FeedbackWHO guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update
Funding for the meetings and reviews involved in the updating of the guidelines came entirely from the United States Agency for International Development (USAID). The experts on the Guideline Development Group (GDG) and the institutions where they work contributed time for the various discussions and other activities involved in the update process.
The Declaration of interest forms were completed by all non-WHO members of the GDG and the External Review Group, as well as the members of the academic centres who were involved in the reviews. Four members of the GDG declared interests that were judged to represent a potential conflict and were excused from the sessions of the meeting on 25–27 October 2010 during which recommendations relating to the drug regimens were discussed. Jaime BAYONA was a consultant for the development of clinical trial design for studies of an anti-tuberculosis drug manufactured by Otsuka Pharmaceutical Co. Ltd (OPC-67683). Charles L. DALEY was chairperson of drug-safety monitoring for two trials conducted by Otsuka Pharmaceutical Co. Ltd. Carole D. MITNICK served as a member of the Scientific Advisory Board of Otsuka Pharmaceutical Co. Ltd and had an advisory role on drug OPC-67683. Ma. Imelda QUELAPIO received support (monetary and non-monetary) for research from Otsuka Pharmaceutical Co. Ltd.
The following members of the academic centres, who performed the reviews of evidence from which the recommendations contained in these guidelines are derived, presented their findings at the meeting: Matthew ARENTZ, Melissa BAUER, Richard MENZIES, Carole D. MITNICK, Olivia OXLADE, Patricia PAVLINAC and Judd L. WALSON. They did not participate in the formulation of recommendations related to the respective reviews of evidence that they performed.
This information is included in the Funding and declarations of interest section in the Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update, page 2, available at: https://apps.who.int/iris/bitstream/handle/10665/44597/9789241501583_eng.pdf.
WHO treatment guidelines for drug-resistant tuberculosis, 2016 update
Guideline Development Group
The scope of the guidelines update, and the composition of the GDG, including their biographies, were made public for comment ahead of the meeting in line with WHO’s conflict of interest policy. All GDG members completed the WHO Declaration of Interest forms. The WHO Guideline Steering Committee, in preparation for the update of the guidelines and the GDG meeting, reviewed the completed forms. The following GDG members declared no conflicting interests: Luis Gustavo do Valle BASTOS, José A CAMINERO, Tsira CHAKHAIA, Michel GASANA, Armen HAYRAPETYAN, Antonia KWIECIEN, Sundari MASE, Nguyen Viet NHUNG, Maria RODRIGUEZ, Holger SCHÜNEMANN, James SEDDON and Alena SKRAHINA.
The following GDG members declared interests that were judged not to be in conflict with the objectives of the meeting:
Farhana AMANULLAH declared having received funding for consultancies (US$ 500/ day) and travel from WHO; and grants from the Global Fund and TB-REACH to cover her salary (10% fulltime equivalent).
Daniela CIRILLO declared having received funding from FIND to conduct evaluation of drugsusceptibility testing (DST) for new drugs (US$ 16 000), and from Otsuka to evaluate DST for delamanid (US$ 25 000). She also declared being the head of a supranational TB reference laboratory in Italy involved in country capacity-building in DST technologies for second-line drugs and new diagnostics for drugresistant TB; and being a member of the Italian national committee for the use of bedaquiline.
Charles L. DALEY declared having received funding from Otsuka to serve as chair of the data monitoring committee for trials of delamanid (US$ 47 000 over 7 years–current).
Kelly DOOLEY declared having received funding to provide expert advice on a trial design for TB/ HI (US$ 2000/ year paid to the university/ employer); she also declared the following activities and roles: co-chair AIDS Clinical Trials Group (ACTG) study assessing bedaquiline and delamanid; principal investigator for adjuvant paclitaxel and trastuzumab (APT) trial assessing pretomanid (PA-824); and investigator in trials assessing high-dose isoniazid for MDR-TB, rifapentine for pregnant women and children with latent TB infection (LTBI), high- dose rifampicin and levofloxacin for paediatric TB meningitis, as well as bedaquiline and delamanid for children with MDR-TB and HIV infection.
Agnes GEBHARD declared that she works for the KNCV TB Foundation, which has two projects funded by the Eli Lilly and Company Foundation: (i) engaging the private sector in diagnosis and treatment of TB and MDR-TB with quality-assured second-line TB drugs, and (ii) the roll-out of QuanTB (a drug forecasting tool) in countries not supported by the Systems for Improved Access to Pharmaceuticals and Services (SIAPS) implemented by Management Sciences for Health. In addition, she declared that the KNCV TB Foundation has a collaborative project with Cepheid in two countries (Nigeria, Viet Nam), with KCNV providing services for the installation and initial training on the use of GeneXpert machines.
Carlos TORRES-DUQUE declared having received honoraria from Janssen Pharmaceuticals for presentations on TB prevention and WHO policy on bedaquiline at a Latin American Meeting on MDR-TB held in 2014 (US$ 2000). Tom SHINNICK declared being an employee of the United States Centers for Disease Control and Prevention (CDC). CDC supports his travel and research related to his work on laboratory services needed for TB control. He declared having often represented CDC’s position on laboratory services needed for TB diagnosis, treatment and control. As part of his official duties for CDC, he served on the Data and Safety Monitoring Board (DSMB) organized by Otsuka for the clinical trial of delamanid. He did not receive any remuneration for serving on the DSMB nor for travel expenses (CDC paid for all travel expenses related to serving on the DSMB). The DSMB has completed its work for the trial.
The following GDG members declared interests that were judged to be in conflict with some of the objectives of the meeting and were thus recused from some of the discussions: Lindsay MCKENNA declared non-commercial support to Treatment Action Group (TAG), her employer, from Stop TB Partnership; Bill & Melinda Gates Foundation; the US Department of Veteran Affairs (on behalf of CDC); Janssen Therapeutics for Hepatitis C and HIV projects and the Global Alliance for TB Drug Development (a public–private entity developing new drugs and regimens for TB treatment). She was thus recused from participating in the 9 November 2015 meeting session on Patients, Intervention, Comparator and Outcomes (PICO) question 1 on MDR-TB regimen composition for adults and children. José A CAMINERO stated in his biosketch that he is a staff consultant of the International Union Against Tuberculosis and Lung Disease (UNION), an agency directly involved in the implementation and evaluation of programmes using shorter MDR-TB regimens. He was therefore recused from the 10 November 2015 meeting session on PICO question 3 on shorter regimens for MDR-TB.
External Review Group
The following ERG members declared no interest related to the objectives of this meeting: Chen-Yuan CHIANG, Celine GARFIN, Michael KIMERLING, Vaira LEIMANE, Gao MENGQIU, Norbert NDJEKA, Ejaz QADEER, Lee REICHMAN, Rohit SARIN and Irina VASILYEVA.
The following two ERG members declared interests which were judged not to be in conflict with the objectives of the guidelines. Guy MARKS declared research support from AERAS (US$ 450 000) related to the evaluation of latent TB infection and the rate of recurrence of TB after initial treatment in Viet Nam. He also declared being the Vice-President (and a board member) of the UNION and Editor-in-Chief of the International Journal of Tuberculosis and Lung Disease (for which he receives an honorarium). Dalene VON DELFT declared having received support from TAG, USAID, UNITAID, Janssen Pharmaceuticals, Critical Path to TB Drug Regimens (CPTR) and AERAS to cover travel costs and accommodation to give presentations/speeches on drug-resistant TB. She declared that in 2011 she received bedaquiline as part of her MDR-TB treatment through a compassionate use access programme.
Evidence Reviewers
The following reviewers declared interests that were judged not to be in conflict with the objectives of the meeting:
Gregory J FOX declared having received research and non-monetary support from the UNION (sponsored by Otsuka) valued at about US$ 5000 to attend the 2015 International UNION Conference and to receive the Young Innovator Award (he declares no work for Otsuka or any relationship of this award with any commercial or research activities with Otsuka).
Katherine FIELDING declared that her employer (LSHTM) was a recipient of an award from Médecins Sans Frontières (MSF) (£26 890) for the period February–December 2015 to provide statistical support for the TB-PRACTECAL study on which she is a co-investigator. The study is a Phase II–III randomized controlled trial (RCT) to evaluate the efficacy and safety of shorter MDR-TB regimens for adults.
Rebecca HARRIS declared she is consulting for a clinical research organization (Cromsource) working for Glaxo SmithKline (GSK) vaccines (~£90 000 in 2013); and on GSK vaccines not related to TB (~£10 000 since 2013) for Manpower Solutions.
David MOORE declared receiving research support from the Wellcome Trust Research Training Fellowship Programme to supervise a PhD student to study MDR-TB in Peru (£207 056 in 2014).
Anneke HESSELING declared that her employer (Stellenbosch University) is a recipient of an award from Otsuka Pharmaceutical (~US$ 70 000 to date) for her work on the Phase III delamanid clinical trials in children.
This information is included in the Declaration of interest section in the WHO treatment guidelines for drug-resistant tuberculosis, 2016 update, pages 2–5, available at: https://iris.who.int/bitstream/ handle/10665/250125/9789241549639-eng.pdf.
WHO guidelines for the treatment of drug-susceptible tuberculosis and patient care, 2017 update
The scope for the update of the Guidelines for treatment of drug-susceptible tuberculosis and patient care and the composition of the Guideline Development Group (GDG), as well as the External Review Group, were established in line with WHO’s policy on conflict of interest. All contributors completed a WHO Declaration of Interest form. All stated declarations of interest were evaluated by three members of the steering group for the existence of any possible financial or intellectual conflict of interest. In some cases there was possible conflict of interest justifying the exclusion from membership of the GDG, and the Director of the WHO Global TB Programme, the WHO Guideline Review Committee and the WHO Legal Office were consulted on this and a decision was made. Diversity and broad representation in the GDG were sought in an effort to address and overcome any potential intellectual conflicts of interest. The GDG was composed of representatives of technical partners and academia, a GRADE methodologist, national TB programme managers from different WHO regions, representatives of civil society organizations, experts from WHO collaborating centres, professional organizations and a representative from the International Organization for Migration (see Annex 2). The biographies of the GDG members were made public ahead of the meeting, and the WHO Guidelines Steering Committee, which was formed in preparation for the update of the guidelines, reviewed the completed forms at the beginning of the meeting with everyone present.
Guideline Development Group
The following members declared no interests: Si Thu AUNG; Frank BONSU; Jeremiah CHAKAYA; Lucy CHESIRE; Daniela CIRILLO; Poonam DHAVAN; Kathy FIEKERT; Andrei MARYANDYSHEV; Nguyen Viet NHUNG; Ejaz QADEER; Abdul Hamid SALIM; Holger SCHÜNEMANN; Pedro SUAREZ; Justin Wong Yun YAW.
The following GDG members declared interests that were judged not to be in conflict with the policy of WHO, or the objectives of the meeting:
Kelly DOOLEY declared that she did not receive any salary support from drug companies for her work in the following roles and activities: Co-chair of the AIDS Clinical Trials Group (ACTG) study assessing bedaquiline and delamanid for MDR-TB; principal investigator, assessing pretomanid for tuberculosis trial, assessing pretomanid (PA-824, investigational drug) for treatment of drug-sensitive TB; investigator on trials assessing rifapentine for pregnant women with latent TB infection, rifapentine for treatment shortening in patients with pulmonary TB, high-dose rifampicin and levofloxacin for paediatric TB meningitis, high-dose isoniazid for MDR-TB, and delamanid for MDR-TB in children with and without HIV.
Mike FRICK declared that his organization received non-commercial support (1) to track investment made in TB research and development; (2) to host a symposium at the UNION meeting; (3) advocate for increased funding for TB research and development, research and access to evidence-based interventions; and (4) management of community research advisors group.
Simon SCHAAF declared receiving grants for pharmacokinetic drug studies in children of secondline drugs and for studying preventive therapy in MDR-TB.
Carrie TUDOR declared that her organization receives funding from Eli Lilly Foundation for activities related to TB and MDR-TB projects.
External Review Group
The following External Review Group members declared no interest related to the objectives of this meeting: Riitta DLODLO, Celine GARFIN, Lee REICHMAN, Vaira LEIMANE, Rohit SARIN, Dalene VON DELFT and Fraser WARES. The following WHO staff from the regional offices reviewed the final draft of the guideline document: Masoud DARA (Europe), Mirtha DEL GRANADO (Americas), Daniel KIBUGA (Africa), Hyder KHURSHID (South-East Asia), Mohamed AZIZ (Eastern Mediterranean), and Nobuyuki NISHIKIORI (Western Pacific).
Evidence Reviewers
The researchers who undertook the systematic reviews of evidence for this revision were the following: Narges ALIPANAH, Cecily MILLER, Payam NAHID (team leader for PICO 1, 2 & 7–10), University of California, San Francisco, United States of America; and Lelia CHAISSON, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America. Richard MENZIES, McGill University, Montreal, Canada (team leader for PICO 3, 4 & 6); and James JOHNSTON, University of British Columbia, Vancouver, Canada. Gregory FOX (team leader for PICO 11) and Jennifer HO, University of Sydney, Sydney, Australia. The evidence reviewers did not participate in the formulation of the policy recommendations.
The following reviewers declared no interest related to the objectives of and their attendance at the meeting: Narges ALIPANAH, Jennifer HO and James JOHNSTON. The following reviewer declared interests that were judged not to be in conflict with the policy of WHO, or the objectives of the meeting: Payam NAHID declared that his research unit received support from the United States Centers for Disease Control and Prevention through a federal contract to support clinical trial units in San Francisco, USA, and in Hanoi, Viet Nam.
This information is included in the Declaration and management of conflict of interest section in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update, pages 6–7, available at: https://apps.who.int/iris/bitstream/handle/10665/255052/9789241550000-eng.pdf.
WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018
Guideline Development Group:
The scope of the guidelines update and the composition of the Guidelines Development Group (GDG), including the biographies of the members, were made public for comment ahead of the meeting, in line with WHO requirements (WHO treatment guidelines for rifampicin- and multidrug-resistant tuberculosis, 2018 update). All GDG members completed the WHO Declaration of interest (DoI) form and agreed to the confidentiality undertaking. The WHO Guideline Steering Committee reviewed the completed forms.
The following GDG members declared no interests conflicting with the objectives of the guidelines: Eden ABADIANO MARIANO, Sarabjit S CHADHA, Fernanda DOCKHORN COSTA JOHANSEN, Edwin HERRERA-FLORES, Ayuko HIRAI, Alexander KAY, Rafael LANIADO-LABORIN, Lawrence MBUAGBAW, Austin Arinze OBIEFUNA, Cristina POPA, Wipa REECHAIPICHITKUL, Maria RODRIGUEZ, Holger SCHÜNEMANN, Adman Skirry SHABANGU and Sabira TAHSEEN.
The following GDG members declared interests that were judged not to be in conflict with the objectives of the guidelines:
Susan ABDEL-RAHMAN declared that a research grant (US$ 196 356) was received by her institution from the Thrasher Foundation in September 2017 for her role as Principal Investigator to study whether second-line TB medicines can be accurately quantified from dried blood spots (funding ongoing). Daniela CIRILLO declared that a grant (US$ 26 000) was provided to her research unit by the Foundation for Innovative New Diagnostics (FIND) to evaluate new TB diagnostics (funding ongoing). In 2014, she received funding from Janssen (US$ 10 000) and Otsuka (US$ 25 000) for work on drug-susceptibility testing (DST) of new drugs. In 2014, Janssen Italy funded her participation in an expert working group on the use of bedaquiline in Italy (US$ 1000). Geraint (Gerry) Rhys DAVIES declared that he was until November 2017 the academic coordinator of the PreDiCT-TB consortium, a public–private partnership funded by the European Union Innovative Medicines Initiative and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Although this role involved engagement with industrial partners (GSK, Sanofi, Janssen) in pre-competitive areas of research into TB drug development, these activities were fully supported by public funding from the European Union (EU) and neither he nor his research institution have received any funding from EFPIA or from the individual industrial partners. He has been asked and intends to provide advice to the STREAM study team on possible PK studies, which may be carried out in future using existing or further prospectively collected samples (no payment or research support has been offered for this activity). In 2017, he was paid fees by WHO for expert consultancies (US$ 5000). He is a member of a steering group convened by Critical Path to TB Regimens to advise on development of the lipoarabinomannan (LAM) biomarker developed by Otsuka in the context of adaptive clinical trials (receives no payment for this activity). Bernard FOURIE declares receiving US$ 16 000 per year (ongoing) to act as a nonexecutive director and member of the Board of the National Bioproducts Institute in South Africa, which is exclusively involved in the production and marketing of blood- and plasma-derived products. Payam NAHID declares an ongoing Federal US Centers for Disease Control and Prevention (CDC) contract to the University of California San Francisco to support clinical trial units in San Francisco and Viet Nam (total amount not specified). Carrie TUDOR declares that her employer receives funding from the Eli Lilly Foundation (~US$ 1000 000 for 2013–2017; ongoing at US$ 243 000 in 2018) to run the International Council of Nurses’ TB/MDR-TB project. The project focuses on building the capacity of nurses and allied professionals on TB and DR-TB care through training and currently operates in China, Eswatini, Ethiopia, Lesotho, Malawi, the Russian Federation, Uganda and Zambia. She also received US$ 20 000 from the KwaZulu Natal Research Institute for TB & HIV (South Africa) and Fogarty/NIH (US) for her dissertation and postdoctoral research on TB until 2014. Zarir UDWADIA declares that he has supported about 40 patients to access bedaquiline and three patients to access delamanid through the compassionate use programmes of Janssen and Otsuka, respectively. He declares that he did not charge fees to the patients involved and there were no financial transactions with the manufacturers. Andrew VERNON declares that he heads a clinical research group at US CDC (Tuberculosis Trials Consortium [TBTC]) doing TB trials. TBTC often collaborates with pharmaceutical companies, which may provide modest support, e.g. drug supplies, funding for PK sub-studies. Sanofi Aventis awarded ~US$ 2.8 million in six unrestricted grants to CDC Foundation in 2007–2015 to facilitate or support TBTC work on rifapentine (e.g. PK studies, staff contracts, travel for invited speakers, preparation of data to support regulatory filings). These funds have not otherwise benefited the research group. TBTC has studies under way with rifapentine (TBTC Study 31) and levofloxacin (Opti-Q, TBTC Study 32). He declares that his branch has supported studies of drug-susceptible TB that have included moxifloxacin (TBTC Study 27, Study 28 and Study 31). His branch has also supported enrolment at two of the three sites involved in the Opti-Q Study. This study evaluates different doses of levofloxacin in the treatment of DR-TB and has no comparator arm. There is no involvement with drug procurement. The principal investigator and management of the study, including data handling, analysis and drug procurement, are at Boston University. The Opti-Q outcomes are not yet known and the final analysis has yet to start. The majority of the study was funded by the US NIH (National Institutes of Allergy and Infectious Diseases [NIAID]). The following GDG member declared an interest that was judged to conflict with the objectives of the guidelines (funding for new medicines for use in MDR-TB regimens). He therefore withdrew from the GDG panel and participated as a technical resource. Gary MAARTENS declared that his laboratory will receive US$ 2 184 608 from the US NIH (NIAID) to undertake drug assays for a trial on the safety, tolerability and PK of bedaquiline and delamanid, alone and in combination, among patients on MDR-TB treatment (AIDS Clinical Trials Group study A5343). He will receive no salary support.
External Review Group (ERG)
The following ERG members declared no interest conflicting with the objectives of the guidelines: Essam ELMOGHAZI, Mildred FERNANDO-PANCHO, Anna Marie Celina GARFIN, Barend (Ben) MARAIS, Andrei MARYANDYSHEV, Alberto MATTEELLI, Giovanni Battista MIGLIORI, Nguyen Viet NHUNG, Rohit SARIN, Welile SIKHONDZE, Ivan SOLOVIC, Pedro SUAREZ and Carlos TORRES.
The following ERG member declared interests that were judged not to be in conflict with the objectives of the guidelines:
Thato MOSIDI declares that she represents people affected by and living with TB on the Global Fund Country Coordinating Mechanism in South Africa. She is also an active member of TB Proof, a notforprofit organization that advocates for patient access to TB medicines.
The following evidence reviewers were from McGill University, Montréal, Canada – Syed ABIDI, Jonathon CAMPBELL, Zhiyi LAN and Dick MENZIES. They declared no interest conflicting with the objectives of the guidelines.
The following evidence reviewer declared interests that were judged not to be in conflict with the objectives of the guidelines: Faiz Ahmad KHAN declared payment by WHO to collect data and carry out a meta-analysis on the shorter MDR-TB regimens for the 2016 guidelines (CAD$ 4080) and travel fees to present these findings at a GDG meeting in 2015. He also declares undertaking an update of the same analysis in 2016–2018 for the ATS guidelines for which he receives no remuneration.
WHO treatment guidelines for isoniazid resistant tuberculosis, 2018
In conformity with the WHO guidelines for declarations of interest1 for WHO experts issued by the WHO Compliance, Risk Management and Ethics Office, members of the Guideline Development Group (GDG), Evidence Review Group (ERG) and evidence reviewers were requested to submit completed WHO Declaration of Interest forms (DoIs) and declare in writing any competing interest (whether academic, financial or other) that could be deemed as conflicting with their role in the development of this guideline. In order to ensure the neutrality and independence of experts, an assessment of the DoI forms, curricula vitae, research interests and activities was conducted by the WHO Guideline Steering Committee. For cases in which potential conflicts were identified, the WHO Compliance, Risk Management and Ethics Office was consulted for further clarification and advice as to how to manage competing interests. If any declared interests were judged significant, individuals were not included in the GDG.
ERG members were also requested to declare interests and these were also assessed for potential conflict. As per WHO rules, the objectives of the guideline development process and the composition of the GDG, including member biographies, were made public 4 weeks ahead of the meeting (WHO treatment guidelines for rifampicin- and multidrug-resistant tuberculosis, 2018 update).
This public notice was conducted to allow the public to provide comments pertinent to any competing interests that may have gone unnoticed or not reported during earlier assessments.
Guideline Development Group
The following GDG members declared no interests: Daniela CIRILLO, Kelly DOOLEY (Co-Chair), Gustavo DO VALLE BASTOS, Raquel DUARTE, Christopher KUABAN, Rafael LANIADO-LABORIN, Gary MAARTENS, Andrei MARYANDYSHEV, Ignacio MONEDERO-RECUERO, Maria Imelda Josefa QUELAPIO, Wipa REECHAIPICHITKUL, Nancy SANTESSO (Co-Chair), Welile SIKHONDZE and Armand VAN DEUN.
Five GDG members declared interests that were judged non-significant and not affecting the neutrality of the guideline development process. Therefore, no restrictions to their participation applied:
Farhana AMANULLAH: (1b) paediatric expert for WHO TB monitoring mission in Indonesia (value US$ 600/day, 14–27 January 2017); (2a) paediatric TB expert for Harvard Medical School Global Health Delivery grant (20% full-time equivalent [FTE]; June 2016–June 2018); (2b) paediatric TB expert for Global Fund grant (20% FTE; June 2016–December 2017).
Tsira CHAKHAIA: (1b) Research coordinator for TB Alliance NC-006 clinical trial (2016); community engagement project coordinator for TB Alliance (current); research coordinator for NiX-TB (from May 2017).
Philipp DU CROS: (2a) Member of the protocol writing committee and steering committee of the TB-PRACTECAL Clinical Trial, which has received a grant of €6.8 million from the Dutch Postcode Lottery to Médecins Sans Frontières, Operational Centre Amsterdam (currently active).
Michael RICH: (1a) employed by Partners in Health to work on clinical care guidelines and in the programmatic management of DR-TB; (1a) WHO consultancies on treatment of drug-resistant TB to national TB programmes; (2a) conduct research and develop regimens for drug-resistant tuberculosis (DR-TB) as a recipient of the UNITAID’s Expand new drug markets for TB [EndTB] grant (all active during the development of the present recommendations).
Rada SAVIC: (1b) Member of the panel of the WHO Meeting on Target Regimen Profiles (value US$ 2500); grant reviewer for European and Developing Countries Clinical Trials Partnership (value US$ 1000); (2a) principal investigator or co-principal investigator of research grants by United States National Institutes of Health (NIH) and Gates Foundation on improving TB treatment options (all currently active).
External Review Group
The following ERG members declared no interests related to the objectives of this meeting: Essam ELMOGHAZI, James JOHNSTON, Enos MASINI, Rohit SARIN, Kitty VAN WEEZENBEEK, Irina VASILYEVA and Piret VIIKLEPP.
The below-mentioned ERG members declared interests that were judged not to be significant to the topic of the guideline. Some of the ERG members were involved in clinical trials not related to the treatment of Hr-TB and therefore no restrictions applied to their participation as expert reviewers.
Charles L. DALEY: (1b) Chair and member of data monitoring committees for delamanid studies (US$ 45 000 provided by Otsuka Pharmaceutical over 8 years; ongoing); Chair of data monitoring committee for clofazimine studies (US$ 2500 provided by Novartis; finished in 2016).
Ingrid OXLEY: (5b) at the Union Conference 2015 in Cape Town, TB Proof campaigns advocated for treatment of latent TB infection (LTBI) among health care workers. She is a health care worker and has had two episodes of TB. Many members of TB Proof who are health care workers may have benefited from the WHO guidelines for the treatment of LTBI or received funding for LTBI treatment. This was not the focus of the current guideline.
Simon SCHAAF: (2a) research support to employer for pharmacokinetics work on second-line TB medicines in children from the NIH and Otsuka Pharmaceutical (approximately ZAR 5 million/year). NIH grant ceased in 2015; Otsuka Pharmaceutical grant is still active.
Helen STAGG: (1b) grant to employer for consultancy work on MDR-TB clinical pathways in eastern Europe (Otsuka Pharmaceutical: £59 925; 2013–2015); (2a) grant to employer for Hepatitis and Latent TB Infection (HALT) study (Department of Health of the United Kingdom; National Institute for Health Research, United Kingdom; £86 000 for HALT study (2014); £315 265 for fellowship, salary, research costs; 2015–2017); (2b) non-monetary support for HALT study (Sanofi provides free rifapentine to the research study participants; 2014–2017); (6d) received International Trainee Scholarship Award (US$ 1000 value) at the American Thoracic Society (ATS) conference 2016 where she presented the results of a review she conducted (1).
Carlos A. TORRES-DUQUE: (5a) & (5b) as member of the National Advisory Committee for Tuberculosis (Ministry of Health of Colombia) participates in the updates of national TB treatment guidelines. His expert opinion is based upon evidence and local/international experience and does not generate any profits for him.
Evidence reviewers
The independent experts who undertook the systematic reviews of evidence for this revision declared no interests related to the topic of the policy guideline objectives.
This information is included in the Declaration of interest section in the WHO treatment guidelines for isoniazid-resistant tuberculosis, pages ix–xi, available at: WHO treatment guidelines for isoniazid-resistant tuberculosis: supplement to the WHO treatment guidelines for drug-resistant tuberculosis.
WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2020
In conformity with WHO guidelines for declaration of interests for WHO experts issued by the WHO Office for Compliance and Risk Management and Ethics, members of the Guideline Development Group, External Review Group and evidence reviewers were requested to submit completed WHO Declaration of Interest forms (DOIs) and declare in writing any competing interest (whether academic, financial or other) which could be deemed as conflicting with their role in the development of this guideline. In order to ensure the neutrality and independence of experts, an assessment of the DOI forms, curricula vitae, research interests and activities was conducted by the WHO Guideline Steering Committee. For cases in which potential conflicts were identified, the WHO Office for Compliance and Risk Management and Ethics was consulted for further clarification and advice as to how to manage competing interests. If any declared interests were judged significant, individuals were not included as members of the Guideline Development Group.
As per WHO rules, the objectives of the guideline development process and the composition of the GDG, including member biographies, were made public ahead of the meeting (https://www.who.int/ news-room/events/detail/2019/09/27/default-calendar/guideline-development-group-meeting-toupdate-the-who-guidelines-on-drug-resistant-tuberculosis). This public notice was conducted to allow the public to provide comments pertinent to any competing interests that may have gone unnoticed or not reported during earlier assessments.
Guideline Development Group
The following Guideline Development Group members declared no conflicts of interest: Holger Schünemann (Chair); Rafael Laniado-Laborin (Co-Chair); Erlina Burhan; Fernanda Dockhorn Costa Johansen; Bernard Fourie; Elmira Gurbanova; Muhammad Amir Khan; Marian Loveday; Mahshid Nasehi; Ben Marais; Beatrice Mutayoba; Maria Rodríguez; Debrah Vambe; and Nguyen Viet Nhung. One member of the Guideline Development Group submitted additional information, which required no further action as this did not result in any conflict.
Ingrid Schoeman: As an XDR-TB survivor, she went through the side-effects of being on treatment for 2 years. She works at TB Proof, and advocacy organization which is often invited to attend key stakeholder meetings where they share the experiences of DR-TB survivors and advocated for high-quality TB care. She has been employed by TB Proof since 2017. She is certain that better evidence-based guidelines for treating DR-TB would benefit her colleagues, friends and local communities.
Six members of the Guideline Development Group declared interests that were judged non-significant and were believed not to affect the independence and impartiality of the experts during the guideline development process. Therefore, no restrictions to their participation applied:
Charles Daley: Participation in the Data Monitoring Committee (DMC) for delamanid. A total of 5000 USD by Otsuka Pharmaceutical for services rendered in 2016 as the Chairman of the Committee. Participation in the DMC for pediatric trials of delamanid (Role Member). A total of 4000 USD by Otsuka Pharmaceutical for current services as a member of the Committee.
Gerry Davies: Participation in the PreDiCT-TB consortium, a public-private partnership funded by the European Union Innovative Medicines Initiative and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Role as academic coordinator (2012–2017) led to engagement with industrial partners in pre-competitive areas of research into TB drug development. All of these activities were fully supported by public funding from the European Union. No financial support was received from EFPIA. Current collaborator on pharmacokinetic sub-studies deriving from the STREAM Stage 1 trial. Funding support will be provided through research institution [University of Liverpool] to support analysis of pharmacokinetic samples and data later in late 2019/early 2020. This works focuses on evaluating clofazimine and fluoroquinolones. Academic co-supervisor of PhD candidate who is currently involved in the TB-PRACTECAL trial (chief investigator) at the London School of Hygiene and Tropical Medicine. Funding support will be provided through research institution [University of Liverpool] from Médecins Sans Frontières to support analysis of pharmacokinetic samples in early 2020. This work will involve bedaquiline, pretomanid, clofazimine, linezolid and moxifloxacin.
Yuhong Liu: China’s New Drug Introduction and Protection Program (NDIP) was supported by the Bill & Melinda Gates Foundation (BMGF) and Janssen Pharmaceutica. Bedaquiline was provided by Janssen Pharmaceutica through the global donation project (4000 patients). BMGF and Janssen Pharmaceutica also project support to doctors’ training, project activity implementation, quality control, etc. A total of 500 000 USD was provided for project implementation by BMGF including training, data collection, project supervision, between 2016–2020. Financial interests (resulting from funding source) that could directly affect, or could appear to affect, the professional judgment of the expert was not identified.
Iqbal Master: Non-monetary support provided by Janssen Pharmaceutica to attend the 2016 International Lung conference in Liverpool. Only flights and accommodation were sponsored. No direct or indirect payments were made. As a manger in the MDR unit, I provide a link for the implementation of research studies, including STREAM 1 and the Nix-TB trial from 2013 onwards. I received no monetary support or remuneration for involvement in these studies. My involvement was purely from an altruistic wish to facilitate research in order to improve treatment regimens and outcomes in MDR patients in general. As a government official, working in at a public health hospital, participation in the roll-out of bedaquiline and delamanid through a Clinical access programme, launched by the National TB programme. Member of the Provincial and National MDR-TB Advisory Committee of South Africa which makes recommendations and advises Government sites on clinical management.
Payam Nahid: Federal CDC contract to support clinical trial units in San Francisco and Hanoi, Vietnam United States Centers for Disease Control and Prevention University of California, San Francisco Federal contract to support clinical trial units in San Francisco and Hanoi, Vietnam. Participation as a member of the DSMB for an MDR-TB clinical trial, TB-PRACTECAL. All DSMB related materials are obviously kept confidential. Discussions are underway with Médecins Sans Frontières (MSF) for future potential participation of Vietnam clinical trial units in Hanoi and HCMC in EndTB MDR-TB clinical trials. No contracts or agreements have been offered, signed or formalized. If agreements are formalized, enrolments into the EndTB trials would be anticipated to begin in 2020.
Carrie Tudor: Grant from Eli Lilly Foundation – Lilly MDR-TB Partnership for TB Project managed by the International Council of Nurses. Award of approximately USD 1 000 000 from 2013–2019.
The below-mentioned members of the Guideline Development Group declared interests which were judged to be significant, and which required further discussion and assessment by the WHO Office for Compliance and Risk Management and Ethics to outline a management plan:
Susan Abdel-Rahman: (Significant) Research Support from the Thrasher Foundation for an amount of 197 000 USD. Funding ended on 30 October 2017. The Thrasher Research Fund provides grants for paediatric medical research. The Fund is currently supporting over 150 projects, including but not limited to research on childhood blindness, nutritional deficiencies, brain injuries, diabetes, asthma, cancer, genetic diseases and a number of infections including HIV, malaria, TB, schistosomiasis, cytomegalovirus and otitis media. Employment & Consultancies: WHO Agreement for performance of work to conduct a summary review of preclinical and EBA data on pretomanid use. Financial interests (resulting from research support) that could directly affect, or could appear to affect, the professional judgment of the expert were not identified. Financial interest resulting from WHO Agreement for performance of work may be perceived to compromise the expert’s objectivity or independent professional judgment in the discharge of GDG duties and responsibilities led to partial exclusion from decision-making and voting limited to BPaL regimen.
Daniela Cirillo: Research grant to measure minimum inhibitory concentrations (MIC) for bedaquiline. Work sponsored through the Ospedale San Raffaele by Janssen Therapeutics. The amount granted was 50 000 USD in 2018. Research grant to study MIC distributions for new TB drugs. Work sponsored through the Ospedale San Raffaele by the TB Alliance. The amount granted was 30 000 USD in 2018. Payment for MIC work for new TB drugs was done through Ospedale San Raffaele and not direct to the individual. Although these interests are tangentially related to the subject of the current guideline development meeting (i.e. diagnostics), a significant conflict of interest was identified for participation in the decision-making process and voting related to funding from the TB Alliance, leading to partial exclusion from decision-making and voting limited to BPaL regimen.
Kelly Dooley: Participation as PI of the “Assessing Pretomanid for TB (APT)” trial, assessing pretomanid for treatment of drug-sensitive TB. Support and funding is from the U.S. FDA. Drug donation from TB Alliance (pretomanid) and Pfizer (rifabutin). No salary support. Participation as investigator on trials sponsored by the NIH, FDA, the U.S. CDC or UNITAID, assessing: Use of rifapentine for TB infection in pregnant women, young children, patients with HIV co-infection; use of rifapentine for treatment shortening in patients with pulmonary TB (rifapentine donated by Sanofi); use of high-dose rifampin and levofloxacin for pediatric TB meningitis (NIH funded); use of high-dose isoniazid for MDR-TB (NIH funded, ACTG A5312); delamanid for MDR-TB in children with HIV infection (NIH funded, IMPAACT 2005; drug donation by Otsuka); bedaquiline for children with MDR-TB and HIV infection (NIH Funded, IMPAACT 1108); meropenem/amox/clav for drugsensitive- and MDR-TB (FDA funded). No salary support. Protocol Co-Chair ACTG study A5343 assessing use of delamanid and bedaquiline among patients with MDR-TB. Drug donation by Otsuka, Janssen and ViiV Healthcare. Support and funding for this trial are provided by the U.S. NIH, Division of AIDS (DAIDS); no salary support. Involvement in the DELamanId BEdaquiline for ResistAnt TubErculosis study (A53439) led to partial exclusion limited to discussions and voting processes related to the combined use of bedaquiline and delamanid.
Agnes Gebhard: Research grant provided to KNCV by the TB Alliance to conduct a situational analysis in 3 countries (Indonesia, Kyrgyzstan, Nigeria) to understand the current infrastructure, resources, and practices for management of all forms of TB, and potential hurdles for integrating regimens (BPaL, BPaMZ, separately and together as a comprehensive solution to TB treatment). Research grant provided by the TB Alliance (305 000 USD – Between 2018 and 2019) to develop a country roadmap for introduction of new regimens. Four countries were chosen as examples (Kazakhstan, Kyrgyzstan, Uzbekistan and Indonesia). These roadmaps are flexible for use with any new (DR) TB regimen. Public support for the approval of Pretomanid in combination with bedaquiline and linezolid submitted to the U.S. FDA Antimicrobial Drugs Advisory Committee in response to a request for comments. Financial interest (Institutional) resulting from research grants provided by the TB Alliance led to partial exclusion from decision-making and voting limited to BPaL regimen.
Alberto Piubello: Involvement in the Union-sponsored study “Treatment Regimen of Antituberculosis Drugs for Patients With Multi-Drug-Resistant TB (STREAM), Stage 2” led to partial exclusion from decision-making and voting limited to the all-oral bedaquiline-containing shorter regimen.
Alena Skrahina: Principal Investigator in the Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s) (TB-PRACTECAL) led to partial led to partial exclusion from decision-making and voting limited to BPaL regimen.
Andrew Vernon: Work in the Division of TB Elimination at CDC which involved collaboration with NIH and Sanofi on the conduct of a multinational phase 3 trial of TB treatment using daily rifapentine. Sanofi provided medications for the trial, and has supported costs of PK testing. Total contribution to CDC Foundation was ~$3million (from 2007–17). No payment was received through these funds. Moreover, these funds were only a small proportion of overall trial costs, the vast majority of which were borne by CDC as the trial sponsor. In his capacity as a TB researcher and clinician at CDC, Andrew participated in meetings, both internal and external, concerned with the development of guidelines for the treatment of active TB and of LTBI in the United States. Role of the U.S. CDC as temporary voting members within the U.S. FDA’s Antimicrobial Drugs Advisory Committee Meeting. The latter interest led to partial exclusion from decision-making and voting limited to BPaL regimen.
External Review Group
The following External Review Group members declared no conflicts of interest: Heather ALEXANDER, Sarabjit Singh CHADHA, Lisa CHEN, Edwin H HERRERA-FLORES, Anna Marie Celina GARFIN, Mathilde JACHYM, Giovanni Battista MIGLIORI, Thato MOSIDI, Welile SIKHONDZE, Bhabana SHRESTHA, Ivan SOLOVIC, Carlos TORRES, Zarir UDWADIA.
The following ERG member declared interests that were judged not to be in conflict with the objectives of the guidelines:
Amanullah FARHANA: Declared that she has been employed and undertaken consultancy work for WHO and that she has had research activities funded by WHO and the Global Fund.
Guy MARKS: Is the President of The Union (IUATLD), which undertakes projects and work in the field of MDR-TB. He is an investigator on the VQUIN trial, an investigated-initiated, publicly funded study on preventive therapy for contacts of patients with MDR-TB.
Andrei MARYANDYSHEV: Declared research undertaken on MDR/RR-TB. The new TB drugs were investigated in the clinical trials in the hospital where Dr Maryandyshev works, i.e. Arkhangelsk clinical antituberculosis dispensary, Russian Federation where he was a main investigator. He participated in the clinical trials of new TB drugs: TMC207-TiDP13-C209 and TMC207TBC3001 phase II-III from 1.02.2012 to 3.10.2016; “An international, multicenter, prospective, randomized, double-blind, controlled study evaluating the efficacy and tolerability of a chemotherapy regimen including SQ 109 in pulmonary tuberculosis patients with multiple drug-resistant M. tuberculosis (phase IIc-III) from 19.08.2014 to 13.07.2016; PBTZ169-A15-C2b-1 “An international multicenter, doubleblind, placebocontrolled, randomized trial to evaluate the efficacy, safety, and pharmacokinetics of PBTZ169 when used in combination therapy for patients with respiratory tuberculosis with bacterial excretion and drug resistance, phase IIb-III” from 13.12.2016 to 29.05.2017; Compassionate use of Delamanid (OPC-6768) for patients MDR TB, 6.12.2016 his hospital has received Delamanid for 5 patients from Otsuka company.
Lawrence MBUAGBAW: Undertook a biostatistical consultation to support FDA reporting requirements for the use of bedaquiline, for Janssen Pharmaceuticals for which he received payment.
Anuj K BHATNAGAR: Is the Co-Principal investigator for the STREAM 2 trial (Medical Research Council Clinical Trials Unit, London), for the Rajan Babu Institute of Pulmonary Medicine and Tuberculosis (RBIPMT) site, Delhi in India. The trial was initiated in this site in March 2019. The monetary aspects of the trial are being looked after by Vital Strategies as an affiliate of IUATLD for refurbishment of the ward, equipment, hiring of staff, upgrading laboratory facilities, access to all laboratory tests and patient support including monetary compensation. No money has been transferred to the institute for this trial. In addition, the National Institute for Research in Tuberculosis, Chennai (NIRT), an organization of the Indian Council of Medical Research (ICMR), Ministry of Health and Family Welfare, Government of India has initiated a Phase 3 trial – called BEAT TB, to study the efficacy and tolerability of a combination of newer drugs for shortening the treatment for pre-XDR and XDR-TB in 5 sites of India. At the RBIPMT site, of which Dr Bhatnagar is the Principal Investigator for this trial, they have just completed a site initiation visit and recruitment of personnel.
The first instalment of the grant for the initiation of this trial by NIRT Chennai has been given for recruitment of staff, equipment, laboratory reagents and patient and DOT provider support.
Evidence reviewers:
The following experts who conducted the evidence for to inform the revision of the recommendations declared the below interests, which require no action beyond reporting for transparency purposes.
Amrita Daftary: Columbia University Consultancy (2016–2021) – This is an ongoing consultancy to provide qualitative expertise to the design and evaluation of an adherence intervention in people with XDRTB-HIV in KwaZulu Natal, South Africa. Commissioned qualitative research for current GDG meeting. IC-IMPACTS funded grant (2015 – 2018) – study has been completed at McGill University; this was an intervention to engage pharmacy providers in Patna, India, to screen and refer TB symptomatic persons for a chest x-ray and doctor for timely TB detection. BMGF funded grant (2017–2020) – This study is held at McGill University where she was based until June 2019; this is an observational study using standardized patients to assess quality of clinical care for TB diagnosis in Cape Town and Durban, South Africa. NIH funded grant (2018 – 2020) – study is based at CAPRISA and Columbia University; this is an intervention to reduce XDRTB-HIV stigma in coinfected patients in KwaZulu Natal, South Africa.
David Dowdy: Research grant Bill and Melinda Gates Foundation Grant to Institution (not owned by me) approx $300,000 current year interest, approximately $50,000. Travel to meetings Bill and Melinda Gates Foundation Travel paid for me to attend, approx. $10,000.
Gabriela Gomez: Consultant providing modelling results for an investment case on a universal drug regimen for TB. Direct funding granted through BMGF for an amount of USD 40000. Funding concluded in 2018. Managed research grant to LSHTM for an economic evaluation of TB-PRACTECAL. Funding provided through MSF to research unit. Approximately £ 150 000. Her involvement stopped August 2019, although the project continues. In addition, a second grant from TB Alliance was granted to conduct an economic evaluation of the BPaL regimen. Approximately £ 60 000. Since 12 August 2019, she has been employed by Sanofi Pasteur. She is the lead for Europe in Vaccine Epidemiology and Modelling. There is no TB vaccine in the commercial pipeline of Sanofi Pasteur to her knowledge currently. She was not representing Sanofi Pasteur at this meeting, but only presenting work done as part of her previous position as Associate Professor at LSHTM.
Richard Menzies: Commissioned WHO evidence reviews (2016-current) to identify, assess and synthesize the evidence for the development of guidelines for treatment of MDR-TB.
Rada Savic: She received research funding from NIH, UNITAID and BMGF. Research funding to her institution (UCSF) where she is a principal investigator. She serves on Scientific Advisory Committee for TB Alliance, but receives no income for that role. She is a member of Core Science Group for NIH clinical trial network (ACTG) and for CDC clinical trial consortia (TBTC).
WHO treatment guidelines for drug-resistant TB treatment, 2022 update
In conformity with WHO guidelines for declaration of interests for WHO experts issued by the WHO Office for Compliance and Risk Management and Ethics, members of the Guideline Development Group, External Review Group and evidence reviewers were requested to submit completed WHO Declaration of Interest forms (DOIs) and declare in writing any competing interest (whether academic, financial or other) which could be deemed as conflicting with their role in the development of this guideline. In order to ensure the neutrality and independence of experts, an assessment of the DOI forms, curricula vitae, research interests and activities was conducted by the WHO secretariat. For cases in which potential conflicts were identified, there was some further consideration as to how to manage competing interests. If any declared interests were judged significant, individuals were either not included as members of the Guideline Development Group or asked to refrain from contributing to the decision-making process under specific PICO questions. As per WHO rules, the objectives of the guideline development process and the composition of the GDG, including member biographies, were made public ahead of the meeting (https://www.who.int/publications/m/item/public-notice-guideline-development-group-for-the-update-of-the-whoconsolidated-guidelines-onthe-treatment-of-drug-resistant-tuberculosis_2022). This public notice was conducted to allow the public to provide comments pertinent to any competing interests that may have gone unnoticed or not reported during earlier assessments.
Guideline Development Group
The following Guideline Development Group members declared no conflicts of interest: Muhwa Chakaya, Geraint Gerry Rhys Davies, Denise Arakaki, Elmira Gurbanova, Yanlin Zhao, Leslie Christine Magsayo-Salon, Asif Mujtaba, Mahshid Nasehi, Nguyen Viet Nhung, Sabira Tahseen, Ye Tun, Debrah Vambe, Paran Winarni, Christian Lienhardt, Graeme Meintjes, Christoph Lange.
On review of the completed DOIs, the following 12 experts declared interests that required further consideration: Charles Daley, Geraint Davies, Daniela Cirillo, Holger Schünemann, Guy Marks, Amita Gupta, Anneke Hesseling, Andrew Nunn, Ingrid Shoeman, Andrew Vernon, Christoph Lange, Padma Chandrakesaran.
Nine members of the Guideline Development Group declared interests that were judged nonsignificant and were believed not to affect the independence and impartiality of the experts during the guideline development process. Therefore, no restrictions to their participation applied.
Charles Daley: Participation in the Data Monitoring Committee (DMC) for delamanid. A total of US$ 4000 by Otsuka Pharmaceutical for services as a member of the Committee. The work ended in 2019.
Gerry Davies: Participation in the PreDiCT-TB consortium, a public-private partnership funded by the European Union Innovative Medicines Initiative and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Role as academic coordinator (2012–2017) led to engagement with industrial partners in pre-competitive areas of research into TB drug development. All of these activities were fully supported by public funding from the European Union. No financial support was received from EFPIA. Since 2017 G. Davies has been an academic partner to the PanACEA clinical trials consortium, funded by the European and Developing Countries Clinical Trials Partnership. Though the consortium has involved contact and collaboration with pharmaceutical partners, his role at the University of Liverpool is as a partner without budget supporting the clinical trials site at the College of Medicine in Blantyre, Malawi. Neither himself, the University of Liverpool nor the University of Malawi College of Medicine receive any funding from pharmaceutical collaborators as part of these activities. G. Davies attended expert advisory meetings relating to TB drug development convened by GSK and Janssen for which I received no payment or benefit (honorarium, expenses, hospitality). In 2017, G. Davies received travel and accommodation expenses from Medecins Sans Frontieres to attend and speak at the 6th Regional TB Symposium (Eastern Europe and Central Asia) in Minsk, Belarus. Academic co-supervisor of PhD candidate who is currently involved in the TB-PRACTECAL trial (chief investigator) at the London School of Hygiene and Tropical Medicine. Funding support will be provided through research institution [University of Liverpool] from Médecins Sans Frontières to support analysis of pharmacokinetic samples in early 2020. This work involves the BPaLM regimen comprising of bedaquiline, pretomanid, clofazimine, linezolid and moxifloxacin. University of Liverpool received a service contract for bioanalytical work related to a pharmacokinetic sub-study of the PRACTECAL trial (£98 741) but G. Davies personally received no direct financial/salary benefit for this work.
Daniela Cirillo: Research grant of €440 000 via Universita Vita Saluute, which is partner in the IMI UNITE4TB consortium (EU funded). This partnership is ongoing. Research grant through the Ospedale San Raffaele by the TB Alliance of US$ 38 000 in 2020 to study MIC distributions for new TB medicine (pretomanid). The microbiological laboratory of Ospedale San Raffaele participates in the EUCAST (European Committee on Antimicrobial Susceptibility Testing). EUCAST coordinated work on standard protocol for different TB medicines involving reference labs.
Holger SCHÜNEMANN: Research on disseminating and presenting WHO tuberculosis recommendations, via employer, McMaster University. $700 000 grant from WHO, ended in 11/2021. The work commissioned by WHO GTB to the McMaster University was to develop better formats for presentation of WHO current policy recommendations in TB, not influencing content or direction of any recommendations.
Amita GUPTA: A significant number of research projects led by the John Hopkins University (JHU) or Amita Gupta as collaborator, principal investigator or protocol chair or co-chair with substantial amounts of funding from multiple institutional donors. However, the focus of the listed research activities does not directly overlap with the scope of the GDG meeting.
Anneke HESSELING: Stellenbosch University, where A. Hesseling is an academician, receives $2 million per annum for several investigator-initiated research studies including with the NIH IMPAACT network, TBTC UNITAID, BMRC/Wellcome Trust and South African MRC, for therapeutic trials and diagnostics in childhood TB. The largest single support is from UNITAID for BENEFIT-KIDS project (led by Stellenbosch University), which includes evidence synthesis, formulation development and also investigator-related clinical trials. This grant and other grants are to the institution, Stellenbosch University. Support to activities directly led by A. Hesseling is an estimated US$ 600 000 per annum at present, including for the TB-CHAMP trial, where A. Hesseling serves as Principal Investigator. Other support to activities directly led by A. Hesseling are: approximately $250 000 per annum, provided by the US CDC, through the TBTC network, for TBTC Study 35 and approximately $150 000 per annum for IMPAACT P1108 from the NIH. The research looks at therapeutic trials and diagnostics in childhood TB. These matters are not the subject of the GDG.
Ingrid SHOEMAN: The employer, TB Proof – a TB advocacy organization based in South Africa, is funded by Bill and Melinda Gates Foundation 2021- 2024, and Stop TB Partnership 2020–2022, Global Fund 2021–2024, Treatment Action Group 2021–2022. As a current board member of The International Union Against Tuberculosis and Lung Disease (The Union) Ingrid Shoeman have received allowances for travel, per diem and accommodation to attend board meetings and conferences. Grant for shortterm contract work to TB Proof received from Capital for Good USA in the amount of $217 198 in July 2016 to December 2017. Multiple conflicts indicated by Ingrid Shoeman were considered not representing a conflict interest as her work and work of the current employer (TB Proof) are matching a role of the patient advocate.
Andrew VERNON: Andrew Vernon works in the Division of TB Elimination at US CDC, where he directs a branch that conducts clinical trials in tuberculosis treatment and prevention. This group has worked with various commercial collaborators for over 2 decades. Most recently, group has collaborated with NIH and Sanofi on the conduct of a multinational phase 3 trial of TB treatment using daily rifapentine. Sanofi provided medications for the trial and has supported costs of pharmacokinetic testing. The group has conducted trials in treatment of latent TB infection and is beginning a new LTBI trial in summer 2022. Sanofi is providing medication for this trial but is not involved in the design or conduct of the trial. Total contribution to CDC Foundation over 10 years was ~$3 million. Sanofi provides drug for a current prevention trial also. US CDC is a National Health Institution involved in multiple kinds of research and development of national level recommendations by its purpose.
Christoph LANGE: Christoph Lange received in the past an honorarium from Janssen pharmaceuticals for a lecture in the amount of $1000.
The below mentioned members of the Guideline Development Group declared interests which were judged to be significant, and which required further assessment to outline a management plan:
Guy MARKS: Guy Marks received public research grants through National Health and Medical Research Council of Australia (NHMRC Australia) for research on TB control and he is currently President of the International Union Against Tuberculosis and Lung Disease. International Union Against Tuberculosis and Lung Disease (The Union) is a membership-based technical and scientific organization established in 1920. The Union members are organizations and individuals from all parts of the world. Although the Union has been supporting clinical trials on treatment of DR-TB (STREAM phase 1 and phase 2) results of these trials are not in the scope of this GDG meeting. The STREAM Stage 2 trial is on-going and the regimen evaluated in the stage 2 trial is almost identical to the regimens that will be discussed in comparisons under several PICOs looking at RR/MDR-TB and FQ-sensitive patient groups (PICO 1, 2, 5, 8, 10). The results of the completed STREAM stage 1 trial have been published and the regimen evaluated is not anymore recommended by WHO. The STREAM Stage 2 trial is ongoing and is expected to complete in 2022. Guy Marks is not directly involved in the STREAM trial management, however his leadership role at the Union and the fact that the regimen evaluated in the stage 2 trial is almost identical to the regimens that will be discussed in comparisons under several PICOs looking at RR/MDR-TB and FQ-sensitive patient groups (PICO 1, 2, 5, 8, 10) led to a conclusion that to avoid any potential intellectual conflicts of interest. Guy Marks was asked to refrain from contributing to the decision-making process under these PICO questions. No significant competing interests identified for the discussion and decision-making under PICO questions 3, 4, 6, 7 and 9 in this GDG as the disclosure is not in conflict with the scope of these questions.
Andrew NUNN: The STREAM trial on which Andrew Nunn is co-chief investigator is partly funded by Janssen Pharmaceuticals and part by USAID and covers part of his salary. STREAM Stage 1 compared a 9–11-month injectable-containing MDR-TB regimen (with fluoroquinolone and injectables and no bedaquiline) and contributed important evidence to support the introduction of shorter MDR-TB regimens. STREAM Stage 2 is evaluating the efficacy, safety, and cost of an all oral, bedaquiline containing regimen that is potentially as effective as, and more tolerable than, injectable-containing regimens like the 9–11-month regimen evaluated in STREAM Stage 1. The results of the completed STREAM stage 1 trial have been published and the regimen evaluated is not anymore recommended by WHO. The STREAM Stage 2 trial is ongoing and is expected to complete in 2022. The regimen evaluated in the stage 2 trial is almost identical to the regimens that will be discussed in comparisons under several PICOs looking at RR/MDR-TB and FQ-sensitive patient groups (PICO 1, 2, 5, 8, 10) therefore, to avoid any potential conflict of interest, Andrew Nunn was asked to refrain from contributing to the decision-making process under these PICO questions. No significant competing interests identified for the discussion and decision-making under PICO questions 3, 4, 6, 7 and 9 in this GDG meeting as the disclosure is not in conflict with the scope of these questions.
Padma CHANDRASEKARAN: Padma Chandrasekaran is a Director of the ICMR -National Institute for Research in Tuberculosis that conducts multiple clinical studies for new drugs in MDR-TB, PreXDR and XDR-TB patients. The disclosed conflict is broadly related to all research work on treatment of TB and DR-TB and is not specific to the specific questions posed to the panel during this GDG. The following studies coordinated by the ICMR are in the scope of the review: 1) BEAT TB Study: an alloral, short course regimen with bedaquiline, delamanid, linezolid and clofazimine for PreXDR & XDR-TB. Funded by USAID for 3 years (2018–2021), grant Amount: $1 122 921; 2) mBPaL study: regimen with bedaquiline, pretomanid with different doses of Linezolid for Pulmonary MDR with FQ-resistant patients. Funded by The UNION (2021-), grant Amount: $1 019 372. Involvement in the mBPaL study may lead to a potential intellectual conflict of interest during review of PICO questions on BPaL regimens. Potential intellectual conflict of interest is considered in relation to the scope of the PICO questions on BPaL or BPaL-like regimens. Padma Chandrasekaran was asked to refrain from contributing to the decision-making process under PICO questions 3–10. No competing interests identified with PICOs 1–2 as the disclosure is not considered to be in conflict with the scope of these questions.
Evidence reviewers:
The following experts who conducted the evidence analysis to inform the revision of the recommendations declared non-monetary support for the research or previous employment, which required no action beyond reporting for transparency purposes: Greg Fox, Tasnim Hasan.
WHO treatment guidelines for drug-resistant TB treatment, 2025 update
On review of the completed DOIs, the following 9 experts out of 18 declared interests that required further consideration:
Charles Daley: Participation in the Data Monitoring Committee (DMC) for delamanid. A total of US$ 4000 by Otsuka Pharmaceutical for services as a member of the Committee. The work ended in 2019.
Gerry DAVIES: In 2011–2017 G. Davies was the academic coordinator of the PreDiCT-TB consortium and continues to be a partner in the UNITE4TB consortium (EU funded), both public-private partnerships funded by the European Union Innovative Medicines Initiative and the European Federation of Pharmaceutical Industries and Associations. However, though these roles involve engagement with industrial partners (GSK, Sanofi, Janssen) in pre-competitive areas of research into TB drug development, these activities were fully supported by public funding from the EU and neither G. Davies nor his research institution received any funding from EFPIA or from the individual industrial partners.
Since 2017 G. Davies has been an academic partner to the PanACEA clinical trials consortium, funded by the European and Developing Countries Clinical Trials Partnership. Since 2020, G.Davies an academic partner to the UNITE4TB consortium. However, though this role he received no funding from EFPIA or from individual industrial partners. G. Davies attended expert advisory meetings relating to TB drug development convened by GSK and Janssen, for which he received no payment or benefit (honorarium, expenses, hospitality). In 2017, G. Davies received travel and accommodation expenses from Medecins Sans Frontieres to attend and speak at the 6th Regional TB Symposium (Eastern Europe and Central Asia) in Minsk, Belarus. In 2021, the University of Liverpool received a service contract for bioanalytical work related to a pharmacokinetic sub-study of the PRACTECAL trial (£98,741) but G. Davies personally received no direct financial/salary benefit for this work.G. Davies is a coinvestigator on a drug interaction study of dolutegravir and high-dose rifampicin (DoRIS) funded by ViiV Healthcare (£374,574) but receives no direct salary or other financial benefits from the grant.
Participation in publicly funded (EU) research consortiums is not considered a conflict of interest. DMC is a group of clinicians and biostatisticians appointed by study sponsors who provide independent assessment of the safety, scientific validity and integrity of clinical trials, therefore, being a member or a chair of the DMC does not represent an intellectual conflict of interest since the DMC has no influence on the design, focus, objectives and analysis of the trial outcomes. Terms of engagement for UNITE4TB are exactly the same as for PreDICT-TB (they are both IMI projects). University of Liverpool (UoL) is a partner to UNITE4TB in the WPs for Clinical Trial Design and Pharmacology and only receives funding from the EU. All funding for academic partners in the consortium comes from EU and none from the industry partners (EFPIA partners). G. Davies is not involved in trials management under these consortia and will be providing some pharmacokinetics and pharmacogenetics work for the trials that may start in the near future (no trials are ongoing at this point in time). Involvement in the UNITE4TB consortium dates back to 2020 and may continue for the duration of this project (7 years). G. Davies is an independent chair of the TRUNCATE-TB steering committee (last 5 years and will end in one year), and RIFASHORT DMC has an independent and advisory role, not influencing the trial setup, main decisions, and changes. One additional in-person meeting of the TRUNCATE-TB steering committee is expected to take place next year. Funding for the TRUNCATE-TB is from the government of Singapore and UK MRC, both public funding streams with no industry funding input. No competing interests identified, as the disclosure is not in conflict with the scope of the work being undertaken by the GDG.
Daniela CIRILLO via Universita Vita Saluute is partner in the IMI UNITE4TB consortium (EU funded coordinating microbiology WP for clinical trials, monitoring of trial sites and re-testing. This partnership via Universita Vita Saluute received a grant. The funds were for implementation of microbiology procedures on the sites, sequencing mic determination for new drugs No funds are allocated to UNISR for biomarkers. Dr Cirillo via microbiological laboratory of Ospedale San Raffaele participates in the EUCAST (European Committee on Antimicrobial Susceptibility Testing). EUCAST coordinated work on standard protocol for different TB medicines involving reference labs. Unite4TB under IMI (Innovative Medicines Initiative of EU).
The aim of UNITE4TB is to accelerate and improve clinical trials of combinations of existing and new drugs, with the goal of developing new and highly active treatment regimens for TB, including drug-resistant TB. Participation in publicly funded (EU) research consortiums is not considered a conflict of interest. In addition, the institution where D. Cirillo works is involved in laboratory work to support the development of the new trial platforms, not influencing the direction or results of the trials. All funding for academic partners in the consortium comes from the EU and none from the industry partners. TB Alliance financed MIC study on pretomanid (new anti-TB medicine) to assess the distribution of MIC to the drug in different lineages. Development of new diagnostic tests for susceptibility of Mycobacteria TB to various TB medicines is an overall positive development as it allows precision medicine, i.e. more effective treatment regimens, be it with first-line or second-line medicines.
EUCAST is a standing committee jointly organized by ESCMID, ECDC and European national breakpoint committees. EUCAST deals with breakpoints and technical aspects of phenotypic in vitro antimicrobial susceptibility testing and functions as the breakpoint committee of EMA and ECDC. EUCAST does not deal with antibiotic policies, surveillance or containment of resistance or infection control.
No competing interests are identified, as the disclosure is not in conflict with the scope of the work being undertaken by the GDG.
Muhwa CHAKAYA: In 2023, he gave two talks at health care worker educational events sponsored by Cepheid and received honoraria from Cepheid. The interest was related to TB research in general and was a one-time event. Although it included small financial support, it could not affect the expert’s professional judgment. No competing interests identified as the disclosure is not in conflict with the scope of the work being undertaken by the GDG.
Anneke HESSELING Stellenbosch University receives $2 million per annum for several investigatorinitiated research studies, including with the NIH IMPAACT network, TBTC UNITAID, BMRC/Wellcome Trust and South African MRC, for therapeutic trials and diagnostics in childhood TB.
Hesseling is an academic at Stellenbosch University, a leading teaching and academic institution in South Africa. The university receives annual grants for several investigator-initiated research studies, including from the NIH IMPAACT network, TBTC, UNITAID, BMRC/Wellcome Trust, and the South African MRC. These studies focus on therapeutic trials and diagnostics in childhood TB, and although these subgroups will be discussed under each PICO question, this is not a key focus of this GDG. No significant competing interests identified as the disclosure is not in conflict with the scope of the work being undertaken by the GDG.
Graeme MEINTJES: He gave a talk at a Gilead internal meeting. Besides, he currently serves as a member of an independent DSMB for Otsuka for one trial and one trial for which the Gates MRI is the Sponsor. G. Mentjes served as an independent member of the Trial Steering Committee for the BEAT-TB trial (no remuneration) and the Independent Scientific Advisory Committee of the endTB trial (no remuneration).
Dr Mentjes’s participation in the advisory committees of two trials, the evidence of which will be reviewed during the GDG, required additional due diligence and a thorough review of the terms of reference of the TSC of the Beat-Tuberculosis trial and the SAC of the end-TB trial. The review of the TSC ToR showed clearly that the committee had a potential influence on both the trial protocol and changes to it. The terms of reference of the SAC of the endTB trial clearly excluded the members of that committee from any critical to the trial protocol or trial management decisions and reserved the deliberations of the SAC to general or specific scientific advice, without any direct influence on the design or conduct of the trial.
The review judged that Dr Mentjes may have a potential intellectual conflict of interest stemming from participation in the TSC of the BEAT-TB trial. Although a potential conflict of interest was also declared due to the membership in the SAC of the endTB trial, the review considered it non-significant. Due to a potential intellectual conflict of interest stemming from the membership in the TSC for the BEAT-TB trial, Dr Mentjes will be asked to abstain from the discussion and decision-making based on the evidence from the BEAT-TB trial during the GDG in June 2024.
Christoph LANGE: He gave a lecture on tuberculosis at symposia sponsored by Gilead, Astra Zeneca, GSK. The topic of the lecture and the content were not influenced by the company. The interest was one-time, and the topic was related to TB research in general. The sponsors did not directly influence the content. Although it included small financial support, it could not affect the expert’s professional judgment. No competing interests identified as the disclosure is not in conflict with the scope of the work being undertaken by the GDG.
Gopalan NARENDRAN was a local PI for the STREAM trial, stage 1, which was completed in September 2022. He received approximately 122 USD for this activity. The STREAM clinical trial is a large-scale, multi-country clinical trial to examine shortened regimens for MDR-TB. The trial was concluded, the trial regimens are not within the scope of this GDG. No competing interests identified as the disclosure is not in conflict with the scope of the work being undertaken by the GDG.
