Towards comprehensive clinical trials for new tuberculosis drug regimens: policy recommendations from a stakeholder analysis

Background Research and development (R&D) of new drugs and regimens against tuberculosis (TB) is evolving to meet new challenges and face limited investments in the sector. To effectively improve and fill existing gaps, researchers and trialists should engage a broad spectrum of stakeholders. With this study, we aim to map the interests in TB R&D raised by the main stakeholders in the TB field. Methods We conducted semistructured, short interviews to gather insight and viewpoints on innovation on TB drugs and regimens R&D of policy-makers, national TB programme officers, donors, funders, non-governmental organisations and research institutions. A composite measure of the relevance of topics that emerged was computed by implementing different models considering the importance for researchers and the urgency to implement those changes during the trial, the number of citations each topic received, and the maximum value of the influence of stakeholders who had raised the topic. Results 50 stakeholders, out of 56 identified, were interviewed and almost half were policy-makers and governmental institutions. Several stakeholders highlighted the importance of disseminating information about clinical trials’ methodology and emerging preliminary results, followed by the need to pursue early discussion around access and pricing of safe and effective TB innovations, although different categories of stakeholders prioritised different topics. Using different methods for ranking topics, the results remained almost unchanged. Notably, post-trial operational research ranked higher in models with higher weight for the parameter considering the number of citations. Conclusion Researchers and research consortia embarking on phase 2 and 3 clinical trials should consider a broad set of elements when planning and designing trials’ protocols, all aiming at lowering the price and improving access to emerging TB innovations, besides meeting regulatory criteria. This can only be achieved by consulting and engaging relevant stakeholders in the discussion.

All stakeholders were classified by the level of influence of their operations (Table S5).
Table S5 Influence levels.

Score
Level Definition 3 High Ability to affect consistently international and national policies, such as international policymakers and international donors (e.g., cooperation agencies), and national governmental implementers.Topics mentioned during interviews with stakeholders were classified by level of importance for researchers and trialists developing a Phase 2 clinical trial for TB drugs (Table S6) as well as for the deemed level of urgency (or timing) to implement those changes throughout a clinical trial (Table S7), by two independent authors (LD and SV).

Score Level Definition
3 High A topic is defined as "high" when its application ensures that the aim of the project is achieved (necessary and sufficient).
2 Medium A topic is defined as a "medium" when its application contributes to the achievement of the aim of the project, but it's not enough to ensure the project is achieved (necessary but not sufficient).1 Low A topic is defined as "low" when its application does not contribute to the aim of the purpose of the project (not necessary and not sufficient).

Score Level Definition
3 High A topic that has to be carried out in the "pre" phase of the project (during years 1 and 2 of the project) is classified as "high" urgency.
2 Medium A topic that has to be carried out in the "during" phase of the project (during years 3 to 6 of the project) is classified as "medium" urgency. 1 Low A topic that has to be carried out in the "post" phase of the project (after year 6 of the project) is classified as "low" urgency.

Outcome variables
For each topic raised by stakeholders, we computed a measure of the topic's importance for researchers and institutions working on Phase 2 clinical trials for TB (Table S8) by considering the number of citations (), the level of importance () and urgency () of a topic based, only in the general model, by the maximum level of the stakeholders who have mentioned the topic ().Different models were created to weigh attributes differently and compare models' output.
The following formulas are weighted with values arbitrarily selected by the authors to account for a similar effect of the level of importance and urgency of a topic and an increasing weight given to the number of citations of each topic (i.e., models from PA to PC).
Table S8.Models and sub-models for computing topic's importance for a Phase 2 clinical trial.

Figure S1
Figure S1 Geographical distribution of the national tuberculosis programmes interviewed.
2 Medium Ability to affect national policies, such as governmental funders (i.e., IDPPR-GAC, USAID, DFAT, FCDO, and SIDA), and others (i.e., GDF and StopTB Partnership). 1 Low Contributing to the decision of national policies taken by others, such as NGOs and research institutes/networks.

Table S2
List of donors and funders identified.

Table S3
List of non-governmental organizations identified.

Table S4
List of research organizations identified.

Table S9 .
Topics emerged with the discussion with policymakers and governmental institutions and corresponding level of emergency and importance, and the priority score computed using different models.