Strict or Stringent National Regulatory Authority for Procurement of anti-Tuberculosis Medicines?

This article examines the requirement of strict or stringent National Regulatory Authority (NRA) environments for procurement of anti-tuberculosis (TB) medicines, with specific focus on the World Health Organisation, United Nations Office for Project Services, Stop TB Partnership/Global Drug Facility and The Global Fund to Fight Aids, Tuberculosis and Malaria

JL ImageAbout Author: Mr John F. Loeber is currently the Chief Procurement Officer in the UN Stabilization Mission in Haiti (MINUSTAH), with over 25 years’ experience in the UN System (UN, UNHCR, WHO, UNICEF), EU, national systems and the private sector. In more than 14 years with the UN, Mr Loeber has overseen procurement totalling about 1 bn US$ and handled international contracts amounting to approximately 4 bn US$. His professional activities have been supplemented by voluntary ones, e.g. as Staff Member of the WHO Board of Appeal, WHO and UNHCR Staff Association Polling Officer, Editorial Adviser of the WHO Bulletin, and also as Board Chair of the Copenhagen International School.

The Global Drug Facility (GDF) operates as the procurement arm of the Stop TB Partnership (TBP) Secretariat, hosted at the World Health Organization (WHO), Geneva, Switzerland, from 2001 until 2014 and forthwith at the United Nations Office for Project Services (UNOPS). The Stop TB Partnership is a network of some 1,300 governments, donors, industry, NGOs, academia and other partners, joined in the common fight against tuberculosis (TB). The TBP i.a. provides access for countries to quality assured, affordable anti-TB medicines via GDF. As of 2014 GDF has delivered medicines for 24 mn TB patients to 133 countries in thirteen years of operation, financed by bilateral and multilateral donors such as USAID, The Global Fund to Fight Aids, Tuberculosis and Malaria (GFATM) and UNITAID. GDF’s annual purchases of TB medicines amounted to about 200 mn US$ in 2013, and the GFATM disbursed approximately 500 mn US$ for TB in 2015.

1. Stringent NRA requirement

A condition for procurement of anti-TB medicines by the GDF or its facilitation of direct procurement by countries has been and continues to be that medicines are approved under the WHO Prequalification Programme or licensed for marketing by stringent National Regulatory Authorities (NRAs). This is established in the GDF Quality Assurance Policy. The same standard is applied by the GFATM as well as other financing institutions and procurement entities such as UNITAID and UNDP.

On further examination, GDF and the GFATM define the term “stringent” as being a Member, Observer or Associate of the International Council for Harmonisation (ICH). The ICH, founded in 1990, is an associationbringing together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration”.

Current ICH Regulatory Members or Associates are Brazil, Canada, the EU, Japan, South Korea, Switzerland and the US. In regard to ICH Members having newly acceded to the EU such as Cyprus, Lithuania, Malta, Poland and Latvia, the GDF Quality Assurance Policy principles additionally provide that “GDF will consult with relevant WHO experts on the progress in adjusting their pharmaceutical legislation to EU laws before recognizing the approval by the national health authorities”.

From 2015, a range of Regulatory Authorities joined the ICH as Observers, namely Australia, Chinese Taipei, Cuba, India, Kazakhstan, Mexico, Russia, Singapore and South Africa [5]. Both GDF’s and the GFATM’s Quality Assurance Policies, which antedate 2015, limit recognition to “an ICH Observer, being the European Free Trade Association (EFTA) as represented by Swiss Medic, Health Canada and World Health Organization (WHO) (as may be updated from time to time)”. Despite the closing adjustment clause, given the significant development in ICH Observers and the generally restrictive nature of both organizations’ policies, including the specific formulation of this provision, referring mainly to associations and only to one individual authority, moreover now an ICH “Standing Regulatory Member”, it cannot be deduced that the nine new ICH Observers are currently recognized as representing stringent regulatory environments. The conclusion must also be drawn in view of issuance of tenders for first- and second-line anti-TB medicines in October and February 2016 with reference to the unchanged GDF Quality Assurance Policy, hence apparent lack of sourcing from those countries on the basis of ICH Observer status, as well as the absence of media releases to the contrary or other forms of clarification by the two organisations since 2015 on these significant developments at ICH.

As a further qualifying option, according to the GDF Policy it will be sufficient that products are “approved or subject to a positive opinion under the Canada S.C. 2004, c. 23 (Bill C-9) procedure, or Art. 58 of European Union Regulation (EC9 No. 726/2004) or United States FDA tentative approval”, i.e. interim approvals have been given by this set of countries/intergovernmental organisation. A next to identical regulation is found in the GFATM’s Quality Assurance Policy.

In the event that none of the above requirements are met, GDF’s Quality Assurance policy then allows that “Products shall be found acceptable to the GDF through a quality risk/benefit assessment process involving an Expert Review Panel (ERP)”. While this specific, exceptional process was managed by the GDF itself until 2009/2010, the ERP assessment was forthwith handled by the GFATM, in cooperation with GDF. The GFATM respectively refers to this process on its website and linked material. Under this backup process, for which approvals are limited to a 12-month period, product submissions must be pending with either the WHO Prequalification Programme or a stringent NRA. Also, the product must have been produced at a manufacturing site that was inspected and found acceptable by either the WHO Prequalification Programme, a stringent NRA or a regulatory authority participating in the Pharmaceutical Inspection Cooperation Scheme (PIC/S).

PIC/S was established in 1995 as an extension to the Pharmaceutical Inspection Convention (PIC) of 1970. There are currently 49 participating authorities (Members) in PIC/S, including beyond the 10 founding members from EFTA the following new entrants from 2000: Argentina (2008), Chinese Taipei (2013), Hong Kong (2016), Indonesia (2012), Israel (2009), Korea (Rep. of) (2014), Malaysia (2002), New Zealand (2013), Singapore (2000), South Africa (2007), Thailand (2016) and Ukraine (2011).

In regard to accepting PIC/S, the GDF Quality Assurance Policy nevertheless contains a similar caveat as for the ICH, stating that “For any new PIC/s Member GDF will consult with relevant WHO experts on the level of equivalence of the GMP inspection level to those of old members PICs countries.

Table 1 AntiTB Medicine



Table 1: Anti-TB Medicines Sourcing according to GDF and GFATM QA Policies


2. Strict NRA standard

The above definitions, despite developments in recent years in expanding membership and observers of ICH and PIC/S, remain in stark contrast to a meanwhile long-standing respective resolution of 2009.

Resolution WHA 62.15 on Prevention and control of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis, adopted by the World Health Assembly (WHA) on 22 May 2009, urged Member States in its Art. 1 (1) (h):

to achieve universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant tuberculosis … by means of:

(h) ensuring uninterrupted supply of first- and second-line medicines for tuberculosis treatment, which meet WHO prequalification standards or strict national regulatory authority standards

The particular wording “strict” instead of “stringent” in regard to NRA standards was agreed on as a compromise after debate among Member States lasting several days since the start of the WHA on 18 May 2009. Draft wordings on either end of the spectrum were put forward, favoring no specific qualification in referring to regulatory authority standards (China), to maintaining the term “stringent” (US, Canada). The discussion resulting in the term “strict” was driven i.a. by Thailand, supported by other developing and middle income countries. Finally, before closing of the WHA on 22 May 2009, the proposed wording “strict” was agreed upon for Resolution WHA 62.15.

While reaching agreement on the Resolution in the final session of the 2009 WHA[3], the text nevertheless omitted to define the new term “strict”. Though the change in terminology was recognized in the subsequent period in some discussions or on an individual level, there is no identifiable public record of formal attempts of stakeholders to capture or further specify the term. It could e.g. have been expected that a Working Group of Experts had been established, deliberating on the term and advising on possible consequences. A risk-based categorization scheme for procurement could have e.g. been an output from such Group, coupled with recommendations on supplementary needed quality control in procurement (pre-shipment inspection, sampling and laboratory testing, post-delivery monitoring and control). Similarly, proposals for simultaneous strengthening of national regulatory authorities which had thus been newly qualified for sourcing pharmaceuticals could have been made by the Group.

In this vein and/or as a consequence, since 2009 no principle change in approach in pharmaceutical procurement for TB medicines, in particular in respect of the applicable quality assurance policy, could be identified at WHO, the Stop TB Partnership/GDF, the GFATM or UNITAID.

This appeared as a missed opportunity, as the change of terminology provided the chance to strengthen sourcing for TB, i.e. widening the supplier base. For such expansion, improved availability and lead times for pharmaceuticals as well as lower prices could regularly have been expected. This would have freed up funds to reach more patients, particularly for drug-resistant TB, and/or provide TB care or meet other related public health needs, for which there was continuous shortage of funds.

Resolution WHA 62.15 on “Prevention and control of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis” of 22 May 2009 urged WHO Member States

to achieve universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant tuberculosis … by means of:

(h) ensuring uninterrupted supply of first- and second-line medicines for tuberculosis treatment, which meet WHO prequalification standards or strict national regulatory authority standards” (Art. 1 (1) (h))

Table 2: WHA Resolution 62.15 of 22 May 2009.

Considering the text of the WHA Resolution and taking into account the history of its drafting process and the achieved agreement among Member States after days of debate, WHA 62.15 appeared as a clear direction to view anti-TB medicines meeting strict national regulatory authority standards as being necessary and sufficient under technical and fair competition aspects in public procurement. Fixing the broader term strict as a starting position, the WHA Resolution would then have the innate intent to expand procurement to forthwith include a next tier of advanced countries among the sources from which medicines could be purchased to treat TB.

The positive development of additional members or observers recently joining ICH and PIC/S, after otherwise years of inaction by TB stakeholders, cannot replace or render WHA Resolution 62.15 obsolete in this regard. A dedicated examination of the Resolution’s meaning and its consequences remain indicated, identifying and closing gaps for implementation. Moreover, as established above, it cannot be deduced that the regulatory authorities having joined ICH as Observers since 2015 indeed meet GDF’s and the GFATM’s definition of stringent Regulatory Authorities.

Additionally, the caveats contained in GDF’s quality assurance policy in ultimately in fact recognising new members as equivalent, i.e. reserving the right to disregard the status of such new entrants, is not systemic and appears unwarranted.

In considering contenders for such second-tier sourcing opportunities for TB medicines, aside from necessary regulatory, administrative and legislative assessments, annual pharmaceutical export volumes may serve as in indication. According to data published by The International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), the following countries – whose national regulatory authorities are currently not ICH Members, Associates or Observers (nine new ones since 2015) – are among the leading pharmaceutical exporters in the world, with more than 500 million US$ in annual sales: Argentina, China, Hong Kong, Israel, Jordan, Panama, Turkey

See in this regard the following comparator table:

Country Pharmaceutical Exports (mn US$) ICH Affiliation PIC/S Member NRA recognised as stringent by GDF/GFATM
Germany 69483 Y Y Y
Switzerland 56628 Y N Y
Belgium 47864 Y Y Y
United States* 36215 Y Y Y
France 35414 Y Y Y
United Kingdom 30763 Y Y Y
Ireland 24715 Y Y Y
Italy 22909 Y Y Y
Netherlands 21077 Y Y Y
Spain 12487 Y Y Y
India 11444 Y N N
Austria 8317 Y Y Y
Sweden 7054 Y Y Y
Israel 6030 N Y N
Singapore 5850 Y Y N
Denmark 5559 Y Y Y
Canada 5007 Y Y Y
Hungary 4095 Y Y ?
China 3550 N Y N
Australia 3285 Y N N
Slovenia 2992 Y Y ?
Poland 2935 Y Y ?
Japan 2826 Y Y Y
Mexico 1503 Y N N
Czech Rep. 1499 Y Y ?
Hong Kong SAR China 1498 N Y N
Greece 1357 Y Y Y
Panama 1338 N N N
Brazil 1221 Y N Y
Romania 1208 Y Y ?
South Korea 1102 Y Y Y
Finland 1005 Y Y Y
Argentina 957 N Y N
Bulgaria 872 Y Y ?
Portugal 863 Y Y Y
Turkey 709 N N N
Norway 677 N Y Y
Russia 648 Y N N
Jordan 615 N N N
Croatia 518 Y Y ?

Table 3: Comparator Table Pharmaceutical Sales 2013 and current ICH, PIC/S Affiliation, GDF/GFATM qualification (*excluding Puerto Rico sales, 40420 mn US$).

National regulatory authorities from these countries would therefore need to be examined with respect to their qualification as strict national regulatory authorities, or runner-ups thereto. Substantial potential sales in global supply markets for TB-medicines, worth several hundred million US$ annually, are currently also not being realised due to this categorisation, particularly since nearly all TB-medicines are off-patent. Some advanced industrialised countries appear as clear contenders for procurement of TB medicines, particularly those already admitted to PIC/S. Progress in countries such as India and China in recent years to reach global standards has also

been noteworthy. Furthermore, national regulatory authorities from countries with lesser sales, but nonetheless reputable regulatory systems may be considered under the new categorisation, such as Indonesia, Malaysia, New Zealand, Thailand, Ukraine, Vietnam and several countries in the Mediterranean Region.

Under the existing quality assurance policies of the major TB medicines procurers considered herein, manufacturers from these next tier countries would be limited in qualifying their products under the WHO Prequalification Programme, applying/awaiting ICH Membership/Observer status, interim procedures with the Canada, EU, US regulatory authorities, or otherwise the exceptional ERP process. This raises also the political and diplomatic question whether manufacturers from these advanced countries can indeed be expected to submit dossiers under the WHO Prequalification Programme in order to be considered for anti-TB medicines procurement. This appears unlikely and could also be a reason why manufacturers from these countries are not widely seen engaging in the business of anti-TB medicines supply or investing in it.

Overriding institutional and functional concerns also raise general doubt on the approach taken in sourcing TB medicines. There is first the issue of UN organizations accepting tied aid from donors. Second, for the core question of determining the markets from which products can be sourced, it does not seem appropriate for public procurement functions of organisations in the UN System to outsource such central issue – moreover without an established accountability relationship – to an external entity, however well qualified it may be. Determining eligible supply sources, or defining these so as to enable direct identification, remains a core function of public procurement in the UN. These could, as mentioned, be well linked to a risk assessment scheme.

In conclusion, TB stakeholders are called on to set about establishing a definition of strict national regulatory authorities and to align their quality assurance policies with such definition. Such undertaking will achieve compliance with WHA 62.15 and would be serving the public interest by realizing fair competition and thereby regularly increasing access to affordable medicines. For TB, this would mean an improvement in global TB-control and contributing to the ultimate elimination of TB, both for drug-resistant and drug-susceptible forms.

Note: The views expressed in this article are those of the author and do not necessarily reflect the views of the United Nations. The author declares there are no competing interests in relation to the article. References available on genuine request.