Abstract
Newly launched WHO target regimen profiles for new anti-TB regimens: process and results of this initiative http://ow.ly/TOUO307po08
Treatment of tuberculosis (TB) relies on a combination of bactericidal and sterilising drugs administered for an adequate duration of time to ensure synergy of action in order to achieve definitive cure and prevent the selection of drug-resistant mutants [1]. Current treatment regimens are, however, not ideal, due to long duration and some toxicity. Particularly unsatisfactory are regimens recommended for the treatment of multidrug-resistant (MDR) (a form of tuberculosis with strains resistant to at least rifampicin and isoniazid) or extensively drug-resistant (XDR)-TB that have lower efficacy, significant toxicity, longer duration and high costs [2–5]. New TB drugs and regimens are needed to improve cure rates, lessen toxicity, and shorten the treatment of both drug-susceptible (DS) and drug-resistant TB (currently at least 6 and 9–20 months, respectively) [6, 7]. Two TB drugs (bedaquiline and delamanid) [8, 9] have become available and are recommended by the World Health Organization (WHO) for the treatment of MDR-TB under certain conditions [10, 11]. However, these drugs have so far been tested for efficacy as add-ons to conventional WHO-recommended treatment for MDR-TB only, and their optimal use in combinations that could lead to increased treatment efficacy while improving safety and reducing toxicity still remains to be established [12–14]. Other novel compounds, as well as re-purposed drugs, are currently in clinical trials, either as part of novel treatment regimens or in addition to the current standard of care [15].
The development of TB drugs is lengthy and costly: if new drugs are added to or substituted within existing regimens one at a time, it would take 15–20 years to develop a new regimen of three to four new drugs to treat TB [6, 7]. Developing a novel regimen without going through intermediary steps to obtain individual drug approvals separately and only then beginning to test novel combinations would substantially reduce the duration of the whole regimen development. It will also reduce the expenditures needed to make significant progress in the field [16, 17]. Combination regimens including one or more promising new or re-purposed drugs should be tested early in the clinical development process to identify optimal combination regimens for the treatment of DS and drug-resistant TB to be tested in phase II and III trials.
Development of shorter and simpler regimens combining new and existing drugs requires detailed information on their respective activity, safety and toxicity [18–20], including potential drug–drug interactions, propensity for development of drug resistance while on therapy [21–24] and clinical use in specific patient populations (such as persons with HIV/AIDS, pregnant women and children [4]). Given these complexities, target product profiles (TPPs) are usually composed as a guide to identifying desired product attributes and characteristics to be considered during the development process [25].
The aim of this editorial is to discuss the concept and role of TPPs for new anti-TB regimens, referred hereafter as “target regimen profiles” (TRPs), and describe the outcomes of the recent process led by WHO to develop these profiles [26].
Objective and role of TRPs for TB treatment
Considering the need for safer, simpler, more efficacious and accessible treatment regimens for all forms of TB, TRPs for TB treatment have been developed in a synergistic effort by the WHO Global TB Programme and the WHO Task Force on New TB Drug Policy Development, with the contribution of a large range of experts and stakeholders.
The novelty of this approach is to have the goal of the treatment regimen in mind very early in the process of drug development, and relies on the fact that TB drug research and development should move rapidly towards developing and testing TB regimens rather than individual drugs. On this basis, TRPs for TB treatment have been developed to describe the targets and specifications that developers should meet for appropriate performance and adequate operational characteristics of new TB treatment regimens, considering the needs of end-users. At a minimum, the TRPs specify the clinical indication of the regimen(s), the goal to be met, the measure of efficacy, the main safety aspects, the target population that will receive the treatment and the intended end-users. In addition, they should outline the most important performance and operational characteristics, with the term “minimal” used to refer to the lowest acceptable output for a characteristic and “optimal” used to refer to the ideal target for a characteristic. The optimal and minimal characteristics define a range: it is therefore expected that new TB treatment regimens meet at least all of the required minimal characteristics and, preferably, as many of the optimal characteristics as possible.
The target audience includes the pharmaceutical industry, academia, research institutions, product development partnerships, nongovernmental organisations, and potential investors and donors [26].
Methods to develop the TRPs
The initial profiles were drafted on the basis of outcomes of expert group meetings, an initial stakeholder survey, mathematical modelling, and interviews of a wide range of experts and stakeholders.
First, the candidate regimen will consist of a minimum combination of drugs targeting all possible populations of bacilli in the patient (i.e. including those proliferating in local acidic conditions or in states of brief sporadic metabolism or replication) and having a clear sterilising effect (so as to ensure nonrelapsing cure within a few months after starting the treatment). In defining the potential TRPs, the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) was assumed to be widely available as a “triage test” under routine programmatic conditions, based on the current worldwide implementation process and scale-up. In that scenario, whether the bacilli harboured by the TB patient are rifampicin susceptible or not will be known from the start. Subsequently, profiles were developed for the treatment of rifampicin-susceptible (RS) and rifampicin-resistant (RR)-TB, respectively, the latter being considered a proxy for MDR-TB. In addition, premised on the potential for a regimen of three to four entirely new anti-TB drugs (i.e. excluding rifampicin, isoniazid and pyrazinamide) for which minimal or no resistance would exist as a result of prior use in the community, a TRP was developed for “pan-TB treatment”. This regimen would be implemented in a simple and streamlined manner without need for drug-susceptibility testing (DST) or for a separate treatment pathway for patients with at least RR-TB (then, whichever rapid tests of drug resistance might be developed/available, they would suitably come as a complement to further refine the patients' needs given the resistance profile).
Mathematical modelling was then used to estimate the relative impact of selected regimen characteristics on population-wide TB incidence and mortality. The selected characteristics were 1) efficacy (achieving high nonrelapsing cure rates), 2) treatment duration, 3) adherence, 4) medical contraindications, 5) barrier to resistance and 6) baseline prevalence of resistance to drugs in the regimen. The influence of each characteristic on expected incidence and mortality outcomes was evaluated as the characteristic ranged from a minimum acceptable value to an optimistic target.
Then, an Internet-based survey was conducted to identify what would be the priority attributes that a wide audience of stakeholders would value for the development of the TRPs. It contained core questions in four main categories (efficacy, safety, adherence and operational considerations) [26]. Finally, a web-based Delphi consultation was organised to gather input from the larger TB control and research community, and a consensus meeting took place to review the draft target profiles. The final document was formally launched at the European Respiratory Society International Congress in London (figure 1).
Picture of the official launch of the World Health Organization document at the European Respiratory Society International Congress 2016.
The details of the three TRPs are presented below.
TRP for RS-TB
Rationale
Despite the wide availability of a highly efficacious, low-cost regimen of 6 months' duration for the treatment of RS-TB, improvements are still needed if we are to achieve the WHO targets set within the context of the End TB Strategy [27]. The current 6-month regimen has several limitations including drug-related adverse events, challenging drug–drug interactions (in particular, with some antiretroviral medicines) and difficulty in ensuring adherence for the full duration of treatment across all settings. By improving adherence to treatment, shorter regimens would result in better outcomes and lower risk of acquisition of resistance, faster recovery, a shorter period at risk of side-effects, and lower patient and programme costs [6, 7]. Future RS-TB regimens would ideally also be active against strains that are monoresistant to any other first-line drug except rifampicin.
Key attributes
The characteristics of the TRP for RS-TB treatment are summarised in table 1. To achieve these, it will be necessary to use multiple-drug combinations with both bactericidal and sterilising efficacy according to well established principles of TB chemotherapy [1] to assure durable and relapse-free cure.
Characteristics of the target regimen profile for rifampicin-susceptible (RS) tuberculosis (TB)
TRP for RR-TB
Rationale
About 480 000 new MDR-TB cases and an additional 100 000 cases of RR disease were estimated to have occurred in the world in 2015 [28]. However, only 125 000 MDR-TB patients were reported by countries to have initiated treatment [28]. The conformity of these regimens to those recommended by WHO and the quality of medicines used is usually unknown, and only about one half of patients treated globally is reported to complete treatment successfully [28, 29].
In the absence of formal randomised controlled trials, the conventional (or longer) MDR-TB treatment recommended by WHO (based on a minimum of five drugs) is the result of expert opinion based on observational studies [30] and there has been no head-to-head comparison of one MDR regimen versus another MDR regimen of any kind (of note, a trial is currently underway to evaluate a short MDR regimen versus the 20-month WHO standard) [31, 32]. As a consequence, using the GRADE system definitions, the available evidence is generally of “low” or “very low” quality [33]. In addition, the complexity and limited efficacy of current regimens may predispose to development of additional resistance [23, 24]. Finally, it is imperative to lower the cost of MDR-TB regimens to make them accessible in the poorest settings [16, 17].
The newly WHO-recommended shorter MDR-TB treatment regimen of 9–12 months has shown rates of relapse-free cure topping 85% in different Asian and African countries as part of observational studies (WHO recommends the use of this regimen conditionally among selected MDR/RR-TB patients, i.e. pulmonary TB cases with no previous exposure or known resistance to fluoroquinolones or injectable drugs) [34–36]. This regimen is composed of seven drugs (five of which are also part of the longer regimen) known to have good bactericidal activity against MDR-TB strains. The two newly available agents, bedaquiline [9, 10] and delamanid [8, 11], have shown potential to improve the efficacy of MDR regimens on top of the conventional WHO-recommended regimen. Some new drugs currently in the drug development pipeline (e.g. pretomanid and sutezolid) [37] show promise for use in MDR-TB regimens together with re-purposed drugs (e.g. linezolid, clofazimine and fluoroquinolones) [3, 38]. The goal of this TRP is to identify a suitable combination regimen early in the development process that would be safe, efficacious and of short duration [39].
Key attributes
The characteristics of this TRP are summarised in table 2. The optimal regimen is expected to be efficacious and safe in all RR-TB patients, whether they have already received TB treatment or not. DST may be needed at the start of treatment to diagnose the resistance pattern to determine whether a particular regimen is indicated. Furthermore, DST will be needed for monitoring amplification of resistance in an individual patient and resistance prevalence in a population.
Characteristics of the target regimen profile for rifampicin-resistant (RR) tuberculosis (TB)
In the optimal case, efficacy (bacteriological cure without relapse in at least 1-year follow-up, among patients who are not lost to follow-up) should approach that of the standard WHO regimen for DS-TB. Furthermore, it is expected that, as the efficacy of drugs included in the regimens increases, the total number of drugs constituting the regimen can decrease. This should minimise the probability of drug–drug interaction/toxicity and increase the ability to coformulate the individual drugs into fixed-dose combinations. Decreased complexity of a RR-TB regimen will likely be readily accepted by national TB programmes as they will be easier to implement.
TRP for pan-TB treatment
Rationale
A highly effective, safe and well tolerated three- to four-drug fully oral regimen that could be administered to any TB patient regardless of drug resistance profile would revolutionise the treatment of TB [26]. To allow for universal adoption, the regimens should be simple to administer (ideally once daily) and have low propensity for drug–drug interactions. As there should be no or minimal prior resistance to the drugs included in the regimen, it may be used empirically without the need for DST, eliminating treatment delays.
Key attributes
The intended use case assumes this simple, novel regimen is simultaneously studied and approved for empirical use in both RS- and RR-TB patients with strains sensitive to the new drugs. This would be particularly important in areas with high prevalence of MDR-TB and low availability of DST, where patients may be treated inappropriately and continue to transmit disease for extended periods (table 3).
Characteristics of the target regimen profile for pan-tuberculosis (TB) treatment
Forecasted role of TRPs for new regimens
The TRPs presented here describe the series of attributes that are considered essential for novel treatment of TB, such as efficacy, safety, toxicity, drug–drug interactions and potential of acquisition of drug resistance. Satisfying all of these characteristics in a single regimen, however, will be difficult to achieve in the short term, and regimen developers might have to face trade-offs: for example, increasing efficacy (cure rates) or safety versus shortening treatment duration, or making regimens simple and well tolerated versus making them more complex and robust to emergence of drug resistance.
It should be understood that, for an infectious disease such as TB with a large global burden and ongoing person-to-person transmission, the efficacy of the new regimens will depend heavily on operational factors that also affect a regimen's ability to fulfil its role (e.g. background antimicrobial resistance, resistance in the MDR-TB patient population to important existing TB drugs, development of resistance to new drugs and slow uptake of new drugs). For these reasons, these TRPs give indications on the respective attributes to be considered at the developmental stage, but these should not be dissociated from the factors to be considered at implementation stage.
All drugs used in a study regimen should meet either WHO prequalification or certification from a stringent regulatory authority or be study drugs that are tested in a facility with good manufacturing practice certification for quality assurance. It would be suitable that each individual drug component or the regimen as a whole be approved for use in TB by at least one stringent regulatory authority. If a regimen is recommended by the WHO using GRADE evidence review, it is expected that the regimen, or its individual components, be widely available in quality assured formulations within 2 years.
Strategies to lower the regimen costs should be considered from the outset, with adherence to the principles of access to medicine. Once a new regimen is established to be superior to current regimens in terms of safety and/or efficacy, then stakeholders should continue to work to bring down the cost of the regimen by working on costs of individual drugs, as well increasing the demand for the new regimen. Finally, it is assumed that within a few years of release, the production for supply of the drugs in the new regimen could be rapidly scaled up to match demand with a corresponding decrease in the price. It is also expected that a new regimen will reduce nondrug cost aspects (e.g. monitoring visits, adherence, patient support and safety aspects), thereby improving simplicity of use, and these benefits may offset increased drug costs.
In conclusion, the TRPs proposed in this document represent a milestone towards the development of new regimens for the treatment of all forms of TB, and will serve consortia linking drug developers, academics, researchers, public health institutions and nongovernmental organisations.
Disclosures
Footnotes
Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com
- Received November 30, 2016.
- Accepted December 1, 2016.
- The content of this work is copyright of the authors or their employers. Design and branding are copyright ©ERS 2017.
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