–2015 Global Plan to Stop TB, has consistently reported funding gaps and in 2014, increasing instability. In the private sector, pharmaceutical companies are running for the exits, disbanding TB research programs as part of an industry-wide pivot away from anti-infectives research toward efforts to develop new biologics, including vaccines, and drugs for chronic illnesses. Following Pfizer’s exit in 2012, AstraZeneca and Novartis announced the closures of their TB drug discovery programs in 2013 and 2014, respectively.
In response to the shuttering of AstraZeneca’s TB drug discovery program, the Global TB Community Advisory Board (TB CAB), Community Research Advisors Group (CRAG) and TAG sent an open letter expressing concern and urging the continued development of TB compound, AZD5847. AstraZeneca responded by reiterating their commitment to advancing AZD5847 through open innovation partnerships, such as the one they have with the U.S. National Institute of Allergy and Infectious Diseases (NIAID).
While drug developer Sequella’s TB program remains open, their lack of funds or collaboration with other researchers has left a potentially important future TB treatment, sutezolid (formerly of Pfizer) in a holding pattern. In July 2013, following the transfer of rights to develop sutezolid from Pfizer to Sequella, the TB CAB, TAG, and the Asia Pacific Network of People Living with HIV wrote an open letter to Sequella urging rapid development of the drug and for the drug to be made available to public, not-for-profit research consortia so that sutezolid's potential can be explored in combination studies with other drugs. The AIDS Clinical Trials Group (ACTG), the Tuberculosis Trials Consortium (TBTC) and the TB Alliance have all designed trials that would include sutezolid, but the drug has not been made available for these critical collaborations.
At the opening plenary of the 45th Union World Conference on Lung Health in Barcelona, activists from across the globe called on country governments and the private sector to #CoughUpTheTBMoney and dramatically increase spending on research and development for new treatments for TB in order to meet the US$2 billion annual minimum required according to the Stop TB Partnership’s 2011–2015 Global Plan to Stop TB. In addition to calling for increased funding for TB R&D, activists, at a separate plenary session, interrupted the Global Fund’s Mark Dybul to call for “a bigger piece of a bigger pie” – for the Global Fund and partners to increase the amount of funds allocated to TB without jeopardizing funding to HIV and malaria and other diseases.
The Global Tuberculosis Community Advisory Board (TB CAB) and the Community Research Advisors Group (CRAG) to the U.S. Centers for Disease Control and Prevention (CDC) Tuberculosis Trials Consortium (TBTC) act in an advisory capacity to institutions conducting TB clinical trials. The TB CAB and the CRAG promote participation of affected communities in tuberculosis (TB) research and work to ensure that research reflects community needs as well as scientific priorities. In addition, both groups have contributed to the development of: guidance materials such as the Good Participatory Practice Guidelines for TB Drug Trials (GPP-TB); published community engagement case studies in both research and access (The evolving role of advocacy in tuberculosis and Engaging communities in tuberculosis research); and a monitoring and evaluation framework for measuring the impact of community engagement.
In 2014, the TB CAB began work with the International Union Against Tuberculosis and Lung Disease (the Union) to reform their community registration track and scholarship application policies, which while good-intentioned and meant to facilitate participation of TB-affected community representatives in the Union’s annual conference, ended up restricting community and civil society attendance and lacking necessary support for travel and accommodation to allow use of granted free registrations. Following an open letter to the Union secretariat expressing their disappointment, civil society organizations and individuals who were able to attend the 45th Union World Conference on Lung Health met with members of the Union secretariat to discuss the way forward and how to better promote meaningful community engagement and participation in future conferences.
In 2015, the Union updated Article 5 of the Union Laws to allow the provision of financial support to conference attendees that are community volunteers and/or members of affected communities. As a result of these changes, one hundred free registrations and 20 travel grants are being offered to community for the 46th Union World Conference on Lung Health in December 2015. Registration and travel support will be granted based on multiple criteria, including a letter of motivation, submission and/or acceptance of an abstract, letters of support, and country of origin. A committee has been established to review applications, and its Terms of Reference (TORs) will be up for review every two years. Separate financial awards will be made available to invited speakers, abstract authors, session chairs/coordinators, section officers, and working group chairs.
Additionally, a Community Advisory Panel (CAP) was formed to address the broader need of purposeful engagement of Civil Society Organizations and affected communities in all aspects of the Union’s work. The panel will advise the Union Board on how to better address community needs by identifying and communicating community priorities to be reflected in Union activities, ensuring engagement of key stakeholders by connecting the Union to members of affected communities, and working with the Union to contribute to conference programming and the dissemination of information.
The Kochon Prize is a US$65,000 award administered annually by the Stop TB Partnership (STBP) to persons or organizations that have made a highly significant contribution to defeating TB. The 2013 Kochon Prize was not given to the Selection Committee’s original recommendation, the Delek Hospital in India as a result of politics within the World Health Organization (WHO). In 2014, shortly after the STBP put out a call for nominations, the TB CAB sent a letter to Dr. Aaron Motsoaledi, Chair of the Stop TB Coordinating Board, to advocate for future fair administration of the Kochon prize independent from the WHO’s influence and politics.
In 2012, a group of activists, researchers, clinicians, implementers, policy makers, and foundation and government staff, tired of unambitious global tuberculosis (TB) targets for reducing disease burden, met in Cambridge, Massachusetts. During the three-day meeting, they developed a new global TB strategy founded on three key realities:
- TB is preventable and curable.
- The main driver of today’s unnecessary TB deaths, new TB infections, suffering, and stigma is lack of political will.
- Every country in the world has the potential to reach the goal of zero TB deaths, zero new TB infections, and zero TB suffering and stigma.
The Zeroes Campaign calls for global action and a new global attitude in the fight against TB. Over 500 individuals and organizations have already signed on and are committed to achieving zero TB deaths, zero new TB infections, and zero TB suffering and stigma, and in 2012 the campaign was endorsed as a strategy by the Stop TB Partnership.
In 2013, following a demonstration where activists and representatives of affected communities stormed the opening plenary of the 44th Union World Conference on Lung Health, demanding faster progress towards eliminating TB and a target of zero TB deaths, the World Health Assembly approved the new post-2015 Global TB Strategy, which aims to end the global TB epidemic, including targets to reduce TB deaths by 95% and to cut new cases by 90% between 2015 and 2035.
Stigma can play a large role in the health outcomes of patients, especially those living with TB. In March 2015, the Community Research Advisors Group (CRAG) and other civil society organizations sent an open letter to the International Union Against Tuberculosis and Lung Disease (the Union) criticizing the continued use of stigmatizing language despite previous agreements by the global TB community to abandon such language in favor of new terms. The Union acknowledged the letter and has stated it will provide guidance and refer future abstract writers and conference participants to the Stop TB Partnership’s (STBP) language guide in addition to pursing appropriate language guidance in its International Journal of Tuberculosis and Lung Disease and Public Health Action. An article published in The BMJ in March 2015 echoes the same sentiments around patient labeling and embracing language that protects the dignity of persons involved in both TB care and research.