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

Tiziana Masini; Janika Hauser; Rutendo Kuwana; Nguyen Nhat Linh; Ernesto Jaramillo

doi:10.1183/13993003.02480-2017

Tables

TABLE 1

Registration status of bedaquiline and delamanid globally^#^,^¶

	Countries in which the medicines have been registered⁺	Countries in which regulatory dossiers have been filed
Bedaquiline	Armenia, China, EU,^§ Hong Kong, India, Moldova, New Zealand, Peru, Philippines, Russia, South Africa, South Korea, Taiwan, Thailand, Turkey, Turkmenistan, USA, Uzbekistan	Bangladesh, Brazil, Burundi,^ƒ Cameroon,^ƒ Ethiopia,^ƒ Ghana,^ƒ Indonesia, Japan, Kenya,^ƒ Mexico, Nigeria,^ƒ Rwanda,^ƒ Tanzania,^ƒ Uganda,^ƒ Vietnam
Delamanid	EU,^§ Hong Kong, India, Japan, Philippines, South Korea, Turkey	China, Indonesia, Peru, South Africa

^#: data are up to date as of October 2017. ^¶: the countries in italics are multidrug-resistant tuberculosis high burden countries. ⁺: in Colombia, bedaquiline is in the country's list of “Medicamentos Vitales No Disponibles”, as an interim alternative for local registration; and in Macau, bedaquiline is considered to be registered in the country, via import licensing, although no formal regulatory approval was pursued by Jannsen. ^§: number of countries included in European Medicines Agency approval is 31. ^ƒ: countries are part of the World Health Organization collaborative registration procedure for stringent regulatory authority-approved products.

TABLE 2

Summary of key findings from surveys and interviews conducted with National TB Programmes (NTPs) and National Medicines Regulatory Authorities (NMRAs) of the 30 multidrug-resistant (MDR) tuberculosis (TB) high burden countries (October 2016 to May 2017)^#

Pre-approval access of new TB medicines^¶	Anecdotal
National guidelines on the use of bedaquiline and delamanid available in 24 and 15 MDR-TB high burden countries, respectively	The NTP respondent from one country stated that the current mechanism used to access bedaquiline through import waivers for patients covered by a partner's project was no longer sufficient to cover country needs (in this country, early implementation experiences and expansion of eligibility criteria have contributed to clinician's growing willingness to prescribe bedaquiline-based regimens)
Three high burden countries have both bedaquiline and delamanid featured in their national essential medicines lists; seven countries have bedaquiline and four have delamanid only	The NTP respondent from one country referenced its overall nascent drug registration procedures but expressed the country's willingness to discuss “the pros and cons of registration” if a dossier were to be submitted
	The NTP respondent from one country expressed the need to continue gathering more information from in-country studies prior to the NMRA reviewing any regulatory dossier
Most countries (92%, 24/26) reported having mechanisms in place for access to drugs under development and/or prior to national regulatory approval (e.g. compassionate use, expanded access programmes and the granting of import waivers)
All NTP respondents of countries where either drug was successfully registered or in the process of being registered, stated that pre-approval access use strongly contributed to greater confidence in the use of the drugs
Countries' perspective on the registration of bedaquiline and delamanid
All NMRAs were aware of both products for the treatment of MDR-TB, and there is widespread agreement over the need for regulatory approval to ensure sustainable access
Most NTP and NMRA respondents rated communication between the two bodies as neutral (67% (12/18) and 56% (10/18))
40% (10/25) of countries reported some NTP involvement in the registration process
Majority of NTP respondents (73% (19/26)) felt that their increased support in promoting the approval for these medicines would likely lead to streamlined regulatory approval; only 30% (6/20) of the NMRA respondents see a potential role of NTPs in streamlining the national regulatory approval
Most NMRA respondents (65% (13/20)) stated that sole responsibility for initiating regulatory approval processes lies with manufacturers only and NMRAs are not willing to take any action prior to the submission of a manufacturer dossier
Majority of NMRA respondents (89% (17/19)) confirmed the presence of legal frameworks for accelerated review of products; four countries indicated to have applied such mechanisms for bedaquiline registration
33% (10/30) countries are participating in the WHO collaborative registration procedure;⁺ among them, three African countries reported being part of, observing or having applied to join other regulatory harmonisation/collaborative programmes
Among the countries that reported to not participate in the WHO collaborative registration procedure or any regulatory harmonisation/collaborative programme, 45% (9/20) of NMRAs expressed their interest in exploring participation
High cost, pharmacovigilance and importation challenges listed as long-term challenges, even post-registration

^#: a total of 29 responses from NTPs and 20 responses from NMRAs were received during the survey period. If a respondent did not answer a question or inconsistencies with data from desk review were noted, the denominator was adjusted and the data were not taken into account in the analysis. ^¶: data from respondents of our survey were cross-checked with Médecins Sans Frontières and Stop TB Partnership Out of Step report 2017 [15] and other data obtained from extensive desk review. ⁺: data from respondents of our survey were cross-checked and complemented with the list of participating countries available on the World Health Organization (WHO) website [25].

High-level advocacy to encourage manufacturers to file for regulatory approval in their country

Informing and sensitising NMRAs on the importance of facilitating these approvals

Capacity building and specific training on bedaquiline and delamanid to facilitate more efficient dossier review

Data sharing on implementation and regulatory approvals, as well as updates on safety and efficacy profiles

WHO prequalification of bedaquiline and delamanid to both ease import and facilitate regulatory approval