Will regulatory issues continue to be a major barrier to access to bedaquiline and delamanid?

Status of registration of bedaquiline and delamanid globally and in MDR-TB high burden countries

As of October 2017, bedaquiline had been registered in 48 countries while delamanid had been registered in 37 countries globally (table 1). It is noteworthy that no low-income countries and only a minority of middle-income countries have regulatory approvals for either drug in place. As of October 2017, dossiers for the registration of bedaquiline had been submitted by Janssen Therapeutics in another 15 countries (of them six MDR-TB high burden countries; five low- and nine middle-income countries); and dossiers for registration of delamanid had been filed in another four countries (all MDR-TB high burden middle-income countries). Licence agreements have been signed by Janssen with JSC Pharmstandard in 2013 for production and commercialisation of bedaquiline in The Commonwealth of Independent States (CIS),^e Georgia, Turkmenistan and Ukraine [20]. Otsuka signed licence agreements with 1) R-Pharm JSC in July 2017 to register delamanid in Russia and to expand registration and commercialisation of delamanid in other CIS countries [21]; and 2) with Mylan in August 2017 to prioritise access of delamanid in South Africa, India and 13 other countries^f with high TB and/or MDR-TB burden [22]. While Mylan has filed a delamanid regulatory dossier in South Africa and successfully registered the drug in India, Pharmastandard's attempts at registering bedaquiline in Kyrgyzstan, Kazakhstan and Azerbaijan have been rejected on account of the lack of phase III clinical trial data.^g

Manufacturer perspectives on bedaquiline and delamanid registration

Given the limited number of dossiers to have been submitted by Janssen and Otsuka to MDR-TB high burden country NMRAs, representatives from both manufacturers were asked about key prioritisation criteria and hurdles.^h The Otsuka representative described that a key priority of the company is the registration of delamanid in countries that are not eligible for drug procurement through the Global Drug Facility (i.e. a major focus on China, Russia and South Africa, which account for 26% of the global drug-resistant TB burden) and in countries where clinical trials had taken place. Although dossiers have been filed in Peru and South Africa and regulatory approval was recently obtained in the Philippines, all locations of Otsuka's trial 213 [24], no dossier has been filed in Moldova, where the same trial took place.ⁱ

Janssen meanwhile places an emphasis on total case load of potentially eligible patients and on the existence of an in-country operating company that could facilitate communication between NMRAs and the manufacturer. This is viewed as a means of streamlining the registration process, which was described as lengthy and confusing in the absence of an intermediate entity.

Otsuka similarly indicated that their approach to dossier submission had been influenced by uncertainty over country-level requirements and the need to invest significant resources in each regulatory process. Acknowledging these limitations, it seems that not only greater collaboration and improved communication between all parties are necessary, but that licence agreements with local manufacturers or in-country partners should be more urgently and widely pursued both to meet NMRA requirements of in-country presence and to overcome communication hurdles.

Despite these hurdles, the initiation of all regulatory processes continues to hinge on manufacturer's willingness to file for regulatory approval. Despite a recent increase in submissions, the number of dossiers submitted remains disappointing, considering the scale of the epidemic and the number of patients who might benefit from these potentially life-saving drugs.

Countries’ perspective on the registration of bedaquiline and delamanid

A summary of key findings from the country survey is presented in table 2.

Most high burden countries have legal mechanisms in place to allow access to medicines prior to or during regulatory approval (e.g. import waivers). However, such pre-approval strategies are just interim stop-gap remedies benefiting a small number of patients.

While our findings suggest most countries' NMRAs are interested in facilitating the regulatory approval of bedaquiline and delamanid, the lack of phase III trial data is still viewed as a major hurdle, coupled with lack of capacity to assess the safety and efficacy of new medicines and put in place appropriate risk mitigation measures that would help with the introduction of medicines of potential significance to individual patients and broader public health benefits [26, 27].

It is also worth noting that, despite WHO encouraging countries to establish a dialogue with pharmaceutical manufacturers without prejudice to final registration outcomes [8], most NMRAs continue to place sole responsibility for initiating registration procedures with manufacturers, with NTPs generally playing a passive role. While international advocacy encouraging manufacturers to file for registration will continue, the uncertainty over regulatory processes referenced by both Janssen and Otsuka could be overcome by MDR-TB high burden countries showing signs of readiness to facilitate regulatory procedures.

Finally, the lack of urgency toward bedaquiline and delamanid approval noted among many NMRAs might be explained by the lack of a holistic country approach and communication between NMRAs and NTPs, preventing those unfamiliar with national MDR-TB crises from fully understanding the implications of regulatory approval of these drugs. Knowledge sharing and the communication of positive experiences from the registration and use of the two drugs also remains minimal between authorities in different countries, and should be pursued more proactively. Importantly, while many NTP respondents confirmed their desire to be involved in the drug registration process, this view was not as pervasive amongst their NMRA counterparts, suggesting a need for national exchanges over how to practically manage an efficient collaboration between the two bodies without compromising the independence of regulatory decisions by the NMRAs.

(Expected) role of WHO and partners in facilitating implementation and/or regulatory approval of new TB medicines

WHO has been playing a facilitative role to support countries with implementation and regulatory approvals [7, 28] including the addition of both drugs in the WHO Essential Medicines List in 2015 [14]. The WHO collaborative registration procedure (CRP) for pre-qualified medicines or medicines approved by national authorities that apply similar or more stringent requirements were established to reduce duplication of work and commit NMRAs to ensure efficient and streamlined review processes while guaranteeing that countries can carry out independent reviews according to their national legislation [25, 29]. Considerable enthusiasm expressed for the WHO CRP by non-participating NMRAs should thus be converted into action as soon as possible, and governments and non-governmental stakeholders are encouraged to make use of the resources and capacity building schemes on offer. WHO organises regular workshops, webinars, or has some specific spots at key conferences to promote the uptake of the CRP by marketing authorisation holders and regulators.

Despite initial challenges, the pilot CRP for bedaquiline (Sirturo® 100 mg) is now performing well, with nine countries from the African region currently being involved (including two MDR-TB high burden countries) (table 1) and particular success in skills-sharing and consensus building (C.G. Mercè; oral presentation at the DIA 2017 Global Annual Meeting, June 2017, Chicago, IL, USA; www.diaglobal.org/flagship/DIA-2017/Program/sched?).

Country-level capacity building needs are great. As countries move to register bedaquiline and delamanid, both NTPs and NMRAs expressed the need for further support from WHO and other stakeholders in many areas, as summarised in box 1. Joint efforts between national bodies, civil societies and WHO are necessary in order to facilitate regulatory approvals for bedaquiline, delamanid and any future innovations in the TB space.