Big Pharma fails in bid to influence WHO regulatory norms on medical products

An attempt by the pharmaceutical industries of Europe, Japan and the US to influence the development of WHO regulatory norms on medical products has been rebuffed. KM Gopakumar reports.

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Pharmaceutical industry influence over medical product regulation at the World Health Organisation (WHO) has been pushed back by governments.

The 67th World Health Assembly (WHA) that took place on 19-24 May adopted a resolution on regulatory system strengthening for medical products after dropping reference to regulatory harmonisation and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

Set up in 1990, ICH brings together the regulatory authorities and pharmaceutical industries of Europe, Japan and the US 'to discuss scientific and technical aspects of drug registration' (see article below).

Its critics note that ICH in effect is a mechanism for the pharmaceutical industry to influence, even set, standards. 'Harmonisation' in this context is a code word for industry-led standard-setting which favours the interests of transnational pharmaceutical corporations by preventing competition from generic medicines.

The resolution had been proposed at the 134th meeting of the WHO Executive Board in January. It was a follow-up to the WHO secretariat report on regulatory system strengthening. There was no consensus at the Executive Board due to concerns from some developing countries and the draft resolution was forwarded with bracketed text to the WHA for health ministers to resolve.

At the WHA, developing countries such as India and China continued to express concern over harmonisation and reference to ICH. India stated that their support for the resolution was based on a common understanding that the development of norms, standards or guidelines as per WHO principles is free from conflict of interest and excludes influence from any initiative driven by industry. China stressed national autonomy and independence in regulatory cooperation, and that harmonisation should be on a voluntary basis.

The removal of the words 'harmonisation and convergence' from the text of the resolution that was finally adopted clearly shows that there is a consensus among WHO member states to accept the concerns over regulatory harmonisation. Secondly, member states clearly expressed concerns with regard to the involvement of industry in WHO's regulatory norms and standard-setting.

The draft resolution that was brought to the WHA from the Executive Board, in Operational Paragraph 1(f), had urged member states to 'implement relevant guidance and science-based outputs of international regulatory harmonisation and convergence efforts such as, where applicable, the Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use'. It further urged member states to promote international cooperation to promote 'convergence' (an indirect reference to harmonisation) in Operational Paragraph 1(3).

In Operational Paragraph 2(1), the resolution requested the WHO Director-General (D-G) to develop appropriate norms and standards, 'taking into account the standards created by existing regional and international initiatives'. Further, it asked the WHO D-G to promote the greater participation of member states in existing international and regional initiatives for collaboration, harmonisation and convergence in accordance with WHO principles and guidelines.

Four days of informal negotiations at the WHA led to the finalisation of the resolution. The resolution is believed to be an effort to further Global Medicines Regulatory Harmonisation (GMRH), an initiative by the World Bank. The World Bank is administering a multi-donor trust fund, which was established in 2011 with an initial contribution of $12.5 million from the Bill & Melinda Gates Foundation (Gates Foundation).

According to the annual report of the GMRH published in 2013, the origins of the initiative go back to 2009: 'In 2009, a consortium of partners including the Pan African Parliament, NEPAD Agency, the World Health Organisation, Bill & Melinda Gates Foundation, UK Department for International Development, and the Clinton Health Access Initiative came together to establish the African Medicines Regulatory Harmonisation (AMRH) Programme.' With the help of Gates Foundation funding, 'it [was] possible for the World Bank to set up GMRH to implement AMRH and to scale up medicines regulatory harmonisation activities in Africa and beyond.'

The US Food and Drug Administration (FDA) and ICH are believed to be important partners (see www.who.int/medicines/areas/policy/IPC_dec2012_Seiter_reg.pdf).

ICH plays an important role in the harmonisation process to determine the common minimum standards for medicine registration. ICH incorporated many of the harmonisation initiatives as part of its Global Cooperation Group (GCG).

Six Regional Harmonisation Initiatives of namely the Asia Pacific Economic Cooperation, Association of South-East Asian Nations, East African Community, Pan American Network for Drug Regulatory Harmonisation, Gulf Cooperation Council and the Southern African Development Community are part of ICH's GCG along with eight other drug regulatory authorities/departments of health, namely Australia, Brazil, China, Chinese Taipei, India, the Republic of Korea, Russia and Singapore.

According to a paper by Ayelet Berman, a researcher who has worked extensively on ICH issues, the ICH standards 'have been to the detriment of entities, companies and countries that lack sufficient resources, and have advantaged resourceful companies and countries. In practice, this means that they have benefited larger, privately held, export-oriented companies, and have been to the detriment of smaller, locally oriented, or governmentally funded companies/entities'.

She further states that 'in certain contexts, they have promoted the commercial interests of the multinational pharmaceutical industry over the interests of patients in receiving much needed medicines or treatments'.

According to Berman, 'the [ICH] members are the main beneficiaries, non-members have been subject to distributional effects that are to their detriment'.

WHO's involvement in ICH activities raises serious concerns on conflict of interest with regard to WHO's role in the norms and standard-setting related to medicines.

The resolution adopted at the WHA amended Operational Paragraph 1(f) which originally urged WHO member states to strengthen national regulatory systems by, as appropriate, 'implementing relevant guidance and science-based outputs of international regulatory harmonisation and convergence efforts such as, where applicable, the Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use'.

The resolution dropped the words 'regulatory harmonisation and convergence efforts such as, where applicable, the Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use'. The amended text urges member states to strengthen national regulatory systems, including, as appropriate and voluntarily, by 'facilitating the use of relevant guidelines and science-based outputs of WHO expert committees and good regulatory practices at the national, regional and international levels'.

In paragraph 2(1), the indirect reference to ICH has been removed. The earlier draft requested the WHO D-G to continue to support countries in the area of regulatory system strengthening, 'including by developing appropriate norms and standards taking into account the standards created by existing regional and international initiatives'.

This is now reflected as new text in Operational Paragraph 2(2) that states: 'to continue to develop appropriate norms, standards and guidelines, including taking into account national, regional and international needs and initiatives in accordance with WHO principles'.

The words 'harmonisation and convergence' were removed from the draft paragraph 2(4) which originally stated: 'to promote the greater participation of Member States in existing international and regional initiatives for collaboration, harmonisation and convergence in accordance with WHO principles and guidelines'.

The amended text now placed as paragraph 2(5) states: 'to promote the greater participation of Member States in existing international and regional initiatives for collaboration and cooperation in accordance with WHO principles and guidelines'.

Similarly, paragraph 2(6) was also amended, removing the words 'harmonisation and convergence'. The draft text had originally read: 'to increase support for and recognition of the significant role of the International Conference of Drug Regulatory Authorities in promoting the exchange of information and collaborative approaches among drug regulatory authorities, and as a resource to guide and facilitate further development of, and regulatory harmonisation and convergence among, these authorities ...'.

The amended version clearly states: 'to increase support for and recognition of the significant role of the International Conference of Drug Regulatory Authorities in promoting the exchange of information and collaborative approaches among drug regulatory authorities, and as a resource to facilitate further development of regulatory cooperation and coherence'.

Even though the resolution removed the reference to ICH and harmonisation, we have yet to see whether the WHO secretariat will make any concrete changes in its approach to regulatory harmonisation, taking into consideration the concerns expressed by member states including India and China.

Sceptics are of the view that without constant monitoring by member states, the secretariat is not going to change its approach. Even though the Assistant Director-General in charge of medical product regulation stated in a side event that the focus is on convergence and not on harmonisation, observers point out that these are different words with the same meaning.

Concerned observers cite the secretariat report to the WHA on regulatory system strengthening which clearly advocates regulatory harmonisation. It states: 'In order to improve the regulation of medical products globally and ensure that the medical products that patients use are of assured quality, more emphasis needs to be placed on regulatory convergence and harmonisation, which offers numerous benefits to both regulatory authorities and the pharmaceutical industry, and which has a positive impact for the protection of public health. Stimulating and/or initiating collaboration between regulators from various countries on regulatory activities based on converging and harmonised technical standards is becoming more and more important.'

Another reason for the secretariat's reluctance to move away from harmonisation emanates from WHO's involvement in various harmonisation initiatives including at the international level (ICH and GMRH) and regional initiatives like the Pan American Network for Drug Regulatory Harmonisation and African Medicines Regulatory Harmonisation initiative.

Further, some observers also point to the fact that even though the words 'harmonisation', 'convergence' and 'ICH' have been removed from the resolution, there are still indirect references to ICH and harmonisation efforts. This may be used by the secretariat to justify its current engagement with ICH and other harmonisation initiatives that may be problematic.

For instance, paragraph 1(f) asks countries to facilitate, as appropriate and voluntarily, the use of relevant guidance of WHO expert committees along with good practices at the national, regional and international levels. The words 'international level' may be used to justify the ongoing engagement with ICH and other harmonisation initiatives.

Similarly, paragraph 2(2) requests the D-G while developing appropriate norms, standards and guidelines to take into account international needs and initiatives in accordance with WHO principles. Again the secretariat can justify its current approach, citing the mandate under this paragraph which allows the D-G to take into account international initiatives.

Yet again, paragraph 2(5) requests the D-G to promote greater participation of member states in the existing regional or international initiatives. Does this mean that WHO promotes the participation of member states in various medical product regulatory harmonisation initiatives, including the World Bank's GMRH?

However, it may not be so easy for the secretariat to push for harmonisation and to continue its current level of engagement with ICH. Operational paragraph 2(2) does not provide a blanket mandate to the secretariat to engage with ALL international initiatives. The D-G is to ensure that while taking into account international initiatives, it should be in accordance with WHO principles. As per the established WHO principles, there should not be any engagement with industry in norms and standard-setting. The ICH engagement is widely seen as being in conflict with WHO principles due to a conflict of interest between industry and WHO.

Member states which are concerned about the secretariat's activities in the area of regulatory system strengthening also have the opportunity for 'gatekeeping' to a certain extent through the Member State Mechanism. Operational Paragraph 2(11) of the resolution requests the D-G 'to ensure that any activity carried out under this resolution does not duplicate or circumvent the work plan and mandate of the Member States mechanism on substandard/spurious/falsely-labelled/falsified/counterfeit medical products'. The Member State Mechanism identified strengthening of drug regulatory authorities as a priority in its work plan.

The removal of the words 'harmonisation and convergence' from the resolution clearly reflects the consensus among member states to accept the concerns over regulatory harmonisation and ICH as well as over the involvement of industry in WHO's regulatory norms and standard-setting.

The translation of the resolution into action now depends on the constant vigilance of the member states.      

KM Gopakumar is a senior researcher with the Third World Network. This article is reproduced from the South-North Development Monitor (SUNS, No. 7814, 2 June 2014).

ICH: Serving Big Pharma's interests? KM Gopakumar ICH was established in 1990 as a public-private partnership (PPP) primarily to lower the norms of registration (marketing approval) of new chemical entities. However, as shown below, increasingly ICH started setting standards to build a set of technical barriers to prevent competition from the generic medicine industry. The founding members of ICH are the drug regulatory authorities of the European Union (European Agency for the Evaluation of Medicinal Products, EMEA), Japan (Ministry of Health, Labour and Welfare, JMHLW) and the US (Food and Drug Administration, US FDA) and the research-based pharmaceutical industry associations of those countries (the European Federation of Pharmaceutical Industries' Associations, EFPIA; the Japan Pharmaceutical Manufacturers Association, JPMA; and the Pharmaceutical Research and Manufacturers of America, PhRMA). According to the ICH website, since its establishment in 1990, each of its six co-sponsors (EMEA, EFPIA, JMHLW, JPMA, US FDA and PhRMA) has had two seats on the steering committee, the highest decision-making body of ICH. The three observers to the committee, which do not enjoy voting rights, are WHO, Health Canada (Canadian regulatory agency) and the European Free Trade Area. The International Federation of Pharmaceutical Manufacturers Associations (IFPMA), a federation of national associations of research-based pharmaceutical industry associations, is a non-voting member of the committee. The ICH secretariat operates out of the Geneva office of IFPMA. According to researcher Stephanie Dagron: 'The steering committee oversees all activities. First, it determines the harmonisation activities to be pursued (i.e. initiative for guidelines and other instruments). Second, it adopts the guidelines and instruments that have been finalised and accepted by the parties through consensus. Third, it supervises the implementation and monitoring of ICH commitments. The IFPMA exercises an important role since it provides the secretariat and participates...' (www.irpa.eu/wp-content/uploads/2012/01/IRPA.WP.2012.2.Dagron.pdf) ICH's Global Cooperation Group (GCG) includes Regional Harmonisation Initiatives, namely, APEC, ASEAN, EAC, GCC, PANDRH and SADC, in addition to eight drug regulatory authorities/departments of health in Australia, Brazil, China, Chinese Taipei, India, the Republic of Korea, Russia and Singapore that are invited to the ICH bi-annual meetings. The representatives of these organisations participate in the Global Cooperation session of the ICH steering committee to discuss capacity-building and share experience/challenges on the implementation of ICH guidelines. Dagron notes: 'In 1999 the [ICH steering committee] created the Global Cooperation Group as a subcommittee, to allow the "participation" of representatives from non-ICH regions. In 2008, the [steering committee] also created a structure called the Regulators Forum. But these two structures do not offer any participation opportunities to their members within the elaboration process of the ICH guidelines. They only constitute platforms for discussion, information, and training. Their role is to allow the dissemination of ICH standards worldwide.' According to the ICH website, representatives also listen to ICH technical topics discussed by the steering committee during meetings and are invited to nominate technical experts in Expert Working Groups/Implementation Working Groups to contribute to the development of ICH guidelines. However, participation in the GCG is without any substantial say and without voting rights. Imported into WHO norms ICH, during the last 24 years, has worked as a partnership between the regulatory agencies of industrialised countries and pharmaceutical industry without any effective participation from developing countries and generic industries. The important question is: how do regulatory agencies and WHO set norms in a body where the industry has a veto power through voting? Thanks to the alliance with WHO, many ICH guidelines found a place in the reports of WHO's Expert Committee on Specifications for Pharmaceutical Preparations. In other words, the norms and standards set by ICH without the participation of a substantial majority of WHO member states got imported into the WHO expert committee process and adopted as norms and standards for the regulation of medicines. For instance, an annex to the 46th report of the Expert Committee on Specifications for Pharmaceutical Preparations, titled 'Pharmaceutical Development of Multisource (Generic) Finished Pharmaceutical Products - Points to Consider', is said to provide 'a structured approach for industry following the International Conference on Harmonisation (ICH) common technical document (CTD) format'. The 44th report of the Expert Committee also contains WHO Good Manufacturing Practices for Active Pharmaceutical Ingredients (API), which are based on the ICH guidelines. It states: 'A major change to the analytical procedure, or in the composition of the product tested, or in the synthesis of the API, will require re-validation of the analytical procedure. Note: Further guidance on validation of analytical procedures is available in the following: Guideline elaborated by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).' The ICH and IFPMA participate in the meetings of the WHO Expert Committee. Commercial interests Researchers also question the ICH claim that its guidelines are purely science-based. They point out that commercial and political interests play an important role in the finalisation of ICH guidelines. A set of research papers shows that ICH has served the interests of transnational pharmaceutical corporations in two ways. First, it set norms to lower the threshold level of technical requirements for the registration of medicines containing new chemical entities and new products obtained by biotechnology through harmonising the drug registration process. Second, ICH started setting norms and standards for generic products and pharmaceutical substances (starting materials) and created a new entry barrier for small brandname and generic companies, especially those in developing countries. Health researchers have warned against the drive for harmonisation. In an article, Karin Timmermans writes: '... increasing the standards beyond the technological capacity of pharmaceutical companies in developing countries would effectively exclude their competitive generic products from the international market.' Another researcher warns: 'The production of generics but also of pharmaceutical starting material in developing countries is endangered. In fact, ICH guidelines have introduced a tightening of specifications for pharmaceutical starting materials, which is not always justified by additional safety benefits. Another source of prohibitive costs for smaller companies is the Good Manufacturing Practice Guide for active pharmaceutical ingredients adopted by ICH in 2000.' The same sentiment is expressed by an expert consultation organised by WHO in 2001. The experts state: 'ICH has relied increasingly on advanced pharmaceutical technology in its standard setting, on the assumption that this technology will lead to greater safety of new drugs, while the ICH guidelines relating to drug quality have introduced a general tightening of specifications for pharmaceutical starting materials. For example, ICH guideline Q3A ("Impurities in new drug substances") includes the requirement that each organic impurity (whether identified or unidentified) present in a substance in the amount of 0.1% or more (in some cases 0.05% or more) should be considered as a qualified impurity (i.e. its safety should be established). This raises the question of the basis for the selection of the borderline figure, as the additional safety benefits from these rigorous standards have not been demonstrated but the costs incurred by manufacturers in meeting the requirements are significant.' Further, the experts warn against making ICH norms global standards. Their report states: 'Setting such norms may have considerable repercussions on current manufacturing practices, as only pharmaceutical companies with substantial resources can achieve the necessary standards. This is a concern if the guidelines are intended for global application. Smaller pharmaceutical companies, generic companies and many larger companies responsible for essential drug production in developing countries may be effectively squeezed out of drug manufacturing if ICH guidelines start to be interpreted as the only global standard.’ However, the experts recommended continuing WHO’s engagement with ICH. 'WHO attends meetings of the ICH Steering Committee and the Global Cooperation Group as an observer. These roles are important and should be maintained. However, appropriate strategies for consultation and communication with Member States need to be developed to ensure that WHO is not seen as de facto automatically endorsing ICH products, but as providing advice on the potential impact of those products on non-ICH Member States.' WHO has continued with the ICH process for some 24 years without the close scrutiny of member states because issues of norms and standards are considered as technical subjects; therefore, the World Health Assembly never deliberates the merits of the expert committee reports, which contain norms and standards for the regulation of medicines. Meanwhile ICH adopts guidelines with political and economic considerations and successfully projects these guidelines as science-based and exports them to WHO expert committees. WHO’s alliance with ICH facilitates this repackaging. In the past, member states had forced WHO to discontinue its engagement with the International Medical Products Anti-Counterfeiting Taskforce (IMPACT) due to the latter's close association with the pharmaceutical industry. The challenge at this point is for member states to scrutinise WHO’s alliance with ICH and prevent any further conflict-of-interest situations.                                                     The above is extracted from an article which first appeared in the South-North Development Monitor (SUNS, No. 7807, 20 May 2014).

*Third World Resurgence No. 286, June 2014, pp 18-22