OpiniãoBefore being considered for group membership, each candidate for the Guideline Development Group (GDG) and External Review Group (ERG) was required to submit a completed declaration of interest (DOI) form. In addition, a preliminary internet search was performed to identify any obvious public controversies or interests that might lead to compromising situations for the World Health Organization (WHO) and the expert concerned.
The candidate’s curriculum vitae and DOI, and information retrieved from the internet, were examined by WHO steering committee members to assess whether there were, or might be, actual or perceived conflicts of interest and, if so, whether a management plan was required. This evaluation process, and resultant management plans, were based on the Guidelines for declaration of interests (WHO experts) (1) and the WHO handbook for guideline development (2ⁿᵈ edition) (2).
Both financial and non-financial interests were considered. A “significant” conflict of interest would include:
- “intellectual bias”, where an individual may have repeatedly and publicly taken a position on an issue under review, which may affect the individual’s objectivity and independence in the global policy development process;
- involvement in research or publication of materials related to issues under review; and
- a financial interest above US$ 5000.
Developers of any assay are never involved in the process of policy development – such involvement is automatically considered a conflict of interest.
Once a determination had been made that either no conflict of interest existed or that any conflict of interest could be appropriately managed, and a decision had been made to appoint the candidate, the name and a brief biography of each candidate were published on the WHO website for at least 14 days before the meeting, for public notice and comment.
DOI statements were summarized by the WHO steering committee at the start of the meeting. Selected individuals with intellectual or research involvement were invited as technical resource persons to provide technical input and answer technical questions. These individuals did not participate in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evaluation process and were excluded from the group discussions when recommendations were developed. The DOI findings are summarized in Table A1.
1. TB antigen-based skin tests for the diagnosis of TB infection
Table A1. Conflict of interest summary for TB antigen-based skin tests for the diagnosis of TB infection
CAD: computer-aided detection; CXR: chest X-ray; EDCTP: European and Developing Countries Clinical Trials Partnership; ERG: External Review Group; FIND: Foundation for Innovative New Diagnostics; GDG: Guideline Development Group; IGRA: interferon-gamma release assay; TB: tuberculosis; USAID: United States Agency for International Development; WHO: World Health Organization
2. Tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) for the diagnosis of TB infection
The members of the GDG and ERG completed a WHO DOI form. All declarations were evaluated by the WHO steering committee for any financial conflict of interest that might warrant exclusion from membership or from certain discussions of the GDG. The completed forms were summarized and presented to all GDG members at the first meeting, at which point the members were asked to update their declarations. Intellectual conflict of interest was not considered a motive for exclusion from the GDG, because expertise on the topic was considered an important criterion for selection and the diversity and representation in the GDG was large enough to balance any individual member’s intellectual interest. The biographies of the GDG members were made public alongside the background document outlining the 2019 update on 1 July 2019, ahead of the GDG meetings.
GDG
The following GDG members declared no interests that could conflict with the objectives of the guidelines: Mohammed Al Lawati, Rolando A. Cedillos, Diana Gibb, Yohhei Hamada, Nasehi Mahshid, Alberto Matteelli, Lindiwe Mvusi, Kuldeep Singh Sachdeva and Irina Vasilyeva
The following GDG members declared interests that were judged not to conflict with the objectives of the meeting:
Helen Ayles declared a research grant received by her institution from European and Developing Countries Clinical Trials Partnership (EDCTP) plus in-kind support for a project in which she is principal investigator (QFT test kits at a subsidized price from QIAGEN and support to try a new, simplified version of the QFT test). Delft diagnostics provides in-kind support in the order of US$ 100 000, to subsidize the cost of using its digital chest radiography and computer-aided detection. Helen is a member of the Technical Review Panel for the Global Fund to Fight AIDS, Tuberculosis and Malaria, which promotes adherence to the normative guidance of WHO.
Padmapriyadarsini Chandrasekaran declared research grants received by her employer, the National Institute for Research in TB in Chennai, India, and collaboration, sponsorships and WHO consolidated guidelines on tuberculosis: tests for TB infection 44 other funding from the United States Agency for International Development (USAID) under a model directly observed treatment short course (DOTS) project. The study is now complete
Anthony D. Harries is a Senior Advisor at The Union, Paris, and was the lead author on a paper titled Challenges and opportunities to prevent tuberculosis in people living with HIV in low-income countries (3). With other Union colleagues, he wrote a review titled Treatment for latent tuberculosis infection in low- and middle-income countries: progress and challenges with implementation and scale-up (4), as part of unpaid work. The paper, which was under review at the time of the GDG meeting, deals largely with the programmatic requirements to scale up the WHO treatment recommendations for TB infection.
Alexander Kay declared a research grant received by his organization from the United Nations Office for Project Services (UNOPS) and the Stop TB Partnership for a “TB Reach” project that is designed to increase the uptake of preventive therapy in children and adolescents exposed to TB (US$ 400 000). This work with the national TB programme (NTP) of Eswatini aims to enhance access to preventive therapy among household contacts, and includes nurseled community-based TB screening and preventive therapy. A shorter preventive therapy regimen (3RH) is used for children and adolescents, and isoniazid in adults and children and adolescents living with HIV; however, no specific regimen is privileged.
Nandi Siegfried declared consultation work with WHO.
Ezio Távora dos Santos Filho declared delivering a talk at the Regional International AIDS Society conference in April 2018 in Mexico City on the need for advanced tools for TB infection treatment, without endorsing any particular study. He also declared that, as a TB advocate, he participated in many discussions with the Global TB Community Advisory Board and the Brazilian National TB Community Advisory Board (CAB) on the implementation of new TB infection treatment methods. The Brazilian TB CAB is now raising awareness of 3HP and TB infection. The affected communities may benefit directly from new guidelines
Marieke van der Werf declared the interest of her employer in the topic and that the European Centre for Disease Prevention and Control is working on TB infection.
Wim Vandevelde declared travel support from the Stop TB Partnership for participation as a speaker in the TB/HIV symposium at the International AIDS Society conference in 2019 in Mexico City and that symposium will cover TB infection.
ERG
The following ERG members declared no interests that could conflict with the objectives of the guidelines: Stephen Graham, Giovanni B. Migliori, Rohit Sarin and Alena Skrahina.
The following ERG members declared interests that were judged not to conflict with the policy of WHO or the objectives of the meeting:
- Connie Erkens declared that a study she was involved in on TB infection screening in migrants to the Netherlands received 1800 QuantiFERON-TB Gold Plus tests from the manufacturer QIAGEN (value EUR 27 000) in 2016–2018. QIAGEN had a role in the study design, implementation, data collection and analysis, and in the decision to publish or in the preparation of the report.
- James Seddon declared that he is employed by Imperial College, London, United Kingdom of Great Britain and Northern Ireland (United Kingdom) to carry out research on childhood Annex 3. Conflict of interest assessment for Guideline Development Group and External Review Group members 45 TB; some of these studies involve the investigation of treatment of TB infection. He also has a grant from Global Trials Scheme (WT/MRC/DFID/HIHR) to carry out a trial of preventive therapy for children and adolescents exposed to multidrug-resistant TB (MDR-TB). He also has a fellowship from the Medical Research Council (MRC) to carry out studies evaluating correlates of risk in MDR-TB exposed children and adolescents. He is also involved in the TB-CHAMP trial (an MDR-TB prevention trial in children aged under 5 years) and has a personal fellowship to examine correlates of risk, using the trial as a research platform. His PhD examined MDR-TB preventive therapy in an observational cohort of children treated in Cape Town. He collaborates with the Unitaid grant CaP TB, which includes household contact tracing and preventive therapy. He has been involved in an application as a co-investigator to the National Institutes of Health (NIH) for an International Research Career Development Award (US$ 43 000) to look at implementation of 3HR in South Africa. He is collaborating on a modelling exercise (funded by the TB Modelling and Analysis Consortium [TB-MAC]) to look at implementation of different types of TB infection treatment, use of the TST and decisions about whom to treat in terms of risk–benefit and cost–effectiveness; also, he has collaborated on modelling the impact of household contact activities on childhood TB burden. The amounts were not disclosed. He is co-investigator in an NIH R01 study that has been submitted (Implementation of child contact management interventions to prevent TB in children and adolescents in Cape Town, South Africa); budget US$ 2.8 million. He has also written reviews on TB infection (including treatment).
- Carrie Tudor declared that she is employed with the International Council of Nurses, which received US$ 1 million from the Eli Lilly Foundation MDR-TB partnership to train nurses between 2013 and 2019.
Evidence reviewers
The evidence reviewers provided the estimates for the evidence summaries but did not participate in formulating the recommendations for policy. The following reviewer declared interests that were judged not to conflict with the policy of WHO or the objectives of the meeting:
- Lynne M. Mofenson declared that in 2018 she served as a consultant for WHO on the use of dolutegravir in pregnancy.
3. Use of interferon-gamma release assays (IGRAs) for the diagnosis of TB disease
Individuals were selected to be members of the Expert Group to represent and balance important perspectives for the process of formulating recommendations. The Expert Group therefore included technical experts, end-users, patient representatives and evidence synthesis methodologists. Interchange by Expert Group meeting participants was restricted to those who attended the Expert Group meeting in person, both for the discussion and follow-up dialogue.
Expert Group members were asked to submit completed DOI forms. These were reviewed by the WHO legal department before the Expert Group meeting. DOI statements were summarized by the co-chair (Karin Weyer, Stop TB Department) of the Expert Group meeting at the start of the meeting.
P. Hill and R. O’Brien declared conflicts of interest that were deemed to be insignificant: P. Hill declared receipt of kits from Cellestis (now QIAGEN) and Oxford Immunotec for research projects, and R. O’Brien declared Foundation for Innovative New Diagnostics (FIND) support to academia to develop a point-of-care serodiagnostic test, including the FIND biomarker discovery project.
Selected individuals with intellectual or research involvement (or both) in the use of IGRAs in low- and middle-income settings were invited as observers to provide technical input and answer technical questions. P. Godfrey-Fausett declared a research grant for the investigation of the use of the QuantiFERON-TB Gold In-Tube assay in South Africa and Zambia, and M. Pai declared conduct of research studies on IGRAs. These individuals did not participate in the GRADE evaluation process and were excluded from the Expert Group discussions when recommendations were developed. They were also not involved in the development of the final Expert Group meeting report, nor in preparation of the Strategic and Technical Advisory Group for Tuberculosis (STAG-TB) documentation or preparation of the final WHO policy statement.
The systematic reviewers (A. Cattamanchi, A. Date, A. Detjen, D. Dowdy, R. Menzies, J. Metcalfe, M. Pai, M. Rangaka, K. Steingart and A. Zwerling) were deemed to have a conflict of interest, and consequently were observers to the meeting, providing technical clarifications on the findings of the systematic reviews. They did not participate in the GRADE evaluation process, did not contribute to the meeting discussions where recommendations were developed, and did not provide comments on the final WHO policy statement.
References for Annex 3
1. Declarations of interest [website]. Geneva: World Health Organization; 2022 (https://www.who. int/about/ethics/declarations-of-interest).
2. Handbook for guideline development, 2nd ed. Geneva: World Health Organization; 2014 (https:// apps.who.int/iris/handle/10665/145714).
3. Harries AD, Schwoebel V, Monedero-Recuero I, Aung TK, Chadha S, Chiang CY et al. Challenges and opportunities to prevent tuberculosis in people living with HIV in low-income countries. Int J Tuberc Lung Dis. 2019;23(2):241–51 (https://www.ncbi.nlm.nih.gov/pubmed/30808459).
4. Harries AD, Kumar AMV, Satyanarayana S, Takarinda KC, Timire C, Dlodlo RA. Treatment for latent tuberculosis infection in low- and middle-income countries: progress and challenges with implementation and scale-up. Expert Rev Respir Med. 2020;14(2):195–208 (https://www.ncbi.nlm. nih.gov/pubmed/31760848).