Harmonization of various elements of drug regulatory activities has taken place in the last decade and has involved intergovernmental initiatives at regional and interregional levels. The driving force behind the harmonization effort is the need to improve availability of pharmaceutical products and respond to the forces of international trade with adequate standardized technical regulations on safety, quality and efficacy. By reducing unnecessary duplication of regulatory requirements, it is proposed that therapeutic advances will be made more rapidly and at a lower developmental cost.

A prerequisite to any harmonized approach to international drug regulation is the existence in each of the participating countries of a functional drug regulatory system. This is understood as full drug registration processes, pharmaceutical inspection services and certified compliance with good manufacturing practice.

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 by the drug regulatory authorities and research-based pharmaceutical industries of the European Union, Japan and USA to focus on new drug development requirements. ICH is a tripartite venture of 17 high-income countries. To date, ICH has produced over 45 guidelines describing technical requirements related to specific components of the drug registration process drawn up by groups of specialists from drug regulatory authorities and pharmaceutical industry of the ICH countries. The scientific level of each guideline is high and reflects state-of-the-art technology. The cost related to full implementation of the guidelines may in some cases be considerable but, it is argued, this is offset by more rapid registration of new drugs in the ICH countries.

The ICH initiative was established to harmonize the documentation needed for drug development and subsequent regulatory evaluation of products containing new chemical entities or products obtained by biotechnology. WHO is accorded observer status within the ICH Steering Committee, but is not directly involved in the process of drafting or developing ICH guidelines and has no control over their approval.

History of ICH

The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 as a tripartite regulatory/research-based industry venture. The major aim of the ICH is to provide a forum for constructive discussion on the real and perceived differences in technical requirements for the registration of new chemical entities. Other objectives are to achieve greater harmonization in the interpretation and application of technical guidelines for the registration of new chemical entities or products obtained by biotechnology by its members, to improve the efficiency of global drug development, and to reduce redundant studies.

The co-sponsors of ICH comprise the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA); the Japanese Ministry of Health and Welfare (JMHW) and the Japanese Pharmaceutical Manufacturers Association (JPMA); and the US Food and Drug Administration (FDA) and the Pharmaceutical Research and Manufacturers of America (PhRMA). These six co-sponsors represent the voting members of the ICH Steering Committee.

The ICH thus represents 17 countries comprising 15% of the world's population and accounting for 90% of the US$ 200 billion annual sales made by the multinational research-based pharmaceutical industry. ICH regulatory authorities are among the first to evaluate new chemical entities and new products obtained from biotechnology. The Secretariat is provided by the International Federation of Pharmaceutical Manufacturers Associations (IFPMA).

WHO, Health Canada and the European Free Trade Association (EFTA) hold observer status in the ICH Steering Committee.

Expanded ICH initiatives

Following the completion of the majority of harmonized ICH objectives in 1997, it was agreed that a further phase of harmonization activities should be continued. The terms of reference of ICH were amended to include provisions for updating existing guidelines and global harmonization. The revised terms of reference are:

• To maintain a forum for constructive dialogue between regulatory authorities and the pharmaceutical industry on the real and perceived differences in the technical requirements for product registration in the European Union, USA and Japan in order to ensure a more timely introduction of new medicinal products, and their availability to patients.

• To monitor and update harmonized technical requirements leading to a greater mutual acceptance of research and development data.

• To avoid divergent future requirements through harmonization of selected topics needed as a result of therapeutic advances and the development of new technologies for the production of medicinal products.

• To facilitate the adoption of new or improved technical research and development approaches which update or replace current practices, where these permit a more economical use of human, animal or material resources, without compromising safety.

• To facilitate the dissemination and communication of information on harmonized guidelines and their use to encourage the implementation and integration of common standards.

As part of the expanded phase of ICH activities, the ICH Steering Committee has established a Global Cooperation Group. Its stated purpose is to "make information available on ICH, ICH activities and ICH guidelines to any country or company that requests the information." The principles and terms of reference for this group were finalized recently and a formal approach has been made to WHO to join the Group. The aim of the Global Cooperation Group is to disseminate finalized ICH guidelines with an anticipated goal of acceptance and adoption of ICH guidelines in non-ICH countries.

The implications of the establishment of the Global Cooperation Group are discussed below.

Globalization of ICH guidelines

Although countries excluded from the ICH process are free to attend some ICH meetings and conferences, they do not make up part of the decision-making process. It is therefore estimated that the interests of approximately 85% of the world's population are not directly represented within the ICH process.

While laudable in its support of ICH members, some countries and nongovernmental organizations excluded from the process have become vocal about perceived shortcomings of the ICH. The composition of the ICH has been a cause for concern from a range of interested parties, including patients and consumer groups. For example, the ICH has produced Guidelines on Good Clinical Practice which include reference to ethics committees and to informed consent. Some consumer groups have argued that while these are central to consumer protection, there has been little consultation with patient or consumer groups in the development of these guidelines. It has also been pointed out that while many clinical trials are conducted in developing countries, there has been no consultation between ICH and key officials from these countries.

While it is fair to assume that the partners within ICH are satisfied with the infrastructure and process, commentators outside have questioned the appropriateness of having the IFPMA coordinate the process and provide the Secretariat. Some critics have stated that this structure has led to an industry driven agenda, with the regulators tending to accept this as the status quo. Similar comments have been made about a perceived lack of sufficient consultation with academics, scientists and the medical profession. While these concerns may be theoretical, specific examples given below tend to support this view.

Over the years, ICH has grown to rely more on advanced pharmaceutical technology in its standard setting on the assumption that this technology will lead to increased safety of new drugs. An example is the ICH Guidelines for Impurities in New Drug Substances (Q3A). The additional safety benefits from these rigorous standards have not yet been demonstrated but the costs incurred by manufacturers in meeting these requirements are significant. Setting such norms allows only the well-resourced pharmaceutical companies to achieve the necessary standards. This will become 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 the drug manufacturing picture if ICH guidelines start to be interpreted as the only global standard. For example, the application of the ICH Guideline on Impurities - Residual Solvents (Q3C) was developed for new products but is being extended to cover all products registered in the European Union. Another example is the ICH Guideline on Stability Testing (Q1) which covers only stability requirements in Climatic Zones I and II (temperate climates), and does not yet cover Climatic Zones III and IV (stability requirements for hot/dry and hot/humid climates).

The public health implications of the application of these guidelines in developing countries may be far reaching. In many countries, essential drugs required for the prevention and treatment of locally endemic conditions are not supplied by the major multinationals, but by local industry or by generic manufacturers. If they are unable to meet what may be unsubstantiated quality standards, the adverse impact of the withdrawal of these drugs on the health of the population would be far more dramatic than that of any hypothetical risk posed by failing to achieve the ICH standards.

Another element of some ICH guidelines is that they describe high safety requirements as appropriate for drugs which are marketed in the high-income countries but many of these products are intended to improve the quality of life of the population. Since the ICH guidelines do not address specific requirements for any category of products they do not cover neglected diseases, including debilitating tropical diseases.

It might be argued that the above scenarios are irrelevant, since the initial aims of the ICH were not to set global standards for drug development and evaluation. Further, ICH has no legal mandate from the international community on which to base such an assumption. However, recent developments concerning the ICH Global Cooperation Group would suggest that ICH activities are set to gain wider international acceptance. During the initial phase of ICH activities, it was made clear that the intentions of the ICH had relevance only to the co-sponsors, to the extent that approaches from other individual countries seeking membership were refused by the Steering Committee as unnecessary and a potential cause of confusion. It should, however, be stressed that ICH advocacy seminars have already been held in different regions of the world, and participating countries look on the ICH guidelines as the international "norm".

This interpretation of the ICH process is a particular challenge for WHO as reflected in the recommendation of the Ninth International Conference of Drug Regulatory Authorities (ICDRA) held in Berlin in 1999 which requests WHO to take into account the full implications for non-ICH countries when participating as an observer in the ICH process.

Benefits of the ICH process

The establishment of ICH ten years ago reflected a need felt by the research-based industry and certain governments to streamline the approval process for the registration of new drugs. The tendency of many countries to regard ICH guidelines as international standards further supports the argument that there was a need for such a process. The widespread reference to ICH guidelines by countries attests to the quality of their technical content. Indeed, many of the scientists involved in the ICH working groups responsible for developing the different guidelines have contributed to the high calibre of technical and scientific content in the recommendations. They argue that while recognizing serious omissions in some of the guidelines, this should not detract from the quality of the content of those already approved.

While the structure of the ICH was clearly exclusive from the outset, this position continues to be defended by its supporters as an appropriate partnership to achieve ICH aims and objectives. The omission of other participants, such as the generics industry, was not seen as a barrier to ICH work, as the original aim was not to harmonize the approval of generic drugs. Similarly, the ICH partners would argue that before countries implement the guidelines, regulatory authorities are able to involve consumer groups who can give comments. Additionally, in all the countries represented within ICH, there are appropriate mechanisms which allow public comment on the guidelines before they are finally adopted.

One of the most important criticisms of the ICH process is that its guidelines have been increasingly perceived as the 'gold standard' for international harmonization. The ICH has never claimed to have formal international authority to produce global standards and it further indicates that it is in no position to compel national drug regulatory authorities to adopt these standards. Nevertheless many countries consider adoption of the guidelines as a necessary move. ICH proponents argue further that the intention of involving WHO as an observer in ICH was to ensure that international concerns about the protection of public health interests are met.

Challenges for WHO

Recommendations about the future role of WHO with respect to ICH must take into account both the current high status achieved by ICH internationally, the applicability of ICH products in non-ICH countries, and valid criticisms of the ICH process. WHO is the only international organization that has a legal international mandate from 191 Member States to set global standards for the promotion and protection of public health. The ICH, in contrast, has been established to harmonize standards for components of specific drug regulatory activities from 17 countries that are economically developed and where multinational research-based pharmaceutical companies involved in new drug development are situated.

Conversely, there is no proof that ICH guidelines will produce additional public safety benefits. Indeed, in replacing existing standards, there may be an impact on the availability of essential drugs in developing countries. This could also disrupt the generics industry and pharmaceutical manufacturers from countries outside the ICH tripartite, particularly with regard to increased costs as a result of implementation of ICH guidelines.

Currently, WHO attends ICH Steering Committee meetings as an observer and WHO has also been asked to become an observer to the work of the Global Cooperation Group. While the Group expresses the desire for the globalization process to be consultative and open, this initiative could give rise to concern for WHO and countries outside the ICH process since WHO, although not a full partner in the decision-making process of ICH, would be looked on as endorsing the globalization of ICH guidelines. Although the terms of reference of ICH are expanding into a wider international arena, there are no indications that ICH intends to broaden its membership base or change its process of guideline development to reflect these new global ambitions.

A concern commonly voiced in this complex debate, is that the setting of different standards for the process of drug regulatory harmonization by ICH and by WHO will effectively produce a dual standard - a higher one for the more affluent countries and a lower one for poorer countries. This concern is untested. However, the raising of standards to such a level that essential drugs cannot be produced would be of tremendous concern. Furthermore, the rationale for introducing new expensive technologies to increase safety in drug production has yet to be proven in many situations.

Present developments in the international harmonization of drug regulation should be seen as a challenge to WHO to revisit the standards and guidelines that it has already set. In the opinion of the Review Team the setting of international standards should rightly remain within the domain of WHO and should be protected from interests beyond those of public health.

The fact that ICH guidelines have increasingly been perceived within countries as a global standard should seriously concern WHO. Before any discussion of global recognition, it is imperative that guidelines should be subjected to an international review for their global applicability. The consultative processes utilized by WHO are necessary in order to promote the public health interests of populations in all countries. In some instances, this may also result in a need for WHO to develop standards for the quality, safety and efficacy of generic products to ensure that supplies of essential drugs are not squeezed off the market by standards that are unrealistic for the settings in which generic and essential drugs are produced and traded.

Recommendations to WHO

The ICH has made clear that it is committed to maintaining the status quo to achieve full effectiveness of the ICH process. However, other groups have influenced the ICH to change some of its procedures. Although it is considered unlikely that the ICH would accept a significant change in either the membership of its Steering Committee or current guideline modification or development, WHO should be encouraged to find ways to work more closely with ICH to engage and seek input from other countries.

The following recommendations are proposed for implementation by WHO. They are dependent on resources being made available for implementation.

• WHO continues to play an observer role within the ICH Steering Committee.

• The review team proposes that observer status takes on a more critical role within ICH. This could take the form of proposals of topics for guideline development and opinions on the potential public health implications of some of the guidelines proposed.

• WHO accepts observer status within the ICH Global Cooperation Group. However, measures should be taken for this not to be considered as an endorsement of ICH guidelines or procedures by WHO Member States.

• WHO establishes a mechanism to review, modify and/or adopt ICH guidelines as WHO international guidelines for drug regulatory activities, as relevant.

Within this mechanism, a series of consultations and meetings should be convened to review the existing ICH guidelines. These meetings should include national representatives, selected experts and academics other than those involved in ICH, as well as senior policy staff and scientific advisers from ICH and non-ICH countries encompassing all levels of regulatory activity.

As part of the process, endorsement could be achieved through WHO governing bodies or similar mechanisms.

• WHO should include the recommendations of the review group as topics for discussion at the Tenth ICDRA which will be held in Hong Kong in November 2001.

The review team also considered that a more active involvement of WHO as a full partner to the ICH process would be beneficial in allowing development of guidelines which would take public health issues fully into account. However, this would represent a significant structural change for the ICH.